AU658664B2

AU658664B2 - Indoline derivatives having an amide function, their preparation, and pharmaceutical compositions containing them

Info

Publication number: AU658664B2
Application number: AU24758/92A
Authority: AU
Inventors: Dino Nisato; Claude Plouzane; Claudine Serradeil-Le Gal; Bernard Tonnerre; Jean Wagnon
Original assignee: Elf Sanofi SA
Current assignee: Sanofi Aventis France
Priority date: 1991-08-02
Filing date: 1992-07-31
Publication date: 1995-04-27
Anticipated expiration: 2012-07-31
Also published as: EP0526348A1; LT3064B; PH30661A; MY110517A; FI931476A0; HU9300951D0; EP0526348B1; FR2679903B1; AU1154195A; FI980175A0; CZ288173B6; AU691223B2; CA2206776C; HUT68927A; NZ243795A; MX9204487A; IL102703A0; NO931262L; UA27238C2; IL117592A0

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

-OPI DATE 02/03/93 AOJP DATE 13/05/93 APPLN. ID 24758/92 PCT NUMBER PCT/FR92/00758 1IIIII I I II 111 1 IIll ii AU9224758 DEMANDE INTERNATIONALE PUBLIEE EN VERTU DU TRAITE DE COOPERATION EN MATIERE DE BREVETS (PCT) (51) Classification internationale des brevets 5 C07D 209/42/401/06,¢401/12 C07D 403/06,/C07C 311/29 C07D 295/18, 295/20 C07C 311/21 (ll) Numero de publication internationale: WO 93/03013 internationale: 18 fevrier 1993 (18.02.93) (21) Numro de la demande internationale: PCT/FR92/00758 (22) Date de dep6t international: 31 juillet 1992 (31.07.92) Donnies relatives A la priorit6: 91/09908 2 aofit 1991 (02.08.91) FR (71) Deposan: ELF SANOFI [FR/FR]; 32-34, rue Marbeuf, F- 75008 Paris (FR).

(72) Inventeurs: WAGNON, Jean 90, rue des Galaxies, Le Hameau de la Rauze, F-34000 Montpellier PLOU- ZANE, Claude 5, allee des Terres Rouges, F-34680 Saint-Georges-d'Orques SERRADEIL-LEGAL, Claudine 45, avenue des Troubadours, F-31750 Escalquens NISATO, Dino 2, rue de Terre-Rouge, F- 34680 Saint-Georges-d'Orques TONNERRE, Bernard Lotissement Le Vallon n'3, F-34570 Vailhauques

(FR).

(74)Mandataires: GILLARD, Marie-Louise etc. Cabinet Beau de Lomenie, 55, rue d'Amsterdam, F-75008 Paris

(FR).

(81) Etats d6signbs: AU, BR, CA, CS, FI, HU, JP, KR, NO,

RU.

Publiee Avec rapport de recherche internationale.

658664 (54)Title: INDOLINE DERIVATIVES HAVING AN AMIDE FUNCTION, THEIR PREPARATION, AND PHARMA- CEUTICAL COMPOSITIONS CONTAINING THEM (54)Titre: DERIVES D'INDOLINE PORTANT UNE FONCTION AMIDIQUE, LEUR PREPARATION, LES COMPOSI- TIONS PHARMACEUTIQUES EN CONTENANT /2 I 4 (1) S02 (57) Abstract (CH 2 )m The invention relates to compounds of formula wherein RI is a halogen atom, CI-C 4 alkyl, hydroxyl, C 1

-C

4 alkoxy, a group benzyloxy, cyano, trifluoromethyl, nitro or amino; R 2 is C 1

-C

6 alkyl, C 3

-C

7 cycloalkyl, C 5

-C

7 cycloalcen, a phenyl unsubstituted or substituted one or a plurality of times, CI-C 4 alkoxy, halogen, a group trifluoromethyl, a group amino, or R 2 is a nitrophenyl unsubstituted or substituted one or a plurality of times; R 3 is a hydrogen atom; R 4 is a carbamyl group having the formula CONR 6

R

7

R

5 is C 1

-C

4 alkyl; naphtyl-l; naphtyl-2; dimethylamino-5 naphtyl-1; a phenyl unsubstituted or substituted one or a plurality of times, or R 5 is nitrophenyl unsubstituted or substituted one or a plurality of times; R 6 is

CI-C

6 alkyl, or R 6 is similar to R 7

R

7 is a group piperidin-4-yl; a group azetidin-3-yl, said groups being substituted or unsubstituted on the nitrogen by CI-C 4 alkyl, by a benzyloxycarbonyl or by an alkoxycarbonyl in Ci-C 4 a group (CH 2 )r itself substituted by a group pyridyl-2, -3 or by a group hydroxyl, by an amino group free or substituted by one or two substituants; or R 6 and R 7 form together with the nitrogen atom to which they are linked a heterocycle selected amongst: morpholin, thiomorpholin, thiazolidin or 2,2-dimethylthiazolidin unsubstituted or substituted by R 8 piperazin unsubstituted or substituted in 4 by a group R" 8 an unsaturated mononitrogenated cycle with 5 links substituted by R 8 or a saturated mononitrogenated cycle with 3, 4, 5, 6 or 7 links substituted by R 8 and R 9

R

8 is R'g or a group (CH 2 )r itself substituted by hydroxyl or by a free amino or substituted by one or two Ci-C 4 alkyls; R'g is a group (CH2)q itself substituted by a carboxyl group, a group C 1

-C

4 alkoxycarbonyl, a benzyloxycarbonyl group, a group carbamoyl free or substituted by a hydroxyl or by one or two Ci-C 4 alkyls, or a group arninocarbothioyl free or substituted by one or two CI-C 4 alkyls; R" 8 is R' 8 or a group

(CH

2 2

NH

2 free or substituted by one or two Ci-C4; R 9 is hydrogen, halogen, a group (CI- 2 )rORio, a group

(CH

2 )rNRIIRi 2 a group (CH 2 )sCONRIIR'n, a group azido; Rio is hydrogen, C 1

-C

4 alkyl, mesyl or tosyl; R 11

R'

1 l and

R

1 2 are each hydrogen or C-C 4 alkyl or R 1 is hydrogen and R 1 is C-C4 alkoxycarbonyl or benzyloxycarbonyl; n is 0, 1 or 2; m is 0, 1, or 2; q is 0, 1, 2 or 3; r is 0, 1, 2 or 3 with the provision that r is different from 0 when R 8 or R 9 is in the alpha position of the intracyclic amidic nitrogen; s is 0 or 1; as well as its optional salts. These compounds are useful in the treatment of affections of the central nervous system, the cardiovascular system and the gastric system in human beings and animals.

Indoline derivatives carrying an amide functional group, their preparation, and the pharmaceutical compositions in which they are present.

The present invention relates to N-sulfonylindoline derivatives, carrying an amide functional group, their preparation and the pharmaceutical compositions in which they are present.

US Patent 3,838,167 describes some N-sulfonylindole derivatives corresponding to the formula: COR"4 (R"2)n'

SO

2

R"

3 in which is hydrogen, an alkyl or a substituted or unsubstituted phenyl;

R"

2 is a halogen, an alkyl, an alkoxy, a nitro or trifluoromethyl;

R"

3 is an alkyl, a phenyl or an alkylphenyl;

R"

4 is an alkyl, a substituted or unsubstituted phenyl, an alkoxy or a phenoxy; n' 0, 1 or 2.

These compounds 1 are synthesis intermediates for the preparation of indole derivatives active on the central nervous system, of formula:

R"

in which R" is an alkyl, a substituted or unsubstituted phenyl or a hydroxyl.

The indoline derivatives according to the present invention have an affinity for the vasopressin and ocytocin receptors.

Vasopressin is a hormone known for its antidiuretic SA' effect and its effect in the regulation of the arterial 2 pressure. It stimulates several types of receptors: V 1

V

2 Vla, Vl and thus exerts cardiovascular, central, hepatic, antidiuretic, emetic and aggregating effects, as well as proliferative and mitotic effects, especially on the vascular and hepatic tissues. Vasopressin receptor antagonists can affect the regulation of the central or Speripheral circulation, especially the coronary, renal and gastric circulations, as well as the metabolism of water and the release of adrenocorticotrophic hormone (ACTH). The vasopressin receptors, like those of ocytocin, are also found on the smooth muscle of the uterus. Ocytocin has a peptide structure similar to that of vasopressin. Its receptors are also found on the myoepithelial cells of the mammary gland and in the central nervous system. (Presse Medicale, 1987, 16 481-485, J. Lab. Clin. Med., 1989, 114 617-632 and Pharmacol. Rev., 1991, 43 73-108).

Thus the compounds according to the invention are useful especially in the treatment of complaints of the central nervous system, the cardiovascular system and the gastric sphere in humans and animals.

The present invention relates to compounds of formula:

OH

(RN~n

RN

I R4

SO

2 (I)

(CH

2 )m

R

in which RI is a halogen atom, a Ci-C, alkyl, a hydroxyl, a Cl-C, alkoxy, a benzyloxy group, a cyano group, a trifluoromethyl group, a nitro group or an amino group;

R

2 is a Cl-C, alkyl, a C,-C 7 cycloalkyl, a C 5

-C

7 cyclo- 019', alkene or a phenyl which is unsubstituted or mono- .substituted or polysubstituted by a Cl-C 4 alkyl, a i i 3

C-C

4 alkoxy, a halogen, a trifluoromethyl group or an amino group, or R z is a nitrophenyl which is unsubstituted or monosubstituted by a trifluoromethyl group or monosubstituted or polysubstituted by a Cl-C, alkyl or a halogen;

R

3 is a hydrogen atom;

R

4 is a carbamoyl group of formula CONR 6 Ry;

R

5 is a Ci-C 4 alkyl; a 1-naphthyl; a 2-naphthyl; a dimethylamino-l-naphthyl; a phenyl which is unsubstituted or substituted by one or more substituents selected from a halogen atom, a C--C alkyl, a trifluoromethyl group, an amino group which is free or substituted by one or 2 C,-C 4 alkyls, a hydroxyl, a Cl-C, alkoxy, a C 2 alkenoxy, a C-C 4 alkylthio, a trifluoromethoxy group, a benzyloxy group, a cyano group, a carboxyl group, a C 1

-C

4 alkoxycarbonyl group, a carbamoyl group which is free or substituted by one or two Ci-C 4 alkyls or a Cl-C 4 alkylamido group, or R, is a nitrophenyl which is unsubstituted or monosubstituted by a trifluoromethyl group or a C 2

-C

4 alkenoxy or mono- or polysubstituted by a halogen, a C,-C, alkyl, a Cl-C 4 alkoxy, a C 1

-C

4 alkythio, a trifluoromethoxy group or a benzyloxy group; Rs is a Cj-C 6 alkyl or R, is similar to R 7

R

7 is a 4-piperidyl group or a 3-azetidinyl group, the said groups being substituted or unsubstituted on the nitrogen by a Cl-C 4 alkyl, by a benzyloxycarbonyl or by a C 1

-C

4 alkoxycarbonyl; a group (CHz), which is itself substituted by a 3- or 4-pyridyl group, by a hydroxyl group or by an amino group which is free or substituted by one or two CI-C 4 alkyls, a carboxyl group, a Ci-C, alkoxycarbonyl group, a benzyloxycarbonyl group or a carbamoyl group which is free or substituted by one or 2 CI-C 4 alkyls; or R 6 and R 7 together, with the nitrogen atom to which they are connected, form a heterocycle selected from: Smorpholine, S" thiomorpholine,

-I

1 4 thiazolidine or 2,2-dimethylthiazolidine, unsubstituted or substituted by R,, piperazine, unsubstituted or substituted at the 4position by a group R" g an unsaturated, 5-membered ring containing a single nitrogen atom and substituted by R, or a saturated, 6- or 7-membered ring containing a single nitrogen atom and substituted by R 8 and R,; R is R'e or a group (CHz) which is itself substituted by a hydroxyl or by an amino which is free or substituted by one or two C 1

-C

4 alkyls; R' is a group (CH 2 )q which is itself substituted by a carboxyl group, a C 1

-C

4 alkoxycarbonyl group, a benzyloxycarbonyl group, a carbamoyl group which is free or substituted by a hydroxyl or by one or 2 C 1

-C

4 alkyls or an aminocarbothioyl group which is free or substituted by one or 2 Ci-C 4 alkyls;

R"

8 is R's or a group (CH 2 2

NH

2 which is free or substituted by one or two Ci-C 4 alkyls;

R

9 is hydrogen, a halogen, a group (CH 2 ),ORio, a group

(CH

2 )rNRiiR1 2 a group (CH 2 ,"ONRiR' or an azido group;

R

10 is hydrogen, a C 1

-C

4 alkyl, a mesyl or a tosyl;

R

11 R'n 1 and R 1 z are each a hydrogen or a C 1

-C

4 alkyl or

R

11 is hydrogen and R 1 is a benzyloxycarbonyl or a Cl-C, alkoxycarbonyl; n is 0, 1 or 2; m is 0, 1 or 2; q is 0, 1, 2 or 3; r is 0, 1, 2 or 3, with the limitation that r is not zero when R, or R, is at the alpha-position of the intracyclic amide nitrogen; s is 0 or 1; as well as their possible salts.

The salts of the compounds of formula according to the present invention comprise those with inorganic or organic acids which make possible a suitable separation or crystallization of the compounds of formula such

L

5 as picric acid, oxalic acid or an optically active acid, for example a mandelic acid or a camphosulfonic acid, and those which form pharmaceutically acceptable salts such as the hydrochloride, the hydrogensulfate, the dihydrogenphosphate, the methanesulfonate, the maleate, the fumarate or the 2-naphthalenesulfonate.

s The salts of the compounds of formula also i comprise the salts with organic or inorganic bases, for example the salts of alkali or alkaline-earth metals such as the salts of sodium, potassium or calcium, the salts of sodium and potassium being preferred, or with an Samine, such as trometamol, or even the salts of arginine or lysine or of any pharmaceutically acceptable amine.

i The compounds exhibit cis-trans isomerism around 15 the 2,3 bond of the indoline. The different isomers form an integral part of the invention.

By convention, the compounds in which R 2 and R 4 Sare on the same side of the ring are called the cis isomers.

By convention, the compounds in which R 2 and R 4 are on opposite sides of the ring are called the trans isomers. R2 (R

"OH

iSO2 (I)

(CH

2 )m

R

Scis isomer

R

2 I R4

I

2 (I)

I

trans isomer 6 Moreover, the compounds according to the invention have 2 asymmetric carbon atoms or more when R, contains one 1 or 2 asyummetric carbons. The optical isomers of the compounds form part of the invention.

In the present description and in the claims which (allow, halogen is understood as meaning a fluorine, chlorine, bromine or iodine atom; alkyl group is understood as meaning linear or branched hydrocarbon groups.

Preferred compounds according to the invention are those in which at least one of the following conditions is satisfied: R is a chlorine or bromine atom or a methoxy group and n R, is a chlorophenyl, a methoxyphenyl or a cyclohexyl;

R

4 is a group CONR 6

R

7 in which R, and R 7 or NRR 7 have one of the following definitions;

SNR

6

R

7 is a pyrrolidino group which is substituted at the 2-position by a group (CH 2 )q which is itself substituted by a carboxyl or carbamoyl group with q 0, 1, 2 or 3.

SNR

6

R

7 is a piperidino group which is substituted at the 4-position by an amino group, a Ci-C 4 alkylamino or a Cl-C 4 dialkylamino,

SNRR

7 is a thiazolidino group which is substituted by a group (CH 2 )q which is itself substituted by a carboxyl or carbamoyl group with q 0, 1, 2 or 3.

SNR

6

R

7 is a pyrrolidino group which is substituted at the 2-position by a group (CH 2 )q which is itself substituted by a carboxyl or carbamoyl group with q 0, 1, 2 or 3 and which is substituted at the 4-position by an amino group, a Cl-C 4 alkylamino or a C 1

-C

4 dialkylamino; R, is a Ci-C 4 alkyl and R 7 is a group (CH 2 which is itself substituted by a carboxyl group or a carbamoyl 35 group with r 1, 2 or 3; R is a phenyl substituted at the 3- and 4-position or at the 2- and 4-position by a methoxy group, or R s is SEC a phenyl substituted at the 4-position by a methyl 1 0 4 s i 0 t -7group; m =O0.

The compounds which are in the form of the cis isomers are particularly preferred.

The following abbreviations are used in the description and the examples.

