HK1008741A1 - Indoline derivatives carrying an amide function, their preparation 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-sulfonyl indoline derivatives having an amide function, their preparation and the pharmaceutical compositions containing them.

US patent 3 838 167 describes certain N-sulfonyl indole derivatives with the formula: in which R'1 represents the hydrogen, an alkyl or a phenyl, if any, substituted;R'2 represents a halogen, an alkyl, an alkoxy, a nitro or a trifluoromethyl;R''3 represents an alkyl, a phenyl or an alkylphenyle;R''4 represents an alkyl, a phenyl, if any, substituted, an alkoxy or a phenoxyn' = 0, 1 or 2.

These compounds are intermediates for the synthesis of indolic derivatives, active on the central nervous system, with the formula: where R' is an alkyl, possibly substituted phenyl or hydroxyl.

Derivatives of N-sulfonyl indoline with formula where R4 may represent a carboxamide group NR6R7 where R7 is hydrogen or a hydrocarbon chain, are described in application EP 0 469 984.

The indolin derivatives of the present invention have affinity for vasopressin and oxytocin receptors.

Vasopressin is a hormone known for its antidiuretic effect and its effect in regulating blood pressure. It stimulates several types of receptors: V1, V2, V1a, V1b and thus exerts cardiovascular, central, hepatic, antidiuretic, emetic, aggregative effects, as well as proliferative and mitotic effects, particularly on vascular and hepatic tissues. Vasopressin receptor antagonists may intervene in the regulation of central or peripheral blood circulation, including coronary, renal and gastric circulation; as well as water metabolism and the disruption of the adrenocorticotrophic hormone (ACTH). Vasopressin receptors such as Glycine, L. recombinase, L. recombinase, L. recombinase, L. recombinase, L. recombinase, L. recombinase, L. recombinase, L. recombinase, L. recombinase, L. recombinase, L. recombinase, L. recombinase, L. recombinase, L. recombinase, L. recombinase, L. recombinase, L. recombinase, L. recombinase, L. recombinase, L. recombinase, L. recombinase, L. recombinase, L. recombinase, L. recombinase, L. recombinase, L. recombinase, L. recombinase, L. recombinase, L. recombinase, L. recombinase, L. recombinase, L. recombinase, L. recombinase, L. recombinase, L. recombinase, L. recombinase, L. recombinase, L. recombinase, L. recombinase, L. recombinase, L. recombinase, L. recombinase, L. recombinase, L. recombinase, L. recombinase, L. recombinase, L. recombinase, L. recombinase, L. recombinase, L. recombinase, L. recombinase, L. recombinase, L. recombinase, L. recombinase, L. recombinase, L. recombinase, L. recombinase,

The compounds of the invention are thus useful in the treatment of diseases of the central nervous system, the cardiovascular system and the gastrointestinal tract in humans and animals.

The present invention relates to compounds with formula: in which R1 represents a halogen atom, an alkyl in C1-C4, a hydroxyl, an alkoxy in C1-C4, a benzyloxy group, a cyano group, a trifluoromethyl group, a nitro group or an amino group; R2 represents an alkyl in C1-C6, a cycloalkyl in C3-C7, a cycloalkene in C5-C7, a phenyl not substituted or substituted once or more by an alkyl in C1-C4, an alkoxy in C1-C4, a halogen, a trifluoromethyl group, an amino group, or R2 represents a nitrophenyl not substituted or substituted once by a trifluoromethyl group or a substituent in C1-C4 or an alkyl or a substituent in C1-C3 or C3-C7; R3 represents a naphthyl or a halogen; C4 represents a halogen or a phenyle in C4 or C5 represents a naphthyl or a dimethyl group in C4 or C4 represents a naphthyl or a naphthyl; R4 represents a naphthyl or a naphthyl group in C4 or C4 represents a naphthyl or a naphthyl; C4 represents a naphthyl or a carbonyl; C4 represents a halogen; C4 represents a naphthyl or naphthyl or a carbonyl; C5 represents a halogen; C6R5 represents a halogen; C6 represents a halogen; C5 represents a halogen; C5 represents a halogen; C5an alkyl in C1-C4, a trifluoromethyl group, a free amino group or one or two alkyl in C1-C4, a hydroxyl, an alkoxy in C1-C4, an alkenoxy in C2-C4, an alkylthio in C1-C4, a trifluoromethoxy group, a benzyloxy group, a cyano group, a carboxy group, an alkoxycarbonyl group in C1-C4, a free carbamoyl group or one or two alkyl in C1-C4 or an alkylamide group in C1-C4, or R5 represents a nitrophenyl group not replaced or replaced by a trifluoromethyl or an alnoxy group in C2-C4 or one or more times by a halogen, one or two times in C1-C4,an alcohol group in C1-C4, an alkylthio in C1-C4, a trifluoromethoxy group or a benzyloxy group;R6 represents an alkyl in C1-C6, or R6 is similar to R7;R7 represents a piperidine-4-yl group; an azetidine-3-yl group, whether or not these groups are replaced on nitrogen by an alkyl in C1-C4, by a benzyloxycarbonyl or by an alcohol-alcohol-alcohol-carbonyl in C1-C4; a group (CH2)r itself replaced by a pyridyl group -2, or -4, by a hydroxyl group, by a free amino group or by one or two alkyl groups in C1-C4, by a carboxyl group, by a benzyloxycarbonyl group in C1-C4, by a benzyloxy alcohol group,a carbamoyl group free or substituted by one or two alkyl groups in C1-C4; or R6 and R7 together with the nitrogen atom to which they are bound constitute a heterocycle selected from: . morpholine, thiomorpholine, thiazolidine or 2,2-dimethylthiazolidine not substituted or substituted by R8, . piperazine not substituted or substituted in 4 by an R'8 group, . an unsaturated 5-chain mono-nitrogen cycle substituted by R8 or a saturated 3-, 4, 5, 6 or 7-chain mono-nitrogen cycle substituted by R8 and R9 , R8 represents R'8 or a group (CH2) r itself substituted by a hydroxyl or a free amino group or one or two alkyl groups in C1-C4 , R'8 represents a group (CH2) q itself substituted by a carboxyl group,an alcohol-carbonyl group in C1-C4, a benzyloxycarbonyl group, a carbamyl group free or substituted by a hydroxyl or by one or two alkyl groups in C1-C4, or an aminocarbonyl group free or substituted by one or two alkyl groups in C1-C4R'8 represents R'8 or a free (CH2) 2NH2 group or substituted by one or two alkyl groups in C1-C4;R9 represents hydrogen, a halogen, a (CH2) rOR10 group, a (CH2) NRr11R12, a (CH2) sCONR11 group, an azide group;R10 represents hydrogen, an alkyl group in C1-C4, a meskyloxy or a toskyloxy R11, R11 and R12 each represents hydrogen or an alkyl group in C1-C4;C11 represents a benzyl group and R12 represents a benzyl group;C11 represents a benzyl group and R4 represents an alkyl group in C1-C12;1 or 2;m is 0, 1 or 2;q is 0, 1, 2 or 3;r is 0, 1, 2 or 3, with the limitation that r is not zero when R8 or R9 is in the alpha position of intracyclic amide nitrogen;s is 0 or 1; and their possible salts.

Salts of formula (I) compounds according to the present invention include those with mineral or organic acids that allow proper separation or crystallization of formula (I) compounds, such as picric acid, oxalic acid or an optically active acid, e.g. mandelic acid or camphosulfonic acid, and those that form pharmaceutically acceptable salts such as hydrochloride, hydrogen sulfate, dihydrogen phosphate, methanesulfonate, maleate, fumarate, 2-naphthalesulfonate.

Salts of compounds of formula (I) also include salts with organic or mineral bases, e.g. salts of alkaline or alkaline earth metals such as sodium, potassium, calcium salts, sodium and potassium salts being preferred, or with an amine, such as tromethamol, or salts of arginine, lysine, or any pharmaceutically acceptable amine.

The compounds (I) have a cis-trans isomer around the 2,3 bond of indoline.

By convention, cis isomers are compounds (I) in which R2 and R4 are on the same side of the cycle.

By convention, trans isomers are compounds (I) in which R2 and R4 are each on one side of the cycle. - What?

In addition, the compounds of the invention have 2 or more asymmetric carbon atoms when R4 contains 1 or 2 asymmetric carbons.

In this description and the following claims, halogen means a fluorine, chlorine, bromine or iodine atom; alkyl means linear or branched hydrocarbon groups.

The compounds (I) of the invention are those in which at least one of the following conditions is met: R1 represents a chlorine, bromine or methoxy atom and n = 1;R2 represents a chlorophenyl, methoxyphenyle or cyclohexyl;R4 represents a CONR6R7 group in which R6 and R7 or NR6R7 have one of the following definitions: . NR6R7 represents a pyrrolidine group substituted at position 2 by a group (CH2) q itself substituted by a carboxyl or carbamoyl group with q = 0,1,2 or 3. NR6R7 represents a piperidine group substituted at position 4 by an amino group, an alkylamine at C1-C4 or a dialkylamine at C1-C4,NR6R7 represents a thiazolidin group substituted by a carboxyl or carbamoyl group (CH2) q itself substituted by a carboxyl or carbamoyl group with q = 0, 1, 2 or 3.. NR6R7 represents a pyrrolidin group substituted in 2 by a carboxyl or carbamoyl group (CH2) q itself substituted in 2 by a carboxyl or carbamoyl group with q = 0, 1, 2 or 3 and substituted in 4 by an amino group, an alkylamino in C1-C4 or a dialkylamino in C1-C4.R6 represents an alkyl in C1-C4 and R7 represents a group (CH2) r itself substituted by a carboxyl or carbamoyl group with r = 1, 2 or 3;R5 represents a phenyl substituted in position 3 and 4 in position 2 and a para-methoxy group,or R5 is a phenyl substituted at position 4 by a methyl; m = 0.

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

In the description and examples, the following abbreviations are used. DCM: dichloromethaneEther iso: isopropyl etherAcOEt: ethyl acetateMeOH: methanolEtOH: ethanolEther: ethyl etherDMF: dimethylformamideTHF: tetrahydrofuranTEA triethylamineDMSO: dimethylsulfoxideDIPEA: diisopropylethylamineDCC: N,N'-dicyclohexylcarbodiimideDBU: 1-8 diazobicyclo [5.4.0] undec-7-Prothyl TBD: triazo-1,5,7 bicyclo [4.0]-5-NaDBNethyl ether: dihydroxyethyl chlorideDTHF: dimethylformamideTHF: tetrahydrofuranTEA triethylamineDMSO: dimethylsulfoxideDIPEA: dihydroxyethylamineDCC: N,N'-dihydroxyethyl carboxylamineDBC: triethyl phosphateDBU: 1-8 dihydroxyethyl phosphate: dihydroxyethyl benzoyl phosphate: dihydroxyethyl benzoyl phosphate: dihydroxylamine: dihydroxylamine: dihydroxylamine: dihydroxylamine: dihydroxylamine: dihydroxylamine: dihydroxylamine: dihydroxylamine: dihydroxylamine: dihydroxylamine: dihydroxylamine: dihydroxylamine: dihydroxylamine: dihydroxylamine: dihydroxylamine: dihydroxylamine: dihydroxylamine: dihydroxylamine: dihydroxylamine: dihydroxylamine: dihydroxylamine: dihydroxylamine dihydroxy: dihydroxy: dihydroxylamine: dihydroxylamine dihydroxy: dihydroxy: dihydroxylamine: dihydroxylamine dihydroxy: dihydroxy: dihydroxylamine dihydroxy: dihydroxy: dihydroxy: dihyd

The present invention also relates to the process of preparation of compounds (I).

This process is characterised by the fact that the (a) a derivative of amino-2 phenone with the formula: where R1, R2 and n have the meanings given above for I, a sulphonyl derivative of formula: - What? The following formulae are used: - What? in which Hal is a halogen, preferably chlorine or bromine, and R5 has the meanings given above for (I) is treated with a halogen derivative of formula: - What? The following table shows the calculation of the CO2 savings: - What? in which Hal' is a halogen, preferably bromine, and A is either the NR6R7 group or the OR group, where R is a tertiobutyl or a benzyl;(d) where A represents an OR group, the ester thus obtained with the formula: is unprotected under appropriate conditions; or its acid chloride of formula: is treated with a compound HNR6R7 using appropriate amide coupling techniques; (e) the compound thus obtained in step (b) or step (d) of formula: (f) the cis and trans isomers of the compound (I) may be separated and the enantiomers separated.

Amino-2 phenone (II) derivatives are known or prepared by 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.

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

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

Alcoxybenzene sulphonyl chloride is prepared from sodium alcoxybenzene sulfonate, which is itself prepared by the action of an alkyl halide on sodium hydroxybenzene sulfonate.

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

Step (a) of the process is carried out in pyridine by heating to a temperature between room temperature and the boiling point of the solvent for a period of time ranging from a few hours to a few days.

Step (b) of the process is carried out between the sulphonamide of formula (IV) and the halogenated derivative of formula (V) in excess in a solvent such as dimethylformamide or dimethylsulfoxide, under an inert atmosphere at a temperature between 0 °C and room temperature, for a period of time between a few hours and 24 hours in the presence of sodium hydride.

When the -NR6R7 group contains a second amine function, i.e. when R6 and/or R7 are substituted by an amino group, a halogen (V) derivative of formula Hal'-CH2 - CO2R in which R is a tertiobutyl or a benzyl may be chosen to be used to prepare the intermediates of formula (VI) and then (VI) '.

Step (d) is then performed under the standard conditions of amide coupling, e.g. in the presence of BOP or HOBT and DCC.

The compounds HNR6R7 are known or prepared by known methods. For example, the stereospecific synthesis of acetic (R) and (S) pyrrolidin-2-yl acids is performed according to H. Rueger et al. in Heterocycles, 1982, 19 (9), 1677 from a proline derivative of appropriate configuration. The preparation of methyl N-Boc dehydro-3,4 (α) prolinate is performed according to J.R. Dormoy, Synthesis, 1982, 753.

