AU662960B2 - N-sulphonyl-2-oxoindole derivatives having affinity for vasopressin and/or ocytocin receptors - Google Patents

Abstract

N-sulphonyl-2-oxoindole derivatives of formula (I), and any salts thereof, preparation thereof and pharmaceutical compositions containing said derivatives. These compounds have an affinity for vasopressin and/or ocytocin receptors.

Description

OPI DATE 01/09/93 APPLN. ID 35043/93 AQJP DATE 28/10/93 PCT NUMBER PCT/FR93/00093 AU9335043 .REVETS (PCT) (51) Classification internationale des brevets 5 Num~ro de publication internationaic: WO 93/15051 CO' )D 209/96, A61K 31/40

A

C07D 209/90, 491/10, 471/10 Al (43) Date de publication internationale: 5 ao~t 1993 (05.08.93) C07D 403/12,_409/12,_209/34 (21) Numiro de In demande internationale: PCT/FR93/00093 (74) Mandataires: GILLARD, Marie-Louise etc. Cabinet Beau de Lom~nie, 55, rue d'Amsterdam, F-75008 Paris (22) Date de d~p~t international: 28janvier 1993 (28.01.93) (FR).

Donn~es relatives i la priorit6: (81) Etats d~sign~s: AU, BR, CA, CZ, Fl, RU, JP, KR, NO, 92/01034 30 janvier 1992 (30.0 1.92) FR NZ, RU, SK, US, brevet europ~en (AT, BE, CH, DE, DK, ES, FR, GB, GR, JE, IT, LU, MC, NL, PT, SE).

(71) D~posant (pour tous les Etats d~sign&s sauf US): ELF SANG- FI 32-34, rue Marbeuf, F-75008 Paris Publi~e (72 Inenturs etAvec rapport de rechierche intern ationale.

Inventeurs/Diposants (US seulement) :FOULON, Loic "iAI [FR/FR]; 14, rue de l'Ousse, F-31 120 Pinsaguel (FR).

GARCIA, Georges [FR/FR]; 27, rue des Aires, F-34980 S.-Genis-du-Fesc NISATO, Dino [IT/FR]; 2, rue 0 de Terre-Rouge, F-34680 Saint-Georges-d'Orques (FR).

ROUX, Richard [FR/FR]; 9, lotissement de l'Arn~de, F- 34570 Vallhaiques SERRADEIL-LEGAL, Claudine [FR/FR]; 45, avenue des Troubadours, F-31750 Escalquens VALETTE, Gerard [FR/FR]; 8, rue de Monts~gur, F-31 120 Lacroix-Sasgarde WAGNON, Jean [FR/FR]; 90, rue des Galaxies, Le Hameau de la Rauze, F-34000 Montpellier (FR).

(54) Title: N-SULPHONYL-2-OXOINDOLE DERIVATIVES HAVING AFFINITY FOR VASOPRESSIN AND/OR OCY- TOCIN RECEPTORS (54) litre: DERIVES DU N-SULFONYL-2-OXOINDOLE AYANT UNE AFFINITE POUR LES RECEPTEURS DE LA VASOPRESSINE ET/OU DE L'OCYTOCINE

(R

6 )m (57) Abstract N-sulphonyt-2-oxoindole derivatives of formula and any salts thereof, preparation thereof and pharmaceutical compositions containing said derivatives. These compounds have an affinity for vasopressin and/or ocytocin receptors.

(57) Abrilg6 L'invention concerne des d~riv~s de N-sulfonyl-2-oxoindole de formule et leurs sels 6ventuels, ainsi que leur pr~paration et les compositions pharmaceutiques en contenant. Ces composes ont une affinit6 pour les r~cepteurs de, la vasopressine et/ ou de l'ocytocine.

N-sulfonvl-2-oxoindole derivatives having affinity for vasopressin and/or ocytocin receptors.

The present invention relates to N-sulfonyl-2-oxoindole derivatives, their preparation and the pharmaceutical compositions in which they are present.

International patent application WO 91/01306 describes 2-oxoindole derivatives which are useful for the treatment of senile dementia. These compounds have the formula

R"

2 N 1

I

COR"4 10 in which

R"

1 is hydrogen, a halogen, an alkyl or an alkoxy;

R"

2 is hydrogen or a lower alkyl;

R"

3 is an alkyl, a cycloalkylmethyl, a benzodioxanylmethyl, or an optionally substituted benzyl; and

R"

4 is a 1-propylbutyl, a pyridyl or an optionally substituted phenyl.

Several patent applications have recently described families of compounds with a non-peptide structure which are active on the vasopressin and/or ocytocin receptors. European applications EP 382185 and EP 444 945, international S: application WO 91/05 549 and, more particularly, Japanese patent application JP 20 03/127732 can be cited in this respect. The latter describes indole-3-propionic .acid derivatives of the formula: S* COR"' 3 S N 2 R"1 in which

R"'

1 is hydrogen, an alkyl, an alkenyl, a phenylalkyl, a tetrahydrofuryl, an alkoxycarb' iyl, an alkoxycarbonylalkyl, a carboxyalkyl or an alkanoyl;

R"'

2 is hydrogen, a hydroxyl, an alkoxy, an alkyl, a phenylalkyl, a phenylalkoxy or a halogen;

R"'

3 is a hydrogen, an alkoxy, a free or substituted amino group or an amino acid residue;

R"'

4 is hydrogen, an alkyl or a phenylalkyl; and

R"'

5 'is a benzoyl, a phenyl, an alkyl, a phenylalkenylcarbonyl, a thienylcarbonyl, a phenylsulfonyl, a pyridylcarbonyl or an imidazolylcarbonyl, it being possible for the phenyl and alkyl groups of the substituent R"'5 to be substituted.