DCM: dichloromethane AcOEt: ethyl acetate MeOH: methanol EtOH: ethanol Ether: ethyl ether DMF: dimethylformamide THF: tetrahydrofuran TEA: triethylainine DMSO: dimethyl sulfoxide DIPEA: diisopropylethylamine DCC: N, N'-dicyclohexylcarbodiimide DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene TBD: l,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 TMIEDA: tetramethylethylenediamine LDA: lithium diisopropylamide HXPA: hexamethylphcophoramide HOBT: 1-hydroxybenzotriazole hydrate BOP: benzotriazolyloxytrisdimethylaminophosphoniun hexafluorophosphate TFA: trifluoroacetic acid Lawesson's reagent: 2,4-bis(4-methoxyphenyl)-l,3dithia-2, 4-diphosphetane-2, 4-disulfide melting point Saline solution: water saturated with sodium chloride Dry ice: solid carbon dioxide TLC: thin layer chromatography HPLC: high performance liquid chromatography NMi~R: nuclear magnetic resonance 8 s: singlet m: multiplet bs: broad singlet d: doublet Hydrochloric water: dilute hydrochloric acid, about

IN

NaH: dispersion of sodium hydride in mineral oil .(Janssen Chemica) Me: methyl Et: ethyl iPr: isopropyl, Pr: propyl iPentyl: isopentyl iBu: isobutyl tBu:tert-butyl, Bu: butyl Bz: benzyl Ph: phenyl RT: room temperature The present invention further relates to the process for preparing the compounds This process is characterized in that it comprises: a) reacting a 2-aminophenone derivative of formula:

CO-R

2 -Cl

(II)

(R1)n

NH

2 in which R 1

R

2 and n have the meanings indicated..above for I, with a sulfonyl derivative of formula: Hal-SO 2

-(CH

2 5 (III) in which Hal is a halogen, preferably chlorine or bromine, m and R 5 have the meanings indicated above for b) treating the resulting compound of formula: i 111__11_ I_ 1 I 9

O-R

2 (RI)n

NH

SO

2

(IV)

(CH

2 )m with a halogenated derivative of formula: Hal'-CH 2 COA

(V)

in which Hal' is a halogen, preferably bromine, and A represents either the group NR 6

R

7 or the group OR in which R is a tert-butyl or a benzyl; c) deprotecting the resulting ester of formula:

.COR

2 (RI)n

N-CH

2

COOR

SO

2

(VI)'

(CH2) m under suitable conditions, if applicable, when A is

OR;

d) treating, if applicable, the resulting acid from Step c) of formula: COR 2 (R)n

N-CH

2

COOH

SO2 (VI)

(CH

2 )m or its acid chloride of formula:

COR

2 so 2 (CH2)m

.R

alkyls, a carboxyl group, a C 1

-C

4 alkoxycarbonyl group, a benzyloxycarbonyl group or a carbamoyl group which is free or substituted by one or 2 C-C 4 alkyls; ./3 I I 10 with a compound HNRR 7 according to suitable amide coupling techniques; e) cyclizing the resulting compound from Step b) or from Step d) of formula:

CH

2

CONR

6 R7 02

(CH

2 )m

R

(VI)

in a basic medium in order to prepare the compound according to the invention; f) separating, if appropriate, the cis and trans isomers of the compound and, if appropriate, separating the enantiomers.

The 2-aminophenone derivatives (II) are known or prepared by known methods, such as those described by A.K. Singh et al., Synth. Commun. 1986, 16 485 and G.N. Walker, J. Org. Chem., 1962, 27, 1929. The 2-amino- 2'-trifluoromethylbenzophenones and the other trifluoromethylated derivatives are prepared according to US Patent 3,341,592.

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

The sulfonyl derivatives of formula (III) are known or prepared by known methods. Thus, for example, 4dimethylaminobenzenesulfonyl chloride is prepared according to C.N. Sukenik et al., J. Am. Chem. Soc., 1977, 99, 851-858; p-benzyloxybenzenesulfonyl chloride is prepared according to European patent application EP 229,566.

The alkoxybenzenesulfonyl chloride is prepared from the sodium alkoxybenzenesulfonate, which is itself prepared by reacting an alkyl halide with sodium hydroxybenzenesulfonate.

The halogenated derivatives of formula are known or prepared by known methods, such as those described by A.I. Vogel: A Text Book of Practical Organic Chemistry: Longman, 3rd ed. 1956, p. 383, or G. Kirchner et al., I i ~r~n.

1 t 11 J. Am. 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 of between a few hours and a few days. If appropriate, the reaction can be carried out in the presence of dimethylaminopyridine, which is used in a catalytic or stoichiometric amount.

Step b) of the process is carried out between the sulfonamide of formula (IV) and an excess of the halogenated derivative of formula in a solvent such as dimethylformamide or dimethyl sulfoxide, under an inert atmosphere, at a temperature of between 0°C and room temperature, for a time of between a few hours and 24 hours, in the presence of sodium hydride.

When the group -NRgR 7 contains a second amine group, that is to say whe- R, and/or R 7 are 3ubstituted by an amino group, it is possible to choose to use a halogenated derivative of formula Hal'-CHz-CO 2 R in which R is a tert-butyl or a benzyl, in order to prepare the intermediates of formula and then In this case, Step c) for the formation of the acid of formula 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 acid medium, when R is tert-butyl, for example in the presence of TFA or in the presence of hydrobromic acid in acetic acid or even in the presence of ZnBr 2 in DCM.

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

The compounds HNRgR 7 are known or prepared by known methods. By way of example, the stereospecific synthesis of and (S)-2-pyrrolidinylacetic acids is carried out according to H. Rueger et al. in Heterocycles, 1982, 19 1677 from a proline derivative of suitable configuration. The preparation of methyl N-Boc-3,4-dehydroi a-prolinate is carried out according to J.R. Dormoy, I S i 12 Synthesis, 1982, 753. The preparation of optically pure derivatives of pipecolic acid is described, for example, in Tetrahedron, 1992, 48 431-442 and Tetrahedron, 1991, 47 (24) 4039-4062.

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

Step e) of the process is closely related to an aldolization reaction: the methylene group in the ai 10 position of the amide is deprotonated and the carbonyl group of the phenone then acts like an internal electrophile, resulting in cyclization with the appearance of two asymmetric carbons The reaction can be illustrated by the following scheme: O C R 2

I

0c- Si I(R 1-

SO

2

H

i (H2)m

R

5 OH

R

IR

The'principles of the aldol addition reaction have been reviewed by C.H. Heathcock in 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 gives rise to the formation of 2 racemic diastereoisomers of p-hydroxyamides in a ratio which depends largely on the experimental conditions used. The following may be mentioned among these conditions: the nature of the inorganic or organic base used, the nature I I- 13 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 undergoing this reaction.

When the groups R 6 and R 7 do not contain a group which is hydrolysable in alkaline medium, 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 a quaternary ammonium hydroxide, for example benzyltrimethylammonium hydroxide in methanol.

In order 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-5ene, 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 a mixture of solvents selected for example from benzene, THF, dichloromethane, methanol and dimethylformamide; the reaction is carried out under an inert atmosphere at between -10°C and 110OC; the amount of base used is at least stoichiometric; the reaction can also be carried out without a solvent, at the temperature of the bath.

Preferentially, Step e) of the process according to the invention is carried out in the presence of 1,8diazabicyclo[5.4.0]undec-5-ene (DBU) in a solvent such as dichloromethane or methanol, at a temperature of between and the reflux temperature of the solvent.

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

The alcoholate is used in a catalytic or stoichiometric amount in an anhydrous solvent, for example an alcohol (if appropriate in the presence of a cosolvent such as THF), or else in a stoichiometric amount in THF, DMF or DMSO, if appropriate in the presence of crown Sethers, for example dicyclohexyl-18-crown-6; the reaction /'z 4 .C; I 14 is carried out at between -15'C and The use of an amide of the type RR'NLi or RR'NMgBr, in which R and R' are monovalent radicals, as a deprotonating agent is a method of forming enolates of amides, which are intermediates in the aldolization reaction; this method has recently been reviewed by R.E.

Ireland et al., J. Org. Chem., 1991, 56, 650. The reaction solvent can be benzene, hexane or THF used in anhydrous form under an inert atmosphere. Adjuvants such as LiF, LiCI, LiBr, LiI, LiBu, TMEDA, DMPU, HMPA or a crown ether can be added. Murakate et al., J. Chem.

Soc. Commun., 1990, 1657). By way of example, there may be mentioned the use of lithium diisopropylamide at between -78 0 C and -30 0 C in anhydrous THF under an inert atmosphere or in THF in the presence of additives such as, for example, tetramethylenediamine, DMPU or HMPA.

Examples of other known amides which can be used are lithium cyclohexylamide and lithium 2,2,6,6-tetramethylcyclohexylamide. It is also possible to prepare other amides by reacting the requisite amount of butyllithium in hexane with linear or cyclic secondary amines, the reaction taking place in one of the solvents mentioned above.

Finally, various publications describe amides of optically active secondary amines: L. Duhamel et al., Bull. Soc. Chim. France, 1984, II, 421; J.K. Whitesell et al., J. Org. Chem., 1980, 45, 755; M. Murakata et al., J.

Chem. Soc. Chem. Commun., 1990, 1657; M. Yamaguchi, Tetrahedron Lett., 1986, 27 959; P.J. Cox and N.S.

Simpkins, Tetrahedron: Asymmetry, 1991, 2 1.

The silylamides of lithium, sodium or potassium constitute another group of bases which can be used, among which there may be mentioned: (Me 3 Si) 2 NLi, (Me 2 PhSi) 2 NLi, (Et 3 Si) 2 NLi, (Me 3 Si) 2 NK, (Me 3 Si)zNNa.

It is also possible to use mixed amides as described by Y. Yamamoto, Tetrahedron, 1990, 46, 4563, for example the lithium salt of N-(trimethylsilyl)benzylamine or an analog in which the benzylamine is replaced with a chiral V F i y~ 15 primary amine such as or (S)-a-methylbenzylamine.

When the compound of formula to be prepared has 2 asymmetric carbon atoms, the use of chiral amides or alcoholates in Step e) makes possible an enantiomeric enrichment of each of the cis or trans stereoisomers. The proportion of each of the enantiomers is then determined by measurement on a chiral high performance liquid chromatography column.

When the compound of formula to be prepared has 3 or 4 asymmetric carbon atoms, the cyclization Step c) can be accompanied by a diastereoisomeric enrichment and the use of a suitable chiral base makes it possible to modify this diastereoisomeric enrichment.

In Step the cis and trans geometric isomers of the compound formed are extracted by conventional methods and separated by chromatography or fractional crystallization.

If appropriate, the optical isomers of each of the cis and trans isomers are separated, for example by preparative chromatography on a chiral column followed, if appropriate, by a fractional crystallization or by formation of an optically active salt in the presence of a suitably selected chiral acid or base.

Thus, when the compound according to the invention has 2 asymmetric carbon atoms, the enantiomers can be separated by chiral HPLC.

When the compound according to the invention has 3 or 4 asymmetric carbon atoms, the diastereoisomers can be separated by using chromatographic methods and fractional crystallization methods.

Several methods can be used to differentiate and characterize the cis isomer and the trans isomer of a Icompound When R 3 is hydrogen, a comparative analysis is performed by high field NMR (250 MHz), coupled for example with the study of the Overhauser effect between, for example, the proton of the indoline (R 3

H)

Sand the proton of the hydroxyl.

I 16 The IR spectra of the cis isomer and the trans isomer in solution in DCM are different. The cis isomer most commonly has a strong, fine and symmetrical absorption band at around 3550-3520 cm" due to the hydroxyl vibration, whereas the trans isomer has no resolved vibration band in this region.

SBy means of the data collected, it has been found that the cis isomer is generally the more mobile in TLC on an aluminum oxide plate (60F254 neutral, Type E, Merck), eluting with DCM containing variable proportions of AcOEt. Similarly, in chromatography on an alumina column (aluminum oxide 90, particle size 0.063-0.200 mm), the cis isomer is most commonly eluted first, the eluent being DCM containing variable proportions of AcOEt or MeOH.

Thus the cis or trans isomerism of a compound (I) according to the invention can most often be determined by an analytical method. It is also possible to utilize the analogy between similar compounds or between compounds prepared from one another.

The absolute configuration of some compounds according to the invention was determined by an X-ray analysis.

By deduction therefrom, taking into account the value of the optical rotation, it is also possible to know the absolute configuration of other compounds obtained in an analogous fashion.

A compound in which R, is an amino group and/or a compound in which R 5 is a phenyl group which is substituted by an amino can be prepared by the conversion of a compound obtained in Step in which R, is a nitro group and/or R 5 is a phenyl group which is substituted by a nitro, the other substituents having the Smeanings desired for by catalytic hydrogenation, for example in the presence of palladium on charcoal, or rhodium on alumina or Raney nickel.

The compounds in which the substituents R, and/or

R

7 or the group NR 6

R

7 contain a C-C, alkoxycarbonyl group make it possible to obtain, by hydrolysis of the ester, 't 1 1 n 17 the compounds in which R 6 and/or R 7 or the group NR6R 7 contain a carboxyl group, the other substituents of (I) being unchanged. Furthermore, the compounds in which R 6 and/or R 7 or NR6R 7 contain a carboxyl group make it possible to obtain, by a conventional amide coupling reaction, the compounds in which R, and/or R 7 or the group NR 6

R

7 contain a carbamoyl group which is free or substituted by one or two C 1

-C

4 alkyls, the other substituents being identical.

Finally, the compounds in which R, and/or R 7 or the group NR 6

R

7 contain a carbamoyl group make it possible to obtain, by a Hofmann rearrangement, the compounds (I) in which R, and/or R 7 or the group NR 6

R

7 contain an amino group, the other substituents being identical Org.

Chem., 1979, 44 1746).

Thus, according to the present invention, the process for preparing compounds in which R 6 and/or R 7 or the group NR 6

R

7 contain an amino group which is free or substituted by one or two Ci-C 4 alkyls can have two variants: i) Step b) of the process is carried out by treating the compound (IV) obtained in Step a) with a halogenated derivative of formula Hal'-CH 2

CONR

6

R

7 in which R 6 and/or R 7 or the group NRR 7 contain a precursor group of the amine, for example a carboxyester, a carboxyl or a carbamoyl; the cyclization Step e) is then carried out and the precursor group of the amine is then converted into the amine, for example the carboxyester group of'the compound thus obtained is hydrolyzed into a carboxyl group, which is then converted into a carbamoyl group and then into an amino group by the Hofmann rearrangement.

ii) Step b) is carried out by treating the compound (IV) obtained in Step a) with an halogenated derivative of formula Hal'-CH 2 COOR in which R is a benzyl or a tert-butyl; the ester of the compound thus obtained is deprotected by a suitable treatment, according to Step a coupling is then carried out with the compound

HNR

6

R

7 in which the amino group of R. and/or R, is, if 3 i: .T- ~C i -ii 1 k -r 18 appropriate, protected; the compound (VI) thus obtained is then cyclized according to Step and, if appropriate, the compound in which the amino group is free is prepared by deprotecticn of the amine.

The compounds in which the groups R 6 and/or R 7 or the group NR 6 R, contain a benzyloxycarbonyl or alkoxycarbonyl group as substituent of an amine group make it possible to obtain the compounds in which the amine group is free, the other substituents being identical.

The compounds of formula useful as intermediates for the preparation of compounds (I) according to the invention, are novel and form part of the invention. Likewise, the compounds and (VI)" are novel and form part of the invention.

