FI107048B - 2-Sulphonamidophenone derivative - 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

107048 2-Sulfonamido phenone derivatives

Divided by application 931476.

The present invention relates to 2-sulfonamidophenone derivatives having an amide functional group. The compounds are intermediates for synthesis.

U.S. Patent 3,838,167 describes N-sulfonyl indole derivatives having the formula: 10 (R 'cor' <

2V I

15 S02R ”3 where R'1! is hydrogen, alkyl, or substituted or unsubstituted phenyl; R "2 is halogen, alkyl, alkoxy, nitro or trifluoromethyl; R" 3 is alkyl, phenyl or alkylphenyl;

R 4 is alkyl, substituted or unsubstituted phenyl, alkoxy or phenoxy; 25 n '= 0, 1 or 2.

These compounds 1 are intermediates for the synthesis of indo- ···. for the preparation of derivatives which are active against the central nervous system and having the formula:

S

/ w 1 / p .. JL ^ -cor '

- · r {R

"I

lv h. ··. Where R "is alkyl, substituted or unsubstituted phenyl or hydroxyl.

The compounds of this invention are useful as intermediates in the preparation of indoline derivatives having aliphatic affinity for vasopressin and oxytocin receptors. The end products are particularly useful in the treatment of diseases of the central nervous system, cardiovascular system and gastrointestinal tract in humans and animals.

Vasopressin is a hormone known for its anti-diuretic effect and for its effect on the regulation of silent blood pressure. It stimulates several types of receptors: V1, V2, Vla, Vlb and thus has cardiovascular, central, hepatic, antidiuretic, emetic and aggregation effects, in particular reproductive and mitotic effects, in particular vascular and hepatic tissue. Vasopressin receptor antagonists may influence central or peripheral blood flow regulation, particularly coronary, renal and gastric circulation, as well as water metabolism and adrenocorticotrophic hormone (ACTH) release. Vasopressin receptors, such as oxytocin receptors, have also been found in uterine smooth muscle. Oxytocin has a similar peptide structure to vasopressin. Its receptors have also been found in • 25 myoepithelial cells of the mammary gland and in the central *: · 1: cerebral nervous system. (Presse Medicale, 1987, 16, (10), 481-485, J. Lab. El. Med., 1989, 114 (6), 617-632 and

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

• · · - • • • • • • 1 • · · ♦ «· • · 4« 4 • 4 · »107048 3

The present invention relates to compounds (6) of the formula: which are intermediates in the preparation of compounds of the formula (I) R 1 R 1 is a halogen atom, C 1-4 alkyl or C 1-4 alkoxy; R 2 is C 3-7 cycloalkyl or phenyl, unsubstituted or monosubstituted with halogen; t R 5 is phenyl substituted with one or more substituents selected from the group consisting of C 1-4 alkyl and C 1-4 alkoxy; R 6 is C 1-6 alkyl or benzyl or - (CH 2) 2 -CO 2 -CH 3; R 4 is a 4-piperidinyl group which is unsubstituted or substituted on the nitrogen atom with C 1 -C 1 alkyl; group • ♦ · 30 (CH 2) r substituted with 2-pyridyl group or amine. a free radical or a substituent substituted by one or two C 1-4 alkyl, a carboxyl group, a C 1-4 alkyl group, a benzooxycarbonyl group or a carbomyl group; or R7 is a group -CH (CH3) C00-C2H5; (3 '1 ® 4 107048 or R 6 and R 6 together with the nitrogen atom to which they are attached form a heterocyclic ring selected from the group consisting of: morpholine, thiomorpholine, thiazolidine, unsubstituted or unsubstituted; substituted by a carbamoyl group, piperazine unsubstituted or substituted at the 4-position by a methyl, a C 1 -C 4 alkoxycarbonyl-10 methyl group or a benzylcarbonyl group; A 3 pyrrolidine substituted by a C 1 -C 4 alkoxycarbonyl group; pyrrolidine monosubstituted with carboxy, carboxymethyl, C 1 -C 6 alkoxy-15-carbonyl or C 1 -C 10 alkoxycarbonylmethyl, carbamoyl group unsubstituted or substituted with C 1 -C 4 hydroxy; N-alkyl, carbamoylmethyl group, aminocarbothioyl group substituted with two C 1 -C 6 alkyl, hydroxy-20-hydroxymethyl a group or an aminomethyl group; or pyrrolidine disubstituted with a C 1 -C 1 -C 4 alkoxycarbonyl group and an amino group unsubstituted or substituted with one or two C 1 -C 4 alkyl groups or with one benzyloxycarbonyl group; or pyrrolidine, f · · · ···, disubstituted with a (C 1 -C 4) alkoxycarbonyl group and a *: ··: azido group; or pyrrolidine which is disubstituted; ***: with carbamoyl and amino which is unsubstituted or substituted with one or two C 1-6 alkyl groups or one benzyloxycarbonyl group; pyrrolidine, * · · 30 substituted at the 2-position with methoxycarbonyl and 4-. in position on N-benzyloxy-N-methylamino: piperidine, substituted with a hydroxy group, a carboxyl group, a C 1-4 alkoxycarbonyl group, or an amino group unsubstituted or substituted with one or two 35 (C 1 -C 4) alkyl groups; or azetidin-1-yl substituted at the 3-position with tert-butoxycarbonylamino; and •>)) o 107048 5 r is 1, 2 or 3.

Salts of compounds of formula (I) include salts with inorganic or organic acids which allow the appropriate separation or crystallization of compounds of formula (I), such as salts of picric acid, oxalic acid or optically active acid such as mandelic acid or camphosulfonic acid, and the like. which form pharmaceutically acceptable salts such as hydrochloride, hydrogen sulfate, dihydrogen sulfate, methanesulfonate, maleate, fumarate or 2-naphthalenesulfonate.

Salts of compounds of formula (I) also include salts with organic or inorganic bases, for example, salts of alkali and alkaline earth metals such as sodium, potassium or calcium, with sodium and potassium being preferred, or with an amine such as trometamol, or even salts of arginine or lysine or any pharmaceutically acceptable amine.

Compounds (I) exhibit cis-trans isomerism around the 2,3-bond of indoline.

R2

- / "" OH

i \! 25 r, <^ n ^ conr6r7

I H

r f0 * a)

Rs *. *. · Cis Isomer · · · · · · · · ·

30 R

OH

9 'conr6r7 (I) U vJ Λ

35 | L

"A ·. r5 • * 'trans isomer 107048 6

Furthermore, the compounds of formula (I) have 2 asymmetric carbon atoms or more when the group CONR6R7 contains 1 or 2 asymmetric carbons. The optical isomers of the compounds (I) form part of the invention.

In this specification and in the following claims, halogen is understood to mean a fluorine, chlorine, bromine or iodine atom; alkyl group is understood to mean straight or branched hydrocarbon groups.

Preferred are compounds in which at least one of the following conditions is true:

Rx is a chlorine or bromine atom or a methoxy group; R 2 is chlorophenyl or cyclohexyl; NR6R7 is a pyrrolidino group substituted at the 2-position by a carboxymethyl, carboxyl or carbamoyl group; NR 5 R 7 is a piperidino group substituted at the 4-position by an amino group, C 1-6 alkylamino or C 1-4 dialkylamino, NR 6 R 7 is a thiazolidino group substituted by 20 carbamoyl groups, where q = 0, 1, 2 or 3, NR 6 R 7 is pyrrolidino , substituted in the 2-position with a carboxy, carboxymethyl or carbamoyl group, a C 1-4 alkylamino or a C 1-3 dialkylamino; • i: R 6 is C 1 -C 4 alkyl and R 7 is a group (CH 2) r one-half. Is substituted by a carboxyl group or a carbamoyl *: ** group, wherein r = 1, 2 or 3; : ***: R5 is phenyl substituted at the 3- and 4-position or 2- and 4-position by a methoxy group, or R5 is phenyl substituted at the • · 4-position by a methyl group.

• · · 30 Compounds (I) in the form of cis isomers. are particularly preferred.

The following abbreviations are used in the description and examples • »·· 1: DCM: dichloromethane 35 AcOEt: ethyl acetate« «• ♦ 107048 7

MeOH: methanol EtOH: ethanol Ether: ethyl ether DMF: dimethyl formamide 5 THF: tetrahydrofuran TEA: triethylamine DMSO: dimethyl sulfoxide DIPEA: diisopropylethylamine DCC: N, N'-dicyclohexylcarbodiimide 10 DBU: 1,8-diazab ] undec-7-ene TBD: 1,5,7-triazabicyclo [4.4.0] dec-5-ene DBN: 1,5-diazabicyclo [4.3.0] non-5-ene DMAP: 4-dimethylaminopyridine DMPU: 1 , 3-Dimethyl-2-oxohexahydropyrimidinone 15 TMEDA: Tetramethylethylenediamine LDA: Lithium diisopropylamide HMPA: Hexamethylphosphoramide HOBT: 1-Hydroxybenzotriazole Hydrate BOP: Benzotriazolyloxitrisdimethylaminophosphate

Lawesson's reagent: 2,4-bis- (4-methoxyphenyl) -1,3-dithia-2,4-diphosphetane-2,4-disulfide:. : M.p .: melting point * * ·· 25 Saline: water saturated with sodium chloride ·: ··; Carbonic acid: solid carbon dioxide: ***; TLC: thin layer chromatography * · ♦ HPLC: high performance liquid chromatography • · NMR: nuclear magnetic resonance • «· 30 s: singlet m: multiplet bs: broad singlet - · <- * d: doublet

* '· *: Hydrochloric water: dilute hydrochloric acid, about 1 N

107048 8 80% Dispersion of NaH: Sodium Hydride in Mineral Oil (Janssen Chemica)

Me: methyl Et: ethyl 5 iPr: isopropyl, Pr: propyl iPentyl: isopentyl iBu: isobutyl tBu: tert -butyl, Bu: butyl Bz: benzyl 10 Ph: phenyl RT: room temperature

Compounds (I) are prepared by: a) a 2-aminophenone derivative of the formula: -H! Wherein R 1 and R 2 have the meanings given above for Formula (I), is reacted with a sulfonyl derivative of the formula: Hal-so 2 -R 5 (m) 25 · · · ·; where: ***; Hal is halogen, preferably chlorine or bromine, · · · R5 has the meanings given above ···. for formula (I); B) the resulting compound of the formula: ry * 0 '* 2

RrvJ-NH (IV) 35 SO2

• I

: V R * 4.1. » .107048 9 is treated with a halogenated derivative of the formula:

Hal 1 -CH 2 COA (V) 5 wherein

Hal 'is halogen, preferably bromine, and A represents either NR 6 R 7 or OR, wherein R is tert-butyl or benzyl; c) from the resulting ester of the formula: 10 ^ yC0R2 LJ-n-cHoCoor

Rj I L

S02 (VI) '15 |

R 5 is deprotected under appropriate conditions if desired, d) if desired, the acid obtained from step c). formula:

1.: 25 r ^ JLn-CH 2 COOH

O 'S02 (711- • · ♦ \ R1 ··· J • · «• · · 30 or its acid chloride of the formula: R ^ vJ-N-CH2coa (Vi) .- ·: ·' so2 35 | 2 · 1 → 1 → 107048 10 is treated with HNR 6 R 7 according to appropriate amide coupling procedures e) Compound of formula b) or d) of formula: 5f 1 -CO 2 R 2 / O 1 - CH 2 CO 2 NR 6 R 7 (VI> 1 SO 2). ίο 1

R 8 is cyclized in an alkaline medium to prepare compound (I) of the invention; F) if desired, separating the cis and trans isomers of compound (I) and, if desired, separating the enantiomers.

The 2-aminophenone derivatives (II) are known or are prepared by known methods, such as those described by A. K. Singh et al., Synth.

20 Commun. 1986, 16, (4), 485 and G.N. Walker, J. Org. Chem. , 27, 192, 1969. 2-Amino-21-trifluoromethylbenzophenones. and other trifluoromethylated derivatives are prepared according to U.S. Patent 3,341,592.

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

The sulfonyl derivatives of formula (III) are known or are prepared by known methods. Thus, for example, 4-dimethylaminobenzenesulfonylchloride is prepared according to C. N. Sukenik et al., J. Am.

e o. ···. Chem. Soc., 1977, 99, 851-858; p-Benzyloxybenzenesulfonyl chloride is prepared according to EP application 229566.

«« «· 107048 11

Alkoxybenzenesulfonyl chloride is prepared from sodium alkoxybenzenesulfonate, which is again prepared by reacting the alkyl halide with sodium hydroxybenzenesulfonate.

The halogenated derivatives of formula (V) are known or are prepared by known methods, such as those described in Al Voge: A Text Book of Practical Organic Chemistry: Longman, 3rd Edition, 1956, p. 383, or G. Kirchner et al. , J. Am. 10 Chem. Soc. , 1985, 107, 24/7072.

Step a) of the process is carried out in pyridine by heating at a temperature between room temperature and the boiling point of the solvent for a period of time ranging from five hours to five days. If desired, reaction 15 may be carried out in the presence of dimethylaminopyridine which is used in a catalytic or stoichiometric amount.

Process step b) is carried out between an excess of a sulfonamide of formula (IV) and a halogenated derivative of formula (V) in a solvent such as dimethylformamide or dimethylsulfoxide under an inert atmosphere at a temperature of 0 ° C to room temperature: *:: between 5 hours and 24 hours in the presence of sodium hydride.

When the group -NR6R7 contains another amine group, i.e., "" when R6 and / or R7 is substituted with an amino group, it is possible to choose to use a halogenated derivative (V) of the formula Hal '-CH, -CO2R wherein R is -butyl or benzyl for the preparation of intermediates of formula (VI) 'followed by (VI) ". In this case, step c) • ♦. ... of formula (VI)" is carried out * either by the action of hydrogen in the presence of a catalyst, such as palladium on charcoal, when R is benzyl, or: in an acid medium, where R is tert-butyl, for example in the presence of 35 TFA or in the presence of hydrogen bromide • ·

«MM

107048 12 acid in acetic acid or in the presence of ZnBr2 in DCM.

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

The compounds HNR5R7 are known or are prepared by known methods. For example, stereospecific synthesis of (R) - and (S) -2-pyrrolidinylacetic acids is carried out according to H. Rueger et al., Heterocycles, 1982, JL910 (9), 1677 with a suitable configuration of a proline derivative. The preparation of methyl N-Boc-3,4-dehydro-α-prolinate is carried out according to J. R. Dormoy, Synthesis, 1982, 753. The preparation of optically pure derivatives of pipecolic acid is described, for example, in Tetrahedron, 1992, 48 (3), 431-442 and Tetrahedron, 1991, 47 (24), 4039-4062.

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

Step e) of the process is closely related to the aldolization reaction: the methylene group at the α-position of the amide deprotonates. then the carbonyl group of phenol and phenone acts like an internal electrophile, whereby cyclization occurs and the two: 'asymmetric carbon (C *) disappear.

'* 25 The reaction can be illustrated by the following scheme: ° o ©> C-

·: ·· 30 S02 H

k

· RV. OH

35 .. JU-H

I * · ': 35 -► Ri. R4 SO2 R * 107048 13

The principles of the aldol addition reaction are described in C. H. Heathcock, Asymmetric Synthesis, vol. 3: Stereodifferentiating addition reactions, part B, 111-112; Academic Press, 1984, edited by J. D. Morrison.