These compounds are vasopressin antagonists.

Patent US 4,803,217 claims hapalindolinones obtained by fermentation, which are vasopressin antagonists. These compounds have the following formula:

CH

3

R

2

CH

CHS

H NC c 3 -0 CH 3

N

H

in which R is H or Cl.

20 The N-sulfonyl-2-oxoindole derivatives according to the present invention have an affinity for the vasopressin and ocytocin receptors.

Vasopressin is a hormone known for its antidiuretic effect and its effect in regulating the arterial pressure. It stimulates several types of receptors, namely V1(Vla, Vlb) and V 2 and thus exerts cardiovascular, hepatic, antidiuretic and platelet-aggregating effects and effects on the central and peripheral nervous systems. Vasopressin receptor antagonists can affect the regulation of the central and peripheral circulations, especially the coronary, renal and gastric circulations, as well as the regulation of hydration and the release of adrenocorticotrophic hormone (ACTH). Non-peptide agonists of vasopressin can advantageously replace vasopressin or its analogs in the treatment of diabetes insipidus; they can also be used in the treatment of enuresia and in the regulation of hemostasis: treatment of hemophilia and of Von Willebrand's syndrom, antidote to plateletaggregating agents; Drug Investigation, 1990, 2 (Suppl. 1-47. The vasopressin receptors, like the ocytocin receptors, 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 myoepithelial cells of the mammary gland and in the central nervous system (Presse m6dicale, 1987, 16 481-485, J. Lab. Clin. Med., 1989, 114 617-632, and Pharmacol. Rev., 1991, 43(1), 73-108). This hormone is involved in parturition, lactation and sexual behaviour.

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

The present invention relates to compounds of the formula R3

RR

g-°-o

SO

2 o (R6 m 'in which 0 R 1 and R 2 are each independently a hydrogen, a hydroxy, a C 1 -C4-a- 20 halogenoalkoxy, a halogen, a C 1

-C

4 -alkyl, a trifluoromethyl, a C1-C 7 alkoxy, a C 1

-C

4 -polyhalogenoalkoxy, a C 2

-C

4 hydroxyalkoxy, an omethoxyalkoxy in which the alkyl is C2-C 4 a C 2

-C

4 -o-aminoalkoxy which is free or substituted by one or two C 1

-C

4 -alkyls a C 3

-C

7 -cycloalkyloxy a cycloalkylmethoxy in which the cycloalkyl is C 3

-C

7 a phenoxy; a benzyloxy; a C 1

-C

4 -alkylthio; a phenylthio; a nitro; an amino which is free or substituted by one or two C 1

-C

4 -alkyls; a cyano; a C 1

-C

4 -acyl; a C 1

-C

4 -acyloxy; a

C

1 -C4-alkylsulfonamido, a phenylsulfonamido, a C 1 -C4-alkylamido, a C 1

C

4 -alkoxycarbonylamino, a ureido which is unsubstituted or substituted by a phenyl or by one or two C 1

-C

4 alkyls;

R

3 and R4 are each independently a C 1

-C

6 -alkyl, a C3-C 7 -cycloalkyl, a phenyl, a benzyl, a cycloalkylmethyl in which the cycloalkyl is C 3

-C

7 or

R

3 and R 4 together form a group -(CH2)pX(CH2)q-; or

R

3 and R 4 together with the carbon atom to which they are bonded, form an optionally fused, saturated or unsaturated C 3

-C

10 hydrocarbon ring which is unsubstituted or substituted by one or more C 1

-C

7 -alkyl groups or by a C 3

C

5 -spirocycloalkyl; or else

R

1 and R4 each have one of the above meanings and R 2 is located in the 4position of the indole and forms a group (CH 2 3 with R 3

R

5 and R6 are each independently a hydrogen, a halogen, a C 1

-C

7 -alkyl, a trifluoromethyl, a cyano, a nitro, an amino which is free or substituted by one or two C 1

-C

7 -alkyls, a hydroxyamino, a hydroxy, a carboxy, a group OR 7 a group SR 7 a C 1

-C

7 -acyl, a C 1

-C

7 -alkoxycarbonyl, a phenoxycarbonyl, a 20 benzyloxycarbonyl, a carbamoyl substituted by groups R' 6 and R" 6 a thiocarbamoyl which is free or substituted by one or two C 1

-C

7 -alkyls, a sulfamoyl, an alkylsulfamoyl or a dialkylsulfamoyl in which the alkyl is C 1

C

7 group SO 2

R'

7 an alkylsulfonamido in which the alkyl is C 1

-C

7 a group

COR'

7 a group NRgR 9 a group CO-NH-CH(R 10

)-COR

1 2 if appropriate, the 25 phenyl group forming part of the substitutent R 5 and/or R 6 can be unsubstituted or monosubstituted or polysubstituted by a C 1

