LT3064B - Indolineamide derivatives, process for the preparation thereof and pharmaceutical compositions containing the same - Google Patents

Abstract

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

Description

These compounds have strong pharmacological activity and are expected to be used in the future in the treatment of central nervous system, cardiovascular and gastric diseases. LT 3064 B

The present invention relates to the field of chemistry, in particular to a class of organic compounds, the N-sulfonylindoline derivatives having an amide function, which possess pharmacological activity.

'5 ^; ~ ''. · '

Hormonal agents, such as vasopressin and oxytocin, are known for their pharmacological activity consistent with the properties of indoline derivatives. Vasopressin is a hormone known for its anti-diuretic action in regulating arterial pressure.

It stimulates various types of receptors: V _and U ₂ , V _la , V _la , and also affects the cardiovascular system,

- <Central nervous system, liver, has atidiuretic, docking effect. Vasopressin antagonistic receptors may influence central and peripheral 7 blood flow regulation, namely coronary, renal and gastric circulation, as well as water metabolism and the release of adrenocorticotropic hormone (ΑΚΤΗ). Vasopressin receptors, like oxytocin receptors, are present in the uterine smooth tissue. Oxytocin has peptide structures similar to vasopressin. These receptors are also found in the mammary glands: in myoepithelial cells and in the central nervous system (see _; Presse Medicale, 1987,3 16 (10), 481-485, '

J. Lab.Clin.Med., 114 (6), 617-632 (1989) and Pharmacol.

Rev., 1991, 43 (1), 73-108).

Closest to structure and features. are Nsulfonylindoline derivatives having the structural formula '(1)

SO ₂ R ” ₃

j. in which; R 6 -hydrogen, / 'alkyl or ifenyl, as appropriate) substituted;

R ', -halogen, alkyl, alkoxyl, nitro or 5-trifluoromethyl;

: R ₃ ' ₃ -alkyl, phenyl or alkylphenyl;

R 4 -alkyl, phenyl, optionally substituted, alkoxy or phenoxy;

n '= 0,1 or 2.

These compounds (1) are. intermediate synthesizers 15. products required for the production of indoline derivatives which are active in the central nervous system. The following formulas have the general formula (2):

wherein: R is alkyl, phenyl, optionally substituted or hydroxyl (see U.S. Patent No. 3,838,167).

It is an object of the present invention to synthesize novel indoline derivatives having 1; with strong pharmacological activity. ''

Said object is achieved by the synthesis of novel indoline derivatives having an amide function, wherein the reaction is carried out between the amino-2-phenone derivative and the corresponding

_:; ^Λ . , 5'5 / sulfonyl derivative by treatment of the resulting compound with halogenated organic derivatives.

subject of the present invention ^; ya derivatives by structural

(I) wherein R._ - a halogen atom, alkyl C ₁ -C _4, hydroxy, alkoxy C ₁ -C ₄ beriziloksigrupė, cyano ,. trifluoromethyl group, nitro group, amino group;

R ₂ - alkyl C ₁ -C ₈ , cycloalkyl C ₃ -C ₇ , cycloalkene 20 C ₅ -C ₇ , phenyl, unsubstituted or singly or multiply substituted by alkyl C _x -C ₄ , alkoxyl C ₁ -C ₆ ,> halogen, trifluoromethyl a group, an amino group, or

R ₂ - nitrophenyl or unsubstituted viępą modified trifluoromethyl group or a single dose or multiply-substituted by alkyl _C} -C ₄ or halogen;

R ₃ is a hydrogen atom;

R ₄ is a carbamoyl group of the formula CONR ₆ R ₇ ;

30 '

R ₅ 5 / alkyl / 1-naphthyl, 2-naphthyl, 5-dimethylamino-1-naphthyl, unsubstituted phenyl or substituted with one or more substituents selected from halogen, alkyl C 1 -C 6, trifluoromethyl, amino or free one or two alkyls C ₇ -C ₄ , hydroxy, alkoxy C ₃ -C ₄ , N 1 -alkenoxyl C ₂ -C ₄ , alkylthio C 1 -C ₄ , trifluoromethoxy group, benzyloxy group, cyano group, carboxyl group , alkoxycarbonyl groups C ₁ -C ₄ , carbamoyl groups free or substituted with one or two alkyls · C ₁ -C ₄ , or alkylamido groups R ₅ is unsubstituted nitrophenyl or one with trifluoromethyl or alkenoxyl C ₂ -C ₄ , or once or many times by halogen, alkyl </ - (/, alkoxyl (/ C / alkylthio, trifluoromethoxy group or benzyloxy group, R ₆ - is Cj-Cg alkyl or R _6th - similar to the ^_R?;:

R _{7 is} piperidin-4-yl, acetidin-3-yl, '. those groups substituted or unsubstituted with nitrogen + alkyl '</ - </, benzyloxycarbonyl or an alkoxycarbonyl group C 1 -C 6; a group (CH ₂ ) _r substituted with 2 -, 3- or 4-pyridyl group, carboxyl group, amino group free or substituted with one or two alkyl C 1 H, Carboxyl group, alkoxycarbonyl

C ₁ -C ₄ group, benzyloxycarbonyl group, -carbamoyl group free or substituted with one or two alkyls

3-C ,; 7 .. ·· '// 73' // · /+..../. +/- 7.73- / + or R ₆ and R ₇ together with the nitrogen atom,. with which they are joined in a heterocycle from:

+ .- -morpholino, ·, + 3 /

-tiomorfolino, .30 thiazolidine or 2,2-dimetiltiazolidino will not change or alter the STU-R _6,

-piperazine - unsubstituted or substituted in the R ₈ group,

- unsaturated monoazotic ring with 5 chain substituted R ₈ or saturated 'monoazotic ring with 3,> 4, 5, 6 or 7 substituted R _e and R ₉ ,

../ <; 74-5- / 4 77 '

R ₈ represents R ' ₈ or a group (CH ₂ ) _r substituted with hydroxy or - or amine, free or substituted with one or two · -4-' 4 -4- -4- '4 ...' .44 alkyls of C 1 -C 4 ^; 5 R _'8 is (CH _{2) q} group substituted with carboxyl group, aikoksikarbonilo by a group E ₁ s _4> benzilkoksikarbbnilo group, carbamoyl group' or substituted by hydroxyl or by one or two alkyl, or an aminokarbotioilo group free or "one or two .pakeista alkyl-C 1 -C 8,

R θ is R 'θ or. a group (CH ₂ ) ₂ / NH ₂ free or substituted by one or two C-C ₄ alkyls,

R ₉ is hydrogen, halogen, the group (CH _{2) r} OR ₁ 0, the group (CH _{2) r} NR ₁₂ IR _1, the group (CH _{2) I 11} .CONR R _'1X, azido _group?' > 7R _lo hydrogen, alkyl C _x -C ₄ , mesyl or. Tosyl,

R _n , R ' _n and R ₁₂ are hydrogen or alkylC 1 -C 6 or R _n is hydrogen, -O- 4 - this is benzyloxycarbonyl or alkoxycarbonyl 0, -O-,

- /// 44 //: / - / --- 4 /,: 44-. // - 4--: / 0 --- -4b - / - /

n this 0 1 or 2, 4b m it 0,. 1 or 2, p it 4, 5 - or '; ·' 6, - / '-'. -..- / ---. /. /. q or 0, 1, 2 or 3 ', r this 0 or Ί, 2, 3 without reducing r, when . / Aug b or / Rg is in the alpha position

for intracyclic amide nitrogen, // - / s it is 0 or 1,, 7.

as well as their possible salts.

'' ..¾¾¾

Salts of the compounds of formula (1) according to the present invention include salts with mineral or organic acids which allow the proper separation or crystallization of compounds of formula * (1), such as picric, oxalic or ethically active acids such as almonds. or camphorsulfonic acid or acids with pharmaceutically active salt forms such as chlorohydrate, hydrogen sulfide, dihydrogen phosphate, methanesulfonate, maleate, fumarate, 2-naphthalene10 sulfonate. .

Salts of the compounds of formula (I) also include salts with mineral or organic bases, such as alkali or alkaline-earth metal salts such as sodium, potassium and calcium salts, mainly sodium and potassium salts, or with an amine such as trometamol or arginine, lysine or any amino acceptable pharmaceutical druskosi / li /, // .. · _y. Z120 compounds by the formula (1) about 2.3 indoli'no 'connections are located cis-trans izameriškai. The present invention includes various isomers.

The isomer will refer to the compounds {!> In which R ₂ is on one side of the ring. // 1¾¾ ^)

The trans isomer represents compounds (1> wherein R ₂ and R _{4 are} each on one side of the ring).

Isomeric trans

In addition, the compounds of the invention have two or more asymmetric carbon atoms, wherein R ₄ includes one or two asymmetric carbon atoms.

In the present invention, the halogen referred to as the fluorine, chlorine, bromine or iodine atom, the alkyl group represents linear or branched hydrocarbons.

- The compounds of the invention must meet at least one of the following 20 conditions:

R ₇ is a chlorine, bromine or methoxy group, o

R ₂ is chlorophenyl, methoxyphenyl or cyclohexyl,

R ₄ is a group CONR ₆ R ₇ wherein R ₆ , R ₇ or NR ₆ R ₇ have one of the following definitions:

·

NR ₆ R is a pyrrolidine group substituted at position 2 with a group (€ € ₂ ) ₉ , also substituted with a carboxyl or carbamoyl group with q = 0, 1, 2 or 3.

NR ₆ R ₇ is a piperidine group substituted at position 4.

amino group, alkylamine C ₁ -C ₄ or dialkylamine C _x C '

NR ₆ R ₇ - is a thiazolidine group substituted with (CH ₂ ) _q , also substituted with a carboxyl or carbamoyl group with q - 0, 1, 2 or 3,

NR ₆ R ₇ is a pyrrolidine group substituted at position 2 by (CH ₂ ) _q as well. substituted with a carboxyl or carbamoyl group with q = 0, 1, 2 or 3, and substituted at position 4 with an amino group such as lamin C ₁ -C ₄ or dialkylamine C ₁ -C ₄ ,

R ₆ is alkyl (C 1 -C ₄ ) and R ₇ is (CH ₂ ) _r substituted with a carboxyl or carbamoyl group with r = 1, 2 or 3,

R _s is phenyl substituted at positions 3 and 4 or at positions 2 and 4 by methoxy or R ₅ . phenyl substituted at position 4 with methyl, m = 0.

('·' · ( ^; '· / ··' - '·'<7 /(/...--,73-/, /3.- '7 /''/ · / 3 //.'- . = (3/3, (1. (

Particular preference is given to the eis-isomeric forms of the compounds (1).

The following abbreviations are used in the description and examples:

' ^? 'D®r7: Dichloroethane /' / {'- J3 {- // = (7' //, {

Isether - isopropyl ether

AcOEt - ethyl acetate

MeOH - methanol

EtOH - Ethanol

Ether - ethyl ether

DMF- dimethylformamide

THF - tetrahydrofuran

7TEA - Triethylamine 3 DMSO · - Dimethylsulfoxide ·

DCC - N, N'-Dicyclohexylcarbodiimide

T. '; x // F / 3 33.; .. 33 f / 39 '33- ../3, .3 ^; f3

DBU - 1-8-diazabicyclo / 5; 4O / undec ~ 7-ena5, /

TBD - Triaza-1,5,7 bicyclo / 4.4.0 / dec-5-ene / /

DBN - Diaza-1,5'-bicyclo / 4.3.0 / non-5-ene 0MAP - Dimethylamino-4-pyridine.

.. 5 DMPU - Dimethyl-1,3 oxo-2 hexahydropyrimidinone

TMEDA - Tetramethylethylenediamine LDA-Lithium Diisopropylamide HMPA - Dosage Form

HOBT - Hydroxy-1 Benzotriazole Hydrate.

3-33-3 BOP - Benzothiazolyloxy Phosphorus Tridimethylamine

....... hexafluorophosphate. ".

TFA - trifluoroacetic acid

Lawesson's Reagent - Bis (Methoxy-4-phenyl) -2,4-dithia-1,3 Disphosphetane-2,4 Disulfide-2,4

Salt solution - water saturated with sodium chloride '

Solid carbon dioxide - solid carbon dioxide. <.. i

- thin layer chromatography

- HPLC - High performance liquid chromatography

BMR (RMN) - nuclear magnetic resonance s - singlet. / ~ 'i- /? m - multipoint

s. e. - extended singletss 3 d - doublet / i.

m.d. (parts per million)

t. v. - volume unit

Chlorohydrated water - hydrochloric acid solution about 1 N. iy.l. ·

NaH80% - Dispersion of sodium hydride in mineral 30 'oil (Janssen Chemica)

Me - Methyl

Ethyl ethyl iPr - isopropyl, Pr propyl iPentyl - isopentyl iBu - isobutyl tBu - tertiary, butyl, Bu - butyl Bz - benzyl.

Ph is phenyl

The present invention also relates to a process for the preparation of compounds (1), characterized in that:

(a) Reaction with 2-aminophenone derivative of formula (XI):

wherein R _and R ₂ and n have the meanings given in formula 15 (I) is contained in a sulphonyl derivative of formula (UI):

Hal-SO _? - (CH->) -R _s (III) wherein Hal is halogen, preferably chlorine or bromine, m and R ₅ have the meanings given in formula (I),

(b) the product thus obtained has the formula '

compounds of formula (V):

Hal '-C-COA' (V) wherein Hal 'is halogen, preferably bromine, and A is one of NR ₆ R ₇ or a group OR wherein R is tertiary butyl or benzyl,

c) where appropriate, when 'A is an OR group, from the ester of formula (VI'):

COR _n% ^ -N-CH ₂ COOR

SO2 (VI ”) removable protection under normal conditions;

d) if necessary, the acid obtained in this way in step (c) of the formula (VI)

(gng> g ^H 2 ^C0 ° ^H (VI)

or the chloro-anhydride formula (VI * '' J:

. (ch ₂ )

BU »I II is treated with HNR ₆ R ₇ using conventional peptide coupling techniques;

(e) The compound obtained in this way in step (b) or (d), of formula (VI):

. .COR-y ² ( ^R l) n%

N-CH ₂ CONR ₆ R ₇ SCb (VI)

Re forms a cycle in an alkaline environment for the compound (according to the invention;

(f) are separable as necessary; trans isomers as well as enantiomers of the compound.

go- and

2-Aminophenone; (II) derivatives; known 'or obtained using known methods such as A, K.

; §Ingh e.a. Synth. Commun. 1986, 16 (4), 485 and G.N.

Walke.r ,. J. Org. Chem., 27, 1929. 1962 ... Amino-2- »trifluoromethyl-2-benzophenones and other trifluoromethyl derivatives prepared according to U.S. Pat. 3341592.

· Chloride dimethoxy-2,4-benzenesulfonyl is obtained. according to. the method described in J. Am. Chem. Soc., 1952, 74, 2000.

Sulfonyl. The derivatives of formula (III) are known and are prepared by known methods (see C, N. Sukenik et al., 'J.

Am. Chem. Soc., 99, 851-858 (1977). p-Benzyloxy benzenesulfonyl chloride ¹ is prepared according to the procedure described in European Patent No. 229566.

Alkoxybenzenesulfonyl chloride is prepared starting from sodium alkoxybenzenesulfonate by treatment with sodium hydroxybenzenesulfonate with alkyl halide /

The halogenated derivatives of formula (V) are known and are prepared by known methods described, for example, in A-J. Vogei:

a Text Book of Practical Organic Chemistry, Longman, 3rd ed. 1956, p. 383, or G '. Kirchner-et al., J. Am. Chem..Soc., Γ985, 107, 24, 7072.

Process step (a) 'is carried out with pyridine by heating to room temperature and boiling the solution for several hours to several days. Catalytic or stoichiometric amounts of dimethylamine pyridine may be employed as required.

Process step (b) is carried out between the -sulfonamide of formula (II ⁷ ) and the excess halogenated derivatives of formula (V), such as dimethylformamide or dimethyl sulfoxide, in an inert atmosphere at a temperature of 0 ° C to room temperature for several hours to 24 hours; , in the presence of sodium hydride.

When the group NR ₆ K _7. Has another amino · function, i.e.. when R ₆ and or R _{7 are} substituted with an amino group, the halogenated derivative of formula (Y) can be selected for use in the preparation of intermediates of formula (VI *), where Hal is -CH ₂ CO ₂ R where R is tertiary butyl or benzyl. and (VI). In this case, the acid-forming step (c) of the formula (VP ') is carried out by treating hydrogen with a catalyst attached, for example palladium-on-carbon when R is benzyl, or in an acidic addition where R is tertiary butyl. plus, for example, TFA or;

, by the addition of bromohydride in acetic acid, or; DCM with the addition of ZnBr ₂ .

Step (d) is performed under classic peptide coupling conditions, for example by adding EOF or HOBT and DCC.

The compounds HKR ₆ R ₇ are known and are known in the art. For example, acetic (R) and (S) pyrrolidin-2-yl acids are obtained according to H. Rueger et al., Heterocycles, 1982,

19 (9), 1677 starting from a powder of the corresponding configuration. N-Boc dihydro-3,4 0 methyl prolinate is obtained according to J-R. Rozmoy. Synthesis ,, 1982, 753- Optically clean pipecolic. the preparation of acid derivatives is described in Tetrahedron, 1992, 48 (3) 431-442 and

Tetrahedron, 1991, 47 (24) 4039-4062.

Carboxyethylenimine · acid derivatives are obtained according to K-Nakajima et al. Bull Chem. Soc. Jap., 51 (5), 1577 (1978)

3Q

Process step (e) involves an aldoline reaction: the methylene in the amide position is deprotonated, the carbonyl in the phenone acts as an internal electrophile, which leads to the cyclization of two asymmetric carbons (C *).

The reaction can be written as follows:

O

base _; solvent

The principles of the aldol docking reaction were discussed in C. H. Heathckock Asymmetric Synthesis, vol: 3: Stereodifferentiating additions reactions, 'part B, 111112; Academic Press, 1984, J.D. Morrison et al.

It is known that the aldol reaction of achiral amide anions leads to the formation of two hydroxyamides of the two racemic diastereoisomers in a ratio depending on the experimentally chosen conditions. Such conditions may include; the nature of the mineral or organic base, the nature of the cations or • counterions, if necessary, the presence of additives in the reaction medium, and the structure of the compound which is affected by the reaction.

When in groups. R ₆ and R ₇ do not have a hydrolyzing function in an alkaline medium, sodium hydroxide can be used, with the addition of a solvent, the addition of or the addition of a phase transfer catalyst; it is also possible to use quaternary ... ammonia, ...... for example benztrimethylammonium hydroxide in methanol.

Organic bases may be used to carry out the aldol reaction, for example:

¹⁶ guanidines as well as triaza-1,5 / 7 bicyclo / 4,4,0/ dec-5-ene;

amides as dyaza-1.8. bicyclo / 5.4.0/ undec-5-ene. 'V .. ·. . . .......

or diaza-1,5 bicyclo / 4,3.0/ non-5-ene.

in the mixture selected, dichloroethane, methanol is carried out under inert conditions

In a solvent or solvent such as benzene, .THF, dimethylformamide, the reaction in the atmosphere between -10 ° C and 110 ° C, the amount of base used is stoichiometric, and it is also possible to carry out the solvent-free reaction at a higher temperature.