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

The step (e) of the process is similar to an aldol reaction: the methylene α group of the amide is deprotonated, and then the carbonyl function of the phenone acts as an internal electrophile, leading to cyclization with the appearance of two asymmetric carbons (C*).

The reaction can be summarized as follows: - What?

The principles of the aldol addition reaction have been reviewed by C.H. Heathcock in Asymetric Synthesis, vol. 3: Stereodifferentiating additions reactions, part B, 111-112; Academic Press, 1984, J.D. Morrison ed.

It is known that the aldol reaction of achiral amide anions leads to the formation of 2 racemic β-hydroxy amide diastereosomers in a ratio which depends largely on the experimental conditions used.

Where groups R6 and R7 are not hydrolysable in alkaline media, soda can be used in water, in the presence of a co-solvent, with or without the addition of a phase transfer catalyst; a quaternary ammonium hydroxide, e.g. benzyltrimethylammonium hydroxide in methanol, can also be used.

To perform this aldolisation reaction, organic bases can also be used, e.g.: Guanidines such as triaza-1,5,7 bicyclo [4.4.0] dec-5-ene,amidines such as diaza-1,8 bicyclo [5.4.0] undec-5-ene or diaza-1,5 bicyclo [4.3.0] non-5-ene, in a solvent or mixture of solvents selected from, for example, benzene, THF, dichloromethane, methanol, dimethylformamide; the reaction is carried out in an inert atmosphere between -10 °C and 110 °C; the amount of base used is at least stoichiometric; the reaction can also be carried out without solvent, at bath temperature.

Preferably, step (e) of the process of the invention is performed in the presence of diaza-1.8 bicyclo[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 solvent.

A primary, secondary or tertiary alcohol alcohol with lithium, sodium, potassium, calcium or magnesium may also be used.

The alcoholate is used in a catalytic or stoichiometric quantity in an anhydrous solvent, e.g. an alcohol (possibly in the presence of a co-solvent such as THF), or in a stoichiometric quantity in THF, DMF or DMSO, possibly in the presence of crown ether, e.g. dicyclohexyl-18 crown-6; the reaction is carried out between -15 °C and 80 °C.

The use of RR'NLi or RR'NMgBr amides, in which R and R' are monovalent radicals, as a deprotonating agent is a method of forming amide enolates, intermediates of the aldol reaction; this method has recently been reviewed by R.E. Ireland et al., J. Org. Chem., 1991, 56, 650. The solvent of the reaction may be benzene, hexane or THF, used anhydrous, in an inert atmosphere. Adjuvants such as LiF, LiCl, LiBr, LiI, LiBu, TMEDA, DMPU, HMIDPA or ether can be added. (M. Murakidate et al. J. Chem., 1657).

Finally, various publications describe starches 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.

Lithium, sodium or potassium silylamidures are another group of usable bases, among which: (Me3Si) 2NLi, (Me2PhSi) 2NLi, (Et3Si) 2NLi, (Me3Si) 2NK, (Me3Si) 2NNa.

Mixed starches as described by Y. Yamamoto, Tetrahedron, 1990, 46, 4563, e.g., the lithium salt of N- (trimethylsilyl) benzylamine, or an analogue in which benzylamine is replaced by a primary, chiral amine such as (R) or (S) α-methylbenzylamine, may also be used.

When the compound of formula (I) to be prepared has 2 asymmetrical carbon atoms, the use of starches or chiral alcohols in step (e) enantiomerically enrich each cis or trans stereoisomer and then determine the proportion of each enantiomer per dosage on a high performance liquid chromatography chiral column.

When the compound of formula (I) to be prepared has 3 or 4 asymmetric carbon atoms, the cycling step (c) may be accompanied by diastereoisomer enrichment and the use of an appropriate chiral base allows this diastereoisomer enrichment to be modified.

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

Optical isomers of each cis- and trans-isomer may be separated, for example, by preparatory chromatography on a chiral column followed by fractional crystallization or by formation of an optically active salt in the presence of a suitably selected chiral acid or base.

Thus, when the compound of the invention has 2 asymmetric carbon atoms, the enantiomers can be separated by chiral HCL.

When the compound of the invention has 3 or 4 asymmetric carbon atoms, the diastereoisomers can be separated using chromatography and fractional crystallization methods.

When R3 is hydrogen, a comparative analysis is performed by high-field NMR (250 MHz), for example, with the study of the Overhauser effect (NOE) between, for example, 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 the DCM are different. The cis isomer most often has a strong, fine, symmetrical absorption band around 3550-3520 cm-1, due to the hydroxyl vibration, whereas the trans isomer has no resolved vibration band in this region.

The data obtained showed that the cis isomer is generally most mobile in CCM on an alumina oxide plate (60F254 neutral, Type E, Merck), by electing by DCM containing varying proportions of AcOEt. Similarly, by chromatography on an alumina column (alumina oxide 90, particle size 0.063-0.200 mm), the cis isomer is most often elected first, the eleant being DCM containing varying proportions of AcOEt or MeOH.

Thus the cis or trans isomer of a compound (I) according to the invention can most often be determined by an analytical method.

The absolute configuration of some compounds according to the invention has been determined by X-ray analysis. By deduction from the value of the rotational power, the absolute configuration of other compounds obtained in an analogous manner can also be known.

A compound (I) in which R1 is an amino group and/or a compound in which R5 is a phenyl group substituted by an amino can be prepared by transformation of a compound (VI) obtained in step (b) in which R1 is a nitro group and/or R5 is a phenyl group substituted by a nitro, the other substituents having the desired values for (I), by catalytic hydrogenation, e.g. in the presence of Palladium on coal, Rhodium on aluminum or Raney's Nickel.

Compounds (I) in which the substituents R6 and/or R7 or the NR6R7 group include an alcohol-carbonyl group in C1-C4 allow the ester hydrolysis of compounds (I) in which R6 and/or R7 or the NR6R7 group include a carboxyl group, the other substituents of (I) being unchanged. Furthermore, compounds in which R6 and/or R7 or NR6R7 include a carboxyl group allow the production of a classical amide coupling reaction, compounds (I) in which R6 and/or R7 or the NR6R7 group include a free carbamoyl group or two alkyl substituents in C1-C4 being the other substituents identical.

Finally, compounds (I) in which R6 and/or R7 or the NR6R7 group comprise a carbamoyl group allow the Hofmann rearrangement to obtain compounds (I) in which R6 and/or R7 or the NR6R7 group comprise an amino group, the other substituents being identical (J. Org. Chem., 1979, 44 (10), 1746).

Thus, according to the present invention, the process of preparation of compounds (I) in which R6 and/or R7 or NR6R7 grouping include a free amino group or one or two alkyl substituents in C1-C4 may be of two variants: (i) step (b) of the process is carried out by treating the compound (IV) obtained in step (a) with a halogen (V) derivative of formula Hal'- CH2CONR6R7 in which R6 and/or R7 or NR6R7 group include an amine precursor group, e.g. a carboxyester, carboxy or carbamol; then the cycling step is carried out;For example, the carboxyester group of the compound (I) thus obtained is hydrolysed into a carboxy group, which is then transformed into a carbamoyl group and then into an amino group by the Hofmann rearrangement. (ii) step (b) is performed by treating the compound (IV) obtained in step (a) by a halogen derivative (V) of the formula Hal'- CH2COOR in which R′ represents a benzyl or a tertiobutyl; then the ester of the compound (VI) thus obtained is unprotected by an appropriate treatment, depending on step (c); a coupling with the compound HNR6R7 is obtained in which the amino group of R6 and/or R7 is possibly protected; the compound (VI) is then cyclically obtained; and (e) depending on the stage,The amino group is then removed by deprotection of the amine.

Compounds (I) in which groups R6 and/or R7 or NR6R7 include a benzyloxycarbonyl or an alkoxycarbonyl group as a substituent of an amine function give compounds (I) in which the amine function is free, the other substituents being identical.

The compounds of formula (VI) useful as intermediates for the preparation of compounds (I) of the invention are new and part of the invention.

Thus the present invention also relates to compounds with formula: in which A' represents a group selected from: NR6R7, OH, OtBu, OBz;R1 represents a halogen atom, an alkyl in C1-C4, a hydroxyl, an alcohol in C1-C4, a benzyloxy group, a cyano group, a trifluoromethyl group, a nitro group or an amino group;R2 represents an alkyl in C1-C6; a cycloalkyl in C3-C7, a cycloalkene in C5-C7, a phenyl not substituted or substituted once or several times by an alkyl in C1-C4, an alcohol in C1-C4, a halogen, a trifluoromethyl group, an amino group, or R2 represents an unsubstituted nitrophenyl or substituted once or several times by a trifluoromethyl group or an alkyl in C1-C4,C1-C4 alcohols or halogens;R5 means an alkyl in C1-C4; a naphthyl-1; a naphthyl-2; a dimethylamino-5 naphthyl-1; a phenyl not substituted or substituted by one or more substituents chosen from a halogen, an alkyl in C1-C4, a trifluoromethyl group, a free amino group or substituted by one or two alkyl groups in C1-C4, a hydroxyl, an alcohol in C1-C4, an alkenoxy in C2-C4, an alkyl in C1-C4, a trifluoromethyoxy group, a benzyloxy group, a cyano group, a carboxy group, an alcohol-carboxy group in C1-C4, a free group or two substituted by an alkyl or a carbamoyl group in C1-C4 or an alkyldol group in C1-C4, aor R5 is an unsubstituted nitrophenyl or a single substitution of a trifluoromethyl or an alkenoxy group in C2-C4, or one or more substitutions of a halogen, an alkyl in C1-C4, an alkoxy in C1-C4, an alkylthyo in C1-C4, a trifluoromethoxy group in C1-C6, or a benzyloxy group; or R6 is similar to R7R7 is a piperidine-4-yl group; or an azetidin-3-yl group, whether or not substituted on nitrogen by an alkyl in C1-C4 by a benzyloxycarbonyl or an alkoxycarbonyl in C1-C4 by a pyrryl group (CHr2); orR6 and R7 together with the nitrogen atom to which they are attached constitute a heterocycle selected from: . morpholine, thiomorpholine, thiazolidine or 2,2-dimethylthiazolidine whether or not substituted with R8, piperazine not substituted or substituted in 4 by an R'8 group, a 5-chain mono-nitrogen unsaturated ring substituted with R8 orsaturated mono-nitrogen cycle with 3, 4, 5, 6 or 7 chains substituted by R8 and R9 ;R8 represents R'8 or a group (CH2) r itself substituted by a hydroxyl or a free amino or substituted by one or two alkyl at C1-C4 ;R'8 represents a group (CH2) q itself substituted by a carboxyl group, an alcohol-carbonyl group at C1-C4, a benzyloxycarbonyl group, a free carbamoyl group or substituted by a hydroxyl or one or two alkyl at C1-C4, or a free aminocarbotyyl group or substituted by one or two alkyls at C1-C4 ;R'8 represents R'8 or a free group (CH2NH2) q itself substituted by one or two alkyls at C1-C4 ;R'9 represents hydrogen,a halogen group, a (CH2) r OR10, a (CH2) r NR11 R12, a (CH2) sCONR11 R11, an azide group;R10 represents hydrogen, an alkyl in C1-C4, a mesyl or a tosyl;R11, R'11 and R12 each represent hydrogen or an alkyl in C1-C4 or R11 represents hydrogen and R12 represents a benzyloxycarbonyl or an alkoxycarbonyl in C1-C4 ;n represents 0, 1 or 2m represents 0, 1 or 2 ;q represents 0, 1, 2 or 3 ;r represents 0, 1, 2 or 3, with the limitation that R8 or R9 is not zero when R8 or R9 is in the amide position of intracyclic alpha nitrogen;0 or 1 represents a

According to another aspect of the present invention, the compounds (I) of the invention in which either R7 or NR6R7 contains a carboxyl group are useful for the preparation of decarboxyl analogue compounds.

Thus, the invention relates in this respect to the use of compounds of formula (I') in which R1, R2, R3, R5, m and n have the meanings given above for compounds of formula (I) RVI represents an alkyl in C1-C6,RVII represents a group (CH2) rCOOH with r = 1, 2 or 3.or RVI and RVII together with the nitrogen atom to which they are bound constitute a heterocycle selected from: . thiazolidine or 2,2-dimethylthiazolidine substituted by a group (CH2) qCOOH,. piperazine substituted in 4 by a group (CH2) q-COOH,. a 5-chain mono-nitrogen unsaturated cycle substituted by a group (CH2) qCOOH., a 3-chain mono-nitrogen saturated cycle,4, 5, 6 or 7 chains replaced by a group (CH2) qCOOH, with q = 0, 1, 2 or 3, for the preparation of a compound of formula (I) ' having the same configuration around the indoline 2, 3 bond as the starting product where:R1, R2, R3, R5, m and n are as defined above,R'VI is an alkyl in C1-C6,R'VII is the group (CH2)rH, or R'VI and R'VII together with the nitrogen atom to which they are bound constitute a heterocycle selected from: . thiazolidine or 2,2-dimethylthiazolidine substituted with a group (CH2) qH. piperazine substituted in 4 by a group (CH2) qH,. a 5-chain mono-nitrogen unsaturated cycle substituted by a group (CH2) qH. a 3, 4, 5, 6 or 7 chain mono-nitrogen saturated cycle substituted by a group (CH2) qH.

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

The affinity of the compounds of the invention for vasopressin receptors was determined in vitro using the method described in J. Biol. Chem., 1985, 260 (5), 2844-2851. This method involves studying the displacement of tritiated vasopressin bound to V1 sites of rat liver membranes. The 50% inhibitory concentrations (CI50) of tritiated vasopressin binding of the compounds of the invention are low, ranging up to 10-9M.