-C

7 -alkyl, a trifluoromethyl, a methoxy, a halogen, a sulfamoyl, an alkylsulfamoyl in which the alkyl is C 1

C

4 a carboxy, an alkoxycarbonyl in which the alkyl is C 1

-C

7 a C1-C7acyloxy or an imidazolyl;

R'

6 and R" 6 are each independently hydrogen, a C 1 -C7 alkyl which is unsubstituted or substituted by R"' 6 a phenyl, a pyridyl, a methylpyridyl, a piperidin-4-yl, a methylpiperidin-4-yl; R111 6 is a hydroxy, a cyano, a carboxy which is free or esterified by a C-7 alkyl or by a benzyl; a phenyl; a pyridyl; a methylpyridyl; an amino which is free or substituted by one or two Cl-C 7 -alkyls;

-R

7 is a C 1

-C

7 -alkyl, a phenyl, a benzyl, a C3-C 7 -cycloalkyl, a C 2

-C

4 alkenyl, a Cl-C 7 -wo-halogenoalkyl, a Cl-C-7-Polyhalogenoalkyl, a C-7 acyl, a C 1

-C

7 -0o-carboxyalkyl which is free or esterified by a Cl-C 4 -alkyl or by a benzyl, a C 2

-C

7 co-aminoalkyl in which the amino group is free, substituted by one or two Cl-C 4 -alkyls or in the form of an ammonium ion;

R'

7 is a piperazin-1-yl group which is unsubstituted or substituted in the 4position by a group R" 7 a piperidino group which is unsubstituted or substituted in the 4-position by a group R 7 an azetidin-1-yl group which is unsubstituted or substituted in the. 3-position by a group R 7 a pyridyl group which is unsubstituted or substituted by a methyl;

R"

7 is a C 1

-C

4 -alkyl, a phenyl, a benzyl, a Cl-C 4 -acyl; R 7 is R" 7 or an amino which is free or carries a protecting group;

R

8 and R 9 are each independently a hydrogen, a Cl-C 7 -alkyl, a phenyl or a benzyl; R 9 can also be a Cl-C 7 -acyl, a C 1

-C

7 -thioacyl, a cycloalkylcarbonyl in which the cycloalkyl is C 3

-C

7 a cycloalkyithiocarbonyl in which the a:::cycloalkyl is C 3

,-C

7 a Cl-C 4 -co-aminoacyl, a Cl-C 4 -rn)-hydroxyacyl, a C 1 C4-aw-benzyloxyacyl, a phcnoxycarbonyl, a thieniocarbonyl, a pyridylcarbonyl, a methylpyridylcarbonyl, a C 1 -C4-alkoxycarbonyl, a bcnzoyl, a phenacetyl, a group CO-CH(Rj 0 )-NRjjR'jj, a group CH(Rl 0 )C0 2

RI

1 a group

(CH

2 )tCORl2, a group CO(CH 2 )tCORl2, a carbamoyl which is unsubstituted or substituted by a phenyl or one or two Cl-C 4 -alkyls; m is 1 or, when R 6 is a halogen, a- Cl-C 7 -alkyl or a C 1

-C

7 -alkoxy, m can also be 2, 3 or 4 or else (RG)m can be m substituents having different meanings selected from halogen, Cl-C 7 -alkyl or Cl-C7-alkoxy; p and q are each integers, it being possible for their sum to vary from 3 to 6; t is an integer which can vary from 1ito X is oxygen, sulfur or a group NR 13 RIO is hydrogen, a C 1

-C

4 -alkyl or a bcnzyl;

R

11 and R'll are each independently hydrogen or a Cl-C 4 -alkyl;

R

12 is a hydroxy, a C 1

-C

4 -alkoxy or an amino which is unsubstituted or substituted by one or two C 1

-C

4 alkyls;

R

13 is hydrogen, a C 1

-C

4 -alkyl, a phenyl, a benzyl, a C 1

-C

4 -acyl, a C1-C4alkoxycarbonyl or a carbamoyl which is unsubstituted or substituted by one or two C 1

-C

4 alkyls; as well as their possible salts.

If a compound according to the invention has one or more asymmetric carbons, the invention includes ali the optical isomers of this compound.

The salts of the compounds of formula according to the present invention include those with mineral or organic acids which permit a suitable separation or crystallization of the compounds of formula such as picric acid, oxalic acid or an optically active acid, for example a mandelic acid or a camphosulfonic acid, and mineral or organic acids which form physiologically acceptable salts such as the hydrochloride, hydrobromide, sulfate, hydrogensulfate, di-hydrogenphosphate, maleate, fumarate or naphthalene-2-sulfonate.

The salts of the compounds of formula also include the salts with organic or mineral bases, for example the salts of alkali metal or -alkaline earth metals, such as the sodium, potassium and calcium salts, sodium and potassium salts being preferred, or with an amine such as trometamol, or else the salts of arginine, lysine, 20 or any physiologically acceptable amine.

According to the present invention, halogen is understood as meaning an atom selected from fluorine, chlorine, bromine and iodine, preferably fluorine or chlorine. Amino-protecting group is understood as meaning a group such as, for example, tert-butoxycarbonyl, benzyloxycarbonyl or benzyl.

