SK42693A3 - Indoline derivatives with amidic group - 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 indoline derivatives of the invention have an affinity for vasopressin and oxytocin receptors.

Vasopressin is a hormone. known to have an anti-diuretic and heat-regulating action. It stimulates several types of receptors - V1, V2. Via. Vib - and also has cardiovascular, central, hepatic, antidiuretic, emetic effects. aggregation as well as proliferation and mitotic. especially vascular and liver tissue. Vasopressin receptor antagonists may intervene to regulate central or peripheral circulation, particularly coronary, renal and gastric; as well as water metabolism and release

Cacth). Vasopressin receptors are also found on smooth adrenocorticotropic hormone as well as oxytocin, with uterine muscle. Oxytocin has a peptide-like structure, close to vasopressin. Its receptors also appear on myoepithelial cells of the mammary gland and in the central nervous system (Presse Médicale, 1987, 16 CIO),

481-485, J. Lab. Clin. Med., 1989, 114 (6), 617-632, and Pharmacol. Rev., 1991, 43 (1), 73-108).

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

The present invention provides compounds of formula I

R5 (I) wherein

R 1 represents a halogen atom. C 1 -C 4 alkyl, hydroxyl, C 1 -C 4 alkoxy, benzyloxy, cyano, trifluoromethyl, nitro or amino.

R 2 represents C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 5 -C 7 cycloalkene, phenyl, unsubstituted or substituted one or more times with C 1 -C 6 alkyl. C-alkoxyl group. halogen, trifluoromethyl, amino, or R 2 is nitrophenyl. unsubstituted or substituted once with trifluoromethyl. or one or more times with C 1 -C 6 alkyl or halogen,

R3 represents a hydrogen atom,

R <represents a carbamoyl group of the formula CONR6R7,

R 5 represents C 1 -C 6 alkyl, 1-naphthyl. 2-naphthyl, 5-dimethylamino-1-naphthyl, phenyl, unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, C 1 -C 6 alkyl. CF. amino, free or substituted by one or two C 1 -C 4 alkyl, hydroxyl. C 1 -C 4 alkoxy, C 2 -C 4 alkenoxy,

C 1 -C 4 alkylthio, tri fluoromethoxy, benzyloxy, cyano, carboxy. C 1 -C 4 alkoxycarbonyl, carbamoyl, free or substituted by one or two C 1 -C 4 alkyl, or C 1 -C 4 alkylamido, or R 5 is nitrophenyl, unsubstituted or substituted once with trifluoromethyl. or C 2 -C 4 alkenoxy or one or more times with halogen, C 1 -C 4 alkyl,

C1-C4alkoxy, C1-C4alkylthio, trifluoromethoxy. or benzyl,

R 6 represents C 1 -C 6 alkyl or is identical to R 7,

R 7 is 4-piperidyl, 3-azetidinyl optionally substituted on C 1 -C 4 alkyl, benzyloxycarbonyl, or C 1 -C 6 alkoxycarbonyl, (CH 2) r substituted with 2-, 3- or 4-pyrides group. hydroxyl, amine. free or substituted by one or two C 1 -C 4 alkyls, a carboxyl group, a C 1 -C 4 alkoxycarbonyl group, a benzyloxycarbonyl group. a carbamoyl group, free or substituted by one or two C 1 -C 4 alkyl.

or R 6 and R 7 together form with the nitrogen atom to which they are attached a heterocycle selected from morpholine, thiomorpholine, thiazolidine or 2,2-dimethylthiazolidine. unsubstituted or substituted by Re.

piperazine, unsubstituted or substituted at the 4-position with R 8.

an unsaturated five membered ring having one nitrogen atom, substituted with R e. or saturated triple. creature, five. a six. or a seven membered ring having one nitrogen atom, substituted with R e and R 9,

R e represents R e or a group (CH 2 -) which is substituted by hydroxyl or amino, free or substituted by one or two C 1 -C 6 alkyl,

R-8 represents a (CH 2) q group which is substituted by a carboxyl group. C 1-6 alkoxycarbonyl, benzyloxycarbonyl, carbamoyl, free or substituted by hydroxyl or one or two C 1 -C 4 alkyl, or aminocarbothioyl, free or substituted by one or two C 1 -C 4 alkyl,

R 18 represents R-8 or the group (CH 2) 2 NH 2. free or substituted by one or two C 1 -C 4 alkyl,

R 8 is hydrogen, halogen, (CH 2> r OR 10, (CH 2> r NR 11 R 12, <CH 2) _with CONR 11 R 11 azido).

R 10 represents hydrogen. C 1 -C 4 alkyl, mesyl or tosyl,

R 11, R 11 and R 12 each represent hydrogen or C 1 -C 2 alkyl or R 11 represents hydrogen and R 12 represents benzyloxycarbonyl or C 1 -C 4 alkoxycarbonyl, or 2, or 2 1, 2 and 1 or 3, or n is 0. m is 0. q represents 0, r represents 0 equal to 0 if R e or R 9 is nitrogen, with the restriction that r is not in the φ position to an intracyclic amide

1, s represents 0 or 1, and their possible salts.

acid, active acid.

Salts of the compounds of formula I according to the invention include salts with mineral or organic acids. which allow the preferred separation or crystallization of compounds of formula I, such as oxalic acid or some optically, for example mandelic acid or camphosulfonic acid, and which form pharmaceutically acceptable salts. such as hydrochloride, hydrogen sulfate. dihydrogen phosphate, methanesulfonate, maleate, fumarate, 2-naphthalenesulfonate.

Salts of the compounds of formula I also include salts with organic or mineral bases, for example alkali metal or alkaline earth metal salts such as sodium, potassium, calcium salts, with sodium and potassium salts, or with an amine such as trometamol, or arginine salts , lysine, or any pharmaceutically acceptable amine.

The compounds of formula I exhibit cis-trans isomers and isomers around the 2,3-indoline bond. Accordingly, various dies also fall within the scope of the invention.

According to the agreement, the cis isomers are called compounds of formula I. wherein R2 and R-4 are on the same side of the ring.

The trans isomers are, by agreement, called the compounds of formula I. wherein R 2 and R 4 are each on the opposite side of the ring.

cis isomer * 5

* 5 trans isomer

Further, the compounds of the invention have two or more asymmetric carbon atoms, since Ra contains 1 or 2 asymmetric carbons. The optical isomers of the compounds I are also part of the invention.

In the description and the following claims, halogen means a fluorine, chlorine, bromine or iodine atom: an alkyl group means a linear or branched hydrocarbon group.

Preferred compounds of the invention are those wherein at least one of the following conditions is met:

R 1 represents a chlorine, bromine or methoxy atom and n = 0.

- R2 represents chlorophenyl, methoxyphenyl or cyclohexyl,

- R-4 represents a group CONR6R7, where Re and R7 or NR6R7 correspond to one of the following definitions:

a pyrrolidino group substituted in which it is substituted with a carboxyl group

NR6R7 represents the 2-position with (CH2> h) or a carbamoyl group wherein q = 0, 1, 2 or 3,

NR 6 R 7 is at the 4-position with the amino group C 1 -C 4 d alkylamino,

NR6R7 represents <CH2> ci. which is piperidino. substituted C 1 -C 6 alkyl or thiazolidino, substituted with carboxyl or carbamoyl, wherein q = 0, 1, 2 or 3.

NR e R 7 is pyrrolidino. substituted at the 2-position with (CH 2) q. which is substituted with a carboxyl or carbamoyl group, wherein q = 0, 1, 2 or 3, and in the 4-position with amino, C 1 -C 4 dialkylamino.

R 6 represents C 1-10 alkyl and R 7 represents (CH 2) 1 -. which is substituted with a carboxyl or carbamoyl group, wherein r = 1, 2 or 3,

- R 5 is phenyl substituted at the 3- and 4-position or at the 2- and 4-position by methoxy, or R 5 is phenyl, substituted at the 4-position by methyl,

- m = 0.

Particularly preferred are compounds I in the form of the cis isomer.

The following abbreviations are used in the description and examples: DCM dichloromethane

AcOEt ethyl acetate

MeOH methanol

EtOH ethanol ether

DMF

THF

TEA

DMSO

DIPEA

DCC

DBU

TBD

DBN

DMA P

DMPU

TMEDA

LDA

HM P A

HOBT

BOP

TEA ethyl ether dimethylformamide tetrahydrofuran triethylamine dimethylsulfoxide diisopropylethylamine

N, N-dicyklohexy1karbodiimid

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

1,5,7-triazabiyklo [4.4.0] dec-5-ene

1,5-diazabicyclo [4.3,0] non-5-ene

4-dimethylaminopyridine

1,3-Dimethyl-2-oxohexahydropyrimidinone Tetramethylethylenediamino-thiimidopropylamide hexamethylphosphonate d

1-hydroxybenzotriazole hydrate hexafluorophosphate benzotriazolyloxytriamethylaminophosphonium trifluoroacetic acid

Lawesson agent 2,4-bis (4-metoxyfeny1) -l. 3-dithia-2,4-diphosphetane-2,4- -disulf id t. t. salt melting point solution water saturated with sodium chloride dry ice solid carbon dioxide TLC thin layer chromatography HPLC high performance liquid chromatography NMR nuclear magnetic resonance imaging with with i nglet m multiplet bs enhanced with inglet D doublet c hydrogen fluoride Water dilute hydrochloric acid, about 1 N 80% NaH dispersion of sodium hydride in mineral oil (Jansen Chemical) Me methyl Ee ethyl 1 i Pr ízopropy1 i Penty1 izopenty1 i Bu izobuty1 Bu t. butyl Bu butyl bz benzy1 ph phenyl TM room temperature

The present invention also relates to a process for the preparation of the compounds of formula (I). that

a) 2k-aminophenone derivative of formula II (Π), wherein R 1. R _{2 and} n are as defined above for formula I is reacted with a sulfonyl derivative of the formula III

Hal-SO ₂ - (CH ₂ > m -R 5 (III) wherein Hal represents halogen, preferably chlorine or bromine, and m and R 5 are as defined in formula I above,

b) to the compound of formula IV thus obtained

R ₅ (IV) is treated with a halogenated derivative of formula V

Hal - CH ₂ COA wherein Hal - represents halogen, preferably bromo, NR 6 R 2. or an OR group. wherein R is benzyl, (V) and A represents either is tert-butyl or

(c) optionally obtained when the ester of formula (VI) is a group

OR, get rid of as follows

(VI) under normal protecting group conditions,

d) optionally acid (VI) thus obtained in step c)

(VI) or its chlorine formula VI;

(VI) ·

R 1 operates by conventional amide coupling methods of HNR 6 R 7.

e) the compound obtained in step b) or d) of formula VI

_{(CH2) m} * 5 (VI) is cyclized in a basic medium the compound of formula I of the invention.

f) optionally resolving into the cis and trans isomers of Compound I and optionally resolving into the enantiomers.

The 2-aminophenone derivatives of formula II are known or are prepared by known methods, for example as described in A.K. Singh and d-. Synth. Commun. 1986, 16 (4), 485, and G. N. Valker, J. Org. Chem., 1962, 27, 1929. 2-Amino-2-trifluoromethylbenzophenones and other trifluoromethylated derivatives are prepared according to U.S. Patent 3,341,592.

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

The sulfonyl derivatives of formula III are known or are prepared by known methods. For example, 4-dimethylaminobenzenesulfonyl chloride is prepared according to C. N. Sukenika et al., J. Am. Chem. Soc., 1977, 99, 851-858, p-benzyl alkoxybenzenesulfonyl chloride is prepared according to European patent application EP 229 566.

Alkoxybenzenesulfonyl chloride is prepared from sodium alkoxybenzenesulfonate, which is obtained by the action of an alkyl halide on sodium hydroxybenzenesulfonate.

Halogenated derivatives of formula V are known or are prepared by known methods, for example according to A. I. Vogel, A Textbook 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 few hours to several days. Optionally, it is possible to work in the presence of dimethylaminopyridine, which is used in a catalytic or stoichiometric amount.

Process step b) proceeds between the sulfonamide of formula IV and the halogenated derivative of formula V in excess, in a solvent such as dimethylformamide or dimethylsulfoxide. in an inert atmosphere at a temperature of from 0 ° C to room temperature for a few hours to 24 hours in the presence of sodium hydride.

When -NR 6 R 7 contains a second amino group. i when R 6 or R 7 is substituted with an amino group. it is possible to use a halogenated derivative V of the formula Hal · -CH 2 -CO 2 R, where R is tert-butyl or benzyl. for the preparation of intermediates of formula (VI) and then VI. In this case, step c), where the acid of formula VI is formed, is carried out or by treatment with hydrogen in the presence of a catalyst such as palladium on carbon when R is benzyl, or in an acid medium such as R tert.-butyl, for example in the presence of TFA. or in the presence of hydrobromic acid in acetic acid, or in the presence of zinc bromide in DMC.

Step d) is then carried out under conventional amide condensation conditions, for example in the presence of BOP or HOBT and DCC.

The HNReRy compounds are known or are prepared by known methods. For example, the stereospecific synthesis of CR) and CS) of 2-pyrrolidinylacetic acid is carried out according to H. Rueger et al. in Heterocycles. 1982, 19 (9). 1677 using the proline derivative of the appropriate configuration. The preparation of N-Boc-methyl-3,4-dehydrol * prolineate is carried out according to J. R. Dormoy, Synthesis, 1982, 753. The preparation of optically pure pipecolic acid derivatives is described, for example, in Tetrahedron, 1992, 48 (3),

431-442, and Tetrahedron. 1991. 47 (C24). 4039-4062.

The preparation of aziridinecarboxylic acid derivatives is carried out according to K. Nakaji et al. in Bull. Chem. Soc. Jap., 51, 5 (5), 1978,

1577th

The step deprotonates carbonyl

e) of the process, the non-ethylene phenone group corresponds to the group in acting as an aldolization reaction: the amide position, then the internal electrophile, resulting in cyclization to form two asymmetric carbon atoms (C-).

The reaction can be illustrated by the following scheme:

r ₅ r ₅

The principles of aldol addition were summarized by CH Heathocock in Asymmetry Synthesis, Vol. 3 ^: Stereodifferentiating addition reactions, Part B, 111-112: Academic Press. 1984. JD Morrison ed.

It is known that the aldol reaction of anionic achiral amides leads to the formation of two racemic n-hydroxyamides in a ratio, d and t of the degree, of which depends on which under the great experimental conditions used. These include the nature of the mineral or organic base used, the nature of the cations or counterions, the possible presence of additives in the reaction medium, the solvent, the reaction temperature, and also the structure of the compound which is subject to the reaction.