Typically, in the process of the invention, step (e) is carried out using diaza-1,8 bicyclo [5.4.0] undec-5-ene (DBU) in a solvent, dichloromethane or methanol at a temperature of the solvent mixture at -10 ° C with reflux.

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

Alkyl alcohol is used in a catalytic or stoichiometric amount in anhydrous solvent, such as alcohol, (if necessary with the addition of a solvent such as THF) or a stoichiometric amount of THF, DMF or DMSO, if necessary with ether rings such as 18dicyclohexyl. 6-ring, the reaction is carried out between -15 ° C and 80 ° C.

The use of metal amides such as RR'NLi or RR'NMgBr where R and R 'monovalent radicals are used as deprotonation agents is a process for the formation of amide enolytes, intermediates in the aldol condensation reaction. That way was recently addressed by R.E. Ireland et al., J. Org.

- .. A '. 7-7 · _; - / ^ '7-7 7' /, / /

Chem. 1991, 56, 650. Reaction solvents may be benzene, hexane or THF used in the anhydrous state under an inert atmosphere. Also available '' 7 7 · 7 ,. · .. 7. · '7 - 7-. .. / 7 · 7 '··· - ·' · .'- '7 · ... ·· _.77: ·. ./. '.' add additives such as LiF, ~ LiCl, LiBr, LiBu, TMEDA, DMPU, HMPA or the ether ring (M. Murakate et al., J. Chem. Soc. Comrnun., 1657, 1990). As an example, the use of lithium diisopropylamide in binding LiBu, at a temperature of -78 ° C to -30 ° C in anhydrous .THF, an inert atmosphere or THF medium with additives such as tetramethylenediamine, DMPU or HMPA.

Other known and used metal amides,. for example, lithium cyclohexylamide, lithium tetramethyl-2, 6, 6, 6-cyclohexylamide. It is also possible to prepare amide compounds of other metals by reacting the required amount of butyl lithium in hexane with secondary linear or cyclic amines, whereby the reaction is carried out in one of the solvents mentioned above.

There are many publications describing secondary amides of amide metal optically active amines: L. Duhamel et al., Bull.

Soc. Chim. France, 1984, II, 421; J.K. Whistesell et al., J .. Org. Chem. 45, 755 (1980); M. Murakata and others,

J. Chem. Soc. Chem. Comrnun., 1990, 1957; M. ¥ amaguchi,

Tetrahedron Lett., 1986, 27 (8), 959; P.J. Cox and N.S.

Simpkins, Tetrahedron, Asymetry, 1991, 2 (1), 1.

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

'30 / 7/7 /////// 7 //./^//-7/'^/-77-y//. .7 - / ^. / ·· /. · //// - / Ay ///// '/ · - / 7 / yj // _; ./ '-.- 7 //. ^ / ^. // -, .. 7 ^

Mixed metal amides such as those described by Y. Yamamoto, Tetrahedron, 1990 may be used.

46, 7: 4563, lithium salt or analog of N- (trimethylsilyl) benzylamine, in which the benzylamine is replaced by a primary chiral amine as (R) or (S) -methylbenzylamine.

When the compound of formula (1) has two asymmetric carbon atoms, the use of metal amides or chiral alcoholates in step (e) assists the eis or transtranenometric enrichment of each of the stereoisomers. In this way

... U ^; S- '.R ··. ·'. · ';. · - ·. ·: ·', ···. '.' ·: · .. ·. _: method - determines the proportion of each of the eis or trans enantiomers. The proportion of each eis or trans isomer is determined by dosage. to a chiral high performance liquid chromatography column.

When the compound of formula (I) is obtained with 3 or 4 asymmetric carbon atoms, the cyclization step · (c) may be accompanied by diastereoisomeric enrichment, and the use of a special chiral base allows modification of the diastereoisomeric enrichment.

In step (f), the isomers are separated geometrically by extraction and transextraction of (I) by classical means and by chromatography or fractional crystallization.

The optical isomers of the cis and trans isomers may be separated, for example, by preparative chromatography on a chiral column followed, if necessary, by fractional crystallization, or by formation of an optically active salt using appropriately selected chiral acids or bases.

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

When the compound of the invention contains 3 or 4 asymmetric carbon atoms, diastereoisomers can be separated using chromatographic techniques and crystallization.

? ίΤ3064Β

Various methods can be used to differentiate and characterize the eis and trans isomers in compound (I). Since R ₃ is hydrogen, comparative analysis with high-field NMR (250 MHz), for example, can be analyzed by Overhauser. effect (NOE) between indoline proton (R ₃ = H) and hydroxyl proton. :

The IR spectra of the cis- and trans-isomers in the DCM solution are 10 different. The cis isomer usually forms a strong absorption band, thin and symmetrical at .3550-3520 cm ^-1 , due to the hydroxyl vibration, whereas the trans isomer does not form any vibration band emitted in that region.

The cis -isomer was found to be more mobile to CCM on an alumina plate (60F245 neutral, type E, Mere) 'washed with DCM containing various proportions of AcOEt. Chromatography on an aluminum column (alumina 90, pellet size 0.063-0.200 mm) .... the cis isomer is eluted ⁰ usually the first time the eluent is DCM having various proportions of -AcOEt or MeOH.

Also, the cis- and trans-isomers of compound (I) according to the invention are usually / can be determined by analytical method. Such assays can be carried out in an analogous manner between close compounds and compounds derived from each other.

The absolute structure of some compounds of the invention was determined by X-ray analysis. Other compounds,. The absolute structure obtained in an analogous manner was determined by deduction with respect to the comparative rotation of the polarization plane.

To obtain the compound (I), wherein R _d is an amino group and / or a compound wherein R ₅ is fenilinė group .pakeista

LT3G64B '{7 ({(20 (- ..

amine transformation of compound · '(VI) obtained in step (b) wherein R _x is a nitro group and / or R _s is a phenyl group, substituted nitro group and other substituents have the meanings required for compound (I), catalytic hydrogenation,

.. for example, in the case of palladium on carbon or radium on aluminum or Renee nickel:.

Compounds (I) in which the substituents R ₆ and / or R ₇ or the group NR ₆ R ₇ include an alkoxycarbonyl group C ₇ -C ₄ allow the ester hydrolysis to provide compounds (I) in which R ₆ and / or R ₇ or group NR ₆ R ₇ includes a carboxyl group. Other substitutions of compound (I) remain unchanged. In addition, the compounds wherein R ₆ and / or R ₇ or NR ₆ R ₇ include a carboxylic group afford the classical amide linkage reaction to provide compounds of formula (I) wherein R ₆ and / or R ₇ or group NR ₆ R ₇ includes a free carbamoyl group or substituted with one or two alkyl C _x -C _{4 /} other substituents remain the same.

Finally, compounds (I) wherein R _{6 '} or R ₇ or the group NR ₆ R ₇ include a carbamoyl group allow Hoffmann's rearrangement to produce compounds (I) wherein said groups include an amino group and the other substituents remain the same. (J. Org. Chem. 1979, 44 (10), 1746)

According to the present invention, the processes for the preparation of compounds (I) wherein R 1 and / or R ₇ or NR ₆ R ₇ have an amino group, free or substituted by one or two allyls, can be provided in two variants:

. , 7

i) in step (b), the compound (IV) obtained in step (a); treated with a halogen derivative (V) of the formula Hal 'CH ₂ CONR ₆ R ₇ , wherein R ₆ and / or R ₇ or the group NR ₆ R ₇ comprises a group of an amino precursor, such as a carboxy ester, a carboxyl or a carbamoylCyclization step ( e) is carried out and then the amine precursor group is converted to the amine of the compound (I)

I T 3064 R '/. : / ,. // -: hydrolysis of the / 21 / - / carboxyester group to the carboxy group which is transformed into the carbamolyl group and then to the amino group by Hofmann rearrangement.

ii) In step (b), the compound (IV) obtained in step (a) is treated with a halogen derivative (V) of the formula Hal'CH ₂ COOR wherein R is b'enzyl or tertiary butyl. The ester of the resulting compound '(IV') is deprotected by appropriate treatment according to step (c).

The coupling is carried out with HNR ₆ R ₇ where the amino group R ₆ and / or R ₇ is protected as required. 'The resulting compound (VI) is cyclized according to step (e) ·. Compound (I) in which the amino group is free can be obtained by amine protection.

Compounds (I) wherein R ₆ and / or R ₇ or NR ₆ R ₇ include benzyloxycarbonyl or alkoxycarbonyl groups as substituents on the amino function afford the compounds (I) on which the amino function is free and the other substituents are the same.

The compounds (VI) are used as intermediates for preparing compounds (I) of the invention is ^{to a} new and form part of the invention. Also, compounds (VI ') and (VI) are novel and form part of the invention. '.

The present invention also relates to compounds of formula (6):

in which

A'tai group selected from NR ₆ R ₇ , OH, OtBu, OBz 7

R 1 is halogen, alkyl C ₁ -C ₄ , hydroxy, alkoxy-C ₁ -C ₄ , benzyloxy, cyano, trifluoromethyl, nitro or amino;

is alkyl, cycloalkyl, C ₁ -C

C 3 -C ₇ , or cycloalkene C ₅ -C ₇ , phenyl substituted one or more times unsubstituted with alkyl C ₁ -C ₄ , alkoxyl-, halogen, trifluoromethyl, amino, or R ₂ is nitrophenyl unsubstituted or substituted once a trifluoromethyl group or by one or more alkyl, Cj-d, alkoxyl C _x 4 or halogen,

R _{5 is} alkyl

-na ft i1as, '2-naft ilas ,. 5-dimethylamino-1-naphthyl, phenyl, substituted or substituted one or more times with several substituents selected from halo, alkyl C ₁ -C _{4 <} amino, · free or two alkyl C ₁ -C ₁ , -ac , trifluoromethyl substituted with one or hydroxy, alkoxylthioalkyl C ₁ -C ₄ , trifluoromethoxy, benzyloxy, cyano, carboxyl, alkoxycarbonyl C ₇ -C ₄ , carbamoyl, free or substituted with one or two alkyl C ₁ -C ₄ -or alkylamide groups. C ₁ -C ₄ or R ₅ is nitrophenyl, unsubstituted or substituted once with trifluoromethyl or alkenoxyl C ₂ -C ₄ , or one or more times with halogen, a 1 C ₇ -C ₄ . alkoxy C, -C ₄ thioalkyl, Cj-C ,,, trifluoromethoxy group or a benzyloxy group, A-A _and C-C .alkenoksilo

4 * · '

R ₆ is alkyl C, -C ₆ or R ₆ is similar to R ₇ ,

R ₇ is a piperidin-4-yl group, the group of which. a substituted or unsubstituted on the nitrogen by alkyl C ₁ -C ₄ alkoxycarbonyl, benzyloxycarbonyl, or C₁-C₄, a group (CH _{2) o} substituted on the 2-, 3- or 4-pyridyl group, a hydroxyl group, amino groups which are substituted with one .Is or with two alkyls C ₁ -C ₄ , a carboxyl group, a C _x C ₄ alkoxycarbonyl group, a benzyloxycarbonyl group, a carbamoyl group, free or substituted with one or two alkyl C ₇ -C ₄ , it is acetidin-4-yl.

or R ₆ and R ₇ together with the nitrogen atom to which they are attached form a heterocycle in the selected medium from morpholine, thiomorpholine, thiazolidine or 2,2-dimethylthiazolidine, substituted or unsubstituted. R ₈ , piperazine substituted or unsubstituted in the 4-position with R ₈ , monoazo unsaturated 5-chain substituted ^! R ₈ or R _g and R ₉ substituted in a monoazo saturated ring with '3, 4, 5, 6 and 7 chains,

R _q is

R ' ₉ or group' (CH ₂ ) _{r 1} 'is also substituted with hydroxy or amine, free or substituted with one or two alkyl C _x -C ₄ ,

R ' _θ is a (CH ₂ ) _q group substituted with a carboxyl group, an alkoxycarbonyl group C 1 -C 4, a benzylcoxycarbonyl group, a carbamoyl group free or substituted with a hydroxyl or one or two alkyl C 1 -C 4, or an aminocarbothioyl group free or substituted with one or two alkyls of C ₁ -C ₄ , -.

R ₈ is R ₈ or the group {CH ₂ ) ₂ NH _2, free or substituted with one or two alkyl C ₁ -C ₄ ,

Rg. it is hydrogen, halogen, group (CH ₂ ), OR ₁₀ , group (CH ₂ ) _r NR _n R ₁₂ , group (CH ₂ ) _S CONR _n R ^! n, azido group,

R _{10 is} hydrogen, alkyl C 1 -C ₄ , mesyl or tosyl,

R _LLF R'p! · And R ₁₂ is then hydrogen or alkyl C ₁ -C ₄ or R _n is hydrogen, · o 'R ₁₂ tai- alkoxycarbonyl benzyloxycarbonyl, or C ₁ -C _4, n is 0, 1 or 2, myths 0, 1 or 2, p it 4, 5 or 6, q it 0, '1,., 2 or 3,' · '/ · Ii · ?. '7-5f 535''...to' - 'ii. 3 '/ 3 .. J /' · '/' k .. · '·.' . 73 - /. (Y J '3.' / 3 - (3 /. · '/ 33' 3 (3 ... / · r it. 0 or 1, 2, 3, together without reducing r, · when: R ₈ or R ₉ is in the alpha position in the intracyclic nitrogen amide, which is 0 or '1.

According to another aspect of the present invention, compounds (I) of the invention wherein R ₇ or the group NR ₆ R ₇ contains a carboxyl group are used to 'obtain' analogous decarboxylic compounds.

The invention also relates to the use of compounds of formula (I ^r ):

^{25 in} which /'.'/.i.

R _r, R _2, R _3, R _5, m and n have the formula e (I) in a reaction-

R _VI or C 1 -C 8 alkyl,

R _VII is a group (CH ₂ ) _r COOH with r = 1, 2 or 3, or R _VI and R _VII together with the nitrogen atom to which they are attached form a heterocycle of the selected environment:

-thiazolidine or 2,2-dimethylthiazolidine substituted with (CH ₂ ) _q COOH,

-piperazine substituted with a group '(CH ₂ ) _{q at} COOH 4;

- a 5-membered (CH ₂ ) _q COOH unsaturated monoazo ring,

- a saturated monoazotene cycle with 3, 4, 5, 6 ar

7-substituted (CH ₂ ) _q COOH at q = 0, 1, 2 or 3 to give a compound of formula (Γ ') with the same configuration about indoline bonds 2,3 as the starting product:

wherein R _1f R ₂ , R ₃ , R ₅ , m and n have the meanings given in formula ii),

R ' _VI is alkyl C 1 -C 8,

R'vj! it is a group (CH ₂ ) _r H, or

75/7 - ./?/:- .7 · / ::.

R * _VI and R _VII together with the nitrogen atom to which they are attached form a heterocycle in the selected environment ^

-thiazolidine or 2, 2-dimethylthiazolidine substituted with 10. (CH ₂ ) _q H,

-piperazine substituted at the 4-position by (CH ₂ ) _q H; ...

-unsaturated monoazotocycle with 5 chains

/.: /.,. substituted with (CH ₂ ) _q fl,

- a saturated monoazo ring with a 3, 4, 5, 6, 7 chain substituted (CH ₂ ) H group.

The radical decarboxylation reaction a't carried out according to D.H.R. Barton et al., J. Chem., Soc. Commun., 1984,

1298. · ''

The affinity of the compounds of the invention for vasopressin receptors was determined in vitro using the procedure described in J. Biol. ' Chem. 1985, 260 (3), 284425 2851 ... This technique consists of studying tritiated fixed vasopressin-angular-Vj in rat liver membranes. Inhibitory concentrations of 50% (Cl 5 _Q ) for tritium-containing vasopressin in the compounds of the invention are weak, reaching 10 '.

- iBeto _f - was. measured the inhibition of plaque adhesion by vasopressin on plaque rich human plasma (human PRP) using the procedure described in e.

- · 35 7 Thrombdsis: 7-Rh ... ^:.: 4 ^ .77 - / ^ / ^ -: -.: / 7 ^ 6/7: / Compounds _: /// by blockade inhibit adhesion / 50-100 · nM. vasopressin concentrations with Dl ₅₀ 7 (inhibitor dose) /: 27 / weak, reaching 10 ' ⁹ M. These results indicate antagonistic effects of the compounds of the invention on the receptor V _x .

Flange (I). V ₂ receptor affinity was measured according to the method adopted by P. Crause et al., Molecular and Cellular Endocrinology, 28, 529541. 1982. The cis -configuration of the indoline 2, 3 bonds according to the invention has V _x selective activity.

The affinity of the compounds (I) for the oxytocin receptors of the invention was determined in vitro by the transport of fixed tritium to the receptors of the membrane extract of pregnant rat rats. The Cl ₅₀ of the compounds according to the invention is low, reaching 10 * ⁵ M-10 ~ ⁸ M.

The compounds of the invention are active by a variety of routes, particularly oral administration.

There were no signs of toxicity at pharmacologically active doses of such compounds.

'• B,', 'b ..? /' /. <Y '''; to ·, ·,' · y · B / B ,, A '·. ^: .B '·· ·. · 'B'BB B' j '.': B '··' / '. ·. - A: · '·

Thus, the compounds of the invention may be used for the treatment or prophylaxis of various diseases dependent on vasopressin, namely cardiovascular diseases such as. hypertension, heart failure, vascular coronary spasms, especially in smokers, central nervous system disorders, brain swelling, psychotic states, memory impairment, renal disease due to renal vasospasm, adrenal cortex necrosis,. gastric diseases, ulcers, abnormal antidiuretic withdrawal syndrome. (SIADH). The compounds of the invention may be used prior to emesis, for example in cancer or atherosclerosis.

7.5 ././-.50528¾

The compounds of the invention may also be used to treat dysmenorrhea, premature birth

The compounds of the present invention are administered orally, after

t.

under the tongue, under the skin, i ,. intramuscular, intravenous, topical, tracheal, nasal, transdermal, or rectal, the active compounds of the formula (I) above or salts thereof may be used in a uniform manner in admixture with classical pharmaceuticals, both for humans and animals. for the treatment or prophylaxis of the above diseases. Treatment forms include tablets, gelatine capsules, powders, granules, oral solutions and suspensions for oral use, sublingual oral administration, tracheal internal, nasal, subcutaneous or intravenous - rectal administration. Topical uses are ointments, pomades or lotions.

In order to obtain the desired prophylactic or therapeutic effect, the active principle may be in the range of 0.01 to 50 mg per kg of body weight per day.

,. / ····. ·. ··. ; ,,.

Each unit dose may contain from 0 ', 5 to

1000 mg, usually from 1 to 500 mg, of active ingredients combined with a pharmaceutical base. Such a uniform dose may be taken 1 to 5 times daily, so that the daily dose is 0.5 to 500 mg, usually 1 to 2500 mg.

In the manufacture of 7 tablets, the main active ingredient is mixed with the pharmaceutical. bases such as gelatin, starch, lactose, magnesium tea. are you, talc, gum arabic / etc. The tablets may be coated with saccharose, cellulose derivatives, etc. 'Means, · to obtain prolonged or delayed action ... 7 / / <' 7 29 Rj, '-.7- / 71.

gelatin capsules are prepared by mixing the active ingredient with a diluent, and the resulting mixture is packaged in hard or soft capsules.

When prepared in the form of syrup, elixir, drops, the active ingredient may contain antiseptics, methylparaben, flavoring and coloring additives.