25 According to the present invention, optionally fused condensed, saturated or S. unsaturated C 3

-C

1 0 hydrocarbon ring is understood as meaning various hydrocarbon rings with a monocyclic, dicyclic or tricyclic structure, for example a cyclobutane, a cyclopentane, a cyclohexane, a cycloheptane, a cyclooctane, an indane, a hexahydroindane, an adamantane, a norbornane, a norborene, a dihydrophenalene, a tricyclo[5.2.1.0 2 6 ]decane or a tricyclo[5.2.1.0 2 6 ]dec-8-ene.

The compounds of formula in which R 1 is in the 5-position of the indole and R 2 is hydrogen are preferred compounds.

The compounds of formula in which R 1 is a chlorine atom or an ethoxy group in the 5-position of the indole and R 2 is hydrogen are preferred compounds.

The compounds of formula in which R 3 and R 4 together with the carbon to which they are bonded, form a C 3

-C

1 0 hydrocarbon ring are preferred compounds; particularly preferred compounds are those in which R 3 and R4, together with the carbon to which they are bonded, form a cycloheptane, an adamantane, a tricyclo[5.2.1.0 2 6 ]dec-8-ene or a cyclohexane which is unsubstituted or substituted by a C 3

-C

5 -spirocycloalkyl or by one or two C 1

C

7 -alkyl groups.

The compounds of formula in which R 3 and R 4 together with the carbon to which they are bonded, form a piperidine-4 or N-methylpiperidine-4 ring are also preferred.

The compounds of formula in which R 5 and R6 are each a methoxy are preferred compounds. Likewise, the compounds in which R 5 in the 2-position is a methoxy and R 6 in the 4-position is a C 1

-C

7 -acylamino, a C 1

-C

4 -dialkylureido or an alkoxycarbonylalkylcarbamoyl in which the alkyl groups are C 1

-C

7 are preferred compounds.

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

DCM: dichloromethane Ether: ethyl ether Iso ether: isopropyl ether Boc: tert-butoxycarbonyl Me, MeO: methyl, methoxy Et: ethyl Pr, iPr, nPr: propyl, isopropyl, n-propyl Bu, iBu, tBu butyl, isobutyl, tert-butyl Ph:phenyl Bz: benzyl Ac: acetyl AcOEt ethyl acetate AcOH: acetic acid MeOH: methanol EtOH: ethanol DMF: dimethylformamide THF: tetrahydrofuran DMSO: dimethyl sulfoxide DIPEA: diisopropylethylamine TEA: triethylamine TFA: trifluoroacetic acid TMEDA tetramethylethylenediamine M.p. melting point Saline solution saturated aqueous sodium chloride solution TLC: thin layer chromatography HPLC: high pressure liquid chromatography Aqueous hydrochloric acid: dilute hydrochloric acid, about 1 N RT: room temperature The present invention further relates to the method of preparing the compounds according to the invention, characterized in that: a benzenesulfonyl halide of the formula Hal-SO 2 1 (R VI m in which R' 5 and RVI are respectively either R 5 and R 6 as defined above for or precursor groups of R 5 and R 6 is reacted with a 2-oxoindole disubstituted in the 3-position, of the formula: R3 R :.R R' 4

(II)

H

in which R' 1 and R' 2 are respectively either R 1 and R 2 as defined above for or precursor groups of R 1 and R 2 and R 3 and R 4 are as defined above for either, if R'I=R 1

R'

2

=R

2 R'5=R 5 and RVI=R 6 the resulting compound of formula is isolated; or, if any one of the groups R' 1

R'

2 R'5 and RVI is respectively a precursor group of R 1

R

2

R

5 and/or R 6 the compound obtained is subjected to a subsequent treatment in order to prepare the compound of formula by conversion of any one of the groups R' 1

R'

2

R'

5 and RVI to R 1

R

2

R

5 and

R

6 respectively.

The reaction is carried out in an anhydrous solvent such as DMF or THF, in the presence of a metal hydride such as, for example, sodium hydride, or in the presence of an alcoholate such as potassium tert-butylate.

The 2-oxoindoles (II) can be prepared using different procedures. Some of these compounds are novel and form part of the invention.

Compounds (II) in which R' 1 and/or R' 2 are a halogen and R 3 and R4, together with the carbon to which they are bonded, form a spirocyclobutane, a spirocyclohexane or a spirocycloheptane are known, for example in D. W.

Robertson et al. J. Med. Chem., 1987, 30 824-829. Also, 5-chloro-3spirocyclopentaneindol-2-one is described in US Patent 3,947,451.

To prepare the compounds (II) in the case where R 3 and R4 are together or separately a hydrocarbon group, it is possible to use the Brunner reaction described by R.F. Moore and S.G.P. Plant in J. Chem. Soc., 1951, 3475-3478, which leads to the preparation of compounds (II) in which CR 3

R

4 is a cyclopentane or a cyclohexane.

This reaction is carried out by cyclizing a phenylhydrazide derivative of the formula:

NH-NH-C-CH.

2 0 4 •V R4 (V) in which R' 1 and R'2 are as defined above for and R 3 and R4 have the meanings indicated above for for example by heating in the presence of 25 calcium oxide and quinoline.

