FI97224B - Process for the preparation of therapeutically useful N-sulfonylindoline derivatives - Google Patents

Abstract

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

Description

1 97224

This invention relates to the preparation of therapeutically useful N-sulfonylindoline derivatives.

U.S. Patent No. 3,838,167 describes certain N-sulfonylindole derivatives of the formula W R'l 10 -ίΛτ-Υ (r, 2) iTTx 11 U-COR'4

n / 'ΪΓ I

SO 2 R 3 wherein R 'is hydrogen, alkyl or phenyl optionally substituted; R '2 is halogen, alkyl, alkoxy, nitro or trifluoromethyl; R'3 is alkyl, phenyl or alkylphenyl; R * 4 is alkyl, phenyl optionally substituted, alkoxy or phenoxy; n 'is 0, 1 or 2.

The compounds of formula 1 are intermediates in the synthesis for the preparation of indole derivatives having central nervous system activity and of formula R'l 25 / \ _ / CK'2> rt ^> l ^ Jj-COR ·

B

Wherein R 'is alkyl, phenyl optionally substituted, or hydroxyl.

The N-sulfonylindoline derivatives of this invention have affinity for vasopressin and oxytocin receptors.

2,97224

Vasopressin is a hormone known for its antiduretic effect and its effect in the regulation of arterial hypertension. It stimulates many types of receptors: V1, V2, Vla, Vlb, and also has cardiovascular effects, effects on the central nervous system and liver, and antidiuretic and aggregating effects. Vaso-pressin receptor antagonists may affect the regulation of the central and peripheral circulatory systems, especially the heart, kidneys and gastrointestinal tract, as well as water metabolism and adrenocorticotropin hormone (ACTH) release. Vasopressin and oxytocin receptors are also present in uterine smooth muscle. Oxytocin has a peptide structure close to that of vasopressin. Its receptors are also found in mammary gland-15 myoepithelial cells and the central nervous system.

[Presse Mfedicale, 16 (10) (1987) pp. 481-485; J. Lab.

Clin. Med., 114 (6) (1989) pp. 617-632, and (10) Pharmacol. Rev., 43 (1) (1991), pp. 73-108].

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

The invention relates to a process for the preparation of therapeutically useful N-sulfonylindo-25 line derivatives of the formula (I) and their salts. ttt 1 iin lujit.

(I> 30 N R 4 SO 2 (CH 2) m 85 3 97224 where

R 1 is a halogen atom, a C 1-4 alkyl, a C 1-4 alkoxy group, a trifluoromethyl group, a nitro group or an amino group; R 2 is C 1-6 alkyl, C 3-7 cycloalkyl, or phenyl which is unsubstituted or substituted by one or more C 1-4 alkyl, C 1-4 alkoxy, halogen or trifluoromethyl groups; R 3 is a hydrogen atom or C 1-4 alkyl; R 4 is a carboxyl group, an alkoxycarbonyl group in which the alkyl group is a C 1-6 alkyl group, a benzyloxycarbonyl group or a carboxamide group of the formula CONR 6 R 7; R 5 is C 1-4 alkyl, 1-naphthyl, 2-naphthyl, phenyl which is unsubstituted or substituted by one or more substituents selected from halogen atom, C 1-4 alkyl, trifluoromethyl group, nitro group, amino group, C 1-4 alkoxy , C 1-4 alkenyloxy, trifluoromethoxy group, benzyloxy group and cyano group; R 6 and R 7 each independently represent hydrogen, C 1-4 alkyl, phenylalkyl wherein alkyl is C 1-4 alkyl, or R 6 and R 7 together form a group - (CH 2) 4 -; n is 0 or 1; and m is 0, 1 or 2.

The compounds of formula (I) exhibit cis-trans isomerism around the 2,3-bond of indoline. The various isomers form part of this invention.

By convention, compounds of formula (1) wherein R 2 and R 4 are on the same side of the ring are termed cis isomers.

By convention, compounds of formula (I) wherein R 2 and R 4 are on different sides of the ring are termed trans isomers.

. 97224 4 5 N / NNX Vr3 (I) SO2 (CH2) m R5 cis-isomer 10

'S - through "0A

(Rl) n "fe Ji JUR3 <D

15 ^ SO2 (CH2) m R5 trans isomer 20

In addition, the compounds of the invention have two asymmetric carbon atoms. Optical isomers of the compounds of formula (I) form part of the invention.

In this specification and in the following claims, a halogen atom means a fluorine, chlorine, bromine or iodine atom, alkyl means a straight-chain or branched hydrocarbon group.

Preferred compounds of formula (1) according to the invention are those in which at least one of the following conditions is met: R 3 is a chlorine or bromine atom or a methoxy group and n <= 1; R 2 is chlorophenyl, methoxyphenyl or cyclohexyl; R3 is hydrogen; J! Itll l.lii 1 '. · 5 97224 R 4 is alkoxycarbonyl, wherein alkyl is C 1-6 alkyl, or a carboxamide group of formula CONR 6 R 7, wherein R 6 and R 7 are C 1-6 alkyl groups; R 5 is phenyl substituted at positions 3 and 4 or 5 at positions 2 and 4 by methoxy groups, or R 5 is phenyl substituted at the 4-position by a methyl group; m is 0.

Particularly preferred are the compounds of formula (I) as the cis isomer.

10 The following abbreviations are used in the description and examples: DCM: dichloromethane iPr ether: isopropyl ether AcOEt: ethyl acetate 15 MeOH: methanol EtOH: ethanol Ether: ethyl ether DMF: dimethylformamide THF: tetrahydrofuran DBM: dimethylsulfoxide DMSO: dimethylsulfoxide DIPO: dimethyl sulfoxide diazabicyclo [5.4.0] undec-7-ene TBD: 1,5,7-triazabicyclo [4.4.0] dec-5-ene DBN: 1,5-diazabicyclo [4.3.0] non-5-ene DMAP: 4-dimethylaminopyridine DMPU: 1,3-dimethyl-2-oxohexahydropyrimidinone TMEDA: tetramethylethylenediamine LDA: lithium diisopropylamide HMPA: hexamethylphosphoramide 30 HMDS: 1,1,1,3,3,3-hexamethyldisilazolium benzimidazane BOP:

M.p .: melting point 6 97224

Brine: water saturated with sodium chloride Dry ice: solid carbon dioxide TLC: thin layer chromatography HPLC: high pressure liquid chromatography 5 NMR: nuclear magnetic resonance s: singlet m: multiplet bs: broad singlet d: doublet 10: 1% aqueous hydrochloric acid, dilute brine: dilute brine dispersion of sodium hydroxide in mineral oil (Janssen Chemica)

Me: methyl Et: ethyl 15 Ph: phenyl

The compounds of formula (I) are prepared according to the invention in that a) a 2-aminophenone derivative of formula 20 * CO-R2

™. <X

N / NH 2 wherein R 1 # R 2 and n are as defined above in connection with formula I is reacted with a sulfonyl derivative of formula

Hal-SO 2 -CH 2 -R 3) (III) wherein Hal is halogen, preferably chlorine or bromine, and R 5 is as defined above for formula I;

Il Ut: t »Iti I I 4-Ml · ♦ 7 97224 b) a compound of the formula thus obtained. CO-R2 s "" O ·!:, (C «2). (iv> * 5 is treated with a halogenated derivative of formula 10

Hal '- CH - R 3 (V) wherein Hal' is halogen, preferably bromine, and R 3 and R 4 are as defined above for formula I; c) cyclizing the compound of formula yv thus obtained C0R2 20 yv / 3 SO2 \ 4 (VI) (CH2) m r5 • 25 in a basic medium to prepare a compound of formula I according to the invention; d) optionally separating the cis and trans isomers of the compound of formula I.

The 2-aminophenone derivatives of formula (11) are known or are prepared by known methods, such as those described by A.K. Singh et al., 8 97224 et al., Synth. Commun. 16 (4) (1986) pp. 485, and G.N. Walker, J. Org. Chem., 27 (1962) p. 1929.

The halosulfonyl derivatives of the formula (III) are known or are prepared by known methods. Thus, for example, 4-dimethylaminophenylsulfonyl chloride is prepared by the method described in C.N. Sukenik et al., J. Amer. Chem. Soc., £ 9 (1977) pp. 851-858; p-Benzyloxysulfonyl chloride is prepared according to EP patent application 229,566).

Alkoxysulfonyl chloride is prepared starting from sodium alkoxysulfonate, which in turn is prepared by reacting an alkyl halide with sodium hydroxyphenyl sulfonate. 2-Amino-2-trifluoromethylbenzophenones and other trifluoromethyl derivatives are prepared according to U.S. Patent 3,341,592.

2,4-Dimethoxybenzylsulfonyl chloride is prepared according to J. Am. Chem. Soc., 74 (1952) p. 2008.

The halogenated derivatives of formula (V) are known or are prepared by known methods, such as those described in A.I. Vogel, A Textbook of Organic Chemistry, Longman, 3rd Edition, 1956, p. 383, or G. Kirchner et al., J. Am. Chem.

: 1 Soc., 107, 24 (1985) p. 7072.

Step a) of the process is carried out in pyridine by heating at a temperature between room temperature and the boiling point of the solvent for a time of a few hours to a few days. Optionally, dimethylaminopyridine used in a catalytic or stoichiometric amount may be used.

Process step b) between the sulfonamide of formula (IV) and the excess halogenated derivative is carried out in a solvent such as dimethylformamide 35 or dimethyl sulfoxide under an inert atmosphere at a temperature of 9 97224 ° C at 0 ° C. and room temperature for a period of a few hours to 24 hours in the presence of sodium hydride.

Step c) of the process is close to the aldolysis reaction: the CH-CH3 group in the α-position of the ester or amide is deprotonated, then the carbonyl group of the phenone acts as an internal electrophile, causing cyclization and the formation of two symmetrical carbons (C *).

The reaction can be plotted as follows:

10 J

C - R2 0 / V - base (R1) n ^ t ϊ "C \> S ° 2 R3 (solvent) 15 (CH2) m R5

OH

"'Ovt- 20' SO 2 (CH 2) m R 5 CH Heathcock has reviewed the principles of the aldol addition reaction in Asymetric Synthesis, 25 Vol. 3: Stereodifferentiating additions reactions, part B, 111-212, Academic Press, 1984, ed. JD Morrison .

It is known that the aldol addition of achiral ester anions (or amide anions) with achiral bases takes place to form two racemic diastereomers of β-hydroxyesters (or β-hydroxyamides) in a ratio which depends largely on the experimental conditions used. These conditions include: the nature of the inorganic or organic base used, the nature of the cations or counterions, the possible presence of additives *> 10 97224 in the reaction medium, the solvent, the reaction temperature and the structure of the compound involved.

When R4 is a carboxamide group CONR6R7, wherein R6 and R7 are as defined above in connection with formula (I), an aqueous solution of sodium hydroxide may be used in the presence of a co-solvent, either with or without the addition of a phase transfer catalyst.