It is known that the aldol reaction of achiral amide anions increases the formation of the racemic diastereoisomer of β-hydroxyamides 2 in a ratio which depends greatly on the experimental conditions used. These conditions include the nature of the inorganic or organic base used, the nature of the cations or counterions, the possible presence of additives in the reaction medium, the solvent, the reaction temperature, and the structure of the compound to which this reaction takes place.

When Rs and R7 do not contain a group which is hydrolyzable in 15 alkaline media, it is possible to use sodium hydroxide in water in the presence of a cosolvent, with or without the addition of a phase transfer catalyst; it is also possible to use quaternary ammonium hydroxide, for example benzyltrimethylammonium hydroxide in methanol.

To carry out this aldolization reaction, it is also possible to use organic bases, for example: · · guanidines such as 1,5,7-triazabicyclo [4.4.0] dec-5-ene, · * · 1 '· 25 amidines such as 1, 8-diazabicyclo [5.4.0] undec-5-ene or 1,5-diazabicyclo [4.3.0] non-5-ene, in a solvent or mixture of solvents which are soluble; the scavengers are selected from, for example, benzene, THF, dichloromethane, methanol and dimethylformamide; the reaction is carried out in an inert atmosphere at a temperature between -10 ° C and 110 ° C; the amount of base used is at least stoichiometric; the reaction may also be carried out in the absence of a solvent at bath temperature.

• · «· · 1 1 ♦ 14 107C48

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

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

The alcoholate is used in a catalytic or stoichiometric amount in an anhydrous solvent, for example alcohol (if desired in the presence of a cosolvent such as THF) or otherwise in a stoichiometric amount in THF, DMF or DMSO, crown ethers e.g. dicyclohexyl 18 In the presence of 6; the reaction is carried out between -15 ° C and 80 ° C.

The use of an amide of the RR'NLi or RR'NMgBr type where R and R 'are monovalent radicals, the deprotonating agent is a process for the formation of enolates of amides which are intermediates in the aldolization reaction; A recent description of this method is described in R.E. Ireland et al., J. Org. Chem. , 56, 650, 1991.

. The reaction solvent may be benzene, hexane or THF, which is used in anhydrous form under an inert atmosphere.

Adjuvants such as LiF, LiCl, LiBr, Lil, LiBu, 25 TMEDA, DMPU, HMPA or crown ether can be added.

4 ♦: .., ί (M. Murakate et al., J. Chem. Soc. Commun., 1657 (1990)).

• ·

For example, mention may be made of the use of lithium diisopropylamide at -78 ° C to -30 ° C in anhydrous THF under an inert atmosphere or in THF in the presence of additives such as tetramethylenediamine, DMPU or HPMA. Examples of other known amides which may be used are lithium cyclohexylamide and • · | Lithium 2,2,6,6-tetramethylcyclohexylamide. It is also possible to prepare other amides by providing the required; Of butyl lithium in hexane to react with linear • 107048 15 or cyclic secondary amines, whereby the reaction occurs in one of the above solvents.

Finally, various publications describe amides of optically active secondary amines: L. Duhamel et al. Bull. Soc. Chim. France, 1984, II, 421; J.K. White-sell et al., J. Org. Chem. 45, 755 (1980); Murakata M. et al., J. Chem. Soc. Chem. Commun., 1657, 1990; M.

Yamaguchi, Tetrahedron Lett., 1986, 27 (8), 959; PJ Cox and NS Simpkins, Tetrahedron: Asymmetry, 1991, 2 (1), 1.10 The silylamides of lithium, sodium, or potassium form a second group of bases which may be used and which may be mentioned: (Et3Si) 2-NLi, (Me3Si) 2NK, (Me3Si) 2NNa.

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

When the compound of formula (I) to be prepared has 2 asymmetric carbon atoms, chiral amides. or the use of alcoholates in step e) enables the enantiomeric enrichment of each of the cis or trans stereoisomers. The proportion of each enantiomer is then determined by measuring a * 25 bar chiral high performance liquid chromatography column.

• ·

When the compound of formula (I) to be prepared has 3 or 4 asymmetric carbon atoms, the diastereoisomeric enrichment ♦ in step c) can be added, and the appropriate chiral ««, ···. the use of a base permits modification of this diastereoisomeric * 'enrichment.

The geometric cis and trans isomers of compound (I) formed in step f) are extracted by conventional procedures and separated by chromatography or fractional crystallization.

«· 107048 16

If desired, the optical isomers of each of the cis and trans isomers are separated, for example, by preparative chromatography on a chiral column, and then, if desired, crystallized or formed an optically active salt in the presence of a suitably selected chiral acid or base.

Thus, the compound of formula (I) has 2 asymmetric carbon atoms, the enantiomers can be resolved by chiral HPLC.

When the compound of formula (I) has 3 or 4 asymmetric carbon atoms, the diastereoisomers may be separated using chromatographic and fractional crystallization methods.

Several methods can be used to separate and characterize the cis isomer and trans isomer of compound (I). Comparative analysis is performed by high-field NMR (250 MHz) coupled, for example, to the Overhauser effect study (N.O.E.) between, for example, an indoline proton and a hydroxyl proton.

The IR spectra of the cis isomer and the trans isomer are different in the solution in DCM, the cis isomer has the usual. the smoothest, sharp and symmetrical absorption band at about 3550-3520 ems due to hydroxyl oscillation, while the * * 'trans isomer does not have a clear oscillation band in this * * 25 region.

· · · · ... · The recorded results have shown that the # · cis isomer is generally more mobile in TLC on an alumina: T: plate (60F254 neutral, Type E, Merck) when eluted with DCM containing varying amounts AcOEt. Similarly, in chromatography on an alumina column (alumina ···, oxide 90, particle size 0.063 - 0.200 mm), the cis isomer '1' is usually eluted first with DCM as eluent · ♦ ♦: contains varying amounts of AcOEtra or MeOH. .

«« «« «107048 17

Thus, in most cases, the cis or trans isomer of compound (I) can be determined by analytical method. It is also possible to use analogy between similar compounds or between compounds prepared from one another.

The absolute configuration of some compounds of formula (I) was determined by X-ray analysis. From these, taking into account the optical rotation value, it is also possible to know the absolute configuration of the other compounds obtained in an analogous manner.

From compounds (I) wherein the substituents R6 and / or R7 or the group NR6R7 contain a C1-6 alkoxycarbonyl group, it is possible to obtain, by hydrolysis of the ester, compounds (I) wherein R6 and / or R7 or the group NRSR7 contain a carboxyl group, ) other substituents do not change. Further, from compounds wherein R6 and / or R7 or NR6R7 contain a carboxyl group, it is possible to obtain compounds (I) in a conventional amide coupling reaction wherein R6 and / or R7 or NR6R7 contains a carbamoyl group which is free or substituted with one or two C1-6 alkyl, wherein the other substituents are the same.

. Finally, from compounds (I) wherein R6 and / or R7 or * group NR6R7 contain a carbamoyl group, it is possible to? A? "Afford the compounds (I), where * R6 and / or R7 or group NR6R7 contain an amino group Where the other substituents are the same (J. Org. Chem., V: 1979, 44 (10), 1746).

: * · *: Thus, a process for the preparation of compounds (I), wherein R6 and / or R7 or the group NR6R7 contain an amino group which is free or substituted by one or two C1-6. alkyl may have two variations: »*! * i) step b) of the process is carried out by treating ♦ ♦ · i '. · Compound (IV) obtained in step a) with a halogenated derivative (V) of the formula Hal' -CH 2 CONR 6 R 7, wherein R 6 35 and / or R 7 or the group NR 6 R 7 contain an amine precursor group, for example a carboxy ester, a carboxyl or a carbamoyl; then the cyclization step e) is performed and then the precursor group of the amine is converted to the amine, for example the carboxylic ester group of compound (I) thus obtained is hydrolyzed to the carboxyl group which is then converted to the carbamoyl group followed by Hofmann rearrangement reaction.

ii) Step b) is obtained by treating the compound (IV) obtained in step a) with a halogenated derivative (V) of the formula Hal '-CH 2 COOR wherein R is benzyl or tert-butyl; the thus obtained ester of compound (VI) 'is deprotected by appropriate treatment according to step c); followed by coupling with HNR6R7, whereby the amino group of R6 and / or R7 is optionally protected; then compound (VI) thus obtained is cyclized according to step e); and, if desired, compound (I) wherein the amino group is free is prepared by deprotecting the amine.

From compounds (I) in which R6 and / or R7 or NR20R7 contains a benzyloxycarbonyl or alkoxycarbonyl group as a substituent on the amine group, it is possible to obtain compounds (I) wherein the amino group is? the substituent it is similar.

The affinity of the compounds of formula (I) for vaso-pressin receptors was determined in vitro using the method described in J. Biol. Chem. , •, ί.ϊ. 1985, 260 (5), 2844-2851. This method consists of studying the substitution of tritiated vasopressin bound to Vi sites on rat: liver membranes. The compounds of the invention have 50% inhibitory concentrations (IC50) of tri. ···. for thiolated vasopressin binding are low '· * ranging up to 10 &quot; 9M.

• · · f f r <| <I i «i« j • · «t 4 ♦ •« * «» 107048 19

In addition, inhibition of platelet aggregation by vasopressin was measured in human platelet-derived plasma (human PRP) using the method described in Thrombosis Res., 1987, 45, 7-16.

The compounds of the invention inhibit aggregation induced by concentrations of 50 to 100 nM vasopressin at low ID50 (inhibitory doses) ranging up to 10'9 M. These results demonstrate the antagonistic activity of the compounds of the invention against 10 V-L receptors.

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

Compounds having the cis configuration around the 2,3-bond of indoline exhibit clear selectivity for β 1 -receptors.

The affinity of compounds (I) for oxytocin receptors was determined in vitro by replacing tritiated oxytocin bound to the receptors of pregnant female rat gland membrane preparation. The compounds of the invention have low IC 50 values between 10'5 M and 10'8 M.

Compounds (I) are active after various modes of administration, particularly oral administration.

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

• «

The compounds are characterized by their melting points (Mp; * · *: ° C) (or their boiling points, Kp) and / or their NMR spectra recorded at 200 MHz in 30 DMSO and / or their optical rotations (aD) with • «-. ···. were measured at 25 ° C (unless otherwise stated).

ui ·· «t I (• · *« <· »· • · <i ·» »« • * · • · • »t ·) I • · .107048 20

The measured value of optical rotation depends on the amount of residual solvent present in the manufactured product.

Unless otherwise indicated, the term "cis-isomer-5i" or "trans-isomer" means that the isolated compound is a mixture of enantiomers, either in the cis-configuration or in the trans-configuration.

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

Example 1 N-Methyl-N-methoxycarbonylmethyl-5-bromo-3- (2-fluorophenyl) -1- (3,4-dimethoxyphenylsulfonyl) -3-hydroxy-2-indolinecarboxamide, cis isomer A) Methyl-N- bromoacetyl sarcosinate This compound was prepared according to TD Harris et al., J. Heterocyclic Chem. 18, 1981, 423.

B) 5-Bromo-2- (3,4-dimethoxyphenylsulfonamido) -2'-fluorobenzophenone 20 g of 2-amino-5-bromo-2'-fluorobenzophenone are heated at 85 ° C for 48 hours in 120 ml of dry pyridine in the presence of 20 g of 3,4-dimethoxyphenylsulfonyl chloride. The mixture is cooled, poured into ice-cold water, the solid is filtered, the solid is extracted with 1 L AcOEt, the organic phase is washed with water, hydrochloric acid (1 N), water and then brine. After drying over magnesium sulfate and evaporation of the solvent in vacuo, a solid is obtained which is recrystallized from a mixture of DCM and isopropyl ether.

30 m = 28 g

Sp. = 125-128 ° C.

. ···. C) 5-Bromo-2- [N- (3,4-dimethoxyphenylsulfonyl) -N- (Ν'-methyl-N '- (methoxycarbonylmethyl) carbamyl] -1-methyl)] amino-2'-fluorobenzof Enonone 21 107048 3.5 g of the compound prepared in Step B are dissolved in anhydrous DMF at 0 ° C using argon as a shielding gas and 250 mg of 80% sodium hydride are added; After 15 minutes, 4.85 g of the compound of Step A are added and the mixture is allowed to stir at RT for 12 hours. The reaction mixture is poured into water, the solid is filtered and then the solid is dissolved in AcOEt, the organic phase is washed with water and then with brine and the solvent is evaporated off under vacuum. The resulting oil is filtered on si-10 dirt eluting with a mixture of DCM and AcOEt (85/15, v / v). It is recrystallized from a mixture of DCM, isopropyl ether and MeOH.

m = 3.2 g

Sp. = 136-137 ° C.

D) N-Methyl-N-methoxycarbonylmethyl-5-bromo-3- (2-fluorophenyl) -1- (3,4-dimethoxyphenylsulfonyl) -3-hydroxy-2-indolinecarboxamide, cis isomer 3.2 g, from the previous step is dissolved in DCM (3 mL), 750 mg of DBU is added and the mixture is allowed to stir at RT for 24 hours. The reaction mixture is poured onto a silica column; eluting with a mixture of DCM and AcOEt (90/10, v / v) gives the product which. is a mixture of two isomers (cis and trans) of the expected compound. This product is triturated in a mixture of hexane and isopropyl 25 liters and the resulting solid filtered.

* ♦ · 107048 22 methoxyphenylsulfonyl) -3-hydroxyindoline, cis isomer and trans isomer A) 1-Bromoacetyl-4- (benzyloxycarbonyl) piperazine 5 A mixture of 22 g of 4-benzyloxycarbonylpiperazine and 10, 1 g of triethylamine in 200 ml of ether are cooled to 0 ° C. 20.2 g of bromoacetyl bromide in 100 ml of ether are added over 30 minutes and the mixture is allowed to return to RT. After 4 hours, the reaction mixture is washed with water, dried, concentrated and then chromatographed on silica. A mixture of DCM and AcOEt (95/5, v / v) elutes the expected compound, which is recrystallized from a mixture of DCM and isopropyl ether.

15 m = 9 g

Sp. = 100-101 ° C.

B) 2 ', 5-Dichloro-2- (3,4-dimethoxyphenylsulfonamido) benzophenone 5.6 g of 2-amino-21,5'-dichlorobenzophenone and 5 g of 3,4-dimethoxyphenylsulfonyl chloride are heated in pyridine at 100 ° C. At C overnight. The pyridine is evaporated to dryness, added, and water and extraction are performed with ethyl acetate. with a small amount of DCM. After washing more than once with water and drying over sodium sulfate, the extract is evaporated in vacuo and 7.7 g of the expected compound is recrystallized from a mixture of DCM and AcOEt.

: V: Sp. = 164 ° C.

: * · *: C) 2 ', 5-Dichloro-2- [N- (3,4-dimethoxyphenylsulfonyl) -N- (4-benzyloxycarbonyl-1-piperazinyl ...: carbonylmethyl) ] aminobenzophenone • · # ··· 2.3 g of benzophenone prepared in Step B are added to 10 mL of DMF and treated with 200 mg of 80%; sodium hydride in oil. After 30 minutes, 5.3 g of the compound prepared in Step A are added, and the mixture is stirred.