As long as R 6 and R 7 do not contain an alkali-hydrolysable functional group, aqueous sodium hydroxide can be used in the presence of another solvent with or without the addition of a phase transfer catalyst: quaternary ammonium hydroxide can also be used. for example, benzyl tri methylammonium hydroxide in methanol.

It is also necessary to use an organic base, for example, to carry out this aldolization reaction

- guanidines such as 1,5,7-triazabicyclo [4.4.0] dec-5-ene, amidines such as 1,8-diazabicyclo [5.4.0] undec-5-ene, or

1,5-diazabicyclo [4.3.0] non-5-ene, solvent or solvent mixture. selected, for example, in benzene. THF. dichloromethane. methanol, dimethylformamide; the reaction is carried out in an inert atmosphere between -10 and 110 ° C; the amount of base used is at least stoichiometric: the reaction can also be carried out without solvent at the bath temperature.

Preferably, it is present in a solvent.

step e) of the process according to the invention is carried out

1,8-diazabicyclo [5.4.0] undec-5-ene, such as dichloromethane or methanol, at (DBU) a temperature between -10 ° C and the reflux temperature of the solvent.

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

The alcoholate is used in a catalytic or stoichiometric amount in an anhydrous solvent such as an alcohol (optionally in the presence of another solvent such as THF) or in a stoichiometric amount in THF, DMF or DMSO, optionally in the presence of crown ethers such as dicyclohexyl-18 6-ether: reaction proceeds between -15 and 80 ° C.

Use of an RR-NLi or RR-NMgBr type amide. wherein R and R 1 are monovalent residues as deprotonating agent as a method of formation of amide enolates. which are intermediate products of the aldolization reaction: this method was recently summarized by R. E. Irelandotc

1991, 56, 650

Additional agents such as LiBu, TMEDA, DMPU, HMPA or Crown Chem. Soc. Commun., 1990, 1657). Akc et al., J. Org. Chem. be benzene, hexane in an inert LiF atmosphere. LiCl, LiBr, Lil (M. Murakata et al.

for example, the use of lithium diisopropylamide between -78 and -30 ° C in anhydrous THF in an inert atmosphere or THF in the presence of additives such as tetramethylenediamine, DMPU or HMPA. Other known and useful amides are, for example, lithium cyclohexylamide and lithium 2,2,6,6-tetramethylcyclohexylamide. It is also possible to prepare further amides by treating the linear or cyclic secondary amines with the necessary amount of butyl lithium in hexane, the reaction being carried out in one of the solvents mentioned above.

Finally, various publications describe amides of optically active Soc. Chim., 1980, secondary amines 45, 755: M-Murakata 1657; M. Yamaguchi,

L. Duhamel et al., Bulla d. J. Chem. Soc. Chem. Commun., 1990, Tetrahedron Lett., 1986, 27 (8). 959; P. J.

Cox and N.S. Simpkins, Tetrahedron · Asymmetry, 1991, 2 Cl), 1.

Lithium, sodium or potassium silylamides constitute another class of useful bases, among which <Me ₃ Si ₁₂ NLi. (Me2PhSi) 2NLi. CEt ₃ Si) 2NLi, CMe ^ i ^ NL, CMe ₃ Si) ₂ NNa.

It is also possible to use mixed amides as described by Y. Yamamot, Tetrahedron, 1990, 46, 4563, for example, the lithium salt of (trimethylsilyl) benzylamine or the analogy in which the benzylamine is replaced by a primary chiral amine. such as (R) or C 5-6 -amethylbenzylamino.

If the compound of formula (I) to be prepared contains two asymmetric carbon atoms, the cyclization step c) may be accompanied by enrichment of the di-stereoisomers and the formation of these di-stereoisomers may be modified by use of a suitable chiral base.

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

Optionally, the optical isomers of the individual cis and trans isomers are then separated, for example by preparative chromatography on a chiral colony, followed by optionally fractional crystallization or formation of an optically active salt in the presence of a suitably selected chiral acid or base.

If the compound of the invention has two asymmetric carbon atoms, the enantiomers may be separated by chiral HPLC.

When a compound of the invention contains three or four asymmetric carbon atoms. diastereoisomers may be separated by chromatographic and fractional crystallization methods.

Several methods can be used to distinguish and characterize the cis and trans isomers of Compound (I). When R 3 is hydrogen, comparative high-field NMR (250 MHz) analysis is performed, for example associated with an Overhauser study (N.O.E.), for example, between an indoline proton (R 3 = H) and a hydroxyl proton.

The IR spectra of cis and trans isomers in solution in DCM are different. The cis isomer most commonly exhibits a strong thin and symmetrical absorption band of about 3550 to 3520 cm ^-1 due to the vibration of the hydroxyl, while the trans isomer has no resolvable vibration band in this region.

Based on the data collected, it was concluded that the cis isomer is generally most mobile in TLC on an alumina plate (60F254 neutral, type E, Merck) eluting with DCM containing a varying fraction of ÄcOEt. Similarly, in column chromatography on alumina (alumina 90, 0.063-0.200 mm granulometry), eluting with DCM containing a varying amount of AcOEt or MeOH most often elutes the cis isomer as the first.

Thus, the isomerism of cis or trans of compound 11 of the invention is most commonly possible to determine an analytical method. It is also possible to use an analogy between similar compounds or between compounds, one of which is prepared from the other.

f v;

The absolute configuration of certain compounds of the invention was determined by X-ray analysis. By deduction and with respect to the rotational value, the absolute configuration of the other compounds obtained in an analogous manner can also be ascertained.

Compound I, wherein R 1 is amino, and / or compound wherein R 5 is phenyl substituted with amino, can be prepared by catalytic hydrogenation of compound VI obtained in step b), wherein R 1 is nitro or R 5 is phenyl substituted with nitro, and the other substituents have the desired meanings for Compound I, for example in the presence of palladium on carbon, born on aluminum or Raney nickel.

Compounds I wherein R 6 or R 7 or NR 6 R 7 contains a C 1 -C 6 alkoxycarbonyl group make it possible to obtain the hydrolysis of the ester to obtain compounds I wherein R 6 or R 7 or NR 6 R 7 contains a carboxyl group and the other substituents of Compound I are unchanged. In addition, compounds wherein R 6 or R 7 or NR 6 R 7 contain a carboxyl group allow classical amide condensation to prepare compounds I wherein R 6 or R 7 or NR 6 R 7 contains a carbamoyl group, free or substituted by one or two C 1 -C 6 alkyl, and the other substituents are identical.

Finally, compounds I wherein R 6 or R 7 or NR 6 R 7 contains a carbamoyl group make it possible to prepare compounds of formula I wherein the R 6 or R 7 or NR 6 R y group contain an amino group and the other substituents are identical (J. Org. Chem., 1979, 44 (10)). , 1746).

The process for the preparation of compounds I, wherein R 6 or R 7 or the group NR 6 R 7 contains an amino group, free or substituted by two C 1 -C 4 alkyls, can therefore have two variants according to the invention:

i) step b) is carried out by treating compound IV obtained in step a) with a halogenated derivative V of the formula Hal - CH 2 CONR 6 R 7, wherein R 6 or R 7 or the NR 6 R 7 group obtained in step a).

an araino precursor, for example, carboxyester, carboxy or carbamoyl; then the cyclization step e) is carried out and then the araino precursor is converted to araine, for example the carboxyester group of the compound I thus obtained is hydrolyzed to a carboxy group which is then converted to a carbamoyl group and then to an amino group by Hormann rearrangement; . The compound of claim 1, wherein compound IV is treated with a halogenated derivative of formula V

Hal - CH 2 COOR, wherein R represents benzyl or tert-butyl; the ester of compound VI thus obtained is deprotected in an appropriate manner according to step c); then condensing with HNR 6 R 7, wherein the amino group R 6 or R 7 is optionally protected; the thus obtained compound VI is then cyclized according to step e) and optionally compound I is prepared wherein the amino group is free by removing the amine protecting groups.

Compounds (I) wherein R e or R 7 or NR e R 7 contains a benzyloxycarbonyl or alkoxycarbonyl group as the substituent of an araino group make it possible to prepare compounds I wherein the amino group is free and the other substituents are identical.

The compounds of formula VI useful as intermediate products for the preparation of the compounds I according to the invention are novel and form part of the invention. Compounds VIa and VI are also novel and form part of the invention.

The invention therefore also relates to compounds of formula 6

(6) * 5 wherein substituted one or more times

A represents a group selected from NR6R7, OH, OtBu, OBz R1 represents a halogen atom, C1-C4alkyl. hydroxyl, C 1 -C 4 alkoxy, benzyloxy, cyano, trifluoromethyl. nitro or amino,

R 2 represents C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 5 -C 7 cycloalkene. phenyl, unsubstituted or substituted one or more times with C 1 -C 4 alkyl. C 1 -C 10 alkoxy, halogen, trifluoromethyl, amino, or R 2 is nitrophenyl. unsubstituted or trifluoromethyl or once

C1-Oialkyl, C1-Oialkoxy or halogen,

R 5 represents C 1 -C 4 alkyl, 1-naphthyl, 2-naphthyl, 5-dimethylamino-1-naphthyl, phenyl. unsubstituted or substituted by one or more substituents selected from the group consisting of halogen. C 1 -C 4 alkyl, trifluoromethyl. amino, free or substituted by one or two C 1 -C 4 alkylamino, hydroxyl, C 1 -C 11 alkoxy, C 2 -C 4 alkenoxy, C 1 -C 6 alkylthio, trifluoromethoxy groups. benzyloxy. cyano, carboxy, C1-C4alkoxycarbonyl, carbamoyl, free or substituted by one or two C1-C4alkyl, or C1-C4alkylamido, or R5 is nitrophenyl, unsubstituted or substituted once by trifluoromethyl, or C2-04alkenoxy or once or C2-04alkenoxy; halogen, C 1 -C 6 alkyl, C 1 -C 4 alkoxy, C 1 -C 6 alkylthio, trifluoromethoxy or benzyloxy.

R 6 represents C 1 -C 6 alkyl or similar to R 7,

R 7 is 4-piperidyl, 3-azetidinyl, optionally substituted on nitrogen with C 1 -C 4 alkyl. benzyloxycarbonyl or C 1 -C 4 alkoxycarbonyl, a <CH 2) r group which is substituted by a 2-, 3- or 4-pyridyl group, a hydroxyl group, an amino group, free or substituted by one or two C 1 -C 4 alkyl, carboxyl, C 1-6 alkyl A C 1-4 alkoxycarbonyl group, a benzyloxycarbonyl group, a carbamoyl group, free or substituted by one or two C 1 -C 4 alkyl groups.

or R 8 and R 7 together form with the nitrogen atom to which they are attached a heterocycle. selected from the group consisting of: morpholine. thioraorpholine, thiazolidine or 2,2-diethylthiazolidinone; unsubstituted or substituted by Re.

piperazine, unsubstituted or substituted in the 4-position by R‘‘8.

an unsaturated five membered ring having one nitrogen atom, substituted with R e. or a saturated three-, four-, five-, six- or seven-membered ring having one nitrogen atom, substituted with R e and R g,

R e represents R-8 or a group CClc. which is substituted by hydroxyl or amino, free or substituted by one or two C 1 -C 6 alkyl,

R * 8 represents a CCH2) q group which is substituted by a carboxyl group, a C1-Cialkoxacarbonyl group, a benzyloxycarbonyl group, a carbamoyl group, free or substituted by hydroxyl or by one or two C1-C6alkyl, or an aminocarbothioyl group, free or substituted by one or two Ci-C ^ alkyl,

R 8 represents R 8 or a group (CH 2> 2NH 2, free or substituted by one or two C 1 -C 4 alkyl,

R9 is hydrogen, halogen, (CH2) r-OR10, (CH2) t-NR11R12, (CH2SCONRuR-11), azido,

R 10 represents hydrogen, C 1 -C 4 alkyl, mesyl or tosyl,

R 11, R-11 and R 12 each represent hydrogen or C 1 -C 4 alkyl;

R 11 is hydrogen and R 12 is benzyloxycarbonyl 1 or C 1 -C 6 alkoxycarbonyl,

n is 0. 1 or 2. - m is 0, 1 or 2 q is 0, First 2 or 3, r is 0, 1 2 or 3, with the restriction that r is not equal 0. if Re is or  R9 in position φ to intracyclic amide nitrogen. with is 0 or 1.

According to another aspect of the invention, the compounds I are of the invention. wherein either R 7 or NR 6 R 7 contains a carboxyl group. suitable for the preparation of analogous decarboxylated compounds.

Accordingly, in this aspect, the invention provides the use of compounds of formula I-

_{(CH2) m} (I) "wherein R, R 2. R3. Rs. m and n are as defined above for the compounds of formula I.

Rvi represents C 1 -C 6 alkyl,

Rvn represents a group CCH 2 jr-COOH, wherein r = 1, 2 or 3, or Rvi and Rvii together with the nitrogen atom to which they are attached form a heterocycle selected from the group consisting of:

thiazolidine or 2.2 dimethylthiazolidine. substituted with CCH 2> qCOOH, piperazine. substituted at the 4-position with CCH2) n-C00H unsaturated five-membered ring with one nitrogen atom, substituted with (CH2> qC00H, saturated three-, four-, five-, six- or seven-membered one nitrogen-substituted ring ₎ where q = 0. 1, 2 or 3, for the preparation of a compound of formula I with the same configuration around the indoline 2.3 bond as the starting product (1)

(C ^H 2) _m where

R1, R2. Ra, R5, m and n are as defined above,

R-vi represents C 1 -C 6 alkyl,

R-v11 represents a group CClphe-H or R-vi and R-vn together with the nitrogen atom to which they are attached form a heterocycle selected from the group consisting of:

thiazolidine or 2.2 dimethylthiazolidine, substituted with CCH 2 qH.

piperazine, substituted at the 4-position with (CH2) qH, an unsaturated five membered ring with one nitrogen atom, substituted with (CH2) qH, a saturated three-, four-, six-, or seven-membered ring having one nitrogen atom, substituted with ( ClfejqH

The radical decarbocylation reaction is carried out according to D. H. R. Barton et al., 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. Biool, Chem., 1985. 260 (5), 2844-2851. This method consists in observing the displacement of tritiated vasopressin, fixed at the Vi sites of mouse liver membranes. The 50% inhibitory concentration (CCI50) of the compounds of the invention for the fixation of tritiated vasopressin are weak and reach up to 10 ^-9 M.

In addition, inhibition of platelet aggregation induced by vasopressin in human platelet-rich plasma (human PRP) was measured using the method described in Thrombosis Res-, 1987, 45, 7-16. The compounds of the invention inhibit aggregation induced by vasopressin concentrations of 50-100 nM, with weak DI50s (inhibitory doses) of up to 10 ^-9 M. These results demonstrate the antagonist activity of the compounds of the invention against the VI receptors.