Organic bases can be used to carry out this reaction, for example: - tertiary organic bases, such as triethylamine, - guanidines, such as 1,5,7-triazabicyclo [4.4.0] dec-5-ene, - amaldines, such as 1,8-diazabicyclo [5.4.0] undec-5-ene or 1,5-diazabicyclo [4.3.0] non-5-ene, in a solvent or solvent mixture selected from, for example, benzene, THF, dichloromethane, methanol, dimethylformamide; the reaction is carried out in an inert atmosphere at a temperature in the range of 25 to 110 ° C; the amount of base used is at least stoichiometric; reaction 20 can also be carried out without solvent at bath temperature.

Lithium, sodium, potassium, calcium or magnesium alcoholate of a primary, secondary or tertiary alcohol may also be used.

The alcoholate is used in a catalytic or stoichiometric amount in an anhydrous solvent, for example alcohol (optionally in the presence of a co-solvent such as THF) or a stoichiometric amount in THF, DMF, or DMSO, optionally with crown ethers, for example 18-30 dicyclohexyl crown. In the presence of -6; the reaction is carried out at a temperature in the range of 0 to 80 ° C. It is also possible to use a base such as sodium hydroxide, lithium hydroxide or potassium hydroxide in a solvent such as ethyl ether, THF, benzene, DMF, or alkali metal thallamide amides used in a solvent such as ammonium ether, ether or toluene. , at a temperature between -30 ° C and 110 ° C.

The use of an amide of the type RR'NLi or RR'NMgBr, where R and R 'are monovalent radicals, as a deprotonating agent is a process for the formation of ester enolates or amides as intermediates in the aldol condensation reaction; this method has recently been described in Ireland, R.E. et al., J. Org. Chem., 56 (1991) p. 650. The reaction solvent may be benzene, hexane or THF used anhydrous in an inert atmosphere. Adjuvants such as LiF, LiCl, LiBr, Lii, LiBu, TMEDA, DMPU, HMPA or crown ether may also be added (Murakate, M. et al., J. Chem. Soc. Chem. Commun., 1990, p. 1657). The effect of the reaction conditions on the proportion of each isomer formed has been studied. An example is the use of lithium diisopropylamide at -78 ° C in anhydrous THF under an inert atmosphere or in THF in the presence of additives such as tetamethylenediamine, DMPU or HMPA. Other known and useful amides are, for example, lithium cyclohexylamide, lithium 2,2,6,6-tetramethylcyclohexylamide. Other amides can also be prepared by reacting the required amount of butyllithium in hexane with unbranched or cyclic secondary amines; this reaction takes place in one of the above-mentioned solvents. Finally, numerous publications describe amides of optically active secondary amines: Duhamel, L. et al., Bull. Chim., France, II, 1984, p. 421; Whitesell, J.K. et al., J. Org. Chem., 45 (1980) pp. 755; Murakata, M. et al., J. Chem. Soc. Chem.

30 Comm., 1990, p. 1657; Yamaguchi, M., Tetrahedron Lett., 27 (8) (1986) pp. 959; Cox, P.J. & Simpkins, N.S., Tetrahedron: Asymetry, 2 (1) (1991), p. 1.

Lithium, sodium or potassium silylamides form another group of useful bases; Of these, (M3Si) 2NLi, (Me2PhSi) 2NLi, (Et3Si) 2NLi, (Me3Si) 2NK and (Me3Si) 2NNa can be mentioned.

Mixed amides such as those described, for example, in Yamamoto, Y., Tetrahedron, 5 46 (1990) p. 4563; for example, a lithium salt of N- (trimethylsilyl) benzylamine or an analog thereof, wherein the benzylamine is replaced by a chiral primary amine such as (R) - or (S) -α-methylbenzylamine.

When chiral amides are used, the two cis and 10 trans diastereomers together or each separately may have optical activity due to asymmetry and enantiomeric enrichment. The proportion of each enantiomer is then determined by means of a chiral HPLC column.

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

Optionally, the optically active isomers of both the cis and trans isomers are separated, for example, by preparative chromatography on a chiral column.

If the two isomers of the compounds of formula (I) are difficult to prepare separately by conventional methods, it is also possible to prepare a compound of formula 25 - / - O-Si (CH3) 3 (R1), r \ A A '! Wherein R 1, R 2, R 3, R 4, R 5, m and n are as defined above for formula I, by reacting hexamethyldisilazane with the corresponding compound of formula (I) . The reaction is carried out with a catalytic amount of imidazole and by heating at 60-120 ° C under an inert atmosphere. The silyl ester is obtained by crystallization from the reaction medium or after chromatography. The two isomers of the compound of formula (VII) are separated by chromatography on silica gel, after which each isomer of the compound of formula (VII) is hydrolysed in an alkaline medium to give both isomers of the compound of formula (I).

Several methods are available for the separation and characterization of the cis-isomer and the trans-isomer of a compound of formula (I). If R3 is hydrogen, a comparative analysis is performed by high field NMR (250 MHz) coupled to study, for example, the Overhauser effect (N.O.E.) between the indoline proton (R3 »H) and the hydroxyl proton.

If R4 is a carboxamide group, then the IR spectra of the cis isomer and the trans isomer in DCM solution are different, the cis isomer most often has a strong, narrow and symmetrical absorption line due to hydroxyl vibration at about 3550-3520 cm-1, while the trans isomer there is no distinct vibration in this area.

Based on the values obtained, it has been found that the cis isomer is generally more mobile on an alumina TLC plate (neutral 60F254, Type E, Merck) when eluted with DCM containing varying amounts of AcOEt.

Similarly, when chromatographed on an alumina column (alumina 90, grain size 0.063-0.200 mm), the cis isomer is most often eluted first when the eluent is DCM containing varying amounts of AcOEt or MeOH.

If R4 is an ester group, TLC can be performed on a silica gel plate (Kieselgel 60F250, Merck) using DCM as eluent, with the cis isomer generally being more mobile if TLC is performed on a mixture of isomers.

Thus, the cis or trans isomer of the compound (I) of the invention can most often be determined by the analytical method 14 97224. An analogous procedure is also used in the case of compounds which are close to one another or compounds one of which is prepared from the other.

Compounds of formula (I) in which R 4 is a carboxy group are prepared by debenzylation of compounds of formula (I) in which R 4 is a benzyloxycarbonyl group by catalytic hydrogenation, for example in the presence of a palladium on carbon catalyst.

Compounds of formula (I) in which R 4 is a carboxamide group CONH 2 may be prepared from the corresponding compounds of formula (I) in which R 4 is a carboxy group, for example by a conventional coupling reaction of peptide synthesis, for example in the presence of BPO or DIPEA .

A compound of formula (I) wherein R 2 is an amino group and / or a compound wherein R 5 is an amino-substituted phenyl group may be prepared from a compound of formula (VI) obtained in step b) wherein R x is a nitro group and / or R 5 is a nitro-substituted phenyl group with other substituents desired for the compound of formula (I), by catalytic hydrogenation in the presence of, for example, a palladium on carbon catalyst or a rhodium alumina catalyst. The compounds of formula (VI) obtained at the end of step b) are novel and form part of the present invention.

The affinity of the compounds of the invention for vaso-25 receptor receptors has been determined in vitro using the method described in J. Biol. Chem., 260 (5) (1985) pp. 2844-2851. This method investigates the replacement of tritiated vasopressin bound to rat spy membranes. Concentrations of the compounds of the invention that inhibit the binding of tritiated vasopressin by 50% (IC50) are low, even nanomolar.

The affinity of the compounds (I) of the invention for oxytocin receptors has also been determined in vitro by replacing tritiated oxytocin bound to a membrane preparation of pregnant rat glands. The compounds of the invention have low IC50 values, up to 10'7 M.

In addition, the inhibition of vasopressin-induced platelet aggregation in human platelet-rich plasma (human PRP) has been measured by the method described in Thrombosis Res., 45 (1987) pp. 7-16. The compounds of the invention inhibit aggregation caused by 50-100 nM vasopressin with low ID50 (inhibitory dose) values of up to 10'8. These results are indicative of the V1 receptor antagonist activity of the compounds of the invention.

The affinity of the compounds (I) of the invention for V2 receptors has been measured by the method developed by Crause, P. et al. [Molecular and Cellular Endocrinol-15 ogy, 28 (1982) pp. 529-541.

The compounds of the invention are active when administered by various routes, especially orally.

No signs of toxicity were observed with these compounds at pharmacologically active doses.

Thus, the compounds of the invention may be used in the treatment or prevention of diseases due to vasopressin, such diseases being in particular cardiovascular diseases such as hypertension, heart failure or cardiovascular spasm, especially in smokers; j 25 central nervous system diseases such as cerebral edema, psychotic conditions and memory disorders; diseases of the renal system, such as renal vasoconstriction, necrosis of the renal cortex; diseases of the gastrointestinal tract, such as gastric ulcers or syndrome of inappropriate antidiuretic hormone secretion (SIADH). In women, the compounds of the invention may also be used to treat menstrual disorders or preterm labor.

In pharmaceutical compositions for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, intravenous, intranasal, intranasal, transdermal or rectal administration, the active compounds of formula (I) or their salts may be administered to animals as with pharmaceutical carriers for the treatment or prevention of the above disorders or diseases. Suitable dosage unit forms include oral forms such as orally administrable tablets, capsules, powders, granules and solutions or suspensions, sublingual, buccal, tracheal or nasal forms, subcutaneous, intramuscular or intravenous forms, and rectal forms. For topical administration, the compounds of the invention may be used in ointments, salves or lotions.

To achieve the desired prophylactic or therapeutic effect, the dose of the active ingredient may vary between 0.01 and 50 mg per kilogram of body weight per day.

Each dosage unit may contain 0.5 to 1000 mg, preferably 1 to 500 mg of active ingredients in combination with a pharmaceutical carrier. This dosage unit may be administered 1 to 5 times a day so that the daily dose becomes 0.5 to 5000 mg, preferably 1 to 2500 mg.

When preparing a solid tablet composition, the active ingredient is mixed with a pharmaceutical excipient such as gelatin, starch, lactose, magnesium stearate, talc, acacia or the like. The tablets may be coated with sucrose, cellulose derivatives or other suitable substances, or may be treated so as to prolong or slow down their action and to release them.

Il,. tltit «in 1.1» * ·. - 17 97224 apply the active substance at a constant rate in a predetermined amount.

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

The preparation in syrup or elixir form or administered in drops may contain the active ingredient together with a sweetening agent, preferably a calorie-free sweetener, methyl paraben or propyl paraben as an antiseptic and a taste and color enhancing agent.

Water-dispersible powders or granules may contain the active ingredient in admixture with dispersing or wetting agents or suspending agents such as polyvinylpyrrolidone and sweetening and flavoring agents.