In addition, inhibition of vasopressin-induced platelet aggregation has been measured in human platelet rich plasma (HPR) using the method described in Thrombosis Res., 1987, 45, 7-16. The compounds of the invention inhibit the aggregation induced by vasopressin at concentrations of 50 to 100 nM with low DI50 (inhibitory doses) up to 10-9M. These results show V1 receptor antagonistic activity of the compounds of the invention.

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

The compounds according to the invention with cis configuration around the 2,3 binding of indolin have marked selectivity for V1 receptors.

The affinity of the compounds (I) of the invention for oxytocin receptors was determined in vitro by displacement of tritiated oxytocin bound to receptors from a membrane preparation of pregnant rat glands.

The compounds of the invention are active after administration by various routes, including oral administration.

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

Thus, the compounds of the invention can be used in the treatment or prevention of various vasopressin-dependent conditions, including cardiovascular conditions such as hypertension, heart failure, thrombosis, or coronary vasospasm, particularly in smokers; central nervous system diseases, brain edema, psychotic states, appetite disorders, memory disorders, for example; kidney system diseases such as renal vasospasm, renal cortex necrosis; gastric system diseases such as ulcers or inappropriate antidiuretic hormone secretion syndrome (DHIA).

The compounds of the invention may also be used as antiemetics, particularly in motion sickness, and as antiproliferative agents, for example in cancer or atherosclerosis.

In women, the compounds of the invention may also be used to treat dysmenorrhea or preterm labor.

The present invention also relates to pharmaceutical formulations containing an effective dose of a compound of the invention or a pharmaceutically acceptable salt and suitable excipients, which are selected according to the pharmaceutical form and the desired route of administration.

In the pharmaceutical formulations of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, intratracheal, intranasal, transdermal or rectal administration, the above active substances of formula I, or their salts, as appropriate, may be administered in unit doses, in combination with conventional pharmaceutical media, to animals and humans for prophylaxis or treatment of the above disorders or diseases. The appropriate unit doses include oral doses such as tablets, capsules, powders, granules and oral solutions or suspensions, sublingual doses, intranatales, intranatales, sublingual doses, intramuscular doses, topical or intramuscular doses, or intramuscular doses, depending on the application.

In order to achieve the desired prophylactic or therapeutic effect, the active substance dose may vary from 0.01 to 50 mg per kg body weight per day.

Each unit dose may contain 0.5 to 1000 mg, preferably 1 to 500 mg, of active ingredients in combination with a pharmaceutical carrier.

When preparing a solid composition in the form of tablets, the main active ingredient is mixed with a pharmaceutical vehicle such as gelatine, starch, lactose, magnesium stearate, talc, gum arabic or analogues.

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

A preparation in the form of syrup or elixir or for administration in the form of drops may contain the active ingredient together with a preferably caloric sweetener, methylparaben and propylparaben as antiseptics, as well as a flavouring agent and an appropriate colouring.

Water-dispersible powders or granules may contain the active ingredient mixed with dispersion agents or wetting agents, or suspension agents, such as polyvinylpyrrolidone, as well as sweeteners or flavour enhancers.

For rectal administration, suppositories are used which are prepared with binders that melt at rectal temperature, for example cocoa butter or polyethylene glycols.

For parenteral administration, aqueous suspensions, isotonic saline solutions or sterile solutions for injection containing dispersing agents and/ or pharmacologically compatible wetting agents, e. g. propylene glycol or butylene glycol, are used.

The active substance may also be formulated in the form of microcapsules, possibly with one or more media or additives.

The compositions of the present invention may contain, in addition to the products of formula I above or any of the pharmaceutically acceptable salts, other active ingredients which may be useful in the treatment of the disorders or diseases indicated above.

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

The following examples illustrate the invention.

The compounds are characterised by their melting point (F°C) (or boiling point Eb) and/or their NMR spectrum recorded at 200 mHz in the DMSO, and/or their rotational power (αD) measured at 25°C (unless otherwise specified).

The measured rotational power value depends on the amount of residual solvent present in the prepared product.

Err1:Expecting ',' delimiter: line 1 column 84 (char 83)

The optical purity of the compounds is studied by high performance liquid chromatography (HLPC).

The following paragraphs are added: N-methyl N-methoxycarbonyl methyl bromo-5 (fluoro-2 phenyl)-3 (dimethoxy-3,4 phenyl sulfonyl)-1 hydroxy-3 indoline-2 carboxamide, cis isomer (A) N-bromoacetyl methyl sarcosinate

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

The following definitions are used:

Heat at 85°C for 48 hours in 120 ml of dry pyridine 20 g of amino-2 bromo-5 fluoro-2' benzophenone in the presence of 20 g of dimethoxy-3,4 phenylsulfonyl chloride. Cool, pour in ice water, filter the solid, extract the solid by AcOEt, wash the organic phase with water, a solution of hydrochloric acid (1N), water, then saline. After drying on magnesium sulfate and evaporation of the solvent underneath, a vacuum solid is obtained which is recrystallized in DCM/isoether. The temperature of the test vessel shall be measured at a temperature of ± 5 °C.

C) Bromo-5 [N- ((dimethoxy-3,4 phenylsulfonyl) N- ((N'-methyl N'-methoxycarbonylcarbamoylmethyl) ] amino-2 fluoro-2' benzophenone.

After 15 minutes, add 4.85 g of the compound prepared in step A and stir at TA for 12 hours. Pour the reaction medium over water, filter the solid, then dissolve the solid in AcOEt, wash the organic phase with water and then with saline water and videopore the solvent under silane. Filter the oil obtained on a base by eluting with a DCM/AcEO mix (85/15 v);/v. Recalcify in a DCM/MeOH mix. The temperature of the water is measured at a temperature of approximately 5 °C.

D) N-methyl N-methoxycarbonyl methyl bromo-5 (fluoro-2 phenyl)-3 (dimethoxy-3,4 phenyl sulphonyl)-1 hydroxy-3 indoline-2 carboxamide, cis isomer

3.2 g of the product obtained in the previous step is dissolved in DCM (3 ml), 750 mg of DBU is added and stirred at TA for 24 hours. The reaction medium is poured over a column of silica; by elevating by DCM/AcOEt (90/10; v/v) a product is obtained which is the mixture of the 2 isomers (cis and trans) of the expected compound. This product is crushed into a hexane-ether iso mixture and the resulting solid is then filtered. The filtration juices are chromatographed on a pre-balanced alumina column in a DCM/AcOEt (70/30 v/v); the polar compound is at least elevated by a DCM/AcOEt (60/v/v) mixture; the mixed hexane/acor is mixed into the DCM/AcOether. Fc = 95°C with gaseous emissions.

EXAMPLES 2 and 3 [[[benzyloxycarbonyl-4) piperazine-1-yl]-carbonyl-2 chloro-5 (chloro-2 phenyl)-3 (dimethoxy-3,4 phenylsulfonyl)-1 hydroxy-3 indole, cis and trans isomer. The following definitions shall apply:

A mixture of 22 g benzyloxycarbonyl-4 piperazine and 10.1 g triethylamine in 200 ml of ether is cooled to 0 °C. 20.2 g bromacetyl bromide is added to 100 ml of ether in 30 minutes and allowed to return to TA. After 4 hours, the reaction medium is washed with water, dried, concentrated and then chromatographed on silica. The mixture DCM/OAcEt (95/5; v/v) elects the expected compound which is recrystallized in DCM/iso ether. The temperature of the water is measured at a temperature of approximately 100-101 °C.

(b) dichlor-2',5 (dimethoxy-3,4 phenylsulfomanide)-2 benzophenone, which is a substance of the

The pyridine is heated overnight at 100 °C, 5.6 g of amino-2 dichloro-2',5 benzophenone and 5 g of dimethoxy-3,4 phenylsulfonyl chloride are added to the pyridine, the pyridine is evaporated at dry conditions, water is added, and ethyl acetate containing a little DCM is extracted. Fc is 164°C.

C) dichlor-2,5, [N- ((dimethoxy-3,4 phenylsulfonyl) -N- ((benzyloxycarbonyl-4 piperazine-1-yl carbonyl methyl) ] amino-2 benzophenone.

2.3 g of the B-step benzophenone is placed in 10 ml of DMF and treated with 200 mg of 80% sodium hydride in oil. After 30 minutes, 5.3 g of the B-step benzophenone is added and stirred for 60 hours at TA. The medium is poured over water, filtered, precipitated, picked up by DCM, dried, then concentrated and chromatographed on silica. The temperature of the water is approximately 175 °C.

D) [benzyloxycarbonyl-4) piperazine-1-yl]-carbonyl-2 chloro-5 (chloro-2 phenyl)-3 (dimethoxy-3,4 phenylsulfonyl)-1 hydroxy-3 indole, cis isomer and trans isomer

After 2 hours, neutralize by adding a little carboglass, dry concentrate and then take up again with water; then extract by DCM, dry and concentrate. The raw product is chromatographed on alumina, the mixture DCM/OAcEt (80/20 v/v) is chosen; successively the 2 isomers.

The least polar isomer is recrystallized from the DCM/hexane mixture. The temperature of the water is approximately 169.9°C.

The most polar isomer is recrystallized from the DCM/iso ether mixture. The temperature of the water is measured at a temperature of approximately 20 °C.

The Commission shall adopt implementing acts. Chloro-5 (chloro-2 phenyl)-3 (dimethoxy-3,4 phenylsulfonyl)-1 hydroxy-3 (piperazine-1-ylcarbonyl)-2 indoline, isomer cis.

200 mg of the cis isomer prepared in the previous example is dissolved in 10 ml of ethanol and 5 ml of THF and hydrogenated to TA in the presence of 10% Pd/C. After 30 minutes, the medium is filtered on Cellite ®, the filtration juices are concentrated and then chromatographed on silica. The temperature of the water is approximately 110 mgFc.

EXAMPLES 5 and 6 Chloro-5 (chloro-2 phenyl)-3 (dimethoxy-3,4 phenylsulfonyl)-1 hydroxy-3 morpholinocarbonyl-2 indoline, cis isomer and trans isomer The following substances are to be classified in the same heading as the product:

5 g of dichloro-2',5 (dimethoxy-3,4 phenylsulfonamide)-2 benzophenone is treated with 350 mg sodium hydride at 80% in 30 ml DMF at TA for 20 minutes. 4.5 g of morpholine bromacetamide is added and then stirred at TA for 48 hours. The medium is poured over water, the precipitate filtered, dissolved in DCM, dried and concentrated. The product formed in the DCM/isoether mixture is recrystallized. 5,4 g is obtained. Fc is 173-176°C.

B) Chloro-5 (chloro-2 phenyl)-3 (dimethoxy-3,4 phenylsulfonyl)-1 hydroxy-3 morpholinocarbonyl-2 indoline, cis isomer

1 g of the product obtained in the previous step is solubilised in the methanol (10 ml) THF (20 ml) mixture and treated with 92 mg of sodium methyllate at TA for 1 hour. The medium is neutralized by carboglass, the solvents are partially evaporated, the medium is taken up by water, extracted in the DCM, dried, concentrated and chromatographed on alumina. m = 215 mg: isomer cisFc = 260 to 264 °C.

C) Chloro-5 (chloro-2 phenyl)-3 (dimethoxy-3,4 phenylsulfonyl)-1 hydroxy-3 morpholinocarbonyl-2 indoline, trans isomer, which is a trans isomer.

The chromatography of the previous step collects a more polar product by electrolysis with the mixture AcOEt/MeOH (90/10; v/v). The test chemical is a transFc isomer.

The Commission has N-methyl N-carboxymethyl bromo-5 (fluoro-2 phenyl)-3 (dimethoxy-3,4 phenylsulfonyl)-1 hydroxy-3 indoline-2 carboxamide, cis isomer

200 mg of the compound prepared in example 1 is dissolved in 3 ml of MeOH and 1 ml of water containing 13 mg of baking soda. After 24 hours agitated in TA, a drop of concentrated baking soda is added to complete the reaction, then after 15 minutes acidified to pH 3 by addition of a solution of acidic potassium sulfate. Water is added, extracted by AcOEt, washed with water, dried on magnesium sulfate and evaporated the solvent under vacuum. The resulting product is recrystallized in DCM/iso ether. The temperature of the water is 20 °C.

EXAMPLES 8 and 9 The following is added to the list of active substances: (A) N-bromoacetyl piperidine-4 carboxylate of ethyl.

This product is prepared from the commercial piperidine-4 ethyl carboxylate.

The substance is to be classified in the additive category 'Fluorocarbons' as defined in point 1 of Annex I to Regulation (EC) No 1907/2006 of the European Parliament and of the Council.

8 g of dichloro-2′,5 (dimethoxy-3,4 phenylsulfonamide)-2 benzophenone is dissolved in 100 ml DMF, then 541 mg of sodium hydride is added. After 30 minutes of stirring, 9.5 g of the step A compound is added and stirred for 18 hours at TA. Concentrate under vacuum, take up with water, extract with ethyl acetate, concentrate and dry. The resulting oil is chromatographed on silica by eluting with the mixture AcOEt/DCM/hexane (40/10/50 v/v/v). The desired product crystallizes in ether. The temperature of the water is measured at a temperature of approximately 5 °C.

C) Chloro-5 (chloro-2 phenyl)-3 (dimethoxy-3,4 phenylsulfonyl)-1 hydroxy-3 (ethylcarboxylate-4 piperidinocarbonyl)-2 indoline, isomer cis, isomer trans.

A mixture containing 3.4 g of the compound prepared in the previous step and 869 mg of DBU is carried at 60 °C for 18 hours in 10 ml of chloroform. The temperature of the water is approximately 700 mgFc.

The pure ethyl acetate elected the trans isomer. The temperature of the water is calculated as m = 610 mgFc = 187°C.