:1: 15 The reaenL inntion hu ri eas! t he Compounds of formula: 14 COR2 (RI) N-CH-, COA' 02 6

(CH

2 )m

R

whenFused as an intermediatesin the preparation of a compound a of formula as defined above in which A' is a group selected from: NRR 7 OH, OtBu, OBz; 20 Ri is a halogen atom, a C 1

-C

4 alkyl, a hydroxyl, a CI-C, alkoxy, a benzyloxy group, a cyano group, a trifluoromethyl group, a nitro group or an amino group;

R

2 is a Ci-C alkyl, a C 3

-C

7 cycloalkyl, a Cs-C 7 cycloalkene or a phenyl which is unsubstituted or monosubstituted or polysubstituted by C-C4 alkyl, a Ci-C 4 alkoxy, a halogen, a trifluoromethyl group or an amino group, or R, is a nitrophenyl which is unsubstituted or monosubstituted by a trifluoromethyl group or monosubstituted or polysubstituted by a C alkyl, a C-C, alkoxy or a halogen; i, 19

R

5 is a Ci-C 4 alkyl; a 1-naphthyl; a 2-naphthyl; a 5-dimethylamino-1-naphthyl; a phenyl which is unsub stituted or substituted by one or more substituents selected from a halogen atom, a C 1

-C

4 alkyl, a trifluoromethyl group, an amino group which is free or substituted by one or 2 Cl-C 4 alkyls, a hydroxyl, a

C

1

-C

4 alkoxy, a C 2

-C

4 alkenoxy, a Ci-C, alkylthio, a trifluoromethoxy group, a benzyloxy group, a cyano group, a carboxyl group, a Ci-C 4 alkoxycarbonyl group, a carbamoyl group which is free or substituted by one or two C 1

-C

4 alkyls or a C 1

-C

4 alkylamido group, or R, is a nitrophenyl which is unsubstituted or monosubstituted by a trifluoromethyl group or a Cz-C, alkenoxy or mono- or polysubstituted by a halogen, a Cl-C 4 alkyl, a Ci-C 4 alkoxy, a C 1

-C

4 alkylthio, a trifluoromethoxy group or a benzyloxy group; R. is a Ci-C 6 alkyl or R, is similar to R,;

R

7 is a 4-piperidyl group or a 3-azetidinyl group, the said groups being substituted or unsubstituted on the nitrogen by a Ci-C 4 alkyl, by a benzyloxycarbonyl or by a C 1

-C

4 alkoxycarbonyl; a group (CH 2 which is itself substituted by a 3- or 4-pyridyl group, by a hydroxyl group or by an amino group which is free or substituted by one or two C 1

-C

4 alkyls, a carboxyl group, a Cl-C, alkoxycarbonyl group, a benzyloxycarbonyl group or a carbamoyl group which is free or substituted by one or 2 C 1

-C

4 alkyls; or R 6 and R, together, with the nitrogen atom to which they are connected, form a heterocycle selected from: morpholine, Sthiomorpholine, thiazolidine or 2,2-dimethylthiazolidine, unsubstituted or substituted by R 8 piperazine, unsubstituted or substituted at the 4-position by a group R" 8 an unsaturated, 5-membered ring containing a single nitrogen atom and substituted by R 8 or -k 20 Sa saturated, 6- or 7-membered ring con- Staining a single nitrogen atom and substituted by R 8 and R,; R, is R'i or a group (CH 2 )r which is itself substituted by a hydroxyl or by an amino which is free or substituted by one or two C 1

-C

4 alkyls;

R'

8 is a group (CH 2 )q which is itself substituted by a carboxyl group, a Ci-C, alkoxycarbonyl group, a benzyloxycarbonyl group, a carbamoyl group which is free or substituted by a hydroxyl or by one or 2 C 1

-C

4 alkyls or an aminocarbothioyl group which is free or substituted by one or 2 Ci-C 4 alkyls; R"8 is R' 8 or a gro,-? (CH) 2

NH

2 which is free or substituted by one or .wo C 1

-C

4 alkyls;

R

9 is hydrogen, a halogen, a group (CH 2 )rOR 0 a group

(CH

2 )rNRnRz2, a group (CH 2 )sCONR,,R', 1 or an azido group;

R

1 0 is hydrogen, a Ci-C 4 alkyl, a mesyl or a tosyl; Rl 1 R'n and R 12 are each a hydrogen or a Cz-C 4 alkyl or

R

1 is hydrogen and R 1 2 is a benzyloxycarbonyl or a C1-C4 alkoxycarbonyl; n is 0, 1 or 2; m is 0, 1 or 2; qis 0, 1, 2 or 3; r is 0, 1, 2 or 3, with the limitation that r is not zero when R, or R, is at the alpha-position of the intracyclic amide nitrogen; s is 0 or 1; According to another aspect of the present invention, the compounds according to the invention in which either R, or the group NR 6

R

7 contains a carboxyl group are useful for the preparation of analogous decarboxylated compounds.

z i 0€ x 0 -r ~r~~l 21 According to this aspect, the invention relates to the use of the compounds of formula R2 n- OH S(R :1 I CONRVIRVII

SO

2 (CH2)m

R

SI' in which R1R 2

,R

3

R

5 m and n have the meanings indicated above for compounds of formula (I) -RVI is a Cl-Cg alkyl, i. 15 -RVII is a group (CH2)rCOOH with r 1, 2 or 3, or RVI and RVII together, with the nitrogen atom to which they are connected, constitute a heterocycle 4 selected from: thiazolidine or 2,2-dimethylthiazolidine, S 20 substituted by a (CH2)qCOOH group, piperazine substituted at the 4-position by a S.(CH2)qCOOH group, San unsaturated, 5-membered ring containing a single nitrogen atom and substituted by a (CH2)qCOOH group a saturated, 6- or 7-membered ring containing a single nitrogen atom and substituted by a (CH2)qCOOH group, with q 0, 1, 2 or 3 for the preparation of a compound of formula via freeradical decarboxylation, said compound of formula having the same configuration around the 2,3 bond of the indoline as the starting material <rt* 22- R2 (R)n R (I)

N

I CONR'VIR'VII S02 in which

R

1

R

2

R

3

R

5 m and n are as defined above, R'VI is a C 1

-C

6 alkyl, R'VII is a group (CH2)rH, or R'VI and R'VII together, with the nitrogen atom to which they are connected, constitute a heterocycle selected from thiazolidine or 2,2-dimethylthiazolidine, substituted by a (CH2)qH group, S. piperazine substituted at the 4-position by a (CH2)qH group, an unsaturated, 5-membered ring containing a single

S

i 20 nitrogen atom and substituted by a (CH2)qH group or a saturated, 6- or 7-membered ring containing a single nitrogen atom and substituted by I: a (CH2)qH group.

The free-radical decarboxylation reaction is S. 25 carried out according to D. H. R. Barton et al. in J.

Chem. Soc; Chem. Commun.; 1984, 1298.

The affinity of the compounds according to the 25 invention for the vasopressin receptors was determined in vitro using the method described in J. Biol. Chem., 1985, 260 2844-2851. This method consists in studying the displacement of tritiated vasopressin bound to the V, sites of rat liver membranes. The 50% inhibitory concentrations (ICso) of the compounds according to the invention for the binding of tritiated vasopressin are Thj i ~11-1 23low, ranging up to 10-9M.

Furthermore, the inhibition of the platelet aggregation induced by vasopressin was measured on a human platelet rich plasma (human PRP) using the method described in Thrombosis Res., 1987, 45, 7-16. The compounds according to the invention inhibit the aggregation induced by 50 to 100 nM concentrations of vasopressin with low ID.

0 values (inhibitory doses) which range up to 9 M. These results show the antagonistic activity of the compounds according to the invention towards the V, receptors.

The affinity of the compounds according to the invention for the V 2 receptors was measured by a method adapted from P. Crause et al., Molecular and Cellular Endocrinology, 1982, 28, 529-541.

The compounds according to the invention of cis configuration around the 2,3 bond of the indoline have a marked selectivity for the V, receptors.

The affinity of the compounds according to the -invention for the ocytocin receptors was determined in vitro by the displacement of tritiated ocytocin bound to the receptors of a membrane preparation of gestating she-rat glands. The IC.5 values of the compounds according to the invention are low, of between 10- 5 M and 10- 8

M.

The compounds according to the invention are active after administration by various routes, especially orally.

No sign of toxicity is observed with these compounds at the pharmacologically active doses.

Thus the compounds according to the invention can be used in the treatment or prevention of various vasopressin-dependent complaints, especially cardiovascular complaints such as hypertension, cardiac insufficiency, thrombosis or coronary vasospasm, in particular in smokers; complaints of the central nervous system, for example cerebral edemas, psychotic states, appetite disorders or memory disorders; complaints of the 1 renal system, such as renal vasospasm or necrosis of the i\"T -24 renal cortex; and complaints of the gastric system, for example ulcers or else the syndrome of inappropriate secretion of antidiuretic hormone (SIADH).

The compounds according to the invention can also be used as antiemetics, especially in motion sickness, and as antiproliferative agents, for example in cancer or Satherosclerosis.

In woman, the compounds according to the invention can also be used for the treatment of dysmenorrhea or premature labor.

The present invention further relates to pharmaceutical compositions containing an effective dose of a compound according to the invention, or of a pharmaceutically acceptable salt, and suitable excipients. Said excipients are chosen according to the pharmaceutical form and the desired mode of administration.

In the pharmaceutical compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, intratracheal, intranasal, transdermal or rectal administration, the active principles of formula I above, or their possible salts, can be administered to animals and humans in unit forms of administration, mixed with conventional pharmaceutical carriers, for the prophylaxis or treatment of the above disorders or diseases. Appropriate unit forms of administration include forms for oral administration, such as tablets, gelatin capsules, powders, granules and solutions or suspensions to be taken orally, forms for sublingual, buccal, intratracheal or intranasal administration, forms for subcutaneous, intramuscular or intravenous administration and forms for rectal administration. For topical application, the compounds according to the invention can be used in creams, ointments or lotions.

To obtain the desired prophylactic or therapeutic effect, the dose of active principle can vary between 0.01 and 50 mg per kg of body weight and per day.

441 1 yYr~-- i 25 Each unit dose can contain from 0.5 to 1000 mg, preferably from 1 to 500 mg, of active ingredients in combination with a pharmaceutical carrier. This unit dose can be administered 1 to 5 times per day so as to administer a daily dosage of 0.5 to 5000 mg, preferably 1 to 2500 mg.

If a solid composition in the form of tablets is prepared, the main active ingredient is mixed with a pharmaceutical vehicle such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic or the like. The tablets can be coated with sucrose, a cellulose derivative or other appropriate substances or they can also be treated so as to have a prolonged or delayed activity and so as to release a predetermined amount of active principle continuously.

A preparation in the form of gelatin capsules is obtained by mixing the active ingredient with a diluent and pouring the resulting mixture into soft or hard gelatin capsules.

A preparation in the form of a syrup or elixir or for administration in the form of drops can contain the active ingredient in combination with a sweetener, which is preferably calorie-free, and methylparaben and propylparaben as antiseptics, as well as with a flavoring and an appropriate color.

Water-dispersible granules or powders can contain the active ingredient mixed with dispersants or wetting agents or with suspending agents such as polyvinylpyrrolidone, as well as with sweeteners or taste correctors.

Rectal administration is effected using suppositories which are prepared with binders melting at the rectal temperature, for example cocoa butter or polyethylene glycols.

Parenteral administration is effected using aqueous suspensions, isotonic saline solutions or sterile and injectable solutions which contain pharmacologically compatible dispersants and/or wetting agents, for example 26 propylene glycol or butylene glycol.

The active principle can also be formulated as microcapsules, if appropriate with one or more carriers or additives.

Apart from the products of formula I above or one of Sthe pharmaceutically acceptable salts, the compositions Sof the present invention can contain other active principles which may be useful in the treatment of the disorders or diseases indicated above.

Thus the present invention relates to pharmaceutical compositions containing a plurality of active principles in association, one of which is a compound according to the invention.

The following examples illustrate the invention.

The compounds are characterized by their melting point (or their boiling point and/or their NMR spectrum recorded at 200 MHz in DMSO, and/or their optical rotation (aD) measured at 25"C (except when otherwise indicated).

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

Except when otherwise indicated, the designation "cis isomer" or "trans isomer" signifies that the isolated compound is a mixture of enantiomers, either of cis configuration or of trans configuration.

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

EXAMPLE 1 N-methyl-N-methoxycarbonylmethyl-5-bromo-3-(2fluorophenyl)-l-(3,4-dimethoxyphenylsulfonyl)-3-hydroxy- 2-indolinecarboxamide, cis isomer.

A) Methyl N-bromoacetylsarcosinate.

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

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

A 1~ c: I-1; I 27 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 off, the solid is extracted with AcOEt, the organic phase is washed with water, a solution of hydrochloric acid water and then saline water. After drying over magnesium sulfate and evaporating the solvent under vacuum, a solid is obtained which is recrystallized from DCM/isopropyl ether.

m 28 g M.p. 125-128 0

C.

C) 5-Bromo-2-[N-(3,4-dimethoxyphenylsulfonyl)-N-(N'methyl-N'-(methoxycarbonylmethyl)carbamylmethyl)]amino- 2'-fluorobenzophenone.

g of the compound prepared in Step B are dissolved in anhydrous DMF at 0°C under argon and 250 mg of sodium hydride are added; after 15 minutes, 4.85 g of the compound prepared in Step A are added and the mixture is left stirring at RT for 12 hours. The reaction mixture is poured into water, the solid is filtered off and then the solid is dissolved in AcOEt, the organic phase is washed with water and then with saline water and the solvent is evaporated under vacuum. The oil obtained is filtered on silica by eluting with a DCM/AcOEt (85/15 v/v) mixture. It is recrystallized from a DCM/isopropyl ether/MeOH mixture.

m 3.2 g M.p. 136-137 0

C.

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

3.2 g of product obtained in the preceding step are dissolved in DCM (3 ml), 750 mg of DBU are added and the mixture is left stirring at RT for 24 hours. The reaction mixture is poured onto a silica column; by eluting with DCM/AcOEt (90/10 a product is obtained which is S the mixture of the two isomers (cis and trans) of the

'-I

l 28 expected compound. This product is triturated in a hexane/isopropyl ether mixture and the solid obtained is filtered. The filtration liquors are chromatographed on an alumina column which was preequilibrated in a DCM/AcOEt (70/30 v/v) mixture. The least polar compound is eluted with a DCM/AcOEt (60/40 v/v) mixture and is then recrystallized from a DCM/hexane/isopropyl ether mixture.

M.p. 95°C with evolution of gas.

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

A) l-Bromacetyl-4-(benzyloxycarbonyl)piperazine.

A mixture of 22 g of 4-benzyloxycarbonylpiperazine and 10.1 g of triethylamine in 200 ml of ether is cooled to 0°C. 20.2 g of bromoacetyl bromide in 100 ml of ether are added over 30 minutes and the mixture is left to return to RT. After 4 hours, the reaction mixture is washed with water, dried, concentrated and then chromatographed on silica. The mixture DCM/AcOEt (95/5 v/v) elutes the expected compound which is recrystallized from DCM/isopropyl ether.

m=9 g M.p. 100-101"C.

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

5.6 g of 2-amino-2',5-dichlorobenzophenone and 5 g of *3,4-dimethoxyphenylsulfonyl chloride are heated in pyridine at 100*C overnight. The pyridine is evaporated to dryness, water is added and extraction is carried out with ethyl acetate containing a small amount of DCM.

After washing more than once with water and drying over sodium sulfate, the extract is evaporated under vacuum and 7.7 g of the expected product are recrystallized in a DCM/AcOEt mixture.

M.p. 164 0

C.

i; ~1_~11_7~ 29 C) 2',5-Dichloro-2-[N-(3,4-dimethoxyphenylsulfonyl)-N-(4benzyloxycarbonyl-l-piperazinylcarbonylmethyl)]aminobenzophenone.

2.3 g of the benzophenone prepared in Step B are placed in 10 ml of DMF and treated with 200 mg of sodium hydride in oil. After 30 minutes, 5.3 g of the compound prepared in Step A are added and the mixture is stirred for 60 hours at RT. The mixture is poured into water, the precipitate is filtered, taken up in DCM, dried and then concentrated and chromatographed on silica. The DCM/AcOEt (90/10 v/v) mixture elutes the expected product which crystallizes from a DCM/isopropyl ether mixture.

m= 2 g M.p. 173-175°C.

D) 2-[(4-Benzyloxycarbonyl)-l-piperazinyl]carbonyl-5chloro-3-(2-chlorophenyl)-l-(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 THF and is treated with 75 mg of sodium methylate. After 2 hours, the mixture is neutralized by the addition of a small amount of dry ice, is concentrated 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 DCM/AcOEt (80/20; v/v) mixture elutes the 2 isomers successively.

The least polar isomer is recrystallized from a DCM/hexane mixture. This compound is the cis isomer.

m 262 mg M.p. 169-179"C.

The most polar isomer is recrystallized from the DCM/isopropyl ether mixture.

m 200 mg M.p. 209-211C.

EXAMPLE 4 5-Chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-3-hydroxy-2-(l-piperazinylcarbonyl)indoline, II 1 L1III ii 30 cis isomer.

200 mg of the cis isomer prepared in the preceding example are dissolved in 10 ml of ethanol and 5 ml of THF and are hydrogenolyzed at RT in the presence of 10% Pd/C.