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

For parenteral administration, aqueous suspensions, isotonic saline solutions or sterile injectable solutions are used which contain pharmacologically compatible dispersing and / or wetting agents, for example, propylene glycol or butylene glycol.

The active ingredient may also be formulated in microcapsules, optionally with one or more carriers or excipients.

The compositions may contain the compounds of formula 1 above or pharmaceutically acceptable; in addition to the acceptable salts, other active ingredients which may be used in the treatment of the abovementioned disorders or diseases.

18 97224

The invention thus relates to compositions containing several active ingredients, one of which is a compound of the present invention.

Examples 1 and 2 Methyl 5-chloro-3-cyclohexyl-3-hydroxy-1- (naphth-1-ylsulfonyl) indoline-2-carboxylate, cis-isomer, trans-isomer A) 5-chloro-2- [ (naphth-1-ylsulfonyl) amino] cyclohexylphenone A mixture of 3 g of 2-amino-5-chlorocyclohexylphenone and 3.2 g of naphth-1-ylsulfonyl chloride is heated in pyridine at 100 ° C for 8 hours. The pyridine is evaporated, water is added, it is extracted with ethyl acetate and then filtered through silica gel, eluting with dichloromethane. 4.27 g of the desired product are obtained.

After recrystallization from DCM / iPr ether, m.p. is 140-142 ° C.

B) 5-Chloro-2 - [(N-methoxycarbonylmethyl) - (N-naphth-1-ylsulfonyl) amino] cyclohexylphenone 4.27 g of the product obtained in the previous step are dissolved in 20 ml of anhydrous DMF under an argon atmosphere. 320 mg of 80% sodium hydroxide are added at 0 [deg.] C., and after 20 minutes, 6.1 g of ethyl bromoacetate are added over 30 minutes and the mixture is stirred at room temperature for 3 hours. The crude product obtained after extraction is recrystallized from DCM / iPr ether mixture to give 2.45 g of the desired compound.

Sp. »130-132 ° C.

C) Methyl 5-chloro-3-cyclohexyl-3-hydroxy-1- (naphth-1-ylsulfonyl) indoline-2-carboxylate 2.4 g of the compound obtained in the previous step are suspended in 30 ml of methanol under a nitrogen atmosphere and added At 0 [deg.] C., 26 mg of sodium methylate and, after 10 minutes at room temperature, again 26 mg of sodium methylate, and finally, after 45 minutes, 1 ml of THF are added to effect dissolution. After one hour, a precipitate is formed by adding powdered dry ice and water. The precipitate is filtered, taken up in ethyl acetate, washed with water and brine and dried. The oil obtained is chromatographed on silica gel using DCM and then DCM containing up to 10% AcOEt as eluent; thus separating the two isomers.

The compounds contained in each fraction are then recrystallized from DCM / iPr ether.

Mp = 155-157 ° C: cis isomer M.p. = 141-142 ° C: trans isomer.

Examples 3 and 4 Methyl 5-chloro-3- (2-fluorophenyl) -3-hydroxy-1- (4-nitrophenylsulfonyl) indoline-2-carboxylate, cis-isomer, trans-isomer A) 5 -Chloro-2'-fluoro-2 - [(4-nitrophenylsulfonyl) amino] benzophenone A mixture of 24.9 g of 2-amino-5-chloro-2'-fluorobenzophenone and 22.1 g of 4-nitrophenylsulfonyl chloride, refluxed in pyridine for 10 hours. Evaporate to dryness, then add water and ethyl acetate, wash with water and brine, dry over magnesium sulphate and evaporate in vacuo. The desired product precipitates on evaporation, is filtered and recrystallized from DCM / iPr-ether. The yield is 20 g.

Sp. = 155 ° C.

B) 5-Chloro-2'-fluoro-2 - [(N-methoxycarbonylmethyl) - (N-4-nitrophenylsulfonyl) amino] benzophenone 5 g of the compound obtained in the previous step are dissolved in 20 ml of DMF at 0 ° C: under argon, 367 mg of 80% sodium hydroxide are added and after 5 minutes 35 g of methyl bromoacetate and again 3.5 g of methyl bromoacetate are added after 1 hour. After 5 hours at room temperature, the reaction mixture is poured into ice water and extracted three times with ethyl acetate, washed three times with water and aqueous sodium chloride solution, then dried over magnesium sulfate. Chromatograph on silica gel using DCM as eluent to give 6.1 g of the desired compound which solidifies in methanol.

C) 3 g of the compound obtained in the previous step are suspended in 50 ml of methanol and cooled in an ice bath. 330 mg (0.1 equivalents) of sodium methylate are added and the mixture is stirred for 60 minutes, allowing the temperature to rise to 10 ° C. Powdered dry ice is added followed by water and extracted three times with ethyl acetate, then washed with water and aqueous sodium chloride solution and evaporated in vacuo. The crude reaction product (6.1 g) is chromatographed on a silica gel column prepared in DCM.

When eluted with DCM, both two isomers elute sequentially.

20 Less polar isomer: cis isomer. When an

After recrystallization from DCM / iPr ether, m.p. = 219 - 220 ° C.

More polar isomer: trans isomer.

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

• I

Examples 5 and 6

Methyl 1- (4-aminophenylsulfonyl) -5-chloro-3- (2-fluorophenyl) -3-hydroxyindoline-2-carboxylate, trans isomer, cis isomer 30 A) 5- chloro-2'-fluoro-2- [N- (methoxycarbonylmethyl) -N- (4-aminophenylsulfonyl) amino] benzophenone

The 5-chloro-2'-fluoro-2- [N- (methoxycarbonylmethyl) -N- (4-nitrophenylsulfonyl) amino] benzophenone prepared in Example 2, step b, is dissolved in 100 ml of ethyl acetate and 5 ml of methanol. and hydrogenated at atmospheric pressure for 2 hours in the presence of 620 mg of a 10% palladium on carbon catalyst; the presence of three compounds (starting material, intermediate and desired product) is detected by TLC. The catalyst is filtered off, the solvent is evaporated off and the residue is chromatographed on silica gel. The desired compound is eluted with DCM containing 1% methanol. After recrystallization from DCM / iPr ether, m.p. = 168-170 ° C.

B) Trans isomer 10 3.4 g of the compound obtained in the previous step are dissolved in 20 ml of methanol and 20 ml of THF at 0 ° C under a nitrogen atmosphere and 190 mg of sodium methylate are added. After stirring for 60 minutes at 5 ° C, the reaction mixture is poured into water and extracted with ethyl acetate. One compound crystallizes, it is recrystallized from DCM containing a little methanol.

Sp. = 215 - 216 eC.

This is a trans compound according to NMR spectroscopy with NOE.

C) Cis Isomer 200 mg of compound 2 prepared in Example 3 are dissolved in 10 ml of ethyl acetate and 2 ml of methanol and hydrogenated under normal pressure for 3 hours in the presence of 50 mg of 10% palladium on carbon catalyst.

The catalyst is filtered off, the filtrate is evaporated to dryness and the residue is chromatographed on silica gel using DCM containing 1% methanol as eluent. The product obtained is recrystallized from a MeOH / iPr ether mixture. The yield is 105 mg.

30 Sp. = 186-190 ° C.

„97224 22

Examples 7 and 8

Methyl 3- (2-fluorophenyl) -3-hydroxy-5-nitro-1-tosylindoline-2-carboxylate, cis-isomer, trans-isomer 5 A) 2'-fluoro-5-nitro-2-tosylaminobenzophenone

A mixture of 10 g of 2-amino-5-nitro-2'-fluorobenzophenone and 7.5 g of tosyl chloride is refluxed in 50 ml of pyridine for 24 hours. The solvent is evaporated to dryness, water and ethyl acetate are added, the Liu-10 lubricant is filtered off, the organic phase is washed with dilute hydrochloric acid solution, water and aqueous sodium chloride solution, dried over magnesium sulphate and evaporated. The residue is chromatographed on silica gel and the desired product is eluted with DCM.

B) 2'-Fluoro-2- [N- (methoxycarbonylmethyl) -N-tosylamino] -5-nitrobenzophenone

4 g of the compound obtained in the previous step are taken up in 40 ml of anhydrous DMF and treated at 0 ° C with 320 mg of 80% sodium hydride and 6 g of methyl bromoacetate after 10 minutes. The mixture is allowed to warm to room temperature, water is added and extracted with ethyl acetate. After evaporation of the solvent, the residue obtained is purified by silica gel chromatography, the oil obtained by eluting with DCM and then with DCM containing up to 2% of AcOEt solidifies completely. Elemental analysis: C23H19FN2O7S

calculated,% C: 56.79 H: 3.94 N: 5.76 obtained,% C: 56.54 H: 3.88 N: 5.54 C) A suspension containing 1.70 g in the previous step. in 30 ml of methanol, cooled to 10 ° C under an argon atmosphere and then treated with 100 mg of sodium methylate for 45 minutes. Add a large amount of water, extract with ethyl acetate, wash the organic phase with water until neutral, wash with aqueous sodium chloride solution, dry over magnesium chloride.

j | : 19! 111! I I I SI

23 97224 sulphate and evaporated in vacuo. The residue is chromatographed on silica gel. The less polar compound is eluted with pure DCM; the yield is 700 mg: cis isomer.

Sp. = 191-192 ° C after recrystallization 5 (DCM / iPr ether).

The more polar compound is eluted with DCM / ethyl acetate (95/5, v / v). After recrystallization from DCM / iPr ether, 650 mg of product are obtained.

Sp. = 206-207 ° C: trans isomer.

10 Example 9

Methyl 5-amino-3- (2-fluorophenyl) -3-hydroxy-1-tosylindoline-2-carboxylate, cis isomer 450 mg of the cis compound obtained in Example 4 are solubilized in 13 ml: ethyl acetate / methanol (10/3, 15 v / v) and hydrogenated at normal pressure and temperature in the presence of 100 mg of 10% palladium on carbon catalyst for 2 hours. The catalyst is filtered off, the solvent is evaporated off and the residue is chromatographed on silica gel using a DCM / ethyl acetate mixture (1/1, v / v) as eluent.

After trituration from a DCM / iPr ether mixture, an external powder is obtained.

Sp. = 203 ° C (cis isomer).

Examples 10 and 11 Methyl 5-chloro-3-cyclohexyl-3-hydroxy-1- (4-methoxyphenylsulfonyl) indoline-2-carboxylate, cis-isomer, trans-isomer A) 5-chloro-1 - [(4 -methoxyphenylsulfonyl) amino] -cyclohexylphenone A mixture of 20 g of (2-amino-5-chloro) phenylcyclohexyl ketone and 18 g of 4-methoxyphenyl chloride is heated in pyridine at 100 ° C overnight, the solvent is evaporated off and the residue is taken up in hydrogen chloride. , extracted with DCM, dried and evaporated. The residue is recrystallized from iPr ether / cyclohexane to give 27 g of the desired compound, which crystallizes. Sp. - 78 - 80 eC.

