SK283463B6 - Indoline derivatives, process for their production, intermediates of this process and pharmaceutical compositions containing them - Google Patents

Abstract

The invention relates to indoline compounds of formula (I), wherein R1, R2, R3, R4 and R5 have the meanings defined in description and n and m are 0, 1 or 2, which show affinity to the antidiuretic hormone and oxytocine. The invention also relates to the process for production of such compounds, to the intermediates of this process and pharmaceutical compositions containing these derivatives.

Description

Technical field

The invention relates to indoline derivatives, in particular N-sulfonylindoline derivatives with an amide functional group, to a process for their preparation and to pharmaceutical compositions containing the indoline derivatives.

BACKGROUND OF THE INVENTION

U.S. Pat. No. 3,838,167 discloses certain N-sulfonylindole derivatives corresponding to the general formula (1)

where

R 1 represents hydrogen, alkyl or phenyl, optionally substituted,

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

R ₃ represents alkyl, phenyl or alkylphenyl,

R ₄ represents alkyl, phenyl, optionally substituted, alkoxy or phenoxy, n '= 0,1 or 2.

Compounds of formula (1) are synthetic intermediates in the preparation of central nervous system indole derivatives of formula (2)

wherein R represents alkyl, phenyl, optionally substituted, or hydroxyl.

SUMMARY OF THE INVENTION

The present invention provides indoline derivatives containing an amide function of formula (I)

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

R ₂ is 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 4 alkyl 1-4 carbon atoms, halogen, trifluoromethyl, amino, or

R ₂ is a nitrophenyl which is unsubstituted or mono- substituted by trifluoromethyl or one or more times by alkyl of 1 to 4 carbon atoms, or halogen,

R ₃ is H,

R ₄ represents a group - CONR ₅ R ₇ ,

R ₅ is C 1 -C 4 alkyl, 1-naphthyl, 2-naphthyl, 5-dimethylamino-1-naphthyl, phenyl, unsubstituted or substituted with one or more substituents selected from halogen, alkyl C 1 -C 4, trifluoromethyl, 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 C 1-4 alkyl, trifluoromethoxy, benzyloxy, cyano, carboxy, C 1-4 alkoxycarbonyl, carbamoyl, free or substituted by one or two C 1-4 alkyl, or C 1-4 alkyl, or C 1-4 alkyl, 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, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio , trifluoromethoxy, or benzyloxy, R ₆ is C 1 -C 6 alkyl or is identical to R ₇ ,

R ₇ represents 4-piperidinyl, 3-azetidinyl optionally substituted on nitrogen by C 1 -C 4 alkyl, benzyloxycarbonyl, or C 1 -C 4 alkoxycarbonyl, (CH ₂ ) _r which is substituted by a 2-, 3- or 4-pyridyl group, a hydroxyl group, an amino group, free or substituted by one or two alkyl groups containing 1 to 4 carbon atoms, a carboxyl group, an alkoxycarbonyl group containing 1 to 4 carbon atoms in the alkoxy moiety, benzyloxycarbonyl, carbamoyl, free or substituted by one or two C 1-4 alkyl groups, 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 sub The substituted by R _8, piperazine, unsubstituted or substituted in position 4 by a group R _8, an unsaturated five-membered ring with one nitrogen atom substituted by R _a, or saturated three-, four-, five-, six-, or seven-membered ring with one nitrogen nitrogen, substituted with R ₈ and R _9,

R ₈ represents R ₁₈ or a (CH ₂ ) _r group which is substituted by a hydroxyl group or an amino group, free or substituted by one or two C 1 -C 4 alkyl groups,

R ' _g represents a (CH ₂ ) _q group which is substituted by a carboxyl group, an alkoxycarbonyl group containing 1 to 4 carbon atoms in the alkoxy moiety, a benzyloxycarbonyl group, a carbamoyl group, a free or substituted hydroxyl or one or two alkyl groups containing 1 to 4 4 carbon atoms, or an aminocarbothioyl group, free or substituted by one or two alkyl groups containing 1 to 4 carbon atoms

R ₈ is R 'or _a group (CH _{2) 2} NH _2, a free or substituted by one or two alkyl groups having 1 to 4 carbon atoms

R ₉ is hydrogen, halogen, (CH ₂ ) _r OR 10, (CH ₂ ) _r NR ₁₁ R ₁₂ , (CH ₂ ) _S CONR ₁₁ R ₁₁ , azido,

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

R'n'B R _lb and R ₁₂ each are hydrogen or alkyl having 1 to 4 carbon atoms, and R _n is hydrogen and R ₁₂ is benzyloxycarbonyl or alkoxycarbonyl having 1 to 4 carbon atoms in the alkoxy part, n is 0.1 or 2, m is 0, 1 or 2 q is 0,1,2 or 3, r is 0, 1, 2 or 3, with the restriction that r is not equal to 0 when R _s or R _{9 is} in the position and wherein the intracyclic amide nitrogen, s represents 0 or 1, in the form of cis and trans isomers and their enantiomers, or in the form of a racemic mixture of these cis and trans isomers and optionally salts of these compounds.

Preferred are indoline derivatives of the above formula (I) wherein R 1 represents chlorine, bromine or methoxy and n = 1.

Within this group, indoline derivatives of formula (I) wherein R ₂ is chlorophenyl or methoxyphenyl or cyclohexyl are preferred.

Also preferred are indoline derivatives of formula (I), wherein R ₅ is phenyl substituted in the 3- and 4-position or the 2 and 4 by methoxy, or _R is phenyl substituted at position 4 by methyl.

Further preferred are indoline derivatives of said general formula (I) wherein m = 0.

Further preferred are indoline derivatives of formula (I) wherein R 4 is CON 1 R 4, and NR ₆ R ₇ is pyrrolidine substituted at the 2-position with (CH ₂ ) _q substituted with carboxyl or carbamoyl, and q = 0,1,2 or 3.

Further preferred according to the invention are indoline derivatives of formula (I) wherein R ₄ is CONR ₆ R ₇ and NR ₆ R ₇ is piperidine substituted at the 4-position with amino, C 1-4 alkylamino or C 1-4 dialkylamino carbon atoms in each alkyl moiety.

Further preferred according to the invention are indoline derivatives of formula (I) wherein R ₄ is CONR ₆ R ₇ and NR ₆ R ₇ is thiazolidino substituted with (CH ₂ ) _q substituted with carboxyl or carbamoyl, aq = 0 , 1, 2, or 3.

Further preferred according to the invention are indoline derivatives of formula (I) wherein R 4 is CONR 4 and NR ₆ R ₇ is pyrrolidino substituted at the 2-position with (CH ₂ ) _q substituted with carboxyl or carbamoyl and substituted with position 4 with an amino group, an alkylamino group having 1 to 4 carbon atoms or a dialkylamino group having 1 to 4 carbon atoms in each alkyl moiety.

Further preferred according to the invention are indoline derivatives of formula (I) wherein R 1 is CONR ₆ R ₇ and R 6 is C 1-4 alkyl and R ₇ is (CH ₂ ) _r substituted with a carboxyl group or carbamoyl, ar = 1, 2 or 3.

Preferred according to the invention are all said indoline derivatives of the general formula (I), in the form of the cis isomer, wherein R ₂ and R 1 are: they are on the same side of the indoline ring.

In particular, an indoline derivative of formula (I) according to claim 1, wherein:

R 1 represents chlorine at the 5-position of the indoline ring

R ₂ is 2-chlorophenyl,

R ₄ is 2-carbamoylpyrrolidinocarbonyl,

R ₅ is 3,4-dimethoxyphenyl, m is 0, and n is 1.

The present invention also relates to a process for the preparation of an indoline derivative of formula (I), in the form of cis and trans isomers and their enantiomers, or in the form of a racemic mixture of cis and trans isomers, which comprises:

a) a 2-aminophenone derivative of formula (II) X / ^CO 2 ^R 2 ^{(, i)} wherein R _b R ₂ and n are as defined in formula (I) are reacted with a sulfonyl derivative of formula (III)

Hal-SO ₂ - (CH ₂ ) _m -R ₅ (III), where

Hal represents halogen, preferably chlorine or bromine, and R ₅ is as defined in formula (I) in claim 1,

(b) the compound of formula (IV) thus obtained;

(IV) wherein R 1, R ₂ , R ₅ , n and m have the same meanings as given for the compound of formula (1), are treated with a halogenated derivative of formula (V):

Ha-CH ₂ COA (V), where

Hal is halogen, preferably bromine, and A is NR ₆ R ₇ ,

c) The compound of formula (VI) R ^C0R2 (Rt 5 $ ^ * - ^CK 2 ^CO * ^R 6 ^R 7 SO (CE) _m (VI) ^ Y ^C0R2 (Κρζζ ^ Ν-ϋΗ, ίΟΟΗ of ₂ (CH 2) _m ^R 5 (VI ··) in which R ₁ , R ₂ , R ₅ , n and m have the same meanings as given for the compound of formula (I) or its acid chloride of formula (VI) in which: R _b R ₂ , R _s , R ("R _7> n" have the same meanings as given for the compound of formula (i), are cyclized in a basic medium to prepare a compound of formula (I),

d) and optionally separating the cis and trans isomers of a compound of formula (I) and optionally separating the enantiomers.

The present invention also provides a process for the preparation of an indoline derivative of formula (I), in the form of cis and trans isomers and their enantiomers, or in the form of a racemic mixture of cis and trans isomers, which comprises:

(a) an aminophene derivative of the general formula (II)

_f t ^t \. ^ 2 ^C0R '(RiíX ^ J ^ CKjCoci a, ^R5 (VI ···) wherein R _p R _{2 and} n are as defined in formula (I), is reacted with a sulfonyl derivative of formula (III)

Hal-SO ₂ - (CH ₂ ) _m -R ₅ (III), where

Hal represents halogen, preferably chlorine or bromine, and R ₅ is as defined in formula (I),

(b) the compound of formula (IV) thus obtained, wherein R _b R ₂ , R ₅ , n and m have the same meanings as given for the compound of formula (I), is treated with a compound of formula HNR ₆ R ₇ ,, and R ₇ have the same meanings as given for the compound of formula (I),

(e) the resulting compound of formula (VI) thus obtained;

I / ^0R2 (R ₁ -) ^N-L XJ CH CO.'ÍR ₆ R ₇ f O, (VI) (IV) wherein R _b R ₂ R _5, us have the same meaning as given for compounds of formula (I), is treated with a halogenated derivative of general formula (V)

Ha-CH ₂ COA (V), where

Hal is halogen, preferably bromine, and A is OR, wherein R is tert-butyl or benzyl,

c) the resulting ester of formula (VI ') wherein R _b R ₂ , R ₅ , R ₍ "R ₇ , n and m" have the same meanings as given for the compound of formula I) is cyclized in a basic medium to prepare compounds of formula (I),

f) optionally separating the cis and trans isomers of the compound of formula (1) and optionally separating the enantiomers.