• I I

23 107048 is run for 60 hours at RT. The mixture is poured into water, the precipitate is filtered off, taken up in DCM, dried and then concentrated and chromatographed on silica. A mixture of DCM and AcOEt (90/10, v / v) elutes the desired product, which is crystallized from a mixture of DCM and isopropyl ether.

m = 2 g

Sp. = 173-175 ° C.

D) 2 - [(4-Benzyloxycarbonyl) -1-piperazinyl-10] carbonyl-5-chloro-3- (2-chlorophenyl) -1- (3,4-dimethoxyphenylsulfonyl) -3-hydroxyindoline, cis isomer and trans isomer 1 g of the compound obtained in the preceding step is suspended in 20 ml of methanol and 20 ml of any THF and treated with 75 mg of sodium methylate. After 2 hours, the mixture is neutralized by the addition of a small amount of carbonated ice, evaporated to dryness and then taken up in water; the mixture is then extracted with DCM, the extract is dried and concentrated. The crude product is chromatographed on alumina and the mixture of 20 DCM / AcOEt (80/20, v / v) elutes 2 isomers in a row.

The least polar isomer is recrystallized. Of a mixture of DCM and hexane. This compound is the cis isomer.

• 2 5 m = 2 6 2 mg

Sp. = 169-179 ° C.

• · ·

The polar isomer is recrystallized from a mixture of DCM and • isopropyl ether.

m: 200 mg 30. Sp. = 209-211 ° C.

Example 4 • ·. · * ·. 5-chloro-3- (2-chlorophenyl) -1- (3,4-dimethoxyphenylsulfonyl) -3-hydroxy-2- (1-piperazinyl)

[0163] 200 mg of the cis isomer prepared in the previous example is dissolved in 10 ml of ethanol and 5 ml of THF and hydrolyzed at 10% r.t. in the presence of Pd / C. After 30 minutes, the mixture is filtered over Celite R, the filtration fluids are concentrated and then chromatographed on silica. A mixture of MeOH and DCM (10/90, v / v) elutes the expected product, which is recrystallized from a mixture of DCM and isopropyl ether, m = 110 mg 10 Mp. = 230-233 ° C.

Examples 5 and 6 5-Chloro-3- (2-chlorophenyl) -1- (3,4-dimethoxoxy-phenylsulfonyl) -3-hydroxy-2-morpholinocarbonyl-indoline, cis isomer and trans isomer 15A) 2 ', 5-Dichloro-2- [N- (3,4-dimethoxyphenylsulfonyl) -N- (morpholinocarbonylmethyl)] aminobenzophenone 5 g of 2', 5-dichloro-2- (3,4-dimethoxyphenylsulfonamido) benzophenone treated with 350 mg of 80% sodium hydride in 30 mL of DMF at RT for 20 minutes.

4.5 g of morpholine bromoacetamide are added and the mixture is then stirred at RT for 48 hours. The mixture is poured into water, the precipitate is filtered off, it is dissolved in DCM, the solution is dried. and concentrated. The resulting product is recrystallized from a mixture of DCM and isopropyl ether. Sending; 5.4 g.

Sp. = 173-176 ° C.

• · · · · · · · B) 5-Chloro-3- (2-chlorophenyl) -1- (3,4-dimethoxy-4 · phenylsulfonyl) -3-hydroxy-2-morpholinocarbonylindole •: »: : line, cis isomer 30 g of the product obtained in the previous example is dissolved in a mixture of methanol (10 ml) and THF (20 ml) and stirred. 92 mg of sodium methylate at RT over 1 hour · *. The mixture is neutralized with ice-cold ice, the solvents are partially evaporated, the mixture is taken up in water, extracted with DCM and the extract is dried, concentrated and chromatographed on alumina. The mixture of DCM and AcOEt (70/30, v / v) elutes the least polar isomer which is recrystallized from a mixture of DCM and isopropyl ether.

5m = 215 mg: cis isomer

Sp. = 260-264 ° C.

C) 5-Chloro-3- (2-chloro-enyl) -1- (3,4-dimethoxy-phenylsulfonyl) -3-hydroxy-2-morpholinocarbonyl-indoline, trans isomer 10 Chromatography of the previous step is recovered by elution with a mixture of AcOEt and MeOH (90/10, v / v). Recrystallize from a mixture of DCM and isopropyl ether to give: 15 m = 513 mg: trans isomer

Sp. = 240-241 ° C.

Example 7 N-Methyl-N-carboxymethyl-5-bromo-3- (2-fluoro-phenyl) -1- (3,4-dimethoxyphenylsulfonyl) -3-hydroxy-2-indolinecarboxamide, cis isomer 200 mg the compound prepared in Example 1 is dissolved in 3 ml of MeOH and 1 ml of water containing. 13 mg sodium hydroxide. After stirring for 24 hours at RT, one drop of concentrated sodium hydroxide solution is added to quench the reaction, and after 15 minutes, the mixture is acidified to pH = 3 · · · *. · Adjusting potassium hydrogen sulfate solution. Water is added, the mixture is extracted with AcOEt and the extract is washed with water and dried: magnesium sulfate and the solvent evaporated in vacuo.

The product obtained is recrystallized from a mixture of DCM and isopropyl ether.

• ·. ···. Sp. = 206-208 ° C.

Examples 8 and 9 i <t:. 5-Chloro-3- (2-chlorophenyl) -1- (3,4-dimethoxyphenylsulfonyl) -3-hydroxy-2- (4-ethylcarboxylate) · · · · · · Thia 26 107048 piperidinocarbonyl) indoline, cis isomer, trans isomer A) Ethyl N-bromoacetyl-4-piperidinecarboxylate This product is prepared from ethyl 4-piperidinecarboxylate which is commercially available.

B) 2 ', 5-Dichloro-2- [N- (3,4-dimethoxyphenylsulfonyl] -N- (4-ethylcarboxylate piperidinocarbonylmethyl)] aminobenzophenone 108 g of 2', 5-dichloro-2- (3 4-Dimethoxyphenylsulfonamido) benzophenone is dissolved in 100 ml of DMF, followed by addition of 541 mg of sodium hydride, stirred for 30 minutes, followed by addition of 9.5 g of the compound of Step A and allowed to stir for 18 hours at RT. in vacuo, taken up in water, extracted with ethyl acetate and the extract dried and concentrated, the resulting oil is chromatographed on silica eluting with a mixture of AcOEt, DCM and hexane (40/10/50, v / v / v) The expected product is crystallized from ether.

20m = 3.5g

Sp. = 128 ° C.

C) 5-Chloro-3- (2-chlorophenyl) -1- (3,4-dimethoxy-phenylsulfonyl) -3-hydroxy-2- (4-ethylcarboxylate * Piperidinocarbonyl) -indoline, cis isomer, trans -iso- * "25 sea *

A mixture of 3.4 g of the compound prepared in the preceding step and 869 mg of DBU in 10 ml of chloro · V: Form is heated to 60 ° C for 18 hours. The reaction mixture is then filtered through an alumina column eluting with a mixture of 30 DCM and AcOEt (90/10, v / v) to give the cis · ...: isomer.

• ·. ···. m = 70.0 mg

Sp. = 110 ° C.

The pure ethyl acetate elutes the trans isomer.

«« 107048 27 ra = 610 rag Sp. = 187 ° C.

Examples 10 and 11 N-Methyl-N- (2-pyridylethyl) -5-chloro-3- (2-5 chlorophenyl) -1- (3,4-dimethoxyphenylsulfonyl) -3-hydroxy-2-indolinecarboxamide, cis isomer , trans isomer A) N- [2- (2-Chlorophenylcarbonyl) -5-chlorophenyl] -N- (3,4-dimethoxyphenylsulfonyl) glycic acid 10 a) 2 ', 5-Dichloro-2- (3,4 -dimethoxyphenylsulfonamido) benzophenone This compound is prepared in Example 2-3 in Step B.

b) 21,5-Dichloro-2- [N- (3,4-dimethoxyphenylsulfonyl) -N-benzyloxycarbonylmethyl] aminobenzophenone 172 g of the product prepared previously are dissolved in 800 ml of DCM and cooled to 0 ° C: a. 11.7 g of 80% sodium carbohydride are added in an increasing amount using nitrogen as a shielding gas, and after 30 minutes 256 g of benzyl bromoacetate are added and the mixture is allowed to stir for 24 hours at RT. The DMF is evaporated. the residue is taken up in water, extracted with DCM and the extract is dried and concentrated. The expected product is crystallized from iso-propyl ether and then recrystallized from a mixture of DCM and? * * Isopropyl ether.

O m = 136.5 g: V: m.p. = 102-104 ° C.

c) N- [2- (2-Chlorophenylcarbonyl) -5-chlorophenyl-30 l] -N- (3,4-dimethoxyphenylsulfonyl) glycic acid 50 g of the benzyl ester obtained above are dissolved, ···. 500 ml of AcOEt and 2.5 g of 5% Pd / C are added - using nitrogen as a shielding gas. The solution is vigorously stirred and a stream of hydrogen is introduced for 5 hours. At the end of hydrogenation, the product crystallizes. The mixture is filtered over Celite, the cake is washed with plenty of hot DCM and then the organic phase is concentrated. The expected product crystallizes and is then recrystallized from a mixture of DCM and isopropyl ether.

5m = 33.7g

Sp. = 177-178 ° C.

B) 2 ', 5-Dichloro-2- [N- (3,4-dimethoxyphenylsulfonyl) -N- (N' - (2- (2-pyridyl) ethyl) -N "-methyl) carbamoylmethyl] aminobenzophenone 10 Place 2 g of the acid prepared in Step A in 30 ml of DCM and add 1.13 g of 2- (2-methylaminoethyl) pyridine followed by 844 mg of triethylamine and finally 1.92 g of BOP and the mixture is allowed to stir for 18 hours at RT, the mixture is taken up in water, the organic phase is separated, washed with brine, dried and concentrated, chromatographed on silica, eluting with a mixture of DCM and MeOH (95). / 5, volume / volume).

20 m = 2 g

Sp. = 150 ° C.

C) N-Methyl-N- (2-pyridylethyl) -5-chloro-3- (2-chlorophenyl) -1- (3,4-dimethoxyphenylsulfonyl) -3-hydroxy-2H-hydroxy-2-indolinecarboxamide A mixture of 1.7 g of the product obtained in the preceding step and 442 mg of DBU in DCM is heated at 11 ° C to 55 ° C for 18 hours. The reaction mixture is chromatographed ali - • · V, J with min oxide A mixture of AcOEt and DCM (40/60, v / v) elutes the cis isomer: 30 m = 410 mg

Sp. = 191 ° C.

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

• · · 1 «29 107C48

Example 12 2- (4-Carboxypiperidinocarbonyl) -5-chloro-3- (2-chlorophenyl) -1- (3,4-dimethoxyphenylsulfonyl-11) 3-hydroxyindoline, cis isomer 5,500 mg of cis-prepared from Example 9 the isomer is introduced into 5 ml of methanol in the presence of 48 mg of sodium hydroxide in 1 ml of water. After stirring for 18 hours, the mixture is poured into water, acidified with dilute hydrochloric acid, then extracted with DCM and the extract is dried and concentrated. The resulting solid is purified by chromatography on silica eluting with a mixture of DCM and MeOH (95/5, v / v) and then the product obtained is crystallized from a mixture of DCM and isopropyl ether, m = 250 mg 15 Mp. = 150 ° C.

Examples 13 and 14 N-Methyl-N- (1-methyl-4-piperidinyl) -5-chloro-3- (2-chlorophenyl) -1- (3,4-dimethoxyphenylsulfonyl) -3-hydroxy-2- indolinecarboxamide, cis-isomer and trans -isomer A) 2 ', 5-dichloro-2- [N- (3,4-dimethoxyphenylsulfonyl) -N- (N-methyl-N' - (methyl-4- piperidinyl) carbamoylmethyl] aminobenzophenone «· · 2 g of Example 10-11, Step A:" 25 Acids in 50 mL of DCM are mixed with 650 mg of 4-methyl-1-methylamino-1-methylpiperidine. in the presence of »·· 1.90 g B0P. After stirring for 2 hours at RT, the organic phase is washed with carbonated water, dried and concentrated, then the residue is chromium-30. is chromatographed on silica eluting with a mixture of DCM and MeOH (90/10, v / v) to give 1.2 g of the expected product.

- m.p. = 165-166 ° C.

(B) N-Methyl-N- (methyl-4-piperidinyl) -5-chloro. - 3- (2-Chlorophenyl) -1- (3,4-dimethoxyphenylsulfonyl) -3-hydroxy-2-indolinecarboxamide, cis isomer and trans isomer 5 650 mg of the product obtained in the preceding step are treated overnight with 100 mg: 11a sodium methylate in 5 ml methanol. Ice carbonate is added, the solvent is evaporated / the residue is taken up in carbonated water, extracted with DCM and the extract is dried and concentrated and then chromatographed on silica. A mixture of methanol and DCM (5/95, v / v) elutes 2 isomers in a row. Each is then recrystallized from a mixture of DCM and isopropyl ether.

the trans isomer is less polar at these conditions, m = 205 mg

Sp. = 181 ° C. cis isomer: m = 150 mg

Sp. = 97 ° C: Contains 0.25 M isopropyl ether. Examples 15 and 16 5-Chloro-3- (2-chlorophenyl) -1- (3,4-dimethoxyphenylsulfonyl) -3-hydroxy-2- [4-methyl-1-pipe-. racinylcarbonyl] indoline, cis isomer and «"; trans isomer • 25 ') 2', 5-dichloro-2- [N- (3,4-dimethoxyphenylsulphonyl) -N - ((4-methyl-1 - piperazinyl) carbamoylmethyl • (ii) aminobenzophenone • This compound is obtained by the action of N-methylpiperazine on the acid-3 O prepared in Example 10-11.

Sp. = 165-167 ° C.

B) 5-Chloro-3- (2-chlorophenyl) -1- (3,4-dimethoxy-phenylsulfonyl) ············· 107048 31 B) -3-Hydroxy-2- [4-methyl-1-piperazinylcarbonyl] indoline, cis isomer and trans isomer 5 The compound of the previous step is cyclized by proceeding as in Example 12-13. The 2 isomers formed are separated by chromatography on alumina. A mixture of DCM and AcOEt (75/25, v / v) elutes a less polar product: the cis isomer, which is recrystallized from a mixture of DCM and isopropyl ether.

Sp. = 120 ° C: Contains 0.25 M isopropyl ether. The mixture of DCM and MeOH elutes the most polar compound, the trans isomer, which is then recrystallized from methanol.

15 M.p. = 189 ° C.

Examples 17 and 18 N-Isopropyl-N-methoxycarbonylethyl-5-chloro-3- (2-chlorophenyl) -1- (3,4-dimethoxyphenylsulfonyl) -3-hydroxy-2-indolinecarboxamide, cis-isomer-20 and trans. isomer A) N-isopropyl-N- (methoxycarbonylethyl) bromoacetamide. 90 g of isopropylamine are added dropwise to a solution of 130 g of methyl acrylate in 300 ml of methanol cooled to -10 ° C. After 72 hours at RT, the mixture is evaporated and then the residue is distilled. The resultant oil (168.3 g) is methyl 3- [(N-isopropyl) aminopropionate.