After 30 minutes, the mixture is filtered on Celites, the filtration liquors are concentrated and then chromatographed on silica. The MeOH/DCM (10/90 v/v) mixture elutes the expected product which is recrystallized from a DCM/isopropyl ether mixture.

m 110 mg M.p. 230-233°C.

EXAMPLES 5 and 6 5-Chloro-3-(2-chlorophenyl)-l-(3,4-dimethoxyphenylsulfonyl)-3-hydroxy-2-morpholinocarbonylindoline, cis isomer and trans isomer.

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

g of 2',5-dichloro-2-(3,4-dimethoxyphenylsulfonamido)benzophenone are treated with 350 mg of I 20 sodium hydride in 30 ml of DMF at RT for 20 minutes.

g of morpholinebromoacetamide are added and then the mixture is stirred at RT for 48 hours. The mixture is poured into water, the precipitate is filtered, it is dissolved in DCM, the solution is dried and concentrated.

The product formed is recrystallized from a DCM/isopropyl ether mixture. 5.4 g are obtained.

M.p. 173-176°C.

B) 5-Chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-3-hydroxy-2-morpholinocarbonylindoline, cis isomer.

1 g of the product obtained in the preceding step is dissolved in the methanol (10 ml) and THF (20 ml) mixture and is treated with 92 mg of sodium methylate at RT for 1 hour. The mixture is neutralized with dry ice, the solvents are partly evaporated, the mixture is taken up in water, extracted with DCM and the extract is dried, concentrated and chromatographed on alumina. The DCM/AcOEt (70/30; v/v) mixture elutes the least polar 31isomer which is recrystallized from a DCM/isopropyl ether mixture.

m 215 mg: cis isomer M.p. 260-264 0

C.

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

By the chromatography of the preceding step, a more polar product is collected by eluting with the AcOEt/MeOH (90/10) v/v) mixture. After recrystallizing from a DCM/isopropyl ether mixture, there is obtained: m 513 mg: trans isomer M.p. 240-241"C.

EXAMPLE 7 N-Methyl-N-carboxymethyl-5-bromo-3-(2-fluorophenyl)- 1-(3,4-dimethoxyphenylsulfonyl)-3-hydroxy-2-indolinecarboxamide, cis isomer.

200 mg of the compound prepared in Example 1 are dissolved in 3 ml of MeOH and 1 ml of water containing 13 mg of sodium hydroxide. After stirring for 24 hours at RT, one drop of concentrated sodium hydroxide solution is added to bring the reaction to an end and then, after minutes, the mixture is acidified to pll 3 by addition of a potassium hydrogensulfate solution. Water is added, the mixture is extracted with AcOEt and the extract is washed with water and dried over magnesium sulfate and the solvent is evaporated under vacuum. The product obtained is recrystallized from DCM/isopropyl ether.

M.p. 206-208"C.

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

A) Ethyl N-bromoacetyl-4-piperidinecarboxylate.

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

i: I s lJ'- tus r"I i 32 B) 2',5-Dichloro-2-[N-(3,4-dimethoxyphenylsulfonyl]-N-(4ethylcarboxylatepiperidinocarbonylmethyl)]aminobenzophenone.

8 g of 2',5-dichloro-2-(3,4-dimethoxyphenylsulfonamido)benzophenone are dissolved in 100 ml of DMF and then 541 mg of sodium hydride are added. After stirring for 30 minutes, 9.5 g of the compound of Step A are added and the mixture is left stirring for 18 hours at RT. The mixture is concentrated under vacuum, taken up in water, extracted with ethyl acetate and the extract is dried and concentrated. The oil obtained is chromatographed on silica, eluting with the AcOEt/DCM/hexane (40/10/50 v/v/v) mixture. The expected product crystallizes from ether.

m 3.5 g M.p. 128"C.

C) 5-Chloro-3-(2-chlorophenyl)-l-(3,4-dimethoxyphenylsulfonyl)-3-hydroxy-2-(4-ethylcarboxylatepiperidinocarbonyl)indoline, cis isomer, trans isomer.

A mixture containing 3.4 g of the compound prepared in the preceding step and 869 mg of DBU in 10 ml of chloroform is brought to 60"C for 18 hours. The reaction mixture is then filtered on an alumina column, eluting with a DCM/AcOEt (90/10; v/v) mixture in order to obtain the cis isomer.

m 700 mg M.p. 110°C.

Pure ethyl acetate elutes the trans isomer.

m 610 mg M.p. 187C.

EXAMPLES 10 and 11 N-methyl-N-(2-pyridylethyl)-5-chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-3-hydroxy-2indolinecarboxamide, cis isomer, trans isomer.

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

a) 2',5-Dichloro-2-(3,4-dimethoxyphenylsulfonamido)- "4 benzophenone.

\X<I

;k -33 ii This compound is prepared in Example 2-3, Step B.

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

172 g of the product prepared previously are V 5 dissolved in 800 ml of DCM and cooled to 0°C. 11.7 g of sodium hydride is added progressively under nitrogen and then, after 30 minutes, 256 g of benzyl bromoacetate are added and the mixture is left stirring for 24 hours at RT. The DMF is evaporated, the residue is taken up in Vt 10 water, extracted with DCM, and the extract dried and concentrated. The expected product crystallizes from isopropyl ether and is then recrystallized from a j DCM/isopropyl ether mixture.

m 136.5 g 15 M.p. 102-104°C.

j c) N-[2-(2-Chlorophenylcarbonyl)-5-chlorophenyl]-N- (3,4-dimethoxyphenylsulfonyl)glycine acid.

g of the benzyl ester obtained previously are dissolved in 500 ml of AcOEt and 2.5 g of 5% Pd/C are added under nitrogen. The solution is vigorously stirred and a stream of hydrogen is passed in for 5 hours. At the end of the hydrogenation, the product crystallizes. The mixture is filtered on Celite®, the cake is washed copiously with hot DCM and then the organic phase is concentrated. The expected product crystallizes and is then recrystallized from the DCM/isopropyl ether mixture.

m 33.7 g SM.p. 177-178 0

C.

B) 2' ,5-Dichloro-2-[N-(3,4-dimethoxyphenylsulfonyl)-N- (N'-(2-(2-pyridyl)ethyl)-N'-methyl)carbamoylmethyl]aminobenzophenone.

2 g of the acid prepared in Step A are placed in ml of DCM and 1.13 g of 2-(2-methylaminoethyl)pyridine, then 844 mg of triethylamine and finally 1.92 g of BOP are added and then the mixture is left stirring for 18 hours at RT. The mixture is taken up with water, the organic phase is separated, washed with a sodium carbonate solution, dried and concentrated. After 4C ti 34 chromatography on silica, the expected product is collected by eluting with the DCM/MeOH v/v) mixture.

m 2 g M.p. 150°C.

C) N-methyl-N-(2-pyridylethyl)-5-chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-3-hydroxy-2indolinecarboxamide.

A mixture containing 1.7 g of the product obtained in the preceding step and 442 mg of DBU in DCM is heated at 55"C for 18 hours. The reaction mixture is chromatographed on alumina. The AcOEt/DCM (40/60); v/v) mixture elutes the cis isomer: m 410 mg M.p. 191 0

C.

Pure AcOEt elutes the trans isomer: m 790 mg M.p. 154 0

C.

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

500 mg of the cis isomer prepared in Example 9 are placed in 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 dried and concentrated. The solid obtained is purified by chromatography on silica, eluting with the DCM/MeOH (95/5; v/v) mixture and the product obtained is then crystallized from a DCM/isopropyl ether mixture.

m 250 mg M.p. 150°C.

EXAMPLES 13 and 14 N-Methyl-N-(l-methyl-4-piperidyl)-5-chloro-3-(2chlorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-3-hydroxy- 2-indolinecarboxamide, cis isomer and trans isomer.

i~i~ -i ,i_;;iil I 41 35 A) 2',5-Dichloro-2-[N-(3,4-dimethoxyphenylsulfonyl)-N- (N'-methyl-N'-(methyl-4-piperidyl)carbamoylmethyllaminobenzophenone.

2 g of the acid prepared in Example 10-11, Step A in 50 ml of DCIM are mixed with 650 mg of 4-methylamino-1methylpiperidine in the presence of 1.90 g of BOP. After stirring for 2 hours at RT, the organic nhase is washed with carbonated water, dried and concentrated. The residue is then chromatographed on silica, eluting with the DCM/MeOH (90/10 v/v) mixture. 1.2 g of the expected product are obtained.

M.p. 165-166 0

C.

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

650 mg of the product obtained in the preceding step are treated overnight with 100 mg of sodium methylate in ml of methanol. Dry ice is added, the solvent is evaporated, the residue is taken up in carbonated water, extracted with DCM and the extract dried and concentrated and then chromatographed on silica. The methanol/DCM (5/95 v/v) mixture elutes the 2 isomers successively.

Each is then recrystallized from a DCM/isopropyl ether mixture.

The trans isomer is the least polar under these conditions, m 205 mg M.p. 181 0

C.

Cis isomer: m 150 mg M.p. 97 0 C: contains 0.25 M of isopropyl ether.

EXAM'PLES 15 and 16 5-Chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-3-hydroxy-2-[4-methyl--piperazinylcarbonyl]indoline, cis isomer and trans isomer.

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

36 This compound is obtained by the action of N-methylpiperazine on the acid prepared in Example 10-11 Step A.

M.p. 165-167"C.

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

The compound of the preceding step is cyclized by proceeding as in Example 12-13. The 2 isomers formed are separated by chromatography on alumina. The DCM/AcOEt (75/25; v/v) mixture elutes the least polar product: the cis isomer, which is recrystallized from a DCM/isopropyl ether mixture.

M.p. 120°C: contains 0.25 M of isopropyl ether.

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

M.p. 189 0

C.

EXAMPLES 17 and 18 N-Isopropyl-N-methoxycarbonylethyl-5-chloro-3-(2chlorophenyl)-l-(3,4-dimethoxyphenylsulfonyl)-3-hydroxy- 2-indolinecarboxamide, cis isomer and trans isomer.

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

g of isopropylamine are added dropwise to 130 g of a solution, cooled to -10°C, of methyl acrylate in 300 ml of methanol. After 72 hours at RT, the mixture is evaporated and the residue is then distilled. The oil obtained (168.3 g) is methyl 3-(N-isopropyl)-aminopropionate.

B.p. 73-78 C at 15 mm Hg.

29 g of the compound obtained in 100 ml 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 water, extracted with ethyl acetate and the extract dried and concentrated. The oil obtained is used as it is in the following step.

B) 2',5.-Dichloro-2-[N-(3,4-dimethoxyphenylsulfonyl)-N- (N'-isopropyl-N'-methoxycarbonylethyl)carbamoylmethyl]- S. aminobenzophenone.

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

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

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

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

M.p. 153-155 0

C.

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

M.p. 182-185"C.

EXAMPLES 19 and N-Methyl-N-methoxycarbonylmethyl-5-chloro-3-(2chlorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-3-hydroxy- 2-indolinecarboxamide, cis isomer and trans isomer.

The 2 isomers of this compound are prepared according to the procedure described in Example 1. They are separated by chromatography on alumina. The DCM/AcOEt (80/20 v/v) mixture elutes the cis isomer. This crystallizes from a DCM/isopropyl ether mixture in the form of a white powder containing 0.25 mola of isopropyl ether. It is converted to a foam by heating in vacuum.

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

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

M.p. 176-178°C.

The NMR spectrum of the trans isomer (Example 20) is given in Figure 2.

A^ S-38- I 38 EXAMPLES 21 and 22 N-Methyl-N-carboxymethyl-5-chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-3-hydroxy-2indolinecarboxamide, cis isomer and trans isomer.

These compounds are each prepared from the compounds described in Examples 19 and 20 according to the procedure described in Example 8.

Cis isomer: M.p. 220-222 0 C after recrystallizing from a DCM/isopropyl ether/MeOH mixture.

Trans isomer: M.p. 222-225"C after recrystallizing from a DCM/isopropyl ether mixture.

EXAMPLES 23 and 24 N-Methyl-N-carbamoylmethyl-5-chloro-3-(2-chlorophenyl)- 1-(3,4-dimethoxyphenylsulfonyl -3-hydroxy-2-indolinecarboxamide, cis isomer and trans isomer.

Each isomer is 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 preceding example are dissolved in 10 ml of DCM, and 435 mg of BOP and 260 mg of DIPEA are added. After minutes at RT, 6 ml of 20% aqueous ammonia are added with vigorous stirring and the mixture is left stirring for 4 hours. A sodium carbonate solution is added and the mixture is then extracted with DCM. The organic phase is washed successively with water, a sodium hydrogensulfate solution, and water and is then dried over magnesium sulfate. After evaporating, the residue is chromatographed on silica gel and is eluted with an AcOEt/MeOH (95/5; v/v) mixture. The product obtained is crystallized twice from a DCM/EtOH mixture at 0°C.

M.p. 236 0

C.

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

Using the same procedure, the cis isomer is prepared.

The expected product crystallizes from DCM/isopropyl ether. The micronized compound, dried in vacuum at 70 C Sfor 8 hours, contains 0.25 mole of isopropyl ether.

Z)

k 1 k 39 The NMR spectrum of the cis isomer (Example 24) is given in Figure 4.

EXAMPLES 25 and 26 5-Chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)- 3 -hydroxy-l-(4-hydroxy-l-piperidyl)carbonylindoline, trans isomer.

This compound is prepared from N-[2-(2-chlorophenylcarbonyl)-5-chlorophenyl]-N-(3,4-dimethoxyphenylsulfonyl)glycine acid described in Example 11-12, Step A.

The process is then carried out as in Example 11-12 for the addition of 4-hydroxypiperidine, in the presence of BOP and triethylamine. The product obtained is then cyclized according to the usual method in the presence of DBU. The 2 isomers are separated by chromatography on alumina. The DCM/MeOH (99/1; v/v) mixture elutes the cis isomer.

The product crystallizes from a DCM/hexane/MeOH mixture and the solid obtained is then triturated in DCM/hexane to provide an amorphous powder.

The cis isomer is characterized by its NMR spectrum at 388 0

K.

1-1.8 ppm:m:4H:CH 2 at positions 3 and 5 of the piperidine 2.8-3.65 ppm:m:5H:CH 2 at positions 2 and 6 of the piperidine and CH at position 4 3.75 ppm:2s:6H:20CH 3 4.15 ppm:d:1H:OH on piperidine 5.45 ppm:s:1H:CH (indoline) 6.1 ppm:s:1H:OH indoline 6.8-7.6 ppm:m:10H:H aromatic DMSO:2.4 ppm DOH:2.75 ppm The DCM/MeOH (97/3; v/v) mixture elutes the trans isomer which is recrystallized from DCM/isopropyl ether.

M.p. 232-234°C.

SYNTHESES in the (L)-Proline series: Examples 27, 28, 29 and 1

S..

7 EXAMPLES 27 and 27a 5-Chloro-3-(2-chlorophenyl)-l-(3,4-dimethoxyphenylsulfonyl)-3-hydroxy-2-[(2S)-(2-methoxycarbonyl)pyrrolidinocarbonyl]indoline, (cis isomers: 2 compounds).

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

g of triethylamine and 20 g of bromoacetyl bromide in 30 ml of DCM are added simultaneously to a solution of 16.7 g of methyl (L)-prolinate hydrochloride in 20 ml of DCM while maintaining the temperature at and the mixture is then stirred at RT for 24 hours. Water is added, and the mixture is washed with a solution of

KHSO

4 with water, with a sodium bicarbonate solution and with water and is then dried over magnesium sulfate.

After evaporating, an oil is obtained which is dried under vacuum. This oil, pure by TLC, is used as it is in the following step.

B) 2',5-Dichloro-2-[N-(3,4-dimethoxyphenylsulfonyl)-N- ((2S)-(2-methoxycarbonyl)pyrrolidinocarbonylmethyl)]aminobenzophenone 4.66 g of 2',5-dichloro-2-(3,4-dimethoxyphenylsulfonamido)benzophenone are dissolved in 40 ml of anhydrous DMF under argon, 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, the extract washed with water, with saline water and then dried over magnesium sulfate and evaporated under vacuum.