According to the same authors, the phenylhydrazide derivative (IV) is S* obtained by reacting a hydrazine derivative of the formula R'1 NH-NH 2 2( in which R' 1 and R' 2 have the meanings indicated above for with an acid halide of the formula: Hal-C-CR 3

R

4 II 3

(VI)

0 in which R 3 and R4 have the meanings indicated above for According to a particular embodiment, if R 3 and R 4 together with the carbon to which they are bonded, form a fused polycyclic hydrocarbon, for example norbornane or norborene, the reaction is carried out by the method described by J. Wolff et al., Tetrahedron, 1986, 42 4267-4272: first of all, a lithium salt of the compound (IV) is prepared by reaction with a lithium reagent such as n-butyllithium, in an inert solvent such as THF, at low temperature, and then the cyclization is effected by heating in a solvent such as naphthalene or prehnitene (1,2,3,4-tetramethylbenzene).

The compounds (II) in which R 1

R

2 H and CR 3 R4 is adamantane are described in I. Fleming et al., J. Chem. Soc., Perkin Trans I, 1991, 3 617-626.

Thus, the compounds (II) in which R 3 and R 4 together with the carbon atom to which they are bonded, form an adamantane and R 1 and R 2 are other than hydrogen, are novel and form part of the invention. They can be prepared by the method described above.

The hydrazine derivatives are known or are prepared by known methods.

SThe same applies to the acid halides (VI).

A 2-oxoindole disubstituted in the 3-position (II) can also be prepared from a 2-oxoindole of the formula

H

in which R' 1 and R' 2 are as defined above for by using various methods.

For example, the method described by A.S. Kende and LC. Hodges in Synth.

Commun., 1982, 12 1-10, involves the addition of an alkylating agent in an appropriate solvent. Thus, to prepare a compound (II) in which R 3 R, the reaction is carried out in THF at -75' C, in the presence of TMEDA, by addition of an alkyllithium such as butyllithium, followed by reaction with a halide of the formula R 3 Hal; if R 3 and R 4 are different, the alkylating reaction can be performed in two steps with 2 different alkyl halides of the formulae R 3 Hal and

R

4 Hal. To prepare a compound (II) in which R 3 and R 4 together form a group of the formula in which n varies from 2 to 7, the reactant used is a compound of formula 7 (CH2)nZ, in which Z is an electron-accepting group such as a halogen, preferably bromine or iodine, a tosyloxy group or a mesyloxy group.

The compounds of formula (II) in which R 3 and R 4 are each independently an alkyl or a phenyl are known. For example, patent DE 3 300 522 describes alkoxy-3,3,-dimethylindol-2-ones.

The compounds of formula (II) in which R 3 and R 4 together with the carbon to which they are bonded, form a C 4

-C

8 hydrocarbon ring substituted by one or more C 1

-C

7 -alkyl groups or by a C3-C5-spirocycloalkyl are prepared in the same manner. These compounds are novel and form part of the invention.

If R 3 and R 4 together form a -(CH2)pX(CH2)q- group, in which p, q and X are as defined above for a 2-oxoindole disubstituted in the 3-position, of V, formula can be prepared from a 2-oxoindole unsubstituted in the 3-position (VII) by reaction with a compound of the formula 2: Z-(CH 2

-X-(CH

2 )qz 20 (VIII) in which Z is as defined above and X, p and q are as defined above for The reaction is carried out in the presence of an alcoholate, for example potassium tert- Sbutylate, in an anhydrous solvent such as, for example, THF.

If X is a nitrogen atom substituted by a C 1

-C

4 -acyl, a C1-C 4 alkoxycarbonyl or a C 1

-C

4 -alkylcarbamoyl, the substitution on X can be effected either on the 2-oxoindole derivative (II) or on the final compound starting from a compound in which the nitrogen atom (X NH) is not substituted.

The compounds in which X NH are preferred compounds according to the invention.

Thus, if X is a nitrogen atom substituted by a C 1

-C

4 -alkoxycarbonyl, the first step is to prepare a compound (II) or in which X is NH, which is then reacted with the appropriate chloroformate to give the desired compound (II) or In the same way, a C 1

-C

4 -alkyl isocyanate is reacted with a compound (II) or (I) in which X NH to give a 2-oxoindole derivative (II) or a compound in which X is a nitrogen atom substituted by an alkylcarbamoyl. An acid chloride or an anhydride is reacted with a compound (II) or in which X NH in order to prepare a compound of formula in which X is a nitrogen atom substituted by an acyl.

The compounds (II) in which R 3 and R4, together with the carbon to which they are bonded, form a pyrrolidine, N-alkylpyrrolidine, piperidine or Nalkylpiperidine ring are described by M. J. Komet in J. Med. Chem., 1976, 19 892-899.

In particular, the horsfiline of the formula Me

N

o o 0* MeO

N

is an alkaloid described in A. Jossang et al., J. Org. Chem., 1991, 56 6527o. 15 6530.