The affinity of the compounds of the invention for V2 receptors was measured by the modified method of P. Crause et al., Molecular and Cellular Endocrinology, 1982, 28, 529-541.

Compounds of the invention having a cis configuration around the 2,3-indoline bond have significant selectivity for Vi receptors.

for the oxyLocin receptors of tritiated oxytocin, the preparation of glandular glands are weak and move

The affinity of the compounds of the invention was determined in vitro by displacement fed to membrane mouse receptors. CI50 values of compounds of the invention between 10 ^-5 and 10 ^-8 M.

The compounds of the invention are effective when administered in a variety of ways, particularly when administered orally.

No signs of toxicity are observed with these compounds at pharmacologically effective doses.

The compounds of the invention may be used in the treatment or prevention of various vasopressin-mediated conditions. in particular, cardiovascular disorders such as hyperenzia, cardiac insufficiency, thrombosis or coronary hypertension. especially in smokers; diseases of the central nervous system, for example, cecum and other endemas. psychiatric conditions, taste disturbances, memory disorders; renal system disorders such as renal vasospasm. renal cortex necrosis; damage to the stomach system, such as ulcers, or further, the syndrome of inappropriate anti-diuretic hormone secretion (SIADH).

The compounds of the invention may also be used as antiemetics, in particular in kinetosis, as well as antiproliferative agents, for example in cancer or arteriosclerosis.

In women, the compounds of the invention may further be used in the treatment of dysmenorrhea or premature labor.

The invention further provides pharmaceutical compositions comprising an effective dose of a compound of the invention, or a pharmaceutically acceptable salt, and suitable vehicles. These vehicles are selected according to the pharmaceutical form and the desired mode of administration.

In the pharmaceutical compositions of the invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical. by intratracheal, intranasal, transdermal or rectal administration, the active compounds of the above formula I or their possible salts can be administered in unit dosage form in admixture with conventional pharmaceutical carriers to animals and humans for the prophylaxis or treatment of the aforementioned conditions or diseases. Suitable unit dosage forms include forms for oral administration such as tablets, capsules, powders, granules and oral solutions or suspensions, forms for sublingual, buccal, intratracheal, intranasal, forms for subcutaneous, intramuscular or intravenous administration or forms for rectal administration. For topical application, the compounds of the invention may be used in creams, ointments or lotions.

In order to achieve the desired prophylactic or therapeutic effect, the dose of active ingredient may be between 0.01 and 50 mg per kg of body weight per day.

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

When preparing a solid composition in the form of tablets. the main active ingredient is mixed with a pharmaceutical vehicle such as gelatin. Starch, lactose, magnesium stearate. talc, gum arabic and the like. The tablets may be coated with sucrose, a cellulose derivative, or other suitable materials, or processed in such a manner. they have a prolonged or retarded activity and release a continuously determined amount of the active ingredient.

A capsule composition is prepared by mixing the active ingredient with a diluent and dispensing the resulting mixture into soft or hard capsules.

The preparation in the form of a syrup or elixir in the form of drops may contain an effective sweetener. preferably non-caloric, and propylparaban as an antiseptic, and further a flavor and with a suitable coloring agent or for administration of the substance in conjunction with methylparaban with the delivery agent

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

For rectal administration, lace is used which is prepared with binders melting at the rectal temperature, for example with cocoa butter or polyethylene glycols.

For parenteral administration, aqueous suspensions, isotonic saline solutions or sterile injectable solutions containing pharmacologically compatible dispersants or wetting agents, for example propylene glycol or butylene glycol, are used.

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

The compounds of the invention may contain, in addition to the products of formula (I) above, or a pharmaceutically acceptable salt thereof, other active ingredients which may be used in the treatment of the aforementioned conditions or diseases.

Accordingly, the present invention also provides pharmaceutical compositions comprising a combination of several active ingredients, one of which is a compound of the invention.

DETAILED DESCRIPTION OF THE INVENTION

In order to illustrate the invention, examples of practice are given.

The compounds are characterized by melting point - m.p. t. (or boiling point - b.p.) in ° C or NMR spectra, measured at 200 MHz in DMSO, or optical rotation ($ d). measured at 25 ° C (unless otherwise specified).

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

Unless otherwise indicated, the terms isomer cis or trans is meant that the isolated compound is a mixture of enantiomers of either the cis configuration or the trans configuration.

Optical purity of the compounds by liquid chromatography (HPLC).

detects high - efficiency

Example 1

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

A) Methyl N-bromoacetyl sarcosinate

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

B) 5-Bromo-2- (3,4-dimethoxyphenylsulfonamido) -2'-fluorobenzophenone

20 g of 2-amino-5-bromo-2-fluorobenzophenone are heated in 120 ml of dry pyridine at 85 DEG C. for 48 hours in the presence of 20 g of 3,4-dimethoxyphenylsulfonyl chloride. The mixture was cooled, poured into ice water, the solid was filtered, extracted with AcOEt. the organic phase is washed with water, 1N hydrochloric acid solution, water and then with aqueous brine. Drying over magnesium sulfate and evaporation of the solvent in vacuo gave a solid. which was recrystallized from DCM / isopropyl ether.

m = 28 g

mp MP 125-128 ° C.

CJ 5-bromo-2- [N- (3,4-dimethoxyphenylsulfonyl) -N- (N-methyl-N-methoxycarbonylcarbamoylmethyl)] amino-2-fluorobenzophenone

3.5 g of the compound prepared in step b) are dissolved in anhydrous DMF at 0 ° C under argon and 250 mg of 80¾ sodium hydride are added; after 15 min 4.85 g of the compound prepared in step a) are added and stirred for 12 h at room temperature. The reaction mixture is poured into water, the solid is filtered off, then dissolved in AcOEt, the organic phase is washed with water and then with brine and the solvent is evaporated off under vacuum. The oil obtained is filtered on silica eluting with DCM / AcOEt (85/15; v / v) and recrystallized from DCM / isopropyl ether / MeOH.

m = 3.2 g

mp MP 136-137 ° C

D) N-Methyl-N-methoxycarbonylmethyl-5-bromo-3- (2-fluorophenyl) -1-

- (3,4-Dimethoxyphenylsulfonyl) -3-hydroxy-2-indolinecarboxamides, cis isomer

3.2 g of the product obtained in the previous step are dissolved in 3 ml of DCM. Add 750 mg of DBU and stir at room temperature for 24 h. Pour the reaction mixture onto a silica column; eluting with DCM / AcOEt ¢ 90/10. v / v), a product is obtained which is a mixture of the two isomers (cis and trans) of the expected compound. This product was triturated in hexane isopropyl ether and the resulting solid was filtered off. The filtrates are chromatographed on an alumina column equilibrated with DCM / AcOEt <70/30; in / in). The least polar compound is eluted with DCM / AcOEt (60/40; v / v) and then recrystallized from DCM / hexane / isopropyl ether.

mp = 95 ° C with gas evolution

Examples 2 and 3

2- [C4-benzyloxycarbonyl) -1) piperazines] carbonyl-5-chloro-3- (2-chlorophenyl) -1- (3,4-dimethoxyphenylsulfonyl) -3-hydroxyindoline, cis isomer and isomer of irans

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

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

m = 9 g

mp M.p. = 100-101 ° C

B) 2 *, 5-Dichloro-2- (3,4-dimethoxyphenylsulfonamido) -benzophenone

5.6 g of 2-amino-2,5-dichlorobenzophenone and 5 g of 3,4-dimethoxyphenylsulfonyl chloride are heated at 100 [deg.] C. overnight in pyridine.

The pyridine is evaporated to dryness, water is added and extracted with ethyl acetate containing a small amount of DCM. After washing with water and drying over sodium sulfate, the mixture is evaporated under vacuum and recrystallized 7.7 g of the expected product from the mixture.

DCM / EtOAc.

mp Melting point = 164 DEG

C) 2-, 5-Dichloro-2- [N- (3,4-dimethoxyphenylsulfonyl) -N- (4-benzyloxycarbonyl-1-piperazinylcarbonylmethyl) amine-benzophenone

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

m = 2 g

mp MP 173-175 ° C

D) 2-1 (4-benzylocycarbonyl) -1-piperazinyl] carbonyl-5-chloro-3- (2-chlorophenyl) -1- (3,4-dimetoyphenylsulfonyl) -3-hydroxyindoline, cis and trans g isomers of the compound The residue obtained in the preceding step is suspended in 20 ml of methanol and 20 ml of THE and 75 mg of sodium methylate are added. After 2 h, the mixture was neutralized by the addition of a small amount of dry ice, concentrated to dryness and then taken up in water: then extracted with DCM. dried and thickened. The crude product is chromatographed on aluminum; DCM / AcOEt (80/20: v / v) eluted sequentially with the two isomers.

The least polar isomer is recrystallized with DCM / hexane. It is a cis isomer.

m = 262 mg, m.p. = 169-179 ° C with the mixture

The most polar isomer is recrystallized from the mixture

DCM / izopropy1éter.

m = 200 mg

mp MP 209-211 ° C

Example 4

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

200 mg of the cis isomer. prepared in the previous example, was dissolved in 10 ml of ethanol and 5 ml of THF and subjected to hydrogenolysis at room temperature in the presence of 10% Pd / C. After 30 min, filter the reaction mixture through Celite ^R , concentrate the filtrate and chromatograph on silica. The expected product was eluted with MeOH / DCM (10/90: v / v) and recrystallized from DCM / isopropyl ether m = 110 mg.

mp Mp = 230-233 ° C

Examples 5 and 6

5-chloro-3- (2-chlorophenyl) -1-3,4-dimethoxyphenylsulfonyl-3-hydroxy-2-morpholinocarbonyl indoline, cis and trans isomers

Al 2-, 5-dichloro-2- [N- (3,4-dimethoxyphenylsulfonyl-N-morpholinocarbonylmethyl) aminobenzophenone]

5 g of 2,5-dichloro-2- (3,4-dimethoxyphenylsulfonamidol-benzophenone) is treated with 350 mg of 80¾ sodium hydride in 30 ml of DMF at room temperature for 20 min. The reaction mixture is poured into water, the precipitate is filtered off, dissolved in DCM, dried and concentrated and the product is recrystallized from DCM / isopropyl ether to give 5.4 g.

mp MP 173-176 ° C

B) 5-chloro-3- (2-chlorophenyl) -1- (3,4-dimethoxyphenylsulfonyl) -3-hydroxy-2-morpholinocarbonylindoline, the cis g isomer of the product obtained in the preceding step is dissolved in a mixture of 10 ml of methanol and 20 mL of THF and treated with sodium methylate at room temperature for 1 h. The reaction mixture was neutralized with dry ice, the solvents were partially evaporated, the residue was taken up in water, extracted with DCM, dried, concentrated and chromatographed on alumina. The DCM / AcOEt (70/30: v / v) mixture eluted at least the polar isomer, which was recrystallized from DCM / isopropyl ether.

m = 215 mg; isomer cis m.p. MP 260-264 ° C

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

Chromatography in the previous step yielded a more polar product eluting with AcOEt / MeOH (90/10: v / v). Recrystallization from DCM / isopropyl ether gave ^: m - 513 mg: isomer trans mp = 240-241 ° C

Example 7

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

200 mg of the compound prepared in Example 1 are dissolved in 3 ml of MeOH and 1 ml of water containing 13 mg of sodium hydroxide. After stirring at room temperature for 24 h, one drop of concentrated sodium hydroxide was added to quench the reaction and then acidified to pH 3 by the addition of hydrogen sulfide solution. extracted with AcOEt, washed with water, magnesium and the solvent evaporated in vacuo.

The product obtained is recrystallized from DCM / isopropyl ether.

mp = 206-208 ° C for 15 min.

32 Examples 8 and 9

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

A) Ethyl N-bromoacetyl-4-piperidinecarboxylate

This product is prepared from commercially available ethyl 4-piperidinecarboxylate.

B) 2-, 5-Dichloro-2- [N-3,4-dimethoxyphenylsulfonyl) -N- (4-ethylcarboxylatepiperidinocarbonylmethyl)] aminobenzophenone g 2,5,5-dichloro-2 - (3,4-Dimethoxyphenylsulfonamido) -benzophenone was dissolved in 100 mL of DMF, then 541 mg of sodium hydride was added. After stirring for 30 min, 9.5 g of the compound from step A is added and stirred at room temperature for 18 h. The mixture was concentrated in vacuo, taken up in water, extracted with ethyl acetate, dried and concentrated. The oil obtained is chromatographed on silica eluting with AcOEt / DCM / hexane (40/10/50: v / v). The expected product crystallizes from ether.

m = 3.5 g m.p. Melting point = 128 DEG

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

A mixture containing 3.4 g of the compound prepared in the preceding step and 969 mg of DBU in 10 ml of chloroform. is heated to 60 ° C over 18 h. The reaction mixture was then filtered on an aluraine column eluting with DCM / AcOEt (90/10: v / v) to give the cis isomer.

m = 700 mg

mp = 110 ° C »

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

Examples 10 and 11

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

A) N- [2- (2-chlorophenylcarbonyl) -5-chlorophenyl] -N- (3,4-dimethoxyphenylsulfonyl) glycine

(a) 2-, 5-dichloro-2- (3,4-dimethoxyphenylsulfonamido) benzophenone

This compound was prepared in Example 2-3, step B.

b) 2, 5-Dichloro-2- [N- (3,4-dimethoxyphenylsulfonyl) -N-benzyloxycarbonylmethyl] aminobenzophenone

172 g of the above product were dissolved in 800 ml of DCM and cooled to 0 ° C. Under nitrogen, 11.7 g of 80% sodium hydride are added sequentially, and after 30 min, 256 g of benzyl bromoacetate are added and the mixture is stirred at room temperature for 24 h. The DMF was evaporated, the residue was taken up in water, extracted with DCM, dried and concentrated. The expected product crystallizes from isopropyl ether and is recrystallized from DCM / isopropyl ether.

m = 136.5 g m.p. MP 102-104 ° C

c) N- [2- (2-chlorophenylcarbonyl) -5-chlorophenyl] -N- (3,4-dimethoxyphenylsulfonyl) glycine g of the benzyl ester prepared in the previous step is dissolved in 500 ml of AcOEt and 2.5 g of 5¾ Pd are added under nitrogen. C. The solution is stirred vigorously and then hydrogen is bubbled through for 5 h After crystallization the product crystallizes, the reaction mixture is filtered through Celite ^R , the cake is washed abundantly with warm DCM and then the organic phase is concentrated. is then recrystallized from DCM / isopropyl ether.