The present invention also includes a compound of formula (6)

.COR ₂

n-ch, coor s ₂ ^R j (VI ') in which R, R _b R ₂ , R _s , n and m have the same meanings as given for the compound of formula (I)>

deprotected by acid hydrolysis when R is tert-butyl, or by hydrogenation when R is benzyl,

d) the compound of formula (VI) thus obtained wherein

A 'is NR ₆ R ₇ ,

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

R ₂ is 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, alkoxy 1-4 carbon atoms, halogen, trifluoromethyl, amino, or

R ₂ represents a nitrophenyl group unsubstituted or substituted once with trifluoromethyl or once or several times with an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms or a halogen,

R ₅ is C 1-4 alkyl, 1-naphthyl, 2-naphthyl, 5-dimethylamino-1-naphthyl, phenyl, unsubstituted or substituted by one or more substituents selected from halogen, alkyl C 1-4 alkyl, trifluoromethyl, amino, free or substituted by one or two C 1-4 alkyl, hydroxyl, C 1-4 alkoxy, C 2-4 alkenoxy, C 1-4 alkyl up to 4 carbon atoms, trifluoromethoxy, benzyloxy, cyano, carboxy, 1 to 4 carbon alkoxycarbonyl, carbamoyl, free or substituted by one or two of 1 to 4 carbon atoms, or 4 to 4 carbon atoms, and 1 to 4 carbon atoms; 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, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio R 6 represents an alkyl group having 1 to 6 carbon atoms or similar to R ₇ , or a carbon atom, a trifluoromethoxy or a benzyloxy group;

R ₇ is 4-piperidyl, 3-azetidinyl optionally substituted on nitrogen with C 1 -C 4 alkyl, benzyloxycarbonyl or C 1 -C 4 alkoxycarbonyl, (CH ₂ ) _r substituted with 2 -, 3- or 4-pyridyl, hydroxyl, amino, free or substituted by one or two C 1 -C 4 alkyl, carboxyl, C 1 -C 4 alkoxycarbonyl, benzyloxycarbonyl, carbamoyl, free or substituted by one or two alkyl groups having 1 to 4 carbon atoms, and R _fi and R ₇ together form with the nitrogen atom to which they are attached, a heterocycle selected from the group consisting of:

morpholine, thiomorpholine, thiazolidine or 2,2-Dimethyl-thiazolidine, unsubstituted or substituted _with R, piperazine, unsubstituted or substituted at the 4-position _with R, an unsaturated five-membered ring with one nitrogen atom substituted by R _8, or saturated three-, four -, five-, six-, or seven-membered ring with one nitrogen atom substituted by _Rg and R _9,

R _g is R ₈ or (CH _{2) r,} substituted hydroxy or amino group, free or substituted by one or two alkyl groups having 1 to 4 carbon atoms

R 5 represents a (CH ₂ ) _q group 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 one or two C 1 -C 4 alkyl groups, or aminocarbothiols an alkyl group, free or substituted by one or two alkyl groups containing 1 to 4 carbon atoms,

R ₈ is R _g, or a group (CH _{2) 2} NH _2, a free or substituted by one or two alkyl groups having 1 to 4 carbon atoms,

R ₉ represents hydrogen, halogen, (CH ₂ ) _r OR 1 _0, (CH _{2) r} NRnR _12, (CH _{2) n} CONR _a R _lb azido,

R ₁₀ represents hydrogen, C 1 -C 4 alkyl, mesyl, or tosyl; R _1b R 11 _and R ₁₂ each represent hydrogen or C 1 -C 4 alkyl, or

R 11 is hydrogen and R ₁₂ is benzyloxycarbonyl or C 1 -C 4 alkoxycarbonyl n is 0, 1 or 2, m is 0,1 or 2, q is 0,1, 2 or 3, r is 0 , 1, 2 or 3, with the proviso that r is not equal to 0 when R ₈ or R is in the α position to the intracyclic amide nitrogen, s is 0 or 1, which compound is an intermediate of the process for preparing an indole derivative of the general formula (I) .

The present invention also includes a pharmaceutical composition for the treatment or prevention of central nervous system, cardiovascular and gastric disorders in which vasopressin or ocytocin receptors are involved, comprising any indoline derivative containing an amide functional group as specified above and a pharmaceutically acceptable a carrier substance.

The indoline derivatives of the invention have an affinity for the vasopressin and oxytocin receptors.

Vasopressin is a hormone known to have an anti-diuretic and heat-regulating action. It stimulates several types of V _b V ₂ , V _1a , V _1D receptors and also has cardiovascular, central, hepatic, antidiuretic, emetic, aggregation, and also proliferative and mitotic effects, particularly on vascular and liver tissue. Vasopressin receptor antagonists may intervene in the regulation of central or peripheral circulation, particularly coronary, renal and gastric; as well as the metabolism of water and the release of adrenocorticotropic hormone (ACTH). Vasopressin receptors, like oxytocin, are also found on smooth uterine muscle. Oxytocin has a peptide structure close to vasopressin. Its receptors are also found on myoepithelial cells of the mammary gland and in the central nervous system (Presse Medicale, 1987, 16 (10), 481-485, J. Lab. Clin. Med., 1989, 114 (6), 617-632, and Pharmacol. Rev., 1991, 43 (1), 73-108).

Thus, the compounds 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.

Salts of the compounds of formula (I) according to the invention include salts with mineral or organic acids which allow for advantageous separation or crystallization of the compounds of formula (I) such as picric acid, oxalic acid or some optically active acid, for example mandelic acid or camphorsulfonic acid, and which form pharmaceutically acceptable salts such as hydrochloride, hydrogen sulphate, 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 salts of arginine, lysine or any pharmaceutically acceptable amine.

The compounds of formula (I) have around the bond

2.3 indoline cis-trans isomerism. Various isomers are therefore within the scope of the invention.

By convention, called the cis isomers of the compound of formula (I) wherein R ₂ and R ₄ are on the same side of the ring.

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

* 3 cis isomer

R5 trans isomer

Further, the compounds of the invention have two or more asymmetric carbon atoms because R 4 contains 1 or 2 asymmetric carbons. The optical isomers of the compounds I are also within the scope of the present invention.

In the description and claims below, halogen means a fluorine, chlorine, bromine or iodine atom; alkyl is understood to mean linear or branched hydrocarbon groups.

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,

- R ₂ is a chlorophenyl, a methoxyphenyl or a cyclohexyl.

- R 1 represents a group CONR ₆ R ₇ where R _f and R ₇ or NR ₇ R ₇ are one of the following definitions:

* NR _e R is pyrrolidino substituted in the 2-position with _{(CH2) q} which is substituted by carboxy or carbamoyl group, wherein q is 0, 1,2 or 3, * NR _'7 R is piperidino substituted in the 4 amino, C1 -C4 alkylamino or C1 -C4 dialkylamino; * NR _t R ₇ is thiazolidino substituted with (CH ₂ ) _q substituted with carboxyl or carbamoyl, wherein q = 0, 1,2 or 3 * DB _€ R ₇ is pyrrolidino substituted in the 2-position with _{(CH2) q} which is substituted by carboxy or carbamoyl group, wherein q is 0, 1, 2 or 3, and the 4-amino group, alkylaminodialkylaminoskupinou 1 -C 4 carbon atoms,

- R _f represents C 1-4 alkyl and R ₇ represents (CH 2), which is substituted by a carboxyl or carbamoyl group, wherein r = 1, 2 or 3,

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

- m = 0.

Particularly preferred are compounds 1 in the form of the cis isomer.

The following abbreviations are used in the description and examples:

DCM dichloromethane, AcOEt acetate, MeOH methanol, EtOH ethanol, ether ethyl ether, DMF dimethylformamide, THF tetrahydrofuran, TEA triethylamine, DMSO dimethyl sulfoxide, DIPEA diisopropylethylamine DCC N, N-dicyclohexylcarbodiimide, DBU l, 8-diazabicyclo [5.4.0] undec-7-ene, TBD l, 5,7-triazabiyklo [4.4.0] dec-5-ene, DBN 1,5-diazabicyclo [4.3.0] non-5-ene, DMAP 4-dimethylaminopyridine, DMPU 1,3-dimethyl-2-oxohexahydropyrimidinon, TMEDA tetramethylethylenediamine, LDA lithium, HMPA hexamethylphosphoramide, HOBT 1-hydroxybenzotriazole hydrate, BOP benzotriazolyloxytrisdi- TFA methylaminophosphonium, trifluoroacetic acid, Lawesso- novo reagent 2,4-bis (4-methoxyphenyl) -1,3-dithia-2,4-diphos- mp Fetan-2,4-disulfide, melting point, saline water saturated with sodium chloride, dry ice solid carbon dioxide, TLC thin layer chromatography, HPLC high performance liquid chromatography, NMR nuclear magnetic resonance, with s. m m, bs Extended Singlet D d. of hydrochloric water dilute hydrochloric acid around 1 A, 80% NaH sodium hydride dispersion in mineral Me oils (Jansen Chemica), methyl, Ee ethyl, Pr isopropyl, -pentyl isopentyl, iBu isobutyl, Bu t. butyl, Bu butyl, bz benzyl, ph phenyl, TM room temperature.

The 2-aminophenone derivatives of formula (II) are known or are prepared by known methods, for example as described in A. K. Singh et al., Synth. Commun. 1986, 16 (4), 485, and G. N. Walker, 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. Sukenik 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 Text Book of Practical Organic Chemistry, Longman, 3rd ed. 1956, p. 383, or G. Kirchner et al., J. Am. Chem. Soc., 1985, 107, 24, 7072.

Step a) of the above 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 catalytic or stoichiometric amounts.

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

If the -NR ₆ R ₇ group contains a second amino group, ie if R 8 and / or R ₇ is substituted with an amino group, the halogenated derivative (V) of formula IIa-CH ₂ -CO ₂ R where R is tert-butyl or benzyl may be chosen , for the preparation of intermediates of formula (VII ') 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 charcoal when R is benzyl or in an acidic environment if R is tert-butyl 1 e.g. 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 HOBTaDCC.

For example, the stereospecific synthesis of (R) and (5) 2-pyrrolidinylacetic acid is carried out according to H. Rueger et al. In Heterocycles, 1982, 19 (9), 1677, using the starting HNR (R ₇ ). The preparation of N-Boc-methyl-3,4-dehydro (a) prolinate is carried out according to JR 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 (24), 4039-4062.

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

Step e) of the process corresponds to the aldolization reaction: deprotonating the methylene group at position a of the amide, then the carbonyl group of the phenone acts as an internal electrophile, resulting in cyclization to give two asymmetric carbon atoms (C *).

The reaction can be illustrated by the following scheme:

The principles of aldol addition were summarized by C. H. Heathocock in Asymmetry Synthesis, Vol. 3: Stereodifferentiating addition reactions, Part B, 111-112; Academic Press, 1984, J.D. Morrison ed.

It is known that the aldol reaction of anionic achiral amides leads to the formation of two racemic diastereoisomers of β-hydroxyamides in a ratio that largely depends on the 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.

If the groups R ₆ and R ₇ do not contain an alkali-hydrolysable functional group, an aqueous solution of sodium hydroxide can be used in the presence of another solvent with or without the addition of a phase transfer catalyst; it is also possible to use quaternary ammonium hydroxide, for example benzyltrimethylammonium hydroxide in methanol.

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

- 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, in a solvent or solvent mixture selected, for example, from 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, step e) of the process of the invention is carried out in the presence of 1,8-diazabicyclo [5.4.0] undec-5-ene (DBU) in a solvent such as dichloromethane or methanol at a temperature between -10 ° C and reflux temperature solvent.