5i30: The compounds (II) in which R3 and R4, together with the carbon to which they are bonded, form a group -(CH2)pX(CH2)q- in which p and q are integers whose sum can vary from 3 to 6 and X is oxygen, sulfur or a group NR 13

R

13 0 being a C 1

-C

4 -acyl, a benzyl, a C 1

-C

4 -alkoxycarbonyl or a carbamoyl which is 20 unsubstituted or substituted by one or two C 1

-C

4 alkyls, are novel and form part of the invention.

t i To prepare a compound of formula (II) in which R 3 and R 4 together with s the carbon to which they are bonded, form a tricyclo[5.2.1.0 2 6 ]decane or a 000 tricyclo[5.2.1.02, 6 ]dec-8-ene, a compound of formula (VII') or a compound S: 25 (VII)" respectively, of the formulae

Z-CH

2 Z-CH 2 i

Z-CH

2

Z-H

2

(VII)'

(VII)"

in which Z is as defined above, is reacted with a compound of formula (VII).

Compounds (VII)' and (VII)" substituted by one or more C 1

-C

4 -alkyl groups are used to prepare compounds (II) in which said carbocycles are substituted.

To prepare a compound (II) in which R 3 and R 4 together with the carbon to which they are bonded, form an indane or a hexahydroindane, a compound (VIII)' or a compound (VIII)" respectively, of the formulae

Z-CH

2 f Z-CH 2

Z-CH

2 Z-CH 2 (VIII)' (Vm)" in which Z is defined as indicated above for (VIII), is reacted with a compound (VII). Compounds (VIII)' and (VIII)" substituted by one or more C 1

-C

4 -alkyl groups are used to prepare compounds (II) in which the indane or the hexahydroindane are substituted.

The compounds (II) in which R 3 and R 4 together with the carbon to which 15 they are bonded; form a tricyclo[5.2.1.0 2 6 ]decane, a tricyclo[5.2.1.0 2 6 ]dec-8- .ene, an indane or a hexahydroindane which are unsubstituted or substituted by one or more C 1

-C

4 -alkyls, are novel and form part of the invention.

If R 3 and R 4 each are a phenyl, the method described in Helv. Chim. Acta, 1946, 29, 415-432, can be used to prepare a compound (II).

20 The 2-oxoindole derivatives (VII) are known or are prepared by known methods. An example which may be cited is J. V. RajanBabu in J. Org. Chem., 1986, 51, 1704-1712.

The compounds of formula (II) which carry certain substituents R' 1 and R' 2 on their benzene moiety are used as precursors for the preparation of compounds of formula (II) which carry other substituents R' 1 and R' 2 For example, the compounds (II) in which R' 1 and/or R' 2 H can be nitrated with the conventional reagents; they can also be acylated by reaction with an acid chloride of formula RCOC1, in which R is a C 1

-C

4 -alkyl, in the presence of a Lewis acid such as aluminium chloride, in order to prepare a compound (II) in which R' 1 and/or R' 2 COR. A compound (II) in which R' 1 is an amino group is prepared by catalytic

I

14 hydrogenation of a compound (II) in which R'l is a nitro group and R' 2 is hydrogen.

The compounds of the formula

R

3

H

in which

R

1 and R 2 are each independently a hydrogen, a hydroxy, a lC-O halogenoalkoxy, a halogen, a Cl-C 4 -alkyl, a trifluoromethyl, a Cj 1

-C

7 alkoxy, a Cl-C4-polyhaogenoalkoxy, a C 2

-C

4 -co-hydroxyalkoxy, an conmehoxyalkoxy in which the alkyl is C 2

-C

4 a C 2

-C

4 -co-aminoalkoxy which is free or substituted by one or two CI-C 4 -alkyls, a C 3

-C

7 -cycloalkoxy, a cycloalkylmnethoxy in which the cycloalkyl is G 3

-G

7 a phenoxy, a benzyloxy, a CI-C 4 -alkylthio, a phenylthio, a nitro, an amino which is free or substituted by one or two Cl-C 4 -alkyls, a cyano, a Cl-C 4 -acyl, a C 1

-C

4 -acyloxy, a **Cl-C4--alkylsulfonamido, a phenylsulfonamido, a Cl-C 4 -alkylamido, a C 1 C4-alkoxycarbonylamino or a ureido which is unsubstituted or substituted by a phenyl or by one air two Cl-C 4 -alkyls; and

R

3 and R 4 together with the carbon to which they are bonded, form an adainantane, an indane or a hexahydroindane which are unsubstituted or substituted by one or more Cl-C 7 -alkyl groups, a tricyclo[5.2.1.0 2 6 ]decane or a tricyclo[5.2.1.02, 6 ]dec-8-ene which are unsubstituted or substituted by one or more CI-C 7 ,-alkyl groups, or- 25 .a G 4

-C

8 hydrocarbon ring substituted by one or more Cl-G 7 -alkyl groups or by a C 3

-C

5 -spirocycloalkyl; or else

R

3 and R4. together form a group -(CH2!)p-X(CHf2)q- in which p and q are integers whose sum can vary from 3 to 6 and X is oxygen, sulfur or a group

NR

13

R

1 3 being a phenyl', a benzyl, a Cl-C 4 -acyl, a Cl-C 4 -alkoxycarbonyl or a carbamoyl which is unsubstituted 'or substituted by one or two Cl-C/ 4 alkyls, with the limitation that if CRZ 3

R

4 is adamhntane, R 1 and R 2 are other than hydrogen, are novel and form part of the invention.