: Kp. = 73-78 ° C at 15 mm Hg.

29 g of the resultant compound in 100 ml of DCM are mixed with 20.2 g of bromoacetyl bromide. ··· in 100 ml of DCM at 0 ° C. After 12 hours at RT, the solvent is evaporated, the residue is taken up in butter / water, extracted with ethyl acetate and the extract is dried. t «m •« «· 107048 32 and concentrated. The resulting oil is used as is in the following step.

B) 2 ', 5-Dichloro-2- [N- (3,4-dimethoxyphenylsulfonyl) -N- (Ν'-isopropyl-N'-methoxycarbonylethyl) -5-carbamoylmethyl] aminobenzophenone This compound is obtained according to the usual method the product prepared in Step A with 2 ', 5-dichloro-2- (3,4-dimethoxyphenylsulfonamido) -benzophenone in the presence of sodium hydride.

10 M.p. = 135-137 ° C (recrystallization: DCM / isopropyl ether).

C) N-Isopropyl-N-methoxycarbonylethyl-5-chloro-3- (2-chlorophenyl) -1- (3,4-dimethoxyphenylsulfonyl) -3-hydroxy-2-indolinecarboxamide, cis isomer and 15 trans isomer This product is obtained by cyclization of the compound prepared in Step B in the presence of DBU, the cis isomer is separated by chromatography on alumina eluting with a mixture of DCM and AcOEt (90/10, v / v). The product is then crystallized from a mixture of AcOEt and hexane.

Sp. = 153-155 ° C.

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

• «* '' 25 M.p. = 182-185 ° C.

* Examples 19 and 20 • · »* ... · N-Methyl-N-methoxycarbonylmethyl-5-chloro-3- (2- • · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ♦ · · ί # ί: 3-Hydroxy-2-indolinecarboxamide, cis isomer 30 and trans isomer The 2 isomers of this compound are prepared according to example · 1 ·. cat 1 according to the method described. They are separated by chromatography on alumina. A mixture of DCM and AcOEt (80/20, v / v) elutes the cis isomer.

This is crystallized from a mixture of DCM and isopropyl ether in the form of a white powder containing 0.25 mol of isopropyl ether. It is converted to foam by heating under vacuum.

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

the trans isomer elutes with pure AcOEt. It is recrystallized from a mixture of DCM and isopropyl ether.

Sp. = 176-178 ° C.

The NMR spectrum of the 10 trans isomers (Example 20) is shown in Figure 2.

Examples 21 and 22 N-Methyl-N-carboxymethyl-5-chloro-3- (2-chlorophenyl) -1- (3,4-dimethoxyphenylsulfonyl) -3-hydroxy-2-indolinecarboxamide, cis isomer and the trans isomer These compounds are each prepared from the compounds described in Examples 19 and 20 according to the procedure described in Example 8.

20 cis isomers: m.p. = 220-222 ° C after recrystallization from a mixture of DCM, isopropyl ether and MeOH.

. trans isomer: m.p. = 222-225 ° C after recrystallization from a mixture of DCM and iso-propyl ether.

V 1 * "25 Examples 23 and 24 * 4 * N-Methyl-N-carbamoylmethyl-5-chloro-3- (2-chloro ··· triphenyl) -1- (3,4-dimethoxyphenylsulfonyl) - 3-Hydroxy-2-indolinecarboxamide, cis-isomer and? · ·:: Trans isomer 30. Both isomers are obtained from the corresponding isomer of the acid prepared in Example 21-22.

. ···. 605 mg of the trans isomer of the acid obtained in the previous example is dissolved in 10 ml of DCM and 435 mg • 1 L of BOP and 260 mg of DIPEA are added. After 5 minutes at RT, 35 ml of 20% aqueous amine is added with vigorous stirring and the mixture is allowed to stir for 4 hours. Sodium carbonate solution is added and the mixture is then extracted with DCM. The organic phase is washed successively with water, sodium hydrogen sulfate solution 5 and water and then dried over magnesium sulfate. After evaporation, the residue is chromatographed on silica gel and eluted with a mixture of AcOEt and MeOH (95/5). The product obtained is crystallized twice from a mixture of DCM and EtOH at 0 ° C.

10 M.p. = 236 ° C.

The NMR spectrum of the trans isomer (Example 23) is shown in Figure 3.

Using the same procedure, the cis isomer is prepared.

The expected product is crystallized from a mixture of DCM and isopropyl ether. The micronized compound dried in vacuo at 70 ° C for 8 hours contains 0.25 moles of isopropyl ether.

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

Examples 25 and 26 5-Chloro-3- (2-chlorophenyl) -1- (3,4-dimethoxy-phenylsulfonyl) -3-hydroxy-1- (4-hydroxy-1-piperidinyl) carbonylindoline, trans Isomer This compound is prepared from N- [2- (2-chlorophenyl- (carbonyl) -5-chlorophenyl] -N- (3,4-dimethoxyphenylsulphenyl) -phenyl) glycic acid as described in Example 11. - 12 «· in step A.

The procedure is then carried out as in Example 11 for addition of 4-hydroxypiperidine in the presence of BOP and triethylamine. The resulting product is then cyclized according to a conventional method in the presence of DBU.

The .2 isomer is separated by chromatography on alumina.

A mixture of DCM and MeOH (99/1, v / v) elutes the cis isomer.

«·« · • 107048 35

The product is crystallized from a mixture of DCM, hexane and MeOH and then the resulting solid is triturated in a mixture of DCM and hexane to give an amorphous powder.

The 5 cis isomer is characterized by its NMR spectrum at 388 ° K.

1-1.8 ppm: m: 4H: CH2 at piperidine positions 3 and 5 2.8 to 3.65 ppm: m: 5H: CH2 at piperidine positions 2 and 6 and CH at position 4 3.75 ppm: 2s: 6H: 2 OCH3 4.15 ppm: d: 1H: OH in piperidine 5.45 ppm: s: 1H: CH (indoline) 6.1 ppm: s: 1H: OH indoline 6.8 to 7.6 ppm: m: 10H: H aromatic 15 DMSO : 2.4 ppm DOH: 2.75 ppm A mixture of DCM and MeOH (97/3, v / v) elutes the trans isomer which is recrystallized from a mixture of DCIV and isopropyl ether.

20 M.p. = 232-234 ° C.

Syntheses in the (L) -proline Series: Examples 27, 28, 29 and 30.

Examples 27 and 27a 5-Chloro-3- (2-chlorophenyl) -1- (3,4-dimethoxy- (2'-yl) -2,5-phenylsulfonyl) -3-hydroxy-2 - [(2S) - (2-methoxy) - • · · * (carbonyl) pyrrolidinocarbonyl] -indoline (cis isomers: 2 compounds) • · ♦ • ♦ A) Methyl (L) -N- (bromoacetyl) prolinate • ♦ *. ·. * 20 g of triethylamine and 20 g of bromoacetyl bromide · ··· ί: 30 in 30 ml of DCM are successively added to a solution of 16.7 g of methyl (L) -prolinate hydrochloride ♦; ♦♦♦ in 20 ml of DCM, while maintaining the temperature at -5 ° C and then stirring the mixture at RT for 24 hours. Water is added and the mixture is washed with KHSO4 solution, water, sodium bicarbonate solution and water and then dried over magnesium sulfate. After evaporation, an oil is obtained which is dried in vacuo. This oil, which is pure by TLC, is used as is in the next step.

5 B) 2 ', 5-Dichloro-2- [N- (3,4-dimethoxyphenylsulfonyl) -N - ((2S) - (2-methoxycarbonyl) pyrrolidinocarbonylmethyl)] aminobenzophenone 4.66 g of 2 ', 5-dichloro-2- (3,4-dimethoxyphenylsulfonamido) benzophenone is dissolved in 40 ml of anhydrous 10 DMF using argon as the shielding gas at 0 ° C, 340 mg of 80% sodium hydride are added and then After 30 minutes, 6.5 g of the compound obtained in Step A. After 4 days at RT, the mixture is poured into water, extracted with AcOEt, washed with water, brine, and then dried over magnesium sulfate and evaporated in vacuo. The solid, containing a small amount of the brominated derivative used as starting material, is eluted with a mixture of DCM and AcOEt (85/15, v / v) on silica gel chromatography. The batch is recycled from a mixture of DCM and isopropyl ether.

m = 1.2 g

Sp. = 141-142 ° C

[α] 25 D = -43.7 ° (c = 1; MeOH / THF: 8/2; v / v). Anal. Calcd. for C20H54.81H: 4.44 N: 4.41 *. found: 54.40 4.54 4.55 C) 5-Chloro-3- (2-chlorophenyl) -1- (3,4-dimethoxy- · * ··· 1 phenylsulfonyl) -3-hydroxy-2- [(2S) - (2-Methoxycarbonyl-1,1,1,1] pyrrolidinocarbonyl] -indoline (cis isomer) 1.1 g of the compound obtained in the preceding step is heated in 4 ml of methylene chloride for 24 hours with a single charge. ; with the equivalent DBU. HPLC analysis of the batch shows the expected 4 isomers. After 24 hours, "·, the reaction mixture is poured onto an alumina column, pre-equilibrated with DCM / AcOEt 1 x 3570 (90/10, v / v) and eluted with DCM / AcOEt (90). / 10, v / v to 70/30, v / v) 510 mg of a mixture of 2 least polar compounds in a ratio of 4/1 (measured by HPLC) are obtained.

5 ° C) Two successive crystallizations from a mixture of DCM and isopropyl ether when cold yield the most important compound.

m = 180 mg? 15 = -247 ° (c = 0.4, chloroform) 10 M.p. = 187-190 ° C.

2 °) Crystallization base solutions of the above compound are chromatographed on alumina eluting with a mixture of DCM and AcOEt (85/15; v / v). The former is thus separated from the second, the latter is dissolved in as little DCM as possible and then precipitated by the addition of as little hexane as possible.

(? 6 = + 136 ° (c = 0.24, chloroform)

Example 28 2 - ((2S) -2-Carboxypyrrolidinocarbonyl) -5-chloro-3- (2-chlorophenyl) -1- (3,4-dimethoxyphenylsulfonyl) -3-hydroxyindoline, cis isomer 430 mg Dissolve the compound prepared in Example 27 in 6 ml of methanol, add 41 mg of sodium hydroxide. oxide in 1 ml of water and the mixture is stirred for 24 hours at 25 ° C. The mixture is acidified to pH 3 with a few

t II

'. dropwise with a solution of potassium hydrogen sulfate and extracted with ethyl acetate. The extract is washed with water and then dried over magnesium sulfate. Chromatography is performed on a silica column initialized with a mixture of DCM and pentane (80/20, v / v), the unreacted ester elutes the expected acid which is then recrystallized from a mixture of DCM and ·; ··· isopropyl ether.

Sp. = 232-234 ° C

α d = -254 ° (c = 0.3, chloroform).

• ♦ φ «107048 38

Examples 29 and 29a 2 - ((2S) -2-Carbamoylpyrrolidinocarbonyl) -5-chloro-3- (2-chlorophenyl) -1- (3,4-dimethoxyphenylsulfonyl) -3-hydroxyindoline (cis isomers: Compounds) 230 mg of the compound prepared in Example 28 are dissolved in 5 ml DCM, 50 mg DIPEA and then 165 mg BOP are added and the mixture is left for 5 minutes at RT. The mixture is cooled in an ice bath and then a stream of ammonia gas is bubbled through it for 1 minute and after 15 minutes for an additional 1 minute. Water and then a large amount of ethyl acetate are added to provide two phases. The organic solution is washed with sodium carbonate solution, water, potassium hydrogen sulfate solution, water and then brine. After drying, the residue is chromatographed on silica, eluting with a mixture of DCM and MeOH (93/7, v / v). The resulting product is triturated in a mixture of DCM, isopropyl ether and hexane. It contains 1/3 mole of isopropyl ether.

[Α] 20 D = -189 ° (c = 0.23, chloroform).

The compound of Example 29 may be prepared according to another method.

A) 2 ', 5-Dichloro-2- [N- (3,4-d-methoxyphenylsulphonyl) -N - ((2S-2-carbamoylpyrrolidinocarbonylmethyl) -1,25 l)] aminobenzophenone • · • Dissolve 33.9 g of the acid prepared in Example 10 - 11, Step A in 300 ml of chloroform, add 15 g · · * ··· 1 thionyl chloride and reflux for 1.5 hours. Evaporate to dryness, then recover the residue to? 30 V DCM and evaporate again, dissolve in 300 ml DCM, cool to 0 ° C and add »1: 10,5 g ( L) -proline amine hydrochloride and then 18 g of DIPEA in 20 ml of DCM is added slowly so that the temperature of the reaction mixture is not allowed to exceed 3 ° C.

»·« · «· ·« »· 107048 39

After one night at RT, the reaction mixture is washed with sodium bicarbonate (twice) and then potassium hydrogen sulfate (twice), the reaction mixture is dried and concentrated. The resulting crude product is dissolved in as little DCM as possible and added dropwise to isopropyl ether (1.2 L) with stirring. After stirring for 2 hours, the resulting precipitate is filtered and then dried in vacuo for 6 hours at 60 ° C. 42 g are recovered.

[Α] 25 D = -40.8 ° (c = 1.007, chloroform).

B) 2 - ((2S) -2-Carbamoylpyrrolidinocarbonyl) -5-chloro-3- (2-chlorophenyl) -1- (3,4-dimethoxyphenylsulfonyl) -3-hydroxyindoline (cis isomers: 2 compounds) 15 g of the product prepared in the preceding step are dissolved in 50 ml of methanol. The solution is cooled to -10 ° C; 1.35 g of DBU are added and the mixture is kept for 60 hours at -10 ° C. The compound is crystallized; it is filtered (cis compound 1). The crystallization fluids are neutralized with KHSO4 and the mixture is evaporated to dryness. It is recovered in water, extracted twice with DCM, and the extracts are dried and concentrated. The crude product obtained is chromatographed on silica eluting with a mixture of AcOEt and DCM (28/72, v / v). A mixture is obtained which is dissolved in

4 I I

!! ' 25 very small amounts of methanol when hot; insoluble * | the material is filtered, then the liquids are placed overnight at '-4 ° C and cis compound 2 crystallizes.

m = 1.25 g • ♦ · · ·, · α = -196 ° (c = 0.351; chloroform).

• · ·:.! 1 H NMR analysis shows the presence of one mole of MeOH per mole of product. Recrystallization of the product from ethanol allows removal of the solvent in the crystals.

] · 'Mp. = 154-162 ° C

i V 35 ai5 = -204 ° (c = 0.3; chloroform) »1 t 4 4 4 I» • ·> · • · · · · · «f« «•« 40 1070.46 α ^ 5 = -131 ° (c = 0.27; chloroform / methanol: 8/2: v / v) This compound, except for the solvent, is identical to the compound prepared in the first method of this example.

The compound which is crystallized in step B) above and is called the cis compound 1 is recrystallized from methanol.