A solid containing a small amount of the starting brominated derivative is eluted with a DCM/AcOEt (85/15; v/v) mixture by chromatography on silica gel. A sample is recrystallized from DCM/isopropyl ether.

m 1.2 g M.p. 141-142°C a D -43.7 0 (c 1; MeOH/THF: 8/2; v/v) Analysis Calculated C:54.81 H:4.44 N:4.41 Found 54.40 4.54 4.55 (1 8 1 1

*'I

i S- 41 C) 5-Chloro-3-(2-chlorophenyl)-l-(3,4-dimethoxyphenylsulfonyl)-3-hydroxy-2-[(2S)-(2-methoxycarbonyl)pyrrolidinocarbonyl]indoline, (cis isomerism).

1.1 g of the compound obtained in the preceding step are heated in 4 ml of methylene chloride for 24 hours with one equivalent of DBU. HPLC analysis of an aliquot shows the existence of the expected 4 isomers. After 24 hours, the reaction mixture is poured onto an alumina column, pre-equilibrated in the DCM/AcOEt (90/10; v/v) mixture and is eluted with the DCM/AcOEt (90/10; v/v to 70/30; v/v) mixture. 510 mg of a mixture of the 2 least polar compounds are obtained in the ratio 4/1 (measured by HPLC).

Two successive crystallizations from DCM/isopropyl ether while cold provide the major compound.

m 180 mg a 5 -247 0 (c 0.4; chloroform) M.p. 187-190"C.

The crystallization mother liquors of the preceding compound are chromatographed on alumina by eluting with DCM/AcOEt (85/15; The preceding compound is thus separated from the second, the latter is dissolved in the minimum amount of DCM and is then precipitated by addition of the minimum amount of hexane.

a26 +1360(c 0.24; chloroform) EXAMPLE 28 2-((2S)-2-Carboxypyrrolidinocarbonyl)-5-chloro-3-(2chlorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-3-hydroxyindoline, cis isomer.

430 mg of the compound prepared in Example 27 are dissolved in 6 ml of methanol, 41 mg of sodium hydroxide in 1 ml of water are added and the mixture is stirred for 24 hours at RT. The mixture is acidified to pH 3 with a few drops of a potassium hydrogensulfate solution and is extracted with ethyl acetate. The extract is washed with water and is then dried over magnesium sulfate. Chromatography is carried out on a silica column prepared in a DCM/pentane (80/20; v/v) mixture. The unreacted ester s, r' 42 elutes the expected acid which is then recrystallized from DCM/isopropyl ether.

M.p. 232-234°C a 6 -254°(c 0.3; chloroform).

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

230 mg of the compound prepared in Example 28 are dissolved in 5 ml of DCM, 50 mg of DIPEA and then 165 mg of BOP are added and the mixture is left for 5 minutes at RT. The mixture is cooled in an ice bath and a stream of gaseous ammonia is then bubbled through for 1 minute and, after 15 minutes, for a further 1 minute. Water and then a large volume of ethyl acetate are added in order to obtain two phases. The organic solution is washed with a sodium carbonate solution, water, a potassium hydrogensulfate solution, water and then saline water. After drying, the residue is chromatographed on silica by eluting with a DCM/MeOH (93/7; v/v) mixture. The product obtained is triturated in a DCM/isopropyl ether/hexane mixture. It contains 1/3 mole of isopropyl ether.

aD -189 (c 0.23; chloroform).

The compound of Example 29 can be prepared according to another procedure.

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

33.9 g of the acid prepared in Example 10-11, Step A are dissolved in 300 ml of chloroform. 15 g of thionyl chloride are added and the mixture is brought to reflux for 1 hour and a half. The mixture is evaporated to dryness, the residue is then taken up in DCM and evaporated again. The mixture is dissolved in 300 ml of DCM, brought to 0°C and 10.5 g of (L)-prolinamide hydrochloride are added, and then 18 g of DIPEA in 20 ml of DCM are slowly added without allowing the temperature of the reaction mixture to exceed 3°C.

43- After one night at RT, the reaction mixture is washed with sodium bicarbonate twice and then with potassium hydrogensulfate twice the reaction mixture is dried and concentrated. The crude product obtained is dissolved in the minimum amount of DCM and added dropwise to isopropyl ether (1.2 1) with stirring. After stirring for 2 hours, the precipitate obtained is filtered and then dried under vacuum for 6 hours at 60"C. 42 g are collected.

Da -40.8 (c 1.007; chloroform).

B) 2-((2S)-2-Carbamoylpyrrolidinocarbonyl)-5-chloro-3-(2chlorophenyl)-l-(3,4-dimethoxyphenylsulfonyl)-3hydroxyindoline, (cis isomers: 2 compounds).

5 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 is added and the mixture is maintained for 60 hours at -10 0 C. A compound crystallizes; it is filtered (cis compound The crystallization liquors are neutralized with KHSO 4 and the mixture is evaporated to dryness It is taken up in water, extracted twice with DCM, and the extracts are dried and concentrated. The crude product obtained is chromatographed on silica by eluting with an AcOEt/DCM (28/72; v/v) mixture. A mixture is collected which is dissolved in the minimum amount of methanol while hot; the insoluble material is filtered off,the liquors are then placed overnight at -4°C and the cis compound 2 crystallizes.

m 1.25 g 5 -196 0 (c 0.351; chloroform).

The analysis of the NMR spectrum shows the presence of one mole of MeOH per mole of product. The recrystallization of the product from ethanol makes it possible to remove the solvent in the crystals.

M.p. 154-162°C 25 a -204° (c chloroform) 25 -131 0 (c 0.27; chloroform/methanol: 8/2: v/v) 1 -44 This compound is identical, the solvent excepted, to that prepared by the first procedure of the present example.

The compound which crystallized in Step B) above, 1 5 called cis compound 1, is recrystallized from methanol.

M.p. 190"C aD +115 (c 0.3; chloroform) EXAMPLE 5-Chloro-3-(2-chlorophenyl)-l-(3,4-dimethoxyphenylsulfonyl)-3-hydroxy-2-[(2S)-2-(hydroxymethyl)pyrrolidinocarbonyl]indoline, cis isomers.

A) 2',5-Dichloro-2-[N-(3,4-dimethoxyphenylsulfonyl)-N-(2- S(hydroxymethyl)pyrrolidinocarbonylmethyl)]aminobenzophenone.

This compound is obtained by reacting (L)-prolinol with the acid prepared in Example 10-11, Step A, by following the usual procedure.

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

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 DCM is added and the mixture is then heated at 40"C overnight. The formation of 3 i 25 major compounds is observed by TLC on silica (eluent AcOEt).

The least polar fraction is eluted by chromatography on silica using DCM/AcOEt (60/40 to 80/20; A chromatography on alumina is then carried out by eluting with DCM/MeOH (99/1; The fraction obtained is homogeneous by TLC. The product is recrystallized three times from DCM/isopropyl ether. The expected product is obtained with an HPLC purity greater than 99%.

m 155 mg M.p. 194-197°C a D -1950 (c 0.2; chloroform).

.iK

<T,

1 45 SYNTHESES in the (D)-Proline series: Example 31.

EXAMPLE 31 5-Chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-3-hydroxy-2-[(2R)-2-(methoxycarbonyl)pyrrolidinocarbonyllindoline, cis isomer.

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

This compound is obtained from the acid prepared in Example 10-11, Step A (3 g) to which are added 1.2 g of methyl (D)-prolinate and 2.8 g of BOP in 10 ml of DCM in the presence of 1.15 g of triethylamine. The mixture is left for 1 hour, at RT and is then diluted with DCM, the organic phase is washed with sodium carbonate and with potassium hydrogensulfate, dried and concentrated. The crude product is chromatographed on silica, eluting with a DCM/AcOEt (95/5; v/v) mixture. The product obtained is then recrystallized from a DCM/isopropyl ether mixture.

M.p. 140-141"C.

D +28.5 0 (c 0.27; chloroform).

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

g of the preceding compound is brought to reflux overnight in 5 ml of DCM in the presence of 360 mg of DBU. The mixture is chromatographed on alumina. The mixture DCM/AcOEt (95/5; v/v) elutes the least polar fraction (m 300 mg) which is recrystallized twice in a DCM/isopropyl ether mixture.

M.p. 186-188"C +2450(c 0.4; chloroform).

This compound is the enantiomer obtained from proline of that described in Example 27.

EthAMPLE 32 and 32a N-Methyl-N-methoxycarbonylmethyl-5-chloro-3-(2-chlorophenyl)-1-(4-ethoxyphenylsulfonyl)-3-hydroxy-2-indolinecarboxamide, trans isomer and cis isomer.

pt ?A .A S- 46 A) 2',5-Dichloro-2-[N-(4-ethoxyphenylsulfonyl)-N-(N'methyl-N'-(methoxycarbonylmethyl) carbamoylmethylaminobenzophenone.

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 are added at 0°C; after minutes, 4.3 g of methyl N-(bromoacetyl)sarcosinate are added. After 48 hours, the expected product is extracted in the usual way and is then purified by chromatography on silica by eluting with DCM/AcOEt (90/10; v/v) and recrystallizing in a DCM/isopropyl ether mixture.

M.p. 158-160°C B) N-Methyl-N-methoxycarbonylmethyl-5-chloro-3-(2-chlorophenyl)-l-(4-ethoxyphenylsulfonyl)-3-hydroxy-2-indolinecarboxamide, trans isomer.

1 g of the compound obtained in the preceding step is dissolved in 4 ml of DCM and treated for 90 minutes at RT with 312 mg of TBD. A solution of potassium hydrogensulfate is added, the DCM is evaporated under vacuum, 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 by eluting with DCM/AcOEt (90/10; v/v).

m 590 mg M.p. 168-171°C after recrystallizing from DCM/hexane.

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

2.96 g of the compound obtained in Step A are suspended in 20 ml of methanol and 10 ml of THF; 100 mg of sodium methylate are added and the mixture is then left for 7 hours in the refrigerator. Water is added, the mixture neutralized with a potassium hydrogensulfate solution and a part of the methanol is evaporated under vacuum. After extracting with AcOEt, the residue is chromatographed on alumina and is then eluted with a V i.l ll tf ii(l a .ll. 'l l W V l-, 47 V DCM/AcOEt (80/20; v/v) mixture. 850 mg of the expected product are obtained which are recrystallized from a DCM/isopropyl ether mixture.

i The NMR spectrum is given in Figure 6.

By using methods similar to those described above, intermediate compounds (VI) for the synthesis of compounds according to the invention were prepared.

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

The compounds prepared are described in Table 2 below.

R'2 -bI

R'

1 R

/R

6 N-CH2-CON soI

SO

2 R7

R'

5 -48 Table 1

R'

2 -N /R 6 M.p. or IR

\R

7 Solvent Br- 3,4-CH 3 0 F- CH 3 82-83

-N-CH

2

CO

2

CH

2

C

6 H 5 DCM/isopropyl ether] Cl- 3,4-CH 3 O cl- CIH 3 164-166

-N-CH

2

CH

2

CO

2

CH

3 DCM/isopropy ether cl- 3,4-GH 3 O Cl- CH3128

-N-CH

2

CH

2 N-Et DCM/isopropyl ether cl- 3,4-CH 3 O cl- 105

-N-CH

2

CH

2

CO

2

CH

3 DCM/isopropyl ether cl ,-C3C- N N-CO 2

CH

2

C

6

H

5 142-143

CH

3 O- 3,4-CH 3 Il CCCOHI 1 cl- 3,4-CH 3 O Cl- iPentyl 83

-NCH

2

CH

2 C0 2

CH

3 Is opropyl e ther/DCM4 Br- 3, 4-CH 3 Cl- -NC 2

C

2

O

2 H IR (2) cl- 3, 4 -CH 3 0 cl- -\s199 DCM/isopropyi ether cl- 3,4-CH 3 O cl- Pr 135 N-C 4 2

CO

2

CH

3 Isopropyl ether/ DCM/AcOH- Cl- 3, 4-CH 3 o cl- Pr 113

N-CH

2

CH

2

-CO

2

CH

3 DCM/isopropyl ether lit -49- Cl- 3, 4-CH 3 O cl- F 160 -N4-CH 2

.CO

2

CH

3 iorp1ether cl- 3, 4-CH- 3 0 Cl- N NH-C0 2 -lBu 197-198 cl- 3,4-CH 3 O ci coC I (3) C 0 2 C 2

C

6 5 IR (DCM) IR (DCM) 1740 cmf' fine 1680 cm- 1 broad 1735 cm- 1 fine 1660-1680 cm'1 split This compound is characterized by its optical rotation: D 5 36.80 (c 0.44; chloroform).

Table 2 CON[ R 6

.\R

7 For each compound of formula which ha the substituents R'I, RI 5

R'

2 and NR 6 R7 of the table below, the cis isomer is shown and then the trans isomer, except when otherwise indicated.

Example R/ 2 6 I.p (C)or NI4R I Solvent

R

7 I 4-CH 3 0 I F- CH3 -N-C H 2 C 0,CH 2 C 6 87-95 ~1

I

100-103 36 Cl- 3,4-CH 3 0 Cl- CH 3 154-157

-N-CH

2

CH

2

CO

2

-CH

3 DC/isopropyl-ether 37 cis Cl- 3,4-CH 3 0 Ci- H 3 140-144

-N-CHCH

2

CO

2 H DC/isopropyl ether 38 Cl- 3,4-CH 3 0 Cl- CR 3 222-225 mixture -N-CH 2

CH

2 N-Et DCM/isopropyl ether 39 Cl- 3,4-CH 3 0 Cl- Ez N1M.

40 ,-CH 2

CH

2

CO

2

CH

3

NM

41 Cl- 3,4-CH 3 0 Cl- Et 166 cis-N-CH 2

CH

2

CO

2 H DC/isopropyl ether 42 /CR 119 43 Cl- 3,4-CH 3 0 Cl- -N N\H AcOEt/isopropyl ether 228 44 Cl- 3,4-CH 3 O Cl- ~H 2

C

6

E{

5 CR3 179 cis -;N-CH 2

CHVNC

3 DC/isopropyl ether 109 Cl- 3,4-CH 3 0 Cl- -N -CH 2 C0 2 Ft DCM/isopropyl ether 46 196 DCI/isopropyl ether 47 134 (iPr).0 48 Cl- 2,4-CH 3 0 Cl- IN N.COCH,C 6 H4 5 1 9 -DCM/isopropyl ether N i 51 49 Cl- 3,4-CH 0 Cl- Et 236 3 cis -N-CH 2

CH

2 CONH 2 isopropyl ether 154 51 CH 3 3,4-CH 3 Cl- Et i-sopropyl ether

CH

2

CH

2

CO

2

C

3 87 isopropyl ether 52 Cl- 2,4-CH- 3 0 Cl- H194 cis MeOH/isopropyl ether 53 Cl- 3,4-CH 3 O Cl- iTentyl 195 cis-N-CH 2

CH

2

CO

2

CH

3 isopropyl ether/DCM 54 138-140 Br- 2,4-C11 3 0 01- FA isopropyl ether

-N-CH

2

CH

2 Co 2

CH

3 140 isopropyl ether I 56 242-245 57 Cl- 3,4-CH 3 O Cl1 -N S DOM/isopropyl ether 225 MeOH/isopropyl ether Cl- 2,4-CH 3 O Cl- 228 58 -Na N(CH 3 2 MeOH/isopropyl ether 58 a 221 DCM/MeOH 131- 134 59 Cl- 3,4-CH 3 O Cl- F DCM/isopropyl ether/ 59a *CHCCHCCt 3 hexane 121 DCH/ether/hexane 7 162-166 Cl- 3,4-GH 3 O C1- iBu DCM/isopropyl ether 61 N-CH 2

CH

2 Co 2

CH

3 13 DCM/isopropyl ether/ hexane 62 Cl- 3,4-GH 3 0 Cl- pr176 63 -N-CH 2

CO

2

CH

3 isopropyl ether/DCM

M

64 Cl- 3,4-CH 3 O Cl- 148 Fr isopropyl ether/DCM

-N-CH

2

CH

2

CO

2

CH

3 2 isopropyl ether/DCM 66 Cl- 3,4-CH 3 O Cl- NHR 67 N-CH 2

CO

2

CH

3 168 isopropyl ether 68 Cl- 3,4-CH 3 O Ci- IiBu 179-182 cis N-C 2 2 0H DCM/isopropyl ether 69 Cl- 3,4-CH 3 0 Cl- 139 cisN-HC H DCM/isopropyl ether Cl- 3,4-CH 3 O Cl- 130 cis N-CH 2

CQ

2 H isopropyl ether 71 Cl- 3,4-CH 3 O Cl- 136 cis N.(CH 2 3 C0 2 H DCM/isopropyl etherj 72 Cl- 3,4-CH 3 O Cl- F 135 cis NC 2 CN DCM/isopropyl etheri .1 53 73 Cl- -3,4-CH 3 O Clj T1 197 74N