(drink non-caloric), propylparaben, also in soluble granules to be mixed with

An active ingredient in powder and water, capable of dispersing or wetting agents such as polyvinylpyrrolidone, as well as sweetening and flavoring agents.

For rectal treatment, suppositories are made by adding a binder that melts at a rectal temperature, such as cocoa fat or polyethylene glycol.

For parenteral treatment, aqueous suspensions, isotonic saline solutions, or sterile injectable solutions and solutions containing dispersions and / or wetting agents, propylene glycol or butylene glycol are used. '

The active element can also be. made by microcapsules. in the form of one or more pyrrhides and primes.

The invention is illustrated by the following examples.

The compounds are characterized by their melting point / (F ° C) j or boiling point (bo.t.) and / or NMR spectra recorded at 200 mHz DMSO and / or their rotation

^'30 : Properties (' D ') measured at - 25 ° C (unless otherwise stated). . ,,

The measured value of the rotational properties depends on the amount of remaining solution in the reconstituted product.

Except to the contrary: data, the name cis-isomer or trans-isomer means that the individual: composition: is a mixture of zinc configuration enantiomers or trans configuration enantiomers, ^ -: /

The optical purity of the compounds is obtained with high precision. efficiency liquid chromatogra.fi its way.

/ (HPLC) <g _; ggv;;, /. <<: '/.: gg. '/ g, 15 ,. '.'. '''g'g.:gi'e ,. gg: g.

·. EXAMPLE.

N-methyl 1-N-methoxycarbonylmethyl-bromo-5 (fluoro-2-phenyl) -3 '. (Dimethoxy-3,4-phenylsulfonyl) -1-hydroxy-3-indoline-2 carboxamide cis -isomer.

A):: N-Bromoacetylmethyl .. sarcos.inate. This compound is obtained according to T .D. Harris et al., _ J. 'Heterocyclic Chem., 18, 423, 1981. '. : g / g g .g g / 'g /' g- g gg · '/ g -ggg /, /. gg g g g:.

B) Bromo-5- (dimethoxy-3,4-phenylsulfonylamide) -2-fluoro-2-benzophenone. '/ g85 at 48 ° C for 48 hours. 120 ml of dry pyridine 30 are heated with 20 'of amino-2-bromo-5-fluoro-2' ;. benzophenone by adding 20 g of dimethoxy-3,4-phenylsulfonyl chloride.

Cool by pouring into ice water, filter, dissolve the precipitate in AcOEt, wash the organic phase with water, then with hydrochloric acid (IN), then again with water and brine, water. The solution was dried over magnesium sulfate. and the solvent is evaporated in vacuo, 10, 15

1 · yields a solid which is recrystallized from a DCM / iso ether mixture.

Yield: 28 g, m.p. = 125-128 ° C

C) Bromo-5- [N- (dimethoxy-3, methyl-N'-methoxycarbonylmethyl)] phenone.

4-Phenylsulfonyl) -N- (N'amino-2-fluoro-2'-benzo) Anhydrous DMF was dissolved in anhydrous DMF at 0 ° C under argon by adding 250 mg of 80% sodium hydride in 15 min. 4.85 g of the compound obtained in Step A with stirring are added and the mixture is kept for 12 hours at room temperature. The solvent was evaporated and the resulting oil was filtered through silica eluting with DCM / AcOE t 7 / (8 5/15 (; i 7 p aga in / 1 u r in) /. / iso ether / in MeOH mixture 7

Obtained: 3.2 g, m.p. =, 136-137 ^c C.

D) N-Methyl-N-methoxycarbonylmethyl-bromo-5- (fluoro-2-phenyl) -. 3- (Dimethoxy-3,4-phenylsulfonyl) -1-hydroxy-3-indoline-2-carboxamide, cis-isomer.

3.2 g of the product obtained in the previous step are dissolved in DCM '(3 ml), and 750 mg of DBU are added in 7 volumes. karna 24 or. Room temperature: 7 Pour the reaction mixture into a glass vial of ¹ ml,. triturate with CH 2 Cl 2 / AcOE t mi thisi / (. / isoethefi-o mixture and the solid obtained is filtered. (The filtrate is chromatographed on an alumina column. equilibrated with DCM / AcOEt mixture (70/30; tv).

.....

washed with DCM / AcOEt '(60/40, v. v) followed by recrystallization from DCM / hexane / iso ether.

Melting point = 95 ° C (dec.).

®5t® '/ <.

EXAMPLES 2 and 3.

[(Benzyloxycarbonyl-4) piperazin-1-yl] carbonyl-2-chloro-5- (chloro-2-phenyl} -3- (dimethoxy-3,4-phenylsulfonyl) -1-hydroxy-3-indoline, e. - and trans isomers.

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

A mixture of 22 g of 15 benzyloxycarbonyl-4-piperazine and 10.1 g of triethylamine is cooled to 0 ° C.

200ml ether. Within 30 minutes 20.2 g of bromoacetyl bromide and 100 ml of ether are added and brought back to room temperature. After 4 or. the reaction medium is washed with water, dried, concentrated, and chromatographed; 2 0 foamed on silica. Mixture DCM / AcOEt. (95/5;

v.v.) washes the liquid fraction which was purified from the DCM / iso ether mixture.

Yield: 9 g, m.p. = 100-101 ° C.

®'®®) t® / ®®® · j / f''®®® ² y ^ ² ^ '' .1® ² -®t, j \ .t; ®® ² ® '. ··. / ·: B) Di-Chloro-2 ^r , 5 - (di-methoxy-3,4-phenylsulfinylamide) -2-benzophenone. Z; '-:) ...:. 17);

··· Pyridine is heated at 100 ° C overnight with 5.6 g of 30 amino-2-dichloro-2 ′, 5-benzophenone and · 5 g of dimethoxy-3,4-phenylsulfonyl chloride. The pyridine is evaporated to dryness, water is added and the mixture is extracted with ethyl acetate containing a little DCM. After washing with water and drying over sodium sulfate, the product is evaporated in vacuo and recrystallized from DCM / AcOEt.

Yield: 7.7 g, m.p. = 164 ° C.

C) Dichloro-2 ', 5 - [N- (dimethoxy-3,4-phenylsulfonyl) -N- (benzyl-oxycarbonyl-4-piperazin-1-ylcarbonylmethyl) -amino] -2-benzophenone.

'.

2.3 g of benzophenone obtained in Step B are dissolved in 10 ml of DMF and treated. 200 ml of 80% sodium hydride in oil. Pp 30 min 5.3 g of the compound obtained in Step A are added and the mixture is shaken for 60 hours. at room temperature. The medium is poured into water, the precipitate is filtered and separated with DCM, further dried, concentrated and chromatographed on silica. DCM / AcOEt (90 / v; v.v.) washes the resulting product which crystallized in DCM / iso ether.

Yield: 2 g, m.p. = 173-175 ° C.

D) [(Benzyloxycarbonyl-4) piperazin-1-yl] carbonyl-2-chloro-5- (chloro-2-phenyl) -3- (dimethoxy-3,4-phenyl-J -su-1-phenyl) -20 l-hydroxy-3 -indoline, eis and trans- isomers.

g. of the compound obtained in the preceding step in the form of a suspension is added to 20 ml of methanol and 20 ml of THF and treated with 75 mg of sodium methylate. After 2 or. neutralized by addition of a small amount of solid carbonic acid, concentrated to dryness and then quenched with water. Evaporated by DCM. dried and concentrated. The product is chromatographed on alumina,

..... DCM / AcOEt mixture (80/20; t.v.) sequentially eluted the two isomers. The less polar isomer is recrystallized from DCM / hexane. This is the cis isomer.

Obtained: 262 mg, m.p. - 169-179 ^c C.

The more polar isomer is recrystallized from

Of DCM / iso ether mixture.

Yield: 200 mg, m.p. = 209-211 ^e C..

. EXAMPLE 4.

· Chloro-5- (chloro-2-phenyl) -3- (dimethoxy-3,4-phenylsulfonyl) -1-hydroxy-3- (piperazin-1-ylcarbonyl) -2-indole, cis isomer.

200 mg of the cis isomer obtained as in the previous step were dissolved in 10 ml of ethanol and 5 ml of THF, hydrogenated at room temperature in the presence of 10% Pd / C. After 30 minutes the medium is filtered on Celite, R, the filtrate is concentrated, and chromatographed on silica. Mixture

DCM / MeOH (90/10; v.v.) washes the resulting product which was recrystallized with DCM / iso ether.

Obtained: 110 mg, m.p. = 230-233 ° C.

EXAMPLES 5 and 6.

Chloro-5- (chloro-2-phenyl) -3- (dimethoxy-3,4-phenylsulfonyl) -1-hydroxy-3-morpholinecarbonyl-2-indoline, cis and trans isomers.

A) Dichloro-2 ¹ , 5- [N-dimethoxy-3,4-phenylsulfonyl-N- (morpholinecarbonylmethyl)] amino-2-benzophenone.

g of dichloro-2 '' - _5- (dimethoxy-3,4-phenylsulfonamide) -2-benzophenone is treated with 350 mg of 80% sodium hydride in 30 ml

DMF at room temperature for 20 hours with morpholine bromoacetamide, after 45 hours at room temperature. The medium R · precipitate is filtered, dried and concentrated. The product from the mixture is crystallized.

min Add 4.5 g of that shaken room to pour out. into water, then dissolved in vDCM, iso ether

Yield: 5.4 g, m.p. = 173-176 ° C

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

The product of the preceding step was dissolved in a mixture of methanol (10 ml) in THF (20 ml) and treated with 92 mg of sodium methylate at room temperature for 1 hour. The medium is neutralized with solid carbonic acid, the solvents are partially evaporated, the water is removed, the DCM is evaporated, dried, concentrated and chromatographed on alumina. The DCM / AcOEt mixture (70/30; -t.v.) elutes the least polar isomer which is recrystallized from the DCM / iso ether mixture.

Obtained: 215 mg of the eis isomer, m.p. = 260-264 ° C.

++ / + //// - ++ ///? · + '· + / -, + ////. / + /' ^+:: '// · 7 ++. //; //,,:++-.+ :. + / - // +, - +: + / / · / '/' + ++++ / 7 / +: //./ ++ / - + / // + / -. / '+' /

C) Chloro-5- (chloro-2-phenyl) -3- (dimethoxy-3,4-phenylsulfonyl) -1-hydroxy-3-morpholinecarbonyl-2-indoline, trans - ++ ++ - 7 + + - / - + · '+ / + ·' · ·; '· .///+'+' · - '·''' · +. '''/ + · ^: ' + +; // - + +++ - ---.--: T Τ '. .- / -. · '' + - + /. +. '· + · +' · + ·· +, + - / // - // -: - + - '. /. +' *: / // + '/* begin..·. + ++ /: · +: +. ' / -: - -, / //: ./ isomer.

+ / ++ '·. + //// -'. + // +; '/ + · +++, / //. / · ./..'+. · '/; /.:-- + // + /: /. ·. / 7+ _; ./ / /.//·/+ //+-/./7 /,.+ /-.·/. -: /./.++- '+ / - +. / - // ++++' /: - · 77 + / -; '/ ·

The more polar product is obtained by chromatography on a mixture of AcOEt / MeOH (90/10 '; v.v.) according to the previous step. After recrystallization from DCM / iso ether mixture: Obtained; 513 mg, trans isomer, m.p. = 240, 241 ° C. ·,

SUCCESS DYS 7.

N-Methyl-N-carboxymethyl'-bromo-S- (fluoro-2-phenyl) (dimethoxy-3,4-phenylsulfonyl) -1-hydroxy-3-indoline-2-carboxamide, cis-isomer. .

Dissolve 200 mg of the compound obtained in Example 1 in 3 ml

MeOH and 1 ml of water containing 13 mg of caustic soda. After 24 hours. at room temperature, add 1 drop of concentrated sodium hydroxide to complete the reaction. After that, after 15 min. 'to. calcium bisulfate is added to the acidified solution to pff 3. Water is added, the mixture is extracted with AcOEt, washed with water, treated with magnesium sulfate and evaporated in vacuo. Received

-3. .3 /'t/./ (· - (.. '35 .5 / 5 · 3.3. '·' ·· * »·· ('·' · 3 · /·./"3'33'-'' ^: j /./ · / 3 /.; {·· // / '5-n / (3 (, ..- 3 / (- (./, (:(.' / 53, ··. () .. '' ./3- ('·. ·,''.> .35 {/ - ///' // - · / '/ · <, / (/ (/./·' / · '· (- / 7-3- '3 -5 - Product recrystallized from' -BCM / isoether mixture).

Lyd.i. = 206-208 ° C '.

. ·. '/·.- / 3 <//' · / ύ. ¹ - ¹ '-i / 5 ^: 5 -. 3 -J, / 3 // 3 · 55 ··. · 3 3-5 / · (/ - /'.'..55. -./7 '-'. / '/·.;/ ./-/-(/ 5 / - / 7.,? // (-.3 - / - 3: /./: ./?. <;. 53 // - ''

EXAMPLES 8 and 9.

Ch / Lor-5- (Chloro-2-phenyl) -3- (dimethoxy-3,4-phenylsulfonyl) -1-hydroxy-3- (ethylcarboxylate-4-piperidinecarbonyl) -2-iudoline, -eis and trans -isomers.

A) N-Bromoacet ii-piperidin-4-ethyl carboxylate.

// · --3 (-.-. 3- / 3.5 // - 53-33./-:(//;-- · (53 ((: 3/5/7 (/.//to/ /./ (5, /// ((55. · '- - /3//-..(5(5(-/3-./(./(((3:(3 :-( 3 / /:/-3///(3./3/5./ -55-u? '- (3-53 / 37 / · {- / 7 / -5 / - {- 7./(,.7 -3 ..- 5 /. /. (5 '' 3 / - _: 5 '(i.e. · 3 /: / This product is obtained from commercial piperidine-4 ethyl carboxylate. 20 B) Dichiar-2 ^r , 5 - [N- (dl · Methoxy-3, 4-phenyl-s.l.fαπyl) -iα- <ethyl-carboxyl-4-piperidinecarbonylmethyl}} amino-2-benzophenone. '25 g of dichloro-2 ^r. , 5- (Dimethoxy-3,4-phenylsulfonyl) -Z-benzophenone is dissolved in 100 ml of DBF / pd and 541 mg of sodium hydride are added and after 30 minutes of stirring, 5 g of the compound of Step A are added and the mixture is regenerated. The resulting oil is chromatographed on silica, eluting with a mixture of AeOEt / DCM / hexane (40/10/503 t ~ vu) ~, and the resulting oil is obtained by stirring in vacuo for 18 hours, concentrated in vacuo, extracted with ethyl acetate, dried and concentrated. the product crystallizes *.

Yield: 3.5 g, m.p. = 128 ° C.

C) Chloro-5- (chloro-2-phenyl) -3- (dimethoxy-3,4-phenylsulfonyl) -1-hydroxy-3- (ethylcarboxyl-4-piperidinecarbonyl) 2-indoline, eis and trans isomers.

At 5-60 ° C for 18 hours. A mixture of 3.4 g of the compound obtained in the preceding step and 869 mg of DBU is dissolved in 10 ml of chloroform. Reaction medium

10th . filtered 'through the column eluting with DCM / AcOEt · mixture cis-isomer. with aluminum (90/10; t.v.). oxide, Incoming Obtained: 700 mg, m.p. - 110 ° C. Purify with ¹ ethyl acetate trans isomer. / Obtained: 610 mg, m.p. = 187 ^U C. 15th / EXAMPLES 10 & 11. '' N-Methyl, 'N- (Pyrid-2-yl ethyl)  chlor-5 {chlor-2 phenyl) -

(dimethoxy-3,4-phenylsulfonyl) -1-hydroxy-3-indoline-2 ', 20'-carboxamide, eis and trans isomers'' A) »4 chloro-2. phenylcarbonyl) -2 'chloro-5-phenyl] -N- (dimethoxy-3,4-phenylsulfinyl)' glycic acid.

.25 a) 'Dichloro-2' ', 5- (dimethoxy-3,4-phenylsulfonamide) -2

·; 'benzophenone. ' ¹ '

This compound was prepared in Steps 2 and 3 of Examples B. 30 b) Dichloro-2 ', 5- [N- (dimethoxy-3,4-phenylsulfonyl) -N-. benzyloxycarbonylmethyl] amino-2 benzophenone. .

172 g of the product obtained above are dissolved in 800 ml of DCM and cooled to 0 ° C. Gradually, 11 * 7 is added under nitrogen. g 80% sodium hydride, after 30 min. 256 g of benzyl bromoacetate are added and 24 hours. stirring at room temperature. Evaporate DMF, recover with water, extract with DCM, · dry and concentrate. The resulting product is crystallized from isopropyl ether and then recrystallized from DCM / iso ether.

Found: 136.5g, m.p. Mp 102-104 ° C.

'c-) N - [(Chloro-2-phenylcarbonyl) -2-chloro-5-phenyl / N - (dimethoxy-3,4-phenylsulfonyl) -glycic acid.

50 g of the benzyl ether obtained above are dissolved in 500 ml

AcOEt and 2.5 N Pd / C in 5% nitrogen are added under nitrogen. The solution is shaken vigorously for 5 hours and hydrogen is bubbled through. At the end of the hydrogenation, the product crystallizes.- The medium is filtered. Celite R, richly 'washed with warm DCM, then concentrated the organic phase. The resulting product is crystallized, then re-crystallized in DCM / iso ether.

Yield: 33.7 g, m.p. 177-178 ° C.

'B) Dichloro-2- [5, 5' '- (dimethoxy-3,4-phenylsulfonyl) -S- (1M-pyrid-2-yl-2-ethyl-N * -methyl) -carbamallomethyl] -amino-2-benzophenone.

Dissolve 2 g of the acid obtained in the preceding step in 1 ml of DCM and add 1.13 g (methylamine-2-ethyl-2-pyridine) followed by 844 mg of triethylamine and finally 1.92 g of BOP, followed by shaking for 18 hours at room temperature. The product is regenerated with water, the organic phase precipitated and washed with sodium carbonate solution, dried and concentrated. After chromatography on silica, the product obtained is washed with a mixture of DCM / .M.eOH (95/5; v / v).

Yield: 2 g, m.p. = 150 ° C "

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

Ϋ. A mixture of 1.7 g of product obtained in the previous step and 442 mg of DBU. of dissolved DCM, is heated for 18 h. At 55 ° C. The reaction medium is chromatographed on alumina. The cis isomer was washed with AcOEt / DCM (40/60; t ~ v. J).

Obtained: 410 mg, m.p. = 191 ° C.

Pure AcOEt elutes the trans isomer .., '. . Obtained: 790 mg, m.p. = 154 ° C.

EXAMPLE .12 (Carboxy-4-piperidinecarbonyl) -2-chloro-5- (chloro-2'-phenyl) -3 '(dimethoxy-3,4-phenylsulfonyl) -1-hydroxy-3-indoline, cis isomer. - ^;

500 mg of the cis isomer obtained in Example 9 are dissolved in 5 ml of methanol. 47 g of caustic soda and 1 ml of water. After 18 or. The beating is washed with water, acidified with hydrochloric acid solution, extracted with DCM, dried and concentrated. The resulting solid product is purified by chromatography on silica, eluting with 95/5 (v / v) DCM / MeOH.

The resulting product is crystallized from DCM / i.zoether.