EXAMPLE 10 and 11 N-methyl N- ((pyrid-2-yl ethyl) chloro-5 (chloro-2 phenyl)-3 (dimethoxy-3,4 phenylsulfonyl)-1 hydroxy-3 indoline-2 carboxamide, cis isomer, trans isomer. A) N-[ (chloro-2 phenylcarbonyl) - 2 chlor-5 phenyl] N- (dimethoxy-3,4 phenylsulfonyl) glycine acid

(a) dichlor-2′,5 (dimethoxy-3,4 phenylsulfonamide)-2 benzophenone; or This compound is prepared in step B.b) dichloro-2′,5 [N- ((dimethoxy-3,4 phenylsulfonyl) N-benzyloxyacarbonylmethyl] amino-2 benzophenone. 172 g of the product previously prepared is dissolved in 800 ml of DCM and cooled to 0 °C. 11.7 g of sodium hydride at 80% are added gradually under nitrogen and after 30 minutes 256 g of benzyl bromoacetate are added and left to agitate for 24 hours at TA. The DMF is evaporated, taken up with water, extracted from the DCM, dried and concentrated. The product to be prepared crystallizes in the iso ether and then recrystallized in the DCM/iso ether mixture. m = 136,The temperature of the test chemical is measured at a temperature of approximately 10 °C. (c) N-[ (i) chlorine-2 phenylcarbonyl) - 2 chlorine-5 phenyl] N- (i) dimethoxy-3,4 phenylsulfonyl) glycine acid 50 g of the benzyl ester obtained previously is dissolved in 500 ml of AcOEt and 2.5 g of Pd/C at 5% is added to the solution with nitrogen. The solution is stirred vigorously and a hydrogen current is passed through for 5 hours. At the end of hydrogenation, the product crystallizes. The medium is filtered on Cellite®, the cake is washed thoroughly with hot DCM and the organic phase is concentrated. The product is crystallized and then recrystallized in the DCM/isoether mixture. The temperature of the water is approximately 7 °C.

The substance is classified in the additive category 'Fluorocarbons' as defined in point 1 of Annex I to Regulation (EC) No 1907/2006 of the European Parliament and of the Council.

2 g of the acid prepared in step A is placed in 30 ml of DCM and 1.13 g of (methylamino-2 ethyl)-2 pyridine is added, then 844 mg of triethylamine and finally 1.92 g of BOP and then stirred for 18 hours at TA. The temperature of the water is measured at the temperature of the water.

C) N-methyl N- ((pyrid-2-yl ethyl) chloro-5 (chloro-2 phenyl)-3 (dimethoxy-3,4 phenylsulfonyl)-1 hydroxy-3 indoline-2 carboxamide.

Heat a mixture containing 1.7 g of the product obtained in the previous step and 442 mg of DBU in DCM at 55°C for 18 hours. The temperature of the water is measured at a temperature of approximately 4 °C.

The pure isomer is trans: The temperature of the water is approximately 790 mgFc.

The Commission has (Carboxy-4-piperidinocarbonyl)-2 chloro-5 (chloro-2-phenyl)-3 (dimethoxy-3,4-phenyl sulphonyl)-1 hydroxy-3 indole, cis isomer

500 mg of the cis isomer prepared in sample 9 is placed in 5 ml of methanol in the presence of 48 mg of soda in 1 ml of water. After 18 hours of stirring, water is poured over, acidified with dilute hydrochloric acid and then extracted from the DCM, dried and concentrated. The resulting solid is purified by silica chromatography by elevating by the DCM/MeOH (95/5; v/v) mixture, and the resulting product is crystallized from the DCM/iso ether. The temperature of the water is not equal to 250 mgFc.

EXAMPLES 13 and 14 N-methyl N-(methyl-1 piperidine-4-yl) chloro-5 (chloro-2 phenyl)-3 (dimethoxy-3,4 phenylsulfonyl)-1 hydroxy-3 indoline-2 carboxamide, cis isomer and trans isomer The substance is to be classified in the additive category 'Fluorocarbons' as defined in point 1 of Annex I to Regulation (EC) No 1907/2006 of the European Parliament and of the Council.

After 2 hours of agitation at TA, the organic phase is washed in carbonated water, dried and concentrated. Then silica chromatography is performed by eluting with the DCM/MeOH mixture (90/10 v/v). 1.2 g of the expected product is obtained. Fc is 165-166°C.

(b) N-methyl N- ((methylpipperidin-4-yl) chloro-5 (chloro-2 phenyl)-3 (dimethoxy-3,4 phenylsulfonyl)-1 hydroxy-3 indoline-2 carboxamide, cis isomer and trans isomer.

650 mg of the product obtained in the previous step is treated overnight by 100 mg of sodium methylate in 5 ml of methanol. Carboglass is added, the solvent is evaporated, the solvent is taken up by carbonated water, extracted in DCM, dried and concentrated and then chromatographed on silica. The methanol/DCM mixture (5/95 ; v/v) successively elects the 2 isomers. Each is then recrystallized from the DCM/iso ether mixture. the least polar trans isomer, under these conditions, m = 205 mgFc = 181°C. cis isomer: The temperature of the water is approximately 150 mgFc = 97°C: contains 0.25 M iso ether.

EXAMPLE 15 and 16 The substance is classified in the additive as a substance of a kind used in the manufacture of foodstuffs for human consumption. The substance is to be classified in the additive category 'Fluorocarbons' as defined in point 1 of Annex I to Regulation (EC) No 1907/2006 of the European Parliament and of the Council.

This compound is obtained by the action of N-methyl piperazine on the acid prepared in example 10-11 step A. Fc is 165 to 167°C.

B) Chloro-5 (chloro-2 phenyl)-3 (dimethoxy-3,4 phenylsulfonyl)-1 hydroxy-3 [ (methyl-4) piperazine-1-yl carbonyl]-2 indoline, cis isomer and trans isomer

The compound in the previous step is cycled as in example 12-13. The 2 isomers formed are separated by chromatography on alumina. Fc = 120°C: contains 0,25 M of iso ether.

The DCM/MeOH mixture elected the most polar compound, the trans isomer which is then recrystallized from methanol. Fc is 189°C.

EXAMPLE 17 and 18 N-isopropyl N-methoxycarbonylethyl chloro-5 (chloro-2 phenyl)-3 (dimethoxy-3,4 phenylsulfonyl)-1 hydroxy-3 indoline-2 carboxamide, cis isomer and trans isomer (A) N-isopropyl N-methoxycarbonylethyl bromoacetamide

90 g isopropylamine is added to 130 g of solution of methyl acrylate cooled to -10 °C in 300 ml of methanol by drip drops. After 72 hours at TA, the medium is evaporated and the residue is distilled. The temperature of the water is approximately 73-78 °C at 15 mm Hg.

At 0°C, mix 29 g of the compound obtained from 100 ml of DCM with 20.2 g of bromacetyl bromide in 100 ml of DCM. After 12 hours at TA, evaporate the solvent, re-use with water, extract to ethyl acetate, dry and concentrate.

The substance is to be classified in the additive category 'Chemical products'.

This compound is obtained by the usual method of action by action of the product prepared in step A on dichlor-2′,5 (dimethoxy-3,4 phenylsulfonamide)-2 benzophenone in the presence of sodium hydride. The test chemical is a chemical that is used to produce a specific chemical.

(C) N-isopropyl N-methoxycarbonylethyl chlor-5 (chloro-2 phenyl)-3 (dimethoxy-3,4 phenylsulfonyl)-1 hydroxy-3 indoline-2 carboxamide, cis isomer and trans isomer

This product is obtained by cyclization of the compound prepared in step B in the presence of DBU. The cis isomer is separated by chromatography on alumina by electrolysis by the mixture DCM/AcOEt (90/10; v/v). The temperature of the water is 153-155°C.

The trans isomer is obtained by eluting the alumina column from the ethyl acetate and then recrystallizing the product in the methanol/iso ether mixture. Fc is 182-185°C.

EXAMPLES 19 and 20 N-methyl N-methoxycarbonylmethyl chloro-5 (chloro-2 phenyl)-3 (dimethoxy-3,4 phenyl sulfonyl)-1 hydroxy-3 indoline-2 carboxamide, cis isomer and trans isomer

The 2 isomers of this compound are prepared in the manner described in Example 1. They are separated by chromatography on aluminum. The mixture DCM/AcOEt (80/20; v/v) elects the cis isomer. This crystallizes from the mixture DCM/iso ether, as a white powder containing 0.25 moles of iso ether. It is transformed into foam by vacuum heating.

The NMR spectrum of the cis isomer (example 19) is shown in Figure 1.

The trans isomer is elected by pure AcOEt. Fc is 176-178°C.

The trans isomer NMR spectrum (example 20) is shown in Figure 2.

EXAMPLES 21 and 22 N-methyl N-carboxymethyl chloro-5 (chloro-2 phenyl)-3 (dimethoxy-3,4 phenyl sulfonyl)-1 hydroxy-3 indoline-2 carboxamide, cis isomer and trans isomer

These compounds are each prepared from the compounds described in Examples 19 and 20 in the manner described in Examples 8. The test chemical is a trans-isomer of the isomer cis: Fc = 220-222°C after recrystallization in the DCM/iso ether/MeOH mixture.

EXAMPLE 23 and 24 N-methyl N-carbamoyl methyl chloro-5 (chloro-2 phenyl)-3 (dimethoxy-3,4 phenyl sulphonyl)-1 hydroxy-3 indoline-2 carboxamide, cis isomer and trans isomer

Each isomer is obtained from the corresponding isomer of the acid prepared in example 21-22.

605 mg of the trans isomer of the acid obtained in the previous example are dissolved in 10 ml of DCM, 435 mg of BOP and 260 mg of DIPEA are added. After 5 minutes at TA, 6 ml of 20% ammonia solution is added under strong agitation and left to agitate for 4 hours. A sodium carbonate solution is added, then extracted by DCM. The organic phase is successively washed with water, a sodium sulphate acid solution, then water, then dried on magnesium sulphate. After evaporation, the residue is chromatographed on silica gel and is elected by a mixture of AcOet/OH (95/5 v/Mev). The resulting product is crystallized twice in the mixture of ACOet/OH at 0 °C. Fc is 236°C.

The trans isomer NMR spectrum (example 23) is shown in Figure 3.

Using the same procedure, the cis isomer is prepared.

The product to be obtained crystallizes in DCM/iso ether. The micronized compound, vacuum dried at 70°C for 8 hours, contains 0.25 moles of iso ether.

The NMR spectrum of the cis isomer (example 24) is shown in Figure 4.

EXAMPLE 25 and 26 The following substances are to be classified in the same heading as the active substance:

This compound is prepared from the acid N-[(chloro-2 phenylcarbonyl) -2-chloro-5 phenyl] N-(dimethoxy-3,4 phenylsulfonyl) glycine described in Example 11-12, Step A.

The product obtained is then cycled according to the usual method in the presence of DBU. The 2 isomers are separated by chromatography on alumina. The mixture DCM/MeOH (99/1 ; v/v) elected the cis isomer.

The product crystallizes in the DCM/hexane/MeOH mixture and the resulting solid is crushed in DCM/hexane to give an amorphous powder.

The cis isomer is characterized by its NMR spectrum at 388°K. The following is the list of substances which are to be classified as ' aromatic substances ' in the Annex to Regulation (EC) No 1907/2006:

The mixture DCM/MeOH (97/3; v/v) elected the trans isomer which is recrystallized into DCM/iso ether. Fc is 232-234°C.

Synthesis in the series (L) Proline: Examples 27, 28, 29, 30. EXAMPLES 27 and 27a Chlorine-3 (di-hydroxy-3- (methyl) phenylenediamine) isomers of cyclic hydrocarbons (including cyclic hydrocarbons) A) N-bromoacetyl) methyl prolinate

A solution of 16.7 g methyl (L) prolinate hydrochloride in 20 ml DCM is simultaneously added 20 g triethylamine and 20 g bromacetyl bromide in 30 ml DCM, maintaining the temperature at -5°C, and then stirred at TA for 24 hours. Water is added, washed with a solution of KHSO4, with water, with a solution of sodium bicarbonate, with water, then dried on magnesium sulfate. After evaporation, an oil is obtained which is dried in vacuum. This oil, pure in CCM, is used as in the next step.

The substance is to be classified in the additive category 'Chemical products'.