m = 33.7 g

1.1. M.p. = 177-178 ° C

B) 2 ', 5-dichloro-2- [N- (3,4-dimethoxyphenylsulfonyl) -N- (N- (2- (2-pyridyl) ethyl) -N) - methyl j carbamoylmethyl] aminobenzophenone g of the acid prepared in step A is taken up in 30 ml of DCM and 1.13 g of 2- (2-methylaminoethyl) pyridine are added, followed by 844 mg of triethylamine and finally 1.92 g of BOP and then stirred for 18 h Then the mixture is taken up in water, the organic phase is decanted, washed with sodium carbonate solution, dried and concentrated, and after chromatography on silica, the expected product is eluted with DCM / MeOH (95/5; v / v).

m = 2 g

mp = 150 ° C

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

A mixture of 1.7 g of the product obtained in the preceding step and 442 mg of DBU in DCM was heated at 55 ° C for 18 h. The reaction mixture is chromatographed on aluminum. The EtOAc / DCM (40/60; v / v) mixture eluted with the isomer cism = 410 mg m.p. Melting point = 191 DEG

Pure AcOEt elutes the transm isomer = 790 mg m.p. = 154 ° C

Example 12

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

J v

35 500 mg of the cis isomer prepared in Example 9 is taken up in 5 ml of methanol in the presence of 48 mg of sodium hydroxide in 1 ml of water. After stirring for 18 h, the mixture was poured into water, acidified with dilute hydrochloric acid, extracted with DCM, dried and concentrated. The solid obtained is purified by chromatography on silica eluting with DCM / MeOH C95 / 5; in / in); then the product obtained is crystallized from DCM / isopropyl ether.

m = 250 mg of m.p. = 150 ° C

Examples 13 and 14

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

(n) 2 *, 5-dichloro-2- [N-C3,4-dimethoxyphenylsulfonyl] -N-N, N-methyl-N-methyl-4-piperidinyl) carbamoylmethyl] aminobenzophenone g acid, prepared in Example 10-11 step A in 650 ml of DCM is mixed with 650 mg of 4-methylamino-1-methylpiperidine in the presence of 1.90 g of BOP. After stirring at room temperature for 2 h, the organic phase is washed with carbonated water, dried and concentrated. Then the chromatograph is on silica eluting with DCM / MeOH C90 / 10; in / in). 1.2 g of the expected product are obtained.

mp Mp = 165-166 ° C

B) N-Methyl-N-methyl-4-piperidyl-5-chloro-3-C2-chlorophenyl) -1-C3,4-dimethoxyphenylsulfonyl) -3-hydroxy-2-indolinecarboximide isomer cis and trans isomer

650 mg of the product obtained in the preceding step are treated overnight with 100 mg of sodium methylate in 5 ml of methanol. Dry ice is added. the solvent is evaporated, the residue is taken up in carbonated water, extracted with DCM, dried and concentrated, then the product is chromatographed. Both isomers are eluted sequentially with methanol / DCM. Each is then recrystallized from DCM / isopropyl ether.

At least the polar trans isomer under the following conditions ^: m = 205 mg tt = 181 ° C isomer cis1.1. = 97 [deg.] C .; contains 0.25 M isopropyl ether

Examples 15 and 16

5-Chloro-3- (2-chlorophenyl) -1- (3,4-dimethoxyphenylsulfonyl) -3-hydroxy-2- [4-methyl-1-piperazinylcarbonyl] indoline isomer and trans isomer

A) 2-, 5-dichloro-2- [N- (3,4-dimethoxyphenylsulfonyl) -N - ((4-methyl-1-piperazinyl) carbamoylmethyl)] aminobenzophenone

This compound is obtained by treating the acid prepared in Example 10-11, step A, with N-methylpiperazine.

mp MP 165-167 ° C

B) 5-Chloro-3- (2-chlorophenyl) -1- (3,4-diraethoxyphenylsulfonyl) -3-hydroxy-2- [4-methyl-1-piperazinylcarbonyl] -indoline cis and trans isomers

The compound of the previous step was cyclized according to the procedure of Examples 12-13. The two isomers formed were separated by chromatography on alumina. The DCM / AcOEt (75/25; v / v) mixture elutes at least the polar product - isomer cis, which is recrystallized from DCM / isopropyl ether.

mp = 120 [deg.] C .; contains 0.25 M isopropyl ether.

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

mp Melting point = 189 DEG

Examples 17 and 18

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

A) N-Isopropyl-N- (methoxycarbonylethyl) bromoacetamide Isopropylamine is added dropwise to a solution of 130 g of methyl acrylate in 300 ml of methanol, cooled to -10 ° C. After 72 h at room temperature, the reaction mixture was evaporated and the residue was distilled. The oil obtained (< 168.3 g) is methyl-3- (N-isopropyl) aminopropionate.

bp = 73-78 ° C at 15 mm Hg

At 0 ° C, 29 g of the compound obtained in 100 ml of DCM is mixed with 20.2 g of bromoacetyl bromide in 1.00 ml of DCM. After 12 h at room temperature the solvent was evaporated and the residue was taken up in water. extract with ethyl acetate, dried and concentrated. The oil obtained is used as such in the next step.

B) 2-, 5-Dichloro-2-N- (3,4-dimethoxyphenylsulfonyl) -N- (N-isopropyl-N-methoxycarbonylethyl) carbamoylimethyl] amine benzenphenone

This compound is prepared by the usual laboratory procedure by treating the product obtained in Step A with 2-, 5-dichloro-2- (3,4-dimethoxyphenylsulfonamidol benzophenone) in the presence of sodium hydride.

mp = 135-137 ° C (recrystallization: DCM / isopropyl ether)

C) N-isopropyl-N-methoxycarbonylethyl-5-chloro-3- (2-chlorophenyl) -1- (3,4-dimethoxyphenylsulphonyl) -3-hydroxy-2-indolinecarboxamide isomer cis and trans isomer

This product is obtained by cyclizing the compound prepared by Input B in the presence of DBU. The cis isomer is separated by chromatography on alumina eluting with DCM / AcOEt <90/10;

in / in). The product is then crystallized from AcOEt / hexane. mp MP 153-155 ° C

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

mp MP 182-185 ° C

Examples 19 and 20

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

Both isomers of this compound were prepared according to the procedure of Example 1- separated by chromatography on alumina. The cis / isomer is eluted with DCM / AcOEt (80/20; v / v). This was crystallized from DCN / isopropyl ether as a white powder containing 0.25 mol of isopropyl ether. By heating under vacuum, it becomes foam. The NMR spectrum of the cis isomer (Example 19) is shown in FIG. First

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

mp = 176-178 [deg.] C .; The NMR spectrum of the trans isomer is shown in FIG. Second

Examples 21 and 22

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

These compounds are prepared individually from the compounds described in Examples 19 and 20, following the procedure described in Example 8. Isomer cis' 1.1. = 220-222 ° C after recrystallization from the mixture

DCM / isopropyl ether / MeOH isomer trans'-t. t. = 222-225 ° C after recrystallization from the mixture

DCM / isopropyl ether

Examples 23 and 24

N-Methyl-N-carbamoylmethyl-5-chloro-3- (2-chlorophenyl) -1- (3,4-diraethoxyphenylsulfonyl) -3-hydroxy-2-indolinecarboxamido cis and Lrans isomer

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

605 mg of the trans acid isomer 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 min at room temperature, 6 ml of 20% ammonia solution are added with vigorous stirring and the mixture is allowed to stir for 4 hours. Sodium carbonate solution was added followed by extraction with DCM. The organic phase is washed successively with water, sodium bisulfate solution, water, then dried over magnesium sulfate. After evaporation, the residue is chromatographed on silica gel and eluted with AcOEt / MeOH (95/5; v / v). The product obtained is crystallized twice from DCM / EtOH at 0 ° C.

1.1. Melting point = 236 DEG C .; The NMR spectrum of the trans isomer (Example 23) is shown in FIG. Third

The cis isomer was prepared by the same procedure. The expected product crystallizes from DCM / isopropyl ether. The micronized compound, dried under vacuum at 70 ° C for 8 h, contains 0.25 mol of isopropyl ether. The NMR spectrum of the cis isomer (Example 24) is shown in FIG. 4th

Examples 25 and 26

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

This compound was prepared from N- [2- (2-chlorophenylcarbonyl) -5-chlorophenyl] -N- (3,4-dimethoxyphenylsulfonyl) -glycine acid as described in Examples 11-12, step A.

The procedure of Example 11-12 is then followed to prepare 4-hydroxypiperidine in the presence of BOP and triethylamine. The product obtained is then cyclized in the usual manner in the presence of DBU. The individual isomers are separated by chromatography on alumina. DCM / MeOH <99/1; v / v) eluting the cis isomer.

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

The cis isomer is characterized by a 388 K NMR spectrum.

1-1.8 ppm: m: 4H.CH2 at positions 3 and 5 of piperidine

2.8- 3.65 ppm: m; 5H; CH2 at the 2- and 6- position of piperidine and CH at the 4-position

3.75 ppm2s-6H-20CH3

4.15 ppm: d: 1H: OH on piperidine

5.45 ppm - with 1H CH (indoline)

6.1 ppm ^; s ^: 1H ^: 0H indoline

6.8-7.6 ppm ^: m ^; 10H ^; armomatické H

DMSO-2.4 ppm

D0H: 2.75

DCM / MeOH <97/3; v / v) eluting the trans isomer, which was recrystallized from DCM / isopropyl ether.

mp Mp = 232-234 ° C

Syntheses in a series of (L) proline: Examples 27, 28, 29, 30.

Examples 27 and 27a

5-Chloro-3- (2-chlorophenyl) -1- (3,4-dimethoxyphenylsulfonyl) -3-hydroxy-2 - [(2S) - (2-methoxycarbonyl) pyrrolidinocarbonyl] indole cis-2 isomers of the compound )

A) (L) methyl 1-N- (bromoacetyl) prolinate

- 41 To a solution of 16.7 g of methylprolinate hydrochloride (L) in 20 ml of DCM is added simultaneously 20 g of triethylamine and 20 g of bromoacetyl bromide in 30 ml of DCM while maintaining the temperature at -5 ° C and then stirred at room temperature for 24 h. Water was added and the mixture was washed with KHSO-4 solution. water, sodium bicarbonate solution, water, then dried over magnesium sulfate. Evaporation gave an oil. which is dried under vacuum. This oil was pure by TLC. is used as such in the next step.

B) 2, 5-Dichloro-2- [N- (3,4-dimethoxyphenylsulfonyl) -N - ((2S) - (2-methoxycarbonyl) pyrrolidinocarbonylmethyl) aminobenzophenone

4.66 g of 2-, 5-dichloro-2- (3,4-dimethoxyphenylsulfonamido) -benzophenone were dissolved in 40 ml of anhydrous DMF under argon at 0 ° C. 340 mg of 80% sodium hydride are added followed by 6.5 g of the compound after 30 min. After 4 days at room temperature, the mixture was poured into water, extracted with AcOEt, washed with water, brine, dried over magnesium sulfate and evaporated in vacuo. A silica gel containing a small amount of the starting brominated derivative is chromatographed on silica gel eluting with DCM / AcOEt (85/15: v / v). A sample thereof is recrystallized from DCM / isopropyl ether.

m = 1.2 g

mp = 141-142 ° C (XD ²⁵ - -43.7 ° C c = 1: MeOH / THF ^: 8/2: v / v) analysis: calculated C 54.81%, H 4.44%, N 4, 41% found 54.40% 4.54% 4.55

C) 5-Chloro-3- (2-chlorophenyl) -1- (3,4-dimethoxyphenylsulfonyl) -3-hydroxy-2 - [(2S) - (2-methoxycarbonyl) pyrrolidinocarbonyl] indoline (cis isomerism)

In 4 ml of methylene chloride, 1.1 g of the compound obtained in the previous step, with an equivalent of DBU, was heated for 24 h. Analysis of the aliquot by HPLC shows the existence of 4 expected isomers. After 24 h, the reaction mixture is poured onto an alumina column, precibrated in DCM / AcOEt (90/10; v / v), and eluted with DCM / AcOEt (90/10; v / v, up to 70/30): in / in). 510 mg of a 4/1 mixture of at least polar compounds (measured by HPLC) are obtained.

1.) Two successive crystallizations in DCM / isopropyl ether in cold yield the title compound.

m = 180 mg

O (d ²⁵ = -247 ° (c = 0.4; chloroform) mp 187-190 ° C)

2.) The mother liquors from the crystallization of the preceding compound are chromatographed on alumina eluting with DCM / AcOEt (85/15: v / v). Thus, the preceding compound is separated from the next compound, which is dissolved in a minimum amount of DCM and precipitated by adding a minimum amount of hexane.

0 (d ²⁶ = + 136 ° (c = 0.24; chloroform)

Example 28

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

430 mg of the compound prepared in Example 27 are dissolved in 6 ml of methanol, 41 mg of sodium hydroxide in 1 ml of water are added and stirred for 24 h at room temperature. The mixture was acidified to pH with a few drops of potassium bisulfate solution and extracted with ethyl acetate. The extract was washed with water and dried over magnesium sulfate. Chromatography is carried out on a column of silica prepared in a DCM / pentane (80/20; v / v) mixture. Ester (compound of Example 27). who did not react. elute with DCM / AcOEt (70/30; v / v). AcOEt / MeOH (80/20; v / v) elutes the expected acid. which is then recrystallized from DCM / isopropyl ether.

mp Mp = 232-234 ° C

[Α] D ²⁶ = -254 ° (c = 0.3, chloroform)

Examples 29 and 29a r43

2- (2S) -2-carbamoylpyrrolidinocarbonyl) -5-chloro-3- (2-chlorophenyl) -1- (3,4-dimethoxyphenylsulfonyl) -3-hydroxyindoline cis-2 isomers of the compound

230 mg of the compound prepared in Example 28 was dissolved in 5 ml of DCM, 50 mg of DIPEA was added, followed by 165 mg of BOP and left at room temperature for 5 min. The mixture was cooled in an ice bath and ammonia gas was bubbled through for 1 min and then again for 1 min after 15 min. Water was added followed by a large volume of ethyl acetate to form 2 phases. The organic solution is washed with sodium carbonate solution, water, potassium hydrogen sulphate solution, water and brine. After drying, chromatography on silica eluting with DCM / MeOH <93/7; in / in). The product obtained was triturated in DCM / isopropyl ether / hexane. It contains 1/3 mol of isopropyl ether.

¢ (D ²⁶ = -189 ° (c = 0.23; chloroform)

The compound of Example 29 may be prepared by another method.