B) 5-Chloro-1- [N- (methoxycarbonylmethyl) -N- (4-5 methoxyphenylsulfonyl) amino] phenylcyclohexyl ketone

The compound obtained in the previous step (27 g) is treated with 2.2 g of sodium hydride in 150 ml of DMF at room temperature under an argon atmosphere for 30 minutes. Add 50 g of methyl bromoacetate and stir overnight. The DMF 10 is evaporated, the residue is taken up in water, extracted with DCM, dried and concentrated. The residue is chromatographed on silica gel using DCM as eluent to give 19.5 g of the desired compound, which crystallizes from methanol.

Sp. - 115 - 116 ° C.

C) The product obtained in the previous step (10 g) is solubilized in 350 ml of methanol and 0.6 g of sodium methylate in 50 ml of methanol are added. After a reaction time of 5 minutes, TLC shows that the reaction is complete. Dry ice is added to the reaction mixture, after which the methanol-20 l is evaporated off. The residue is taken up in water, extracted with methylene chloride and chromatographed on silica gel using methylene chloride as eluent.

The first fractions contain a weaker polar isomer which is recrystallized from isopropyl ethers.

Sp. 100 ° C (cis isomer).

The more polar isomer is then recovered. Sp. <145 ° C (trans isomer).

Examples 12 and 13 Methyl 5-chloro-3-hydroxy-3-pentyl-1-tosylindoline-2-carboxylate, cis-isomer, trans-isomer A) 4-chloro-2-hexanoyl-N-tosylaniline Mixture containing 15 g of 4-chloro-2-hexanoyl-35 aniline and 10.5 g of tosyl chloride is heated in 100 ml of pyridine at 100 ° C overnight. The solvent is evaporated off, the residue is taken up in aqueous hydrogen chloride solution, extracted with methylene chloride, dried and evaporated. The crude reaction product crystallizes from isopropyl ether, yield 5 is 14.5 g.

Sp. »78-80 eC.

B) 4-Chloro-2-hexanoyl-N-methoxycarbonylmethyl-N-tosylaniline 14 g of the compound obtained in the previous step are treated at 0 [deg.] C. under an argon atmosphere with 1 g of sodium hydride in DMF. After stirring for 15 minutes, 22.5 g of methyl bromoacetate are added and the mixture is stirred overnight at room temperature. After evaporation of the solvent and the excess bromine derivative by means of a vacuum pump, the residue is taken up in water, extracted with methylene chloride, dried and evaporated, after which the crude reaction product is chromatographed on silica gel using a DCM / pentane mixture (50/50, v / v) as eluent. 12.1 g of the expected product are obtained.

20 Sp. = 68-70 eC.

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

Sp. = 95-96 ° C: cis isomer.

The more polar isomer is recrystallized from isopropyl ether. 2 g of product are obtained.

35 Sp. = 102-104 ° C (trans isomer).

26 97224

Examples 14 and 15

Methyl 1-butylsulfonyl-5-chloro-3- (2-chlorophenyl) -3-hydroxyindoline-2-carboxylate, cis-isomer, trans-isomer 5 A) 2-Butylsulfonamido-25-dichlorobenzophenone 11 g of 2 ', 5-aminobenzophenone and 8.2 g of n-butanesulfonyl chloride are stirred in 40 ml of pyridine for 9 days at room temperature. The pyridine is evaporated in vacuo, water is added, the mixture is extracted with three volumes of ethyl acetate, the organic phase is washed with aqueous hydrogen chloride solution and aqueous sodium chloride solution and dried over magnesium sulfate. The solvent is evaporated off, then chromatographed on silica gel and the desired product is eluted with a pentane / ethyl acetate mixture (90/10, 15 v / v). The yield is 4.4 g.

B) 2- (N-Butylsulfonyl-N-methoxycarbonylmethyl) amino-2 ', 5-dichlorobenzophenone 4 g of the product obtained in the previous step are dissolved in 40 ml of DMF at 0 [deg.] C. under an argon atmosphere, treated with 320 mg 80% sodium hydride for 15 minutes and then 6.5 g of ethyl bromoacetate are added over 2 hours and the mixture is kept at room temperature for 6 hours. Water is added, then the reaction product is extracted and filtered through silica gel using DCM as eluent. The desired product is obtained in the form of a thick oil.

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

The first isomer is eluted with DCM.

27 97224

Sp. = 140-143 ° C: cis isomer (recrystallization from DCM / iPr ether).

The second isomer (trans isomer) is eluted by recrystallization from a DCM / iPr ether mixture.

5 Sp. 161-163 ° C: trans isomer (recrystallization from DCM / iPr ether).

Examples 16 and 17

Methyl-5-chloro-3- (2-chlorophenyl) -1- (2,5-dimethoxyphenylsulfonyl) -3-hydroxyphenylindo-2-one - carboc-10 ylate, cis-isomer, trans-isomer A) 2 ', 5-dichloro-2- (2,5-dimethoxyphenylsulfonamido) benzophenone This compound is prepared by the procedure described in the above examples.

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

Sp. = 129-131 ° C.

C) Methyl 5-chloro-3- (2-chlorophenyl) -2- (2,5-dimethoxyphenylsulfonyl) -3-hydroxyindoline-2-carboxylate

The cyclization step can be carried out in the presence of various reagents.

a) 1 g of the compound obtained in the previous step is dissolved in 10 ml of DCM at 0 ° C, 145 mg of DBU 35 are added and the reaction mixture is kept for 24 hours at + 5 ° C. The reaction mixture »28 97224 is poured directly onto a silica gel column. Elute with DCM.

First, the eluted compound (231 mg) is recrystallized from DCM / iPr ether.

5 Sp. = 168-169 ° C (cis isomer).

The trans isomer then elutes.

Sp. = 193-195 ° C. Recrystallization from DCM / iPr-eet mixture.

b) 800 mg of the compound obtained in step B are dissolved in 10% of anhydrous THF, 0.8 ml of HMPA are added and the mixture is cooled to -78 [deg.] C. under an argon atmosphere. Using a burette, add 1 ml of a solution of the complex LDA.TFA (1.5 M) in cyclohexane; After 45 minutes, an additional 0.3 mL of LDA is added, then water is added at -78 ° C and extracted with ethyl acetate.

NMR analysis of the obtained product shows the presence of the cis isomer (39%) and the trans isomer (61%).

c) 400 mg of the compound obtained in step B are dissolved in 3 anhydrous THFs under an argon atmosphere, cooled to 20-78 ° C and then 0.9 ml of a molar solution of LiHMDS in THF is added, followed by 0.4 ml of HMPA in 2 ml of THF. After stirring for 60 minutes at -78 ° C, a further 0.3 ml of LiHMDS is added and after 10 minutes water is added at -78 ° C, followed by extraction with ethyl acetate.

NMR analysis of the obtained product shows the presence of the cis isomer (60%) and the trans isomer (40%).

d) 400 mg of the compound obtained in step B are dissolved in 3 anhydrous THFs under an argon atmosphere, cooled to 30-78 ° C and then 1.8 ml of KHMDS solution (0.5 M) in 1 ml of toluene and 0.4 ml of HMPA in 1 ml of THF are added. The resulting solution is kept at -78 ° C for 20 minutes, then water is added and extracted with ethyl acetate.

NMR analysis of the obtained product shows the presence of cis isomer 35 (32%) and trans isomer (68%).

I: 1) Mi) I 1 4 M <<29 97224 e) 2 ml of THF and 0.4 ml of HMPA are cooled to -70 ° C under argon and a 0.9 ml molar solution of LHHMDS is added. in THF; then 400 mg of the compound prepared in step B dissolved in 3 ml of THF are added dropwise.

After keeping the mixture at -70 ° C for one hour, water is added and then extracted with ethyl acetate. NMR analysis of the obtained product shows the presence of the cis isomer (63%) and the trans isomer (37%).

10 f) 1 g of 1,3-diphenyl-1,3,3,3-tetramethyldisilazane is dissolved in 4 ml of anhydrous THF and 2.2 ml of a 1.6 M solution of butyllithium are added under an argon atmosphere at -10 ° C. in hexane and 1.8 mL of THF.

In the second procedure, 400 mg is dissolved in step B.

The prepared compound is added to 3 ml of anhydrous THF under argon at -78 ° C and 2.2 ml of the solution prepared above and then 0.4 ml of HMPA are added over 5 minutes. After 1 hour, 0.5 ml of the solution prepared above is added again, after which the mixture is allowed to stand for 1 hour at -78 [deg.] C. and finally water is added and extracted with ether.

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

Examples 18, 19 and 20 Isopentyl 5-chloro-3-cyclohexyl-3-hydroxy-1-tosylindoline-2-carboxylate, trans isomer, cis isomer, and isopentyl 5-chloro-3- cyclohexyl-3-trimethylsilyloxy-1-tosylindoline-2-carboxylate, cis isomer 30 A) 5-Chloro-2-tosylaminophenylcyclohexylchetone This compound is prepared by the procedure described in the previous examples.

30 97224 B) 2- (N-Tosyl-N-isopentyloxycarbonylmethyl) amino-5-chlorophenylcyclohexyl ketone 5.7 g of the compound prepared in the previous step are dissolved in 50 ml of anhydrous DMF, 420 mg of 80% strength are added. sodium hydride and then after 15 minutes 12 g of isopentyl bromoacetate and the mixture are stirred for 8 hours at room temperature. After extraction, chromatography on silica gel and eluents from pentane / DCM mixtures (20/80, v / v) to pure DCM elutes 10 oil.

C) Isopentyl 5-chloro-3-cyclohexyl-3-hydroxy-1-tosylindoline-2-carboxylate, trans isomer 1.6 g of the compound obtained in the previous step are dissolved in 10 ml of anhydrous 3-methylbutanol. Cool to 0 ° C and add 7 mg of sodium methylate, then bring to normal temperature within 150 minutes. Powdered dry ice and water are added, extracted by decantation, washed with water and aqueous sodium chloride solution and dried over magnesium sulfate. The solvent 20 is evaporated in vacuo and then chromatographed on silica gel. A mixture of the two isomers (1.6 g) is eluted with DCM, recrystallized from a DCM / iPr ether mixture: SR 47275 (trans isomer).

D) Isopentyl 5-chloro-3-cyclohexyl-3-trimethylsilyloxy-1-tosylindoline-2-carboxylate, cis isomer

The mother liquors obtained by crystallization of the trans isomer (980 mg) are dissolved in 8 ml of hexamethyldisilazane containing 100 mg of imidat-30 sol under an argon atmosphere and the mixture is heated to 120 ° C. The reaction is monitored by TLC on silica gel using DCM as eluent.

A weakly polar product appears after 1 hour and after one night another compound appears a little more polar than the previous one. The solution is evaporated to dryness in vacuo and the residue is chromatographed on silica gel.