4.66 g of dichlor-2',5 (dimethoxy-3,4 phenylsulfonamide) - 2 benzophenone is dissolved in 40 ml of anhydrous DMF under argon at 0 °C, 340 mg of 80% sodium hydride is added, and after 30 minutes 6.5 g of the compound obtained in step A. After 4 days in TA, it is poured into water, extracted by AcOEt, washed with water, salt water, dried on magnesium sulphate and evaporated under vacuum. m = 1,2 g Fc = 141-142°C The following table shows the results of the analysis: - What?

analyse	calculé	C : 54,81	H : 4,44	N : 4,41
	trouvé	54,40	4,54	4,55

C) Chloro-5 (chloro-2 phenyl)-3 (dimethoxy-3,4 phenylsulfonyl)-1 hydroxy-3 [(2S) ((methoxycarbonyl-2) pyrrolidinocarbonyl]-2 indoline, (cis isomer)

After 24 hours, the reaction medium is poured on a column of alumina, pre-balanced in the DCM/AcOEt mixture (90/10; v/v) and elected by the DCM/AcOEt mixture (90/10; v/v; up to 70/30 v/v). 510 mg of a mixture of the 2 least polar compounds in the ratio 4/1 (measured by HPLC) is obtained. 1°) Two successive crystallizations in DCM/isoether at cold temperatures give a majority compound.m = 180 mgαD25 = -247°(c = 0.4; chloroform)Fc = 187-190°C.2°) The crystallization parent waters of the former compound are chromatographed on alumina by elevating by DCM/AcOEt (85/15; v/v). The former compound is thus separated from the latter, the latter is dissolved in a minimum of DCM and then precipitated by the addition of a minimum of hexane. αD26 = +136 (c = 0,24; chloroform)

The Commission has not yet adopted a decision. (C010-C010-C010-C010-C010-C010-C010-C010-C010-C010-C010-C010-C010-C010-C010-C010-C010-C010-C010-C010-C010-C010-C010-C010-C010-C010-C010-C010-C010-C010-C010-C010-C010-C010-C010-C010-C010-C010-C010-C010-C010-C010-C010-C010-C010-C010-C010-C010-C010-C010-C010-C010-C010-C010-C010-C010-C010-C010-C010-C010-C010-C010-C010-C010-C010-C010-C010-C010-C010-C010-C010-C010-C010-C010-C010-C010-C010-C010-C010-C010-C010-C010-C010-C010-C010-C010C010-C010C010C010C010C010C010C010C010C010C010C010C010C010C010C010C010C010C010C010C010C010C010C010C010C010C010C010C010C0 to the other products of the other products of which are not included in this subheadings are the following:

430 mg of the compound prepared in sample 27 is dissolved in 6 ml of methanol, 41 mg of soda is added in 1 ml of water and stirred for 24 hours at TA. Acidified at pH 3 by a few drops of a solution of potassium acid sulfate, and extracted by ethyl acetate. Washed with water and then dried on magnesium sulfate. Chromatographed on a column of silica prepared in the mixture DCM/pentane (80/20 v/v). The ester (composite of sample 27) that has not reacted is elected by the mixture DCM/OO (70/30 v/v). The mixture AcO/Me (80/20 OH/v) vents; the acrylic acid is then isolated and recrystallized in DCM/AcAcAc. The following is a list of the active substances which may be used in the preparation of the active substance:

EXAMPLES 29 and 29a (C2S) carbamoyl-2 pyrrolidinocarbonyl-2 chloro-5 (chloro-2 phenyl)-3 (dimethoxy-3,4 phenyl sulfonyl)-1 hydroxy-3 indole, (isomers of cis: 2 compounds) with a molecular weight of not more than 0,01 g/cm3

230 mg of the sample 28 compound is dissolved in 5 ml of DCM, 50 mg of DIPEA is added, 165 mg of BOP is added, and 5 minutes of TA is allowed. The medium is cooled in an ice bath and then a stream of gaseous ammonia is stirred for 1 minute, and after 15 minutes, again for 1 minute. Water is added and then a large volume of ethyl acetate is added to obtain 2 phases. The organic solution is washed with a solution of sodium carbonate, water, a solution of potassium sulphate acid, salt water. After sifting, the mixture is chromatographed on silica by extracting DCM/Me (93/7 v/OH); the mixture is ground into the DCM/M/M isoether. The following table shows the results of the analysis:

The compound in sample 29 may be prepared by another method.

The substance is classified in the additive category 'Chemical products'.

33.9 g of the acid prepared in sample 10-11, step A are dissolved in 300 ml of chloroform. 15 g of thionyl chloride are added and carried backstream for 1 hour and a half. The medium is evaporated dry, then the medium is taken up by DCM and evaporated again. The medium is dissolved in 300 ml of DCM, carried to 0°C and added 10.5 g of prolinamide (L) hydrochloride, then 18 g of DIPEA are added slowly to 20 ml of DCM, without allowing the temperature of the reaction medium to exceed 3°C. After a night in TA, the reaction medium is washed with sodium bicarbonate (2 times) and then potassium sulfate (2 times) for 60 hours and a half. The raw material is dissolved in a droplet of DCM and dried in a dry solution. The following table shows the results of the analysis:

B) (2S) carbamoyl-2 pyrrolidinocarbonyl)-2 chloro-5 (chloro-2 phenyl)-3 (dimethoxy-3,4 phenylsulfonyl)-1 hydroxy-3 indole, (isomers of cis: 2 compounds)

5 g of the product prepared in the previous step is dissolved in 50 ml of methanol. It is cooled to -10 °C; 1.35 g of DBU is added and maintained at -10 °C for 60 hours. A compound crystallizes; it is filtered (cis-1 compound). The crystallization waters are neutralized by KHSO4 and the medium is evaporated dry. It is taken up by water, extracted 2 times in the DCM, dried and concentrated. The resulting crude is chromatographed on silica by eluting with a mixture of AcOEt/DCM (28/72 ; v/v). The following table shows the results of the analysis:

The analysis of the NMR spectrum shows the presence of one mole of MeOH per mole of product. The following is a list of the substances which are to be used in the preparation of the product:

This compound is identical to the solvent in the first method of operation in this example.

The compound that crystallized in step B above, called cis-1 compound, is recrystallized into methanol. The following is the list of active substances which are to be classified in the additive:

The Commission has The following substances are to be classified in the same heading as the active substance: The substance is classified in the additive category 'Chemical products'.

This compound is obtained by the action of (L) prolinol on the acid prepared in Example 10-11, step A, following the usual procedure.

The substance is a mixture of hydroxy-3- (hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hydroxy-hyd

1.5 g of the compound in the previous step is cycled in the presence of 380 mg of DBU in 2 ml of DCM. After 3 days at TA, 1 ml of DCM is added and then heated at 40°C overnight.

The resulting fraction is homogeneous in CCM. The product is recrystallized three times in DCM/acetate iso. The product obtained is the expected product with a purity of CLHP >99%. The temperature of the water is calculated as the temperature of the water.

Synthesis in the series (D) Proline: Example 31. The Commission has not yet adopted a decision. The chemical composition of the product is determined by the following equation: The substance is to be classified in the immediate vicinity of the product.

This compound is obtained from the acid prepared in sample 10-11, step A (3 g) to which 1.2 g of methyl (D) prolinate and 2.8 g of BOP are added in 10 ml of DCM in the presence of 1.15 g of triethylamine. It is left in TA for 1 hour and then diluted with DCM, washed in the organic phase with sodium carbonate, potassium hydrogen sulphate, dried and concentrated. The crude is chromatographed on silica by eluting with a mixture of DCM/AcOEt (95/5 ; v/v). The resulting product is then recrystallized in the mixture of DCM/iso ether. The temperature of the water is approximately 140-141 °C.

B) Chloro-5 (chloro-2 phenyl)-3 (dimethoxy-3,4 phenylsulfonyl)-1 hydroxy-3 [(2R) ((methoxycarbonyl-2) pyrrolidinocarbonyl]-2 indoline, cis isomer

The medium is chromatographed on alumina. The DCM/AcOEt mixture (95/5; v/v) elects the least polar fraction, (m = 300 mg) which is recrystallized 2 times in the DCM/iso ether mixture. The following table shows the results of the analysis of the product characteristics:

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

Example 32 and 32a N-methyl N-methoxycarbonylmethyl chloro-5 (chloro-2 phenyl)-3 (ethoxy-4 phenyl sulfonyl)-1 hydroxy-3 indoline-2 carboxamide, trans isomer and cis isomer The substance is to be classified in the additive category 'Fluorocarbons' as defined in point 1 of Annex I to Regulation (EC) No 1907/2006 of the European Parliament and of the Council.

In 40 ml of DMF, dissolve 5,7 g of dichlor-2′,5 ethoxy-4-phenylsulfonamide-2 benzophenone in argon and add 400 mg sodium hydride at 80 °C; after 15 minutes add 4,3 g of methyl N-bromacetyl sarcosinate. After 48 hours extract the expected product in the usual way and purify by silica chromatography by DCM/OEt (90/10; v/v Ac) eluting and recrystallize in the DCM/iso ether mixture. Fc is 158-160°C.

(b) N-methyl N-methoxycarbonyl methyl chloro-5 (chloro-2 phenyl)-3 (ethy-4 phenyl sulfonyl)-1 hydroxy-3 indoline-2 carboxamide, trans isomer.

1 g of the compound obtained in the previous step is dissolved in 4 ml of DCM and treated for 90 minutes at TA by 312 mg of TBD. A solution of potassium sulphate acid is added, the DCM is evaporated under vacuum, extracted by AcOEt, washed and dried on magnesium sulphate. m = 590 mgFc = 168-171°C after recrystallization in DCM/hexane.

C) N-methyl N-methoxycarbonyl methyl chloro-5 (chloro-2 phenyl)-3 (ethy-4 phenyl sulphonyl)-1 hydroxy-3 indoline-2 carboxamide, cis isomer

The solution is placed in suspension in 20 ml of methanol and 10 ml of THF, with 2,96 g of the step A compound; 100 mg of sodium methyllate is added and left in the refrigerator for 7 hours. Water is added, neutralized by a solution of potassium sulphate acid and some of the methanol is evaporated in a vacuum. After extraction by AcOEt, the alumine is chromatographed and then electrolytically electrolytically electrolytically electrolytically electrolytically electrolytically electrolytically electrolytically electrolytically electrolytically electrolytically electrolytically electrolytically electrolytically electrolytically electrolytically electrolytically electrolytically electrolytically electrolytically electrolytically electrolytically electrolytically electrolytically electrolytically electrolytically electrolytically electrolytically electrolytically electrolytically electrolytically electrolytically electrolytically electrolytically electrolytically electrolytically electrolytically electrolytically electrolytically electrolytically electrolytically electrolytically electrolytically electrolytically electrolytically electrolytically electrolytically electrolytically electrolytically electrolytically electrolytically electrolytically electrolytically electrolytically electrolytically electrolytically electrolytically electrolytically electrolytically electrolytically electrolytically electrolytically electrolytically electrolytically electrolytically electrolytically electrolytically electrolytically

The MRI spectrum is shown in Figure 6.

By using processes similar to those described above, intermediate (VI) compounds have been prepared for the synthesis of compounds (I) according to the invention.

The prepared (VI) compounds are described in Table 1 below.

The compounds (I) prepared are described in Table 2 below. - example 34 - What?

Analyse :	calculé	C : 55,54	H : 4,24	N : 3,93
	trouvé	55,72	4,57	3,83

The frequency range of the NEMO is defined as the frequency range of the NEMO.

Example 34: Figure 5Example 38 The following is a list of the most commonly used chemical compounds: The following is a list of the most commonly used aromatic substances: The following is the list of substances which are to be used in the preparation of the test chemical:3-5.7 ppm: 2S: 1H: H (indoline)6.6-8.2 ppm: m: 11H: OH + aromatics example 63 The following is a list of the most commonly used aromatic substances: 0 to 1.5 ppm: m: 3H: CH2-CH32,3 to 5,8 ppm: m: 14H: CH2-CH3, NCH2COOCH3, 2OCH3, H (indoline)6,1-8,3 ppm: m: 11H: OH + aromatics example 75 1,95 ppm: S.E.: 2 H:NH22,7 to 5,3 ppm: m: 12H: 2OCH3, 2NCH2, H (indoline), CH NH26 to 8.3 ppm: m: 11H: OH + aromatics example 76 bis αD25 = + 102 (c = 0,35; chloroform) example 76 ter The following table shows the results of the analysis:

Some compounds of the invention described in Table 2 are useful for the preparation of other compounds of the invention. For example, compound 41 was obtained from compound 39 by treatment in the basic medium in methanol MeOH/H2O. From compound 41 compound 49 was prepared by treatment with ammonia in the presence of DIPEA and BOP.

The Commission has not yet adopted a decision. N-ethyl N- ((amino-2ethyl) chloro-5 (chloro-2phenyl)-3 (dimethoxy-3,4 phenylsulfonyl)-1 hydroxy-3 indoline-2 carboxamide, (cis isomer)

500 mg of compound 49 is dissolved in 10 ml of acetonitrile and 10 ml of water, 252 mg of pyridine and 380 mg of bis (trifluoroacetoxy) iodobenzene are added. After 2 hours of stirring, it is taken up again with a solution of hydrochloric acid, extracted with ether, alkalinized with soda, extracted with DCM, dried and concentrated. An oil is obtained, and then the product to be obtained crystallizes in ether. The temperature of the water is not less than 150 °C.

The Commission has not yet adopted a decision. N-ethyl N-[(1S) ((ethoxycarbonyl-1) ethyl] chloro-5 (chloro-2 phenyl)-3 (dimethoxy-3,4 phenylsulfonyl)-1 hydroxy-3 indoline-2 carboxamide, (cis isomer) (A) Chloride of N-[chlorine-2 phenylcarbonyl]-2 chlorine-5 phenyl] N-dimethoxy-3,4 phenylsulfonyl) glycine acid

Heat for 1 hour at 60°C a mixture containing 11 g of the acid prepared in sample 10-11, step A) and 5 g of thionyl chloride in 10 ml of chloroform. The following information shall be provided for each test procedure:

The substance is to be classified in the additive category 'Chemical products'.

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

10 ml of TFA is treated at 0°C, 5.15 g of (L) Boc (N-Et) AlaOEt to remove the Boc group. Concentrate under vacuum, take up 20 ml of DCM, cool to -78°C and add 2 TEA equivalents and the acid chloride prepared in the previous step, dissolved in DCM. After 18 hours in TA, extract by DCM, wash with water, then chromatograph on silica by eluting by a DCM/AcOEt mixture (90/10; v/v). The product to be obtained crystallizes in the isoether. Fc = 112°Cm = 8 g

C) N-ethyl N-[(1S) ((ethoxycarbonyl-1) ethyl] chloro-5 (chloro-2 phenyl)-3 (dimethoxy-3,4 phenylsulfonyl)-1 hydroxy-3 indoline-2 carboxamide, (cis isomer)

The compound obtained in the previous step is agitated at TA for 18 hours in 10 ml of THF and 20 ml of ethanol in the presence of 1.46 g of DBU. NMS 0-0.9 ppm: d divided: 3 H: CH-CH30.9-1.7 ppm: m: 6 H: 2CH3 (ethyl) 2,6 to 5,8 ppm: m: 12 H: 2OCH3, NCH2, OCH2, NCH, COCH6,1 to 8,3 ppm: m: 11 H: OH-10H aromatic

EXAMPLE 79 and 80 N,N-di-methy-carbonyl-2-ethyl) chloro-5 (chloro-2 phenyl)-3 (dimethoxy-3,4 phenyl sulfonyl)-1 hydroxy-3 indoline-2 carboxamide, cis isomer and trans isomer A) N,N-di (methoxycarbonyl-2-ethyl) benzylamine

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

In an ice bath, 107 g of benzylamine is cooled in 200 ml of ethanol and 172.2 g of methyl acrylate is slowly added to 250 ml of ethanol. The temperature of the water is between 135-140°C at 0.6 mm Hgm = 30 gIR: 1730 cm-1

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

27.9 g of the amine obtained in the previous step are placed in 500 ml of methanol, mixed with 3 g of palladium on 5% charcoal and treated under hydrogen pressure for 1 hour.