The compounds of the formula N 0

I)

in which

R

1 is a hydroxy, a Cl-C 4 -o-halogenoalkoxy, a halogen, a Cl-C 4 -alkyl, a trifluerom,-.thy1, a C 1

-C

7 -alkoxy, a Cl-C4-polyhalogenoalkoxy, a I~ oy~kx, an (o-methoxyalkoxy in which the alkyl is C 2 -,a co-amino-slkoxy which is free or substituted by one or two C 1

-C

4 -alkyls, a

C

3

-C

7 -cycloalkoxy, a cycloalkylmethoxy in which the cycloalkyl is C 3

-C

7 a phenoxy, a benzyloxy, a C 1

-C

4 -alkylthio, a phenylthio, a nitro, an amino which is free or substituted by one or two Cl-C 4 -alkyls, a cyano, a C-4 acyl, a Cl-C 4 -acyloxy, a Cl-C4-alkylsulfonamido, a phenylsulfonamido, a

C

1

-C

4 -alkylamido, a C 1 -C4-alkoxycarbonylarnino or a ureido which is unsubstituted or substituted by a phenyl or by one or two Cl-C 4 -alkyls;

R

3 and R4. together form a group -(CHl 2 )p X(CH2)q-; or

R

3 and R 4 together with the carbon to which they are bonded, form an .2E~ optionally fused, saturated or unsaturated C 3

-C

1 0 hydrocarbon ring which is ::20 unsubstituted or substituted by one or more C 1

-C

4 -alkyl groups or by a C 3 -pand q are each an integer, it being possible for their sum to vary from 3 to 6; X. Xis oxygen, sulfur or a group NR 1 3 and

R

13 is hydrogen, a Cl-C 4 -alkyl, a phenyl, a benzyl, a Cl-C 4 -acyl, a C-4 alkoxycarbonyl or a carbamoyl which is unsubstituted or substituted by one or 2

C

1

-C

4 -alkyls, with the limitation that if R 1 is methoxy, CR 3

R

4 is other than a pyrrolidine-3 which is unsubstituted or N-substituted by a Cl-C 4 -alkyl, and if R 1 is a halogen, CR 3

R

4 is other than a pentane, are novel and form part of the invention.

2a,3,4,5-Tetrahydrobenz[c,d]indol-2(Hy--one of the formula N

O

H

is commercially available; its derivatives are known or are prepared by known methods.

The benzenesulfonyl halides (III) are known and are prepared by known methods. Thus, for example, 4-dimethylaminobenzenesulfonyl chloride is prepared according to C.N. Sukenik et al., J. Amer. Chem. Soc., 1977, 99, 851- 858. More generally, the benzenesulfonyl halides (III) in which the substituent is a dimethylamino group are known or are prepared by known methods; pbenzyloxybenzenesulfonyl 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.

15 2,4-Dimethoxybenzenesulfonyl chloride is prepared according to J. Am.

Chem. Soc., 1952, 74, 2008.

The halogenoalkoxybenzenesulfonyl chlorides can be prepared according to patent US 2 540 057.

The benzenesulfonyl halides of the formula

SO

2

CI

OAlk

(III)'

YRV

in which Alk is a C 1

-C

7 -alkyl; YisOorS; and RV is a C 1 -C7-alkyl, a C3-C7-cycloalkyl, a C 2

-C

4 -alkenyl, a C1-C7-ohalogenoalkyl, a C1-C 7 -polyhalogenoalkyt, t benzyl, a C 1

-C

7 -acyl or a C 1

C

7 carboxyalkyl esterified by a C 1

-C

4 -alkyl or by a benzyl, are novel and form part of the invention.

These compounds are prepared according to D. Hofmann et al. in Liebigs Ann. Chem., 1982, 287-297. Benzene compounds carrying the substituents YRV and OAlk in the 1- and 3-positions are reacted with trimethylsilyl chlorosulfonate in a solvent such as DCM, at RT. The method of R. Passerini et al. in Gazz. Chim.

Ital., 1960, 90, 1277-89, is then applied and this is followed by neutralization, for example with alkali metal carbonate, and then by reaction with a halide such as POC1 3 to give the desired benzenesulfonyl halide.

The benzenesulfonyl halides (III) in which the substituent R' 5 is an alkoxycarbonyl, a phenoxycarbonyl, a benzyloxycarbonyl, an alkylthio, a phenylthio, a benzylthio or a group SR 7

R

7 being as defined for are prepared according to Col. Czechoslov. Chem. Commun., 1984, 49, 1184, from an aniline derivative substituted by the same grouping R' 5 said aniline derivative itself being obtained from the corresponding nitrated derivative.

The nitrobenzoic acid derivatives are known; the corresponding alkyl and S: phenyl esters are obtained by subjecting this acid to an appropriate esterification 20 reaction.

The benzenedisulfonyl dihalides (III, R' 5

SO

2 Hal) are known or are prepared by known methods. For example, 2,4-dimethoxybenzene-l,5-disulfonyl dichloride is described in R.J.W. Cremlyn, J. Chem. Soc. C, 1969, 1344.

The halogenoalkoxybenzenesulfonyl chlorides (III, R' 5 o- 25 halogenoalkoxy) are used to prepare compounds according to the invention in which the substituent R 5 is an a-aminoalkoxy which is unsubstituted or substituted by one or two alkyls, according to the following equation: S-O-Alk'-Hal NHR 8

R

9 -OAlk'-NR 8

R

9 in which Alk' is a C 1

-C

4 -alkyl.