Il i »« ti Hrltt I l 31 97224

Iillä. The less polar compound is eluted with a DCM / pentane mixture (50/50, v / v). 304 mg of product are obtained and recrystallized from DCM / iPr-ether.

Sp. = 118 - 121 ° C.

5 E) Isopentyl 5-chloro-3-cyclohexyl-3-hydroxy-1-tosylindoline-2-carboxylate, cis isomer

To a suspension of the mother liquor (220 mg) of the cis isomer isolated above in 1 mL of water and 3 mL of THF is added 2.4 mg of solid sodium hydroxide. After 3 hours, water is added, some of the THF is evaporated and extracted in vacuo at room temperature by conventional methods. The residue is chromatographed on silica gel using a DCM / pentane mixture (95/5, v / v) as eluent. According to the NMR spectrum, the obtained compound is 87% to 15% in cis form.

Example 21

Butyl 1-5-chloro-3-cyclohexyl-3-hydroxy-to-cycloindoline-2-carboxylate This compound is prepared by the reaction of butyl bromoacetate with 5-chloro-2-tosylaminophenylcyclohexyl ketone followed by cyclization with sodium in the presence of methylate in butanol.

The compound formed is a trans isomer.

Sp. = 115 ° C.

25 Examples 22 and 23

Methyl 5-chloro-3- (2-chlorophenyl) -3-hydroxy-2-methyl-1-tosylindoline-2-carboxylate, cis isomer, trans isomer

A mixture of 0.5 g of 2 ', 5-dichloro-2- [N- (1-30 methoxycarbonylethyl) -N-tosyl] aminobenzophenone, 0.1 g of sodium methylate and 2 ml of DMF is stirred for 20 hours at room temperature under a nitrogen atmosphere. . The mixture is evaporated in vacuo, the residue is taken up in water, the precipitate is filtered off and washed with water. The residue is chromatographed on 32 97224 silica gel using DCM as eluent. 60 mg of the cis isomer and 250 mg of the trans isomer are obtained.

Example 24

Methyl 5-chloro-3- (2-chlorophenyl) -1- (4-cyano-5-phenylsulfonyl) -3-hydroxyindoline-2-carboxylate, cis-isomer A) 2- [N- (4-cyanophenylsulfonyl) ] amino-2 ', 5-dichlorobenzophenone 10 g of 2-amino-2', 5-dichlorobenzophenone and 7.7 g of 4-10 cyanophenylsulfonyl chloride are heated at 100 ° C for 48 hours in pyridine with 4.6 g of DMAP The mixture is evaporated to dryness, water and ethyl acetate are added, the organic phase is washed with dilute aqueous hydrogen chloride solution, water and aqueous sodium chloride solution, dried over magnesium sulphate and the solvent is evaporated off under vacuum. The precipitate formed is filtered and then recrystallized twice from a DCM / iPr ether mixture to give the desired product.

Sp. = 172-173 ° C.

B) 2- [N- (4-cyanophenylsulfonyl) -N-methoxycarbonylmethyl] amino-2 ', 5-dichlorobenzophenone 10 g of the compound obtained in the previous step are dissolved at 0 DEG C. under an argon atmosphere of 70 g of DMF, then 740 mg are added. 80% sodium hydride and after 25 minutes 14 g of methyl bromoacetate. After 24 hours, water is added, the aqueous phase is decanted, the solid obtained is extracted with ethyl acetate, the organic phase is washed with water and aqueous sodium chloride solution, dried over magnesium sulphate and evaporated in vacuo. The desired product is obtained, which is recrystallized from a DCM / iPr ether mixture.

Sp. = 186 - 188 eC.

C) 2 g of the compound obtained above are suspended at 40 ° C in 40 ml of a MeOH / THF mixture (1/1, v / v) and 35 mixtures are treated with 100 mg of sodium methylate. After • i M-t a iu i> * ** 33 97224 the mixture has been kept for 3 hours at room temperature, complete dissolution is observed. Some of the solvents are evaporated in vacuo, a large amount of water is added and extracted with ethyl acetate. Wash with water and aqueous sodium chloride, dry over magnesium sulfate and evaporate in vacuo. The residue is chromatographed on silica gel. Methylene chloride sequentially elutes both two isomers.

The less polar isomer is recrystallized from a DCM / iPr ether mixture.

10 Sp. = 222-223 ° C.

Examples 25 and 26

Methyl 5-chloro-3- (2-chlorophenyl) -1- (3,4-dimethoxyphenylsulfonyl) -3-hydroxyindoline-2-carboxylate, trans isomer, cis isomer 15 A) 2 ', 5-Dichloro-2- (3,4-dimethoxyphenylsulfonylamido) benzophenone 5.6 g of 2-amino-2', 5-dichlorobenzophenone and 5 g of 3,4-dimethoxyphenylsulfonyl chloride are heated in pyridine overnight at 100 ° C: in. The pyridine is evaporated to dryness, water and ethyl acetate containing a little DCM are added and the mixture is extracted. Wash with water and dry over sodium sulfate, then evaporate in vacuo and recrystallize 7.7 g of the desired product from a DCM / iPr-ether mixture.

; 25 Sp. = 164 ° C.

B) 2 ', 5-Dichloro-2- [N- (3,4-dimethoxyphenylsulfonyl) -N-methoxycarbonylmethyl] aminobenzophenone 7.2 g of the compound obtained in the previous step are dissolved in anhydrous DMF at 0 ° C under a nitrogen atmosphere. Add 500 mg of sodium hydride and, after 10 minutes, 9.5 g of ethyl bromoacetate. After one night, add excess water and filter the precipitate formed. The precipitate is dissolved in DCM, dried over magnesium sulphate and the solvent is evaporated. 7.7 g of the desired product are recrystallized from DCM / iPr ether.

Sp. = 164 ° C.

<34 97224 C) Trans isomer 7 g of the product obtained in the previous step suspended in 90 ml of methanol containing 2 ml of THF are cooled to 0 [deg.] C. under a nitrogen atmosphere and the mixture is treated with 720 mg of sodium methylate. After 2 hours at room temperature, the unreacted starting material is filtered off, a large amount of water and dry ice are added and extracted with ethyl acetate. TLC shows 4 products. The highest product is recrystallized twice from 10M DCM / iPr ether.

Sp. = 184-185 ° C: trans isomer.

D) Cis-isomer 1.3 g of the compound obtained in step B are dissolved at 0 [deg.] C. in 13 ml of DCM containing 180 mg of DBU. The mixture is stirred overnight, after which the reaction mixture is poured directly onto a silica gel column packed with DCM, and eluting with DCM, the mixture of compounds formed in the cyclization is thus separated. Chromatography is then carried out on alumina using a DCM / iPr ether mixture (70/30, v / v) as eluent. This isolates the cis isomer.

NMR spectrum at 200 MHz in DMSO at 370 ° K:

Delta Form Integration Cause 25 2.50 DMSO 3.15 S 3 H CO 2 CH 3 3.80 s 3 H 0CH 3 3.85 s 3 H 0CH 3

5.10 S 1 H CH

30 6.50 S 1 H OH

7.00-7.80 m 10 H aromatic hydrogens

Il Ut.t M li M l »> 35 97224

Examples 27, 28, 29 and 30

Benzyl 5-chloro-3- (2-chlorophenyl) -3-hydroxy-1β-tosylindoline-2-carboxylate, trans isomer, cis isomer and 5-chloro-3- (2-chlorophenyl) -3-Hydroxy-1β-tosylindoline-2-carboxylic acid, trans isomer and cis isomer A) 2 ', 5-Dichloro-2- (N-tosyl-N-benzyloxycarbonylmethyl) aminobenzophenone 10 20 g 2 ', 5-Dichloro-2- (N-tosylamino) benzophenone (prepared by a conventional method) and 1.6 g of sodium hydride are reacted in 100 ml of DMF. The mixture is stirred for 15 minutes, then 34 g of benzyl bromoacetate are added and the mixture is allowed to stand overnight at room temperature. The DMF is evaporated off, the residue is taken up in water, extracted with methylene chloride, dried and evaporated. The crude product obtained is chromatographed on silica gel, eluting with DCM. The product obtained, 14.39 g, is recrystallized from iPr ether.

20 Sp. = 99-101 ° C.

B) Benzyl 5-chloro-3- (2-chlorophenyl) -3-hydroxy-1β-tosylindoline-2-carboxylate, trans isomer 1 g of the compound obtained in the previous step is treated at -78 ° C 1, 2 mL of concentrated (1.5 M) LDA in cyclo-25 hexane. After 3 hours, the mixture is taken up in water, extracted with DCM, dried and evaporated. The crude reaction product is chromatographed on silica gel, eluting with DCM and the mixture of the two isomers is separated. The more polar isomer is recrystallized twice from a DCM / iPr ether mixture. 600 mg of trans isomer are obtained.

Sp. = 168-169 ° C (recrystallization from DCM / iPr-ether).

36 97224 C) Benzyl 5-chloro-3- (2-chlorophenyl) -3-hydroxy-1β-tosylindoline-2-carboxylate, cis isomer 2 g of the compound obtained in step A are dissolved in DCM at 0 ° C. and 540 mg of DBU is added. The mixture is kept at 50 ° C for 20 minutes, then potassium sulphate solution and water are added, followed by extraction, drying and evaporation. The residue is chromatographed on silica gel, eluting with DCM, to give 450 mg of the less polar product (cis isomer) and 700 mg of the more polar product (trans isomer).

The cis isomer is obtained as a foam.

Elemental analysis: calculated,% C: 61.25 H: 4.05 N: 2.46 obtained,% 61.29 4.20 2.48 D) 5-chloro-3- (2-chlorophenyl) -3-hydroxy β-tosylindoline-2-carboxylic acid, trans isomer 500 mg of the trans isomer of the compound prepared in Step B are dissolved in 300 ml of ethyl acetate containing 100 mg of palladium on carbon catalyst. Hydrate for 20 minutes, after which the product crystallizes. The palladium is filtered off and the crystals are dissolved in hot DMF. The DMF is evaporated and the residue is taken up in a large volume of THF. Evaporate, add methanol and the product crystallizes. 175 mg of the desired product (trans isomer) are obtained. 25 NMR:

Delta Form Integration Cause 2.44 s 3 H CH3 (tosyl) 4.87 s 1H H6 (2-chlorophenyl) 30 6.74 s 1H H4 (indole)

6.98 s 1H OH

7.28-7.53 m 7 H aromatic hydrogens

7.88 d OH

35 (J = 8.6 Hz) 2 H H 2, H 6 (tosyl) 11! MM I I li l i MK. t 37 97224

In a similar manner, the cis-isomer of the acid is prepared by hydrogenating the benzyl ester obtained in formula C.

Sp. = 209 - 212 eC.

Example 31 5-Chloro-3- (2-chlorophenyl) -1- (3,4-dimethoxyphenylsulfonyl) -3-hydroxy-1-indoline-2-carboxylic acid, cis-isomer This acid is prepared by proceeding as described in the previous example via the benzyl ester of said acid.