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

The alcoholate is used in a catalytic or stoichiometric amount in an anhydrous solvent 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-crown- 6-ether; the reaction takes place between -15 and 80 ° C.

The use of the RR'NLi or RR'NMgBr type amides, where R and R 'are monovalent residues, as a deprotonating agent, is a method of formation of amide enolates which are intermediates of the aldolization reaction; this method was recently reviewed by R. E. Ireland et al., J. Org. Chem., 1991, 56, 650. The reaction solvent may be benzene, hexane or THF, used in anhydrous form under an inert atmosphere. Additional agents such as LiF, LiCl, LiBr, LiI, LiBu, TMEDA, DMPU, IIMPA or crown ether may be added (M. Murakata et al., J. Chem. Soc. Commun., 1990, 1657). An example is the use of lithium diisopropylamide between -78 and -30 ° C in anhydrous THF in an inert atmosphere or in THF in the presence of additives such as tetramethylenediamine, DMPU or HMPA. Other known and useful amides are, for example, lithiumcyclohexylamide 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 butyllithium in hexane, the reaction being carried out in one of the solvents mentioned.

Finally, various publications describe amides of optically active secondary amines: L. Duhamel et al., Bull. Soc. Chim., 1980, 45, 755; Murakata et al., J. Chem. Soc. Chem. Commun., 1990, 1657; Yamaguchi, M., Tetrahedron Lett., 1986, 27 (8), 959; P.J. Cox and N.S. Sitnpkins, Tetrahedron: Asymmetry, 1991, 2 (1), 1.

Lithium, sodium or potassium silylamides form another group of useful bases, among which (Me ₃ Si) ₂ NLi, (Me ₂ PhSi) ₂ NLi, (Et ₃ Si) ₂ NLi, (Me ₃ Si) ₂ NK, ( Me ₃ Si) ₂ NNa.

It is also possible to use mixed amides such as those described by Y. Ymamot, Tetrahedron, 1990, 46, 4563, for example the lithium salt of N (trimethylsilyl) benzylamine or an analogue in which benzylamine is replaced by a primary chiral amine such as (R) or (5). ) α-methylbenzylamine.

If the compound of formula (I) to be prepared contains two asymmetric carbon atoms, the cyclization step c) may be accompanied by enrichment with diastereoisomers and the formation of these diastereoisomers may be modified by using 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 column, 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.

If the compound of the invention contains three or four asymmetric carbon atoms, the 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 carried out, for example, associated with an Overhauser (NOE) study, 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 often has a thick, thin and symmetrical absorption band of about 3550 to 3520 cm ^-1 due to hydroxyl vibration, 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 (60F 254 neutral, type E, Merck) eluting with DCM containing a varying portion of AcOEt. Similarly, in column chromatography on alumina (alumina 90, granulometry 0.063-0.200 mm), eluting with DCM containing a varying amount of AcOEt or MeOH most often elutes the cis isomer as the first.

Thus, the cis or trans isomerism of a compound of formula (I) of the invention is most commonly determined by 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.

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.

A compound of formula (I) wherein R 1 is amino, and / or a compound wherein R ₅ is phenyl substituted with an amino group can be prepared by catalytic hydrogenation of compound VI obtained in step b) wherein R 1 is nitro or R ₃ is phenyl a nitro substituted group and other substituents have the desired meanings for Compound I, for example in the presence of palladium on carbon, rhodium on alumina, or Raney nickel.

The compounds of formula (I), wherein R 'and / or R _7, or NR ₆ R ₇ includes an alkoxycarbonyl group having 1 to 4 carbon atoms in the alkoxy allow ester hydrolysis to obtain compounds I wherein R ₆ and / or R ₇ or the group NR ₆ R ₇ contains a carboxyl group and the other substituents of compound I are unchanged. In addition, compounds wherein R 6 and / or R ₇ or NR ₇ R ₇ contains a carboxyl group make it possible by classical amide condensation to prepare compounds of formula (I) wherein R ₇ and / or R ₇ or NR ₇ R ₇ contain a carbamoyl group, free or substituted one or two C 1-4 alkyl, and the other substituents are the same.

Finally, the compound of formula (I), wherein IU, and / or R ₇ or NR ₆ R ₇ contains a carbamoyl group make it possible to prepare the Hofmann rearrangement of a compound of formula (I), wherein R $ and / or _R7 or the group NR E ₇ comprising amino and other substituents are identical (J. Org. Chem., 1979, 44 (10), 1746).

A process for the preparation of compounds of formula (I) wherein R ₆ and / or R ₇ or NR ₆ R ₇ contains an amino group, free or substituted by two C 1 -C 4 alkyls, may thus have two variants:

(i) step (b) is carried out by treating a compound of formula (IV) obtained in step (a) with a halogenated derivative of formula (V) of formula IIa-CH, CONR ₆ R ₇ , wherein R ₇ and / or R 7 ₇ or NR @ 1 - R @ - contains an amino precursor, for example a carboxyester, carboxy or carbamoyl; then the cyclization step e) is carried out and then the amino precursor is converted to an amine, 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; by treating the compound IV obtained in step a) with a halogenated derivative of the formula IIa-CH ₂ COOR, wherein R represents benzyl or tert-butyl; the ester of the compound of formula (VII ') thus obtained is deprotected in an appropriate manner according to step c); followed by further condensation with a compound HNR _O R ₇ wherein R ₆ and the amino group R ₇ is optionally protected; the thus obtained compound VI is then cyclized according to step e) and optionally the compound of formula (I) wherein the amino group is free is prepared by removing the amine protecting groups.

The compounds of formula (I), wherein R ₆ and / or R _7, or NR _e R ₇ comprises a substituent of the amino group is benzyloxycarbonyl or alkoxycarbonyl group enable the compounds of formula (I) wherein the free amino group and the other substituents are the same.

Compounds of formula (VI) useful as intermediates in the preparation of compounds (I) of the invention are novel and are therefore within the scope of the present invention. Compounds VII and VI are also novel and are also within the scope of the present invention.

The invention therefore also relates to the compounds of formula (6).

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 V sites and in the membranes of mouse liver. The 50% inhibitory concentration (CI ₅₀ ) of the compounds of the invention for the fixation of tritiated vasopressin is weak, reaching up to 10 ^-9 M.

In addition, vasopressin-induced platelet aggregation inhibition 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 to 100 nM, with weak DI ₅₀ (inhibitory doses) of up to 10 ^-9 M. These results demonstrate the antagonist activity of the compounds of the invention against the V 1 receptors.

The affinity of the compounds I according to the invention for the V ₂ receptors was measured by the 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 the V1 receptor.

The affinity of the compounds of formula (I) of the invention for oxytocin receptors was determined by in vitro displacement of tritiated oxytocin, fixed on receptors of the membrane preparation of glandular mice. The IC ₅₀ values of the compounds of the invention are weak and are 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 hypertension, cardiac insufficiency, thrombosis or coronary vasospasm, particularly in smokers; diseases of the central nervous system such as cerebral endemas, psychotic conditions, appetite disorders, 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 atherosclerosis.

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

The present 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, intratracheal, intranasal, transdermal or rectal administration, the active compounds of formula (I) or their possible salts may be administered in unit dosage form in admixture with conventional pharmaceutical carriers for animals and humans for the prophylaxis or treatment of said 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, subcutaneous, intramuscular or intravenous administration or rectal administration forms. 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 can be administered 1 to 5 times a day so that the daily dose is 0.5 to 5000, preferably 1 to 2500 mg.

When a solid composition is prepared in the form of tablets, the main active ingredient is mixed with a pharmaceutical vehicle such as gelatin, starch, lactose, magnesium stearate, talc, acacia and the like. The tablets may be coated with sucrose, a cellulose derivative, other suitable materials, or processed in such a way that 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 syrup or elixir form or for application in the form of drops may contain the active ingredient in association with a sweetening agent, preferably non-caloric, with methylparaben and propylparaben as antiseptics, and further with a flavoring agent and a suitable colorant.

Water dispersible powders or granules 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, suppositories are used which are 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 also be formulated in the form of microcapsules, optionally with one or more carriers or excipients.

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

Accordingly, a further aspect of the present invention are pharmaceutical compositions comprising the combination of several active ingredients.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 shows the NMR spectrum of the cis isomer (Example 19).

Figure 2 shows the NMR spectrum of the trans isomer (Example 20).

Figure 3 shows the NMR spectrum of the trans isomer (Example 23).

Figure 4 shows the NMR spectrum of the cis isomer (Example 24).

Figure 5 shows the NMR spectrum of the cis isomer (Example 34).

Figure 6 shows the NMR spectrum of the cis isomer (Example 32c).

DETAILED DESCRIPTION OF THE INVENTION

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

Compounds are characterized by melting point - tt (or boiling point -1, v.) In ° C or NMR spectra measured at 200 MHz in DMSO, or optical rotation (α _D ) measured at 25 ° C (unless otherwise stated) ).

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 "cis isomer" or "trans isomer" mean that the isolated compound is a mixture of enantiomers of either the cis configuration or the trans configuration.

The optical purity of the compounds is determined by high performance liquid chromatography (HPLC).

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

A) Methyl N-bromoacetyl sarcosinate

This compound was prepared according to T. D. Harris et al. in J. Heterocyclic Chem., 1981, 18, 433.

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 ° C for 48 h in the presence of 20 g of 3,4-dimethoxyphenylsulfonyl chloride. The mixture is cooled, poured into ice water, the solid is filtered off, extracted with AcOEt, the organic phase is washed with water, 1 N hydrochloric acid solution, water and then with aqueous brine. After drying over magnesium sulfate and evaporation of the solvent in vacuo, a solid is obtained which is recrystallized from DCM / isopropyl ether.

m = 28 g

1.1. = 125-128 ° C.

C) 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 80% 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). Recrystallize from DCM / isopropyl ether / MeOH.

m = 3.2g

1.1. Mp = 136-137 ° C

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

3.2 g of the product obtained in the previous step are dissolved in 3 ml of DCM, 750 mg of DBU are added and stirred for 24 h at room temperature. Pour the reaction mixture onto a silica column; elution with DCM / AcOEt (90/10, v / v) gave the product as 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; v / v). The least polar compound was eluted with DCM / AcOEt (60/40; v / v) and then recrystallized from DCM / hexane / isopropyl ether.

1.1. = 95 ° C with gas evolution

Examples 2 and 3

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

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. Within 30 min. 20.2 g of bromoacetyl bromide in 100 ml of ether are added and the mixture is allowed to reach room temperature. After 4 h, the reaction mixture was washed with water, dried, concentrated and then chromatographed on silica. The expected compound is eluted with DCM / AcOEt (95/5; v / v) and recrystallized from DCM / isopropyl ether.

m = 9 g

1.1. 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 DCM / AcOEt.