Sp. = 190 ° C

10 α D = + 115 ° (c = 0.3, chloroform)

Example 30 5-Chloro-3- (2-chlorophenyl) -1- (3,4-dimethoxyphenylsulfonyl) -3-hydroxy-2 - [(2S) -2- (hydroxymethyl) pyrrolidinocarbonyl] -indoline, cis -iso-15-mers A) 2 ', 5-Dichloro-2- [N- (3,4-dimethoxyphenylsulfonyl) -N- (2- (hydroxymethyl) pyrrolidinocarbonylmethyl)] aminobenzophenone This compound is obtained by reacting (L) -prolinol is reacted with the acid prepared in Step A of Example 10-11 according to the usual procedure.

B) 5-Chloro-3- (2-chlorophenyl) -1- (3,4-dimethoxyphenylsulfonyl) -3-hydroxy-2 - [(2S) -2- (hydroxymethyl) -,. pyrrolidinocarbonyl] indoline, cis isomer "" "1.5 g of the compound of the preceding step is cyclized. in the presence of 380 mg of DBU in 2 ml of DCM. After 3 days at RT, 1 ml of · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · s · s DCM is added and the mixture is heated at 40 ° C overnight. is detected by TLC on silica gel with AcOEt as eluent.

The least polar fraction is eluted on a chromatographic silica gel with a mixture of DCM and AcOEt (60/40 -1 · "·. 80/20, v / v). The chromatography is then carried out on alumina. ♦ 1 · · · 1 35 DCM: MeOH (99/1 v / v) The fraction obtained is · · · · 107048 41 homogeneous by TLC The product is recrystallized three times with DCM and isopropyl ether. The expected product is obtained with an HPLC purity of greater than 99% m = 155 mg

5 M.p. = 194-197 ° C

[α] 25 D = -195 ° (c = 0.2, chloroform).

Syntheses in the (D) -proline Series: Example 31.

Example 31 5-Chloro-3- (2-chlorophenyl) -1- (3,4-dimethoxy-10-phenylsulfonyl) -3-hydroxy-2 - [(2R) -2- (methoxycarbonyl) pyrrolidinocarbonyl] indoline, cis isomer A) 21,5-dichloro-2- [N- (3,4-dimethoxyphenylsulfonyl) -N - ((2R) -2- (methoxycarbonyl) pyrrolidinocarbon-15-ylmethyl)] aminobenzophenone This compound is obtained from Example 10- 11 of the acid prepared in Step A (3 g) to which 1.2 g of methyl (D) -prolinate and 2.8 g of BOP in 10 ml of DCM are added in the presence of 1.15 g of triethylamine. The mixture is allowed to stand for 1 hour at RT and then diluted with DCM, the organic phase is washed with sodium carbonate and potassium hydrogen sulfate, dried and concentrated. The crude product is chromatographed on silica eluting with DCM and

AcOEt (95/5, v / v). The resulting product is then recrystallized from DCM and isopropyl ether. blade.

Sp. = 140-141 ° C.

♦ ♦♦ * * ... * otp5 = + 28.5 ° (c = 0.27; chloroform).

· · * · · · · · B) 5-Chloro-3- (2-chlorophenyl) -1- (3,4-dimethoxymethylsulfonyl) -3-hydroxy-2 - [(2R) ) -2- (Methoxycarbonyl) pyrrolidinocarbonyl] -indoline, cis isomer; ··· 1.5 g of the above compound is refluxed in 5 ml of DCM overnight in the presence of 360 mg of DBU. The mixture is chromatographed on alumina. Mixture of DCM and AcOEt (35/5, 95/5, v / v) elutes the least polar fraction (m / 300 mg) which is recrystallized. twice from a mixture of DCM and isopropyl ether.

Sp. = 186-188 ° C

[α] 25 D = + 245 ° (c = 0.4, chloroform).

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

Examples 32 and 32a N-methyl-N-methoxycarbonylmethyl-5-chloro-3- (2-chlorophenyl) -1- (4-ethoxyphenylsulfonyl) -3-hydroxy-2-indolinecarboxamide, trans isomer and cis isomer A) 2 ', 5-dichloro-2- [N- (4-ethoxyphenylsulfonyl) -N- (Ν'-methyl-N' - (methoxycarbonylmethyl) carbamoylmethyl] aminobenzophenone 5.7 g of 2 ', 5-dichloro-2- (4-ethoxyphenylsulfonamido) -benzophenone are dissolved under argon in 40 mL of DMF and 400 mg of 80% sodium hydride at 0 ° C are added; After 15 minutes, 4.3 g of methyl N- (bromoacetyl) sarcosinate are added, after 48 hours, the expected product is extracted in the usual way and then purified by chromatography on silica eluting with a mixture of DCM and AcOEt (90/10, v / v) and recrystallize from a mixture of DCM and isopropyl ether.

Sp. = 158-160 ° C

B) N-Methyl-N-methoxycarbonylmethyl-5-chloro-3- • * • · · *. (2-Chlorophenyl) -1- (4-ethoxyphenylsulfonyl) -3-hydroxy-2-indolinecarboxamide, trans isomer 1 g of the compound obtained in the preceding step. is added to 4 mL of DCM and treated over 90 minutes at 30 RT with 312 mg TBD. Potassium hydrogen sulfate solution is added, DCM is evaporated in vacuo, the mixture is extracted with ····· AcOEt and the extract is washed and dried over magnesium sulfate. The expected product is obtained by chromatography on silica gel eluting with a mixture of DCM and AcOEt (90/10, v / v 35 v / v).

• · »« 107048 43 m = 590 mg

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

C) N-Methyl-N-methoxycarbonylmethyl-5-chloro-3-5 (2-chlorophenyl) -1- (4-ethoxyphenylsulfonyl) -3-hydroxy-2-indolinecarboxamide, cis isomer 2.96 g. the resulting compound is suspended in 20 ml of methanol and 10 ml of THF; 100 mg of sodium methylate are added and then the mixture is left for 10 hours in a refrigerator. Water is added, the mixture is neutralized with potassium hydrogen sulfate solution and a portion of the methanol is evaporated in vacuo. After extraction with AcOEt, the residue is chromatographed on alumina and then eluted with a mixture of DCM and AcOEt (80/20, v / v). 15,850 mg of the expected product are obtained, which is recrystallized from a mixture of DCM and isopropyl ether.

The NMR spectrum is shown in Figure 6.

Using procedures similar to those described above, intermediate compounds (VI) were prepared for the synthesis of compounds (I) of the invention.

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

The prepared compounds (I) are described in Table 2 below.

1 25 • · * · · * 'yy! 7 "> n-ch2-con S02 R7 ΰ Λ

rj 'O

• · • '· • · 1 ♦ »V · f c» · 44 107048

table 1

R'i R's il ': .n ^ R6 Sp. (° C) or IR

5 Solvent

Br-3,4-CH 3 O-FH 3 82-83 -N-CH 2 CO 2 CH 2 C 6 H 5 DCM / isopropyl ether

Cl-3,4-CH2 O Cl-CH3 164-166 -N-CH2CH2CO2CH3 DCM / isopropyl ether

Cl-3,4-CH30 Cl-CH3 ft 128 -N-CH2CH2N-E: DCM / isopropyl ether 15 Cl-3,4-CH30 Cl-ft 105 -N-CH2CH2CO3CH3 DCM / isopropyl ether

Cl-2,4-CH30 Cl- ^ n.CO CH c6H3 142'143

\ 1 MeOH

20 i ca, 0. 3,4- = ¾ Cl- .i.CH2CH2COiCH3 18 <l>

Cl-3 p4-CH30 Cl-iPentyl 85 -n-ch2ch2co2ch3 isopropyl _____ ether / DCM__

• Br '3,4-CH 3 Cl- -N-CH 2 CH 2 CO 2 CH 3 IR

m - 1 I I I I II Il II. .11 --------- - - • * ... Cl- 3,4-CH30 Cl- / \ 199

N S

V '. DCM / isopropyl:: _____ ether 30 Cl- 3,4-CH30 Cl- * 135 N-CH2CO2CH3 isopropyl ether / DCM / ___ AcOH___ 1

Cl-3,4-CH-10 Cl-Pr 113

.. I

: · ': N-ch, ch, -co, ch, DCM / isopropyl 35 _ [____ 23 ether_ • »•» • «« 107048 45

Cl-3,4-CH30 Cl-ft 160 -N-CH3-CO3 CH3 isopropyl ether 5 Cl-3,4-CH30 Cl-NH-CO3-tBu 197-198

Cl-3,4-CH30 Cl- ~ NvJ I (3) 3 - ^ - co2ch2c6h3 I___10 IR (1) (DCM) 1740 cm'1 sharp 1680 cm'1 wide IR (2) (DCM) 1735 cm'1 sharp 1660-1680 cm-1 distributed (3) This compound is characterized by its optical rotation 15: α D 5 = -36.8 ° (c = 0.44, chloroform).

Table 2 20 T ~ 0: 25 ^ F con ^ * 6 1 * · * SO ^ R-t S Λ

RV

• · · ^ * · ttl::: 30

For each compound of formula (I) having the substituents R 13, R 15, R 12 and NR 6 R 7 in the table below, the cis isomer followed by the trans: V 35 isomer unless otherwise indicated.

*> 1 «· •« «• * • t» • · t · «• l I X« • 4 107048 46

Be- R'x R'j R'2 R6 Sp. (° c) or NMR

character -N

nd Solvent _____K7____ 33 Br- 3,4-CH30 F-CH3 .87-95 5 34 -N-CH2CO2CH2C6H5 nmr 35 100-103 36 Cl- 3,4-CH30 ClfH3 154-157 -N-CH2CH2CO2CH3 DCM / isopropyl ether 10 37 cis Cl- 3,4-CH 3 O-Cl 140-44 -n-ch 2 ch 2 CO 2 H DCM / isopropyl ether 38 Cl-3,4-CH 3 O Cl-CH 3 ^ 222-225 mixture -N-CH 2 CH 2 N- Et DCM / isopropyl ether 15 ----- = ---

39 Cl- 3,4-CH30 Cl- Et NMR

40 '-n-ch2ch2co2ch3 ^ 41 Cl-3,4-CH30 Cl- Et 166 -M-CH2CH2CO2H DCM / isopropyl-20 cls ether 42 ΓΓ / CH3 119 43 Cl-3,4-CH30 Cl- -N γΝν AcOEt / isopropyl- \ - {ch3 lieett ^^ i

'' 'MeOH

25______ 'ί' * 44 Cl- 3,4- CH30 Cl- 9H2C6HJ CH 179; ***; cis -N-Ch2ch2nCch3 DCM / isopropyl-_____-ether_____ · 45,109 V * "" - -io / n / d / DCM / isopropyl-30 Cl-3,4-CH30 Cl- -N N-CH2CO2Et ether 46 '196 * DCM / isopropyl ·. ···. ether__

I 4 I

47 134 (iPr) 20 48 Cl-2,4-CH 3 Cl--N M-CO 2 CH, c 6 Hj 195 DCM-isopropyl ether 47 107046 49 Cl- 3,4-CH 3 O Cl- Et 236 5 cis -N- CH2CH2CONH2 isopropyl ether 50,154 isopropyl-51 CH3 3,4-CH3 Cl- Et ether -N'CH2CH2CO2CH3 g7 isopropyl ether-52 Cl-2,4-CH30 Cl- / \ 194

-K NH

- / - MeOH / isopropyl-C1S______-ether 53 Cl- 3,4-CH30 Cl-iPentyl 195 15 C8 -S-N-ch2ch2co2ch3 isopropyl -______ ether / DCM_ 54 138-140 55 »r-2,4-GH30 Cl-SS "11" -N-CH 2 CH 2 CO 2 CH 3 140 20 Isopropyl-______-ether 56-242-245 57 urea C 1 DCM / isopropyl-57 C 1 * 3,4-CH 3 O-Cl ether-N- / 225 'MeOH / isopropyl- 1 · 25 lieeters «· · · · * * Cl- 2,4- CH30 Cl- 228 V?” ^ OH / IJOJCOKW-::: 58 a 221 * ·

DCM / MeOH

30 ------ 131-134 ί 59 ci- 3 4 -CHO Cl- & DCM / isopropyl. * ··. I '3 -n-ch2ch2ch2co2ch3 ether / hexane •,.,' 159a: v. I 121 '·'! DCM / ether / 35 µl hexane • »48 107048 5 162-166 60 Cl-3,4-CH30 Cl-DCM / isopropyl-61 n-ch2ch2co2ch3 ethereal DCH / isopropyl ether / hexane 10 62 Cl-3,4-CH30 Cl-Pr 176 63 -N-CH, C09CH, isopropyl

1 1 J ether / DCM

NM

64 Cl- 3,4-CH30 Cl- 148 15 p isopropyl

-N-CH 2 CH 2 CO 2 CH 3 ether / DCM

65 2 2 2 3 122 Isopropyl

ether / DCM

66 Cl- 3,4-CH30 Cl- ψ NMR

20 67 N-CH 2 CO 2 CH 3 168 isopropyl-______-ether 68 Cl- 3,4-CH 3 O Cl-j Bu 179-182. :: cis N-CCH 2 CO 3 H DCM / isoisopropyl !! '_____ · ___ ether_; '· 25 69 Cl- 3,4-CH30 Cl- f 139 139 cls N-CH2CO2H DCM / isoptopyl ______ether__ • 70 Cl- 3,4 -CH3Q Cl- fr 130 cis n-ch2CO2k isopropyl * 20o ether ....: 71 Cl- 3,4-CHjO Cl- ft 136 • · N- (CH,) 3C0, H. . .

... cis 232 DCM / isopropyl »t» e »: ether« <- - --- --- - ------ 72 Cl- 3,4- ch3o Cl- ft 135. ··. 35 cis N-CH 2 -CONH 2 DCM / isopropyl-1 · .1 ____ ether 19 4907048 I --- 1 73 Cl- 3,4 -CH 30 Cl- 197 MHco cfCH ϊ MeOH / isopropyl-Nv> nhco 2 C (ch 3) 3 letter 74 V 211 i

5 HeOH

75 Cl-3,4-CH30 Cl-n H1 N2 NMR

cis / 10 7δ C1 '3,4-CH30 Cl-j-v Fumarate cis -NH2 152-156 DCM / isopropyl-___.___ ether ** 76a Cl-3,4-CH30 Cl-137-N isopropyl - 15 CO 2 CH 2 C 6 H 5 ether / MeOH / 176H-hexane 183-185 hexane 20 - Example 34 Analysis: Calculated: C: 55.54 H: 4.24 C: 3.93 Found: 55.72 4.57 3.83 NMR spectra at 200 MHz (DMSO: 2.5 ppm):.:: - Example 34: Figure 5

I I

'· 25 - Example 38 ·: 1 ·: 0.7 - 1.1 ppm: m: 6H, 2 CH 3 (Et) 2-4 ppm: m: 17H: 2CH 2 (Et), 2 CH 2 -N, N -CH3.2OCH3 · · · 5.2 - 5.7 ppm: 3s: 1H: H (indoline) • · 6.2 - 8.2 ppm: m: 11H: OH + aromatic • · · 30 - Example 39 0.3 - 1.2 ppm: m: 3H: CH 3 (Et) · 1.5 · 4.3 ppm: m: 15H: CH 2 -CO, CH 2 (Et), CH 2 -N, 2 OCH 3, CO 2 CH 3 5, 2-5.6 ppm: 3s: 1H: H (indoline) 35 6.2-8.2 ppm: m: 11H: OH + aromatic • · · · 107048 50 - Example 40 0.8 - 1.1 ppm : m: 3H: CH 3 (Et) 2.2 - 3.9 ppm: m: 15H: CH 2 CO, CH 2 (Et), CH 2 N, CO 2 CH 3, 2 OCH 3 5.3 - 5.7 ppm: 2s: 1H: H (indoline) δ , 6- 8.2 ppm: m: 11H: OH + aromatic - Example 63 0.4-1 ppm: partitioned t: 3H: CH 2 -CH 2 -CH 3 5 ppm: m: 2H: CH 2 -CH 2 -CH 3 2.5-4 , 4 ppm: m: 13H: CH2-CH2-CH3, NCH2COOCH3, 20OCH3 5.2 - 5.8 ppm: bs: 1H: H (indoline) 6.5 - 8.3 ppm: m: 11H: OH + aromatic Example 66 0-1.5 ppm: m: 3H: CH2-CH3

2.3-5.8 ppm: m: 14H: CH2 -CH3, NCH2COOCH3, 2OCH3, H

15 (indoline) 6.1 - 8.3 ppm: m: UH: OH + aromatic - Example 75 1.95 ppm: bs: 2H: NH2 2.7 - 5.3 ppm: m: 12H: 2 OCH3, 2 NCH2, H (indoline), CHNg2 20 6-8.3 ppm: m: 11H: OH + aromatic - Example 76a

C 5 + 5 102 (c = 0.35, chloroform) - Example 76b <: als = -158 (c = 0.2, chloroform).