Sp. = 130 - 132 eC.

The methyl esters of formula (I) were prepared by analogous procedures. They are shown in Table 1 below.

15

Table 1 \ - / oh ΒιΉΓ JL Jr-C02CH3 20 so2

Rs

For each compound of formula (I) having the substituents Rx, R2 and Rs given in the following table, the cis isomer is shown first, then the trans isomer, unless otherwise stated.

For example, R2 Rs Sp. ° C Solvent 30 32 H phenyl p-tolyl 154 33 170 34 5-C1 cyclopentyl p-tolyl 187-190 35 DCM / MeOH 1 2 «153 - 157 2 DCM / iPr ether

Eg Rx R2 R5 Sp. ° C Solvent 38 97224 36 5-Cl cyclohexyl p-tolyl 180 ether / cyclohexane 5 37 144 ether / cyclohexane 38 5-Cl cyclohexyl 2-naphthyl 177

10 MeOH

39,150 ether / cyclohexane 15,405-Cl isopropyl p-tolyl 158 DCM / iPr ether 41,172 DCM / iPr ether 20 42 5-Cl 2 -F-phenyl p-tolyl 165-166 DCM / iPr ether 43,212 - 213 25 DCM / iPr ether 44 5-Cl phenyl p-tolyl 206

(*) DCM / iPr-ether / MeOH

30 45 193 - 194

EtOAc / MeOH

46 5-Cl cyclohexyl p-tolyl 170-172 iPr ether 35 47 154-155 48 5-Cl 2 -Cl-phenyl p-tolyl 174 40 49 255 50 5-Cl cyclohexyl 4-dimethyl-184-185 li-4 -amino phenyl 45 51 198 - 200 DMC / iPr-ether 52 5-Cl cyclohexyl 2,4,6-tri-139-142 50 methyl-DCM / ether phenyl 15 55 [mu] l aniimuction 200 - 203 DCM / iPr-ether

Eg R3 R2 R5 Sp. ° C Solvent 39 97224 54 5-C1 cyclohexyl n-butyl 150-153

MeOH / iPr ether 5 55 5-C12-Cl-phenyl 2-CF3-phenyl 21 2-CF3-phenyl 225 5 5 -Cl2-Cl-phenyl 4-benzyl-166-hydroxy-DCM / iPr-ether phenyl 15 58 195 DCM / iPr-ether 59 5-C12-Cl-phenyl 4-Cl-phenyl 174 20 60 230 61 5-C14-Cl-phenyl p-tolyl 224 25 62 186

EtOH

63 5-C1 2-CH3-phenyl p-tolyl 168 30 64 238

AcOEt 65 5-Cl 2 -Cl-phenyl 4-OH-phenyl RMN (**) 35 66 163

MeOH / iPr ether 67 5-C12-Cl-phenyl 3-Cl-phenyl 175 40 68 186 69 5-C12-Cl-phenyl-m-tolyl 173 70 229 45; 71 5-C1-2-methoxy-p-tolyl 165 phenyl 72 240 50 73 5-C1-3-phenyl-p-tolyl 137 1,210

Eg Rx R2 Rs Sp. ° C Solvent 40 97224 75 5-C1 2-methyl-3,4-di-Cl-196 phenyl phenyl 5 76 175 77 5-C1 2-Cl-phenyl 3-methoxy-132 phenyl 10 78 5-C1 2-Cl -phenyl 2,3,4-tri-207 methoxyphenyl 15 79 183 80 5-C1 2-Cl-phenyl 4-butoxy-124-125 phenyl hexane 20 81 190 - 192

MeOH / iPr ether 82 5-Cl 2 -Cl-phenyl 4-trifluoro-170-methoxy-phenyl 83,166 84 5-Br 2 -F-phenyl-3,4-dimethyl-162-164 30 methoxy-phenyl 85,162 - 165 DCM / iPr ether 35 86 5-C1 2-Cl-phenyl phenyl 148 iPr-ether 87 230 40 DCM / iPr-ether 88 5-C1 2-Cl-phenyl 4-methoxy-173 phenyl hexane / iPr ether 45 89,217 hexane / iPr ether 1 2 5-Br 2-Cl-phenyl 3,4-dimethyl-160-162 toxoxyphenyl 50 2 199

Pre·. Rx Rj R, Sp. * C Solvent 41 97224 92 5-C12-Cl-phenyl 4-ethoxy-174 phenyl hexane / iPr-ether 5 93 186 hexane / iPr-ether 94 2-CH30 2-C1p-tolyl 215 10 trans 95 5-CH3 2-Cl-phenyl p-tolyl 165 96 216 EtOH 15 97 5-CF3 2-CF3-phenyl p-tolyl 189 98 202 20 99 5-C1 2-CF3-phenyl p-tolyl 166 100 205 101 5-C1 2- C1-Phenyl 3-methoxy-206.5 25 trans phenyl 102 5-C12-Cl-phenyl 4-CF3-phenyl-191 li 30 103 180 * From this compound a silyl derivative (VII) was prepared: cis isomer, m.p. = 176 - 178 eC.

35 ** Example 65: NMR spectrum at 200 Hz in DMSO, temp

lassa T - 380 ° K

Delta Shape Integration Causer

40 2.45 DMSO

3.10 s 3 H CO 2 CH 3

5.00 S 1 H CH

6.30 S 1 H OH

6.80 to 7.80 m 11 H aromatic 45 hydrogens 42 97224

Examples 104 and 105 N, N-Dimethyl-5-chloro-3-cyclohexyl-3-hydroxy-1-tosylindoline-2-carboxamide, trans isomer and cis isomer 5 A) 5-Chloro-2-tosylaminophenylcyclohexyl ketone This compound is the compound prepared in Example 18, Step A.

B) Dimethylacetamide bromide A solution of 56 g of bromoacetyl bromide in 100 ml of DCM is cooled to 0 ° C and gaseous dimethylamine is bubbled through it until the reaction mixture is basic. Filter, dry and evaporate to give the crude amide product as an oil (22 g).

C) 2- (N-Tosyl-N-dimethylcarbamoylmethyl) -5-chlorophenylcyclohexyl ketone 4.3 g of 5-chloro-2-tosylamino-phenylcyclohexyl ketone are mixed with 20 ml of DMF containing 360 mg of 80% by weight. sodium hydride, and after keeping the mixture at room temperature for 15 minutes, 5.4 g of the compound prepared in Step B are added and the mixture is stirred overnight at room temperature. The reaction mixture is poured into water, the precipitate is filtered off and then the precipitate is taken up in DCM, dried and evaporated. The product obtained crystallizes from isopropyl ether.

m = 3.9 g

Sp. = 184-187 ° C.

D) N, N-Dimethyl-5-chloro-3-cyclohexyl-1-tosyl-indoline-2-carboxamide, trans isomer 1.5 g of the compound obtained in the previous step are cooled to -78 ° C. In 20 ml of anhydrous THF, 2.3 ml of a 1.5 molar solution of cyclohexane in LDA are added and the mixture is stirred for 2 hours at -78 ° C. The mixture is poured into water, extracted with DCM, dried and evaporated. The crude product 35 obtained is chromatographed on silica gel; An AcOEt / DCM mixture (10/90, ||: IKI II »Ml *» 43 97224 v / v) elutes the compound whose NMR spectrum shows it to be the trans isomer. It is recrystallized from iPr-ether / DCM.

Sp. = 179-182 ° C.

5 E) N, N-Dimethyl-5-chloro-3-cyclohexyl-3-hydroxy-1-tosylindoline-2-carboxamide, cis isomer 1.5 g of the product obtained in step C are treated with 950 mg of DBU in 10 ml of DCM for 24 hours at room temperature. The reaction mixture is then chromatographed on silica gel using a DCM / AcOEt mixture (95/5, v / v) as eluent to give the second isomer (cis isomer). It is recrystallized from isopropyl ether, m = 120 mg M.p. = 152 - 155 eC.

Examples 106 and 107 N, N-dimethyl-5-chloro-3- (2-chlorophenyl) -3-hydroxy-1-tosylindoline-2-carboxamide, trans isomer and cis isomer A) 2 5-Dichloro-2-tosylaminobenzophenone This compound is prepared by a conventional method.

B) 2- (N-Tosyl-N-dimethylcarbamoylmethyl) -amino-2 ', 5-dichlorobenzophenone 8.4 g of 2', 5-dichloro-2-tosylaminobenzophenone '25 are dissolved in 40 ml of DMF and treated with 0 , 7 g of 11% 80% sodium hydride; After 15 minutes, 10 g of dimethylacetamide bromide prepared in Example 1 are added and the mixture is stirred overnight at room temperature. The reaction mixture is poured into water, the precipitate formed is filtered off, taken up in DCM, dried and evaporated.

; Recrystallization from isopropyl ether gives 9.2 g of the desired product.

Sp. = 154 - 157 ° C.

44 97224 C) N, N-Dimethyl-5-chloro-3- (2-chlorophenyl) -3-hydroxy-1-tosylindoline-2-carboxamide, trans isomer 1.5 g of the compound obtained in the previous step are handled - At 78 ° C in 100 mL of anhydrous THF in 2.6 mL of a 1.5 molar solution of cyclohexane in LDA for 3 hours. The mixture is poured into water, extracted with DCM, dried and evaporated. Chromatograph on silica gel using DCM / AcOEt (94/6, v / v) as eluent. First a small amount of a less polar compound is obtained and then a more polar compound, the trans isomer, is eluted.

It is recrystallized from a DCM / iPr ether mixture.

Sp. = 232-233 ° C.

D) N, N-Dimethyl-5-chloro-3- (2-chlorophenyl) -3-hydroxy-1-tosylindoline-2-carboxamide, cis isomer 1.5 g of the compound obtained in step B are refluxed for 24 hours in DCM, where is 900 mg DBU. Chromatograph on a silica gel column using DCM / AcOEt (95/5, v / v) as eluent. Recrystallize from isopropyl ether to give 190 mg of the desired product.

Sp. = 220 - 221 eC.

E) The compound of step B (1.0 g) is dissolved in acetonitrile (25 ml) and 109 mg of sodium hydroxide in 2 ml of water are added. The reaction mixture is heterogeneous, stirred vigorously at 45 ° C for 1 hour using a turbine and compressed air, either in the presence of 110 mg of benzyltriethylammonium chloride or without the addition of this reagent.

After extraction, the product obtained as a mixture of two isomers (cis and trans) is analyzed. The ratio of the two isomers detected in DMSO at 360 ° K NMR is 1/1.