1.1. Melting point = 164 DEG

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

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) are added and stirred for 60 h at room temperature. The reaction mixture is poured into water, the precipitate is filtered off, taken up in DMC, then dried, concentrated and chromatographed on silica. The expected product is eluted with DCM / AcOEt (90/10; v / v) and crystallized from DCM / isopropyl ether.

m = 2g

1.1. Melting point = 173-175 ° C

D) 2 - [(4-Benzylocycarbonyl) -1-piperazinyl] carbonyl-5-chloro-3- (2-chlorophenyl) -1- (3,4-dimetoyphenylsulfonyl) -3-hydroxyindoline, cis isomer and trans g isomer of compound The residue obtained in the previous step is suspended in 20 ml of methanol and 20 ml of THF and 75 mg of sodium methylate is added. After 2 h, the mixture is 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 concentrated. The crude product is chromatographed on alumina; 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

1.1. Mp = 169-179 ° C

The most polar isomer was recrystallized from DCM / isopropyl ether.

m = 200 mg

1.1. 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 is eluted with MeOH / DCM (10/90; v / v) and recrystallized from DCM / isopropyl ether. m = 110 mg

1.1. Mp = 230-233 ° C

Examples 5 and 6 5-Chloro-3- (2-chlorophenyl) -1,3,4-dimethoxyphenylsulfonyl) -3-hydroxy-2-morpholinocarbonylindoline, cis and trans isomers

A) 2 ', 5-Dichloro-2- [N- (3,4-dimethoxyphenylsulfonyl) -N-morpholinocarbonylmethyl] aminobenzophenone

5 g of 2 ', 5-dichloro-2- (3,4-dimethoxyphenylsulfonamido) -benzophenone was treated with 350 mg of 80% sodium hydride in 30 ml of DMF for 20 min at room temperature. 4.5 g of bromoacetamide are added and then stirred at room temperature for 48 h. The reaction mixture was poured into water, the precipitate was filtered off, dissolved in DCM, dried and concentrated. The resulting product was recrystallized from DCM / isopropyl ether. It will be obtained

5,4 g.

1.1. Mp = 173-176 ° C

B) 5-Chloro-3- (2-chlorophenyl) -1- (3,4-dimethoxyphenylsulfonyl) -3-hydroxy-2-morpholinocarbonylindoline, cis isomer of the product obtained in the preceding step is dissolved in a mixture of 10 ml methanol and 20 ml 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

1.1. MP 260-264 ° C

C) 5-Chloro-3- (2-chlorophenyl) -1- (3,4-dimethoxyphenylsulfonyl) -3-hydroxy-2-morpholinocarbonylindoline, trans isomer

Chromatography in the previous step yielded a more refined product eluting with AcOEt / MeOH (90/10; v / v). Recrystallization from DCM / isopropyl ether gave:

m = 513 mg; isomer trans

1.1. Mp = 240-241 ° C

Example 7 N-Methyl-N-carboxymethyl-5-bromo-3- (2-fluorophenyl) -1- (3,4-dimethoxyphenylsulfonyl) -3-hydroxy-2-indolinecarboxairide, 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 after 15 min. acidified to pH 3 by addition of potassium hydrogen sulphate solution. Water was added, extracted with AcOEt, washed with water, dried over magnesium sulfate, and the solvent was evaporated in vacuo. The product obtained is recrystallized from DCM / isopropyl ether.

1.1. MP 206-208 ° C

Examples 8 and 9 5-Chloro-3- (2-chlorophenyl) -1- (3,4-dimethoxyphenylsulfonyl) -3-hydroxy-2- (4-ethylcarboxylatepiperidinocarbonyl) indoline, cis isomer, trans isomer

A) Ethyl N-bromoacetyl 4-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-dichloro-2- (3,4-dimethoxyphenylsulfonamido) -benzophenone Dissolve in 100 mL of DMF, then add 541 mg of sodium hydride. After 30 min. stirring is added

9.5 g of the compound of Step A 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

1.1. 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 of 3.4 g of the compound obtained in the preceding step and 969 mg of DBU in 10 ml of chloroform was heated to 60 ° C over 18 h. The reaction mixture was then filtered on an alumina 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

1.1. Melting point = 187 DEG

Examples 10 and 11 N-Methyl-N- (2-pyridynlethyl) -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 gradually added and then 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 then recrystallized from DCM / isopropyl ether.

m = 136.5 g

1.1. = 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 added under nitrogen.

2.5 g of 5% Pd / C. The solution was stirred vigorously and hydrogen was bubbled through the solution for 5 h. Upon completion of hydrogenation, the product crystallizes. The reaction mixture is filtered through Celite ¹ *, the cake is washed extensively with warm DCM and then the organic phase is concentrated. The expected product crystallizes and 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) carbamoylmethyl] aminobenzophenone g prepared by in step A, was taken up in 30 mL of DCM and 1.13 g of 2- (2-methylaminoethyl) pyridine was added, followed by 844 mg of triethylamine and finally 1.92 g of BOP, and then the mixture was stirred at room temperature for 18 h. Then the mixture is taken up in water, the organic phase is decanted, washed with sodium carbonate solution, dried and concentrated. After chromatography on silica, the expected product is eluted with DCM / MeOH (95/5; v / v).

m = 2g

1.1. = 150 ° C

C) N-Methyl-N- (2-pyridylethyl) -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 alumina. AcOEt / DCM (40/60; v / v) eluted with cis: m = 410 mg

1.1. Melting point = 191 DEG

Pure AcOEt elutes trans: m = 790 mg

t. t. = 154 ° C

Example 12 2- (4-Carboxypiperidinocarbonyl) -5-chloro-3- (2-chlorophenyl) -1- (3,4-dimethoxyphenylsulfonyl) -3-hydroxyindoline, cis isomer

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 (95/5; v / v); then the product obtained is crystallized from DCM / isopropyl acetate.

m = 250 mg

1.1. = 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

A) 2 ', 5-Dichloro-2- [N- (3,4-dimethoxyphenylsulfonyl) -N- (N'-methyl-N'-methyl-4-piperidyl) carbamoylmethyl] aminobenzophenone g of the acid prepared in Example 10 to Step 11, in 50 mL of DCM, was 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. It is then chromatographed on silica eluting with DCM / MeOH (90/10; v / v). 1.2 g of the expected product are obtained.

1.1. Mp = 165-166 ° C

B) N-Methyl-N- (methyl-4-piperidyl) -5-chloro-3- (2-chlorophenyl) -1- (3,4-dimethoxyphenylsulfonyl) -3-hydroxy-2-indolinecarboxymide isomer cis a isomer trans

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 on silica. 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

1.1. = 181 ° C cis isomer:

1.1. = 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 d. and the trans isomer

A) 2 ', 5-Dichloro-2- [N- (3,4-dimethoxyphenylsulfonyl) -N - ((4-methyl-1-piperazinyl) carbamoylmethyl)] aminobenzenenone

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

1.1. Mp = 165-167 ° C

B) 5-Chloro-3- (2-chlorophenyl) -1- (3,4-dimethoxyphenylsulfonyl) -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.

1.1. = 120 [deg.] C .; contains 0.25 M isopropyl ether.

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

1.1. 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 trans isomer

A) N-Isopropyl-N- (methoxycarbonylethyl) bromoacetamide g 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.

t. in. = 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 100 ml of DCM. After 12 h at room temperature, the solvent was evaporated, the residue was taken up in water, extracted 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) carbamoylmethyl] aminobenzophenone

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

1.1. = 135-137 ° C (recrystallization: DCM / isopropyl ether)

C) N-Isopropyl-N-methoxycarbonylethyl-5-chloro-3- (2-chlorophenyl) -1- (3,4-dimethoxyphenylsulfonyl) -3-hydroxy-2-indolinecarboxamide cis and trans isomers

This product is obtained by cyclizing the compound prepared by Input B in the presence of DBU. The cis isomer was separated by chromatography on alumina eluting with DCM / AcOEt (90/10; v / v). The product is then crystallized from AcOEt / hexane.

1.1. 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.

1.1. M.p. = 182-185 ° C

Examples 19 and 20 N-Methyl-N-methoxycarbonylmethyl-5-chloro-3- (2-chlorophenyl) -1- (3,4-dimethoxyphenylsulfonyl) -3-hydroxy-2-indolinecarboxamide cis and trans isomers

Both isomers of this compound were prepared by the procedure of Example 1. They were 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.

1.1. M.p. = 176-178 ° 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 cis and trans isomers

These compounds were prepared individually from the compounds described in Examples 19 and 20, following the procedure described in Example 8.

cis isomer; t. t. = 220 - 222 ° C after recrystallization from DCM / isopropyl ether / MeOH isomer trans: m.p. t. M.p. = 222-225 ° C after recrystallization from DCM / isopropyl ether

Examples 23 and 24

N-Methyl-N-carbamoylmethyl-5-chloro-3- (2-chlorophenyl) -1- (3,4-dimethoxyphenylsulfonyl) -3-hydroxy-2-indolinecarboxamide isomer cis and trans 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. 6 ml of a 20% ammonia solution are added at room temperature 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, described in Example 11-12, step A.

The procedure of Examples 11-12 is followed in the preparation

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. The cis / isomer is eluted with DCM / MeOH (99/1; v / v).

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 NMR spectrum at 388 K:

1-1.8 ppm: m: ₂ 4H.CH in the 3 and 5 of piperidine,

2.8 - 3.65 ppm: m: 5H: _CH2 at position 2 and 6 of the piperidine and CH at position 4,

3.75 ppm: 2s: 6H: 2 OCH _3,

4.15 ppm: d: 1H: OH on piperidine,

5.45 ppm: s: 1H: CH (indoline),

6.1 ppm: s: 1H: OH indoline,

6.8 - 7.6 ppm: m: 10H: armomatic H,

DMSO: 2.4 ppm,

DOH: 2.75.

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

1.1. Mp = 232-234 ° C

Syntheses in Proline (L): 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] indoline (cis isomers of 2 compounds)

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

To a solution of 16.7 g of methyl (L) methylprolinate hydrochloride in 20 ml of DCM was added simultaneously 20 g of triethylamine and 20 g of bromoacetyl bromide in 30 ml of DCM, 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 was dried in vacuo. This oil, pure by TLC, was 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 are dissolved under argon at 0 [deg.] C. in 40 ml of anhydrous DMF, 340 mg of 80% sodium hydride are added and then after 30 min. 6.5 g of the compound obtained in Step A. 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

1.1. = 141-142 ° C and _D ²⁵ = -43.7 ⁰ (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, pre-equilibrated in DCM / AcOEt (90/10; v / v), and eluted with DCM / AcOEt (90/10; v / v, up to 70/30; v / v). in). 510 mg of a 4/1 mixture of at least polar compounds (measured by HPLC) are obtained.

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

m = 180 mg and _D ²⁵ = -247 o (c = 0.4; chloroform)

1.1. 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. α _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 mixture (80/20; v / v). The ester (Example 27) which did not react was eluted 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.

1.1. = 232-234 ° C and _D ²⁶ = -254 ⁰ (c = 0.3; chloroform)

Examples 29 and 29a 2- (2S) -2-Carbamoylpyrrolidinocarbonyl) -5-chloro-3- (2-chlorophenyl) -1- (3,4-dimethoxyphenylsulfonyl) -3-hydroxyindoline isomers of cis: 2 compounds

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 for 5 min. at room temperature. The mixture was cooled in an ice bath and ammonia gas was bubbled through for 1 min. and then after 15 min. again 1 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 is carried out on silica eluting with a DCM / MeOH (93/7; v / v) mixture. The product obtained was triturated in DCM / isopropyl ether / hexane. It contains 1/3 mol of isopropyl ether.