C. (N,N-dimethoxycarbonyl-2 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 is added by drops and left to agitate for 48 hours in TA. The test shall be carried out in accordance with the procedure described in Annex I.

The substance is to be classified in the additive category 'Chemical products'.

14.3 g of dichloro-2′,5 (dimethoxy-3,4 phenylsulfonamide) - 2 benzophenone is placed in 180 ml DMF and added in portions of 1.1 g of sodium hydride. After 1 hour of stirring in TA, it is cooled in an ice bath and 14.3 g of the product prepared in the previous step is added and left to stir in TA for 72 hours. The temperature of the water is measured at the temperature of the water.

E) N,N-di[(methoxycarbonyl-2) ethyl] chloro-5 (chloro-2 phenyl)-3 (dimethoxy-3,4 phenylsulfonyl)-1 hydroxy-3 indoline-2 carboxamide, cis isomer

At 0 °C, 12 g of the compound prepared in the previous step and 0.930 g of sodium methylate are mixed in 150 ml of methanol and then stirred overnight at TA. The reaction medium is neutralized by addition of KHSO4 at 5% and the solvent is evaporated under vacuum. The residue is chromatographed under alumina by eluting with a DCM/AcOEt mixture (8/2 v/v). 2.4 g of the product is recovered until it crystallizes in methanol. Fc = 175°C

The following is added to the list of active substances:

The chromatography of the previous step is continued and a mixture of DCM/MeOH (9.5/0.5·v/v) is elected to obtain 1.82 g of trans isomer which crystallizes in the iso ether. Fc = 85°C

Example 81,82 and 83 (R) carbamoyl-2 thiazolidinocarbonyl)-2 chloro-5 (chloro-2 phenyl)-3 (dimethoxy-3,4 phenylsulfonyl)-1 hydroxy-3 indole, (isomer cis: 2 compounds and trans isomer) A) (L) thiazolidine carboxamide-4

This compound is prepared according to J. Med. Chem., 1981, 24, 692.

B. Dichloro-2′,5 [N-dimethoxy-3,4 phenylsulfonyl] N-dichloro-carbamoyl-2] thiazolidinocarbonyl methyl] amino-2 benzophenone

This compound is obtained by the usual methods from the acid prepared in example 10-11, step A). Fc = 125°C after crystallization in ether.

C) (2R) carbamoyl-2 thiazolidinocarbonyl)-2 chloro-5 (chloro-2 phenyl)-3 (dimethoxy-3,4 phenylsulfonyl)-1 hydroxy-3 indole.

4,3 g of the product obtained in step B) in 90 ml of MeOH are cycled to TA in the presence of 1 g of DBU. Concentrate, take up with water and DCM, decant, wash with KHSO4 then dry and concentrate. Chromatography on alumine is performed by eluting with DCM/MeOH (97/3; v/v). The compound is obtained in cis form (mixture of 2 diasteroisomers): 1,5 g, then in trans form (mixture of 2 diasteroisomers): m = 1 g. (a) The cis fraction is crystallized in MeOH/DCM to obtain the cis 1 compound. Fc = 176°C after crystallization in isoether.αD = + 57°(c = 0.1 chloroform).b) The crystallization waters of the foregoing product are chromatographed on silica by electrolysis by AcOEt/DCM (30/70· v/v). The cis 2 compound obtained is recrystallized in ether. Fc = 205°CαD = - 185°c = 0.3 chloroform. c) The trans fraction (mixture of 2 diasteroisomers) is recrystallized in the iso ether. Fc = 170°C

Examples 84, 85, 86 and 86bis Chloro-5 (chloro-2 phenyl)-3 (dimethoxy-3,4 phenylsulfonyl)-1 hydroxy-3 (N,N-(2S)dimethylthiocarbamoyl-2 pyrrolidinocarbonyl)-2 indoline, isomeric cis (2 compounds), (trans isomeric: 2 compounds) isomeric isomeric isomeric isomeric isomeric isomeric isomeric isomeric isomeric isomeric isomeric isomeric isomeric isomeric isomeric isomeric isomeric isomeric isomeric isomeric isomeric isomeric isomeric isomeric isomeric isomeric isomeric isomeric isomeric isomeric isomeric isomeric isomeric isomeric isomeric isomeric isomeric isomeric isomeric isomeric isomeric isomeric isomeric isomeric isomeric isomeric isomeric isomeric isomeric isomeric isomeric isomeric isomeric isomeric isomeric isomeric isomeric isomeric isomeric isomeric isomeric isomeric isomeric isomeric isomeric isomeric isomeric isomeric isomeric isomeric isomeric isomeric isomeric isomeric isomeric isomeric isomeric isomeric isomeric isomeric isomeric isomeric isomeric isomeric isomeric isomer isomeric isomer isomeric isomeric isomer isomeric isomer isomeric isomeric isomer isomer isomer isomer isomer isomer isomeric isomer isomer isomeric isomer isomer isomer isomer isomer isomer isomer isomer isomer isomer isomer isomer isomer isomer isomer isomer isomer isomer isomer isomer isomer isomer isomer isomer isomer isomer isomer isomer isomer isomer isomer isomer isomer isomer isomer isomer isomer isomer isomer isomer isomer isomer isomer isomer isomer isomer isomer isomer isomer isomer isomer isomer isomer isomer isomer isomer isomer isomer isomer isomer isomer isomer isomer isomer A. (L) N,N-dimethyl (N′-Boc) proline thioamide.

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

In anhydrous toluene, 2.36 g of N,N-dimethyl (N′-Boc) prolinamide is heated 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, isopropanol is added. The precipitate formed is decanted, isopropanol is evaporated and silica chromatography is performed by elevating by hexane/AcOtherEt (30/70,; v/v). The resulting product is recrystallized cold in DCM/acrystal (30/70; v/v). Fc = 62°C

The substance is classified in the additive category 'Chemical products' as defined in point 1 of Annex I to Regulation (EC) No 1907/2006 of the European Parliament and of the Council.

3 g of the product prepared in the previous step is dissolved in 10 ml of DCM and treated at 0 °C for 2 hours with 10 ml of TFA. Evaporate at dry point and then add at 0 °C 20 ml of DCM, 6.1 g of the acid prepared in example 10-11, step A) and neutralize with 3 g of DIPEA. Dissolve 5.15 g of BOP in 30 ml of DCM and add this solution to the previous solution at 0 °C for 30 minutes; maintain at neutral pH by adding DEA and agitate for 3 hours at 0 °C. After a night in TAIP, extract as usual and then chromatise on silica by DCM/Acrystallisation (O85v/15 v); The resulting product is isolated in the ether. The test chemical is a chemical compound with a high molecular weight.

C) Chloro-5 (chloro-2 phenyl)-3 (dimethoxy-3,4 phenylsulfonyl)-1 hydroxy-3 (N,N-(2S) dimethylthiocarbamoyl-2 pyrrolidinocarbonyl)-2 indoline, (cis isomer with 2 compounds and trans isomer with 2 compounds).

3.8 g of the compound obtained in the previous step is dissolved in 15 ml of DCM and heated at low temperature for 36 hours in the presence of 850 mg of DBU. (a) By DCM/AcOET (85/15; v/v), the expected compound is first selected as a mixture of 2 cis diasteroisomers. The least soluble diasteroisomer is crystallized twice from the DCM/iso-methanol ether mixture, then recrystallized in a minimum of DMF at 60°C, then 2 volumes of ethanol are added. Fc = 270°CαD = - 278 (c = 1, chloroform) b) The crystallization waters of the previous mixture are taken up and the second diastereoisomer cis crystallizes from the DCM/iso ether mixture.- What? (c) The last chromatographic fractions elected and the crystallization water of fractions (a) and (b) are combined and a new chromatography on silica is performed by electing by hexane/AcO (20/80; v/v). First a fraction is isolated which is recrystallized 3 times from the DCM/isoether mixture and an insoluble isomer is removed on paper between each recrystallization. Fc = 191-193αD = + 74.5°(c=0.2 ; chloroform) d) the second fraction contains the trans 2 isomer which is recrystallized from the DCM/iso ether mixture and crystallizes with 1/3 mole of iso ether.- What? The temperature of the water is approximately 170°CαD.

The Commission has not yet adopted a decision on the application of Article 108 (3) of the Treaty. (C2S) Carbamoyl-2 pyrrolidinocarbonyl-2 chloro-5 cyclohexyl-3 (dimethoxy-3,4 phenylsulfonyl)-1 hydroxy-3 indole, (isomers cis: 2 compounds, trans isomer) (A) A) Chloro-5 [N-dimethoxy-3,4 phenylsulfonyl] amino]-2 cyclohexylphenol.

A solution of 35.6 g amino-2 chloro-5 cyclohexylphenolone and 39.5 g dimethoxy-3,4 phenylsulphonyl chloride is left to agitate in TA for 24 hours in 340 ml of pyridine. The solvent is evaporated under vacuum and washed with water and an acid solution (HCl 0.5 N). The temperature of the water is not less than 135 °C.

B) [N-benzyloxycarbonylmethyl N-dimethoxy-3,4 phenylsulfonyl) amino]-2 chloro-5 cyclohexylphenol.

Add 3.2 g of sodium hydride in portions to 52.6 g of the compound prepared in the previous step in 520 ml of DMF and stir for 1 hour at TA. After cooling in the ice bath, add 21 ml of benzyloxycarbonyl methyl bromide by drops and stir for 24 hours at TA.

The solvent is evaporated in a vacuum and taken up by water, extracted in DCM and washed with water, and the resulting product is used as it is in the next step.

C) N-chloro-hexylcarbonyl-2) phenyl, N-dimethoxy-3,4 phenylsulfonyl-glycine.

The compound obtained in the previous step is placed under hydrogen (1 atmosphere) with 3.9 g of Palladium on 5% charcoal in 700 ml of acetic acid. At the end of the reaction, the Palladium on Cellite® is filtered and rinsed with hot acetic acid; the solvent is evaporated under vacuum and taken up by water. Fc = 160°Cm = 22.4 g

D) Chlorine-5 [N- ((dimethoxy-3,4 phenylsulfonyl) N- (((2S) carbamoyl-2 pyrrolidinocarbonyl methyl) ] amino-2 cyclohexylphenol.

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 is added to DCM and maintained at pH7 by addition of DIPEA. The medium is removed from the DCM, washed with a saturated NaHCO3 solution, a saline solution, a 5% KHSO4 solution, and again a saline solution. The reaction is carried out in the presence of a solvent, which is a solvent.

E) (2S) ((Carbamoyl-2 pyrrolidinocarbonyl)-2 chloro-5 cyclohexyl-3 (dimethoxy-3,4 phenylsulfonyl)-1 hydroxy-3 indole, cis isomer (2 compounds), trans isomer

The solvent is evaporated in a vacuum, water is added, extracted from the DCM and washed with a 5% solution of KHSO4. The aluminum is chromatographed by DCM/MeOH (98/2) electrolysis. (a) The least polar fraction contains the 2 cis isomers. This fraction is recrystallized in methanol. The first compound thus obtained (cis 1) is pure in CLHP. Fc = 185°C By recrystallization of the mother water in MeOH, a second compound (cis 2) is obtained. Fc = 132°Cb) The most polar fraction contains the trans isomer as an apparently unique compound obtained by recrystallization in methanol. The following is the list of substances which are to be classified in the Annex to this Regulation:

The following paragraphs are added: (C2S) Carbamoyl-2 pyrrolidinocarbonyl-2 chloro-5 cyclohyexyl-3 (dimethoxy-3,4 phenylsulfonyl)-1 hydroxy-3 indole, cis isomer (2 compounds), trans isomer

Using a similar procedure to that described in Examples 87, 88, 89, a serial analogue (D) proline is prepared.

The compound obtained after crystallization in a DCM/MeOH mixture has the trans configuration. The test chemical is a chemical that is used to produce a specific chemical.

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

The Commission has Chlorine-5 (chloro-2 phenyl)-3 (dimethoxy-3,4 phenyl sulphonyl)-1 [(2S) ((N-methylaminocarbonyl)-2 pyrrolidinocarbonyl]-2 hydroxy-3 indole, cis isomer

920 mg of the compound prepared in example 28 is agitated in 20 ml of DCM containing 371 mg of BOP for 15 minutes, then a current of monomethylamine is stirred for 10 minutes and the agitation is maintained for another 30 minutes. The maximum value of the test chemical is calculated as the following:

By the same process as in the examples described above (examples 27 to 31 and 90) and using derivatives of (L) proline (unless otherwise stated) other intermediate (VI) compounds have been prepared for the synthesis of the compounds (I) according to the invention.

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

The compounds (I) prepared are described in Table 4 below. - What?

The compound in example 107 is the enantiomer of that in example 106.

The compound in Example 108bis was prepared from the compound in Example 28 by action of hydroxylamine hydrochloride in DMF and activation by the BOP reagent in the presence of DIPEA.

Some of the compounds of the invention described in Table 4 above are useful for the preparation of other compounds, so that the compound in Example 99 can be used to produce the compound in Example 101, then in Example 103 and finally in Example 104.