25 *: * ·: Some compounds of the invention described in Table 2 are: ***; the compounds are useful in the preparation of other compounds of the invention. For example, Compound 41 was obtained from Compound 39 by treatment with MeOH / H 2 O in basic medium. Compound 49 was prepared from compound. 41 by treatment with aqueous ammonia in the presence of DIPEA and BOP.

»·» • «• ♦ * • ·« »* ♦ *» • a «« 51 107048

Example 77 N-Ethyl-N- (2-aminoethyl) -5-chloro-3- (2-chlorophenyl) -1- (3,4-dimethoxyphenylsulfonyl) -3-hydroxy-2-indolinecarboxamide (cis- isomer) 500 mg of compound 49 is dissolved in 10 ml of acetonitrile and 10 ml of water and 252 mg of pyridine and 380 mg of bis (trifluoroacetoxy) iodobenzene are added. After stirring for 2 hours, the mixture is taken up in hydrochloric acid solution, extracted with ether, made alkaline with dilute sodium hydroxide solution, extracted with DCM and the extract is dried and concentrated. The oil is obtained and the expected product is then crystallized from ether, m = 150 mg m.p. = 164 ° C Example 78 N-Ethyl-N - [(1 S) -1- (ethoxycarbonyl) ethyl] -5-chloro-3- (2-chlorophenyl) -1- (3,4-dimethoxyphenylsulfonyl) -3-Hydroxy-2-indolinecarboxamide (cis isomer) 20A) N- [2- (2-Chlorophenylcarbonyl) -5-chlorophenyl] -N- (3,4-dimethoxyphenylsulfonyl) glycic acid chloride

A mixture of 11 g of the acid prepared in Example 10-11 in Step A) and 5 g of thionyl chloride M in 10 ml of chloroform is heated for 1 hour at 60 ° C.

The mixture is allowed to return to RT, concentrated in vacuo and the residue taken up in DCM (twice). A yellow oil is obtained which is used as is in the next step.

IR · 1800 cm -1 (C = O) 30 B) 2 ', 5-dichloro-2- [N- (3,4-dimethoxyphenylsulfonyl) phenyl] -N- (N' -ethyl-N). '- ((IS) -1- (Ethoxycarbonylethyl • · ... l) ethoxycarbamoylmethyl)] aminobenzophenone' · '1 · This compound was prepared according to J.

j 'Org. Chem., 1985, 5-10, 945-950.

5.15 g of (L) -Boc- (N-Et) -AlaOEt are treated with 10 ml of TFA at 0 ° C to remove the Boc group. The mixture is concentrated in vacuo, taken up in 20 ml of DCM, cooled to -78 ° C and 2 equivalents of TEA 5 and the acid chloride prepared in the previous step dissolved in DCM are added. After 18 hours at RT, the mixture is extracted with DCM, the extract is washed with water and then chromatographed on silica, eluting with a mixture of DCM and AcOEt (90/10, v / v). The expected product is crystallized from isopropyl ether.

Sp. = 112 ° C

m = 8 g C) N-ethyl-N - [(1 S) -1- (ethoxycarbonyl) ethyl] -5-chloro-3- (2-chlorophenyl) -1- (3,4-dimethoxyphenylsulfonyl) - 3-Hydroxy-2-indolinecarboxamide (cis isomer)

The compound obtained in the preceding step is stirred at RT for 18 hours in 10 ml of THF and 20 ml of ethanol in the presence of 1.46 g of DBU. The mixture is concentrated in vacuo, the residue is taken up in DCM, washed with water, concentrated and the product is chromatographed on alumina eluting with AcOEt: DCM (10/90, v / v).

1 H NMR

4 4 * · 25 25 0 - 0.9 ppm: partitioned d: 3H: CH-CH 3 *: **: 0.9-1.7 ppm: m: 6H: 2 CH 3 (ethyl)

· · · *; 2.6-5.8 ppm: m: 12H: 2 OCH3, NCH2, OCH2, NCH, COCH

• · · 6.1 - 8.3 ppm: m: 11H: OH - 10H Aromatic • · • «· • · · · · · 53107048

Examples 79 and 80 N, N-Di- [2- (methoxycarbonyl) ethyl] -5-chloro-3- (2-chlorophenyl) -1- (3,4-dimethoxyphenylsulphonyl) -3-hydroxy-2- indolinecarboxamide, cis isomer 5 and trans isomer A) N, N-di- [2- (methoxycarbonyl) ethyl] benzylamine

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

107 g of benzylamine benzyl in 200 ml of ethanol are cooled in an ice bath and 172.2 g of methyl acrylate in 250 ml of ethanol are added slowly. After 13 days at RT, the solvent is evaporated in vacuo and then part of the oily residue is distilled off.

Kp. = 135-140 ° C at 0.6 mm Hg m = 30 g IR: 1730 cm @ -1 B) N, N- (2-Dimethoxycarbonyl) ethyl] amine 27.9 g of the amine obtained in the preceding step. 500 ml of methanol, mixed with 3 g of 5% palladium on charcoal and treated under hydrogen pressure for 1 hour. The mixture is filtered over Celite R, rinsed with methanol and the solvent evaporated in vacuo; ; The 25 remaining oils are used as such in the following *: **: step.

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

A mixture of 14.3 g of the amine prepared in the preceding step, 100 ml of DCM and 10.6 ml of TEA. cooling in an ice bath; 15.3 g ... of bromoacetyl bromide are added dropwise and then the mixture is allowed to stir for 48 hours at RT. The mixture is extracted with DCM, the extract is washed with water and then chromatographed on silica. «· 107048 54 eluting with a mixture of DCM and MeOH (97/3 v / v). The expected product is obtained in the form of an oil, m = 15.9 g IR: 1650 cm-1 and 1730 cm-1 5 D) 2 ', 5-dichloro-2- [N- (3,4-dimethoxyphenylsulfonyl) -N- [?, N-Di- (2- (methoxycarbonyl) ethyl) cacbamoylmethyl]] aminobenzophenone 14.3 g of 2 ', 5-dichloro-2- (3,4-dimethoxyphenylsulfonamido) benzophenone are placed in 180 ml. DMF and li-10 are adjusted in portions of 1.1 g of sodium hydride. After stirring for 1 hour at RT, the mixture was cooled in an ice bath and 14.3 g of the product prepared in the preceding step are added and the mixture is allowed to stir for 72 hours at RT. The mixture is extracted with DCM, the extract is washed with water and then chromatographed on silica eluting with DCM and AcOEtm.

mixture (93/7, v / v). m = 28.4 g. = 130 ° C

E) N, N-Di- [2- (methoxycarbonyl) ethyl] -5-chloro-3-20 (2-chlorophenyl) -1- (3,4-dimethoxyphenylsulfonyl) -3-hydroxy-2-indolinecarboxamide, cis- isomer 12 g of the compound prepared in the previous step and 0.930 g of sodium methylate in 150 ml of methanol ··· · l are stirred at 0 ° C and then allowed to stir overnight at RT. The reaction mixture is neutralized by the addition of 5% KHSO 4 and then the solvent is evaporated in vacuo [**]. The residue is chromatographed on alumina, eluting with a mixture of DCM and AcOEtm (8/2, v / v).

2.4 g of the expected product are obtained, which is crystallized from 30 methanol.

Sp. = 175 ° C · · · · · · · · 1 · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · 5517070 F) N, N-di- [2- (methoxycarbonyl) ethyl] -5-chloro-3- ) -1- (3,4-Dimethoxyphenylsulfonyl) -3-hydroxy-2-indolinecarboxamide, trans isomer

Chromatography from the previous step is continued and elution is carried out with a mixture of DCM and MeOH (9.5 / 0.5, v / v). 1.82 g of the trans isomer are obtained, which is crystallized from isopropyl ether.

Sp. = 85 ° C.

Examples 81, 82 and 83 10 2 - ((2R) -2-Carbamoylthiazolidinocarbonyl) -5-chloro-3- (2-chlorophenyl) -1- (3,4-dimethoxyphenylsulfonyl) -3-hydroxyindoline (cis) isomer: 2 compounds and trans isomer) A) (L) -4-Thiazolidinecarboxamide This compound is prepared according to J. Med. Chem., 1981, 24, 692.

B) 2 ', 5-Dichloro-2- [N- (3,4-dimethoxyphenylsulfonyl) -N - ((2R) -2-carbamoylthiazolidinocarbonylmethyl)] aminobenzophenone This compound is obtained according to the usual procedures in Example 10-11. A) from the prepared acid.

Sp. = 125 ° C after crystallization from ether.

C) 2 - ((2R) -2-Carbamoylthiazolidinocarbonyl) -5-M: chloro-3- (2-chlorophenyl) -1- (3,4-dimethoxyphenylsulphonyl) -3-hydroxyindoline 4.3 g of the product obtained in Step B) are cyclized: ***: in 90 ml of MeOH at RT in the presence of 1 g of DBU.

• * ·

The mixture is concentrated, the residue is taken up in water and DCM, the layers are separated, the organic layer is washed with 30 KHSO4 and then dried and concentrated. The residue is chromatographed on alumina, eluting with a mixture of DCM and ... MeOH (97/3 v / v). The compound is obtained in cis form (mixture of 2 diastereoisomers): 1.5 g, and then in trans form (mixture of 2 diastereoisomers): m = 35 1 g. · 56 107048 a) The cis fraction is crystallized from a mixture of MeOH and DCM to give cis 1.

Sp. = 176 ° C after crystallization from isopropyl ether.

5D = +57 (c = 0.1, chloroform).

b) The crystallization fluids from the preceding product are chromatographed on silica eluting with a mixture of AcOEt and DCM (30/70, v / v). The resulting cis compound 2 is recrystallized from ether.

10 M.p. = 205 ° C

α D = -185 ° (c = 0.3, chloroform).

c) The trans fraction (mixture of 2 diastereoisomers) is recrystallized from isopropyl ether.

Sp. = 170 ° C

Examples 84, 85, 86 and 86a 5-Chloro-3- (2-chlorophenyl) -1- (3,4-dimethoxyphenylsulfonyl) -3-hydroxy-2 - [(2S) -2- (N, N -di-methylthiocarbamoyl) pyrrolidinocarbonyl] -indoline, cis-isomer (2 compounds), (trans-iso-20mer: 2 compounds) A) (L) - (Ν'-Boc) -N, N-dimethylproline thioamide This compound prepared according to J. Med. Chem., 1989, 2178.

--- · 2.36 g of (.beta.-Boc) -N, N-dimethylproline amide

I I

i * ·· 25 are passed over anhydrous toluene using argon-*! * '! as a gas at 80 ° C for 4 hours in the presence of 2.3 g

Lawesson's reagent. After 24 hours, the solvent is evaporated and isopropanol is added. The precipitate formed is separated, the isopropanol is evaporated and the residue is chromatographed on silica eluting with a mixture of hexane and AcOEt #. (30/70, v / v). The resulting product is recrystallized cold from a mixture of DCM and isopropyl ether • · * · ** (30/70, v / v).

: ***: m.p. = 62 ° C

57 107048 B) 2 ', 5-Dichloro-2- [N- (3,4-dimethoxyphenylsulfonyl) -N - ((2S) -2- (N', N'-dimethylthiocarbamoyl) pyrrolidinocarbonylmethyl) aminobenzophenone 3 g of the product prepared in the previous step 5 are dissolved in 10 ml of DCM and treated at 0 ° C for 2 hours with 10 ml of TFA. The mixture is evaporated to dryness, then 20 ml of DCM and 6.1 g of the acid prepared in Example 10-11, Step A) at 0 ° C are added and the mixture is neutralized with 3 g of DIPEA. 5.15 g of BOP is dissolved in 30 ml of DCM and this solution is added to the previous solution at 0 ° C for 30 minutes; The pH is kept neutral by the addition of DIPE-A and the mixture is allowed to stir for 3 hours at 0 ° C. After one night at RT, the mixture is extracted in the usual way and then chromatographed on silica-15 eluting with a mixture of DCM and AcOEt (85/15, v / v). The product obtained is recrystallized from isopropyl ether.

Sp. = 182-185 ° C

α D = -72 ° (c = 0.32, chloroform).

20 C) 5-Chloro-3- (2-chlorophenyl) -1- (3,4-dimethoxyphenylsulfonyl) -3-hydroxy-2 - [(2S) -2- (N, N-dimethylthiocarbamoyl) pyrrolidinocarbonyl ] indoline (cis-isomer: 2 compounds and trans-isomer: 2 compounds): 3.8 g of the compound li-«·: * ·· 25 obtained in the preceding step are leached in 15 volumes of DCM and heated to reflux * Σ ** ί with cooling for 36 hours in the presence of 850 mg DBU.

: ***: The different isomers formed are separated by successive chroma- to · ·; * · *: tography runs on silica.

· · A) Using a mixture of DCM and AcOEt (85/15, ti-30 v / v), the expected compound is first eluted in the form of a mixture of 2 cis-diastereoisomers. The less soluble · · ... diastereoisomer is crystallized twice from a mixture of DCM, • isopropyl, · * · '' ether and methanol and then re-: · '; is crystallized from a minimum amount of DMF 35 at 60 ° C followed by addition of 2 volumes of ethanol.

»• * · • · · •« • · 107048 58

Sp. = 270 ° C

α D = -278 ° (c = 1, chloroform).

b) The crystallization fluids from the previous mixture are recovered in a mixture of DCM and isopropyl ether and the other 5 cis diastereoisomer is crystallized therefrom.