Obtained: 250 mg, m.p. = 150 ° C. 35

N-Methyl-N- (methyl-1-piperidin-4-yl) -chloro-5 (chloro-2-phenylphenyl-4-phenylisulfonyl) -I-bldr0 / ksi-3 ~ 5-Elidbin < 2-Phenylphosphate ^ / :: Cisv / <and: /: trans '/ Isomers'

A) Dichloro-2 ', 5 - [(N- (dimethoxy-3,4-phenylsulfonyl) -N- (Ν'methyl-N'-methylpiperidin-4-yl) carbamoylmethyl] amino-2-563-22.σ £ © ηοηΗ3.

b / to / '*. 17 g - / - / -, - / 7 g of the acid obtained according to Steps 10 and 11 of Examples A is dissolved in 50 ml of DCM, mixed with 650 mg of methylamine-4-methyl-1-piperidine at 1.90 g of BOP. After 2 hours, the organic phase is washed with water at room temperature. saturated with carbonic acid, dried and concentrated. Chromatography on silica, washing with DCM / MeQH (90/10; v.v.).

Yield: 1.2 g, m.p. ::: -.; / 165-165 ° C. / / 11 / <.

/ '/' i '· - ·· / /; / / _? '-, -'jb7; b / 77 /; - ..//b-bb 7.1- '. '

B) N-Methyl-N- (methylpiperidin-4-yl) -chloro-5- (chloro-2-phenyl) -3 (dimethoxy-3,4-phenylsulfone) -1-hydroxy-3-indoline-2-carboxamide , eis- and t raus ^ isomers.

650 mg of product obtained in the previous step overnight

4 '/ exposed / o-lOO / - ^? / "G/'<.hatium methylate dissolved in 5 ml of 7 / methanol, / '/ by the addition of b / solid carbonic acid, · evaporation of the solvent, / regeneration with water-saturated carbonic acid, refluxing"-l-DO ^ //: jibberin-- / ir _; .b concentrates. It is then / chromatographed on silica. / Mixture ^ sediment / kllai / washes - /; / two isomers. Thereafter 1 each / isomer / is recrystallized with DCM / iso ether mixture. .

Trans-humming least polar under those conditions ....

Obtained: 205 mg, m.p. 4 = 181 ° C.

//1///:Ci.s-iz.omeras ;//1 '1- .: - /

Obtained: 150 mg, m.p. = 97 ° C _; has 0.25 M isoether.

EXAMPLES 15 and 16.

Chloro-5- (chloro-2-phenyl) -3- (dimethoxy-3,4-phenylsulfonyl) -1-hydroxy-3- (methyl-4) piperazip-1-yl 'carbonyl)] -2-indoline, cis and trans isomers .-

A) Dichloro-2 * 5- [N- (3,4-dimethoxy-phenylsulfonyl) -N // ^7l: l / 11 / - (7ė7il / 4 ⁱ / pl77f7zin ^ l / ^71:) karbąmdilmatįl /] iamind '-21i / i :: 1''/^;'''''benzophenone. . .

il / f / Sifi; /: 7ūngih7s' - // 1: 73-hhamas ./:/':/ vęil77at / '1177netiipi77rązl7u1; to.S // -. 7i1''bSgsby /// gaUtas- / pagaI \' / example: jUU / l70i: / and / 4i'iėbapą1'7 // i1 '' '' 1/1/1

1 to 7j1 / 7: iyd / to ^ 1 ////// j: //: ///.

/ 11 // j / B) /; // 7/1 /// 77: / 1 / chloro-5- (chloro-2-phenyl) -3- (dimethoxy-3,4-d, 120-phenylsulfonyl) -1- hydroxy-3- [l (7bfi'-174j: piperazin / ll / l - '. 1-.:1 ii) carbonyl] -2-indoline, eis and trans isomers.

/^././//1/1^7^37^//173^/33 iniAhkšb.ęšhiame ':' ⁱ <ietnpę /: / yri - // ckiziz ^: swinging: s by Examples 1.2-13, Forming the two isomers are separated:

chromatography on aluminum oxide. Mixture of DCM / AcOEt isomer which is recrystallized with DCM / iso ether mixture.

melts = 120 ° C, has 0.25 M isoether.

Such a DCM / MeOH mixture washes the more polar trans isomer, which is then recrystallized with methanol, m.p. Mp = 189 ° C.

EXAMPLES 17 and 18.

N-isopropyl N-methoxycarbonylethyl chlo.r-5 (2-chloro phenyl) '-71 fdiraetoks i 3 _r 4-phenylsulfonyl) -1-hydroxy-3 iAdolrn carboxamide 2, cis and trans isomers.

A) N-Isoprapil-S-methoxycarbanylethyl Chromacetainide.

One drop is added - 90 g isoprdpilamine to 130 g 1Ό methacrylate. of dissolved-300 in methanol and cooled to -105. After 72 or. - evaporation of the medium at room temperature, -. the residue is distilled. Received. oil (168 _g 3 g) is in the (K-zopropyl) amino-3 methyl p region.

bo.t .. = 73-78 ° G at 15 nm Hg /75-.-:>'·”·' · Χ5 ---- 7: - 77757 //. 75-75» 5 ...... /(d--....-/75/5-. 7 / - 5/5 .57-7-7 .- / 7 ^: ·· / ^; ./5 7-- · //7.G At 29 ° C, 29 g of the title compound is mixed with 100 ml of DCM and 20.2 g of bromoacetyl bromide in 100 ml of DCM After 12 hours at room temperature, the solvent is evaporated, recrystallized with water, extracted with ethyl acetate, 7/5 --- / 77-7 /.7-/77 5: -7 / -7 -:,. /, -.,. / 7-./-:-7--, .. / - / 777 / -. - / .- 77.77.-y '^ k -:; · /; /, / ^ 5 ////: .. 75-77-./-: /; / 75/5; 77>/; · // / '57 / V-7-7 / 5 / '/ 7 / - / - 7 / -: 5-7 / ·''55 ///// 5 / </// · 7 '· /./:/ · 7 / -; / 5- /-.7-7.7 dried and concentrated The resulting oil is used as described in the following step.

B) Dichloro-2 *, 5 [N- (dimethoxy-3,4-phenyl-ulphonyl) -N- (N'-25 isopropyl-N * -methoxycarbonyl-ethyl] -carbamoylmethyl-amino-2-benzophenaneThis compound is obtained by conventional method: obtained in Step A, dichloro-2 ', 5 (dimethoxy-3,4-phenylsulfonyl30-amide) -2-benzophenone by the addition of sodium hydride.

accompanying - = 535-1375 (recrystallization: DCM / isoether)

...... ·.: .. ·: Λ ·. .

.. I

C) N-Isopropyl-N-mephoxycarbonylethyl-chloro-5 (chloro-2'35-phenyl) -3- (dimethoxy-3,4-phenylsulfonyl) -1-hydroxy-3-indoline-2-carboxamide, eis and trans isomers .

This product is obtained by cyclization of the compound obtained in Step B in the presence of DBU. The cis isomer is separated by chromatography on alumina, washing out

DCM / AcOEt · (90/10; v / v) .- The product is then crystallized from AcEt / hexane. , 0 melts = 153-155 ° C.

The trans isomer is obtained by leaching - / aluminum. · Oxide 10 'column with ethyl acetate. The BB-product is then recrystallized from MeOH / iso ether.

_: melt.t = 182-185 ² C. // - ¾¾

EXAMPLES 19 and 20. B / 7 / ¾ '' -'- N -methyl-N-methoxycarbonylmethyl-chloro-5 (chloro-2-phenyl) -.

? - (3-Dimethoxy-3,4-phenylsulfonyl) -1-hydroxy-3-indoline-2- * carboxamide, eis and trans isomers.

<7, / '// - B' - //. // - 7 /.//.-///B 0.0 //

The two isomers of this compound are prepared according to the procedure described in Example 1. They are separated by chromatography on alumina. Mixture DCM / AcOEt (80/20; v / v).

/ washes the "cis isomer <which crystallizes

B DCM / iso ether /./-/ mixture, a white powder containing 0. 25 M iso ether. While heating. in a vacuum / 'it is transformed into foam.

// The NMR spectrum of the cis isomer (Example 19) is shown in Fig. 1. / 30 / / .B. · / '/ / 7' // / / /./ .. '/ / /'/-////./ // - ///// / / - /// ¾. .

Trans isomer / eluted with AcOEt.

Recrystallize with DCM / iso ether.

melts = 176-178 ° C. // SS '// · / /'/,/.0-:-/'/ Z / B / -0 0.//;'0/' · ^Λ // · '///' // 0- - '/'.

7 / - The NMR spectrum of the trans isomer (Example 20) is shown in Fig.//2.///.

EXAMPLES 21 and 22.

N-Methyl N -carbsimethyl-ctool: or -5 (chloro-2-phenyl) -3- (dimethoxy-3,4-phenylsulfonyl) -1-hydroxy-3-indoline-2-carboxylic acid. siamamide, eis-; and / tracheoisomers. /

These units are obtained using the base units obtained in Examples 19 and 20, which are prepared as described in Example 8.

Cis-isomer: m.p. = 220-222 ° C after recrystallization

In DCM / isoether / MeOH mixture.

Trans isomer: m.p. = 222-225 ° C after recrystallization

In DCM / isoether mixture.

EXAMPLES 23 and 24.

F i N -methyl N -carbamoylmethyl chloro-5- (chloro-2-phenyl) -20- (dimethoxy-3,4-phenylsulfonyl) -1-hydroxy-3-indoline-2-carboxamide, eis and trans isomers.

Each isomer is obtained from the corresponding: acid ^? isomer based on Examples 21-22.

/ 'i5 / - /' ^ F - '/ 3? //'; F. F / F- ./F

The 605 mg of the acid trans isomer obtained in the previous step was dissolved in 10 mL of DCM, 435 mg of BOP and 260 mg of DIPEA were added. In 5 mins' at room temperature sharply

..F .: 6 ml of 20% ammonia solution and 4 hrs.

left - stirring. Sodium carbonate solution is added, followed by extraction with DCM. Washable organic phase,

F · -j is successively dried over calcium sulfate with water, sodium bisulfate solution, water. The residue after evaporation. Chromatography on silica gel and washing with .35 F: AcOEt / MeOH (95/5; v.v.). The product was crystallized twice in DCM / EtOH at 0 ° C. .

melts = 236 ° C. '3 ·'

The NMR spectrum of the trans isomer (Example 23) is shown in Figure 3. / 'd /''- -7,. '= -.: = 7; /// ^:; - ':' - '. <5'X // {/ {(In. / 77 {/../. _ 3. {7 ^ 7 // {7. ·; 7/3;

In the same way, the cis isomer is obtained.

The resulting product is crystallized from DCM / iso ether. Micronized compound dried under vacuum at 70 ° C for 8 hours. has 0.25 M isoether.

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

EXAMPLES 25 & 26. {(7.77 {p; {(/; / (: 1-5 /: /: - (((3 /// 3. (73 = 7/3 /// 7 /// (3 ((/. 7 / = / 7 / {(. 3 ((/: 3 \ {/ 3 ^ {(3 ((/// 7 ^

Chloro-5- (chloro-2-phenyl) -3- (dimethoxy-3,4-phenylsulfonyl) -1-hydroxy-3- (hydroxy-4-piperidin-1-yl) carbonyl-1-.

indoline-s, trans-isomer /.

This compound obtains N- [(chloro-2-phenylcarbonyl) -2-chloro-5-phenyl] -N- (dimethoxy-3,4-phenylsulfonyl) -glyconic acid according to Row ⁴ described in Examples 11, 12, Step-I /; : / 7 = / = // 0 = / - 3 =: ==

It is then cultivated as in the above examples with the addition of 25 hydroxy-4 piperidine in the presence of BOP and triethylamine.

The product obtained is then cyclized in the usual manner: in the presence of a DBU. The isomers are separated by chromatography on alumina, the DCM / MeOH (99/1; v.v.) mixture eluting with the eis' isomer. . '-' = (// '= :( 7 =.-.- / = -. =

--30 (: ./ (= // /7..(((:'/ (/ 7 .-- / .. //. 7. ({3 3 (7 '= (3 // (7 // / 7 ': {// 7 // {({^ 3/3 {/ {///: =' The product .crystallizes in DCM / hexane / MeOH.

The resulting solid, triturated · is converted into a powder in DCM / hex ano amorphous powder. · .//(/

The cis isomer · is crystallized by NMR at 388 ° K.

1-1.8 md: m: 4H: CH _? 3 and 5 piperidine

2.8-3.65 md: m: 5Η: CH ₂ 2 and 6′piperidine and CH at -4 3.75 md: 2s: 6H: 20CĘ ₃ / -..... _r , y / '/. / ·.

: 4.15 md: d: 1H: OH on piperidine · '·· .. ·'·; ·. · - 5.45 md: · s: 1H: CH (indoline) '· - .. y </ · 6 _Λ , 1 m-.d .: s: 1H: CH indoline -.

6, 8-7, 6 md; m: 1CH: H aromatic '/ ^: 7 // 7 /

DMSO: 2.4 ppm. '' 'Γ

DOH: 2.75 ppm.

y mixture of DCM / MeOH (97/3; yt. v.) is washed trans isomer which is then-to ^- recrystallized DCM / izoeterio mixture., m.p. = 232-234 ° C. .

yy (L) Syntheses of Proline sherry see p. EXAMPLES 27, 28,: //: 7/729, y'3o ////// y7 + '/ - ++ /: + + /: /// 7 ///. / + // / + 0: '// ++ EXAMPLE 27 & 27L ·.' : / Chloro-5- (chloro-2-phenyl) -3 (dimethoxy-3,4-phenylsulfonyl) .7.1-hydroxy-1 - 3 [(2S) (methoxycarbonyl-2) pyrrolidinecarbonyl] -: 7 2 indoline, eis -isomer, two compounds.

7y7; y A) (L) N - (Bromoacetyl) methyl prolinate // 25 - /// +. 7 //: .7 / + // ++ / 7./7/+/-'/'/7 /// + /// 7: + //: ^ /// //: To 16.7 g of (L) methyl prolinate chlorohydrate solution 20:

'/ y / · / ml of DCM is added simultaneously with 20 g of tertiary laminate and 20 / g of bromoacetyl bromide dissolved in 30 ml of DCM / - at room temperature / -5 ° C, and is then stirred at room temperature

3.0 / 24 or. Add water, wash with KHSO ₄ solution, water, sodium bicarbonate 7, water, and dry over magnesium sulfate. After evaporation, an oil is obtained which is dried under vacuum. This oil, pure y 7 CCM, is used in the next step ..

• 35 7 '

: ./ 0 // AcOEt, washable 7 / .. magnesium '/ with 1 fa tu / 7, y / graph on / 7' mixture 7/7 (85/15; small amount / / / - / / ., .. _47.:. // '// B) / dichloro-2', 5 [N- (dimethoxy-3, 4-f nilsulfonil) N- ((2S) me- toksikarbonil 7-2) pirolidixikarbonilmetil] amino-2-benzophenone.

. · Dissolve 4.66 g of (dichloro-2 ', 5 (dimethoxy-3,4-phenylsulfonamide) -2-benzophenone / 40 ml of DMF in anhydrous argon /

At 0 ° C. 340 mg &gt;% sodium hydride is added, after 30 min. 6.5 g of the compound of Step A obtained. After 4 days at room temperature, it is placed in water, extracted with water ^; brine, dried / / and evaporated / vacuum / 7 / Chromium tosilica gel, / / // washed with DCM / AcOEt (tv). The resulting solid · body contains / starting: bromine / 7 derivatives. The sample is recrystallized with a mixture of DCM / iso ether. // // -7 //,: -,.

Yield: 1.2 g, m.p. == 141-142 ^ 0.77 · = _43 _z 7 _{(c =} ! _{Z Me0} H / THF: 8, / 2; tv) 7

07 .-. ^: 7-7 / 77. / 7/7/7/7 7 //7.,/7/// 1 / // i. '/ / 7 · 7.///7 ^: 7 / - / 77-: A.///:/ \

Analysis: Calculated: C 54.81 H 4.44 N 4.41 Found: C 54.40 H 4.54 N 4.55 _: ^ '··

..- / 70./77 Cha-5- (chloro-2-phenyl) -3- (dimethoxy-3,4-phenylsulfonyl) -1-hydroxy-3 - ((2S) (methoxycarbonyl-2) pyrrolidine. 7 Carbonyl] -2-indoline, cis-isomer. : / · /// · '' / 7/7, 1/1 g of the compound obtained in the previous step 7. -, /: 307 / -7 equivalent 'of DBU is heated in 4 ml of methylene chloride' for 24 hours. Aliquot; HPLC / analysis indicates 4 isomers are obtained. After 24 or. the reaction medium is eluted on an aluminum column pre-mixed with DCM / AcOEt (90/10; 71v), washed with DCM / AcOEt 7 (90 / vol; v / v to 70/30; ). 510 mg of a mixture consisting of two at least polar compounds is obtained. at a ratio of 4/1 (by HPLC). / .7

3064Β. 1) Two. sequential crystallization in cold DCM / isoether yields the major compound.

Obtained: 180 mg; D ²⁵ = - -247 (c = 0.4 chloroform) *>

melting. = 187-190 ° C. '/: 2) Crystallization solutions of previous composition. 'Chromatograph on aluminum with a mixture,

DCM / AcOEt (85/15; v / v). This separates the previous 10 · / compound: from //; subsequent, / subsequent dissolved: / in a minimum amount of DCM, then precipitated by the addition of a minimum amount of hexane.

k- · 'D ²⁵ ./--/ +136 (c ~ 0.24; chloroform). - ///. '<

EXAMPLE 28.

//. · '// ((2S) (Carboxy-2-pyrrolidinecarbonyl) -2-chloro-5 (chloro-2-phenyl) -3- (dimethoxy-3,4-phenylsulfonyl) -1-hydroxy-320 indoline; cis-isomer .

430 mg of the compound obtained in Example 27 / is dissolved in 6 ml of methanol, 41 mg of caustic soda is added to 1 ml of water and; beat 24 or. at room temperature. Acidify ⁷ 25 to pH 3 / several 7 drops of sodium, bisulphate and extract with ethyl acetate. Washable ../water//. .// 'dried over magnesium sulfate. Chromatograph on silica / column with / DCM / pentane / 80/20;

- ///. · T. v.). / - / .Esteri s - '·· - (sample 27 j), 3 / which s 30 / unreacted, was washed with DCM / AcOEt mixture (70/30;

t.V.). 7th

X - -.

AcOEt / MeOH (80/20; v.v.) washes the acid which was then recrystallized. DCM / izoete / riu.

'//'/·/.'-- / 7/7 / //, / 77.7 // /7.//7 melt. = 232-234 [deg.] C. ap25 = -254 (c = 0.3, chloroform)

R'RRR - '' r R., 'RR. Λ 'f' '<5 RRr

EXAMPLE 29 and 29b.

(2S) (Carbamoyl-2-pyrrolidinecarbonyl) -2-chloro-5- (chloro-2-phenyl-3- (dimethoxy-3,4-phenylsulfonyl) -1-hydroxy-35-indoline, cis-isomer. Two compounds.

230 mg of the compound of Example 28 were dissolved in 5 ml of DCM, 50 mg of DIPEA was added followed by 165 mg of BOF- and left for 5 min. at room temperature. The medium is cooled in a beaker, then 1 min. gaseous ammonia was sprayed and after 15 min. spray again for 1 min. Water is added followed by a large amount of 'ethyl acetate' to give two phases. The organic solution is washed with sodium carbonate solution, water, potassium bisulfate solution, water, then brine. After drying, it is chromatographed on silica, eluting with DCM / MeOH (93/7; v.v.). The resulting product was triturated with DCM / iso ether / hexane. It contains 1/3 M of the iso ..