The Commission has not yet adopted a decision. The following is added to the list of active substances: The following substances are to be classified in the same heading as the product:

Heat 15 g of the acid prepared in sample 10-11, step A, and 6.25 g of (2S,4R) hydroxy-4 methyl prolinate hydrochloride, in the presence of 7.4 g of DIPEA, to 0 °C in 150 ml of DCM. Add a 12.7 g BOP solution in 30 ml of DCM, drop by drop, in 30 minutes, and add the amount of DIPEA needed to neutralize the solution. After a night in TA, extract in the usual way and silica chromatography by eluting with a DCM/EtO mixture (Ac60/40 v/v). The desired product crystallizes from the DCM/Ether/Isother mixture. The following is the list of substances which are to be classified in the additive:

The substance is to be classified in the additive category 'Fluorocarbons' as defined in point 1 of Annex I to Regulation (EC) No 1907/2006 of the European Parliament and of the Council.

2 g of the compound obtained in the previous step are dissolved at 0 °C in 10 ml of DCM. 550 mg of triethylamine is added, then 550 mg of methanesulfonyl chloride and left at 0 °C for 20 hours. Water is added, washed with 0.5 N hydrochloric acid, water, then with a sodium bicarbonate solution, dried on magnesium sulphate and evaporated. The resulting oil is used as in the next step.

C) [N-((2S,4S) azido-4-methoxycarbonyl-2 pyrrolidinocarbonylmethyl) -N-(dimethoxy-3,4-phenylsulfonyl) amino-2 dichloro-2′,5 benzophenone.

Heat 11 g of the product prepared in the previous step in 60 ml of DMSO at 80°C to 90°C in the presence of 2.7 g of sodium acid for 18 hours, pour into water, extract with ethyl acetate, wash with water, dry and chromatograph on silica by elevating with a mixture of pentane/AcOEt (50/50); v/v. The test chemical is used to determine the concentration of the active substance in the test medium.

D) ((2S,4S) azide-4 methoxycarbonyl-2 pyrrolidinocarbonyl)-2 chloro-5 (chloro-2 phenyl)-3 (dimethoxy-3,4 phenylsulfonyl)-1 hydroxy-3 indole, cis isomer

3,38 g of the product obtained in the previous step are cycled under normal conditions in the presence of DBU. The test chemical is used to determine the concentration of the active substance in the test medium.

The Commission has not yet adopted a decision. [(2S,4S) ((N-benzyloxycarbonyl-N-methyl) amino-4 methoxycarbonyl-2 pyrrolidinocarbonyl]-2 chloro-5 (chloro-2 phenyl)-3 (dimethoxy-3,4 phenylsulphonyl)-1 hydroxy-3 indole, cis isomer. A) methyl ester of N-Boc hydroxy-4 proline.

The starting point is the chloride of the methyl ester of (2S, 4R) hydroxy-4 proline.

19 g of this compound are suspended in 100 ml of THF and 22.9 g of (Boc) 2O are added and then cooled to 0°C. 21,2 g of triethylamine are added in 25 ml of THF, then stirred for 12 hours at 0°C and 4 hours at 60°C. Water is added, extracted by ethyl acetate, washed with water, by a solution of potassium sulphate acid (4 times), by water, then by salt water.

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

A 22.9 g solution of the product prepared in the previous step is cooled to 0 °C in 250 ml of DCM. 22.9 g of mesyl chloride is added to 10 ml of DCM by drip, then 9.4 g of triethylamine is added to 100 ml of DCM by drip and left to return to TA overnight.

C) Methyl ester of (2S,4S) N-Boc azido-4 proline.

This compound is prepared from the one obtained in step B. Dissolve in 70 ml of DMSO 15.2 g of N-Boc mesyloxy-4 proline methyl ester and heat at 90°C for 5 hours in the presence of 3.05 g of sodium azide. Cool, add water, extract by AcOEt, wash with water, saline water, dry on MgSO4. The resulting oil is purified by silica chromatography by eluting by the mixture AcO/Ethexane (40/60 ; v/v). The following table shows the results of the analysis of the results of the analysis:

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

The catalyst is filtered, half of the methanol is evaporated, 100 ml of 0.5 N HCl is added, then the rest of the methanol is evaporated and extracted by AcO and the unreacted starting product. The aqueous phase is treated with sodium carbonate and the fraction containing the expected product (m = 4.35g) is extracted by AcO and the catalyst is filtered.

E) Methyl ester of (2S,4S) N-Boc (N′-benzyloxycarbonylamino)-4 proline.

The raw product obtained in the previous step is dissolved in 15 ml of ether and 15 ml of DCM at 0°C. Add 2.3 g of DIPEA and then 3.03 g of benzyl chloroformate to 5 ml of DCM, in 70 minutes at 0°C. After 3 hours, evaporate the solvents in vacuum TA; add water and ethyl acetate, wash the organic phase successively with a solution of potassium sulphate acid (3 times), with water (3 times), with a solution of sodium carbonate (3 times), with water (3 times), with saline water. αD = -16,4 (c = 0,3; chloroform)

F) Methyl ester of (2S,4S) N-Boc (N′-benzyloxycarbonyl-N′-methyl) amino-4 proline.

2 g of the compound obtained in the previous step are 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 is added in fractions and then stirred at 0 °C for 90 minutes. The organic phase is extracted with water and ethyl acetate; the organic phase is washed with salt water. αD = -38,8 (c = 0,38; chloroform)

G) Dichloro-2′5 [(2S,4S) N- ((dimethoxy-3,4 phenylsulfonyl) N- (((N′-benzyloxycarbonyl-N′-methyl) amino-4 methoxycarbonyl-2) pyrrolidinocarbonyl methyl] amino-2 benzophenone.

This product is obtained by the usual methods. αD = -22,4 (c = 0,37; chloroform)

H) [((2S,4S) N-benzyloxycarbonyl-N-methyl) amino-4 methoxycarbonyl-2 pyrrolidinocarbonyl]-2 chloro-5 (chloro-2 phenyl)-3 (dimethoxy-3,4 phenylsulfonyl)-1 hydroxy-3 indole, cis isomer

This product is obtained by cyclization in the presence of DBU by the usual methods. The crystals formed are crystallized in DCM/iso.Fc = 129°CαD = - 129° (c = 0.321; chloroform).

The isomeric purity of CLHP is 99%

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

The compound in Example 112 allows the compounds in Examples 115 and 116 described in Table 6 below to be prepared successively and the compound in Example 114 allows the compound in Example 116a to be prepared.

The compound in Example 116a may be prepared either by transformation of the compound in Example 114 or from (2S, 4S) N-Boc dimethylamino-4 prolinamide, the preparation of which is carried out as follows: 1) the (2S, 4S) N-Boc amino-4 methyl prolinate is prepared from the (2S, 4S) azido-4 methyl prolinate according to T.R. Webl in J. Org. Chem., 1991, 56, 3009.2) (2S, 4S) N-Boc dimethylamino-4 methyl prolinate. Dissolve 4 g of the compound prepared in 1) in 50 ml of acetonitrile, add 12.8 ml of 30% formaldehyde and then in 5 minutes 3 g of sodium cyanoborohydride.After 2 hours of contact, acetic acid is added to bring the solution to pH 6. After 3 hours, acetonitrile is evaporated, then water, potassium carbonate and solid sodium chloride are added and extracted by 4 volumes of ethyl acetate. The organic phase is evaporated, the residue is dissolved by hydrochloric acid 1 N and extracted by AcOEt. Solid sodium carbonate is added and then solid sodium chloride in the aqueous phase and extracted by AcOEt. After evaporation, the surplus silica is chromatographed by mixing DCM/OHMe (95/5,v/v), an oil is isolated that solidifies. m = 2.1 gIR (DCM) : 1755 cm-1, 1695 cm-1.3) 534 mg of the ester prepared in 2) are dissolved in 4 ml of MeOH and treated with baking soda (116 mg) in 1 ml of water for 48 hours at TA. Acidify with hydrochloric acid 0.5 N at pH 3.5 and evaporate at dry.After 15 minutes, a gas ammonia stream is stirred twice for 30 minutes. After 2 hours at TA, the DCM is evaporated, carbonated water, sodium chloride are added, then 4 volumes of AcOEt are extracted. After evaporation, the residue is chromatographed on silica. A solid (m = 185 mg) is elected from the mixture (DCM/MeOH/NH4 ; 84.5/15/OH5 v/0.5 v/v) and recrystallized in the DCM/isoether mixture. The temperature of the water is approximately -183 °C.

The Commission has not yet adopted a decision. Decarboxylation of N- ((carboxy-2 ethyl) -N-ethyl (chloro-2 phenyl) -3-chloro-5 (dimethoxy-3,4 phenylsulphonyl) -1-hydroxy-3 indoline-2 carboxamide, cis isomer

After 5 minutes of stirring, add 127 mg of N-hydroxypyridine-2 thione, 101 mg of TFA and maintain at -15 °C for 15 minutes, then add 900 mg of tert-butylmercaptan and let it return to TA. Then irradiate the reaction medium for 1 hour 30 with a Tungsten filament lamp (150 watts). Then concentrate the medium, extract from the water, dry it in DCM, silica and concentrate. The residual is chromed by eliciting v/Octane (9/Octane) on DCM. The temperature of the water is not less than 300 mgFc.

This compound is similar to that of example 125 described in European patent application EP 469984 and has the cis configuration around the 2,3 bond of indoline as the starting product.

The first is the number of people who are The following is added to the list of active substances:

The same procedure as in the previous example is followed from the compound described in Example 102.

The resulting product is recrystallized from the DCM/iso ether mixture. This compound is ((2S) methyl-2 pyrrolidinocarbonyl)-2 chloro-5 (chloro-2 phenyl)-3 (dimethoxy-3,4 phenylsulfonyl)-1 hydroxy-3 indoline, cis isomer.

The first is the Decarboxylation of (carboxy-2 pyrrolidinocarbonyl)-2 chloro-5 (chloro-2 phenyl)-3 (dimethoxy-3,4 phenylsulfonyl)-1 hydroxy-3 indole, cis isomer

The product obtained is recrystallized from the iso/DCM ether mixture using the compound prepared in Example 28 as the starting product. The following is the list of substances which are to be classified in the additive:

This compound is pyrrolidinocarbonyl-2 chloro-5 (chloro-2 phenyl)-3 (dimethoxy-3,4 phenylsulfonyl)-1 hydroxy-3 indoline, cis isomer.

Claims (16)

1. A process for preparing a compound of formula (I):    in which

   - R₁ is a halogen atom, a C₁-C₄ alkyl, a hydroxyl, a C₁-C₄ alkoxy, a benzyloxy group, a cyano group, a trifluoromethyl group, a nitro group or an amino group ;

   - R₂ is a C₁-C₆ alkyl, a C₃-C₇ cycloalkyl, a C₅-C₇ cycloalkene or a phenyl which is unsubstituted, monosubstituted or polysubstituted by a C₁-C₄ alkyl, a C₁-C₄ alkoxy, a halogen, a trifluoromethyl group or an amino group, or R₂ is a nitrophenyl which is unsubstituted or monosubstituted by a trifluoromethyl group or monosubstituted or polysubstituted by a C₁-C₄ alkyl or a halogen ;

   - R₃ is a hydrogen atom;

   - R₄ is a carbamoyl group of formula CONR₆R₇ ;

   - R₅ is a C₁-C₄ alkyl, a 1-naphthyl, a 2-naphthyl, a 5-dimethylamino-1-naphthyl, a phenyl which is unsubstituted or substituted by one or more substituents selected from a halogen, a C₁-C₄ alkyl, a trifluoromethyl group, an amino group which is free or substituted by one or two C₁-C₄ alkyls, a hydroxyl, a C₁-C₄ alkoxy, a C₂-C₄ alkenoxy, a C₁-C₄ alkylthio, a trifluoromethoxy group, a benzyloxy group, a cyano group, a carboxyl group, a C₁-C₄ alkoxycarbonyl group, a carbamoyl group which is free or substituted by one or two C₁-C₄ alkyls or a C₁-C₄ alkylamido group, or R₅ is a nitrophenyl which is unsubstituted or monosubstituted by a trifluoromethyl group or a C₂-C₄ alkenoxy or mono- or polysubstituted by a halogen, a C₁-C₄ alkyl, a C₁-C₄ alkoxy, a C₁-C₄ alkythio, a trifluoromethoxy group or a benzyloxy group ;

   - R₆ is a C₁-C₆ alkyl or R₆ is similar to R₇ ;

   - R₇ is a 4-piperidinyl group or a 3-azetidinyl group, the said groups being substituted or unsubstituted on the nitrogen by a C₁-C₄ alkyl, by a benzyloxycarbonyl or by a C₁-C₄ alkoxycarbonyl ; a (CH₂)_r group which is itself substituted by a 2-, 3- or 4-pyridyl group, by a hydroxyl group or by an amino group which is free or substituted by one or two C₁-C₄ alkyls, a carboxyl group, a C₁-C₄ alkoxycarbonyl group, a benzyloxycarbonyl group or a carbamoyl group which is free or substituted by one or two C₁-C₄ alkyls.