α _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) -2-carbamoylpyrrolidinocarbonylmethyl)] 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 refluxed 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 prolineamide hydrochloride (L) 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 for 6 h in vacuo. Yield 42 g.

α _D ²⁵ = -40.8 "(c = 1.007; chloroform)

B) 2 - ((2S) -2-Carbamoylpyrrolidinocarbonyl) -5-chloro-3- (2-chlorophenyl) -1- (3,4-dimethoxyphenylsulfonyl) -3-hydroxyindoline (cis: 2 compounds) g product prepared in the previous step is dissolved in 50 ml of methanol. The mixture is cooled to -10 ° C, 1.35 g of DBU is added and the mixture is maintained at -10 ° C for 60 h. The compound crystallizes and is filtered off (compound cis 1). The mother liquors were neutralized with potassium hydrogen sulphate and the mixture was evaporated to dryness. The residue was taken up in water, extracted twice with DCM, dried and concentrated. The crude product is chromatographed on silica eluting with AcOEt / DCM (28/72; v / v). A mixture is obtained which is dissolved 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 and _D ²⁵ = -196 (c = 0.351; 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.

1.t. = 154-162 ° C and at ²⁵ = -204 ⁰ (c = 0.3; chloroform) and _D ²⁵ = -131 ° (c = 0.27; chloroform / methanol 8/2; v / v)

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

The compound which crystallized in step B), called cis 1, was recrystallized from methanol. mp = 190 ° C and _D = + 115 ° (c = 0.3; chloroform)

Example 30 5-Chloro-3- (2-chlorophenyl) -1- (3,4-dimethoxyphenylsulfonyl) -3-hydroxy-2 - [(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; v / v). 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 HPLC purity > 99%.

m = 155 mg

1.1. = 194-197 ° C. _D ²⁵ = -195 H (c = 0.2; chloroform)

Syntheses in Proline (D): Example 31.

Example 31 5-Chloro-3- (2-chlorophenyl) -1- (3,4-dimethoxyphenylsulfonyl) -3-hydroxy-2 - [(2R) -2 (methoxycarbonyl) pyrrolidinocarbonyl] indoline isomer cis

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

This compound was obtained from the compound prepared in Examples 10-11, step A) (3 g), to which was added 1.2 g of (D) methylprolinate 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 hour, 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.

1.1. = 140-141 ° C and _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.

1.1. = 186-188 ° C _D ²⁵ = +245 ⁰ (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- (N'-methyl-N'-methoxycarbonylmethyl) carbamoylmethyl] aminobenzophenone

5.7 g of 2 ', 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- (bromoacetyl) sarcosinate are added. 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 recrystallization from DCM / isopropyl ether.

1.1. Melting point = 158-160 ° C

B) N-Methyl-N-methoxycarbonylmethyl-5-chloro-3- (2-chlorophenyl) -1- (4-ethoxyphenylsulfonyl) -3-hydroxy-2-indolinecarboxamide, the trans g isomer of the compound obtained in the preceding step, is treated with Dissolve in 4 mL DCM and 90 min. at room temperature was treated with 312 mg TBD. 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) gave the expected product.

m = 590 mg

1.1. = 168-171 ° C after recrystallization from DCM / hexane

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

2.96 g of the compound obtained in Step A are suspended in 20 ml of methanol and 10 ml of THF, 100 mg of sodium methylate are added, and the mixture is then left in the refrigerator for 7 hours. Water was added, neutralized with potassium hydrogen sulphate solution, and some of the methanol was evaporated in vacuo. After extraction of AcOEt, chromatography on alumina and elution with DCM / AcOEt (80/20; v / v) mixtures are performed. 850 mg of the expected product is obtained, which is recrystallized from 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 15 products of VI are shown in Table 1. The prepared compounds I are shown in Table 2.

Table 1

R. ·. · R, · R, Tt ( ^e C) or IR dissipated Br 3,4-CH, O F- CH, N-Hs ^ CHjCOjCHjC 82-93 µM / isopropyl ether Cl 3.4-cap Cl CH, —N-CH3CH3CO3CH, 164-166 DMC / t-propyl ether Cl 3.4-CH, O Cl chloro and _{N-CH3 CH3} N- & 128 DCH / isopropyl Cl 3.4 * CH, O Cl Bt 1 —N-CH ₃ CH ₂ CO ₃ CH ₃ 105 DCN / isopropyl ether Cl 2,4-chjo Cl -> ξ ^ __ ^ H- EHJ COjCH 142-143 MeOH CH, O- 3,4-CH, Cl Et 1 —N-CH ₃ CH ₃ CO ₃ CH ₃ , IR (1) Cl 3,4-CH, O Cl IPentyl — N-CH ₃ CH ₂ CO ₂ CH 3 85 Isopropyl ether Br 3,4-CH, O C T — N-CH ₃ CH ₃ CO ₃ CH ₃ IR (2)

Cl 3.4-CH, O Cl / - \ ___/WITH 199 OCH11zopropyléter Cl 3,4-chjo Cl Pr N-CH 3 CO 3 CH, 135 Isopropyl ether / CCM / aOK Cl 3.4-CH, O C pr N-CKjCHjCOjCHj 113 BCK / ižepropyiéter Cl 3,4-chjo Cl bt N-CHjCOjCHj 160 Isopropyl ether Cl 3,4-CH, O Cl n -> - NHCO 3 -Bu 191-198 Cl 3,4-chjo Cl “ ^N C_ (31

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: α _D ²⁵ = -36.8 ⁰ (c = 0.44; chloroform)

Table 2

For each compound of formula (I) with the substituents R ' _b R' ₅ , R ' ₂ and NIQR7 shown in the table below, isomer cis, then isomer trans, unless otherwise indicated.

Table 2

Example · R, · R, R ' -n- ^Rí % (° C> or RMR Solvent) 33 34 Br 3,4-CH, O F- C »» -N- CHjCO ₃ CH ₃ C _e H 87-95 JMR 35 36 Cl 3.4-CH, O Cl C, —N — CH3CH3CO3CH3 100-183 154-157 BCE / nippylether 37 cis Cl 3,4-CH, O Cl <f H _S —N — CH 3 CH 3 CO 3 H 140-144 DCM / líopropyléter 38 smés Cl 3,4-chjo Cl CH ³ Bt 1 ³ 1 —N-CH ₃ CH ₃ N-Et 222-225 DCK / lzopropylŕter 39 40 Cl 3,4-chjo Cl Et 1 - N - CH ₃ CH ₂ CO ₃ CH ₃ NMR NMR 41 Ci8 Cl 3,4-chjo Cl Bt 1 —n-ch ₂ ch ₃ every ₃ h 166 DCM / isopropyl ether 42 43 Cl 3,4-CH, O Cl / ~ \ -CH, \ _ / ch 119 AcOEt / isopropyl ether 228 MeOH 44 cis Cl 3,4-chjo Cl ^{1 of} CH 3 -n-ch ₃ chK _ch > 179 DCR / lzopropyléter 5 46 Cl 3,4-chjo Cl N —N N-CH.CO.Ei \ y ^{1 1} 109 DCK / i2Opropylene 196 DCM / isopropyl ether 47 48 Cl 2,4-CH, O Cl / “Λ —__ y * ~ CO ₂ CH 3 C ₄ H ₃ : 134 (Pr) and : 195 t / C / t-propyl ether 49 cis Cl 3,4-chjo Cl Et f —N-CH3CH3CONH3 236 Isopropyl ether 50 51 CH, 3,4-CH.O C PART N-CHjCHjCOjCHj 154 isopropyl ether 87 isopropyl ether 52 cis Cl 2,4-CH, O Cl r ~ x 194 MeOR / lzopropyléter

53 cis Cl 3,4-chjo Cl lpentyl — 'N-CHjCHjCOjCH, 195 isopropyl ether / DOl 54 55 Br 2,4-CH, 0 Cl Et 1 - N - CH ₃ CH _: CO ₃ CH ₃ 138-140 isopropyl ether 140 isopropyl ether 56 57 Cl 3.4-CH, O CJ r ~ \ 242-245 DCM / isopropyl ether 225 HeOH / isopropyl ether r 58 58 a CL -CH 2.4> 0 Cl -NICH.) 228 MeOH / isopropyl ether 221 DCM / MCOI 59 59 a Cl 3,4-chjo Cl Et I —N — CH ₃ CH ₃ CH ₂ CO ₃ CH ₃ 131-134 D € M / isopropyl ether / bexene 121 DCM / ether / hexanes 60 61 Cl 3,4-CH, O Cl IBu N-CH3CH3CO3CH, 162-166 DCN / i isopropyl ether 130 DCM / 1-isopropyl ether / hexane 62 63 CL 3,4 -CH, O Cl Pr 1 —N-CH3CO3CH3 176 Isopropyl ether / DCM 1MR 64 65 Cl 3.4 cm, 0 Cl pr 1 N-CHjCHjCOjCHj 148 isopropyl ether / DCN 122 Isopropyl ether / DCM 66 67 Cl 3,4-chjo Cl et 1 N-CHjCOjCHj @ 1 H NMR; 168 _; isopropyl 68 cle Cl 3.4 -CH, O Cl IBu N - (CH ₂ ) 3 CO 3 H 179-182 DCM / isopropyl ether 69 cis Cl 3,4-chjo Cl Et 1 N-CH ₃ CO ₃ H 139 DCM / isopropyl ether 70 cis Cl 3,4-CH, O Cl pr 1 N-CHjCOjH 130 isopropyl ether 71 cis Cl 3,4-CH, O Cl et 1 N (CH) jCOjH 136 DCN / isopropyl 72 cis Cl · 3,4-CH, O Cl et 1 N-CH 3 - CONH, 135 1DCN / lzopropyléter

74 Cl 3.4-CH.O Cl nQ — HHCO, C (CH3), 19? MEOA / isopropyl 211 MeOH • »5 cis Cl 3,4-chjo Cl HXR 76 cis Cl 3,4-CH, O Cl íusarát 152-156 DCM / lzoprupyléter 76a 75b Cl 3,4-chjo Cl —Wd T — COjCHjC ^H, H : 137 isopropyl ether (MeOH) > hexane ; 183-185 hexane

Example 34 Analysis: calculated C 55.54%, H 4.24%, N 3.93% found 55.72% 4.57% 3.83%

NMR spectra at 200 MHz (DMSO: 2.5 ppm)

Example 34: FIG. 5

- Example 38

0.7-1.1 ppm: m: 6 H: 2 CH ₃ (Et)

- 4 ppm: m: 17H: 2CHj (Et) 2 CH ₂ N, N-CH _3, CH 2 OCH ₃

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

6.2-8.2 ppm: m: 11h: OH +

- Example 39

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

1.5 - 4.3 ppm: m: 15H: _{CH2-CO, CH2} (Et), CH ₂ -N, 2 OC _3, CO ₂ CH ₃

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

6.2 - 8.2 ppm: 11H: 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§, CH ₂ N, CO ₂ CH ₃ , 2OCH ₃

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

6.6-8.2 ppm: u: 1H: OH + aromatic

- Example 63

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

2.5 - 4.4 ppm: m: 13 H: CH ₂ CH ₂ CH _3, NCHjCOOCHj, 2 OCH ₃

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

6.5-8.3 ppm: u: 1H: OH + aromatic

- example 66

0-1.5 ppm: m: 3H: _CH2-CH

2.3 - 5.8 ppm: m: 14H: CH2-CH _3, NCH ₂ COOCH _3, CH 2 OCH _3, H (indoline)

6.1-8.3 ppm: u.c.: 1H: OH + aromatic

- Example 75

1.95 ppm: bs: 2H: _NH2

2.7 - 5.3 ppm: m: 12H: 2 OCH _3, 2 NCH _2, H (indoline), C H NH ₂ 6 to 8.3 ppm: m: 11 H: OH + aromatics

- Example 76a and ^₂₅ = + 102 ° (c = 0.35, chloroform)

Example 76b and _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 MeOH / H ₂ O in methanol. Compound 49 is prepared by treatment with ammonia in the presence of DIPEA and BOP.