A) 2, 5-dichloro-2 [N- (3,4-dimethoxyphenylsulfonyl) -N- (2S) -2carbamoylpyrrolidinocarbonylmethyl) aminobenzophenone

33.9 g of the acid prepared in Examples 10 to 11, step A, are dissolved in 300 ml of chloroform. 15 g of thionyl chloride are added and the mixture is maintained at reflux temperature for 1 h. It is then evaporated to dryness, the residue is taken up in DCM and evaporated again. The mixture was taken up in 300 mL of DCM, cooled to 0 ° C, and 10.5 g of <L) prolinamide hydrochloride was added, then slowly adding the reaction mixture to not exceed 3 ° C, adding 18 g of DIPEA in 20 mL of DCM. . After leaving at room temperature overnight, the reaction mixture was washed with sodium bicarbonate (2 times) and then with potassium bicarbonate (2 times), then dried and concentrated. The crude product was dissolved in a minimum amount of DCM and added dropwise to isopropyl ether (<1.2 L) with stirring. After stirring for 2 h, the precipitate obtained is filtered and then dried at 60 ° C under vacuum for 6 h. Yield 42 g.

Φ _d 25 = -40.8 ° (c = 007, chloroform)

B) 2 - ((2S) -2-carbamoylpyrrolidinocarbonyl) -5-chloro-3- (2-chlorophenyl) -1- (3,4-dimethoxyphenylsulfonyl) -3-hydroxyindoline (cis-2 isomers of the compound) g of the product, prepared in the previous step, is dissolved in 50 ml of methanol. The mixture was cooled to -10 ° C and added

1.35 g DBU and the mixture was maintained at -10 ° C for 60 h. The compound crystallizes and is filtered off (compound cis 1). The mother liquors were neutralized with potassium bisulfate and the mixture was evaporated to dryness. The residue is taken up in water. extract 2 times with DCM, dried and concentrated. The crude product is chromatographed on silica eluting with cOEt / DCM (28/72; v / v). A mixture is obtained. which dissolves cold in a minimum amount of methanol; the insoluble matter is filtered off and the liquid is left overnight at -4 ° C; crystallizes compound cis 2. 4 m - 1.25 g

Q (θ25 - -196 o (c = 0.35i; chloroform)

Analysis by NMR shows the presence of 1 mol MeOH per mole of product. Recrystallization of the product from ethanol allows removal of the solvent in the crystals.

mp Mp = 154-162 ° C

D ²⁵ = -204 ° (c = 0.3; chloroform) d ²⁵ -131 ° <c = 0.27; chloroform / methanol 8/2; in / in)

This compound is. with the exception of the solvent, identical to the compound prepared by the first procedure of this example.

The compound which crystallized in step B) above, called the cis compound, was recrystallized from methanol.

mp Melting point = 190 DEG

C (d = + 115) (c = 0.3; chloroform)

Example 30

5-Chloro-3- (2-chlorophenyl) -1- (3,4-dimethoxyphenylsulfonyl) -3-hydroxy-2-1 (2S) -2- (hydroxymethyl) pyrrolidinocarbonyl] indoline isomers cis

A) 2-, 5-Dichloro-2-N- (3,4-dimethoxyphenylsulfonyl) -N- (2- (hydroxymethyl) pyrrolidinocarbonylmethyl) aminobenzophenone

This compound is obtained by treating (L) prolinol with the acid prepared in Examples 10-11, step A) in a conventional manner.

B) 5-Chloro-3- (2-chlorophenyl) -1- (3,4-dimethoxyphenylsulfonyl) -3-hydroxy-2 - [(2S) -2- (hydroxymethyl) pyrrolidinocarbonyl] indoline, cis isomer

1.5 g of the compound of the preceding step was cyclized in the presence of 380 mg of DBU in 2 mg of DCM. After 3 days at room temperature, 1 mL of DCM was added and then the mixture was heated at 40 ° C overnight. The formation of 3 major compounds (AcOEt eluent) is observed by TLC on silica.

Chromatography on silica elutes at least the polar fraction of DCM / AcOEt mixtures < 60/40 to 80/20; in / in). Chromatography on alumina is then performed, eluting with DCM / MeOH (99/1; v / v). The fraction obtained is homogeneous by TLC. The product was recrystallized 3 times from DCM / isopropyl ether. The expected product is obtained in an HPLC purity of> 99 m 155 mg

mp Mp = 194-197 ° C

D ²⁵ = -195H (c = 0.2; chloroform)

Syntheses in Proline (D): Example 31.

Example 31

5-Chloro-3- (2-chlorophenyl) -1- (3,4-dimethoxyphenylsulfonyl) -3-hydroxy-2-1 (2R) -2- (methoxycarbonyl) pyrrolidinocarbonyl] indoline isomer cis

A) 2-, 5-Dichloro-2- [N- (3,4-dimethoxyphenylsulfonyl-N - ((2R) -2- (methoxycarbonyl) pyrrolidinocarbonylmethyl) amine-benzophenone

This compound was obtained from the compound prepared in Examples 10-11 of Step A) (3 g) to which was added 1.2 g of (D) methylpropionate and 2.8 g of BOP in 10 mL of DCM in the presence of 1.15. g triethylamine. The mixture is left at room temperature for 1 h, then diluted with DCM, the organic phase is washed with sodium carbonate, potassium hydrogen sulphate, dried and concentrated. The crude product is chromatographed on silica eluting with DCM / AcOEt (95/5: v / v). The product obtained is then recrystallized from DCM / isopropyl ether.

mp = 140-141 ° C ΰζ d ²⁵ = +28.5 ° (c = 0.27; chloroform)

B) 5-chloro-3- (2-chlorophenyl) -1- (3,4-dimethoxyphenylsulfonyl) -3-hydroxy-2 - [(2R) -2- (methoxycarbonyl) pyrrolidinocarbonyl] indoline, cis isomer

1.5 g of the title compound was refluxed overnight in 5 ml of DCM in the presence of 360 mg of DBU. Alumina chromatography is then carried out. The DCM / AcOEt mixture (95/5: v / v) eluted at least the polar fraction (m = 300 mg), which was recrystallized twice with DCM / isopropyl ether. = 186-188 ° C ¢ ( _d 25 +2 +245 ° (c = 0.4: chloroform)

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

Examples 32 and 32a

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

A) 2-, 5-Dichloro-2- [N- (4-ethoxyphenylsulfonyl) -N-CN-methyl-N-methoxycarbonylmethyl) carbamoylmethyl] aminobenzophenone

5.7 g of 2,5,5-dichloro-2- (4-ethoxyphenylsulfonamido) benzophenone are dissolved in 40 ml of DMF under argon and 400 mg of 80% sodium hydride are added at 0 ° C; after 15 min, 4.3 g of methyl N- (bromoacetate Dsarcosinate) is added and after 48 h the expected product is extracted in the usual manner, which is then purified by chromatography on silica eluting with DCM / AcOEt (90/10; v / v) and recrystallized from DCM / isopropyl ether mixtures.

mp MP 158-160 ° C

B) N-Methyl-N-methoxycarbonylmethyl-5-chloro-3- (2-chlorophenyl) -1- (4-ethoxyphenylsulfonyl) -3-hydroxy-2-indinecarboxamide.

the trans g isomer of the compound obtained in the preceding step is dissolved in 4 ml of DCM and treated with 312 mg of TBD for 90 min at room temperature. Potassium bisulfate solution was added, the DCM was evaporated in vacuo, the mixture was extracted with AcOEt, the extract was washed and dried over magnesium sulfate.

Chromatography on silica gel eluting with DCM / AcOEt (90/10; v / v) yields the expected product.

m = 590 mg

mp = 168-171 ° C after recrystallization from DCM / hexane

C) N-Methyl-N-methoxycarbonylmethyl-5-chloro-3- (2-chlorophenyl) -1- (4-ethoxyphenylsulfonyl) -3-hydroxy-2-indolinecarboxamide.

isomer cis

2.96 g of the compound obtained in Step A are suspended in 20 ml of methanol and 10 ml of THE, 100 mg of sodium methylate are added, and the mixture is then left in the refrigerator for 7 h. Water was added, neutralized with potassium hydrogen sulphate solution and some of the methanol was evaporated in vacuo. After extraction of AcOEt, chromatography is performed on alumina and elution with DCM / AcOEt (80/20; v / v) mixtures. 850 mg of the expected product are obtained. which is recrystallized from the mixture

DCM / isopropyl ether. The NMR spectrum is shown in FIG. 6th

Intermediates VI for the synthesis of compounds of the invention are prepared by similar procedures. The prepared intermediates VI are shown in Table 1. The prepared compounds I are shown in Table 2.

Table 1

R ' R \ R: ies MP: (° C) or IR solvent Br 3,4-chjo F- CH ³ _{1-n-CH2 CO2 CH2 C6 H5,} 82-83 ¹ DCM / isopropyl ether Cl 3,4-chjo Cl CH, 1-n-ch ₂ ch _{2 and 2} ch ₃ 164-166 DCM / isopropyl ether Cl 3,4-chjo Cl CH, Et ³ 1 1 N-CH ₂ CH ₂ N Et 128 DCM / isopropyl ether Cl 3,4-CH ₃ O Cl Et 1 —n-ch ₂ ch ₂ co ₂ ch ₃ 105 DCM / isopropyl ether Cl 2,4-chjo Cl r ~ \ -_ _/ N-CO ₂ CH ₂ C ₆ H ₅ 142-143 MeOH CHjO- 3,4-CH Cl Et 1 —n-ch ₂ ch ₂ co ₂ ch ₃ IR (1) Cl 3,4-chjo Cl iPentyl 1 — n-ch ₂ ch ₂ co ₂ ch ₃ 85 isopropyl Br 3,4-chjo Cl Et 1 —n-ch ₂ ch ₂ co ₂ ch ₃ IR í 2)

Cl 3.4-chjo Cl - b / \ 199 DCM / isopropyl ether Cl 3,4-chjo Cl Pr 1 n-ch ₂ co ₂ ch ₃ 135 Isopropyl ether / DCM / flOH Cl 3,4-chjo Cl Pr 1 n-ch ₂ ch _{2 and 2} ch ₃ 1Í3 DCM / isopropyl ether Cl 3,4-chjo Cl Et - N - CH ₂ CO ₂ CH 3 160 isopropyl Cl 3,4-chjo Cl nQ> —NHCO ₂ - tBu 197-198 Cl 3,4-chjo Cl ' ^N CL CO ₂ CH ₂ C ₆ H ₅ (3)

IR (1) (DCM) 1740 cm ^-1 thin 1680 cm ^-1 wide

IR (2) (DCM) 1735 cm ^-1 thin

1660-1680 cm ^-1 double (3) compound is characterized by optical rotation: d ²⁵ '-36.8 ° (c = 0.44; chloroform)

Table 2

For each compound of formula I with R 1, R 5, R 2, and NR d R v, the cis isomer is shown in the table below, then the trans isomer, unless otherwise indicated.

- 52 Table 2

Example R '. R's R ¹ , Mp (° C) or NMR Solvent 33 34 Br 3,4-chjo F- CH ³ _{1-n-CH2 CO2 CH2} C ₆ 87-95 NMR 35 36 Cl 3,4-CH, 0 Cl CH ³ _{1-n-CH2 CH2 CO2 CH3} 100-103 154-157 DCM / isopropyl ether 37 cis Cl 3,4-CH, 0 Cl CH ³ _{1-n-CH2 CH2 CO2} hours 140-144 DCM / isopropyl ether 38 mixture Cl 3,4-CH3O Cl CH, Et ³ 1 1 N-CH ₂ CH ₂ N Et 222-225 DCM / isopropyl ether 39 40 Cl 3,4-chjo Cl Et 1 —n-ch ₂ ch ₂ co ₂ ch ₃ NMR NMR 41 C sharp C 3,4-chjo Cl Et 1 —n-ch ₂ ch ₂ co ₂ h 166 DCM / isopropyl ether 42 43 Cl 3,4 -CH, O Cl ΛΛ, ch ₃ —N) —N. \ _y ch ₃ 119 AcOEt / isopropyl ether 228 MeOH 44 C sharp Cl 3,4-chjo Cl ch ₂ c ₆ h ₅ i ^{2 6 3} _X CH, -N-CH, CH, N. ^{2 2} ch ₃ 179 DCM / isopropyl ether 5 46 Cl / 3,4-chjo Cl - N - N - CH ₂ CO ₂ Et 109 DCM / isopropyl ether 196 DCM / isopropyl ether 47 48 Cl 2,4-chjo Cl N-CO ₂ CH ₂ C ₆ H ₅ ; 134 (iPr) ₂ 0; 195 L DCM / isopropyl ether 49 C sharp Cl 3,4-CH, 0 Cl Et 1 —N-CH ₂ CH ₂ CONH ₂ 236 isopropyl 50 51 CH, 3,4-CH, O Cl Et 1 —n-ch ₂ ch ₂ co ₂ ch ₃ 154 isopropyl ether ⁸⁷ and isopropyl ether 52 C sharp Cl 2,4-chjo Cl / - \ - _ / N H 194 MeOH / isopropyl ether

53 C sharp Cl 3,4-CH3O Cl ipentyl 1-n-ch ₂ ch ₂ co ₂ ch ₃ 195 isopropyl ether / DCM 54 55 Br 2,4-chjo Cl Et 1 —n-ch ₂ ch ₂ co ₂ ch ₃ ; 138-140 isopropyl ether : 140 isopropyl 56 57 Cl 3,4-chjo Cl - b / \ in_/ 242-245 DCM / isopropyl ether 225th MeOH / isopropyl ether r 58 58 a Cl 2,4-chjo Cl - N (CH ₃ ) ₂ 228 MeOH / isopropyl ether 221 DCM / MeOH 59 59 a Cl 3,4-chjo C Et 1 —n-ch ₂ ch ₂ ch ₂ co ₂ ch ₃ 131-134 DCM / isopropyl ether / hexane ¹²¹ DCM / ether / hexane 60 61 Cl 3,4-chjo Cl iBu I n-ch ₂ ch ₂ co ₂ ch ₃ 162-166 DCM / isopropyl ether 130 DCM / isopropyl ether / hexane 62 63 Cl 3,4-chjo Cl Pr 1 —n-ch ₂ co ₂ ch ₃ 176 isopropyl ether / DCM IMR 64 65 Cl 3,4-chjo Cl Pr 1 —n-ch ₂ ch ₂ co ₂ ch ₃ ; 148 isopropyl ether / DCM 122 isopropyl ether / DCM 66 67 Cl 3,4-chjo Cl Et 1 n-ch ₂ co ₂ ch ₃ 1 NMR; 168 _; isopropyl 68 C sharp Cl 3,4-CH ₃ O Cl iBu 1 N - (CH ₂ ) ₂ CO ₂ H 179-182 DCM / isopropyl ether 69 C sharp Cl 3,4-chjo Cl Et 1 n-ch ₂ every ₂ h 139 DCM / isopropyl ether 70 C sharp Cl 3,4-chjo Cl Pr 1 n-ch ₂ every ₂ h 130 isopropyl 71 C sharp Cl 3,4-CH, O Cl Et 1 N - (CH ₂ ) ₃ CO ₂ H 136 DCM / isopropyl ether 72 C sharp Cl 3,4-CH, O Cl Et 1 n-ch ₂ —conh ₂ : 135 1 DCM / isopropyl