D ²⁶ ₌ -189 (c = 0.23, chloroform).

The compound of Example 29 may be obtained by other means.

A) Dichloro-2 ', 5- [N- (dimethoxy-3,4-phenylsulfonyl) -N - {(2S) carbamoyl-2-pyrrolidinecarbonylmethyl)] amino-2-benzophenone.

33.9 g of the acid obtained in step 11.12 (A) of the pagfid samples are dissolved in 300 ml of chloroform, added with 15 g of 'thionyl chloride and refluxed for 1.5 hours. Evaporate to dryness, recover with DCM and evaporate again. Dissolve the medium in 300 mL DCM and add 10.5 g (L) prolinamide chlorohydrate at 0 ° C, then slowly add 18 g DIPEA in 20 mL DCM, and the reaction temperature should not exceed 30 ° C. After overnight at room temperature, the reaction medium is washed twice with sodium bicarbonate, then twice with potassium bisulfate, dried and concentrated. Obtained ^{: The} crude material is dissolved in: ./ minimal DCM and added dropwise to the iso ether (1.21) with shaking. After Τ 'or. sediment resulting from whipping

... filtered,. dried .vacuum G. or. at 60 ° C. 5. Receiving * -42 g. /: B «D ²⁵ = -40.8 (c = 1.007; chloroform). - /: /. B) ((2S) 2-carbamoyl-pįrdiidinkafbonil) -2-ęhįor 5fch.lQrf 10-2-phenyl) ¹ -3 (3,4-dimethoxy-phenylsulfonyl) -l-hydroxy-3- .// / Bindoline: (eis-isomer; two -j / ng),. / B ·. BB, '5 g of the compound obtained in the preceding step are dissolved in -50 ml' 7: 7 'methanol7 / Cooled to -10 ^G C ,. 1.35 g DBU added and - maintained at 60 / hr. B /: at -10 ° C. The compound. crystallized ^; B filtered / 7 (eis-1 / B -. '. B' compound) '.

// Kr ist ai i zatic. solution .neutral water B with KSO ₄ - · and. the medium is evaporated to dryness. Regenerated with water, double extraction. DCK -Ambient dried ,: B / 7, ^and:; / Concentrate 7 The resulting crude is chromatographed on

Of silicone B by eluting with AcOEt / DCM (28/727: v / vj -:. B . _; mixture.-.

/ 7: The mixture is collected; and is dissolved in a minimum amount of hot methanol. after filtering. insoluble materials, the filtrate is left overnight at -4 ° C / - and / / precipitated a second eis compound. k -'- RBcf: / ::

m = 1.25 g - 7B :: / // 'B;/.' / 77 / D ²⁵ = -196 (c = 0.351; chloroform).

NMR spectral analysis indicates the presence of one mole of MeOH per mole of product. .

Product-crystallization / in ethanol z removes solvents from the crystals. .

/ 35 // - 7: / --- 7/7 -: 7 / - // melting point U = 154 ~ 162 ° C 7 /: ^a D ²⁵ = -204 (c = 0.3; chloroform) / / _{; ;} γ / y si _: ^a D ²⁵ - -131 (c = Q, 27; chloroform / methanol 8/2; v / v).

This compound is indented to the compound according to the first method of this example ..;

The compound crystallized in step (B), named compound cis-1, crystallized from the isomer in methanol, m.p. = 190 ° C γ // γγί / 4 / Υ 3 Y / A · ^; υ33α · Α A ', / ^a D ²⁵ = -115 {c = 0.3; chloroform).

example 30. · α // α; α ^λ υ

Chloro-5- (chloro-2-phenyl) -3- (dimethoxy-3,4-phenylsulfonyl) -15-hydroxy-31 (2R) methoxycarbonyl-2) pyrrolidinecarbonyl] -2-indoline, cis-isomer.

A) Dichloro-2 ¹ , 5-1 N- (dimethoxy-3,4-phenylsulfonyl) -N - ((2E) (methoxycarbonyl-2) pyrrolidinecarbonylmethyl] amino-220 benzophenone y This compound is obtained · '·· -. from the acid obtained according to Steps 10 and 11 of Examples A and 3 (3 g), to which 1.2 g of (D) methyl'rolinate and 2.8 g of BOP dissolved in 10 ml are added.

DCM,. at l / \ 15 · g triethylamine .. Leave for 1 hour. at room temperature / then dissolved in DCM, the organic phase washed with sodium carbonate followed by potassium hydrosulfate. dried and concentrated. The crude material is chromatographed on silica eluting with A / l

DCM / AcOEt (95/5; v / v). The resulting product was recrystallized from DCM / iso ether. /,:

A A · · melts. = 140-141 ° C.

. ? D ²⁵ = +28.5 (c = 0.27, chloroform).

\ y γ 'Α.γ'; ' γ a;

.B) Chloro-5- (chloro-2-phenyl) -3- (dimethyl-ethoxy-3,4-phenylsulfonyl) -1-hydroxy-3 - {{(2 R,, (methoxycarbohyl-2}) -pyrrolidinecarbonyl} - 2.indaline, cis-isomer *

1, «5 ~ <to the preceding one - the compound - is refluxed with 5 ml, D € M per. overnight, .esant-360 mg DBG. · Medium: .chromatography, on -aluminium-oxide * The mixture 'DCM / AcOEt (95/5;' vol.) washes, - least polar fraction - (obtained - · 300: - mg) ) ® which .'-. Two. · Times

10 ', • recrystallized in pojsaoa'.DCM / isoether mixture .. ,,.

melts - 186-188 ^Q C «q25 _ -i-245. (C-0.4 _z . Chloroform) ...

Is this compound an enantiomer? -incoming. <jE>> the proline described in Example 27 _f ., Ί, EXAMPLE '31.

'Chloro-5-chloro-'2-phenyl> -3-7 <dimethoxy-3 _P 4 -phenylsulfonyl] -1-hydroxy-3f (2Si, (hydroxymethyl-2) pyrrolidinecarbonyl] -2-indoline ,. -eis — isomer * '·

A) dichlo ?? 2 * _J 5- ((E-dimethoxy-3, 4-phenylsulfonyl) E-5'hid2 roksimetil-2) pi.rolidinkarboni IMET I] amino-2 -benzofenonas.

This compound is obtained by treatment of (L) prolinolic acid obtained in the ExamplesG and 11-step. A, in the usual way.

\ 1. · .r ,,, / ..- // 'λ''' .i? 7 ^Λ / '- ρ ·''ή; / ί / 7ρ77Γ <777i7d 7.jp ·'·; - / · /'/.':-'/ 7 · · ·

B) chloro-5- <2-chloro-phenyl) -3 _R 4-phenylsulfonyl) -1-hidroksi3 [(2S) (2-hydroxymethyl) -2-pirolidinkarbonilj indolinazg cis-isomer.

1.5 g of the compound obtained in the preceding step is cyclized.

at 380 mi DBG 2'.ml.DCM * After 3 · days at room temperature, 1 mL DCM was added followed by heating to -40 ° C overnight. There are 3 majoritarian compounds observed ^: formation of ' ^λ · 53' from CCM on silica (AcOEt eluent) ./: · '

Chromatography on silica elutes 5 less polar fractions with DCM / AcOEt (60/40 to .80 / 20vol). It is then chromatographed on alumina, eluting with 'DCM / MeOH <99/1; etc.),

The resulting fraction from CCM is homogeneous. The product is three times · recrystallized from .DCM / iso ether; Received. product by HPLC ^? contains> 99% purity.

Found: .155 mg, m.p. = 194-197 ° C.

Y ²⁵ = -195 <c = 0.2 chloroform).

'EXAMPLE' 32'and 32b.

N-Methyl N-Methoxycarbanonyl triethyl-chloro-5- (chloro-2-phenyl) '3 (ethoxy-4-phenylsulfonyl) -1-hydroxy-3-indoline-2-carboxamide, eis and trans isomers.

A) 2 ^dichloro-1, 5 to N- (4-ethoxy-phenylsulfonyl) N ^(N? -Methyl N -metoksikarbonilmetil *)] 2-amino-benzophenone.

5.7 g · dichloro-2 ’, 5 ethoxy-4-phenylsulfonylamid-2-benzophenone are dissolved in 1 ml of DMF under argon and 400 mg of 80% sodium hydride are added at 0 ° C. 4.3 g of methyl N-bromoacetyl sarcosinate are added. After 48 or. The product obtained is extracted by conventional means, purified, chromatographed on silica, eluted with · DCM / AcOEt (90/10; v.v.) and recrystallized in DCM / iso ether.

melts = 158 ~ 1 € 0 ° C,

B) Trans isomer of N-methyl-N-methoxycarbonylmethyl-chloro-5- (chloro-2-phenyl) -3- (ethoxy-4-phenylsulfonyl) -1-hydroxy-3'-indoline-2H / carboximidazole. :.

Dissolve 4 g of the product obtained in the preceding step in 4 ml DCM and 90 min. while operating at room temperature.312 mg of TBD. Add a solution of-potassium bisulfate, in vacuo

4h evaporated · DCM, extracted with AcOEt, washed and dried over magnesium sulfate. Chromatography on silica gel eluting with DCM / AcOEt (90/10;

t. v

Obtained: 590 mg, m.p. = 160-171 ° C after recrystallization. DCM / in hexane.? /:; - λΖ · 7). 'Ζ.) ΖΖΖ ^); / <- Ζ''^;Ζ''7ΖΖΖ / ^; ): /.- f ji ·· a ’; ///

C> N -methyl-N-methoxycarbonylmethyl-chloro-5 (chloro-2-phenyl) 15

3- (Ethoxy-4-phenyl-sulphenyl) -N, N, -N, N, N, N, N, N, N, I;

x Add 100 mg of methanol and 10 ml of THF to a suspension of the compound obtained in step (A) ·

Ζζ sodium methylate, leave to stand for 7 hours in the refrigerator. Z Water is added, neutral water is added to the bisulfate solution and part of the methanol is evaporated off under vacuum. After

Z is chromed with AcOEt to form aluminum onto the chromium, followed by washing with DCM / AcOEt (80/20; vol.).

850 mg of product are obtained, which is recrystallized from DCM / iso ether mixture. idxZzZZyyyyz //> Z / Z /) '/ i /////' x

Table 1

^R 'r / > / WR / .. K ' ₂ R n RR -r ! · '. \. J R R Solvent, melts C or IR Br- CH ₃ O-3/4 F- ch ₃ ' R. 82-83 RR · ' i R, ' R-N-OįOOyOOC ^ DCM / isoether .. 'Čl-Λ i CH ₃ O-3.4 Cl- ch ₃ 'r - - Xr 1 Ar-ArR / II' -N-O-CiįOO ^ Hg. R 1 _: RR64-166 ..- R'- i-.R DC ^ cl-rr: CH ₃ 0-3.4 Cl- CH,. Et K ^b WiAR <\ αί -N-CHpCBNREt 1 R 128 R R R / DCM / isoether Cl- 01.0-3.4 Cl- Et · <R Ά ′ · 1. -n-oi ₇ ch ₇ oo ₇ ch, r .r · AR''r105RR-ArR · 'DCM / isoether Cl- ch ₃₀ o-2.4 ; ci-'i A / zaR-IR '·' ' -N N-CO? CH ^ C ^ H? R ' \ _7 ^ R- 142-143; 1 MeOH ch ₃ o- \ Ctis - 3.4 < ^: i C1-R R · Et <. - ·>U;; rR: <VRl / -; Rl ^ RR - ;; RR -N-CI.OI ₇ 00 ₇ CH, RR, · Cl- CH ₃ O-3.4 ci / iPentyl ^:: -n-ch ₇ ch ₇ oo ₇ ch. R rrR185R-r'RR · ' iso ether / DCM Br-. o CK ₃ O-3.4 • A-R; Et 'R ·? ·' ·. R '··' - · '··''-'- z / R Ri <2Rl ^ /? LRl .-. Il-? Rl / l.Rl -N-CH _? CH ₂ CD ₇ CH, '··,. IR (2) A rI'-C Cl- CH ₃ O-3.4 Cl- 1R = RR · i ¹ . DCM / isoether Cl- CH ₃ O-3.4 Cl- Pr J -n-ch ₇ oo ₇ ch. 135 R; -b ether iodo / DCM / AcOH Cl- CH, O-3.4 Cl- Ms. . 1 •• -RR..4: ·· ';' / -N-CH ^ ą-ocçc < \ 'y.R 113' R R DCM isoether · Cl- CH ₃ O-3.4 Cl- Et '1 -n-ch ₇ oo ₇ ch, · C'RRrc '160 'R isether. : Cl - R CH ₃ O-3.4 Cl- RA - -N VNH-C0 ₂ 4Bu 197-1-98 Ar i

Cl- CH ₃ O-3.4 ; Cl. : // - <[> -L.C0 ₂ CH ₂ C _i H ₅ , ..: (- :: -:,: ../-: // 3) - + /

IR (1) JDCM) 1740 cm ' ¹ thin

1680 cm ' ¹ wide

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

1660-1680 cm ' ¹ split (3) this compound is distinguished by its rotational properties:

'D ²⁵ -' - «S'i + .Ž toC ^ ū ', 44; chloroform).

Table 2

Pavyz- dys R il / t |; // ii //  -3 * / 7 - Solvent, m.p. t. ° C or .. // + / _: BMR ' 33 34 (Brf / CH, O-3.4 / fi // - ch ₃ i -N-CH _? CO _? CH _? C _r H _s . // /:, /: 87-95 35 36 , / here /: CH.p.-3.4 Cl- ch ₃ 1 -N-CH _? CE _? CO _? Come on 100-103 154-157 DCM isomer 37 will go ęą- + CH ₃ O-3.4 Č1 -. + ch ₃ . //1+Π/+::.'/·///// /, - /// // + / -N-CąCIįCO / i 140-144 DCM isoe'ether 38 mixture non- ch ₃ o-3.4 _; : CH / . CBj Hey 222-22S / -N-CH ₂ CH Na /:: ff ™ i = - = ri5

39. . ,, 40 / non- CH ₃ O-3.4 Cl- Et 1 · ^; / · '- </, / -N-CH _? CH _? 00 ₇ CH ₃ 0 NMR NMR 0 4.1 cis Cl- . * CH ₃ O-3.4 Cl- No. 1 -N-O / O / OO ^ H /.,· 166 DCMizoeter ⁴² 43 Cl- CH ₃ O-3.4 Cl- z ~ \ ·, CH, -N / b / '- V- / ^X CH ₃ L - / SU 119 AcOEtizoeter • 228 MeOH g 44 will go Cl- CH ₃ O-3.4 Cl- · ΙΓ * CH ₂ C ₆ H ₅ 179 gj-CH ₂ CH ₂ N: acquis3 / ^ DCMizoether / ^{; GRC;?} // // g. -N N-CH ₂ CO ₂ Height 45 ⁴ 6 Cl- CH ₃ O-3.4 / Cl- 109 DCMizoeter 196 DCMizoeter ' 00/47 48 Cl- CH ₃ O-2.4 Cl- // --- / gy '/.' <g /// 134 (iPr) ₂ ° 0, <- 195 /; /// / DCMizoether / 49 c non- CH, O-3.4 Cl- / Et ./ 'i -NC.H, CH _? CONH _{? :} / - / ','., 236 //// isoether - .- 50 51 CH ₃ < CK, -3.4 non- Et 1 · 'g - .. ··' · -? ·. '// -n-ch ₂ ch ₂ oo ₂ ch, /. / 154; 0 isether / 0/87 </ '///' - isether / 2 c C1-. / 0 / 0-2, 4: Ci- gg '<///// ^ NH - // ,, 194 ^; MeOHizoether 0 0/3 .-- c // no / 0 / 0-3, 4 Cl- iPentyl ··. Ι // ·; '' · -. '\ · ^.' ^^ ^; - / ·> /: ···; ί: -N-CH _? CH _? CO _? CH, /// 0 //// 195 //, / isoether / DCM 0 54 55 Br- 0 / 0-2, 4 no-y -'-. Et, / 'gc ^l c <.//./. <G -Ν-α / Ο / ω ₂ α / 138-140 isoether <t /./--/140//'/.'/: '. o isether 56 57 Cl- 0 / 0-3.4 Cl- // - '^ - /. // .. 242-245 DCMizoeter 225 MeOHizoether. ^: 58 58b Cl-; 0 / 0-2.4 Cl- -> θ-Ν (0Η ₃ ) ₂ 228 MeOHizoether ./.-:221: 'o /' / o DCM / MeOH /

59 59b Cl- CH ₃ O-3.4 Cl-  c Et / ·· 7.. 1 7 '/' -n-ch ₂ ch ₂ ch ₂ ce / ch ₃ • 131-134 ( DCMizoeter 7hexane 121 DCMeter / hexane e 60 61, ⁴ -7 '·''-S-'.'7·' ·, ' cr- CH ₃ O-3.4 Cl- iBu / 7 / -n-ce ₂ ch ₂ oo ₂ ch ₃ 162-166 DCMizoeter / y: / .. 130 DCMizoether / .( hexane (; 62 63 non- CH ₃ O-3.4 Cl- Pr 1 -n-ch ₂ co ₂ ch ₃ 176 iso ether (DCM. BMR / 7 (7 ^; 64-65 Cl- CH ₃ O-3.4 / no- / Pr 1 -n-ch ₂ ch ₂ oo ₂ ch., 1 148 isomer ether DCM 122 '. · //. {. isomer (DCM - 66 67 Cl- CH ₃ O-3.4 jciC Not 1 -N-CH _? OO _? CH, NMR 168: (isoether) 68 c no / CH-P-3.4 Cl- iBu 1 -N- (CH _? ) _? CO _? H 1 ((/: / 1 179-182 7 ( DCM / isoether ( 69 c 'no- / CH, O-3.4 Cl- Et T -N-CH ₂ O ₂ H 139 /(../ DCM / isoether: 70 c non- CH, O-3,4 Cl- i; Ms. 1 -N-CHjOO-ini 130 /, (77 / isether 71 c ,. non- CH3O-3.4 Cl- _Et .. 1 -N- _(CH?) OO. _Z .H /. 7 -7: (/^(((/..(/136//(1..// DCMizoeter (' 72c non- CH, O-3.4 non- 7, Et7 ((- / ':(' -7 //. 7 7 1 -N-C-CDNE, / 7135 ((/ (/ 7 / {. . ' DCMizoether, 73 74 non- CH ₃ O-3.4 Cl- N '-NHCO-> C {CHd 777 ^ 7 {/ 7 / {7- / 7/7 (/(/.(/(/ 197 ((: / (: - (/, MeOHizoether - / I // 21177 MeOH / -: - - (1 75 c non- CH ₃ O-3.4 T · - / ./. ηκττπ, Cl-  N T-NH? \ / . · 7. . · /. hW \ i 76 c Cl- CH-p-3.4. non- N ^ ~ ^ bNH ₂ Fumarat 1 152-156 ( • DCMizo'ether 76 b 7 76 t Cl- CH ₃ O-3.4 Cl- 71 <- N - 77.CO ₂ CH ₂ C ₆ H ₅ i 777 {/ h77 / · t 137 1 isomer of MeOH (183-185 hexane

Use j on. as described above. Intermediate (I) synthesis of compound (I). ·

The resulting compound (VI) is described in Table 1.