Il! »T idit nm 45 97224

Example 108 N, N-Dimethyl-1- (4-allyloxyphenylsulfonyl) -5-chloro-3- (2-chlorophenyl) -3-hydroxyindoline-2-carboxamide, cis-isomer 5 A) Sodium 4-allyloxyphenylsulfonate 30 g of sodium phenylsulfonate are dissolved in 60 ml of ethanol and 50 ml of 15% sodium hydroxide, 20 g of allyl bromide are added and the mixture is refluxed for 48 hours. The ethanol is evaporated and the precipitate obtained is filtered off, then the precipitate is dried in vacuo in the presence of phosphoric anhydride. 23.3 g of the expected product are obtained.

B) 4-Allyloxyphenylsulfonyl chloride

The product from the previous step (23.3 g) is treated with 24 g of phosphorus pentachloride overnight at reflux in 300 ml of DCM. The reaction medium is filtered and evaporated to give an oil (16.5 g).

C) 2- [N- (4-Allyloxyphenylsulfonyl) amido] -2,2,5-dichlorobenzophenone

The sulfonyl chloride obtained in the previous step is added to 19 g of 2 ', 5-dichloro-2-aminobenzophenone in 100 ml of pyridine. The mixture is kept overnight at room temperature, the pyridine is evaporated, the residue is taken up in aqueous hydrogen chloride solution, extracted with DCM, dried and evaporated. The crude product is chromatographed on silica gel, eluting with a DCM / pentane mixture (50/50, v / v) the desired product, which is recrystallized from a DCM / iPr ether mixture. 8.5 g of the expected product are obtained.

Sp. = 96-97 ° C.

D) 2- [N- (4-allyloxyphenylsulfonyl) -N- (N ', N'-30 dimethylcarbamoylmethyl) amino] -2 * 5-dichlorobenzophenone 4 g of the product obtained in the previous step are dissolved in 20 ml of DMF under a nitrogen atmosphere. , 310 mg of 80% sodium hydride are added, the mixture is stirred for 15 minutes at room temperature and then 3.1 g of bromo-N, N-46 97224 dimethylacetamide are added. The mixture is kept overnight at room temperature, then poured into water, the product is filtered, taken up in DCM, dried and evaporated and then crystallized from a mixture of DCM / iPr ether to give 5 g of the desired product, which is finally recrystallized from the same solvent mixture.

Sp. - 133 - 135 ° C.

E) N, N-Dimethyl-1- (4-allyloxyphenylsulfonyl) -5-chloro-3- (2-chlorophenyl) -3-hydroxyindoline-2-10 carboxamide, cis isomer 3.8 g in the previous step the product obtained is treated at 30 [deg.] C. with 1.8 g of DBU in 20 ml of DCM for 3 days. The reaction mixture is chromatographed on alumina, eluting with DCM a less polar compound which is recrystallized from a DCM / iPr ether mixture. The yield is m = 840 mg.

Sp. = 181-182 ° C.

Example 109 N-Benzyl-N-methyl-5-chloro-3- (2-chlorophenyl) -20 3-hydroxy-1- (3,4-dimethoxyphenylsulfonyl) indoline-2-carboxamide, cis-isomer A) N- methyl N-benzylbromoacetamide 10 g of bromoacetyl bromide dissolved in 20 ml of DCM are added at 0 ° C to a solution of 6 g of methylbenzylamine and 5 g of triethylamine in 50 ml of DCM. The mixture is kept overnight at room temperature, after which ether is added, the precipitate formed is filtered off and evaporated to give 12 g of crude compound.

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

t «Η I 4 Iti Utit ··: 47 97224 C) 2 ', 5-Dichloro-2- [N- (3,4-dimethoxyphenylsulfonyl) -N- (N'-methyl-N'-benzylcarbamoylmethyl) amine -no] benzophenone 5.5 g of the product described in step B are dissolved in 30 ml of DMF and treated with 400 mg of sodium hydride. After 15 minutes, 12 g of the brominated derivative prepared in step A are added and stirred at room temperature for 24 hours. The DMF is evaporated off, the residue is taken up in water, extracted with DCM, dried and evaporated. The crude product is chromatographed on silica gel, eluting with the desired product. m = 2.1 g

Sp. = 148 - 150 ° C.

D) N-Benzyl-N-methyl-5-chloro-3- (2-chlorophenyl) -3-hydroxy-1- (3,4-dimethoxyphenylsulfonyl) indoline-2-carboxamide, cis-isomer 2 , 1 g of the product obtained in the previous step is treated with 1 g of DBU in 20 ml of DCM for 3 days. The reaction mixture is poured onto an alumina column, whereupon the less polar isomer (870 mg) elutes with DCM as an oil. After drying, a foam is obtained which is characterized by NMR.

2.81 ppm: s: 3H: N-CH3 3.60 ppm: m: 8H: 20CH3 + N-CH2-C6H5 5.35 ppm: s: 1H: CH (2-indoline) 6.20-7, 80 ppm: m: 16H: aromatic hydrogens + OH Examples 110 and 111 5-chloro-3- (2-chlorophenyl) -1- (3,4-dimethoxyphenylsulfonyl) -3-hydroxy-2-pyrrolidinocarbon-30-carbonylindoline, cis-isomer and trans-isomer This compound is prepared in a conventional manner by reacting pyrrolidine bromoacetamide with 2- (3,4-dimethoxyphenylsulfonamide) -2 ', 5-dichlorobenzophenone and then cyclizing the product obtained with DBU in chloro-35 form. One product 48 97224 DCM / AcOEt (90/10, v / v) is eluted on the alumina column; it is a cis-isomer.

Sp. = 237 ° C.

AcOEt elutes the trans isomer, which is then recrystallized from AcOEt.

Sp. = 230 ° C.

Example 112 5-Chloro-3- (2-chloro-phenyl) -1- (3,4-dimethoxy-phenylsulfonyl) -3-hydroxy-indoline-2-carbox-10-amide, Trans-Isomer A) 2 ', 5-Dichloro 2- (3,4-Dimethoxyphenylsulfonamido) benzophenone 114 g of 2-amino-5,2'-dichlorobenzophenone and 100 g of 3,4-dimethoxyphenylsulfonyl chloride are mixed with 15,300 ml. After stirring for 4 days at room temperature, the pyridine is evaporated, the residue is taken up in aqueous hydrogen chloride solution, extracted with DCM, dried and evaporated. The product obtained then crystallizes from a DCM / iPr ether mixture.

20 m - 181 g

Sp. = 159-161 ° C.

B) 2 ', 5-Dichloro-2- [N- (3,4-dimethoxyphenylsulfonyl) -N-benzyloxycarbonylmethyl] aminobenzophenone 172 g of the product prepared above are dissolved in 25,800 ml of DCM and cooled to 0 ° C. . Gradually 11.7 g of 80% sodium dyride are added under a nitrogen atmosphere and then, after 30 minutes, 256 g of benzyl bromoacetate are added and the mixture is stirred for 24 hours at room temperature. The DMF is evaporated off, the residue is taken up in water, extracted with DCM, dried and evaporated. The desired product is crystallized from isopropyl ether and then recrystallized from DCM / iPr ether.

m = 136.5 g

Sp. = 102-104 ° C.

49 97224 C) Benzyl 5-chloro-3- (2-chlorophenyl) -1- (3,4-dimethoxyphenylsulfonyl) -3-hydroxyindoline-2-carboxylate, trans isomer 3 g of the product obtained in the previous step are treated -5 to 740 mg of TBD in 20 ml of DCM at room temperature for 1 hour. The reaction mixture is chromatographed on silica gel, eluting with DCM the desired product as the trans isomer, which is the only isomer formed in the cyclization reaction.

The resulting compound is recrystallized from DCM / iPr-ether-10.

m = 2 g

Sp. = 190-192 ° C.

D) 5-Chloro-3- (2-chlorophenyl) -1- (3,4-dimethoxyphenylsulfonyl) -3-hydroxyindoline-2-carboxylic acid, trans isomer

The benzyl ester obtained in the previous step is treated with hydrogen in 50 ml of AcOEtra containing 100 mg of 10% Pd / C for 30 minutes. The reaction mixture is filtered through Celite R, washed with hot methanol and evaporated. 20 The desired product is crystallized from a DCM / iPr ether mixture.

m = 1.5 g

Sp. = 218-221 ° C.

E) 5-Chloro-3- (2-chlorophenyl) -1- (3,4-dimethoxyphenylsulfonyl) -3-hydroxyindoline-2-carboxamide, trans isomer 180 mg of the compound obtained in the previous step in 15 ml: DCM is treated with 140 mg of BPO, with a sufficient amount of DIPEA to dissolve the acid. After 15 minutes, gaseous ammonia is introduced into the mixture for 10 minutes. The reaction mixture is poured into saturated sodium hydrogen carbonate solution, extracted, dried and then evaporated. The crude product is chromatographed on silica gel using a DCM / AcOEt mixture (80/20, v / v) as eluent to give the desired compound, which is then recrystallized from a DCM / iPr ether mixture.

50 97224 m> 63 mg

Sp. - 183 - 185 ° C.

Examples 113 and 114 N-isopentyl-5-chloro-3-cyclohexyl-3-hydroxy-5'-tosylindoline-2-carboxamide, cis isomer and trans isomer A) 2- (N-tosyl) amino-5 -chlorophenylcyclohexyl ketone is prepared by a conventional method.

B) 2- [N- (N'-Isopentyl) carbamoylmethyl-N-tosyl] amino-5-chlorophenylcyclohexyl ketone 7.2 g of the compound obtained above are cooled in 130 ml of DMF to 0 [deg.] C. and placed under an argon atmosphere. , 1.1 equivalents of sodium hydride are added and the mixture is allowed to warm to room temperature. 15.2 g of N-isopentyl-2-bromoacetamide are then added and the mixture is stirred overnight at room temperature. The DMF is evaporated off, the residue is taken up in water, extracted with DCM, dried and evaporated. The crude product is chromatographed on silica gel using an ether / pentane mixture (70/30, v / v) as eluent.

C) N-Isopentyl-5-chloro-3-cyclohexyl-3-hydroxy-1-tosylindoline-2-carboxamide, mixture of isomers To 3 g of the product obtained above in 50 ml of anhydrous THF is added - At 20 ° C, 2.1 equivalents of LDA, then the temperature is maintained at + 4 ° C for 30 minutes. The reaction mixture is poured into saturated ammonium chloride solution, extracted, dried and evaporated. Chromatography on silica gel eluting with methylene chloride gives the desired product as a mixture of two isomers.

m = 2 g.

D) N-Isopentyl-5-chloro-3-cyclohexyl-3-trimethylsilyloxy-1-tosylindoline-2-carboxamide 1 g of the product obtained above is heated to 100 [deg.] C. under an argon atmosphere in 5 g of HMDS, containing 0.1 g of imidazole for 12 hours. The reaction medium is evaporated, the residue is taken up in DCM and chromatographed on silica gel. DCM elutes successively the weaker polar isomer, which is recrystallized from iPr ether; m = 345 mg m.p. - 137 - 138 ° C, 5 and then the more polar isomer. This recrystallization is from iPr ether; m = 165 mg m.p. = 175-176 ° C.