73 74 Cl 3,4-chjo Cl N -> NHCO ₂ C (CH ₃ ) ₃ 197 MeOH / isopropyl ether 211 MeOH 75 C sharp Cl 3,4-chjo Cl n ^> - nh ₂ NMR 76 C sharp Cl 3,4-chjo Cl NH, f uraarát 152-156 DCM / isopropyl ether 76a 76b Cl 3,4-chjo Cl -nd H : 137 : isopropyl ether (MeOH) - hexane • 183-185 hexane

Example 34 Analysis ^: Calculated C 55.54% Found 55.72%

H 4.24 N 3.93 S 4.57% 3.83%

NMR spectra at 200 MHz (DMSO: 2.5 ppm)

Example 34 ^: FIG. 5

- Example 38

0,7-1.1 ppm: m: 6 H: CH2 ₃ <Et)

2-4 ppm: ^m: 17H: 2 CH ₃ (Et). 2CH ₂ -N. N-CH _3, 20CH ₃

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

6.2-8.2 ppm: u.c.: 11h: 0H +

- Example 39

0.3-1.2 ppm: m: 3H: _CH3 (Et)

1.5- 4.3 ppm = m: 15H: CH2-C0 ₂ CH (Et) _CH2-N. 20C ₃ . C02CH ₃

Λ

5.2- 5.6 ppm: 3s: 1H.H (indoline)

6.2- 8.2 ppm ^: HH ^: OH + aromatic

- Example 40

0.8-1.1 ^ppm: m: ^3H: _CH3 (Et)

2.2- 3.9 ppm: m ·· 15HCH 2 CO. CH 2 (Et ₂ CH ₂ N, CO ₂ CH ₃ , 20 CH ₃₎

5.3- 5.7 ppm: 2s: 1H'-H (indoline)

6.6- 8.2 ppm: m: 11H ^: 0H + aromatic

- Example 63

0.4-1 ppm: doubled t: 3H-CH 2 -CH 2 -CH ₃ ppm: m: 2H: CH 2 -CH ₂ CH ₃

2.5- 4.4 ppm: trans: 13 H: CH ₂ CH ₂ CH _3, NCH ₂ COOCH _third 20CH ₃

5.2- 5.8 ppm ^: bs: 1H ^: H (indoline)

6.5-8.3 ppm: m: 11H: 0H + aromatic

Example 66 0-1.5 ppm: mC 3 H: CH 2 -CH

2.3- 5.8 ppm: m: 14H: _{CH2-CH third} NCH ₂ C00CH ₃ , 20CH ₃ . H (indoline) 6.1-8.3 ppm ^: m -1 · 11H: OH + aromatic

Example 75 1.95 ppm ^: bs ^: 2H ^; NH2

2.7-5.3 ppm: u.c.: 12H: 20CH3. 2NCH ₂ , H (indoline), CHNH ₂

6-8.3 ppm: m: 11H: OH + aromatic

- Example 76a o (d ²⁵ = ⁺ 102 ⁰ (c = 0.35; chloroform)

- Example 76b q (d ²⁵ = -158 ° (c = 0.2; chloroform)

Some of the compounds of the invention listed in Table 2 are suitable for the preparation of other compounds of the invention. For example, compound 41 is obtained from compound 39 by treatment with basic in methanol MeOH / IfeO. From compound 41 is prepared compound 49 by treatment with ammonia in the presence of DIPEÄ and BOP.

Example 77

N-ethyl-N- (2-aminoethyl) -5-chloro-3-C2-chlorophenyl) -1- (3,4-dimethoxyphenylsulfonyl) -3-hydroxy-2-indolinecarboxamido d isomer cis

500 mg of compound 49 was 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 stirring for two hours, the mixture is taken up in a hydrochloric acid solution. It was extracted with ether, basified with dilute sodium hydroxide, extracted with DCM and the extract was dried and concentrated. An oil is obtained, the expected product is then crystallized from ether.

m = 150 mg of m.p. Melting point = 164 DEG

Example 78

N-ety1-N - [(1 S) -1- (etoxykarbony1) ety1] -5-ch1ór-3- (2-ch1órfeny1)

The 1- (3,4-dimethoxyphenylsulfonyl) -3-hydroxy-2-indolinecarboxamide cis isomer.

- 57 (a) N- [2- (2-chlorophenylcarbonyl) -5-chlorophenyl] -N- (3,4-dimethoxyphenylsulphonyl) glicinic acid chloride

A mixture containing 11 g of the acid prepared in Examples 10-11 of Step A and 5 g of thionyl chloride in 10 ml of chloroform was heated at 60 ° C for 1 h. It was then allowed to cool to room temperature, concentrated in vacuo, and the residue taken up in DCM (twice). A yellow oil is obtained. which is used as such in the next step.

IR ^: 1800 cm ¹ (C = 0)

B) 2, 5-Dichloro-2- [N- (3,4-dimethoxyphenylsulfonyl) -N-N-ethyl-N - ((1S) -1- (ethoxycarbonylethyl) ethoxycarbamoylimethyl] aminobenzophenone

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

5.15 g of (L) -Boc (N-Et) Ala0Et was treated with 10 ml of TFA at 0 ° C to remove the Boe group. The mixture was concentrated in vacuo, taken up in 20 mL of DCM. Cool to -78 ° C and add two equivalents of TEA and acid chloride prepared in the previous step, dissolved in DCM. After 18 h at room temperature, the mixture was extracted with DCM. Wash with water then chromatograph on silica eluting with DCM / AcOEt (90/10; v / v). The expected product crystallizes from isopropyl ether.

mp &Gt; 112 [deg.] C. m = 8 g

C) N-Ethyl-N- (1S) -1- (ethoxycarbonyl) ethyl] -5-chloro-3- (2-chlorophenyl) -1- (3,4-dimethoxyphenylsulfonyl) -3-hydroxy-2- Indolinecarboxamide (cis isomer)

The compound obtained in the preceding step is stirred at room temperature for 18 h in 10 ml of THE and 20 ml of ethanol in the presence of 1.46 g of DBU. The mixture was concentrated in vacuo, the residue taken up in DCM. Wash with water, concentrate and chromatograph the product on alumina eluting with AcOEt / DCM (10/90; v / v).

NMR:

0 to 0.9 ppm: split d: 3H: _CH-CH3

0.9-1.7 ppm: m: 12H: 20CH _3, NCH _second OCH 2. NCH, COCH

6.1-8.3 ppm: m: 11H: 0H-10 aromatic H

Examples 79 and 80

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

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

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

107 g of benzylamine in 200 ml of ethanol are cooled in an ice bath and 172.2 g of methyl acrylate in 250 ml of ethanol are slowly added. After 13 days at room temperature, the solvent was evaporated in vacuo and then a portion of the oily residue was distilled off.

bp = 135-140 ° C at 0.6 mm Hg m = 30 g

IR: 1730 cm ^-1

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

27.9 g of amine. The mixture obtained in the previous step, in 500 methanol, is mixed with 3 g of 5% palladium on carbon and the mixture is treated for 1 hour under hydrogen pressure. Filter the mixture through Celite ^R , wash with methanol and evaporate the solvent in vacuo; the oil obtained is used as such in the next step.

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

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

m = 15.9 g

IR · - 1650 cm ¹ and 1730 cm ¹

D) 2-, 5-Dichloro-2- [N- (3,4-dimethoxyphenylsulfonyl) -N- [N-, N-di (2- (methoxycarbonyl) ethyl) carbamoylmethyl] -1-aminobenzophenone

14.3 g of 2, 5-dichloro-2- (3,4-dimethoxyphenylsulfonamido) benzophenone are poured over 180 ml of DMF and 1.1 g of sodium hydride are added in portions. After stirring at room temperature for 1 h, the mixture is cooled in an ice bath, 14.3 g of the product obtained in the preceding step are added and the mixture is left stirring at room temperature for 72 hours. Extract DCM is washed with water and chromatographed on silica eluting with DCM / AcOEt (93/7; v / v).

m = 28.4 g m.p. = 130 ° C

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

At 0 ° C in previous methanol and the mixture was mixed 12 g of the compound prepared in the step and 0.930 g of sodium methylate in 150 ml were left stirring at room temperature overnight. The reaction mixture was neutralized by the addition of 5% potassium bisulfate and then the solvent was evaporated in vacuo. The residue is chromatographed on alumina eluting with DCM / AcOEt (8/2; v / v). 2.4 g of the expected product are obtained, which is crystallized from methanol.

1.1. = 175 * C

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

Chromatography from the previous step eluting with DCM / MeOH (9.5 / 0.5: v / v). 1.82 g of trans isomer is obtained, which crystallizes from isopropyl ether.

mp = 85 ° C

Examples 81, 82 and 83

2 - ((2R) -2-carbamoylthiazolidinocarbonyl) -5-chloro-3- (2-chlorophenyl) -1- (3,4-dimethoxyphenylsulphonyl) -3-hydroxyindoline isomer of two compounds, trans isomer

A) (D-4-thiazole id inkarboxam i d

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

962nd

B) 2-. 5-Dichloro-2- [N- (3,4-dimethoxyphenylsulfonyl) -N - ((2R) -2-carbamoylthiazolidinocarbonylmethyl)] aminobenzophenone

This compound is obtained by conventional procedures from the acid prepared in Examples 10-11, step A.

mp = 125 ° C after crystallization from ether

C1 2-C (2R) -2-carbamoylthiazolidinocarbonyl) -5-chloro-3- (2-chlorophenyl) -1- (3,4-dimethoxyphenylsulfonyl) -3-hydroxyindoline

4.3 g of the product obtained in step B, in 90 ml of MeOH, are cyclized at room temperature in the presence of 1 g of DBU. The mixture is concentrated. taken up in water and DCM, decanted, washed with potassium hydrogen sulphate, dried and concentrated. Chromatograph on aluminum eluting with DCM / MeOH (97/3; v / v). The compound is obtained in the form of cis (a mixture of two diastereoisomers) in an amount of 1.5 g. then in the form of trans (mixture of two diastereoisomers), m = 1 g.

a) The cis fraction was crystallized from MeOH / DCM to give cis 1.

mp = 176 ° C after crystallization from isopropyl ether

[Α] D = +57 ° (c = 0.1, chloroform)

b) The mother liquors from the crystallization of the previous product are chromatographed on silica eluting with AcOEt / DCM (30/70;

in / in). The resulting cis 2 compound is recrystallized from ether, m.p. Melting point = 205 DEG

C (d = -185 ° (c = 0.3, chloroform))

c) The trans fraction (mixture of two diastereomers) is recrystallized from isopropyl ether.

mp Melting point = 170 DEG

Examples 84, 85, 86 and 86a

5-Chloro-3- (2-chlorophenyl) -1- (3-dimethoxyphenylsulphonyl) -3-hydroxy-2 - [(2S) -2- (N, N-dimethylthiocarbamoyl) -pyrrolidinocarbonyl) indole The isomerism of the cis-2 compound, the isomerism of the trans-2 compound

A) (L) - (N -Boe) -N, N-dimethylpropionamide

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

2.36 g of (N-Boc) -N, N-dimethylprolinamide are heated in anhydrous toluene for 4 h under argon in the presence of 2.3 g of Lavesson reagent. After 24 h, the solvent was evaporated and isopropyl alcohol was added. The resulting precipitate was decanted.

the isopropyl alcohol was evaporated and chromatographed on silica eluting with hexane / AcOEt (30/70; v / v). acquired

DCM / isopropyl ether (30/70; v / v).

mp = 62 ° C

B) 2-, 5-Dichloro-2- [N- (3,4-dimethoxyphenylsulfonyl) -N - ((2S) -2 (N-, N-dimethythiocarbamoyl) pyrrolidinocarbonylmethyl)] aminobenzophenone g Product prepared in the previous step, was dissolved in 10 ml of DCM and treated for 2 hours with 10 ml of TE at 0 ° C. The mixture was evaporated to dryness and then 20 ml of DCM, 6.1 g of the acid prepared in Example 10-11, step A, were added at 0 ° C and neutralized with 3 g of DIPEA. 5.15 g of BOP are dissolved in 30 ml of DCM and this solution is added to the previous solution over 30 min at 0 ° C: the pH is kept neutral by the addition of DIPEA and the mixture is allowed to stir for 3 h at 0 ° C. After leaving overnight at room temperature, extraction is carried out in the usual manner and then chromatographed on silica eluting with DCM / AcOEt (85/15;

in / in). The product obtained is recrystallized from isopropyl ether.

mp = 182-185 [deg.] C ([deg.] D = -72 [deg.] (C = 0.32, chloroform)

C) 5-Chloro-3- (2-chlorophenyl-1- (3,4-dimethoxyphenylsulfonyl) -3-hydroxy-2 - [(2S) -2- (N, Ndimethylthiocarbamoyl) pyrrolidinocarbonyl] -indoline ( cis - 2 compound isomerism, trans - 2 compound isomer)

3.8 g of the compound obtained in the preceding step are dissolved in 15 ml of DCM and then heated at reflux for 36 h in the presence of 850 mg of DBU. The individual isomers are separated by sequential chromatography on the reverse side.

a) The DCM / AcOEt (85/15; v / v) mixture elutes the initially expected compound as a mixture of the two diastereoisomers cis. The least soluble diastereomer is crystallized twice from DCM / isopropyl ether-methanol, then recrystallized from a minimum amount of DMF at 60 ° C and then two volumes of ethanol are added.

mp = 270 ° C (d = -278 ° (c = 1, chloroform)

b) The mother liquors are selected from the crystallization of the previous mixture and the second diastereoisomer cis crystallizes from the DCM / isopropyl ether mixture. = 249-251 ^{° C} (X. D = + 42 ° (c = 0.22, chloroform)

c) Combine the last eluted chromatography fraction and the mother liquors from the crystallization of fractions a) and b) and carry out a new chromatography on the elution with hexane / AcOEt (20/80; v / v). First, a fraction is isolated, which is recrystallized three times from DCM / isopropyl ether and the solids are always removed between the crystallizations. This gives the trans 1 isomer.

mp = 191-193 ° C

D = +74.5 ° C (c = 0.2; chloroform)

d) The second fraction contains the trans 2 isomer, which is recrystallized from DCM / isopropyl ether and crystallized with 1/3 mol of isopropyl ether.

mp - 170 ° C d = -266 ° (c = 0.14, chloroform)

Examples 87. 88 and 89

2 - ((2S) -2-carbamoylpyrrolidinocarbonyl) -5-chloro-3-cyclohexyl-1- (3,4-dimethoxyphenylsulfonyl) -3-hydroxyindoline (cis ^: 2 compounds, trans isomer)

A) 5-Chloro-2- [N- (3,4-dimethoxyphenylsulfonyl) amino] cyclohexylphenone

A solution of 35.6 g of 2-amino-5-chlorocyclohexylphenone and 39.5 g of 3,4-dimethoxyphenylsulfonyl chloride in 340 ml of pyridine is left under stirring at room temperature for 24 hours. The solvent was evaporated in vacuo, and the residue was washed with water and an acidic solution (0.5 N hydrochloric acid). The expected product crystallizes from ethanol.

mp = 135 ° C m = 56.1 g

B) 2 - [(N-Benzyloxycarbonylmethyl-N- (3,4-dimethoxyphenylsulfonyl) amino] -5-chlorocyclohexylphenone

To 52.6 g of the compound obtained in the previous step, in 520 ml of DMF, 3.2 g of sodium hydride are added portionwise and the mixture is left stirring at room temperature for 1 hour. After cooling in an ice bath, 21 ml of benzyloxycarbonylmethyl bromide are added dropwise and left to stir at room temperature for 24 hours. The solvent was evaporated in vacuo and the residue was taken up in water. Extract DCM and wash with water:

the product obtained is used as such in the next step.