NHCO

2 C(CH3)3 MeOH-/isopropyl ether 211 MeOH Cl- 3,4-CH- 3 0 ClDN2 M cis 76 Cl- 3,4-CH 3 O Cl- Fuinarate cis Na NH 2 152-156 DCt4/isopropyl ether 76a Cl- 3,4-CH- 3 0 Cl- N 137 76b-N~j ~isopropyl ether/HeOH/ 76b

H

183- 185 hexane Example 34 analysis: calculated C:55.54 H: 4.24 N:3.93 found 55.72 4.57 3.83 NMR spectra at 200 M4Hz (DMSO: 2.5 ppm) Example 34: Figure Example 38 0.7-1.1 ppm: m:6H:2CU 3 (Et) 2-4 ppm:m:17H:2CH 2 2CHm-N, N-CH 3 20CH3 5.2-5.7 ppm:3s:1H:H (indoline) 6.2-8.2 ppm:m:11H:OH aromatics Example 39 0.3-1.2 ppm~m:3H:CH 3 (Et) 1.5-4.3 ppm:m:15H:CH.-CO,

CU

2

CH

2 20CH3, CO 2

CH

3 5.2-5.6 ppm:3s:lH:H (indoline) 6.2-8.2 ppM:m:l1H:OH aromatics Example 0.8-1.1 ppm:m:3H:CH 3 (Et) 2.2-3.9 ppm:m:15H:CH 2 CO, CH 2

CH

2 N, CO 2

CH

3 20CH 3 I 54- Ij 6.6-8.2 ppm:m:ll1i:OH aromatics -Example 63 0. 4-1 ppm: split t: 3H: CH -CH -CH 3 ppm: m: 2H: CH 2

CH-CH

3 2. 5- 4. 4 ppm: m:l13H: CH -CH -CH 3

NC

2

COOCH

3 20CR 3 5.2-5.8 ppm; bs :1H:H (indoline) 6.5-8.3 ppm:m:llH:OH aromatics I Example 66 0 to 1.5 ppm:m:3H:CH 2

-CH_

2.3-5.8 ppm:m:14H*CH.-CH 3 NCH2C00CH, 20CR 3 H (indoline) 6.1-8.3 ppm:m:llH:OH aromatics Example 1.95 ppm:bs:2H:Ni 2 2.7 to 5.3 ppm:m:12H:20CH 3 2NCH 2 H(indoline) CH1N1J 6 to 8.3 ppm:m:l1H:OH aromatics -Example 76a 5= +102 (c 0.35; chloroform) -Example 76b D= -158 (c 0.2; chloroform).

Some compounds according to the invention described in Table 2 are useful in the preparation of other compounds according to the invention. For example, compound 41 was obtained from compound 39 by treatment in basic I medium in methanol MeOH/H 2 0. Compound 49 was prepared from 125 compound 41 by treatment with aqueous ammonia in the presence of DIPEA and BOP.

EXAMPLE 77 N-Ethyl-N- (2 -aminoethyl) -5-chloro-3- (2-chlorophenyl) -1- (3,4-dimethoxyphenylsulfonyl)-3-hydroxy-2-indolinecarboxamide, (cis isomer) 500 mg of compound 49 are 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 talken up in a solution of hydrochloric acid, extracted with ether, alkalized with dilute sodium hydroxide solution, extracted with DCM and the extract is dried and con- ~.centrated. An oil is obtained and the expected product 1 55 then crystallizes from ether.

m 150 mg M.p. 164 0

C

EXAMPLE 78 N-Ethyl-N-[(1S)-1-(ethoxycarbonyl)ethyl]-5-chloro-3-(2chlorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-3-hydroxy- 2-indolinecarboxamide, (cis isomer).

A) N-[2-(2-Chlorophenylcarbonyl)-5-chlorophenyl]-N-(3,4dimethoxyphenylsulfonyl)glycine acid chloride.

A mixture containing 11 g of the acid prepared in Example 10-11, Step A) and 5 g of thionyl chloride in ml of chloroform is heated for 1 hour at 60"C. The mixture is left to return to RT, concentrated under vacuum and the residue taken up in DCM twice A yellow oil is obtained which is used as it is in the following step.

IR: 1800 cm- 1

(C=O)

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

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

5.15 g of (L)-Boc(N-Et)AlaOEt is treated with 10 ml of TFA at 0"C in order to remove the Boc group. The mixture is concentrated under vacuum, taken up in 20 ml of DCM, cooled to -78"C and 2 equivalents of TEA and the acid chloride prepared in the preceding 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 by eluting with a DCM/AcOEt (90/10; v/v) mixture. The expected product crystallizes from isopropyl ether.

M.p. 112 0

C

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

[I

11

II

Ii iJ$ i l i, ii

I

j c 56 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 under vacuum, the residue is taken up in DCM, washed with water, concentrated and the product chromatographed on alumina by eluting with AcOEt/DCM (10/90; v/v).

NMR

0-0.9 ppm: split d:3H:CH-CH3 0.9-1.7 ppm:m:6H:2CH 3 (ethyl) 2.6 to 5.8 ppm:m:12H:20CH3, NCH,, OCH, NCH, COCH 6.1 to 8.3 ppm:m:11H:OH 10H aromatics EXAMPLES 79 and N,N-Di[2-(methoxycarbonyl)ethyl]-5-chloro-3-(2-chloro- 15 phenyl)-1-(3,4-dimethoxyphenylsulfonyl)-3-hydroxy-2indolinecarboxamide, cis isomer 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 in 200 ml of ethanol are cooled in an ice bath and 172.2 g of methyl acrylate in 250 ml of ethanol are slowly added. After 13 days at RT, the solvent is evaporated under vacuum and a part of the oily residue is then distilled.

B.p. 135-140"C at 0.6 mm Hg m 30 g IR: 1730 cm" 1 B) N,N-(2-dimethoxycarbonyl)ethylJamine.

27.9 g of the amine obtained in the preceding step, 30 placed in 500 ml of methanol, are mixed with 3 g of palladium on charcoal and are treated under hydrogen pressure for 1 hour. The mixture is filtered on Celite', rinsed with methanol and the solvent evaporated under vacuum; the residual oil is used as it is in the following step.

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

A mixture containing 14.3 g of the amine prepared in the preceding step, 100 ml of DCM and 10.6 ml of TEA is 57-- V1 ,<57 cooled in an ice bath; 15.3 g of bromoacetyl bromide are added dropwise and the mixture is then left stirring for 48 hours at RT. The mixture is extracted with DCM, the extract is washed with water and then a chromatography is carried out on silica by eluting with a DCM/MeOH (97/3 v/v) mixture. The expected product is obtained in the form of an oil.

m 15.9 g IR: 1650 cm 1 and 1730 cm 1 D) 2',5-Dichloro-2-[N-(3,4-dimethoxyphenylsulfonyl)-N- -di(2-(methoxycarbonyl)ethyl)carbamoylmethyl]]aminobenzophenone.

14.3 g of 2',5-dichloro-2-(3,4-dimethoxyphenylsulfonamido)benzophenone are placed in 180 ml of DMF and 1.1 g of sodium hydride are added in portions. After stirring for 1 hour at RT, the mixture is cooled in an ice bath and 14.3 g of the product prepared in the preceding step are added and the mixture is left stirring for 72 hours at RT. The mixture is extracted with DCM, the extract is washed with water and then chromatographed on silica by eluting with a DCM/AcOEt (93/7; v/v) mixture.

m 28.4 g M.p. 130"C.

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

12 g of the compound prepared in the preceding'step and 0.930 g of sodium methylate in 150 ml of methanol are mixed at 0°C and the mixture is then left stirring overnight at RT. The reaction mixture is neutralized by addition of 5% KHSO 4 and the solvent is then evaporated under vacuum. The residue is chromatographed on alumina by eluting with a DCM/AcOEt v/v) mixture. 2.4 g of the expected product are recovered which are crystallized from methanol.

M.p. 175"C.

j 9 i~ 4 P Ih n hC~ I 58 ti !:3 i i i i! i i ir !,i ii j i: i i: t j i i i i i l-"

I;

ii r.l i i i j j.

r:: ii F) N,N-Di[2-(methoxycarbonyl)ethyl]-5-chloro-3-(2-chlorophenyl)-l-(3,4-dimethoxyphenylsulfonyl)-3-hydroxy-2indolinecarboxamide, trans isomer.

The chromatography of the preceding step is continued and elution is carried out with a DCM/MeOH v/v) mixture. 1.82 g of the trans isomer is obtained which crystallizes from isopropyl ether.

M.p. EXAMPLES 81, 82 and 83 10 2-((2R)-2-Carbamoylthiazolidinocarbonyl)-5-chloro-3-(2chlorophenyl)-l-(3,4-dimethoxyphenylsulfonyl)-3-hydroxyindoline, (cis isomer: 2 compounds and trans isomer).

A) (L)-4-Thiazolidinecarboxamide.

15 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.

20 This compound is obtained by the usual methods from the acid prepared in Example 10-11, Step A).

M.p. 125"C after crystallizing from ether.

C) 2-((2R)-2-Carbamoylthiazolidinocarbonyl)-5-chloro-3- (2-chlorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-3hydroxyindoline.

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 30 layer is washed with KHSO, and then dried and concentrated. The residue is chromatographed on alumina by eluting with DCM/MeOH (97/3; The compound is obtained in the cis form (mixture of 2 diastereoisomers): g, and then in the trans form (mixture of 2 diastereoisomers): m 1 g.

a) The cis fraction is crystallized from MeOH/DCM in order to obtain cis compound 1.

c, r~7 r 9 0.

59- M.p. 176 0 C after crystallizing from isopropyl ether.

aD +57 (c 0.1; chloroform).

b) The crystallization liquors of the preceding product are chromatographed on silica by eluting with AcOEt/DCM (30/70; The cis compound 2 obtained is V recrystallized from ether.

M.p. 205C SD -185 0 (c 0.3; chloroform).

i 10 c) The trans fraction (mixture of 2 diastereoisomers) is recrystallized from isopropyl ether.

M.p. 170°C EXAMPLES 84, 85, 86 and 86a 5-Chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-3-hydroxy-2-[(2S)-2-(N,N-dimethylthiocarbamoyl)pyrrolidinocarbonyl]indoline, cis isomerism (2 compounds), (trans isomerism: 2 compounds).

SA) (L)-(N'-Boc)-N,N-Dimethylprolinethioamide.

i This compound is prepared according to J. Med.

Chem., 1989, 2178.

2.36 g of (N'-Boc)-N,N-dimethylprolinamide are heated in anhydrous toluene under argon at 80"C for 4 hours in the presence of 2,3 g of 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 by eluting with hexane/AcOEt (30/70; The product obtained is recrystallized while- cold O from DCM/isopropyl ether (30/70 v/v).

M.p. 62°C 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 preceding step are dissolved in 10 ml of DCM and treated at 0°C for 2 hours with 10 ml of TFt. 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) are added at 0°C and the mixture is neutralized with 3 g of DIPEA. 5.15 g of BOP are dissolved in 30 ml of DCM and this solution is added to the preceding solution at 0°C over 30 minutes; the pH is maintained at neutral by the addition of DIPEA and the mixture is left stirring for 3 hours at 0°C. After one night at RT, the mixture is extracted in the usual way and then chromatographed on silica by eluting with DCM/AcOEt (85/15; The product obtained is recrystallized from isopropyl ether.

M.p. 182-185°C ,D -72° (c 0.32; chloroform).

C) 5-Chloro-3-(2-chlorophenyl)-l-(3,4-dimethoxyphenylsulfonyl)-3-hydroxy-2-[(2S)-2-(N,N-dimethylthiocarbamoyl)pyxrolidinocarbonyl]indoline (cis isomerism 2 compounds, and trans isomer: 2 compounds).

3.8 g of the compound obtained in the preceding step are dissolved in 15 ml of DCM and the mixture is heated at reflux for 36 hours in the presence of 850 mg of DBU.

The different isomers formed are separated by successive chromatographic runs on silica.

a) Using DCM/AcOEt (85/15; the expected compound is eluted first in the form of a mixture of 2 4 cis diastereoisomers. The least soluble diastereoisomer is crystallized twice from a DCM/isopropyl ether/ methanol mixture and is then recrystallized from the minimum amount of DMF at 60°C followed by addition of 2 volumes of ethanol.

M.p. 270°C

S

D -278 (c 1; chloroform).

b) The crystallization liquors of the preceding mixture are taken up in and the second cis diastereoisomer crystallizes from a DCM/isopropyl ether mixture.

M.p. 249-251°C aD +42 0 (c 0.22; chloroform).

c) The chromatography fractions eluted last, as well as the crystallization mother liquors of fractions a) and are combined, and are chromatographed again on silica by eluting with hexane/AcOEt (20/80; Isolated first 2

I

x t 61is a fraction which is recrystallized 3 times from a DCM/isopropyl ether mixture and an insoluble material is removed on a paper between each recrystallization. The trans isomer 1 is thus obtained.

M.p. 191-193 QD +74.50 (c 0.2; chloroform).

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

M.p. 170°C aD -266° (c 0.14; chloroform).

EXAMPLES 87, 88 and 89 2-((2S)-2-Carbamoylpyrrolidinocarbonyl)-5-chloro-3cyclohexyl-l-(3,4-dimethoxyphenylsulfonyl)-3-hydroxyindoline, (cis isomers: 2 compounds, trans isomer).

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

A solution of 35.6 g of phenone and 39.5 g of 3,4-dimethoxyphenylsulfonyl chloride in 340 ml of pyridine is left stirring for 24 hours at RT. The solvent is evaporated under vacuum and the residue is then washed with water and with an acid solution (0.5 N HC1). The expected product crystallizes from ethanol.

M.p. 135°C m 56.1 g.

B) 2-[(N-Benzyloxycarbonylmethyl-N-(3,4-dimethoxyphenyl- 3.2 g of sodium hydride are added in portions to 52.6 g of the compound prepared in the preceding step in 520 ml of DMF and the mixture is left stirring for 1 hour at RT. After cooling in the ice bath, 21 ml of benzyloxycarbonylmethyl bromide are added dropwise and the mixture is left stirring for 24 hours at RT. The solvent is evaporated under vacuum 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 it is in the following step. -14 62 C) N-(5-Chloro-2-(cyclohexylcarbonyl)phenyl)-N-(3,4dimethoxyphenylsulfonyl)glycine.

The compound obtained in the preceding step is placed with 3.9 g of 5% palladium on charcoal in 700 ml of acetic acid under hydrogen (1 atmosphere). At the end Sof the reaction, the palladium is filtered on Celite" and rinsed with hot acetic acid; the solvent is evaporated under vacuum and the residue is taken up in water. It is Sextracted with DCM and the extract is washed with water and then with a concentrated NaHCO 3 solution. The residue Iobtained is chromatographed on silica by eluting with a DCM/MeOH (97/3; v/v) mixture. The expected product crystallizes from ethanol.

M.p. 160°C m 22.4 g.

D) 5-Chloro-2-[N-(3,4-dimethoxyphenylsulfonyl)-N-((2S)- 2-carbamoylpyrrolidinocarbonylmethyl)]-aminocyclohexyl- 8 phenone.

A mixture containing 9.92 g of the acid prepared in the preceding step, 3 g of (L)-prolinamide hydrochloride and 3.5 ml of DIPEA in 75 ml of DCM is cooled to 0

°C.

i 8.84 g of BOP in solution in DCM are add- and the pH is maintained at 7 by addition of DIPEA. The mixture is left stirring for 24 hours at RT. The mixture is extracted with DCM, and the extract washed with a saturated NaHCO 3 solution, a saline solution, a 5% KHSO 4 solution and again with a saline solution. The product is chromatographed on i silica by eluting with a DCM/MeOH (96/4; v/v) mixture.

The expected product solidifies in isopropyl ether.

M.p. 110°C m 7.3 g UD -53.9°(c 1; chloroform) E) 2-((2S)-2-Carbamoylpyrrolidinocarbonyl)-5-chloro-3cyclohexyl-l-(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 .I 63 i under vacuum, water is added, the mixture is extracted with DCM and the extract is then washed with a 5% KHSO 4 solution. The product is chromatographed on alumina by eluting with DCM/MeOH (98/2; v/v).

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

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

M.p. 185"C.

i By recrystallization of the mother liquors from MeOH, a second compound is obtained (cis HPLC purity: (it contains 25% cis 1).