.5 -7 '.-. Z. .7 '/ 7 Received7 compound. (I) is described in Table 2.

For each j (e) containing (I) substituents R ', R' ₅ , R ' ₂ and NR _e R _? The following tables indicate the first and then the trans isomer, except for the opposite.

For example, 34. Analysis: Excluded: 7 C.'55,54.7. * '· & .4,24N 3, 93 /3//.3 Found: //.·;' f C 55.72 H 4.57 N 3.83 3

NMR spectrum at 200 MHz (DMSO: 2.5 ppm)

Ex.34: FIG. 5

Ex. 38: 0.7-1.1 md: m: 6H: 2CH ₃ (Et). 2-4 md: m: 17H: 2CH ₂ (Et), 2CH ₂ -N, N-CH ₃ , 20CH,

5.2-5.7 da.::3S:1H:H (indoline)

6.2- 8.2 da.:m:llH:OH-Aromatic compounds?

^: Eg / 39i-73; O33-1,2 ^; .m / d: ./ mi3H ..:. CH ₃ -IEt); 3

3; 7 '\ i-3; 3 / j3534j:' 3 / in'm7d2 . ^:: m ': 15H; GH ₂ 3G0; i3OH / (Et), 3''/: CH ^ N; /' • 20CH ₃ , CO _? CH ₃ 7>'

5.2-5.6 m, d: 3S: 1H: H (indoline):

/ 7-6; 2-8.2 da.:m:llH:OH- aromatic compounds

Ex .40: 0, 8-1, '1 md: m: 3H: CH ₃ (Et): /3/.3-.

2.2- 3.9 ppm: m: 15 H: CH ₂ CO, CH ₂ (et), CH ₂ N,

CO ₂ CH ₃ , 20CH ₃ '//'.7 7''; 7, ^<: 3

5, 3-5.7 ppm. : 2S: 1H: H (indoline) 3- / '

6.6-8.2 ppm. : m ': HH: OH-aromatic compounds

Ex .63 0.4-1 bn; t decomposed: 3H: CH ₂ -CH ₂ -CH ₃

Δ 5 md: m: 2H; CH ₂ -CH ₂ -CH ₃ ^: 3 · / ^: 3 ^; 3 3 ·: '' /

J 2.5-4.4 md: m: H: CH ₂ -CH ₂ -CH ₃ ,. NCH ₂ COOCH ,, .3 2OCH, 3 3 .. /; f

5., 2-5.8 ppm. : s, e .: 1H (indoline) 7 .6.5-8.3 da.w. : m. : 11H: OH 7 +3 aromatic compounds

/

For example.66 0 to 1.5 ppm: m: 3H: CH ₃ CHI-i 2.3 to 8.5 ppm: m: CH _2: CH _3, 2OCH _3, H (indoline) - 6.1 to 8.3 m, d: m: 11H: OH + or ohm t in: nch ₂ cooch ₃ , lai jungins P / z.75 1.95 md: s, e .: 2H: NH ₂ 2.7-at / 5.3 md: m: 12H: 2OCH ₂ , 2NCH ₃ , H

(indoline), CHNH ₂

Ex .76b ^a D ²⁵ = + 102 (c = 0, 36; chloroform)

Ex .76ter 'D ²⁵ = 7l58 (c = Q, 2; chloroform)

Ka i who: j ųng ihia i describe the invention in the table 2.1 used to get it other compounds of the invention, example / compound: 41 was obtained from compound 39,

under MeOH / H ₂ O in the main methanolic medium, Compound 41 was obtained from Compound 41 under ammonia in the presence of DIPEA and BOP. /./.-71-. .- / 1 / j / 7- '·. 1-11ΕΑνΥ2ΌΫ3 / 16ΐ7ΐ77 / ΐ7 / ΐ1; · 1 / ί177 / 17.’7

N-Methyl N- (amino-2-ethyl) -chloro-5- (chloro-2-phenyl) -3- (dimethoxy-3,7H-phenylsulfonyl) -1-hydroxy-3-indoline-2-carboxamide. isomers. Of the compound obtained in Example 4 9 (see Table 2) was dissolved in 10 ml of acetonitrile and 10 ml of water, 252 mg of pyridine and 1380 mg of bis (trifluoroacetoxy) -benzoate were added after 2 hours. beating. the solution is regenerated with hydrochloric acid solution, extracted with ether, and basified. from sodium chloride, trichloromethane DCM, dried and concentrated. Incoming oil.

The product obtained is crystallized from ethers

Obtained: 150 mg, m.p. - 164 ° C \

EXAMPLE 77 '·': ^'61

N-Ethyl-N- (amino-2 / ethyl) -chloro-5- (chloro-2'-phenyl) -3- (dimethoxy-3,4-phenylsulfonyl) -1-hydroxy-3-indoline-2-carboxyamide, cis isomer.

: 5. 500 mg of compound '49 is dissolved in 10 ml of acetonitrile / 10 ml of water, 252 mg of pyridine and 380 mg of bis (trifluoroacetoxy) iodine benzene are added. After 7/2. with stirring, the mixture is regenerated with hydrochloric acid, (extracted with ether, basified with dissolved sodium,. - extracted with DCM, dried and /.

The oil is obtained. The resulting product is crystallized from 3 ///// in ether ////: / (:. 5 / --7 (-. 7: - //

3/3 /, (5? M3ld0 / mg / 5dyd. / _? T / - '/ - == / 7l64 ⁰ C ^: ' / · / ///--(.//7-7

15? {3/4 {/ {3 {/ {¾ {- / - ^ 5

EXAMPLE 78.-5.3 ((.: 5/75 - (/, ((.N-ethyl N - [(1S) - (ethoxycarbonyl-1) ethyl) chloro-5- (chl.or-2- 4

-3 // 7. - phenyl) -3- (dimethoxy-3,4-phenylsulfonyl) -1-hydroxy-3-7-: -: 773: 5 /: 7.3- / -7 / ..... 5- / 4, -..- 55 ////, // / ./ '/ 4 & · -..-- / - .. /-^7--/.:--/3 /, - -7-: 520 Indoline-2-carboxamide, cis -isomer. // .77 (A) {to (N - [(Chloro-2-phenylcarbonyl) -2-chloro-5-phenyl] -N- (dimethoxy-3,4-phenylsulphonyl) -glycic acid anhydride. // - 7. /

- (25 // 7-7 (/ /: / 47 3 {/ - 7 (((33./ - ... _; ,... - (7/35, (/,. :( 5, . -. /

At 60 ² C for 1 or. heated mixture,.

4 (5 containing 11 g of the acid obtained according to, for example, 10.11 (A) and 5 g of thionyl chloride in 10 ml of chloroform. Cooled to room temperature, concentrated 55 in vacuo, regenerated in vacuo 2 times with DCM.

The resulting yellow oil is used in the following /

z .--- stage. (4 '-? 4 -'45

IR: 1800cm- ^J (C = 0). i

B j j / / - 'B

B) Dichloro-2 · ', 5 N (dimethoxy-3,4-phenylsulfonyl) -N- [N' -. . et ii N '- ((1S) ethoxycarbonylethyl-1) ethoxycarbamoylmethyl] amino-2 benzophenone.

This compound is prepared according to J. Org. Chem.

945-950. _V / - / 7 <BB- / ¾ B

G / Treat with 10 mL TFA at 0 ° C; 5.15 g (L) Boc (NEtjAlaOEt to 'remove / Boc group <nKdncehtrudjama10 // in vacuo), regenerate with 20 mL DCM, cool to -78 ° C and add 2 equivalents TEA and chloro-anhydride,

- Obtained in the previous step dissolved in DCM, · After 18 h. extracted with DCM at room temperature, rinsed with water, chromatographed on silica, rinsed with DCM / AcOEt (90/10; ·: · .B / tv). 0 ^; B The product is crystallized in iso ether.

Mp = 112 ° C, m = 8g. 0 / 0B

0 C) N-Ethyl-N - [(1 S) (ethoxycarbonyl-1-yl] chloro-5 (chloro-phenyl) -3- (dimethoxy-3,4-phenylsulfonyl) -1-hydroxy-3-indoline-2- carboxyamide, cis -isomer. // 0 / -0

The compound obtained in the previous step was stirred at room temperature for 18 hours. with 10 ml of THF and 20 ml / ethanol,

0 / at / 1.46 g DBU. Concentrate in vacuo and recover the precipitate with. - DCM, washed with water, concentrated and the product chromatographed on aluminum, washed with AcOEt / DCM (10/91; tv). 30 B. no ' ^? B - ^ B.b'b-B '/ bB'-b /.(- ^? ''V-'.'.-'' i- e ^; .-.... /,. / NMR: 0- 09d ^- d split: 3H: CB-CH ·,

0.9-1.7 and, .c .: vol: 6B: 2CH, ethyl)

2.6 to 5, 8 / ppm, m: 12H - '2OCH _3: / y = CH ₂ OCH _2, \' = CH, COCH -. B.

6.1 at 8.3 da.:m:11H:OH-10H aromatic compounds'

EXAMPLES 79 and 80.

N, N-di (methoxycarbonyl-2-ethyl) chloro-5 (chloro-2-phenyl) - (dimethoxy-3,4-phenylsulfonyl) -1-hydroxy-3-indoline-25-carboxamide; eis and trans isomers,

A) N, N-Di (methoxycarbonyl-2-ethyl) -benzylamine

Manufactured according to J. Am. Chem. Soc., 1950, 72, 3298 ·.

I || iB Ji y;

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

Mp = 135-140 ° C at 0.6 mm Hg, m = 30 g, IR: 1730 cm @ ^-1 .

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

27, '9g of amino, obtained in the preceding step, is added to 500 ml * of methanol, mixed with 3 g of palladium on carbon to

5% is 1 or. is treated with .hydrogen pressure. Media: Filter on 'Celite ^R ,' wash with methanol and evaporate the solvent in vacuo. The remaining oil is used in the next step '.

C) (N, N-Dimethoxycarbonyl-2-ethyl) bromoacetamide

In a glass bath, a mixture of 14.3 g of the amine obtained in the preceding step, 100 ml of DCM and 10.6 ml of TEA is cooled, followed by dropwise addition of 15.3 g of bromoacetyl bromide. leave for 48 hours at room temperature. Extract in DCM, wash with water, 'chromate35' on silica, 'wash'. DCM / MeOH (97/3; t.v.). The product obtained is in the form of an oil.

m = 15.9 g, IR: 1650 cm ^-1 . 1730 cm ^-1 .

D) Dichloro-2 ', 5 {N-dimethoxy-3,4-phenylsulfonyl) -N - [(Ν'), (methoxycarbonyl-2-ethyl) carbamoylmethyl] -amino-2

- benzo-phenone.

14.3 g of dichloro-25 (dimethoxy-3,4-phenylsulfonamide) -2-benzophenone are added in 180 ml of DMF and 1.1 g of sodium hydride are added in portions, cooled in an ice bath after stirring 1 _x or at room temperature, and 14.3 g of the product obtained are added. in the previous stage, ir.waiting 72 hours. at room .temperature. Extract with * .CCM, wash with water, extract with DCM / AcOEt (9'3 / 7; t; v.) On silica. '~ m = 28.4 g, m.p. t. = L30 ° C

E) N, N-Di [(Methoxycarbonyl-2) ethyl] chloro-5 (chloro-2-phenyl) -3 (dimethoxy-3,4-phenylsulfonyl) -1-hydroxy-3 Y / Y / Y ^ ĖiYolcšid ^ idąsjs ^

Stir at 0 ° C. 12 g of the compound obtained in the previous step and 0.930 g of sodium methylate in 150 ml of methanol are stirred overnight at room temperature. Reaction medium, neutralized by addition of 5% KHSO ₄ , the solvent is evaporated in vacuo, the residue is chromatographed on aluminum, and the residue is distributed in the form of YY: //; Y /; / .3υ'ι>; /: Υ7 '; / υ / ;? | υυ / || ο «' γ 'y / · y

F) N, N-Di [(methoxycarbonyl-2) ethyl] chloro-5- (phenyl-2-phenyl) -3- (dimethoxy-3,4-phenylsulfonyl) -1-h-hydroxy-3-.

35 '// ⁿ ' // indolihYY-carboxamide , ^; / tr'ans-i2omere ^; / ^; ; / 'Y ^; ./ ^'65

Continuation of the previous step chromatography eluting with / DCM / MeOH / (9.5 / 0.5; v.v.). 1.82 g of the trans isomer are obtained, which is crystallized by isoethylation. / ///. 7 // /./-,///.

((2R) -Carbanoyl-2-thiazolidinecarbonyl) -2-chloro-5-chloro-210-phenyl) -3- (dimethoxy-3,4-phenylsulfonyl) -1-hydroxy-3-indoline, cis-isomer; two compounds and a trans isomer.

A) (L) Thiazolidinecarboxamide-4

15 ' ⁷ ' ⁷ // 7 / '' / 7 7 // - /; / '7'///; 7 /): - / -.: / 7 - /// 7 // '/ // - ////. This compound is prepared according to J. Med. Chem., 24, 1981,

..: // 7/7 ^ 92/7 // '

B) Dichloro-2 ', 5 - [N - (dimethoxy-3,4-phenylsulfonyl) - N - (((2R) carbamoyl-2) thiazolidinecarbonylmethyl)] amino-2: -bis-benzophenyl] -N- - '^; This compound is prepared in the usual manner from the acid obtained according to Step 10.11 (A) of Examples.

- / f //: //../; ..//'/7/./'/ A · -; ⁷ ' ⁷ // ¾' /

7/7/7 Mon t. = 125 ° C after crystallization in the setter.

C) ((2R) 4mMbambyl / 2 / thiazoleyl-2-chloro-5 (chloro-2/2 + -hehl) -73 (dimethylcis / indoline.)

4 g of the product obtained in (B) / step-cyclized in 0 ml MeOH ⁷ with ethanol / water and DCM are precipitated, washed with KHSO ₄ , dried and concentrated. Chroma 'is printed on aluminum, washed with / DCM / MeOH / {97/3; t .v). 1.5 g of the cis compound (mixture of two diasteroisomers) are obtained, followed by 1 g ^{of the} trans compound (mixture of two diasteroisomers).

a} The cis fraction is crystallized with MeOH / DCM to give * · »

the compound cis-1 was obtained.

M.p. = 176 ° C after crystallization from ether. ^a D = + 57 {c = Q-, 1; Chlorine forms} '.

b) The crystallization solution of the preceding product is chromatographed on silica eluting with AcOEt / DCM (30/70; v.v.).

The compound ei s-2 is obtained by crystallization from ether.

isi, 'Zi ² ®®®®®O®®®®®S®®®l®®i®®®Sx3®®

Lyd. mp = 205 ° C.

^a D = -185 (c = 0.3, chloroform)

c) The trans fraction (mixture of 2 diastereoisomers) i is recrystallized in iso ether.

Melting point = 17'0 ° C '

EXAMPLES 84, 85-, 86, and 86b. Chloro-5 (chloro-2-phenyl) -3 (dimethoxy-3,4-phenylsulfonyl) -! hydroxy-3 (N, N- (2.S) -dimethylthiocarbarnoyl-2-pyrrolidinecarbonyl) -2-indoline, cis-isomeric compounds, trans-isomeric compounds.

A) (L) of N, N-dimethyl (N -Boc ^r) proli.nt.ioamidas

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

To the toluene anhydride at 80 ° C for 4 hours was added 2.36 g of N, N-dimethyl- (N ^T -Boc) proline, in the presence of 2.3 g Lawes: son reagent. /.

.evaporated, isopropanol added. The residue is evaporated and the isopropanol is evaporated off and chromatographed on silica eluting with hexane / AcOEt (30/70; tv). Product obtained. recrystallize in cold - DCM / isoether. y-y '' -5 _; y

B) Dichloro-2 ', 5 [N- (dimethoxy-3,4-phenylsulfonyl) -N - ((2S) amino-2-benzophenone).

3g of the product obtained in the previous step is dissolved in 10 ml 'DCM at 0 ° C, treated with 2 or 10 ml TFA. Evaporate 15 'to dryness, then at 0 ° C add 20 ml' DCM, 6.1 g 'of the acid obtained in step (A) (Examples 107.11) and neutralize with 3 g DIPEA-. 5.15 g'BOP is added to the 'previous solution at 0 ° C for 30 min, maintained' at neutral pH by the addition of DIPEA and stirring for 3 h. at 055 After overnight extraction at room temperature in the usual manner, then chromatography on silica eluting with

DCM / AcOEt (85/15; tv). The product obtained ^is recrystallized from iso ether.

Ref., Vol. = 182-1855 D = -72 (c = 0.32, chloroform).

C) Chloro-5- (chloro-2-phenyl) -3 (dimethoxy-3,4-phenylsulfonyl) -1-hydroxy-3 (N, N- (2S) -dimethylthiocarbamoyl-2-pyrrolidinecarbonyl) -230 'indoline (cis isomer: 2) compounds, trans isomer: two compounds).

The 3.8 g of the compound obtained in the previous step was dissolved in 15 ml of DCM and refluxed for 36 hours at ~ 850 mg of DBU. The various isomers obtained are separated by sequential chromatography on silica.

a) Elution with DCM / AcOEt (85/15; v.v.) yields the resulting eis compound of the two diasteroisomers. The least soluble diasteroisomer is recrystallized twice with DCM / i2.oether / MeOH, then recrystallized in minimum

- DMF at 0 ° C followed by two volumes of ethanol. ',

M.p. = 270 ° C t '', ^a D = -278 {c = 1, chloroform} lllilSSSIi ^

(b) Recrystallization of the previous mixture from the mixture, recrystallization and crystallization from a second cis-diastereoisomer with DCM / iso ether. J 15 Melting point = 249-251-C - · * '/' · / -'j '- ^a D = + 42 (c = 0, 22, chloroform)

c) The previous chromatographic fractions as well as the -motinal crystallization solution of fractions a) - and b) are combined and subjected to a new chromatography on silica eluting with hexane / AcOEt (20/80; v.}). which was recrystallized three times from the DCM / iso ether mixture, and the insoluble material was removed 'on the paper between each of the crystallizers, thus yielding the trans-1' isomer .. '- m.p. = 191-193 ° C />. = + 74.5 (c = 0.2, chloroform) iiSfSliSils ^

(d) in the second fraction. is the trans-2 isomer which is recrystallized from DCM / isoether. , a mixture. and crystallized from l / '3 mole of iso ether. ·

Lyd. = 17 ° C. "D = -266 (c = 0.14, chloroform)

(<

EXAMPLES 87, 88, 89.

{(2S) Carbamoyl-2-pyrrolidinecarbonyl) -2-chloro-5-cyclohexyl-. '3 (Dimethoxy-3,4-phenylsulfonyl) -1-hydroxy-3-indoline, (eis5 · isomer: 2 compounds, trans isomer)

A) Chloro-5- [N- (dimethoxy-3,4-phenylsulfonyl) 'amino] -2-cyclohexylphenone. ·

24 or. stirring at room temperature to leave a mixture of -35.6 g of amino-2-chloro-5 cyclohexylphenone and. 39.5 g of dimethoxy-3, 4 phenylsulfonyl chloride dissolved in 340 ml of pyridine. The solvent was evaporated in vacuo, washed with water and with a solution of acid (0.5 N HCl). The product is crystallized from ethanol.