   - or R₆ and R₇ together with the nitrogen atom to which they are bonded, form a heterocycle selected from :

   . morpholine,

   . thiomorpholine,

   . thiazolidine or 2,2-dimethylthiazolidine, unsubstituted or substituted by R₈,

   . piperazine, unsubstituted or substituted at the 4-position by an R''₈ group,

   . an unsaturated, 5-membered ring containing a single nitrogen atom and substituted by R₈ or a saturated, 3-, 4-, 5-, 6- or 7-membered ring containing a single nitrogen atom and substituted by R₈ and R₉ ;

   - R₈ is R'₈ or a (CH₂)_r group which is itself substituted by a hydroxyl or by an amino which is free or substituted by one or two C₁-C₄ alkyls ;

   - R'₈ is a (CH₂)_q group which is itself substituted by a carboxyl group, a C₁-C₄ alkoxycarbonyl group, a benzyloxycarbonyl group, a carbamoyl group which is free or substituted by a hydroxyl or by one or two C₁-C₄ alkyls or an aminocarbothioyl group which is free or substituted by one or two C₁-C₄ alkyls ;

   - R''₈ is R'₈ or a (CH₂)₂NH₂ group which is free or substituted by one or two C₁-C₄ alkyls ;

   - R₉ is hydrogen, a halogen, a (CH₂)_rOR₁₀ group, a (CH₂)_rNR₁₁R₁₂ group, a (CH₂)_sCONR₁₁R'₁₁ group or an azido group ;

   - R₁₀ is hydrogen, a C₁-C₄ alkyl, a mesyl or a tosyl ;

   - R_11, R'₁₁ and R₁₂ are each a hydrogen or a C₁-C₄ alkyl or R₁₁ is hydrogen and R₁₂ is a benzyloxycarbonyl or a C₁-C₄ alkoxycarbonyl ;

   - n is 0, 1 or 2 ;

   - m is 0, 1 or 2 ;

   - q is 0, 1, 2 or 3 ;

   - r is 0, 1, 2 or 3, with the limitation that r is not zero when R₈ or R₉ is at the alpha-position of the intracyclic amide nitrogen ;

   - s is 0 or 1 ;

      as well as its possible salts,    characterised in that :

   a) a 2-aminophenone derivative of formula :    in which R₁, R₂ and n have the meanings indicated above, is reacted with a sulfonyl derivative of formula :         Hal-SO₂-(CH₂)_m-R₅     (III)    in which

   - Hal is a halogen, preferably chlorine or bromine,

   - m and R₅ have the meanings indicated above ;

   b) the thus obtained compound of formula :    is treated with a halogenated derivative of formula :         Hal'-CH₂COA     (V)    in which

   Hal' is a halogen, preferably bromine, and A represents either the NR₆R₇ group or the OR group in which R is a tert-butyl or a benzyl ;

   c) the thus obtained ester of formula :    is deprotected under suitable conditions, if applicable, when A is an OR group ;

   d) if applicable, the thus obtained acid from Step c) of formula :    or its acid chloride of formula :    is treated with a HNR₆R₇ compound according to suitable amide coupling techniques ;

   e) the thus obtained compound from Step b) or from Step d) of formula : is cyclised in a basic medium in order to prepare compound (I);

   f) if appropriate, the cis and trans isomers of compound (I) are separated and, if appropriate, the enantiomers are separated, the compounds of formula (I) being optionally converted into their salts with mineral or organic acids or with mineral or organic bases.
2. A process according to claim 1 for obtaining a compound of formula (I) in which R₁ is a chlorine or bromine atom or a methoxy group and n = 1, characterised in that a compound of formula (II) in which R₁ and n are as defined above is used in step a).
3. A process according to one of claims 1 or 2, for preparing a compound of formula (I), in which R₂ is a chlorophenyl, a methoxyphenyl or a cyclohexyl, characterised in that a compound of formula (II) in which R₂ is as defined above is used in step a).
4. A process according to any one of claims 1 to 3, for preparing a compound of formula (I), in which R₅ is a phenyl substituted at the 3- and 4-positions or at the 2- and 4-positions by a methoxy group, or else R₅ is a phenyl substituted at the 4-position by a methyl, characterised in that a compound of formula (III) in which R₅ is as defined above is used in step a).
5. A process according to any one of claims 1 to 4, for preparing a compound of formula (I), in which m = 0, characterised in that a compound of formula (III) in which m = 0 is used in step a).
6. A process according to any one of claims 1 to 5, for preparing a compound of formula (I), in which R₄ is CONR₆R₇ and NR₆R₇ is a pyrrolidino group substituted at the 2-position by a (CH₂)_q group which is itself substituted by a carboxyl group, or a carbamoyl group with q = 0, 1, 2 or 3, characterised in that a compound of formula (V) in which A is a NR₆R₇ group as defined above is used in step b).
7. A process according to any one of claims 1 to 5, for preparing a compound of formula (I), in which R₄ is CONR₆R₇ and NR₆R₇ is a piperidino group substituted at the 4-position by an amino group, a C₁-C₄ alkylamino or a C₁-C₄ dialkylamino, characterised in that a compound of formula (V) in which A is a NR₆R₇ group as defined above is used in step b).
8. A process according to any one of claims 1 to 5, for preparing a compound of formula (I), in which R₄ is CONR₆R₇ and NR₆R₇ is a thiazolidino group substituted by a (CH₂)_q group which is itself substituted by a carboxyl group or a carbamoyl group with q = 0, 1, 2, or 3, characterised in that a compound of formula (V) in which A is a NR₆R₇ group as defined above is used in step b).
9. A process according to any one of claims 1 to 5, for preparing a compound of formula (I), in which R₄ is CONR₆R₇ and NR₆R₇ is a pyrrolidino group substituted at the 2-position by a (CH₂)_q group which is itself substituted by a carboxyl group or a carbamoyl group and substituted at the 4-position by an amino group, a C₁-C₄ alkylamino or a C₁-C₄ dialkylamino, characterised in that a compound of formula (V) in which A is a NR₆R₇ group as defined above is used in step b).
10. A process according to any one of claims 1 to 5, for preparing a compound of formula (I), in which R₄ is CONR₆R₇, R₆ being a C₁-C₄ alkyl and R₇ being a (CH₂)_r group which is itself substituted by a carboxyl group or a carbamoyl group with r = 1, 2 or 3, characterised in that a compound of formula (V) in which A is a NR₆R₇ group as defined above is used in step b).
11. A process according to any one of claims 1 to 10, for preparing a compound of formula (I), in the form of a cis isomer in which R₂ and R₄ are on the same side of the indoline ring, characterised in that the cis isomer is separated from the trans isomer by chromatography or fractionated crystallization in step f).
12. A process for preparing a compound of formula 6: in which    A' is a group selected from : NR₆R₇ , OH, OtBu or OBz;

    - R₁ is a halogen atom, a C₁-C₄ alkyl, a hydroxyl, a C₁-C₄ alkoxy, a benzyloxy group, a cyano group, a trifluoromethyl group, a nitro group or an amino group ;

    - R₂ is a C₁-C₆ alkyl, a C₃-C₇ cycloalkyl, a C₅-C₇ cycloalkene or a phenyl which is unsubstituted, monosubstituted or polysubstituted by a C₁-C₄ alkyl, a C₁-C₄ alkoxy, a halogen, a trifluoromethyl group or an amino group, or R₂ is a nitrophenyl which is unsubstituted or monosubstituted by a trifluoromethyl group or monosubstituted or polysubstituted by a C₁-C₄ alkyl, a C₁-C₄ alkoxy or a halogen ;

    - R₅ is a C₁-C₄ alkyl, a 1-naphthyl, a 2-naphthyl, a 5-dimethylamino-1-naphthyl, a phenyl which is unsubstituted or substituted by one or more substituents selected from a halogen, a C₁-C₄ alkyl, a trifluoromethyl group, an amino group which is free or substituted by one or two C₁-C₄ alkyls, a hydroxyl, a C₁-C₄ alkoxy, a C₂-C₄ alkenoxy, a C₁-C₄ alkylthio, a trifluoromethoxy group, a benzyloxy group, a cyano group, a carboxyl group, a C₁-C₄ alkoxycarbonyl group, a carbamoyl group which is free or substituted by one or two C₁-C₄ alkyls or a C₁-C₄ alkylamido group, or R₅ is a nitrophenyl which is unsubstituted or monosubstituted by a trifluoromethyl group or a C₂-C₄ alkenoxy or mono- or polysubstituted by a halogen, a C₁-C₄ alkyl, a C₁-C₄ alkoxy, a C₁-C₄ alkylthio, a trifluoromethoxy group or a benzyloxy group ;

    - R₆ is a C₁-C₆ alkyl or R₆ is similar to R₇ ;

    - R₇ is a 4-piperidinyl group or a 3-azetidinyl group, the said groups being substituted or unsubstituted on the nitrogen by a C₁-C₄ alkyl, by a benzyloxycarbonyl or by a C₁-C₄ alkoxycarbonyl ; a (CH₂)_r group which is itself substituted by a 2-, 3- or 4-pyridyl group, by a hydroxyl group or by an amino group which is free or substituted by one or two C₁-C₄ alkyls, a carboxyl group, a C₁-C₄ alkoxycarbonyl group, a benzyloxycarbonyl group or a carbamoyl group which is free or substituted by one or two C₁-C₄ alkyls ;

    - or R₆ and R₇ together with the nitrogen atom to which they are bonded, form a heterocycle selected from ;

    . morpholine,

    . thiomorpholine,

    . thiazolidine or 2,2-dimethylthiazolidine, unsubstituted or substituted by R₈,

    . piperazine, unsubstituted or substituted at the 4-position by an R''₈ group,

    . an unsaturated, 5-membered ring containing a single nitrogen atom and substituted by R₈ or

    . a saturated, 3-, 4-, 5-, 6- or 7-membered ring containing a single nitrogen atom and substituted by R₈ and R₉ ;

    - R₈ is R'₈ or a (CH₂)_r group which is itself substituted by a hydroxyl or by an amino which is free or substituted by one or two C₁-C₄ alkyls ;

    - R'₈ is a (CH₂)_q group which is itself substituted by a carboxyl group, a C₁-C₄ alkoxycarbonyl group, a benzyloxycarbonyl group, a carbamoyl group which is free or substituted by a hydroxyl or by one or two C₁-C₄ alkyls or an aminocarbothioyl group which is free or substituted by one or two C₁-C₄ alkyls ;

    - R''₈ is R'₈ or a (CH₂)₂NH₂ group which is free or substituted by one or two C₁-C₄ alkyls ;

    - R₉ is hydrogen, a halogen, a (CH₂)_rOR₁₀ group, a (CH₂)_rNR₁₁R₁₂ group, a (CH₂)_sCONR₁₁R'₁₁ group or an azido group ;

    - R₁₀ is hydrogen, a C₁-C₄ alkyl, a mesyl or a tosyl ;

    - R₁₁, R'₁₁ and R₁₂ are each a hydrogen or a C₁-C₄ alkyl or R₁₁ is hydrogen and R₁₂ is a benzyloxycarbonyl or a C₁-C₄ alkoxycarbonyl ;

    - n is 0, 1 or 2 ;

    - m is 0, 1 or 2 ;

    - q is 0, 1, 2 or 3 ;

    - r is 0, 1, 2 or 3, with the limitation that r is not zero when R₈ or R₉ is at the alpha-position of the intracyclic amide nitrogen ;

    - s is 0 or 1,

       characterised in that:

    a) a 2-aminophenone derivative of formula :    in which R₁, R₂ and n have the meanings indicated above for I, in claim 1, is reacted with a sulfonyl derivative of formula :         Hal-SO₂-(CH₂)_m-R₅     (III)    in which

    - Hal is a halogen, preferably chlorine or bromine,

    - m and R₅ have the meanings indicated above for (I) in claim 1 ;

    b) the thus obtained compound of formula : is treated with a halogenated derivative of formula :         Hal'-CH₂COA     (V) in which

    Hal' is a halogen, preferably bromine, and A represents either the group NR₆R₇ or the group OR in which R is a tert-butyl or a benzyl;

    c) if applicable, the thus obtained ester of formula :    is isolated or, if applicable, deprotected under suitable conditions, when A is an OR group and the thus obtained acid of formula : is isolated ;

    d) or, if applicable, the thus obtained acid from step c) is treated with a HNR₆R₇ compound according to suitable amide coupling techniques to obtain a compound of formula
13. A process for preparing a compound of formula (I)'' having the same configuration around the 2,3 bond of the indoline as the starting product in which

    - R₁, R₂, R₃, R₅, m and n are as defined for the compounds of formula (I) in claim 1,

    - R'_VI is a C₁-C₆ alkyl_,

    - R'_VII is a (CH₂)_rH group,

    - or R'_VI and R'_VII together with the nitrogen atom to which they are bonded, form a heterocycle selected from :

    . thiazolidine or 2,2-dimethylthiazolidine substituted by a (CH₂)_qH group,

    . piperazine substituted at the 4-position by a (CH₂)_qH group,

    . an unsaturated, 5-membered ring containing a single nitrogen atom and substituted by a (CH₂)_qH group or

    . a saturated, 3-, 4-, 5-, 6- or 7- membered ring containing a single nitrogen atom and substituted by a (CH₂)_qH group,

    characterised in that a compound of formula (I)' in which R₁, R₂, R₃, R₅, m and n have the meanings given for the compounds of formula (I), in claim 1, and

    - R_VI is a C₁-C₆ alkyl,

    - R_VII is a (CH₂)_rCOOH group wherein r = 1, 2 or 3,

    - or R_VI and R_VII together, with the nitrogen atom to which they are bonded, form a heterocycle selected from :

    . thiazolidine or 2,2-dimethylthiazolidine substituted by a (CH₂)_qCOOH group,

    . piperazine substituted at the 4-position by a (CH₂)_qCOOH group,

    . an unsaturated, 5-membered ring containing a single nitrogen atom and substituted by a (CH₂)_qCOOH group or

    . a saturated, 3-, 4-, 5-, 6- or 7-membered ring containing a single nitrogen atom and substituted by a (CH₂)_qCOOH group,

    with q = 0, 1, 2 or 3, is subjected to radical decarboxylation.
14. Process for preparing a pharmaceutical composition, characterised in that a compound of formula (I) prepared by the process according to any one of claims 1 to 11 is mixed as an active principle with a pharmaceutically acceptable vehicle.
15. Process for preparing a pharmaceutical composition, characterised in that a compound of formula (I) prepared by the process according to any one of claims 1 to 11 in association with another active principle is mixed as an active principle with a pharmaceutically acceptable vehicle.