Sp. = 249-251 ° C

aD = + 42 ° (c = 0.22; chloroform) c) The last eluted chromatographic fractions and the crystallization medium solutions of fractions a) and b) are combined and chromatographed again on silica eluting with a mixture of hexane and AcOEt (20/80, v / v). ). First, the fraction which is recrystallized 3 times from a mixture of DCM and isopropyl ether is isolated and the insoluble material is removed on the paper between each recrystallization. This gives the trans isomer 1.

Sp. = 191-193 ° C

α D = + 74.5 ° (c = 0.2, chloroform).

d) The second fraction contains the trans isomer 2 which is recrystallized from a mixture of DCM and isopropyl ether and crystallizes with 1/3 mole of isopropyl ether.

Sp. = 170 ° C

α D = -266 ° (c = 0.14, chloroform).

Examples 87, 88 and 89 2 - ((2S) -2-Carbamoylpyrrolidinocarbonyl) -5-

«I

• <25 chloro-3-cyclohexyl-1- (3,4-dimethoxyphenylsulfate: 1: phenyl) -3-hydroxyindoline (cis isomers: 2 compounds, trans isomer) - chloro-2 - [N- (3,4-dimethoxyphenylsulfonyl) amino] cyclohexylphenone · · · 30 A solution of 35.6 g of 2-amino-5-chloro . ricyclohexylphenone and 39.5 g of 3,4-dimethoxyphenylsulphonyl chloride in 340 ml of pyridine are allowed to stir for 24 hours at RT. The solvent is evaporated in vacuo and the residue is then washed with water and an acid solution (0.5 N in HCl). The expected product is crystallized from ethanol.

»» »O 107048 59

Sp. = 135 ° C

m = 56.1 g.

B) 2 - [(N-Benzyloxycarbonylmethyl-N- (3,4-dimethoxyphenylsulfonyl)) amino] -5-chlorocyclohexyl-5-phenone 3.2 g of sodium hydride are added portionwise to 52.6 g of the compound prepared in the preceding step. is in 520 ml DMF and the mixture is allowed to stir for 1 hour at RT. After cooling in an ice bath, 21 ml of benzyloxycarbonylmethyl bromide are added dropwise and the mixture is allowed to stir for 24 hours at RT. The solvent is evaporated in vacuo and the residue is taken up in water. It is extracted with DCM and the extract is washed with water; the product obtained is used as is in the next step.

15C) N- (5-chloro-2- (cyclohexylcarbonyl) phenyl) -N- (3,4-dimethoxyphenylsulfonyl) glycine

The compound obtained in the preceding step is charged with 3.9 g of 5% palladium on charcoal in 700 ml of acetic acid under a hydrogen atmosphere (1 atmosphere). At the end of reaction 20, palladium is filtered on Celite® and rinsed with hot acetic acid; the solvent is evaporated in vacuo and the residue is taken up in water. It is extracted with DCM and the extract is washed with water and then with concentrated NaHCO 3 solution.

: The residue obtained is chromatographed on silica, eluting with a mixture of DCMr 4 → 25 · MeOH (97/3 v / v). Expected *: · 1: The product is crystallized from ethanol.

: 1 · 1: m.p. = 160 ° c ··· m = 22.4 g.

♦ 1- · 1% φ D) 5-Chloro-2- [N- (3,4-dimethoxyphenylsulfonyl) -? · 30 N - ((2S) -2-carbamoylpyrrolidinocarbonylmethyl)] aminocyclohexylphenone • · «· ·

A mixture of 9.92 g of the acid prepared in the preceding step, 3 g of (L) -proline amine hydrochloride and · 1 · 1: 3.5 ml of DIPEA in 75 ml of DCM is cooled to 0 ° C.

«« 35 Add 8.84 g of BOPra as a solution in DCM and maintain the pH i t · * «·» 4 • ·

»'·, B

107048 60 at value 7 by adding DIPEA. The mixture is allowed to stir for 24 hours at RT. The mixture is extracted with DCM and the extract is washed with saturated NaHCO 3 solution, brine, 5% KHSO 4 solution and again with brine. The product is chromatographed on silica eluting with a mixture of DCM and MeOH (96/4 v / v) on silica. The expected product becomes solid in isopropyl ether.

Sp. = 110 ° C m = 7.3 g 10 α D = -53.9 ° (c = 1; chloroform) E) 2 - ((2S) -2-carbamoylpyrrolidinocarbonyl) -5-chloro-3-cyclohexyl-1- ( 3,4-Dimethoxyphenylsulfonyl) -3-hydroxyindoline, cis isomer (2 compounds), trans * isomer 5.9 g of the compound prepared in the preceding step and 1.67 g of DBU are placed in 60 ml of methanol with stirring At 0 ° C for 48 hours. The solvent is evaporated in vacuo, water is added, the mixture is extracted with DCM and then the extract is washed with 5% KHSO 4 solution. The product is chromatographed on alumina, eluting with a mixture of DCM and MeOH (98/2, v / v).

a) The least polar fraction contains 2 cis-isomers. This fraction is recrystallized from methanol.

The first compound thus obtained (cis 1) is pure by HPLC * 25.

"· *: M.p. = 185 «c.

:: Recrystallization of the mother liquor from MeOH gives another compound (cis 2). HPLC purity: 75% (containing 25% cis 1).

• · · 30 Sp. = 132 ° C.

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

ΓΛ Sp. = 240 ° C

35aD = -55.1 ° (c = 1, chloroform).

• »· • ·« 107048 61

Example 89a 2 - ((2S) -2-Carbamoylpyrrolidinocarbonyl) -5-chloro-3-cyclohexyl-1- (3,4-dimethoxyphenylsulfonyl) -3-hydroxyindoline, cis -isomer (2-y-dist.) , trans isomer Using a procedure similar to that described for Examples 87, 88 and 89, an analogue is prepared in the (D) -proline series.

After crystallization from a mixture of DCM and MeOH, the compound obtained has a trans configuration.

Sp. = 238 ° C

aD = +164 (c = 0.245; chloroform / methanol, 8.2, v / v).

The NMR spectra of this compound and the compounds described in step E15 b) of the previous example are identical. Example 90 5-Chloro-3- (2-chlorophenyl) -1- (3,4-dimethoxyphenylsulfonyl) -2 - [(2S) -2- (N-methylaminocarbonyl) pyrrolidinocarbonyl] -3-hydroxy- indoline 20 cis isomer 920 mg of the compound prepared in Example 28 is placed under stirring in 20 ml DCM containing 371 mg BOP over 15 minutes, the mono-methylamine stream is bubbled through for 10 minutes and stirring is continued. : 25 anyone for another 30 minutes. The mixture is taken up in water, ·: **: the layers are separated, the organic layer is washed with potassium water, thiosulfate and sodium carbonate, dried and concentrated. The residue is chromatographed on silica eluting with a mixture of DCM and methanol (97.5 / 2.5, v / v) (30) The expected product which is crystallized is recovered from a mixture of isopropyl ether and DCM.

| tt 'm = 750 mg

Sp. 158 ° C

i · '· 1; α D = -216 ° (c = 0.3, chloroform).

• »•) t • i • · e I | «« I · • a · • · • 3 • ·; ', 1 • t 62 10 7 C 4 8

By proceeding as previously described (Examples 27-31 and 90) and using (L) -proline derivatives (unless otherwise stated), other intermediate compounds (VI) were prepared for the synthesis of compounds (I) of the invention.

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

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

10

Table 3 • Ότ'-Ρ, N-CH ^ -CO-Nv I 2 nR7 S07 2 ° • · «·« «I • • 1 1 · 0 0 0 • • · ' · »· 4 · · 0 · · • II 1 f« <<4 «4 4 · I« 4 · • · · ♦ 4 »* · 107048 63 - __ R's -Νχ Sp. (4C) α 25 R 7 (chloroform) -7- 3.4- CH 3 O + 45 5 H -: c - 1.015 - CONH, 1 3.4 - CH 3 O - N 16 - 161-163 - 70.8 H 1. DCM / isopropyl-c - 0.48 ___CQOCH3 ether__ 10 / - 2.4 - CH30 -N 145-148 -17.5 C - 3.36 _COOCH3___ '3.4-CH3O h'N'110 cu / DCM / isopropyl -__2 \ - f_ether__ 3.4- CH3O -N148ΓΓisopropyl _Eh2cooch3 [ether / MeOH _ 20 Table 4 "xx $ b:.:: 25 ^ Ϊ * COtC'1 * 6 ·: ·· .. so2 Z ': f \: V : 50 30 I -: - T-1-1 V 'Pres- R' x R'j _N '6 Sp. (9C) Q ^ 5 character \ (chloroform-_____ 1___ mi) _: 91 cis 1 Cl 3,4-CH3O / 115 + 188 35 Hl-MeOH c - 0.33 92 cis 2 CONH2 204 -114 * '·; · * Cl MeOH / DMF c - 0.31 • · * 1 ”1” - ^ 1 1 ^^^^^ - 1 'in ···· * 107048 64 _____ _ __ 198-201 93 cis Cl 3,4-CH30 DCM / isopropro-κ IJ Pylether COOCHj 5 ---: ------- -> / 205-207 94 cis Cl 2,4-CH30 H "'H DCM / isoproproocHj Pylether 10 -j / 221 - 242 95 cis Cl 2,4-CH 3 O DCM / isopropro - 0.254 CQQH Pylether -t / 15 \ -234 COOCH, -f 7 96 cis Cl 3,4-CH 3 O 1 = / c - 0.32 -tf H> .. \ - Γ -214

is CON (CH, U

20 97 cis Cl 3,4-CH 3 O - ^ c - 0.32 J-105-115 + 174.6

-OF

98 cis 1 Cl 3,4-CH30 h -. \ DCM / isopro ^ :: - 0,3 ch2cooch3 Pylether 25 i ** ·· 99 cis 2 175 -214,6 *: * ·; DCM / isopropro - 0.3 Pylether • · 100 trans 1 -155 30 c - 0.2 • · · 101 trans 2 177 +95.2. DCM / isopropyl-0.2 pyrylether: * · *: 35 102 cis 1 Cl 3,4-CH 3 O -N 135 -162 H 1 -J-1 isopropyl * · * · * ch, coH 4 ether 107048 65 —- -χ \ 145 * 167 103 cis 1 Cl 3,4-CHjO Η> ·· \ —I) CM / isopropro - 0.4 ch2conh2 Pylether 5 “----- 103a Cl 3,4-CH30 -k els 1 ·. CH, CONH, 10 cis 2 2 2.

104 cis 1 Cl 3,4-CH30., / Η 210 -177.5 H "'\ ether c - 0.2 ch2nh2 15 ----: -: --- 104a Cl 3,4-CH30.

cis 1 'N

cis 2 i ch2nh2 20 200 -195 105 CH30 3,4-CH30 -j / l EtOH c - 0.2

Η "·· \ -I

106 c ° NH2 215 +127

HeOH c - 0.2:,: 25 ----; --- Γ * .. -63.3: ··: 107 CH30 3.4- ^ 30 (Dj -N / 198 c - 0.117

· * '; H: (CHCl 3 / MeOH

- CONH2 872 •. vol / vol '.

·: ·. 30 -; ---; ----- »· · y- 274 -225 108 Cl 2,4 -CH 3 OH", N 1 -DMCM / MeOH c- 0.372

'' ,, 'ςο ^, Η {CHCla / MeOH

2 8/2; · 'Til / vol.

\ \ JJ - .- ..- - —— ------- - - -. , -, "-. ,,.

108a Cl 3,4-CH30 -n -198.7 Η "·· \ - ... Cis i c - 0.24: ·: CQtfHPH 1 \ • '_t_I_I ______—-- 1 66 107046

Example 107 is the enantiomer of Example 106.

The compound of Example 108a was prepared from the compound of Example 28 by reacting with hydroxylamine hydrogen-5 chloride in DMF and activating with BOP reagent in the presence of DIPEA.

Some of the compounds of the invention described in Table 4 above are useful in the preparation of other compounds. Thus, from Example 10, compound 10, it is possible to obtain the compound of Example 101, then the compound of Example 103, and finally the compound of Example 104.

Example 109 2 - ((2S, 4S) -4-Azido-2- (methoxycarbonyl) pyrrolidinocarbonyl) -5-chloro-3- (2-chlorophenyl) -1-15 (3,4-dimethoxyphenylsulfonyl) -3- hydroxyindoline, cis isomer A) 2 ', 5-Dichloro-2- [N- (3,4-dimethoxyphenylsulfonyl) -N - ((2S, 4R) -4-hydroxy-2- (methoxycarbonyl) - Pyrrolidinocarbonylmethyl)] aminobenzophenone 20 g of the acid prepared in Example 10-11, Step A) and 6.25 g of methyl (2S, 4R) -4-hydroxyprolinate hydrochloride are heated to 0 ° C in 150 mL of DCM. 7.4 g of DIPEA are present. A solution of 12.7 g of BOP in 30 ml of: 25 DCM is added dropwise over 30 minutes and the required amount of DIPEA is added to neutralize the solution. After standing overnight at RT, the mixture is extracted as usual and chromatographed; ***: eluting with a mixture of DCM and AcOEtm (60/40 v / v) on silica. The expected product is crystallized from DCM, • ·. ··. ·. Of a mixture of 3 O and isopropyl ether.

»· ·

Sp. = 128-131 ° C

. α D = + 8.5 ° (c = 0.38, chloroform).

(B) 2 ', 5-dichloro-2- [N- (3,4-dimethoxyphenylsulfonyl) -N- ((2S, 4R) -4-Mesyloxy-2- (methoxycarbonyl) -pyrrolidinocarbonylmethyl)] aminobenzophenone 2 g of the compound obtained in the preceding step are dissolved at 0 ° C in 10 ml of DCM. 550 mg of triethylamine is added followed by 550 mg of methanesulfonyl chloride and the mixture is left at 0 ° C for 20 hours. Water is added and the organic layer is washed with 0.5 N aqueous hydrochloric acid, water and then with sodium bicarbonate solution, dried over magnesium sulfate and evaporated. The resulting oil is used as is in the next step.

C) 2- [N - ((2S, 4S) -4-Azido-2- (methoxycarbonyl) pyrrolidinocarbonylmethyl) -N- (3,4-dimethoxyphenylsulfonyl)] amino-2 ', 5-dichlorobenzophenone 11 g the product of the previous step is heated in 60 ml of DMSO at 80-90 ° C in the presence of 2.7 g of sodium azide for 18 hours. The mixture is poured into water, extracted with ethyl acetate, the organic layer is washed with water, dried and chromatographed on silica, eluting with a mixture of pentane and AcOEt (50/50, v / v). An oil (10 g) is obtained.

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

D) 2 - ((2S, 4S) -4-Azido-2- (methoxycarbonyl) -pyrrolidinocarbonyl) -5-chloro-3- (2-chlorophenyl) -1- (3,4-i '* ··· dimethoxyphenylsulfonyl) -3-hydroxyindoline, cis isomer 3.38 g of the product obtained in the preceding step are cyclized under standard conditions in the presence of DBU.

The expected product is obtained which is recrystallized from a mixture of DCM and isopropyl ether.

. m = 755 mg

Sp. = 200-202 ° C

··· 'aD = -176 ° (c = 0.21; chloroform, T = 26 ° C).