M.p. 132"C.

b) The most polar fraction contains the trans isomer I in the form of an apparently single compound which is obtained by recrystallizing from methanol.

i M.p. 240 C i aD -55.1° (c 1; chloroform).

EXAMPLE 89a 2-((2S)-2-Carbamoylpyrrolidinocarbonyl)-5-chloro-3cyclohexyl-l-(3,4-dimethoxyphenylsulfonyl)-3-hydroxy- H indoline, cis isomer. (2 compounds), trans isomer.

V By using a procedure similar to that described for I Examples 87, 88 and 89, an analogous compound in the V proline series is prepared.

The compound obtained after crystallizing from a DCM/MeOH mixture has the trans configuration.

M.p. 238"C a, +164°(c 0.245; chloroform/methanol, 8.2, v/v).

!i The NMR spectrum of this compound and of that described in Step E b) of the preceding example are identical.

EXAMPLE 5-Chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-2-[( 2 S)-2-(N-methylaminocarbonyl)pyrrolidinocarbonyl]-3-hydroxyindoline, cis isomer.

920 mg of the compound prepared in Example 28 are placed, with stirring, in 20 ml of DCM containing 371 mg o f BOP for 15 minutes, a stream of monomethylamine is 'ij *a u, ff 64 bubbled through for 10 minutes and the stirring is maintained for an additional 30 minutes. The mixture is taken up in water, the layers separated, the organic layer washed with potassium hydrogensulfate and with sodium carbonate, dried and concentrated. The residue is chromatographed on silica by eat.ing with DCM/methanol (97.5/2.5; The expected product is collected which crystallizes from an isopropyl ether/DCM mixture.

m 750 mg M.p. 158°C aD -216 0 (c 0.3; chloroform).

By operating as in the previously described examples (Examples 27 to 31 and 90) and by using derivatives of (L)-proline (except when otherwise indicated), other intermediate compounds (VI) for the synthesis of the compounds according to the invention were prepared.

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

The Compounds prepared are described in Table 4 below.

Table 3 CCl

./R

6 N-CH2-CO-N \R7

SO

2

I

r 65 /R62 R7 (chloroform) 3,4-CH 3 O H-N c 1.015 CON

H-

3,4-GH 3 0 161-163 -70).8 -OC DCM/isopropyl ether c -0.48 2,4-CH 3 0 145-148 -17.5 H, c 3.36 COOCH 3 3,4-CH- 3 0 HIG 110

~OC

2 J DCM/isopropyl ether 3,4- Ci- 3 0 148 HCOOCH3 isopropyl ether/MeOH Table 4 C1 R11

OH

H-

NR

I CON 6

RR

Examiple R1 5 /NR6 H.P.( 0 C) R7 (chloroform) 91 cis 1 CI 3,4-CH 3 0 D)115 188 H e0H c -0.33 92 cis 2 CONH 2 204 14 Cl eOH/DMF c -0.31 66 198-201 93 cis ci 3,4-CH 3 -N DCM/isopropyl 41 ether COOCH3 -N 205-207 94 cis Cl 2,4-CH 3 0 CM/isopropyl C00CH3 ether 221 -242 cis Cl 2,4-CH 3 0 H DCM/isopropyl c 0.254 ether -234 96 cis Cl 3,4-CH 3 O COOCH c 0.32

-N

Hi--214 97 cis Cl 3,4-C- 3 0 c 0.32 105-115 +174.6 98 cis 1 Cl 3,4-GH 3 DCM/isopropyl 0.3

HCOOCH

3 ether 99 cis 2 175 -214.6 DCM/isopropyl :t 0.3 ether 100 trans 1 -155 c 0.2 101 trans 2 177 +95.2 DCM/isopropyl c 0.2 ether 2 cis 1 Cl 3,4-CH 3 O -N7 135 -162 isopropyl ether CHZCOOH Ct 1 -~T1 67 j, 145 -167 03 cis 1 Cl 3,4-CH 3 0 OM/isopropyl c 0.4

CH

2 CONH, ether 03a Cl 3,4-CH 3

O

cis 1 cis 2 CH 2

CONH

2 104 cis 1 Cl 3 4 CH30 Np210 -177.5 HI ether c 0.2 04'. Cl 3,4-CH30 cis 1 cis 2 CH NH 200 -195 105 CH 3 0 3,4-3CH30 EtOH c-0.2 HI N 106 COH2215 +127 MeOH c- 0.2 -63.3 107 CH 3 0 3,4-CH 3 O f 198 c 0.117 H (C1 3 /MeOH

CONH

2 /2;v/v) 274 -225 108 Cl 2,4-01130 -N DM/MeOH c 0.372

CONH

2 ({C1 3 /4eO1 8/2;v/v) 108a Cl 3,4-CH30 7 -198.7 cis H''NHO 1 c 0.24

I

68 Example 92: Other measured optical rotation: 25 a 5 -39.5°(c 0.17; CHC1 3 /MeOH: 8/2:v/v).

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

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

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

EXAMPLE 109 2 -((2S,4S)-4-Azido-2-(methoxycarbonyl)pyrrolidinocarbonyl)-5-chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-3-hydroxyindoline, cis isomer.

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

S,

4 R)-4-hydroxy-2-(methoxycarbonyl)pyrrolidinocarbonylmethyl)]aminobenzophenone.

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 in the presence of 7.4 g of DIPEA, A solution of 12.7 g of BOP in 30 ml of DCM is added dropwise over 30 minutes and the amount of DIPEA necessary to neutralize the solution is added. After one night at RT, the mixture is extracted in the usual way and chromatographed on silica by elution with a DCM/AcOEt (60/40; v/v) mixture. The expected product crystallizes from a DCM/ether/isopropyl ether mixture.

M.p. 128-131°C aD +8.5 (c 0.38; chloroform).

B) 2',5-Dichloro-2-[N-(3,4-dimethoxyphenylsulfonyl)-N- 2

S,

4 R)-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

J

lr~ L-l 69 triethylamine and then 550 mg of methanesulfonyl chloride are added and the mixture is left at 0 C for 20 hours.

Water is added and the organic layer is washed with 0.5 N hydrochloric water, with water and then with a sodium bicarbonate solution, dried over magnesium sulfate and evaporated. The oil obtained is used as it is in the following step.

C) 2-[N-((2S,4S)-4-azido-2-(methoxycarbonyl)pyrrolidinocarbonylmethyl)-N-(3,4-dimethoxyphenylsulfonyl)]amino- 11 g of the product prepared in the preceding step are heated in 60 ml of DMSO at 80-90 0 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 washed with water, dried and chromatographed on silica by eluting with a pentane/AcOEt (50/50; v/v) mixture. An oil (10 g) is obtained.

C, -25.5 0 (c 0.39; chloroform, T 26°C).

D) 2-((2S,4S)-4-Azido-2-(methoxycarbonyl)pyrrolidinocarbonyl)-5-chloro-3-(2-chlorophenyl)-l-(3,4-dimethoxyphenylsulfonyl)-3-hydroxyindoline, cis isomer.

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

m 755 mg M.p. 200-202 0

C

D -176 0 (c 0.21; chloroform, T 26"C).

EXAMPLE 110 2 2

S,

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

A) Methyl ester of (N-Boc)-4-hydroxyproline.

The starting material is the hydrochloride of the methyl ester of (2S,4R)-4-hydroxyproline.

19 g of this compound are suspended in 100 ml of THF, 22.9 g of (Boc) 2 0 are added and then the mixture is Js 4 -V 70 cooled to 0°C. 21.2 g of triethylamine in 25 ml of THF are added dropwise and then the mixture is stirred for 12 hours at 0°C and 4 hours at 60 0 C. Water is added, the mixture is extracted with ethyl acetate, the organic layer is washed with water, with a potassium hydrogensulfate solution (4 times), with water and then with saline water. The solvent is evaporated and an oil (21.6 g) is isolated which contains a small amount of (Boc) 0.

B) Methyl ester of (2S,4R)-(N-Boc)-4-mesyloxyproline.

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 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 left to return to RT overnight. The mixture is evaporated to dryness, water is added, the mixture is extracted with AcOEt, the organic layer is washed with water and saline water and dried over magnesium sulfate. After a second evaporation, an oil is obtained which is used as it is in the following step.

C) Methyl ester of (2S,4S)-(N-Boc)-4-azidoproline.

This compound is prepared from that obtained in Step B. 15.2 g of the methyl ester of (N-Boc)-4-mesyloxyproline are dissolved in 70 ml of DMSO and the solution is heated at 90 0 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 saline water and dried over MgSO 4 The oil obtained is purified by chromatography on silica by eluting with the AcOEt/hexane (40/60; v/v) mixture.

aD -37.8 0 (c 3; chloroform) lit. a -36.6 2.8; chloroform) D.J. Abraham et al., J. Med. Chem., 1983, 549, 26.

D) Methyl ester of (2S,4S)-(N-Boc)-4-aminoproline.

8.45 g of the compound obtained in Step C are dissolved in 100 ml of methanol, 500 mg of 10% Pd/C are 71added and the mixture is hydrogenated at 40 0 C for 18 hours. The catalyst is filtered off, half the methanol is evaporated, 100 ml of 0.5 N HC1 are added, the remainder of the methanol is then 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 AcOEt.

E) Methyl ester of (2S,4S)-(N-Boc)-4-(N'-benzyloxycarbonylamino)proline.

The crude product obtained in the preceding step is dissolved in 15 ml of ether and 15 ml of DCM at 0°C.

2.3 g of DIPEA and then 3.03 g of benzyl chloroformate in 5 ml of DCM are added, over 70 minutes at 0°C. After 3 hours, the solvents are evaporated at RT under vacuum; water and ethyl acetate are added and the organic phase is washed successively with a potassium hydrogensulfate solution (3 times), with water (3 times), with a sodium carbonate solution (3 times), with water (3 times) and with saline water. The product is chromatographed on silica by eluting with hexane/AcOEt (40/60; v/v) mixture in order to obtain the expected product.

SQ, -16.4 (c 0.3; chloroform).

i F) Methyl ester of (2S,4S)-(N-Boc)-4-(N'-benzyloxycarbonyl-N'-methyl)aminoproline.

2 g of the compound obtained in the preceding step i are dissolved in 20 ml of DMF at 0°C, under argon, in the presence of 2.25 g of methyl iodide. 170 mg of 80% sodium S; hydride are added in portions and then the mixture is stirred at 0C for 90 minutes. The mixture is extracted with water and ethyl acetate; the organic phase is washed with water and then saline water. The product is chromatographed on silica by eluting with a hexane/AcOEt (50/50; v/v) mixture. 1.55 g of the expected product is obtained.

CD -38.8 O(c 0.38; chloroform).

fl-.i -72 G) 2 ',5-Dichloro-2-[(2S,4S)-N-(3,4-dimethoxyphenyl- V sulfonyl)-N-(4-(N-benzyloxycarbonylN'methyl)amino.2- (methoxycarbonyl)pyrrolidinocarbonylmethyl)]-aminobenzophenone.

This product is obtained by the usual methods.

UD -22.4 0 (c 0.37; chloroform).

H) 2-[(2S,4S)-4-(N-Benzyloxycarbonyl-N-methyl)amino-2- (methoxycarbonyl)pyrrolidinocarbonyl..chlor o3 (2 chlorophenyl)-l-(3,4-dimethoxyphenylsulfonyl)-3-hydroxyindoline, cis isomer.

This product is obtained by cyclizing in the presence of DBU according to the usual methods. The crystals formed -are crystallized from DCM/isopropyl ether.

M.p. 129 0

C

D= -129' (c 0.321; chloroform).

The isomeric purity by HPLC is 99%.

The compounds prepared in Examples 109 and 110 are used to prepare the compounds according to the invention described in Table 5 below: Table C1 C1 HHQ HH (4S) I CO-NN~ 2 (2S)

COOCH

3 OCH3

OCH

3 .4 ~II- *p-l i_ 73 Example R, ,(chloroform) 111 cis -NH 2 -189.6 c 0.4 -174 112 cis -NHCOOCH 2 c 0.24 113 cis -NHCH 3 -152.6 c 0.28 114 cis -191 -N(CH3)2 c 0.19 The compound of Example 112 makes it possible to successively prepare the compounds of Examples 115 and 116 described in Table 6 below and the compound of Example 114 makes it possible to prepare the compound of Example 116a.

Table 6

-R

9 (4S)

CONH

2

OCH

3 -74 Example

R

9 ae (chloroform) 115 cis -151 -NHCOOCH c 0.27 116 cis -NH 2 -161.4 c 0.26 116a cis -N(CH 3 2 The compound of Example 116a can be prepared either by conversion of -the compound of Example 114, or from (2S,4S)-(N-Boc)-4-(dimethylamino)prolinamide, the preparation of which is carried out as follows: 1) Methyl (2S,4S)-(N-Boc)-4-aminoprolinate is prepared from methyl (2S,4S)-4-azidoprolinate according to T.R. Webl in J. Org. Chem., 1991, 56, 3009.

2) Methyl (2S,4S)-(N-Boc)-4-(dimethylamino)prolinate.

4 g of the compound prepared in 1) are dissolved in ml of acetonitrile, 12.8 ml of30% formalin are added and then, over 5 minutes, 3 g of sodium cyanoborohydride.

After the reactants have been in contact for 2 hours, acetic acid is added to bring the solution to a pH of 6.

After 3 hours, the acetonitrile is evaporated, water, potassium carbonate and solid sodium chloride are added and the mixture is extracted with 4 volumes of ethyl acetate. The organic phase is evaporated, the residue is dissolved in 1 N hydrochloric acid and extraction is carried out with AcOEt. Solid sodium carbonate and then solid sodium chloride are added to the aqueous phase and extraction is carried out with AcOEt. After evaporating, the residue is 'chromatographed on silica gel by eluting with a DCM/MeOH (95/5; v/v) mixture and an oil which solidifies is isolated.

m 2.1 g IR (DCM): 1755 cm 1 1695 cm r s

V^

I 75 3) 534 mg of the ester prepared in 2) are dissolved in 4 ml of MeOH and are treated with sodium hydroxide (116 mg) in 1 ml of water for 48 hours at RT. The mixture is acidified with 0.5 N hydrochloric acid to a pH of and is evaporated to dryness. An azeotropic drying of the residue is carried out in the presence of benzene times) and then the residue is dried under vacuum for 8 hours. 2 ml of DMF and 3 ml of DCM are then added and the mixture is cooled to 0°C. 865 mg of BOP, and DIPEA, are added to bring the reaction mixture to neutrality. After minutes, a stream of gaseous ammonia is bubbled through twice for 30 minutes. After 2 hours at RT, the DCM is evaporated, carbonated water and sodium chloride are added and the mixture is extracted with 4 volumes of AcOEt. After evaporating, the residue is chromatographed on silica. The mixture (DCM/MeOH/NH 4 OH; 84.5/15/0.5; v/v/v) elutes a solid (m 185mg) which is recrystallized from a DCM/isopropyl ether mixture.

M.p. 183-186 0

C.

a5 -63.1 (c 0.24; chloroform).

EXAMPLE 117 Decarboxylation of N-(2-carboxyethyl)-N-ethyl-3-(2chlorophenyl)-5-chloro-l-(3,4-dimethoxyphenylsulfonyl)- 3-hydroxy-2-indolinecarboxamide, cis isomer.

630 mg of the compound prepared in Example 41 are placed in solution in 20 ml of THF under an argon atmosphere and then 101 mg of N-methylmorpholine at and 118 mg of isobutyl chloroformate are added. -After stirring for 5 minutes, 127 mg of N-hydroxy-2pyridinethione and 101 mg of TFA are added, the mixture is held at -15°C with stirring for 15 minutes, 900 mg of tert-butylmercaptan are then added and the mixture is left to return to RT. The reaction mixture is then irradiated for 1 hour 30 with a tungsten filament lamp (150 watts). The mixture is concentrated, taken up in water, extracted with DCM and the extract dried and concentrated. The residue is chromatographed on silica by eluting with DCM/AcOEt (95/5; The expected product L 'i 75 3) 534 mg of the ester prepared in 2) are dissolved in 4 ml of MeOH and are treated with sodium hydroxide (116 mg) in 1 ml of water for 48 hours at RT. The mixture is acidified with 0.5 N hydrochloric acid to a pH of and is evaporated to dryness. An azeotropic drying of the residue is carried out in the presence of benzene times) and then the residue is dried under vacuum for 8 hours. 2 ml of DMF and 3 ml of DCM are then added and the mixture is cooled to 0°C. 865 mg of BOP, and DIPEA, are added to bring the reaction mixture to neutrality. After minutes, a stream of gaseous ammonia is bubbled through twice for 30 minutes. After 2 hours at RT, the DCM is evaporated, carbonated water and sodium chloride are added and the mixture is extracted with 4 volumes of AcOEt. After evaporating, the residue is chromatographed on silica. The mixture (DCM/MeOH/NH 4 OH; 84.5/15/0.5; v/v/v) elutes a solid (m 185mg) which is recrystallized from a DCM/isopropyl ether mixture.