Example 77

N-Ethyl-N- (2-aminoethyl) -5-chloro-3- (2-chlorophenyl) -1- (3,4-dimethoxyphenylsulfonyl) -3-hydroxy-2-indolinecarboxamide 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 (trifluoroacethoxy) iodobenzene were added. The extract is dried and concentrated to give an oil, the expected product is then crystallized from ether. m = 150 mg

1.1. Melting point = 164 DEG

Example 78

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

A) N- [2- (2-chlorophenylcarbonyl) -5-chlorophenyl] -N- (3,4-dimethoxyphenylsulfonyl) glicinic acid chloride

A mixture containing 11 g of the acid prepared in Examples 10 to 11, 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, the residue taken up in DCM (twice). A yellow oil is obtained which is used as is in the following stage.

IR: 1800cm-1 (C = 0)

B) 2 ', 5-Dichloro-2- [N- (3,4-dimethoxyphenylsulfonyl) -N-N' -ethyl-N '- ((1S) -1- (ethoxycarbonylethyl) ethoxycarbamoylmethyl) 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) AlaOEt 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, cooled to -78 ° C, and two equivalents of TEA and the acid chloride prepared in the previous step dissolved in DCM were added. After 18 h at room temperature, the mixture was extracted with DCM, washed with water and then chromatographed on silica eluting with DCM / AcOEt (90/10; v / v). The expected product crystallizes from isopropyl ether.

1.1. M.p. = 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 previous step was stirred at room temperature in 10 ml of THF and 20 ml of ethanol for 18 h in the presence of 1.46 g of DBU. The mixture was concentrated in vacuo, the residue taken up in DCM, washed with water, concentrated and the product chromatographed on alumina eluting with AcOEt / DCM (10/90; v / v).

NMR:

0.9 ppm: doubled d: 3H; CH-CH3

0.9 -1.7 ppm: m: 12H: 20CH3, NCH _second OCH 3, NCH, COCH

6.1-8.3 ppm: u.c.: 1H: OH -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 isomer cis a isomer trans

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.

t r = 135-140 ° C at 0.6 mm Hg m = 30 g IR: 1730 cm ^-1

B) N, N- [2- (Dimethoxycarbonyl) ethyl] amine

27.9 g of the amine obtained in the previous step, in 500 methanol, are 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 alone in the next step.

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

A mixture containing 14.3 g of the amine prepared in the preceding step, 100 ml of DCM and 10.6 ml of TEA is cooled in an ice bath; 15.3 g of bromoacetyl bromide are added dropwise and 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 as an oil.

m = 15.9 g

IR: 1650 cm ^-1 and 1730 cm ^-1

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

14.3 g of 2 &apos;, 5-dichloro-2- (3,4-dimethoxyphenylsulfonamido) benzophenone are poured over 180 ml of DMF and added portionwise

1.1 g of sodium hydride. 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 chromatography on silica eluting with DCM / AcOEt (93/7; v / v).

m = 28.4 g

1.1. = 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, 12 g of the compound prepared in the preceding step and 0.930 g of sodium methylate are mixed in 150 ml of methanol and the mixture is 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. Melting point = 175 DEG

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

Chromatograph 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.

1.1. = 85 ° C

Examples 81, 82 and 83 2 - ((2R) -2-Carbamoylthiazolidinocarbonyl) -5-chloro-3- (2-chlorophenyl) -1- (3,4-dimethoxyphenylsulfonyl) -3-hydroxyindoline isomer cis: two compounds, isomer trans

A) (L) -4-Thiazolidinecarboxamide

This compound was prepared according to J. Med. Chem., 1981, 24,962.

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.

1.1. = 125 ° C after crystallization from ether

C) 2 - ((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 was concentrated, taken up in water and DCM, decanted, washed with potassium hydrogen sulfate, 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 a trans (mixture of two diastereoisomers), m = 1 g.

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

1.1. = 176 ° C after crystallization from isopropyl ether and _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; v / v). The obtained cis 2 compound is recrystallized from ether.

1.1. = 205 ° C and _D = -185 ° (c = 0.3, chloroform)

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

1.1. Melting point = 170 DEG

Examples 84, 85.86 and 86a 5-Chloro-3- (2-chlorophenyl) -1- (3-dimethoxyphenylsulfonyl) -3-hydroxy-2 - [(2S) -2- (N, N-dimethylthiocarbamoyl) -pyrrolidinocarbonyl ) indoline isomerism cis: 2 compounds, trans isomerism trans: 2 compounds

A) (L) - (N'-Boc) -N, N-dimethylprolintioamide

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

It is heated under argon in anhydrous toluene for 4 h

2.36 g of (N'-Boc) -N, N-dimethylprolinamide in the presence

2.3 g of Lawesson's 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). DCM / isopropyl ether obtained (30/70; v / v).

1.1. = 62 ° C

B) 2 ', 5-Dichloro-2- [N- (3,4-dimethoxyphenylsulfonyl) -N - ((2S) -2- (N', N'-dimethylthiocarbamoyl) pyrrolidinocarbonylmethyl)] aminobenzophenone g of the product prepared in the previous step , was dissolved in 10 mL of DCM and treated with 10 mL of TEA at 0 ° C for 2 h. The mixture was evaporated to dryness, 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.

Dissolve 5.15 g of BOP in 30 mL of DCM and add this solution 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 at 0 ° C for 3 h. 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; v / v). The product obtained is recrystallized from isopropyl ether.

1.1. 182-185 ° C and _D = -72 ° (c = 0.32, chloroform)

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

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

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.

1.1. = 270 ° C and _D = -278 ⁰ (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.

1.1. = 249-251 DEG C. _D = +42 ⁰ (c = 0.22, chloroform)

c) Combine the fraction from the last eluted chromatography and the mother liquors from the crystallization of fractions a) and b) and re-chromatograph on silica eluting 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.

1.1. = 191-193 ° C and _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.

1.1. = 170 ° C and _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 a

39.5 g of 3,4-dimethoxyphenylsulfonyl chloride in 340 ml of pyridine is left under stirring at room temperature for 24 h. 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.

M.p. = 135 DEG 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-dimethoxyphenylsulfonyl) glycine

The compound obtained in the previous step was placed under 3.9 g of 5% palladium on carbon in 700 ml of acetic acid under hydrogen (1 atmosphere). After completion of the reaction, the palladium is filtered off on Celite ^R 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.

1.1. M.p. = 160 DEG C. m = 22.4 g

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

A mixture containing 9.92 g of the acid prepared in the preceding step, 3 g of (L) -prolinamide hydrochloride and

3.5 mL of DIPEA in 75 mL of DCM was 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 is extracted with DCM, washed with saturated sodium bicarbonate solution, 5% potassium hydrogen sulfate solution and again with brine. Chromatograph on silica eluting with DCM / MeOH (96/4; v / v). The expected product solidifies in isopropyl ether.

1.1. = 110 ° C m = 7.3 g ct _D = -53.9 ° (c = 1, chloroform)

E) 2 - ((2S) -2-Carbamoylpyrrolidinocarbonyl) -5-chloro-3-cyclohexyl-1- (3,4-dimethoxyphenylsulfonyl) -3-hydroxyindoline, 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 are stirred at 0 DEG C. for 48 h. Evaporate the solvent in vacuo, add water, extract with DCM and then wash with 5% potassium bisulfate solution. Chromatograph on alumina eluting with DCM / MeOH (98/2; v / v).

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

1.1. = 185 ° C

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

1.1. = 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 and _D = -55.1 "(c = 1, chloroform)

Example 89a

2 - ((2S) -2-Carbamoylpyrrolidinocarbonyl) -5-chloro-3-cyclohexyl-1- (3,4-dimethoxyphenylsulfonyl) -3-hydroxyindoline isomer 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 the trans configuration.

1.1. = 238 ° C and _D = +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-hydroxyindoline isomer cis

920 mg of the compound prepared in Example 28 was taken for 15 min. Stir in 20 mL of DCM containing 371 mg of BOP, then leave for 10 min. a stream of monomethylamine was bubbled through and a further 30 min. stirring is maintained. 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. = 158 ° C and _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 α

R ' x ^R 6 —nC * 7 MP: CC) (Chloroform) 3,4-chjo r ~ ^<D> ^ CONH] > 45 c · 1.015 3,4 -CH, O tulle COOCH, 161-163 DOI / isopropyl -70.8 C · 0.48 2,4-chjo COOCHj 145-148 -17.5 c = 3.36 3,4-CH _0} -P « coocHj — σ ý > 110 pCK / isopropyl ether 3,4-01,0 ty] CHjCOOCHj 149 IsopropyWter / NeOR

Table 4

Example · R, R \ - <* · R, MP: t'C) i »(chloroform) 91 cle 1 Cl 3.4 -CK, O (W —N 115 MeOH * 188 C. 0.33 92 cle 1 Cl HA-1 CONH 204 MeOH / OMF • 114 C «0.31 93 C sharp Cl 3,4-CH, O tulle COOCHj 198-201 DCM / isopropyl ether 94 C sharp Cl 2,4-CH, 0 tfl COOCHj 295-207 DCM / isopropyl ether 95 C sharp Cl 2.4-CH, O tfl COOH 221 & CH / lz propyl ether -242 e «0.254 95 C sharp Cl 3,4-chjo COOCHi — C 7 -234 C «0.32

SK 283463 Β6

97 cis Cl 3,4-CH | H s CON _(CH3) j -214 c «0.32 99 cle i 99 duty 2 100 trans 1 101 trans 2 Cl 3.4-σί, Ο s CHjCOOCHj 105-115 DCV from ether 175 DCN / lzoprowUter 17? DCH / isopropyl * 374.6 C - 0.3 -214.6 c - 0.3 -155 C, 0.2 * 95.2 C 0,2 0.2 102 cle 1 Cl 3,4-chjo s CHjCOOH 135 isopropyl ether -162 103 cl »1 Cl 3,4-CH, O τΡ CHiCONH ₂ 145 DCl / isophyl ether 103a cis 1 cis 2 Cl 3,4-chjo clay ČHjCONHj 104 cis 1 Cl 3,4-chjo s CHjHHj 210 ether -177.5 c = 0.2 104a cis cis Cl 3,4-CH, O s ČHjNHj

105 106 CH, O 3,4-CH, O s CON] 200 ECOH 215 NeOH -195 c = 0.2 ♦ 127 c 0.2 107 CH, O 3,4-CH, O 's CON, 198 -63.3 c · 0.117 (CHCl 3) MeOH β / 2 · ν / ν) 108 Cl 2,4-CH) H s CON] 274 DCM / MeCH -225 C = 0.372 (CHCl 3 / MeOH 6/2; v / v) 108a C sharp Cl 3,4 -CH, O s CONROH -198.7 ° C 0.24

* Example 92: other measured optical rotation: α _D ²⁵ = -39.5 ° (c = 0.17; CHCl 3 / MeOH, 8/2, v / v)

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

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

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), isomer cis

A) 2 ', 5-Dichloro-2- [N- (3,4-dimethoxyphenylsulfonyl) -N - ((2S, 4R) -4-hydroxy-2- (methoxycarbonyl) pyrrolidinocarbonylmethyl)] 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. Within 30 min. a solution of 12.7 g of BOP in 30 ml of DCM is added dropwise, 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.