C) N- (4-chloro-2- (cyclohexylcarbonyl) phenyl) -N- (3,4-dimethoxyphenylsulfonylglycine)

The compound obtained in the preceding step is placed under 3.9 g of 5 Pd / C in 700 ml of acetic acid under hydrogen (1 atmosphere). After completion of the reaction, the palladium is filtered off on Celite® and the mixture is washed with warm acetic acid; the solvent is evaporated in vacuo and the residue is taken up in water. Extract DCM, wash with water and then concentrated sodium bicarbonate solution. The residue is chromatographed on silica eluting with DCM / MeOH (97/3; v / v). The expected product crystallizes from ethanol.

mp = 160 ° C; m = 22.4 g

D) 5-Chloro-2- [N-3,4-dimethoxyphenylsulfonyl) N - ((2S) -2-carbamoyl pyrrolidinocarbonylmethyl)] aminocyclohexylphenone

A mixture of 9.92 g of the acid prepared in the previous step, 3 g of (L) -prolinamide hydrochloride and 3.5 ml of DIPEA in 75 ml of DCM is cooled to 0 ° C. 8.84 g of BOP in solution in DCM are added and the pH is maintained at 7 by addition of DIPEA. The mixture is left under stirring at room temperature for 24 h. Then the mixture was extracted with DCM, washed with saturated sodium bicarbonate solution. 5% potassium hydrogen sulphate solution and again with brine. Chromatograph on silica eluting with DCM / MeOH (96/4; v / v). The expected product solidifies in isopropyl ether.

mp = 110 ° C m = 7.3 g (λ D = -53.9 ° (c = 1. chloroform)

E) 2 - ((2S) -2-carbamoylpyrrolidinocarbonyl) -5-chloro-3-cyclohexyl-1- (3,4-dimethoxyphenylsulfonyl) -3-hydroxy indoline, cis (2 compounds) isomer, trans isomer

5.9 g of the compound obtained in the preceding step and 1.67

DBU in 60 mL of methanol was stirred at 0 ° C for 48 h. The solvent was evaporated in vacuo, water was added, extraction was performed with DCM and then washed with 5% potassium bisulfate solution. Chromatograph is on alumina eluting with DCM / MeOH (98/2; v / v).

a) At least the fraction of the fraction contains two cis isomers. This fraction was recrystallized from methanol. The first compound (cis 1) thus obtained is pure by HPLC.

mp = 185 ° C

Recrystallization of the mother liquors from MeOH gave the second compound (cis 2). HPLC purity = 75% (contains 25% cis 1).

mp = 132 ° C

b) The most polar fraction contains the trans isomer in the form of a seemingly uniform compound obtained by recrystallization from methanol.

1.1. = 240 ° C d = -55.1 ° (c = 1, chloroform)

Example 89a

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

In analogy to Examples 87, 88 and 89, an analogous compound was prepared in the (D) -proline series.

The compound obtained after recrystallization from DCM / MeOH has a trans configuration.

mp = 238 ° C (λd = +164 ° (c = 0.245; chloroform / methanol. 8/2, v / v)

NMR spectra of this compound and the compound described in Step E

b) of the preceding example are identical.

Example 90

5-Chloro-3- (2-chlorophenyl) -1- (3,4-dimethoxyphenylsulfonyl) -2 - [(2S) 2- (N-methylaminocarbonyl) pyrrolidinocarbonyl-3-hydroxy indoline isomer cis

920 mg of the compound prepared in Example 28 is stirred for 15 minutes in 20 ml of DCM containing 371 mg of BOP, then a stream of monomethylamine is bubbled for 10 minutes and stirring is maintained for a further 30 minutes. The mixture is taken up in water, decanted, the organic layer is washed with potassium hydrogen sulphate, sodium carbonate, dried and concentrated. The residue was chromatographed on silica eluting with DCM / methanol (97.5 / 2.5: v / v). The expected product is crystallized from isopropyl ether / DCM.

m = 750 mg

1.1. Melting point = 158 DEG

[Α] D = -216 ° (c = 0.3: chloroform)

Using the same procedure as in the previous examples (Examples 27 to 31 and 90), other intermediates VI for the synthesis of compounds I of the invention were prepared using (L) -proline derivatives (unless otherwise stated).

Prepared compounds VI are shown in Table 3. Prepared compounds I are shown in Table 4.

Table 3

Cl

R's - < ^R 7 R 7 MP: CC) (Chloroform) 3,4-CH3O (D) - CONH + 45 c = 1.015 3,4-CH3O - N H ¹ - coc ) CH ₃ 161-163 DCM / isopropyl ether -70.8 c = 0.48 2,4-chjo —In ^H -yJ coo ch ₃ 145-148 -17.5 c = 3.36 3,4-chjo -NH4-COC ^{, CH2} = 110 DCM / isopropyl ether 3,4-chjo - N H ¹ - ch ₂ COOCHj 148 isopropyl ether / MeOH

Table 4

Cl

Example R ' R's - <r ₇ MP: CC) and? (chloroform form) 91 cis 1 92 cis 1 Cl Cl 3,4-CH3O (D) - / H «4— CONH 115 MeOH 204 MeOH / DMF + 188 c = 0.33 -114 c = 0.31 93 cis Cl 3,4-chjo —N ^H ^ - C0 ( DCHj 198-201 DCM / isopropyl pyléter 94 cis Cl 2,4-chjo -NH4-COC ) CH 205-207 DCM / isopropyl ether 95 cis Cl 2,4-CH, 0 —NH3 - COC H 221 DCM / isopropyl ether -242 c = 0.254 96 cis Cl 3,4-CH3O -N coo ^CH2 -234 C = 0.32

U zt

97 cis Cl 3,4-CH, 0 - H '- ^ - CON _{(CH3) 2} -214 c = 0.32 98 cis 1 99 cis 2 100 trans 1 Cl 3,4-chjo —N ^H V ch ₂ COOCHj 105-115 DCM / isopropyl ether 175 DCM / isopropyl ether +174.6 c = 0.3 -214.6 c = 0.3 -155 c = 0.2 101 trans 2 177 DCM / isopropyl ether + 95.2 c = 0.2 102 cis 1 Cl 3,4-chjo —N HV ch ₂ COOH 135 isopropyl ether -162 103 cis 1 Cl 3,4-chjo —K ^H V ch ₂ conh ₂ 145 DCM / isopropyl Pyléter 103a cis 1 cis 2 Cl 3,4-chjo —N H * r — ch ₂ conh ₂ 104 cis 1 Cl 3,4-chjo —I / H ^ - ch ₂ nh ₂ 210 ether -177.5 c = 0.2 104a cis 1 cis 2 Cl 3,4-chjo - N - čh ₂ nh ₂

105 106 chjo 3,4-CH, O -NH4-COh »2 200 ECOH 215 MeOH -195 c = 0.2 + 127 C = 0.2 107 CH 0 3,4-chjo (D) - / - chon ₂ 198 -63.3 c = 0.117 (CHCl 3 / MeOH 8/2; v / v) 108 Cl 2,4-chjo -N H '-' j - COf> ÍH ₂ 274 DCM / MeOH -225 c = 0.372 (CHCl 3 / MeOH 8/2; v / v, 108a C sharp Cl 3,4-chjo - / H · - - CON HOH -198.7 C = 0.24

* Example 92 · Other measured optical rotation: d ²⁵ = -39.5 ° (c = 0.17; CHCl 3 / MeOH. 8/2, v / v)

The compound of Example 107 is an enantiomer of the compound of Example

106th

Example 108a was prepared from Example 28 by treatment with hydroxylamine hydrochloride in DMF and activated with BOP in the presence of DIPEÄ.

Some of the compounds of the invention listed in Table 4 are suitable for the preparation of other compounds. Thus, the compound of Example 99 makes it possible to obtain the compound of Example 101, then the compound of Example 103, and finally the compound of Example 104.

Example 109

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

A) 2, 5-Dichloro-2-CN- (3,4-dimethoxyphenylsulfonyl) -N - ((2S, 4R) -4-hydroxy-2- (methoxycarbonyl) pyrrolidinocarbonylmethyl) 1-aminobenzophenone

15 g of the acid prepared in Example 10-11, step A, and 6.25 g of (2S, 4R) -methyl-4-hydroxyprolinate hydrochloride in the presence of 7.4 g of DIPEA are heated to 0 ° C in 150 ml of DCM.

A solution of 12.7 g of BOP in 30 ml of DCM is added dropwise over 30 min, and then DCM is added in an amount necessary to neutralize the solution. After leaving overnight at room temperature, extraction and chromatography on silica is carried out by a conventional method, eluting with DCN / AcOEt (60/40; v / v). The expected product crystallizes from DCM / ether / isopropyl ether.

mp MP 128-131 ° C

Α d = +8.5 ° (c = 0.38; chloroform)

Β) 2 ', 5-Dichloro-2- [Ν-3,4-dimethoxyphenylsulphonyl) -N - ((2S, 4R) -4-mesyloxy-2- (methoxycarbonal) pyrrolidinocarbonylImethyl)] aminobenzophenone g of the compound prepared in the previous step, at 0 ° C dissolved in 10 mL DCM. 550 mg of triethylamine and then 550 mg of methanesulfonyl chloride are added and the mixture is left at 0 ° C for 20 h.

Water was added, the organic layer was washed with 0.5 N hydrochloric acid, water. then with sodium bicarbonate solution, dried over magnesium sulphate and evaporated. The oil obtained is used as such in the next step.

C) 2- [N - ((2S, 4S) -4-azido-2- (methoxycarbonyl-pyrrolidinocarbonyl Imethyl) -N- (3,4-dimethoxyphenylsulfonyl)] amino-2 ', 5-dichlorobenzophenone g of the product prepared in The mixture was poured into water, extracted with ethyl acetate, the organic layer was washed with water, dried and chromatographed on silica eluting with hexane (60 ml) for 18 h at 80-90 ° C in the presence of 2.7 g of sodium azide. pentane / AcOEt (50/50; v / v) to give an oil (10 g).

D = -25.5 ° (c = 0.39; chloroform, T = 26 ° C)

D) 2 - ((2S, 4S) -4-azido-2- (methoxycarbonyl) pyrrolidinocarbonyl) -5-chloro-3- (2-chlorophenyl) -1- (3,4-dimethoxyphenylsulfonyl) -3-hydroxyindoline, isomer cis g of the product obtained in the preceding step, under normal conditions in the presence of DBU, the product is recrystallized

Obtained from mixture i

3.38 cycles expected

DCM / isopropyl ether.

m = 755 mg

mp D = -176 ° (c = 0.21; chloroform, T = 26 ° C)

Example 110

2 - [(2S, 4S) -4- (N-benzyloxycarbonyl-N-methyl) amino-2-methoxycarbonyl) pyrrolidinocarbonyl-5-chloro-3-C2-chlorophenyl) -1- (3,4-dimethoxyphenylsulfonyl) -3-hydroxyindoline, isomer cis

A) (N-Boc) -4-hydroxyproline methyl ester

Starting from (2S, 4R) -4-hydroxyproline methyl ester hydrochloride. This compound (19 g) was suspended in THF (100 mL), 22.9 g (Boc) 2 O was added and the mixture was cooled to 0 ° C. 21.2 g of triethylamine in 25 ml of THF are added dropwise and the mixture is stirred for 12 h at 0 ° C and 4 h at 60 ° C. Water is added. extract with ethyl acetate, wash the organic phase with water. potassium hydrogen sulphate solution (four times), water and then brine. After evaporation, an oil (21.6 g) was isolated. containing a small amount of (Boc) ₂ 0B) of (2S, 4R) - (N-Boc) -4-mesyloxyprolínu

A solution of 22.9 g of the product prepared in the previous step in 250 ml of DCM is cooled to 0 ° C. 22.9 g of mesy chloride in 10 ml of DCM are added dropwise, then 9.4 g of triethylamine in 100 ml of DCM are added dropwise. the mixture was allowed to reach room temperature overnight. Evaporate to dryness, add water. Extract the AcOEt, wash with water, brine and dry over magnesium sulfate. Evaporation gave an oil which was used in the next step.

C) (2S, 4S) - (N-Boc) -4-azidoproline methyl ester

This compound is prepared from the compound obtained in Step B.

15.2 g of (N-Boc) -4-mesyloxyproline methyl ester are dissolved in 70 ml of DMSO and the mixture is heated at 90 ° C for 5 h in the presence of 3.05 g of sodium azide. Cool, add water, extract with AcOEt, wash with water, brine and dry over magnesium sulfate. The oil obtained is purified by chromatography on silica eluting with AcOEt / hexane (40/60; v / v).

[α] D (-37.8 °) (c = 3; chloroform) lit. d = -36.6 ° (c = 2.8; chloroform), D.J. Abrah.

Med. Chem., 1983, 549,26.

(7> 1 D) (2S, 4S) - (N-Boc) -4-aminoprolyl methyl ester

8.45 g of the compound obtained in Step C are dissolved in 100 ml of methanol, 500 mg of 10% Pd / C are added and hydrogenated at 40 ° C for 18 h. The catalyst was filtered off. half of the methanol was evaporated. 100 ml of 0.5 N hydrochloric acid are added, then the residue of methanol is evaporated and the unreacted starting product is extracted with AcOEt. The aqueous phase is treated with sodium carbonate and the fraction containing the expected product (Cm = 4.35 g) is extracted with AcOEt.

E) (2S, 4S) - (N-Boc) -4-N-benzyloxycarbonylamino) -propyl ester

The crude product obtained in the previous step was dissolved in 15 mL of ether and 15 mL of DCM at 0 ° C. 2.3 g of DIPEA are added, followed by 3.03 g of benzyl chloroformate in 5 ml at 0 ° C over 70 min.