M.p. = 135 ° C, m = 56.1 g .20 B) (((B-Benzyloxycarbonylmethyl-N-dimethoxy-3,4'-phenylsulfonyl) amino) '- 2-chloro-5-cyclohexylphenone.

Portions of 3.2 g of sodium are added _and 52.6 -hidrido The compound obtained in the previous stage, 520 ml of DMF and stirred for 1 h.

. at room temperature- After cooling in an ice bath. 21 ml of benzyloxycarbonylmethyl bromide are added dropwise

-and left stirring for 24 hours. at room temperature. The solvent is evaporated off under vacuum and is regenerated with water. Extract with DCM and wash with water.

The resulting product is used in the next step.

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

3-5 The compound obtained in the preceding step is placed in a hydrogen atmosphere (1 atm) with 3.9 g of 5% palladium on carbon in 700 ml of acetic acid / at the end of which the palladium is filtered off with Celite. and. rinse with hot acetic acid, evaporate the solvent under vacuum and recover with water. - Extract with DCM, wash with water, - then with concentrated EaHCO ₃ solution. Gantt. The residue is chromatographed on silica eluting with DCM / MeOH (97/3; v / v) / The product is crystallized from ethanol.

Lyd. t. = 160 ° C, m = 22.4.

D) Ghloro-5- [N- (dimethoxy-3,4-phenylsulfonyl) -N- ((23) carbamoyl-2-pyrrolidinecarbonylmethyl)} amino-2-cyclohexylphenone.

A mixture of 9.92 g of the acid obtained in the previous step, 3 g (1) of protinamidine chlorohydrate and 3.5 ml of DI'PEA in 75 ml is cooled at 0 ° C.

A solution of 8.84 g of salt in BOP dissolved in DCM was added and the pH was maintained by addition of DT'PEA. 24 or. maintained at room temperature. The medium is extracted with DCM, washed with concentrated KaHCO ₃ saline, 5% KHSQ ₄ solution and again. Chromatograph on silica, eluting with DCM / MeOH (96/4; tv). The Gant product is crystallized from ether.

Lyd. m.p. = HQ ° C, m = 7.3 g.

^a D - 53, 9 (c = 1, chloroform)

E) (2S) (Carbamoyl-2-pyrrolidinecarbonyl) -2-chloro-5-cyclohexyl-3- (dimethoxy-3,4-phenylsulfonyl) -1-hydroxy-330 indoline / cis isomer (two compounds), trans -isomer.

5.9 g of the compound obtained in the previous step are stirred at 0 ° C for 48 hours. with 1.67 g of DB (J in 60 ml of methanol. The solvent was evaporated in vacuo, water was added, extracted. 35 DCM, washed with 5% KHSO _4. Chromatograph on aluminum, washing with DCM / MeOH (98/2; v / v).

a) The less polar fraction contains two cis-isomers. This fraction is recrystallized from methanol./ The cis-1 compound thus obtained is purified by HPLC.

Lyd. t ^ = 1/85 ° Č '/.,'/// ^?

Recrystallization of the mother liquor from MeOH gives the second compound (cis-2). Purity 'HPLC: 75% (Contains 25% cis-1). .

Lyd '. mp = 132 ° C

b) the more polar fraction contains the trans isomer, in the form of an externally homogeneous product obtained by recrystallization from methanol.

Melting point = 240 ° C "D = -55, l (, c = 1, chloroform)"

EXAMPLE 89b.

((2S) Carbamoyl-2-pyrrolidinecarbonyl) -2-chloro-5-cyclohexyl-3- (dimethoxy-3,4-phenylsulfonyl) -1-hydroxy-3-indazine. - /, / 7, 'i ·. </ ·:. '../J 7-, y' 7 A-, - // 7- / -77 / '..' 77 ·, '. // 7 .'7 ·,' · ';. · /; . // '· /;' / ''. ·.

cis-isomer (two compounds), trans-isomer.

Using a method similar to that described, e.g. 87, 88, '89, produces a compound analogous to series (D) proline.

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

M.p. = 238 ° C ^a D = + 164 (c = 0, 245; chloroform / methanol, 3/2; -t.7

The NMR spectrum of the compound is described in / previous / Example (b) step (b). 1 ^ 2, .. 7 / 7.77

EXAMPLE 90 '// i ·· / · X, ·. 7th

Chloro-5- (chloro-2-phenyl) -3- (dimethoxy-3,4-phenylsulfonyl) 1 - [(2S) (N-methylaininocarbonyl) -2-pyrrolidinecarbonyl] -25-hydroxy-3-indoline, cis-isomer .

9z.O mg of the compound obtained e.g. 28 stirring is added. to .20 mL DCM containing 371 mg BOP, after 15 min. within 10 minutes ¹ injection of monomethylamine and another 30 min. stirring.

Regenerated with water, precipitated, washed with potassium bisulphate, sodium carbonate, dried and, Λ.Ι'ς ^ νίρη, όρηΙ.Ιύρ ^ άιή ^ / ^ ίί / Χ ^ ίΐβνΡΚίόώΜίΡρΙ ^ .ίρρ jirttap ;; _: ąht7šiXidiO. ^; eluting with DCM / MeOH (97.5 / 2.5; tv).

Collected: yields _> 77 product, 7: ///the crystallization is carried out in iso ether / DCM.

m = 750 mg, Fc = 178 ° C.

(c = 0, 3, chloroform). ·, '

Proceeding as described in Examples 27-31 and 90, and using (L) prodrug derivatives (except to the contrary), provides other compounds (VI) for the intermediate synthesis (I) of the invention. . .

Compounds (VI) are described in Table 3.

Compounds (I) are described in Table 4

/ ^ 6 -N  X Melting point ° C '/' ·· '· -7- / «D ²⁵ : ++. / '· (Chloroform) CH ₃ O-3.4 (D) -N • hA- + //: S r nh ₂ +45 c = 1.015 • '7' '· · - / 4 CH ₃ O-3.4 , -Z ^- J-Ji ΐ «· - ch ₃ .161-163 /+7.7 ++,:, DCMizoeter -70.8 c = 0.48 CH ₃ O-2.4 coock ₃ ; : ++ 7: -7 // 1457148 + 7 + // + / + / 7 -17.5 c = 3.36 CH ₃ O-3, 4 ' / ~ Ί -N H ·· ^ —— COOCH- //+/=110'+++/+.+++++:+':++:. /: DCM / isoether CH ₃ O-3.4 -N ch ₂ cooch ₃ ./+-./:/--+-//-/14.8+/.++++//+/+:+ isether etherMeOH - / .. - + '+ .: - +.' / - + '+

The compound of EXAMPLE 107 is the enantiomer of EXAMPLE 106. '

EXAMPLE 108 was prepared according to EXAMPLE 28 by reacting hydroxysilamine chlorohydrate in DMF · medium and activating with BOPesant DIPEA reagent.

Some of the compounds of the invention described in Table 4 10 are used to provide other compounds. Yes, the compound of Example 799 affords the compound of Example 101, followed by the compound of Example 103, and finally the compound of Example 104. ^15th

EXAMPLE 109..

b ((2S, 4S) azid-4-methoxycarbonyl-2-pyrrolidinecarbonyl) -2-chloro-5- (chloro-2-phen-1) -3- (dimethoxy-3,4-phenyl phenylsulfonyl) -5. l-hydroxy-3-indoline, cis-isomer.

A) Dichloro-2 ', 5- [N- (dimethoxy-3,4-phenylsulfonyl) -N - ((2S, 4R), hydroxy-4-methoxycarbonyl-1,2-pyrrolidinecarbonylmethyl)] amino-2-benzophenone.

^10th

At 0 ° C for 150 ml. DCM was heated with 15g of the acid obtained in Step 10.11 (A) of Examples 10 and 6, 25g of (2S, 4R) e hydroxy-4 methylprolinate chlorohydrate in the presence of 7.4g of DIPEA. After a drop of 30 min. 12.7 g of BOP solution in 30 ml'DCM and DIPEA are added over the period to neutralize the solution. After overnight at room temperature, the mixture was extracted with silica gel using DCM / AcOEt (60/40; v. V.) As usual. the product falls into the form of DCM / i zoe ter i o blend e r -j <r.

Mp = 128-131 ° C ^α D = + 8.5 (c = 0.38, chloroform)

B) Dichloro-2 ', 5- [N- (dimethoxy-3,4-phenylsulfonyl) -N25 ((2S, 4R) mesyloxy-4-methoxycarbonyl-2-pyrrolidinecarbonylmethyl)] amino-2-benzophenone.

2g of the compound obtained in the preceding stage ^c at 0 C was dissolved in 10 ml DCM. 550 mg of triethylamine are added followed by 550 l of methanesulfonyl chloride and the mixture is kept at 0 ° C for 20 hours. Add water, wash C.5 N.

.. · Chlorohydrate //. solution, water, sodium. bicarbonate solution, dried over magnesium sulfate, evaporated.

p The resulting oil is used in the next step.

b., · ^; ow _? .btp, pb. 7, ..... 7. '/' / '.

C) [N - ((2S, 4S) Azid-4-Methoxycarbonyl-2-pyrrolidinecarbonylmethyl) -N- (dimethoxy-3,4-phenylsulfonyl)] -amino} -2-dichloro-2 ', 5-behzophenone

97 will go no ch ₃ 0- 3.4 -N ΐΐ ,,, λ- CO1 rcr ₃ 7 ,, -214 c = 0.32 98 you go j / Cl // / Of 7 / B -ii H ».. \ - CH ^ i . · L. cooch ₃ 105-115 DCM / iso- ether + 174.6 c = 0.3 99 will go 2 100 trans 1 - 101 trans 2 175. DCM / iso- / Butterfly: '177 DCM / iso- ether -214.6 c = 0.3 -155 c = 0.2 +95/2 c = 0.2 102 will go 1 Cl ch ₃ o- 3,4 ' -N · ' H7 ' CH , COOH · U,. - ' 135 isether -162 103 will go 1 Cl ch ₃ 0- 3.4 -N H - 7 // »/ ch ^; , conh ₂ : / 7: 747: //// 'DCM / iso /: daddy :: -167 c = 0.4 103 b. will go 1 will go 2 no ch ₃ o- '3,4 -N CH _? CONH _? 104 you go Cl ch ₃ 0- 3.4 Z -N 'H' j - CH _? nh ₂ 210 · ETHER .1 -177.5 c = 0.2 104 bis' will go 1 will go 2 Cl ch ₃ 0- 3.4 -n chh ₂ NH ₀ - ///: 105: /: 106; / 0% // - / -: - 0 ///:. CRp- 3.4 / -N cor • j Ψ 4H-, : 200 EtOH 215 MeOH B -195 c = 0.2 + i27: c = 0.2

107 ' ch ₃ 0 CH ₃ O3.4 ' (D) -N ČC ? 198 -63 ,? - c = 0.117 (CHCl3 / MeO ' H 8 / 2v / v) 108 yci® jOzBl CO? jh ₂ . 274. DCM / MeO H -225 c = 0 _f 372 (CHCl 3 / MeO H 8 / 2v / v) 108 bis will go Cl ch ₃ 0- 3.4 / -N CON ΗΌΗ '-198.7  c = 0.24.

g of product obtained in the previous step is heated for 18 hours. at 80-90 [deg.] C. in 60 ml of DMSO in the presence of 2.7 g of sodium azide. The oil obtained (lOg).

^a D = -25.5 (c = 0.39, chloroform ·, T = 26 ° C)., ¹⁰ vol

D) - ((4S 2Sj) azido-4-methoxycarbonyl-2-pirolidink ( 'rbonilj _to 2-chloro-5 (2-chloro-phenyl) -3- (dimethoxy-3 4fenilsulfonil) -l-hydroxy-3-indoline , cis-isomer.

3.38 g of product obtained in the previous step is cyclized under normal conditions in the presence of DBU. The resulting product is recrystallized from DCM / iso ether mixture.

m = 755 mg, m.p. = 200-202 ° C ^a D = -176 (c = 0.21, chloroform, Te 26 ° C -

EXAMPLE 110. '.

[(2S, 4S) (N-Benzyloxycarbonyl-N-methyl) amino-4-Z methoxycarbonyl-2-pyrrolidinecarbonyl] -2-chloro-5- (chloro-2-phenyl) -3- (dimethoxy-3,4-phenylsulfonyl) -1 -hydroxy-3indoline,. cis-isomer.

A) N-Boc-hydroxy-4 proline methyl ester ...

The (2S, 4S) hydroxy-4 proline methyl ester chl.orhydrate is first produced.

19 g of the compound are added in 100 ml suspension

THF, added 22, 9g (Boc) ₂ 0, cooled at 0 ° C. 21.2 g of triethylamine dissolved in 25 ml of THF are added dropwise and the mixture is stirred for 12 hours. at 0 ° C for 4 hours. at -60 ° C. Add water, extract with ethyl acetate, wash with water, 4 times potassium bisulfate solution, water, brine. The oil (21.6 g), which is low in (Boc) ₂ 0, is evaporated and separated.

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

A solution of 22.9 g of the product obtained in the preceding step in 250 ml of DCM is cooled to 0 ° C. A drop of 22.9 g of mesyl chloride in 10 ml of DCM was added followed by a drop of 9.4 g of triethylamine dissolved in 100 ml of DCM overnight. water and dried over magnesium sulfate. After evaporation again, an oil is obtained which is used in the next step.

C) (2S, 4S) N-Boc-azide-4 proline methyl ester.

This compound is obtained from the compound obtained in step (B). 70 ml of DMSO 'are dissolved in 15.2 g of N-Boc-mesyloxy-4 .proline methyl ester and heated at 9 0' for 5 'in the presence of 3.05 g of sodium azide. Cool, wash with water, extract with AcOEt., Wash again with water, brine, and dry over magnesium sulfate. The resulting oil is purified by chromatography on silica;

//.=// 2. ^ hpLeuhant / AcOEt / Heksano {40Z60r, / t, vj, mixture // / 3 // { ^a D = -37.8 (cfO; chloroform).

Literature data: D = -36.6 {c = 2, 8; -chloroform) D. J. Abraham et al., J. Med. Chem., 1983, 549, -26.

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

8.45 g of compound obtained in Step (C). dissolved in 100 ml of methanol, added 500 mg of 10% Pd / C and hydrogenated at 40 ° C for 1 hour. The catalyst is filtered off, evaporated with 1/2 methanol, added with 100 mL of 0.5 N 'HCl, then the methanol residue is evaporated and the crude product which is not involved in the reaction is extracted with AcOEt. The aqueous phase is treated with sodium carbonate and the fraction containing the final product (m = 4.35g) ///: /: // = / reextracted with /: AcOEt / == - '

E) (2S, 4S ') N-Boc {N'-Benzyloxycarbonylamino) ~ 4 Proline = -' = // // annual/fes=beris.//'=/=..-=='==-=. '/ =; = // 3; t /;. ^: 0 '/// rv / ^: ' = /?: /..// '--./,:,// - // 3 .- //

The crude product obtained in the previous step was dissolved in 15 ml of ether and 15 ml of DCM at 0 ° C. 2.3 g DIPEA is added followed by 3.03 g benzyl chloroformate in 5 ml DCM over 70 min. at oC. After 3 or. in vacuo at room temperature · evaporate the solvents, add water and ethyl acetate, wash the organic phase successively with potassium sulfate solution (3 times), water (3 times), sodium carbonate solution (3 times), andene (3 times), brine. Chromatograph the ama on silica eluting with hexane / AcOEt (40/607 / IU (j =: mišlhiu, / = / to: receive / r-ė.ikiamą / product. / ^A D = - / l 4.6 (c = 0.3 / chloroform) .35

5, /// ///ΰ/δΟ///);/^/..//·. ': /' /. <

F) (2S, 4S) N-Boc (N * -benzyloxycarbonyl-N'-methyl) amino-4-proline methyl ester.

Dissolve 2 g of the compound obtained in the previous step in 20 ml

5 '' V ·. ·· V. · · .. .--,. 6 '' 7 Λ, '.

DCM at 0 ° C under argon in the presence of 2.25 g of methyl iodide. 170 mg of 80% sodium hydride are added in portions, stirred for 90 min. at 05. Extract with water and ethyl acetate; the organic phase was washed with water, ^- after salt water. Chromatography on silica, washing with hexane / AcOEt (50/50; tv). Yielding - b, 55g of product.

^a D = -38.8 (c = 0.38, chloroform)

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

This product is manufactured in the usual way.

D = -22.4 (c = 0.37, chloroform).

H) [((2S, 4S) -N-Benzyloxycarbonyl-N-methyl) amino-4-methoxycarbonyl-2-pyrrolidinecarbonyl] -2'-chloro-5 (chloro-2-phenyl) -3 (dimethoxy-3,4-phenylsulfonyl) ) -1-hydroxy-3-indoline, cis-isomer.

This product is obtained by cyclization with DBUs in conventional ways. The resulting crystals are crystallized from DCM / iso ether.

M.p. = 1295 ' ^a D = -129 (c = 0.321, chloroform)

Isomeric. purity of HPL.C is 99% / j + / J ^ obtained in Examples 109 and 110 are used to obtain the compounds of the invention described in Table 5.

».....

For example, compound 112 affords the subsequent 5. Examples 115 and 116 are described in Table 6, while Example 114 provides an example

Compound 116b.

The compound of Example 116b 'can be obtained either by rearrangement of the compound of Example 114' or from (2S, 4S) N-Boc dimethylamino-4 prolinamide, which is obtained as follows: *

1) The methyl (2S, 4S) N-Boc amino-4 prolinate from methyl (2S, 4S) azid-4 prolinate was obtained according to T. R. Webl, J. Org. Chem., 1991, 56, 3009.

2) (2S / 4SD) N-Boc Dimethylamiho-4 methyl prolinate.

4g of the resultant compound (1) are dissolved in 50 ml of acetonitrile, 12.8 ml of 30% formalin are added, followed by 5 min. Add 3 g or vinegar. acetonitrile // ++ /: · '. '/ + i <{7 / J / 3 // + / \ <7; / +++ -; //' + //// / jV3 + 'j? //' // potassium carbonate and sodium cyanoborohydride. After acid to reach pH 6 + / ++. +.: // '+': '* / · + / /./'/ / + //; /' + + + ./ ''' ^: ''; · +: '. + //.//+(·''3/·+/// //' is evaporated, water is added, solid sodium chloride is extracted with four volumes of ethyl acetate.The organic phase is evaporated, the residue is dissolved in IN 'hydrochloric acid. solution, and extracted with AcOEt. Solid sodium carbonate is added followed by solid sodium chloride to the aqueous phase and extracted with AcOEt. After evaporation, the residue is chromatographed on silica gel eluting with DCM / MeOH ($ 5/5; tv) to give a solidifying oil. · 'M = 2, lg

LT3064JB + // ++ /:: + / +: 82: /:

Table 5

An example Rg · 'D (chloroform) 111 will go -NH ₂ -189.6 c = 0, 4 112 will go -NHCOOCH ₂ J. -174 c = 0.24 113 will go -NHCH ₃ -152.6. c = 0.28 114 will go . -N (CH ₃ ) ₂ '-191 c = 0.19

IR (DCM): 1755 cm ^-1 , 1695 cm ^-1 / + / 'v'; / · +. ' +: y y./+/./.-+ + /: - / + / + y. / +. '/': / <// ++ 7 +7 -./-+. _{; /} . y · /; - + / + 7- + -. ++ / :: / - // ++ / + // + //; + 7: -77 / + ^ / - /// .. ·: / yy 7 / - -7 + /: +++ / // · / 7y +: + - ++ - / -:

3) 534 g of the ester obtained according to 2) is dissolved in 4 ml of MeOH and 48 hours. 116 mg of caustic soda are treated at room temperature, - dissolved in 1 ml of water. After acidification with 0.5 N hydrochloric acid to pH 3.5, evaporate to dryness. The residue is dried aceotropically in the presence of benzene (5 times) and then vacuum dried for 8 hours. 2 ml DMF and 3 ml DCM were added and cooled to 0 ° C. 865 mg of BOP and DIPEA are added to neutralize the reaction medium? After 15 minutes twice, within 30 minutes injected double ammonia./ After 2 hours. DCM was evaporated at room temperature, carbonated water, sodium chloride was added, followed by extraction with 4 volumes of AcOEt. After evaporation, the residue is chromatographed on silica. The resulting solid was washed with DCM / MeOH / NH, OH (δ 4.5 / 15 / 0.5; v.v.), and recrystallized from DCM / iso ether.