1.1. = 128-131 ° C and _D = + 8.5 ^° (c = 0.38; chloroform)

B) 2 ', 5-Dichloro-2- [N-3,4-dimethoxyphenylsulfonyl) -N - ((2S, 4R) -4-mesyloxy-2- (methoxycarbonal) pyrrolidinocarbonylmethyl)] aminobenzophenone g of the compound prepared in the previous step, was dissolved in 10 mL of DCM at 0 ° C. 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 sodium bicarbonate solution, dried over magnesium sulfate and evaporated. The oil obtained is used as such in the next step.

C) 2- [N - ((2S, 4S) -4-Azido-2- (methoxycarbonyl-pyrrolidinocarbonylmethyl) -N- (3,4-dimethoxyphenylsulfonyl)] amino-2 ', 5-dichlorobenzophenone g of the product obtained in the previous step The mixture was poured into water, extracted with ethyl acetate, the organic layer was washed with water, dried and chromatographed on silica eluting with a pentane / hexane mixture. AcOEt (50/50; v / v) to give an oil (10 g) and _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 C sharp

3.38 g of the product obtained in the previous step are cyclized under conventional conditions in the presence of DBU. The expected product is recrystallized from DCM / isopropyl ether.

m = 755 mg

1.1. = 200-202 ° C and _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- (2-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 then the mixture is stirred for 12 h at 0 ^° C and 4 h at 60 ° C. Water is added, extracted with ethyl acetate, the organic phase is washed with water, potassium hydrogen sulphate solution (four times), water and then brine. After evaporation, an oil (21.6 g) containing a small amount of (Boc) ₂ O was isolated.

B) (2S, 4R) - (N-Boc) -4-Mesyloxyproline methyl ester

A solution of 22.9 g of the product prepared in the previous step in 250 ml of DCM was cooled to 0 ° C. 22.9 g of mesyl chloride in 10 ml of DCM are added dropwise, then 9.4 g of triethylamine in 100 ml of DCM are added dropwise and the mixture is allowed to reach room temperature overnight. Evaporate to dryness, add water, extract with 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). a _D = -37.8 ₀ (c = 3; chloroform) lit. _D = -36.6 ° (c = 2.8; chloroform), DJ Abraham et al., J. Med. Chem., 1983,549, 26.

D) (2S, 4S) - (N-Boc) -4-aminoproline 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 is filtered off, half of the methanol is 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 is extracted with AcOEt (m = 4.35 g).

E) (2S, 4S) - (N-Boc) -4-N '-benzyloxycarbonylamino) proline methyl ester

The crude product obtained in the previous step was dissolved in 15 mL of ether and 15 mL of DCM at 0 ° C. Add 2.3 g of DIPEA, then over 70 min. at 0 ° C 3.03 g of benzyl chloroformate in 5 mL of DCM. After 3 h the solvents were evaporated in vacuo at room temperature; water and ethyl acetate are 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. Chromatograph on silica eluting with hexane / AcOEt (40 / 60Ô v / v) to give the expected product. α _D = -16.4 ° (c = 0.3, chloroform)

F) (2S, 4S) - (N-Boc§-4- (N'-Benzyloxycarbonyl-N'-methyl) aminoproline methyl ester g of the compound obtained in the previous step at 0 ° C under argon is dissolved in 20 ml of DMF in the presence of 25 g of methyl iodide 170 mg of 80% sodium hydride are added in portions and then stirred at 0 [deg.] C. for 90 minutes, extraction is performed with water and ethyl acetate, the organic phase is washed with water and then with brine. hexane / AcOEt (50/50; v / v) to give 1.55 g of the expected product, [α] _D = -38.8 ° (c = 0.38, chloroform)

G) 2 ', 5-Dichloro-2 - [(2S, 4S) -N- (3,4-dimethoxyphenylsulfonyl) -N- (4- (N'-benzyloxycarbonyl-N'-methyl) amino-2- (methoxycarbonyl) pyrrolidinokarbonylmetyl)] amino-benzophenone

This product is obtained by conventional means. α _D = -22.4 ⁰ (c = 0.37; chloroform)

H) 2 - [(2S, 4S) -4- (N-Benzyloxycarbonyl-N-methyl) amino-2- (methoxycarbonyl) pyrrolidinocarbonyl] -5-chloro-3- (2-chlorophenyl) -1- (3, 2-chlorophenyl) 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.

1.1. = 129 ° C and _D = -129 ° (c = 0.321; chloroform)

The isomeric purity by HPLC was 99%.

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

Table 5

OCH

Example R 0 «(chloroform) 111 duties NH, -189.6 C and 0.4 112 cis -NHCOA, - -174 C and 0.24 113 cis NHCH, -152.6 C and 0.28 114 cis N (CH,), -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

Example R % (chloroform) 115 cis -NHCOOCHj- -151 c x 0.27 116 cis —NH ₂ -161.4 c = <3.26 116a cis —N (CH3) ₃

Example 116a can be prepared from either Example 114 or (2S, 4S) - (N-Boc) -4- (dimethylamino) prolinamide, as follows:

SK 283463 Β6

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

2) (2S, 4S) -Methyl (N-Boc) -4- (dimethylamino) prolinate g of the compound prepared in paragraph 1) is dissolved in 50 ml of acetonitrile, 12.8 ml of 30% formalin is added and then 5 min. 3 g of sodium cyanoborohydride. 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 1 N hydrochloric acid and extracted with AcOEt. Solid sodium carbonate and solid sodium chloride were added to the aqueous phase and extraction was performed with AcOEt. After evaporation, the residue is chromatographed on silica gel, eluting with DCM / MeOH (95/5; v / v); the oil solidifies. m = 2.1 g

IR (DCM): 1755 cm ^{@ -1} , 1695 cm @ -1.

3) 534 mg of the ester prepared in 2) is dissolved in 4 ml of MeOH and treated with sodium hydroxide (116 mg) in 1 ml of water at room temperature for 48 h. Acidify with 0.5 N hydrochloric acid to pH

3.5 and the mixture was 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. The mixture is left twice for 30 min. a stream of ammonia gas is bubbled through. After 2 h at room temperature, DCM was evaporated, water saturated with carbon dioxide, sodium chloride was added and then the mixture was extracted with 4 volumes of AcOEt. After evaporation, the residue is chromatographed on silica. DCM / MeOH / NH ₄ OH (84.5 / 15 / KOH; v / v) eluted with a solid (m = 185 mg) which was recrystallized from DCM / isopropyl ether.

1.1. = 183-186 ° C and _D ²⁵ = -63.1 ° (c = 0.24; chloroform)

Example 117

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

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, maintaining the mixture for 15 min. with stirring at -15 ° C, 900 mg of tert-butyl mercaptan is added and the mixture is allowed to warm to room temperature. The reaction mixture was then irradiated with a tungsten filament lamp (150 W) for 1 h. 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; v / v). The expected product is obtained.

m = 300 mg

t. t. Melting point = 215 DEG

This compound is similar to the compound of Example 125 of EP 469984. It has a cis configuration around the 2,3-indoline bond as the starting product.

Example 118

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

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

1.1. = 215-220 ° C and _D = -214.5 ⁰ (c = 0.2; chloroform)

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

Example 119

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

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

1.1. = 263 ° C and _D = -201.5 ° (c = 0.2; chloroform)

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

Claims (16)