M.p. 183-186°C.

a -63.1 (c 0.24; chloroform).

630 mg of the compound prepared in Example 41 are placed in solution in 20 ml of THF under an argon atmosphere and then 101 mg of N-methylmorpholine at and 118 mg of isobutyl chloroformate are added. After stirring for 5 minutes, 127 mg of N-h t droxy-2pyridinethione and 101 mg of TFA are added, the mixture is held at -15"C with stirring for 15 minutes, 900 mg of tert-butylmercaptan are then added and the mixture is left to return to RT. The reaction mixture is then irradiated for 1 hour 30 with a tungsten filament lamp (150 watts). The mixture is concentrated, taken up in water, extracted with DCM and the extract dried and concentrated. The residue is chromatographed on silica by eluting with DCM/AcOEt (95/5; The expected product is obtained.

m 300 mg M.p. 215 0

C.

This compound is similar to that of Example 125 described in the European Patent Application EP 469984.

It has the cis configuration around the 2,3 bond of the indoline as in the starting material.

EXAMPLE 118 Decarboxylation of 2-((2R)-2-(carboxymethyl)pyrrolidinocarbonyl)-5-chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-3-hydroxyindoline, cis isomer.

The operation is carried cut as in the preceding example from the compound described in Example 102.

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

M.p. 215-220°C 0, -214.5" (c 0.2; chloroform).

This compound is 2-((2S)-2-methylpyrrolidinocarbonyl)-5-chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-3-hydroxyindoline, cis isomer, EXAMPLE 119 Decarboxylation of 2-(2-carboxypyrrolidinocarbonyl)- 5-chloro-3-(2-chlorophenyl)-l-(3,4-dimethoxyphenylsulfonyl)-3-hydroxyindoline, cis isomer.

The operation is carried out as in the preceding example by using the compound prepared in Example 28 as the starting material. The product obtained is recrystallized from an isopropyl ether/DCM mixture.

M.p. 263°C a D -201.5° (c 0.2; chloroform).

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

4'

Claims

1. A compound of formula: 2 OH N R 3 1 R4 SO 2 (CH 2 )m R "v in which RI is a halogen atom, a C -C 4 alkyl, a hydroxyl, a Ci-C 4 alkoxy, a benzyloxy group, a cyano group, a trifluoromethyl group, nitro group or an amino group; R 2 is a Ci-C 6 alkyl, a C 3 -C 7 cycloalkyl, a C 5 -C 7 cycloalkene or a phenyl which is unsubstituted or monosubstituted or polysubstituted by a Cl-C 4 alkyl, a Ci-C, alkoxy, a halogen, a trifluoromethyl group or an amino group, or R 2 is a nitrophenyl which is unsubstituted or monosubstituted by a trifluoro- methyl group or monosubstituted or polysubstituted by a C 1 -C 4 alkyl or a halogen; R 3 is a hydrogen atom; R 4 is a carbamoyl group of formula CONR 6 Ry; R 5 is a C 1 -C 4 alkyl; a 1-naphthyl; a 2-naphthyl; a dimethylamino-l-naphthyl; a phenyl which is un- substituted or substituted by one or more substi- tuents selected from a halogen atom, a Ci-C 4 alkyl, a trifluoromethyl group, an amino group which is free or substituted by one or 2 C 1 alkyls, a hydroxyl, a C,-C 4 alkoxy, a C 2 -C 4 alkenoxy, a C 1 -C 4 alkylthio, a trifluoromethoxy group, a benzyloxy group, a cyano group, a carboxyl group, a CI-C 4 alkoxycarbonyl group, a carbamoyl group which is free or substituted by one or two Ci-C 4 alkyls or a CI-C, alkylamido group, or R 5 is a nitrophenyl which is unsubstituted or monosubstituted by a trifluoro- 78 methyl group or a C 2 -C 4 alkenoxy or mono- or poly- substituted by a halogen, a Cl-C 4 alkyl, a C 1 -C 4 alkoxy, a CI-C 4 alkythio, a trifluoromethoxy group or a bei zyloxy group; R, is a Ci-C 6 alkyl or R 6 is similar to R,; R 7 is a 4-piperidyl group or a 3-azetidinyl group, the said groups being substituted or unsubstituted on the nitrogen by a C 1 -C 4 alkyl, by a benzyloxy- carbonyl or by a CI-C 4 alkoxycarbonyl; a group (CH 2 which is itself substituted by a 3- or 4-pyridyl group, by a hydroxyl group or by an amino group which is free or substituted by one or two Ci-C 4 alkyls, a carboxyl group, a Ci-C 4 alkoxycarbonyl group, a benzyloxycarbonyl group or a carbamoyl group which is free or substituted by one or 2 CI-C 4 alkyls; or R 6 and R 7 together, with the nitrogen atom to which they are connected, form a heterocycle selected from: morpholine, thiomorpholine, thiazolidine or 2,2-dimethylthiazolidine, unsubstituted or substituted by R 8 piperazine, unsubstituted or substituted at the

4-position by a group R" an unsaturated, 5-membered ring containing a single nitrogen atom and substituted by R, or a saturated, 6- or 7-membered ring containing a single nitrogen atom and substituted by R, and Rg; R 8 is or a group (CH 2 )r which is itself substituted by a hydroxyl or by an amino which is free or substituted by one or two C1-C 4 alkyls; is a group (CH 2 )q which is itself substituted by a carboxyl group, a alkoxycarbonyl group, a benzyloxycarbonyl group, a carbamoyl group which is free or substituted by a hydroxyl or by one or 2 CI-C 4 alkyls or an aminocarbothioyl group which is L 79 free or substituted by one or 2 C1-C 4 alkyls; R"a is or a group (CHz) 2 NH 2 which is free or substituted by one or two Cl-C, alkyls; R 9 is hydrogen, a halogen, a group (CHZ),ORio, a group (CH 2 NR,, R 2 a group (CH 2 ),CONRn1R' or an azido group; R 10 is hydrogen, a Cl-C 4 alkyl, a mesyl or a tosyl; R 1 R'n and R 12 are each a hydrogen or a C 1 -C 4 alkyl or Rt 1 is hydrogen and R 12 is a benzyloxycarbonyl or a Ci-C 4 alkoxycarbonyl; n is 0, 1 or 2; m is 0, 1 or 2; is 0, 1, 2 or 3; r is 0, 1, 2 or 3, with the limitation that r is not zero when R 8 or R 9 is at the alpha-position of the intracyclic amide nitrogen; s is 0 or 1; as well as its possible salts. 2. Compound according to claim 1, in which RI is a chlorine or bromine atom or a methoxy group and n 3. Compound according to any one of claims 1 or 2 in which R 2 is a chlorophenyl or a methoxyphenyl or a cyclohexyl. 4. Compound according to any one of claims 1 to 3 in which Rs is a phenyl substituted at the 3- and 4-positions or at the 2- and 4-positions by a methoxy group, or else Rs is a phenyl substituted at the 4-position by a methyl.

5. Compound according to any one of claims 1 to 4 in which m 0.

6. Compound according to any one of claims 1 to 5 in which R 4 is CONRR, and NR 6 R, is a pyrrolidino group 80 substituted at the 2-position by a group (CH,)q which is itself substituted by a carboxyl group, or a carbamoyl group with q 0, 1, 2 or 3.

7. Compound according to one of claims 1 to 5, in which P4 is CONRR 7 and NR6R 7 is a piperidino group substi- tuted at the 4-position by an amino group, a C 1 -C 4 alkylamino or a Ci-C 4 dialkylamino.

8. Compound according to any one of claims 1 to 5 in which R 4 is CONRsR 7 and NR 6 R 7 is a thiazolidino group substituted by a group (CH 2 )q which is itself sub- stituted by a carboxyl group or a carbamoyl group with q 0, 1, 2 or 3.

9. Compound according to any one of claims 1 to 5 in which R 4 is CONR 6 R 7 and NRR, 7 is a pyrrolidino group substituted at the 2-position by a group (CH 2 )q which is itself substituted by a carboxyl group or a carbamoyl group and substituted at the 4-position by an amino group, a C 1 -C 4 alkylamino or a C 1 -C 4 dialkyl- amino.

10. Compound according to any one of claims 1 to 5 in which R 4 is CONRR,, R 6 being a C 1 -C 4 alkyl and R 7 being a group (CH 2 which is itself substituted by a carboxyl group or a carbamoyl group with r 1, 2 or 3.

11. Compound according to any one of claims 1 to in the form of a cis isomer in which R 2 and R 4 are on the same side of the indoline ring.

12. Process for preparing a compound according to claim 1, characterized in that it comprises: a) reacting a 2-aminophenone derivative of formula: -81 CO-R 2 x (I I (R1) NH 2 in which R 1 R 2 and n have the meanings indicated above for I in claim 1, with a sulfonyl derivative of formula: Hal-SO 2 (CH 2 (III) in which Hal is a halogen, preferably chlorine or bromine, m and R 5 have the meanings indicated above for (I) in claim 1; b) treating the resulting compound of formula: O-R 2 (R1)n NH (IV) SO 2 (CH 2 )m R with a halogenated derivative of formula: Hal' -CH 2 COA (V) in which Hal' is a halogen, preferably bromine, and A repre- sents either the group NR 6 R 7 or the group OR in which R is a tert-butyl or a benzyl; c) deprotecting the resulting ester of formula: COR 2 (R)n N-CH 2 COOR SO 2 (VI)' (CH 2 )m R under suitable conditions, if applicable, when A is OR; I" 82 d) treating, if applicable, the resulting acid from Step c) of formula: COR2 (R nI) N-CH2 COOH SO 2 (VI)" SO 2 (CH2)m R or its acid chloride of formula: COR 2 (R N1)n' N-CH 2 COCI so 2 (CH 2 )m R with a compound HNR 6 R, according to suitable amide coupl'ng techniques; e) cyclizing the resulting compound from Step b) or from Step d) of formula: COR 2 (R n CH 2 CONR 6 R 7 ~2 (VI) (CH 2 )m R in a basic medium in order to prepare the compound according to claim 1, f) separating, if appropriate, the cis and trans isomers of the compound according to claim 1, and if appropriate, separating the enantiomers. e r" -83-

13. Use of a compound of formula: OH (RnN SCONRFtIRII SO 2 (C1H,)m R" in which R 1 R 2 R 3 R 5 m and n have tlic meanings given for the compounds of formula in claim 1 and RVI is a C 1 -C 6 alkyl, RVII is a group (CH 2 )rCOOH with r 1, 2 or 3, or RVI and RVII together, with the nitrogen atom to which they are bonded, constitute a heterocycle selected from: thiazolidine or 2,2-dimethylthiazolidine, substituted by a (CH 2 )qCOOH group, piperazine substituted at the 4-position by a (CH 2 )qCOOH group, an unsaturated, 5-membered ring containing a single nitrogen atom and substituted by a (CH 2 )qCOOH group or a saturated, 6- or 7-membered ring 25 containing a single nitrogen atom and substituted by a **0 (CH 2 )qCOOH group, with q 0, 1, 2 or 3 for the preparation of a compound of formula via free- radical decarboxylation, said compound of formula 30 having the same configuration around the 2,3 bond of the indoline as the starting material S950202,p:\operdab,24758.spe,83

522.;oe4a.278se8 -84- CONRVIRV I SO 2 1 in which R 1 R 2 R 3 R 5 m and n are as defined above, R'VI is a C 1 -C 6 alkyl, R'VII is a group (CH 2 )rH, or R'VI and R'VII together, with the nitrogen atom to which they are bonded, constitute a heterocycle selected from: thiazolidine or 2,2-dimethylthiazolidine, substituted by a (CH2)qH group, piperazine substituted at the 4-position by a (CH2)qH group, an unsaturated, 5-membered ring containing a single nitrogen atom and substituted by a (CH 2 )qH group or a saturated, 6- or 7-membered ring containing a single nitrogen atom and substituted by a (CH2)qH group. 14. Pharmaceutical composition in which a compound according to one of claims 1 to 10 is present as the active principle and a pharmaceutically acceptable carrier. S" 15. Pharmaceutical composition in which a compound according to any one of claims 1 to 10 is present in association with another active principle. l950202,p\pedab,24758.spe 84 85 16. Compounds of formula processes for their preparation, pharmaceutical compositionis containing them or uses involving them, substantially as hereinbefore described with reference to the Examples and/or drawings. DATED this 3rd day of February, 1995 Elf Sanofi By Its Patent Attorneys DAVIES COLIJISON CAVE C. :0. 9522, **M245.se8 ABSTRACT The invention relates to compounds of formula (I) SR 4 (I) SO2 (CH 2 in which R1 is a halogen atom, a C 1 -C 4 alkyl, a hydroxyl, a C1-C4 alkoxy, a benzyloxy group, a cyano group, a trifluoromethyl group, nitro group or an amino group; R 2 is a CI-C alkyl, a C3-C7 cycloalkyl, a C5-C 7 cycloalkene, a phenyl which is unsubstituted or monosubstituted or polysubstituted, a C 1 -C 4 alkoxy, a halogen, a trifluoromethyl group or an amino group, or R 2 is a nitrophenyl which is unsubstituted or monosubstituted or polysubstituted; R 3 is a hydrogen atom; R 4 is a carbamoyl group of formula CONR 6 R 7 R 5 is a C1-C 4 alkyl; a l-naphthyl; a 2-naphthyl; a 5-dimethylamino-1-naphthyl; a phenyl which is unsubstituted or monosubstituted or polysubstituted or R 5 is a nitrophenyl which is unsubstituted or monosubstituted or polysubstituted; R 6 is a C 1 -C 6 alkyl or R 6 is similar to R7; R 7 is a 4-piperidyl group or a 3-azetidinyl group, the said groups being substituted or unsubstituted on the nitrogen by a C 1 -C 4 alkyl, by a benzyloxycarbonyl or by a C1-C 4 alkoxycarbonyl; a group (CH2) r which is itself substituted by a 3- or 4-pyridyl group, by a hydroxyl group or by an amino group which is free or substituted by one or two substituents; or R 6 and R 7 together, with the nitrogen atom to which they are bonded, form a heterocycle selected from: morpholine, thiomorpholine, thiazolidine or 2,2-dimethylthiazolidine, unsubsti- tuted or substituted by R 9 pipjrazine, unsubstituted or substituted at the 4-position by a group R"8, an unsaturated, 5-membered ring containing a single nitrogen atom and substituted by R 8 or a saturated, 6- or 7-membered ring containing a single nitrogen atom and substituted by R 8 and R 9 R 8 is R' 8 or a group (CH2) r which is itself substituted by a hydroxyl or by an amino which is free or substituted by one or two C 1 -C 4 alkyls; R' is a group (CH 2 )q which is itself substituted by a carboxyl grouy a C 1 -C 4 alkoxycarbonyl group, a benzyloxycarbonyl group, a carbamoyl group which is free or substituted by a hydroxyl or by one or 2 C1-C 4 alkyls or an aminocarbothioyl group which is free or substituted by one or 2 C 1 -C 4 alkyls; R" is R'8 or a group (CH 2 2 NH 2 which is free or substituted by one or two C 1 -C alkyls; R 9 is hydrogen, a halogen, a group (CH 2 )rORI0 a group (CH 2 rNRiiR12 a group (CH 2 CONR 11 R'11 or an azido group; R10 is hydrogen, a C -C 4 alkyl, a mesyl or a tosyl; R11, R'1I and R12 are each a hydrogen or a C 1 -C 4 alkyl or R 11 is hydrogen and R12 is a benzyloxycarbonyl or a C 1 -C 4 alkoxycarbonyl; n is 0, 1 or 2; m is 0, 1 or 2; q is 0, 1, 2 or 3; r is 0, 1, 2 or 3, with the limitation that r is not 918 fS- zero when R 8 or R 9 is at the alpha-position of the intracyclic amide nitrogen; s is 0 or 1; as well as its possible salts. These compounds are useful in the treatment of complaints of the central nervous system, the cardiovascular system and the gastric sphere in humans and animals. 7