E) Nisopentyl-5-chloro-3-cyclohexyl-3-hydroxy-1-tosylindoline-2-carboxamide, cis isomer 150 mg of the less polar isomer obtained above is treated with 10 mg of sodium hydroxide at 0 ° C: in 5 ml of THF and 2 ml of water for 3 hours. The mixture is taken up in water, extracted with DCM, dried and evaporated. The crude product 15 is recrystallized from a DCM / iPr ether mixture.

m = 120 mg M.p. = 189-191 ° C.

F) N-Isopentyl-5-chloro-3-cyclohexyl-3-hydroxy-1-tosyl-indoline-2-carboxamide, trans isomer 150 mg of the more polar isomer obtained in step D are treated with 10 mg of sodium hydroxide in 5 ml of: in THF and 2 ml of water for 2 hours at room temperature. The mixture is taken up in water, extracted with DCM, dried and evaporated. The desired product is crystallized from a DCM / iPr ether mixture.

.25 m = 65 mg

Sp. = 195-196 ° C.

Following the procedure described in the previous examples, the compounds of the invention described in Table 2 below were prepared.

30 4 52 97224

Table 2 • \ SO2 R7 S> p '

10 V

For each compound of formula (I) having the substituents R 1 # R 2 and R 5 given in the following table, the cis isomer is shown first, then the trans isomer, unless otherwise stated.

15

., * 6 Sp. * C

Κ · 1 ·. R2 Crystallized solvent 20 115 5-C1 2-Cl-phenyl 3,4-dimethylBi N (CH3) 2 201 DCM / IPr-ether 116 222 DCM / IPr-ether 25 117 5-C1-cyclohexyl 4-CH3 NHCH2 224-225 DMC / iPr- * ether 118 141 - 148 30 DCM / IPr-ether 119 5-C1 2-Cl-phenyl 3,4-dimethoxy NHCH3 148 trans »DCM / IPr-ether 35 120 5-C1 2-F-phenyl 3,4- dlmetokel N (CH3) 2 165 DCM / IPr-ether 121 214 DCM / IPr-ether 40 122 5-C1 2-Cl-phenyl 2,5-dimethoxy N (CH3) 2 140 - 142 cl · DCM / IPr-ether 123 5- C1-2-Cl-phenyl 4-methocene N (CH3) 2,240 45 DCM / hexenyl 124,187 DCM / hexane 50 125 5-C1-2-Cl-phenyl 3,4-dimethocene H (CH2CH3) 2,213 hexene / 1Pr-etherl 126,200 hexane / iPr ether 5 53 97224

^, * 6 Sp. * C

XAL>. H2 (R 'j) _ "- Crystallized · - TLj solvent 127 5-Cl2-Cl-phenyl 3,4-dimethocyano N (CK3) -CH2 125-130 -CH2-CH6H5 hexane / iPr ether 128 140 - 142

10 DCM / iPr-eetterX

129 5-Cl 2-Cl-phenyl 2,4-dimethocaine N (CH 3) 2,213 130 206 15 131 5-Cl 2-methocaiphenyl 2,4-dimethocaine N (CH 3) 2 205 hexane / iPr ether 132 206 20 hexane / 1Pr -etherl 133 5-CH3 2-Cl-phenyl 3,4-dimethoxy N (CH2CH3) 2,189 iPr-ether 25 134 191 iPr-ether 135 5-CH, 2-Cl-phenyl 2,4-dimethoxy N (CH, CH, ), 208-209 1Pr-ether 30 136 214 - 215 iPr-ether1 137 5-Cl 2 -Cl-phenyl 2,4-dimethocaine N (CH, CH 2), 225 35 2 3 138 200 139 5-Cl 2- Cl-phenyl 4-cyano NfCH 2 242-243

THF, EtOH

40 140 228 - 231 DCM / iPr ether 141 5-Cl 2 -Cl-phenyl 3,4-dimethoxy N (C 4 H 9) 2 203 45 cis DCM / iPr ether 142 5-Cl acyclohexyl 3,4-dimethoxy NtCH 2 Cl 2 120

• 143 RMN

50 144 5-Cl 2 -F-phenyl 4-nitro »(CH 3) 2 230 cia 1 2 3 4 5 6. »NMR spectrum 2

Example 143: trans isomer 3 0.2-1.8 ppm: m: 17H: 2CH3 (ethyl) 11H cyclohexyl 4: 2.8-3.5 ppm: m: 4H: N- (CH2) 2-5 3.7 ppm: s: 3H: OCH3 δ 3.75 ppm: s: 3H: OCH3 4.7 ppm: s: 1H: H (indoline) 54,97224

Examples 145 and 146

Methyl 5-chloro-3- (2-chlorophenyl) -3-hydroxy-1-tosylindoline-2-carboxylate, dextrorotatory cis-isomer, dextrorotatory cis-isomer 5 Methyl-5-chloro described in Example 48 of Table 1 The optical isomers of 3- (2-chlorophenyl) -3-hydroxy-1-tosylindoline-2-carboxylate were separated by preparative chromatography on a chiral column.

The product of Example 48 is first subjected to analytical chromatography in supercritical phase.

The column used is Chiralcel 0DR marketed by DAICEL. This column consists of silica gel coated with cellulose carbamate.

The eluent is a mixture of carbon dioxide / 2-propanol / di-15 ethylamine (75/25 / 0.3, v / v / v) used at a rate of 2 ml / min. The outlet pressure is 160 atm, the temperature is 32 ° C and the UV detection is performed at 226 nm.

The chromatogram contains two peaks of equal area with residence times of about 4 minutes and 5.4 minutes.

Preparative chromatography also uses a Chiralgel® column.

A sample of the product to be chromatographed is dissolved in methanol (30 mg / ml) and 1 ml of the solution is injected onto the column.

; The eluent is a mixture of hexane / 2-propanol (80/20, v / v) used at a rate of 1.5 ml / min. UV detection is performed at 226 nm. The analysis time is 45 minutes. 12 fractions are collected and analyzed in the supercritical phase.

30 An injection of 13 to 30 mg is then performed under the same conditions. Fractions corresponding to the first peak collected between 16 and 24 minutes are pooled and fractions corresponding to the second peak collected between 29 and 42 minutes are pooled. After passing both batches through a stream of 55,97224 nitrogen, each is recrystallized from a DCM / iPr ether / hexane mixture.

The first peak gives a product with a chromatographic purity of more than 99.9%, it is the dextrorotatory 5 cis isomer.

a “= +236 (chloroform)

Sp. = 174-177 ° C (recrystallized from DCM / hexane / iPr-ether). m = 130 mg.

10 The second peak gives a product with a chromatographic purity of more than 99.5%, the levorotatory cis isomer.

ajP = -238 (chloroform)

Sp. = 174-177 ° C (recrystallized from DCM / hexane / iPr ether). m = 83 mg.

Claims (9)

56 97224 A process for the preparation of therapeutically useful N-sulfonylindoline derivatives of formula (I) and their salts, wherein R x is a halogen atom, C 1-4 alkyl, C 1-4 alkoxy , a trifluoromethyl group, a nitro group or an amino group; R 2 is C 1-6 alkyl, C 3-7 cycloalkyl, or phenyl which is unsubstituted or substituted by one or more C 1-6 alkyl, C 1-4 alkoxy, halogen or trifluoromethyl groups; R 3 is a hydrogen atom or C 1-4 alkyl; R 4 is a carboxyl group, an alkoxycarbonyl group in which the alkyl group is a C 1-6 alkyl group, a benzyloxycarbonyl group or a carboxamide group of the formula CONR 6 R 7; R 5 is C 1-4 alkyl, 1-naphthyl, 2-naphthyl, phenyl which is unsubstituted or substituted by one or more substituents selected from halogen atom, C 1-4 alkyl, trifluoromethyl group, nitro group, amino group, C 1-4 alkoxy , C 1-4 alkenyloxy, trifluoromethoxy group, benzyloxy group and cyano group; R 6 and R 7 each independently represent hydrogen, C 1-6 alkyl, phenylalkyl wherein alkyl is C 1-4 alkyl, or R 6 and R 7 together form a group - (CH 2) 4 -; 35. is 0 or 1; and Il! lit1) I II! > t «« I '> 57 97224 «m is 0, 1 or 2; characterized in that a) a 2-aminophenone derivative of formula 5 / v "" "" 'Vy, 10 wherein Rx, R2 and n are as defined above, is reacted with a sulfonyl derivative of formula Hal-SOj- (CH2) a) b-R 5 (III) wherein Hal is halogen, preferably chlorine or bromine, and R 5 is as defined above, b) the compound thus obtained of formula (R 1) n -N 1 -NH I (IV) (CH 2) m R 5 is treated with a halogenated derivative of the formula Hal '- CH - R 3 (V) \ R 4 wherein Hal' is halogen, preferably bromine, and R 3 and R 4 are as defined above, c) the compound thus obtained has the formula 35 58 97224. COR2 (k.) Y ^ nc / 3 (vi) X / SO2 NyR4 5 (CH2) m R5 is cyclized in a basic medium to prepare a compound of formula (I), 10 d) optionally separating the cis- and trans-compounds of the compound of formula (I) isomers which may be converted into salts. Process for the preparation of a compound of formula (I) according to claim 1, characterized in that Rx is a chlorine or bromine atom or a methoxy group, n - 1 and the other substituents are as defined in claim 1 in connection with formula (I). Process for the preparation of a compound of formula (I) according to claim 1, characterized in that R 2 is methoxyphenyl, chlorophenyl or cyclohexyl and the other substituents are as defined in claim 1 in connection with formula (I). Process for the preparation of a compound of formula (I) according to claim 1, characterized in that R 3 is hydrogen and the other substituents are as defined in claim 1 in connection with formula (I). Process for the preparation of a compound of formula (I) according to Claim 1, characterized in that R 4 is alkoxycarbonyl, the alkyl group of which is C 1-8 alkyl, and the other substituents are as defined in claim 1 in connection with formula (I). Process for the preparation of a compound of formula (I) according to claim 1, characterized in that R 4 is a carboxamide group CONR 6 R 7, in which R 6 and R 7 are C 1-6 alkyl groups, and the other substituents are in claim 1. defined in connection with formula (I). Process for the preparation of a compound of formula (I) according to claim 1, characterized in that R 5 is phenyl substituted in the 3- and 4-positions or in the 2- and 4-positions by a methoxy group, or R 5 is phenyl substituted in the 4-position. position with a methyl group, and the other substituents are as defined in claim 1 in connection with formula (I). Process for the preparation of a compound of formula (I) according to claim 1, characterized in that m is 0 and the other substituents are as defined in claim 1 in connection with formula (1). Process for the preparation of a compound of formula 15 according to claim 1, characterized in that R 2 and R 4 are on the same side of the indoline ring. 60 97224