• · * • · «· • • • • • • • •« «· 107048 68

Example 110 2 - [(2S, 4S) -4- (N-Benzyloxycarbonyl-N-methyl) amino-2- (methoxycarbonyl) pyrrolidinocarbonyl] -5-chloro-3- (2-chlorophenyl) -1- (3 , 4-Dimethoxy-5-phenylsulfonyl) -3-hydroxyindoline, cis isomer A) (N-Boc) -4-hydroxyproline methyl ester The starting material is the hydrochloride of (2S, 4R) -4-hydroxyproline methyl ester.

10 g of this compound are suspended in 100 ml of THF, 22.9 g of (Boc) 20 are added and then the mixture is cooled to 0 ° C. 21.2 g of triethylamine in 25 ml of THF are added dropwise and the mixture is then stirred for 12 hours at 0 ° C and for 4 hours at 60 ° C. Water is added, the mixture is extracted with ethyl acetate, the organic layer is washed with water, potassium hydrogen sulfate solution (4 times), water and then brine. The solvent is evaporated and an oil (21.6 g) containing a small amount of (Boc) 20 is isolated.

20 B) Methyl ester of (2S, 4R) - (N-Boc) -4-mesyloxyproprol

A solution of 22.9 g of the product prepared in the preceding step in 250 ml of DCM is cooled to 0 ° C. 22.9 g of mesyl chloride · 25 in 10 ml of DCM are added dropwise, then 9.4 g of triethylamine in 100 ml of DCM are added dropwise and the mixture is allowed to return to RT overnight. The mixture is evaporated to dryness, added. ***; water, the mixture is extracted with AcOEt, the organic layer is washed with water and brine and dried over magnesium sulfate. After the second evaporation, an oil is obtained which is used directly in the next step.

. C) (2S, 4S) - (N-Boc) -4-azidoproline methyl ester This compound is prepared from the compound obtained in Step B. 15.2 g of (N-Boc) -4-mesyloxyproline methyl · '· *: 35 esters are dissolved in 70 ml of DMSO and the solution is heated under reflux. The mixture is cured at 90 ° C for 5 hours in the presence of 3.05 g of sodium azide. The mixture is cooled, water is added, the mixture is extracted with AcOEt, the organic layer is washed with water and brine and dried over MgSO 4. The resulting oil 5 is purified by chromatography on silica eluting with a mixture of AcOEt.-hexane (40/60, v / v). α D = -37.8 ° (c = 3, chloroform) m.p. α D = -36.6 ° (c = 2.8; chloroform), D.J. Abraham et al., J. Med. Chem., 549, 26, 1983.

10 D) (2S, 4S) - (N-Boc) -4-Aminoproline Methyl Ester 8.45 g of the compound obtained in Step C are dissolved in 100 ml of methanol, 500 mg of 10% Pd / C are added and the mixture is hydrogenated At 40 ° C for 18 hours. The catalyst is filtered off, half of the methanol is evaporated, 100 ml of 0.5 N HCl are added, then the remaining methanol is evaporated and the unreacted starting material is extracted with AcOEt. The aqueous phase is treated with sodium carbonate and the fraction containing the expected product (m = 4.35 g) is extracted with AcOEtr.

E) (2S, 4S) - (N-Boc) -4- (N'-Benzyloxycarbonyl-20-amino) -proline methyl ester

The crude product obtained in the previous step is dissolved in 15 ml of ether and 15 ml of DCM at 0 ° C. 2.3 g DIPEA and then 3.03 g benzyl chloroformate in 5 ml DCM are added over 70 minutes at 0 ° C. 3 hour ku-; After 25 h, the solvents are evaporated at RT under vacuum; water and ethyl acetate are added and the organic phase is washed ·····; successively with potassium hydrogen sulfate solution (3 times) with water. ***; (3 times), sodium carbonate solution (3 times), water ··· (3 times) and brine. The product is chromatographed on silica eluting with hexane / AcOEt (40/60, v / v) to afford the expected product. sex.

α D = -16.4 ° (c = 0.3; chloroform).

«F II <1 a · 1« 1 <· 1) 1>> • 10704 δ 70 F) (2S, 4S) - (N-Boc) -4- (Ν'-benzyloxycarbonyl-N'-methyl) aminoproline methyl ester 2 g of the compound obtained in the previous step are dissolved in 20 ml of DMF at 0 ° C using argon as a protective gas in the presence of 2.25 g of methyl iodide. 170 mg of 80% sodium hydride are added portionwise and the mixture is then stirred at 0 ° C for 90 minutes. The mixture is extracted with water and ethyl acetate; the organic phase is washed with water and then with brine. The product 10 is chromatographed on silica eluting with a 50/50 v / v hexane / AcOEt mixture. 1.55 g of the expected product are obtained.

α D = -38.8 ° (c = 0.38M, chloroform).

G) 2 ', 5-Dichloro-2 - [(2S, 4S) -N- (3,4-dimethoxyphenylsulfonyl) -N- {4- (5'-benzyloxycarbonyl-N'-methyl) amino- 2- (methoxycarbonyl) pyrrolidinocarbonylmethyl) aminobenzophenone This product is obtained by conventional methods.

α D = -22.4 ° (c = 0.37, chloroform).

20 H) 2 - [(2S, 4S) -4- (N-Benzyloxycarbonyl-N-methyl) amino-2- (methoxycarbonyl) pyrrolidinocarbonyl] -5-chloro-3- (2-chlorophenyl) -1- ( 3,4-Dimethoxyphenylsulfonyl) -3-hydroxyindoline, cis isomer This product is obtained by cyclization in the presence of DBU according to conventional methods. The formed crystals are crystallized from a mixture of DCM and isopropyl ether,

• fi Sp. = 129 ° C

[α] D: -129 ° (c = 0.321; chloroform).

··· tV. The isomeric purity by HPLC is 99%.

The compounds i · «prepared in Examples 109 and 110 are used in Table 5 according to the invention. for the preparation of compounds: I I <^ \ III t · * · • * · * Il «* • · • · 71 10704b

Table 5:. ° Or | Ö.

/ ~ TR9 f XCO-N? 2 (2S)) - 1 COOCH3

10 L I

EXAMPLE R 8 O 'D' (Chloroform) 111 cis -NH 2 -189.6 c - 0.4 20 cf 174 112 Cis -NHCOOCH 2 - ^ J> X c = 0.24 113 cis -NHCH 3 -152, 6 c = 0.28 25:. 114 cis -191 -N <CH3> 2 c - 0.19 «♦ • · • · ----- --— I ———— --- - - • · • · · • · 10704 {3 72

Table 6 5 - / “Τ 19 co co (nS) ° 2 cm · sK conh 2 10 W ^ 3 och 3 15 Example R 9 <1„ (chloroform) 115 cis //-151 -NHCOOCH 3 - _ J c = 0 , 27 20 116 cis -NH 2 -161.4 c = 0126 116a cis -N (CH 3) 2 25

The compound of Example 116a can be prepared either pre- ···. by conversion of the compound of brand 114 or (2S, 4S) - (N-Boc) -4- · (dimethylamino) proline amide, prepared as follows: *** 30 1) Methyl- (2S, 4S) - (N- Boc) -4-aminoprolinate is prepared from methyl (2S, 4S) -4-azidoprolinate according to the method described in 1111 TR Webl, J. Org. Chem., 1991, 56, 3009.

2) Methyl (2S, 4S) - (N-Boc) -4- (dimethylamino) -prop,, linate (4 g) The compound prepared in (1) is dissolved in 50 ml. of acetonitrile, add 12.8 ml of 30% formalin followed by 5 g of sodium cyanoborohydride over 5 minutes, and after contacting the reagents for 2 hours, acetic acid is added to adjust the pH of the solution to 6. after which the acetonitrile is evaporated, water, potassium carbonate and solid sodium chloride are added and the mixture is extracted with 4 volumes of ethyl acetate. After evaporation, the residue is chromatographed on silica gel eluting with a mixture of DCM and MeOH (95/5, v / v) and the oil which solidifies is isolated.

m = 2.1 g IR (DCM): 1755 cm -1, 1695 cm -1.

3) 534 mg of the ester prepared in 2) is dissolved in 4 ml of MeOH and treated with sodium hydroxide (116 mg) in 1 ml of water for 48 hours at RT. The mixture is acidified to pH 3.5 with 0.5 N hydrochloric acid and evaporated to dryness. The residue is subjected to azeo-. tropical drying in the presence of benzene (5 times); and

«« «I

The residue is then dried in vacuo for 8 hours. Then, 2 ml of DMF and 3 ml of DCM are added and the mixture is cooled. To 0 ° C. 865 mg of B0P and DIPEA are added to neutralize the reaction mixture. After 15 minutes, a stream of gaseous ammonia is bubbled through twice for 30 minutes.

* · * For 3 0 years. After 2 hours at RT, DCM

evaporate, add carbonated water and ***** sodium chloride, and extract with 4 volumes of AcOEt.

After evaporation, the residue is chromatographed on silica. A mixture of DCM, MeOH and NH4OH (84.5 / 15 / 0.5, 35 vol / vol) elutes a solid (m = 107048 74 185 mg) which is recrystallized from DCM and isopropyl ether mixture.

Sp. = 183-186 ° C.

[Α] 25 D = -63.1 ° (c = 0.24, chloroform).

• · • «· • · * · • · · · · 1« e

Claims (4)

75 107048 Claim A compound of the formula: -V-2 R 1 -N 1 -C 1 - CONR 6 R 6 SO, R 5 R 10 is a halogen atom, C 1 -C 4 alkyl or C 1 -C 4 alkoxy; R 2 is C 3-7 cycloalkyl or phenyl unsubstituted or monosubstituted with halogen; R5 is phenyl substituted with one or more substituents selected from the group consisting of C1-6 alkyl and C1-6 alkoxy; R 6 is C 1-8 alkyl or benzyl or - (CH 2) 2 -CO 2 -CH 3; R 7 is a 4-piperidinyl group which is unsubstituted or substituted on the nitrogen atom by C 1-4 alkyl; a group (CH 2) r substituted with a 2-pyridyl group or an amino group which is free or substituted. one or two C 1-6 alkyl, with a carboxyl group, a C 1-4 alkyl group, a carboxyl group, a benzyloxycarbonyl group, or a carbomyl group; or R 7 is -CH (CH 3) COO-C 2 H 5; . ·· *. or R 6 and R 7 together with the nitrogen atom, · · I]! to which they are attached, a heterocyclic ring selected from the group consisting of: • · · · '· * * 30 morpholine, thiomorpholine, * ·' * · thiazolidine, unsubstituted or substituted. supported by a carbamoyl group, I 4 76 107046 piperazine, unsubstituted or substituted at the 4-position by methyl, a C 1 -C 4 alkoxycarbonyl-methyl group or a benzylcarbonyl group; A3-pyrrolidine substituted with a C1-C4 alkoxy-5 carbonyl group; aziridine substituted with a benzyloxycarbonyl group; pyrrolidine monosubstituted with a carboxy, carboxymethyl, C 1 -C 4 alkoxycarbonyl or C 1 -C 4 alkoxycarbonylmethyl group, a carbamoyl group unsubstituted or substituted with hydroxyl or one or two C 1 -C 4 alkyl groups, an aminocarbothioyl group substituted with two C 1 -C 6 alkyl, a hydroxymethyl group, or an aminomethyl group; or a pyrrolidine disubstituted with a C 1 -C 4 alkoxycarbonyl group and an amino group which is unsubstituted or substituted with one or two C 1 -C 4 alkyl groups or one benzyloxycarbonyl group; or pyrrolidine disubstituted with a (Cx-C4) alkoxycarbonyl group and an azido group; or pyrrolidine disubstituted with carbamoyl and amino which is unsubstituted or substituted with one or two C 1 -C 4 alkyl groups or one benzyloxycarbonyl group; pyrrolidine substituted at the 2-position with methoxycarbonyl and 4-, p-substituted position with N-benzyloxy-N-methylamino: piperidine substituted with hydroxy, carboxyl, C 1-4 -alkoxycarbonyl, or amino. is unsubstituted or substituted with one or two alkyl radicals (C 1 -C 4); or azetidin-1-yl, which is a subs * * *.! titered at the 3-position with tert-butoxycarbonylamino; and '30 r is 1, 2 or 3. • 1 • 2 • 77 107048 Förening med formeln: 5 IL N-CH2CONR ^ 17 6 so2 10 k Rx is halogen, C 1-6 alkyl eller C ^ -alkoxi; R2 is C3-7-cycloalkyl eller phenyl, som and substituent eller monosubstituted med halogen; R 5 is phenyl, som and substituents are selected from the group consisting of C 1-4 alkyl and C 1-4 alkoxy; R 6 is C 1-6 -alkyl eller benzyl eller - (CH 2) 2 -CO 2 -CH 3; R7 is 4-piperidinyl, and the substituents are unsubstituted or C1-C4 alkyl; en group (CH2) r, som substituents med en 2-pyridyl group eller en. j: amino group, som e fri eller substituents med en eller flera C1-4 alkyl group, en carboxyl group, en C1-4 alkoxy. ··· carbonyl group, en benzylosxicarbonyl group eller en carba-. ···. moylgrupp; eller R7 is -CH (CH3) COO-C2H5; Ell R6 and R7 Tillamans Medium, Until Vilken De Bundna, Bildar en Heterocyclic Ring, Som · · · * 30 Rolls Frupp Gruppen bestäende av: morpholine, * 'thiomorpholine, * · · thiazolidine, som substitution substituents eller. substituents med en carbamoyl group, · 78 107C48 piperazine, som substitution substituents eller som 4-substituent and substituents med methyl, en C 1-4 alkoxycarbonylmethyl eller en benzyloxycarbonyl group: Δ 3-pyrrolidine, som C substituents med. C 1-6 -5-coxycarbonyl; aziridine, som and substituents med en benzyloxycarbonyl; pyrrolidine, monosubstituted or substituted med en carboxyl, carboxymethyl, C 1-4 -alkoxy-carbonyl-alkyl, C 1-4 -C 6 -alkoxycarbonylmethyl, en carbamoyl, substituted or unsubstituted med en el-10 liters. C 1-4 -alkyl, en carbamoylmethyl, enaminocarbothioyl, substituted or unsubstituted C 1-4 -alkyl, hydroxymethyl, or aminomethyl; eller pyrrolidine, som substituent med en C 1-4 -alkoxycarbonyl moiety eller en amino group, som substitution substituent med en eller substituent C 1-8 -alkylgroup eller en benzyloxycarbonyl moiety eller pyrrolidine, som disubstituted med ( -C 1-4 alkoxycarbonyl and azidogroup; eller pyrrolidine, somersubstituted med carbomoyl and amino, somersubstituted eller substituents, heteroarylC1-4C1alkylgroups eller en benzyloxycarbonyl; pyrrolidine, som 2 -stylamine, and substituents med methoxycarbonyl and 4-stylamine med N-benzyloxy-N-methylamino; piperidine, and substituents med en:, hydroxy, carboxyl, en, C1-C4-alkoxycarbonyl, eller en amino, somersubstituted ell, (Cx-C4) alkyl; eller .1 · 1. azetidin-1-yl, som 3-substituent and substituent med * ·· tert-butoxycarbonylamino; och • · ·!.! r är 1, 2 eller 3. • · · 't · · • 1 ··· I {I 4 · I I t