PATENT CLAIMS An indoline derivative comprising an amide functional group of formula (I) wherein R 1 represents a halogen atom, a C 1 -C 4 alkyl group, a hydroxyl group, a C 1 -C 4 alkoxy group, a benzyloxy group, a cyano group, a trifluoromethyl group, a nitro group or an amino group, R ₂ is alkyl having 1 to 6 carbon atoms, cycloalkyl having 3 to 7 carbon atoms, cycloalkene of 5 to 7 carbon atoms, phenyl unsubstituted or substituted once or more by alkyl of 1 to 4 carbon atoms, alkoxy of 1 1-4 carbon atoms, halogen, trifluoromethyl, amino, or R ₂ is a nitrophenyl which is unsubstituted or mono- substituted by trifluoromethyl or one or more times by alkyl of 1 to 4 carbon atoms, or halogen, R ₃ is H, R ₄ represents a group - CONR 6 R ₇ , R ₅ is C 1 -C 4 alkyl, 1-naphthyl, 2-naphthyl, 5-dimethylamino-1-naphthyl, phenyl, unsubstituted or substituted with one or more substituents selected from halogen, alkyl C 1-4 alkyl, trifluoromethyl, amino, free or substituted by one or two C 1-4 alkyl, hydroxyl, C 1-4 alkoxy, C 2-4 alkenoxy, C 1-4 alkylthio C 1 -C 4, trifluoromethoxy, 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 alkyl, or C 1 -C 4 alkyl, 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, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio R ₆ represents an alkyl group having 1 to 6 carbon atoms, or is identical to R ₇ , carbon, trifluoromethoxy, or benzyloxy, R ₇ represents 4-piperidinyl, 3-azetidinyl optionally substituted on nitrogen by C 1 -C 4 alkyl, benzyloxycarbonyl, or C 1 -C 4 alkoxycarbonyl, (CH ₂ ) _r which is substituted by a 2-, 3- or 4-pyridyl group, a hydroxyl group, an amino group, free or substituted by one or two alkyl groups containing 1 to 4 carbon atoms, a carboxyl group, an alkoxycarbonyl group containing 1 to 4 carbon atoms in the alkoxy moiety, benzyloxycarbonyl, carbamoyl, free or substituted by one or two C 1-4 alkyl groups, or R ₁₁ 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 s substituted with R ₈ , piperazine, unsubstituted or substituted in the 4-position with R ₈ , an unsaturated five-membered ring with one nitrogen atom, substituted with R ₈ , or a saturated three-, four-, five-, six-, or seven-membered ring with one atom nitrogen substituted _with R ₈ and R ₉ , _R is R _'8 or a (CH _{2) r,} substituted with hydroxy, or amino group, free or substituted by one or two alkyl groups having 1 to 4 carbon atoms, R 'is (CH ₂ ) _q which is substituted by carboxyl, C 1 -C 4 alkoxycarbonyl, benzyloxycarbonyl, carbamoyl, free or substituted by hydroxyl or C 1 -C 4 alkyl groups , or an aminocarbothioyl group, free or substituted by one or two alkyl groups containing 1 to 4 carbon atoms, Rspredstavuje R _g or a (CH _{2) 2} NH _2, a free or substituted by one or two alkyl groups having 1 to 4 carbon atoms R ₉ is hydrogen, halogen, (CH ₂ ) _r OR 10, (CH ₂ ) _r NR ₁₁ R ₁₂ , (CHACON R ₁₁ R ₁₁ ), azido, R ₁₀ is hydrogen, C 1-4 alkyl, mesyl or tosyl, R _Ib R _n and R ₂ each are hydrogen or alkyl having 1 to 4 carbon atoms, and R _n is hydrogen and R ₁₂ is benzyloxycarbonyl or alkoxycarbonyl having 1 to 4 carbon atoms in the alkoxy part, n is 0, 1 or 2, m is 0, 1 or 2, q is 0,1, 2, or 3, r is 0, 1, 2 or 3, with the limitation that r is equal to 0, where _p and R jc R ₉ in positions where intracyclic amide nitrogen, s being 0 or 1, in the form of the cis and trans isomers and their enantiomers, or in the form of a racemic mixture of these cis and trans isomers and optionally salts of these compounds. An indoline derivative of the formula (I) according to claim 1, wherein R 1 represents a chlorine, bromine or methoxy atom and n = 1. An indoline derivative of the formula (I) according to any one of claims 1 or 2, wherein R ₂ is chlorophenyl or methoxyphenyl or cyclohexyl. An indoline derivative of the formula (I) according to any one of claims 1 to 3, wherein R 5 represents a phenyl group substituted at the 3 and 4 positions or at the 2- and 4-positions by a methoxy group, or R ₅ represents a phenyl group substituted at the 4-position by a methyl group. An indoline derivative of the general formula (I) according to any one of claims 1 to 4, wherein m = 0. An indoline derivative of the formula (I) according to any one of claims 1 to 5, wherein R 4 is CONR 1 R-7 and NR 4, R ₇ is a pyrrolidine group substituted at the 2-position with (CH ₂ ) _q substituted carboxyl or carbamoyl, aq = 0.1, 2 or 3. An indoline derivative of formula (I) according to any one of claims 1 to 5, wherein R 4 is CONfUR- and NR ₆ R ₇ is piperidino substituted at the 4-position with amino, C 1-4 alkylamino or C 1-4 dialkylamino. 4 carbon atoms in each alkyl moiety. An indoline derivative 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 a thiazolidino group substituted with a (CH ₂ ) _q group which is substituted with a carboxyl group or a carbamoyl group, aq = 0, 1, 2 or 3. An indoline derivative of formula (I) according to any one of claims 1 to 5, wherein R ₄ is CONR 5 R ₇ and NR ₁₁ R ₇ is pyrrolidino substituted at the 2-position with (CH ₂ ) _q substituted with carboxyl or carbamoyl, and substituted at the 4-position with amino, C 1-4 alkylamino or C 1-4 dialkylamino in each alkyl moiety. An indoline derivative of the formula (I) according to any one of claims 1 to 5, wherein R ₄ is CONIUR ₇ and R 1 is C 1-4 alkyl and R ₇ is (CH ₂ ) _r substituted carboxyl or carbamoyl, ar = 1, 2 or 3. An indoline derivative of the formula (I) according to any one of claims 1 to 10 in the form of the cis isomer, wherein R ₂ and R 6 are on the same side of the indoline ring. SK 283463 Β6 An indoline derivative of the formula (I) according to claim 1, wherein: R 1 represents chlorine at the 5-position of the indoline ring, R ₂ is 2-chlorophenyl, R4 is 2-carbamoylpyrrolidinocarbonyl, R ₅ is 3,4-dimethoxyphenyl, m is 0, and n is 1. A process for the preparation of an indoline derivative of the formula (I) according to claim 1, in the form of cis and trans isomers and their enantiomers, or in the form of a racemic mixture of cis and trans isomers, characterized in that (a) 2-aminophenone derivative of formula (II) CO-R, ( ^cii) wherein R 1, R ₂ and n are as defined in formula (I) in claim 1, reacted with a sulfonyl derivative of formula (ΙΠ) Hal-SO ₂ - (CH ₂ ) _m -R ₅ (III), where Hal represents halogen, preferably chlorine or bromine, and R ₅ is as defined in formula (I) in claim 1, (b) the compound of formula (IV) thus obtained (IV) in which R _b R ₂ , R ₅ , n and m have the same meanings as in claim 1, is treated with a halogenated derivative of formula (V): Ha-CH ₂ COA (V), where Hal is halogen, preferably bromine, and A is NR _{C 1} R ₇ , (c) the compound of formula (VI) thus obtained; -X-CH ₂ CONR ₆ R ₇ S 7 ° CCH ₂ ) _m (VI) wherein R _b R ₂ , R 5, R 6, R ₇ , n and m have the same meanings as in claim 1, is cyclized in a basic medium to prepare a compound of formula (I) according to claim 1, d) and optionally separating the cis and trans isomers of the compound of formula (I) and optionally separating the enantiomers. A process for the preparation of an indoline derivative of formula (I) according to claim 1, in the form of cis and trans isomers and their enantiomers, or in the form of a racemic mixture of cis and trans isomers, characterized in that (a) an aminophene derivative of formula (II) wherein R _b R ₂ and n are as defined in formula (I) in claim 1, reacted with a sulfonyl derivative of formula (III) Hal-SO ₂ - (CH ₂ ) _m -R ₅ (III), where Hal represents halogen, preferably chlorine or bromine, and R ₅ is as defined in formula (I) in claim 1, (b) the compound of formula (IV) thus obtained; R _s (IV) wherein R 1, R ₂ , R 5, n and m have the same meanings as in claim 1, are treated with a halogenated derivative of the general formula (V) Ha-CH ₂ COA (V), where Hal is halogen, preferably bromine, and A is OR, wherein R is tert-butyl or benzyl, c) the resulting ester of formula (VI ') ₂ .cor N-CH, COOR with ₂ TCH) _N * 5 (vi ·) wherein R, R _b R _2, R _5, us have the same meaning as in Claim 1, is deprotected by acid hydrolysis in the case of R represents a tert-butyl group or hydrogenation when R represents a benzyl group, d) The compound of formula (VI) of y ^C0R2 (R1 ^ 2 ^{COOK TA A-5 O} 2 (VI ··) _{(CH2) m} * 5 in which Ra, R _2, R _5, us have the same meaning as in the to claim 1, or an acid chloride of formula (VI) (VI ···) wherein R _t, R _2, R _5, us have the same meaning as in claim 1, is treated with a compound of formula HNR ^ R ;, the wherein R ₆ and R ₇ have the same meanings as in claim 1, e) the resulting compound of formula (VI) (VI) f, ^R 5 thus obtained, wherein R _1; R ₂ , R 5, R ₆ , R ₇ and n have the same meanings as in claim 1, cyclized in a basic medium to prepare a compound of formula (I) according to claim 1, (i) optionally separating the cis and trans isomers of the compound of formula (I) and optionally separating the enantiomers. 15. A compound of formula 6 A 'is NR ₅ R _7' R 1 represents a halogen atom, a C 1 -C 4 alkyl group, a hydroxyl group, a C 1 -C 4 alkoxy group, a benzyloxy group, a cyano group, a trifluoromethyl group, a nitro group or an amino group, R ₂ is 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, alkoxy 1-4 carbon atoms, halogen, trifluoromethyl, amino, or R ₂ represents a nitrophenyl group unsubstituted or substituted once with trifluoromethyl or once or several times with an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms or a halogen, R ₅ is C 1-4 alkyl, 1-naphthyl, 2-naphthyl, 5-dimethylamino-1-naphthyl, phenyl, unsubstituted or substituted by one or more substituents selected from halogen, alkyl C 1-4 alkyl, trifluoromethyl, amino, free or substituted by one or two C 1-4 alkyl, hydroxyl, C 1-4 alkoxy, C 2-4 alkenoxy, C 1-4 alkyl up to 4 carbon atoms, trifluoromethoxy, benzyloxy, cyano, carboxy, 1 to 4 carbon alkoxycarbonyl, carbamoyl, free or substituted by one or two of 1 to 4 carbon atoms, or 4 to 4 carbon atoms, and 1 to 4 carbon atoms; or R ₅ represents nitrophenyl, unsubstituted or substituted once with trifluoromethyl or alkenyl of 2 to 4 carbon atoms or one or more times with halogen, (C 1 -C 4) alkyl, (C 1 -C 4) alkoxy, (C 1 -C 4) alkylthio group carbon atoms, trifluoromethoxy and benzyloxy, R <, is alkyl having 1 to 6 carbon atoms or is similar to R _7, R ₇ is 4-piperidyl, 3-azetidinyl optionally substituted on nitrogen by C 1 -C 4 alkyl, benzyloxycarbonyl or C 1 -C 4 alkoxycarbonyl, (CH ₂ ) _r substituted with 2 -, 3- or 4-pyridyl, hydroxyl, amino, free or substituted by one or two C 1 -C 4 alkyl, carboxyl, C 1 -C 4 alkoxycarbonyl, benzyloxycarbonyl, carbamoyl, free or substituted by one or two alkyl groups having 1 to 4 carbon atoms, or R @ _d and R @ ₇ together form with the nitrogen atom to which they are attached, a heterocycle selected from the group consisting of: morpholine, thiomorpholine, thiazolidine or 2,2-dimethylthiazolidine, unsubstituted or substituted with R ₈ , piperazine, unsubstituted or substituted in the 4-position with R ₈ , an unsaturated five-membered ring having one nitrogen atom, substituted with R ₈ , or a saturated three-, four- - a five-, six- or seven-membered ring having one nitrogen atom, substituted with R ₈ and R ₉ , R ₈ is R ₈ or a (CH ₂ ) _T group which is substituted by a hydroxyl or amino group, free or substituted by one or two C 1 -C 4 alkyl groups, R ₈ represents a (CH ₂ ) _q group which is substituted by a carboxyl group, a C 1-4 alkoxycarbonyl group, a benzyloxycarbonyl group, a carbamoyl group, free or substituted by hydroxyl or one or two C 1-4 alkyl groups, or an aminocarbothiolyl group a group which is free or substituted by one or two alkyl groups containing 1 to 4 carbon atoms, R ₈ is R _g, or a group (CH _{2) 2} NH _2, a free or substituted by one or two alkyl groups having 1 to 4 carbon atoms, R ₉ is hydrogen, halogen, (CH _{2) r} OR _10, (CH _{2) r} NR ₁₁ R _12, (CH _{2) n} CONR _{a R) -1,} azido, Rio is hydrogen, alkyl having 1 to 4 carbon atoms, a mesyl radical or a tosyl radical, R _n, RiiaR ₁₂ each is hydrogen or alkyl having 1 to 4 carbon atoms, or R 1 is hydrogen and R ₁₂ is benzyloxycarbonyl or C 1 -C 4 alkoxycarbonyl n is 0, 1 or 2, m is 0, 1 or 2, q is 0,1,2 or 3, r is 0 , 1, 2 or 3, with the restriction that r is not equal to 0 when R 1 or R _{9 is} in the position and to the intracyclic amide nitrogen, s represents 0 or 1 as an intermediate of the process for preparing an indole derivative of the general formula (I) according to claim 1. A pharmaceutical composition for treating or preventing central nervous system, cardiovascular and gastric disorders in which vasopressin or ocytocin receptors are involved, said composition comprising an indoline derivative comprising an amide functional group according to claims 1 to 10 and a pharmaceutically acceptable a carrier substance.