DCM. After 3 h the solvents were evaporated in vacuo at room temperature; water and ethyl acetate were added. the organic phase is washed successively with potassium hydrogen sulphate solution (three times), water (three times), sodium carbonate solution (three times), water (three times) and brine. The chromatograph is also eluted with hexane / AcOEt (40 / 60Ô v / v) to give the expected product.

D = -16.4 ° (c = 0.3; chloroform)

E) (2S, 4S) - (N-Boc-4- (N-Benzyloxycarbonyl-N-methyl) -amino) -propionine methyl ester The compound obtained in the previous step was dissolved in 20 ml at 0 ° C under argon. DMF in the presence of 2.25 g of methyl iodide, 170 mg of 80% sodium hydride are added in portions and then stirred at 0 ° C for 90 min, extracted with water and ethyl acetate, and the organic phase is washed with water and then brine. eluting with hexane / AcOEt (50/50; v / v) to give 1.55 g of the expected product.

D = -38.8 ° (c = 0.38: hairy)

G) 2, 5-d the Lor-2-1 and E 2 R, 4 S) -N-t ^_ d 3.4 IMET jtyf phenyl ^ lf they LSU 1) N-4- (N-benzyl-1 · ^ oxycarbonyl 1 - N - (methyl) amino-2- (methoxycarbonyl) pyrrolidinocarbonylmethyl) amine nobenzophenone

This product is obtained by conventional means, ξχ d = -22.4 ° (c = 0.37; chloroform)

H) 2 - [(2S, 4S) -4- (N-Benzyloxycarbonyl-N-methyl) amino-2- (methoxyethoxycarbonyl) pyrrolidinocarbonyl] -5-chloro-3- (2-chlorophenyl) -1 - (3,4-dimethoxyphenylsulfonyl) -3-hydroxyindoline, isomer cis

This product is obtained by cyclization in the presence of DBU by conventional methods. The crystals formed crystallize from DCM / isopropyl ether.

mp = 129 ° C ([α] D = -129 ° (c = 0.321: chloroform)

The isomeric purity by HPLC is 99

The compounds prepared in Examples 109 and 110 are used to prepare the compounds of the invention listed in Table 5.

Table 5

Cl

Example R and _B (chloroform) 111 cis —Nh ₂ -189.6 c = 0.4 112 cis —Nhcooch ₂ - -174 C = 0.24 113 cis -NHCH -152.6 c = 0.28 114 cis -N _{(CH3) 2} -191 c = 0.19

The compound of Example 112 allows the compounds of Examples 115 and 116 shown in Table 6 to be produced sequentially, and the compound of Example 114 allows the compound of Example 116a to be prepared.

Table 6

Cl

Example R and _D (chloroform) 115 cis —Nhcooch ₂ - -151 c = 0.27 116 cis —Nh ₂ -161.4 c = 0.26 116a cis -N _{(CH3) 2}

The compound of Example 116a can be prepared either from the compound of Example 114 or from (2S, 4S) - (N-Boc) 4- (dimethylamino) prolineamide, as follows:

1) Prepare (2S, 4S) -methyl- (N-Boc) -4-aminoprolinate from (2S, 4S) -methyl-4-azidoprolinate according to T.R. Vebla, J. Org., Chem., 1991, 56, 3009.

(2S, 4S) -methyl-C-N-Boe) -4- (dimethylamino) propionate of the compound prepared in (i), is dissolved in 50 ml of acetonitrile, 12.8 ml of 30% is added. formalin followed by 3 g of sodium cyanoborohydride over 5 min. After 2 hours of contact, acetic acid is added to adjust the pH of the solution to 6: After 3 h, acetonitrile is evaporated, then water, potassium carbonate and solid sodium chloride are added and the mixture is extracted with 4 volumes of ethyl acetate. The organic phase is evaporated, the residue is dissolved in 1N hydrochloric acid and extracted with AcOEt. Solid is added to the aqueous phase

carbonate sodium and solid and sodium chloride with extraction * AcOEt. After evaporation the rest of the chromatograph is at si 1ikagele with elution DCM / MeOH (95/5; v / v); isolate oil that - stiffens. m = 2, i g IR (DCM): 1755 cm &^lt; -1 ^&gt; 1695 cm ^-1 .

3) 534 mg of the ester prepared in 2) is dissolved in 4 ml of MeOH and treated with sodium hydroxide (116 mg) in 1 ml of water at room temperature for 48 h. Acidification with 0.5 N hydrochloric acid to pH 3.5 is carried out and the mixture is evaporated to dryness. Azeotropically dry the residue in the presence of benzene (five times) and then vacuum dry for 8 h. Then 2 ml of DMF and 3 ml of DCM are added and the mixture is cooled to 0 ° C. 865 mg and DIPEA are added to neutralize the reaction mixture. After 15 min, a stream of ammonia gas was bubbled through the mixture twice for 30 min. After 2 h at room temperature, DCM was evaporated.

- L ».

carbonated water, sodium chloride are added and then the mixture is extracted with 4 volumes of AcOEt. After evaporation, the residue of the chromatograph is on silica. DCM / MeOH / NH 3 OH <84.5 / 15 / KO, 5; v / v) eluting a solid (m = 185 mg) which was recrystallized from DCM / isopropyl ether.

mp = 183-186 ° C (XD ²⁵ ₌ -63.1 ° <c = 0.24; chloroform)

Example 117

N- (2-carboxyethyl) -N-ethyl-3- (2-chlorophenyl) -5-chloro-1- (3,4-dimethoxyphenylsulfonyl) -3-hydroxy-2-indole incarboxamide decarboxylation, isomer cis

630 mg of the compound prepared in Example 41 are introduced into a solution in 20 ml of THF under an argon atmosphere, and 101 mg of N-methylmorpholine and 118 mg of isobutyl chloroformate are added at -15 ° C. After stirring for 5 min, 127 mg of N-hydroxy-2-pyridintione, 101 mg of TFA are added, the mixture is kept under stirring at -15 ° C for 15 min, 900 mg of tert-butyl mercaptan is added and the mixture is allowed to warm to room temperature. Thereafter, the reaction mixture 1i is irradiated with a tungsten lamp (<150 W). The mixture was concentrated, taken up in water, extracted with DCM, dried and concentrated. The residue is chromatographed on silica eluting with DCM / AcOEt <95/5; in / in). The expected product is obtained.

m = 300 mg m.p. Melting point = 215 DEG

This compound is listed in the European cis configuration around the product.

similar to the compound of Example 125, patent application EP 469984. It has 2,3 indoline bonds as the starting material

Example 118

Decarboxylation of 2- (2R) -2- (carboxymethyl) pyrrolidinocarbonyl) -5-chloro-3- (2-chlorophenyl) -1- (3,4-dimethoxyphenylsulphonyl) -3-hydroxyindoline. isomer cis

The procedure is as in the previous example, starting from the compound of Example 102. The product obtained is recrystallized from DCM / isopropyl ether.

mp = 215-220 ° C d = -214.5 ° (c = 0.2; chloroform)

This compound is 2 - ((2S) -2-methylpyrrolidinocarbonyl) -5-chloro-3-C2-chlorophenyl) -1- (3,4-dimethoxyphenylsulfonyl) -3-hydroxyindoline. isomer cis.

Example 119

Decarboxylation of 2- (2-carboxypyrrolidinocarbonyl) -5-chloro-3- (2-chlorophenyl) -1- (3,4-dimethoxyphenylsulfonyl) -3-hydroxyindoline.

isomer cis

The procedure was as in the previous example, starting from the compound prepared in Example 28. The product was recrystallized from isopropyl ether / DCM.

mp = 263 ° C (Ad = -201.5 ° (c = 0.2; chloroform)

The top compound is 2-pyrrolidinocarbonyl-5-chloro-3- (2-chloro-phenyl) -1- (3,4-dimethoxyphenylsulfonyl) -3-hydroxyindoline, isomer cis.

Claims (11)

A compound of formula (I) _: wherein: R 1 represents a halogen atom, C 1 -C 4 alkyl, hydroxyl, C 1 -C 4 alkoxy, benzyloxy, cyano, trifluoromethyl, nitro or amino, R 2 is C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 3 -C 7 cycloalkene, phenyl, unsubstituted or substituted one or more times with C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogen, trifluoromethyl, amino, or R 2 is nitrophenyl, unsubstituted or unsubstituted or one or more times with C1-C4 alkyl or halogen, R3 represents a hydrogen atom, R4 represents a carbamoyl group of the formula CONReR7, R 5 represents C 1-6 alkyl, 1-naphthyl, 2-naphthyl, 5-dimethylamino-1-naphthyl, phenyl, unsubstituted or substituted with one or more substituents including halogen, C 1 -C 4 alkyl, amino, free or two C 1 -C 10 alkyl, hydroxyl. selected from the group of a trifluoromethyl group substituted with one C 1 -C 6 alkoxy. C2 -C4a1kenoxy, C 1 -C 4 -alkylthio, trifluoromethoxy, carboxy. benzyloxy, cyano, C 1 -C 4 alkoxycarbonyl, carbamoyl, free or substituted by one or two C 1 -C 4 alkyl. or C 1 -C 4 alkylamido. or f 1 is nitrophenyl, unsubstituted or substituted once with trifluoromethyl, or C 2 -C 8 alkenoxy, or one or more times with halogen, C 1 -C 4 alkyl. C 1 -C 4 alkoxy, C 1 -C 4 alkyl 1 thio, trifluoromethoxy, or benzyl. R e represents C 1 -C 6 alkyl or is identical to R 7. R y represents a 4-piperidyl group, a 3-azetidinyl group optionally substituted on a nitrogen of a C 1 -C 6 -alkylora, a benzyloxycarbonyl, or a C 1 -C 4 alkoxycarbonyl group (CH 2 R 3 which is substituted with a 2-, 3- or 4-pyridyl group) , hydroxyl, amino, free or substituted with one or two C 1 -C 6 alkylra, carboxyl, C 1-6 alkoxycarbonyl, benzyloxycarbonyl, carbamoyl, free or substituted with one or two C 1 -C 6 alkyl, or R e and R 7 together form with a nitrogen atom to which they are attached, a heterocycle selected from morpholine, thiomorpholine, thiazolidine or 2,2-dimethylthiazolidine, unsubstituted or substituted with R 5, piperazine, unsubstituted or substituted in the 4-position with R 8, an unsaturated five membered ring having one nitrogen atom , substituted with Re, or saturated three-, five-, six-, or seven membered ring with one nitrogen atom substituted by R e and R g, R6 is R6 or CCH2Jr. which is substituted by hydroxyl or amino, free or substituted by one or two C 1 -C 4 alkyl, R-8 represents a group (CH 2> q which is substituted by a carboxyl group, a C 1 -C 4 alkoxycarbonyl group, a benzyloxycarbonyl group, a carbamoyl group, free or substituted by hydroxyl or by one or two C Cgalkylmi. or an aminocarbothioyl group, free or substituted by one or two C 1 -C 6 alkyl. R e represents R e or a (CH ₂ ) ₂ NH _{2 group} , free or substituted by one or two C 1 -C 4 alkyl. R 8 represents hydrogen. halo. (CH ₂ ) r OR 10, (CH ₂ ) r -NR 11 R ₁₂ . (CH ₂₎ i R sCONRi 11th azido. R 10 represents hydrogen, C 1 -C 4 alkyl, mesyl or tosyl, R 11, R 11 and R ₁₂ each represent hydrogen or C 1 -C 6 alkyl, or R 11 represents hydrogen and R ₁₂ represents benzyloxycarbonyl or C 1 -C 6 alkoxycarbonyl, n is 0, or 2. m is 0, 1 or 2 q is 0, 1. 2 or 3, r is 0. d. 2 or 3, with the restriction that r is not equal to 0, when R e or R g is in the φ position to the intracyclic amide nitrogen, s represents 0 or 1, and their possible salts. A compound of formula I according to claim 1, wherein R 1 is chlorine, bromine or methoxy and n = 0. A compound of formula (I) according to any one of claims 1 or 2, wherein R ₂ is chlorophenyl or methoxyphenyl or cyclohexyl. A compound of formula (I) according to any one of claims 1 to 3, wherein R 5 is phenyl substituted at the 3- and 4-positions or at the 2- and 4-positions by methoxy, or R 5 is phenyl substituted at the 4-position by methyl. A compound of formula I as claimed in any one of claims 1 to 4, wherein m = 06. A compound of formula I as claimed in any one of claims 1 to 5, wherein R 6 is CONR 6 R 6 and NR 6 R 7 is IV-substituted, substituted at the 2-position. a group (Clfelq. which is substituted with a carboxyl group or a carbamoyl group, aq = 0, 1, 2 or 3). A compound of formula (I) according to any one of claims 1 to 5, wherein CONReRv and NReRy are piperidino substituted at the 4-position with amino, C 1 -C 4 alkylamino or C 1 -C 6 dialkylamino. A compound of formula I according to any one of claims 1 to 5, wherein R 4 is CONR 6 R 7 and NR 6 R 7 is thiazolidino. substituted with (CH 2) q. which is substituted by carboxyl or carbamoyl, and q = 0, 1, 2 or 3. A compound of formula I according to any one of claims 1 to 5, wherein R 4 is CONR 6 R 7 and NR 8 R y is pyrrolidino. substituted at the 2-position by a group (C1-6) which is substituted by a carboxyl or carbamoyl group and substituted at the 4-position by amino, C1-C4 alkylamino or C1-C4 dialkylaro. A compound of formula (I) according to any one of claims 1 to 5, wherein K 4 is CONR 6 R 7 and R 6 is C 1 -C 6 alkyl, and Ry is <CH 2 I 1 - substituted with carboxyl or carbamoyl, ar = 1, 2 or third A compound of formula I according to any one of claims 1 to 10 in the form of the cis isomer, wherein R 2 and R 4 are on the same side of the indoline ring. A process for the preparation of a compound of formula I according to claim 1, characterized in that: a) a 2-aminophenone derivative of the Formula II (II) wherein R 1. R2 and n are as defined in formula I in claim 1 and reacted with a sulfonyl derivative of formula III Hal-SO ₂ - (CH ₂ ) m -R 5 (III) wherein Hal represents halogen, preferably chlorine or bromine, am and R 5 are as defined in formula I in claim 1, b) to the compound of formula IV thus obtained R 5 (IV) is treated with a halogenated derivative of formula V Hal - CH ₂ COA (V) wherein Hal - represents halogen, preferably bromine, and A represents either NR 6 R 7 or OR, where R is tert-butyl or benzyl. c) optionally, when A represents an OR group. the ester of formula VI-