M.p. = 183-186 ° C /. // '®D = -63.1 {c = 0.24 / chloroform)

Table

An example 'D (chloroform) 115 will go -NHCOOCHg ^ ^- ^ -151 c = 0.27 116 will go 7 / .717 // -NH ₂ 7 ''/;'/'/<'.// 7 ' -161.4 c = 0.26 116 bis going to 7/7 '/// - N (CH,) _? ^ //> / 77./

EXAMPLE 117.

Decarboxylation of the cis isomer of N- (carboxy-2-ethyl) -N-ethyl (chloro-2-phenyl) -3-chloro-5 (dimethoxy-3,4-phenylsulfonyl) -1-hydroxy-3-indoline-2-carboxamide

630 mg of the compound obtained in Example 41 are added to 20 ml of THF under argon, followed by addition of 101 mg of N-methylmorpholine at -15 ° C and 118 g of isobutyl chloroformate. After 5 minutes

127 mg of N-hydroxypyridine-2-thione, 101 mg of TFA were added under stirring and kept under stirring for 15 min. at -15 [deg.] C., then 900 mg of tert-butyl mercaptan are added and the mixture is kept at room temperature. The reaction medium is then -1.5 h irradiated with a Tungsten lamp (150 W). The medium is concentrated, washed with water, extracted with DCM, dried and concentrated. The residue was chromatographed on silica eluting with DCM / AcOEt (95/5; v.v.).

m = 300 mg, m.p. = 21.5 ° C.

This · compound is similar to. Example 125 is disclosed in European Patent Application EC 469984. It has a cis15 configuration with about 2.3 bonds of indoline.

EXAMPLE 118.

Decarboxylation of the cis isomer of ((2R) carboxymethyl-2-pyrrolidinecarbonyl) -2-chloro-20 (chloro-2-phenyl) -3 (dimethoxy-3,4-phenylsulfonyl) -1-hydroxy-3-indole.

Work up as in the previous example using the compound obtained in Example 102. as the starting product. the product is recrystallized from DCM / iso ether.

M.p. = 215-220 ° C ^a D = -214.5 (c = 0.2, chloroform)

This compound is (cis -isomer of ((2S) methyl-2-pyrrolidinecarbonyl) -2-chloro-5- (chloro-2-phenyl) -3- (dimethoxy-3,4-phenylsulfonyl) -1-hydroxy-3).

' ^V '////<7-7.7· 85 / '7 /. '7 - - 7 /// 7: / 7 /'

EXAMPLE 119.

Decarboxylation of the cis isomer of (carboxy-2-pyrrolidinecarbonyl) -2-chloro-5- (chloro-2-phenyl) -3 (dimethoxy-3,4-phenylsulfonyl) -1-hydroxy-35-indoline.

Work up as in the previous example using the compound obtained in Example 28 as the starting product. The resulting product is recrystallized from an iso ether / DCM mixture.

Mp ~ 263 ° ^C D = -201.5 (c = 0.2, chloroform)

This compound is pyrrolidinecarbonyl-2-chloro-5- (chloro-215: - phenyl) -3- (dimethoxy-3,4-phenylsulfonyl) -1-hydroxy-3-indoline, cis-isomer.

Claims (5)

DEFINITION OF INVENTION 1. Structural formulas of amoline-indoline derivatives; (CH ₂ > (I) R < which, - R _d is halogen -atomas, alkyl C ₁ C _4., hydroxy> alkoxy C₁-C₄, benzyloxy, cyano, .trif luormetilo, nitro or amino; , _r · - R ₂ is alkyl C _x -C _6, cycloalkyl C ₃ -C ₇ cycloalkenyl, C ₅ -C _7, phenyl, unsubstituted or substituted with one or more alkyl, C _l -C _4, alkoxyl C _x -C ₄ halo, group, or that Trifluoromethyl group, amino nitrophenyl. unsubstituted -or-substituted once with trifluoromethyl or once or several times with alkyl C _x -C ₄ or halogen; - R ₃ is a va'ndenil atom; R ₄ is a carbamoyl group of formula CONR ₆ R ₇ ; - R ₅ 'or alkyl 1-naphthyl; 2-naphthyl; 5-di35 methylamino-1-naphthyl; phenyl unsubstituted or substituted with one or more substituents selected from halogen, alkyl C ₁ -C ₄ , trifluoromethyl, amino 1.//--/,7- groups, free or substituted with one or two alkyl C ₁ -C ₄ , hydroxy, alkoxyl C ₁ -C ₄ , alkenoxyl C ₂ -C ₄ , alkylthio C ₁ -C ₄ trifluoromethoxy groups, benzyloxy group, cyano group, carboxy group, alkoxycarbonyl group 5 - C _x -C ₄ , carbamoyl groups, free or substituted with one or two alkyl C _x -C ₄ , or alkylamide C _x -C ₄ ; or R ₅ nitrophenyl, unsubstituted or substituted once with trifluoromethyl or alkenoxyl C ₂ -C ₄ , or one or more times halogen, alkyl C _x -C ₄ , alkoxyl 10 C _x -C _4, alkylthio C _x -C _4, or trifluoromethoxy; · ·: '. , · ..R. t R-RV-R: R ·: · '· benzyloxy; - R ₆ is Cy-C ₈ alkyl, or R _{6 is} similar to R ₇ ; 15 - R- is a piperidin-4-yl group, an azetidin-3-yl group, these groups being substituted or unsubstituted with nitrogen alkyl C _x C ₄ , benzyloxycarbonyl or · alkoxycarbonyl C ₁ -C ₄ ; group (GH ₂ ) _r , also substituted with a 2-, 3- or 4-pyridyl group, or a hydroxyl group, or an amino group, free Or substituted with one or two alkyls C _x -C ₄ , a carboxyl group, an alkoxycarbonyl group C _x -C ₄ , a benzyloxycarbonyl group, a carbamoyl group, free or substituted by one or two alkyl C _x -C ₄ ; - or R ₆ and R _? along with the nitrogen atom with which 30S from: connected, make up one heterocycle, selected morpholino, tiomo.rfolino, thiazolidine or 2.2- dimethylthiazolidine, unchanged or modified Rg, ' piperazine, unchanged or replaced by 4 position R e 30 groups; a monoazotic, unsaturated 5-membered ring, substituted R or a monoazoic saturated ring, 3,4,5,6 or 7-substituted R ₈ and R ₉ ; - R ₈ is R'g or a group (CH ₂ ) _r , also substituted 35 hydroxy or an amino group, free or substituted with one or two alkyl C ₁ tC ₄ ; - R'g is a group (CH ₂ ) _q also substituted with a carboxyl group, an alkoxycarbonyl group C _x -C ₄ , a benzyloxycarbonyl group, a carbamoyl group, free or substituted with a hydroxyl or a VI or two alkyl. or aminocarbothiol 5 group free or substituted by one or two alkyl C _r -C _4; - R ₈ is R'g or. a group (CH ₂ ) ₂ NH ₂ , free or substituted with one or two alkyl C ₁ -C ₄ ; R ₁₀ is hydrogen, halogen, (CH ₂ ) ₂ OR ₁₀ , (CH ₂ ) ₂ NR '{ ₁ R ₁₂ , (CH ₂ ) _S CON R ₁₁ R' _n , azido; - R _lo represents hydrogen, alkyl Ο _χ -Ο ₄ , mesyl or tosyl; - R _n , R ' _{X 1} and R _{12 are} each hydrogen or alkyl ¢ / -¾ or. R _1X is hydrogen and R ₁₂ is benzyloxycarbonyl or alkoxycarbonyl C ₁ -C ₄ ; - n = 0,1'or 2; - m = 0,1 or 2; - p = 4.5 or .6; - q = 0,1,2 or 3; λ - r = 0,1,2Barba 3, with the proviso that r is equal to zero when R _g or R ₉ is in the alpha position in the intracyclic amidic nitrogen; B - s = 0 or 1 as well as the corresponding salts having pharmacological activity. 2. A compound according to claim 1, wherein R ₇ is a chlorine or bromine atom or a methoxy group, at = 1. . 5 - 3. A compound according 1'ir 2, characterized in that it R ₂ is chlorophenyl or methoxyphenyl or cyclohexyl. A compound according to any one of claims 1 to 3, wherein R ₅ is phenyl substituted at the 3 and 4 or 2 and 4 'methoxyl group or R ₅ is phenyl substituted at the 4 position by methyl. A compound according to any one of claims 1-4. k i15 given that m = 0. 6. A compound according to one of claims 1 to 5, characterized in that R ₄ is a pyrrolidone group substituted with a group (CH ₂ ) _{q in the} substituent at position _{2 in the} group CONR ₆ R ₇ and NR ₆ R ₇ , yes Or a substituted carboxyl group or a carbamoyl group when q = 0, 1, 2 or 3; or NR ₆ R ₇ represents a piperidine group substituted at the 4-position by an amino group, an alkylamino group or a C 5 -C 7 alkyl dialkyl group or a ₄ R ₆ R ₇ - thiazolidine group substituted by (CH ₂ ) _q , as well as Substituted by a carboxyl group or a carbamoyl group when q = 0, 1, 2 or 3 '; or NR ₆ R ₇ is a pyrrolidine group ¹ substituted at the 2 position (CH ₂ ) _q , also substituted with a carboxyl group or a carbamoyl group, and substituted at the 4 position by an amino group, an alkylamino group C 1 -C 4 or 30 dialkylamino group C ₁ -C ₄ ; or NR ₆ R ₇ is alkyl C ₁ -C ₄ and R ₇ is a single group (CH ₂ ) _r also substituted with a carboxyl group or a carbamoyl group when r = 1, 2 or 3. Compound according to one of Claims 1 to 6, characterized in that it is in the form of a cis isomer, wherein R ₂ and R ₄ are on one side of the indoline ring. δΙΛ A process for the preparation of a compound (I) as claimed in claim 1, characterized in that (a) The reaction proceeds between a 2-aminophenone derivative having a total fhrmule of 5: tl (Rf) S - b (II). wherein R _and R ₂ and n have the meanings given in claim 1 and a sulfonyl derivative having the general formula: Hal-SO ₂ - (CH ₂ ) _m -R _s (III) in which - Hal is halogen,. Usually chlorine or bromine, m and Rr have the meanings given in point 1, (b) the compound thus obtained: CO-R < ^R l> n NH f s ° ₂ (IV) processes with derivatives: halogenated using the formula below Hal'-CH ₂ COA (V) in which e - * Hal is halogen, typically bromine 'and A is a group NR ₇ R _€ or a group OR, wherein R is tertiary butyl or benzyl; c) where appropriate, when A is an OR group, from the ester of formula thus obtained; s COKr -r so. (VI ") Rs removes protection under normal conditions; D) if necessary, the acid obtained in step (c): ^ ^; \ ^ ^COR 2 .Jr J ''. {Rl ^^^^ N ^ HnCOOH so ₂ . 4 ^H 2) m ^R 5 (VI) (VI ** ·). or acid anhydride: , C0R ₂ ^ ^H 2 ^c ° al * I ·. · '· -¾ processes with compound. NR _& R _T manner consistent with the use of amidine compounds; (E) compounds of formula lb) or step <d) of the formula: COR. C ^R l) nV ^jL -f ⁱ - ^CH 2 ^CONR 6 ^R 7 (VI) - SO ₂ (CH ₂ ) _i ^R 5 Cyclizing in an alkaline medium to obtain compound (I) according to claim 1; f) the eis and trans isomers of the compound (I) can be separated and the enantiomers can also be separated. 7'7 / 7 .. ... 'P /. 7 // 7 / :: - 7-7 m ?. 7 / 7-7-7 / '- // - to / / 7', / 777-7 :: '·: JO /: / -: /. 7-7,.: 177: 77/7 // 777/7 777 777 K / SF'Seifts * ' IBM® / ...... A /; // 93 / 9 "Compound of formula: 10 in which - Δ is a group selected from NR ₆ R ₇ , hydroxy, tertiary butyloxy or benzyloxy; wherein - R _r is a halogen atom, alkyl C _x -C ₄ , hydroxyl, alkoxy 15 ° C _x -C _4, benzyloxy, cyano., - a trifluoromethyl group, a nitro group or an amino group; - R ₂ is alkyl C ₁ -C 8, cycloalkyl. C ₃ -C ₇ , cycloalkene C ₅ -C ₇ , phenyl, - · unsubstituted or substituted by one or more 20- several times alkyl C _x -C ₄ , alkoxyl C _x -C ₄ , halogen, trifluoromethyl, amino, - or R ₂ or? nitrophenyl, unsubstituted or substituted once with trifluoromethyl or one or more alkyl, C _x -C ₄ , alkoxyl, C _x -C ₄ or halogen; - K ₅ or alkyl C _x -C ₄ ; 1-naphthyl; 2-naphthyl; 5-dimethylamino-1-naphthyl; phenyl unsubstituted or substituted with one or more substituents selected from the group consisting of 'halogen, alkyl C _x -C ₄ , trifluoromethyl, amino 30', free or substituted with one or two alkyl C 1 -C 4, hydroxyl, alkoxyl C. , -C ₄ , alkenoxy C ₂ -C ₄ , alkylthio C _x -C ₄ trifluoromethoxy group, benzyloxy group, cyano group, carboxy group, C _x -C ₄ alkoxycarbonyl group, carbamoyl group, free or substituted 35 'with one or two alkyls _χ -0 ₄ or alkylamide groups C _x -C ₄ ; or 'R _{5 is} nitrophenyl, unsubstituted or substituted once by trifluoromethyl or alkenoxyl, C 1 -C 2, or once or' repeatedly halogen, alkyl-C 1 -C ₄ , alkoxyl-C ₁ -C ₄ , alkyl-C 1 -C ₆ , trifluoromethoxy or benzyloxy; 5 - R ₆ is alkyl, Cj-Cg, or R _& similar to R _7; - R ₇ or piperidin-4-ii. a group, an azetidin-3-yl group, those groups being substituted or unsubstituted with nitrogen alkyl C ₄ C ₄ , benzyloxycarbonyl or alkoxycarbonyl gC; Group 10 (CH) is also substituted with a 2-, 3- or 4-pyridyl group. or a hydroxyl group or an amino group, free or substituted by one or two alkyls C ₁ -C ₄ , a carboxyl group, an alkoxycarbonyl group C _x -C ₄ , a benzyloxycarbonyl group, a carbamoyl group, free or substituted by one or 15 for two alkyl C 1 -C 4; - or R ₆ and R ₇ together with the nitrogen atom to which they are attached form a single heterocycle selected from: morpholine, thiomorpholine, thiazolidine. or 2,220 dimethylthiazolidine, unsubstituted or substituted with R ₈ ; piperazine, unsubstituted or substituted at the 4 R 8 position; of monaotic,. unsaturated ring with 5 chains substituted by R ₈ monoazotic saturated ring with 3, 4,5,6 or 7 chains substituted by the R ₈ and R _9; - R ₈ ^R 8 is R or a group (CH _{2) r,} is also substituted with hydroxy or amino groups, free or substituted by one or two alkyl C ₁ -C _4; 30 - R'8 is a group (CH ₂ ) _q also 'substituted with carboxyl ·: 35 - R 8 or R '8 one or two or alkyl group (C H ₂ ) ₂ NH ₂ , free or substituted with C _x -C ₄ ; 5 R _? it is a group of water (CH ₂ ) _n NR ₁₁ R _{L 2} , ( lis, halogen, (CH ₂ ) _r OR ₁₀ , CH ₂ ) _S CONR ₁₁ R ^, 11, azido; ·;? · '. · \ 1 R ... M / .. '·' · '' /// 7 / · /,. '.. <.''/ · Rl / I -7 - R _1D is a ve tosyl; indeni lis, alkyl C _x -C ₄ , mesyl or 10th ~ Rii 'R'n i ^r alkyl C ₁ -C ₄ benzyloxycarb · R ₁₂ k: or ony Each of them is hydrogen or R _u is hydrogen, 0 &lt; ₁₂ &gt; or carbon monoxide C _X ~ C ₄ ; ' T C - - n = 0,1 or -2;: -1; - m = 0,1 or 12; .. '' to'l ;. - p / = - 4.5 or 6; -7 20th - q = 0,1,2 or. 3; - r =; 0,1,2 a: when R ₈ or in amide azo : ba 3 R ₉ 'te you; . with the constraint that r is equal to zero in the alpha positioninr «cyclic 25th / -s = 0 or 1 1 'i ·· /'. /.y - -, 1 / .7 / <r </ - / 1 /.-. 10. The compound of formula (I) having the formula: : 7 (/ (/ 9: 6/7. - (: in which R _t , R ₂ , R ₃ , R _s , m and · n. are the same as in the compound of claim 1. (I), u / (<7 (/,., - R _VI is alkyl C 1 -C 8,? / 5; / j 'j / 37;.'J> glS77 '/ ^ (((-7) : ^ - ^ '{''- y {' / {'(( - R _VII is a group (CH ₂ ) _r CQOH with r = 1, '2 or 3, - or R _VI and R _vn together with the nitrogen atom to which they are attached. form a single heterocycle selected from: 10 thiazolidine or 2,2-dimethylthiazolidine substituted with (CH ₂ ) _q COQH; 7 piperazine substituted at position 4 by (CH ₂ ) _q COOH; an unsaturated monoazotic ring with 5 chains substituted by (CH ₂ ) _q COOH; saturated monoazotic cycle with 3,4,5,6 or 7 chains, Substituted with (CH ₂ ) _q COOH, q = 0,1,2 or 3, to obtain compounds of the formula; (1), the same configuration about. indoline linkage 2,3 as in the parent product: wherein R _r , R ₂ , R ₃ , R ₅ , m and n are the same as 30 / above, - R. ' vr or alkyl (λ-Οθ; 7 - R \ _n is a group (CH ₂ ) _q H, - (/ 35 '73. . 37 '3 7'. . - or R ' _yI and R' _VII together with the nitrogen atom to which they are attached form a single heterocycle selected from: . 97 /: '7 / Thiazolidine or 2,2-dimethylthiazolidine substituted with (CH ₂ ) _q H, piperazine substituted with 4 (CH ₂ ) _q H, unsaturated monoazo ring with 5 chain substituted (CH ₂ ) _q H, saturated monoazotic cycle with 3,4,5,6 5 'and 7, substituted with CH (CH2OH).