For certain meanings of the substituents R 1

R

2

R

5 and/or R 6 the compounds according to the invention can be prepared from a precursor of formula substituted by a group R'1, R' 2

R'

5 and/or RVI, called a precursor group of R 1

R

2

R

5 and/or R6.

18 The description which follows describes the preparation of the compounds of formula carrying substituents R 1 and/or R 5 the same methods apply to the preparation of the compounds in which the substituents R 2 and/or R 6 are defined as indicated for R 1 and The compounds in which R 1 and/or R 5 are a hydroxy can be obtained by the catalytic hydrogenation of a compound of formula in which R' 1 and/or R' are a benzyloxy, for example in the presence of palladium-on-charcoal.

The compounds in which R' 1 and/or R' 5 are a hydroxy can be used to prepare compounds in which R 1 and/or R 5 are an alkoxy by reaction with an alkyl halide in the presence of a base such as a metal hydride or an alkali metal or alkaline earth metal carbonate like K 2

CO

3 or Cs 2

CO

3 in a solvent such as THF or DMF. Likewise, the compounds of formula in which R 1 and/or R 5 are an 0aminoalkyloxy are prepared by reacting an o-chloroalkylamine with the compounds in which R' 1 and/or R' 5 OH; similarly, the compounds in which R 1 and/or R 5 are an o-hydroxyalkoxy are prepared by reaction with a chloroalkyl alcohol; in the particular case of the preparation of a compound in which R 1 Sand/or R 5

O(CH

2 2 0H, it is also possible to react ethylene carbonate with a compound in which R' 1 and/or R' 5

OH.

The compounds of formula in which R 1 and/or R 5 are an acyloxy are S. 20 obtained by reacting an acid halide or an anhydride with a compound in which

SR'

1 and/or R' 5 are a hydroxy.

To prepare compounds of formula in which R 1 and/or R 5 are a monoalkylamino or a dialkylamino, the compounds of formula in which R' 1 and/or R' 5 are an amino can undergo reductive alkylation. If R' 1 and/or R' 5 are an 25 amino, it is also possible to perform a nitrosation, for example in the presence of nitrous acid or an alkyl nitrite, to prepare a compound in which R 1 and/or R are a diazonium salt; reactions known to those skilled in the art then afford the compounds according to the invention in which R 1 and/or R 5 are a cyano, a halogeno or a C 1

-C

4 -thioalkyl. Finally, compounds in which R 1 and/or R 5 are one of the groups of the formulae RCONH-, ROCONH-, RNHCONH- and

RSO

2 NH-, in which R is a C 1

-C

4 -alkyl, can be prepared by conventional reactions starting from compounds in which R' 1 and/or R' 5

NH

2 The compounds of formula in which the substitucnt R' 5 is a phenoxycarbonyl can be used to obtain the compounds in which R 5 is a phenylcarbamoyl or an alkylcarbamoyl by,reaction with an aniline or an alkylamine. A substituted aniline or an alkylamine substituted on the alkyl can be 19 used to obtain compounds of formula in which R 5 is a phenylcarbamoyl or, respectively, an alkylcarbamoyl substituted on the alkyl.

The compounds of formula in which R' 5 is a benzyloxycarbonyl can be used to obtain the compounds in which R 5 is a carboxy by catalytic hydrogenation. Reaction with a thionyl halide gives the compounds of formula (I) in which R 5 is a halogenocarbonyl. Such compounds are used to prepare compounds of formula in which R 5 is an N-substituted carbamoyl by reaction with a substituted amine.

The compounds of formula in which R 5 is a group COR" 7 are prepared from corresponding compounds in which R' 5 is a phenoxycarbonyl by reaction with a substituted piperazine or azetidine.

A compound in which R' 5 is a nitro group can be used to obtain a compound in which R 5 is an amino group by catalytic hydrogenation, for example in the presence of platinum oxide; other compounds in which the amino group is substituted can then be prepared by using reactions well known to those skilled in the art.

For example, if it is desired to obtain a compound according to the invention in which R 5 is a group NRgR 9

R

9 being an optionally substituted :"benzoyl, the benzoyl chloride in which the phenyl carries the appropriate S. 20 substituent is reacted with a compound in which R' 5 is an amino group, in the presence of an amine such as triethylamine. For example, 4-chlorosulfonylbenzoyl chloride can be reacted in order to prepare a compound in which R'5 is a 4chlorosulfonylbenzamido group, after which a compound in which the Ssubstituent R 5 is a 4-sulfamoylbenzamido group or a 4-alkylsulfamoylbenzamido S• 25 group is obtained by reaction with ammonia or a C 1 -C4-alkylamine respectively.

In the same way, if it is desired to prepare a compound in which R 5 is a group NR 8

R

9

R

9 being a C 1

-C

7 -acyl, the appropriate anhydride is reacted with a compound in which R' 5 is an amino group, in the presence of an amine such as triethylamine.

In another preparative example, a compound in which R 5 is an alkylsulfonamido group is obtained by reacting an alkylsulfonyl halide with a compound in which R' 5 is an amino group.

The compounds of formula in which R' 5 is an amino group are also useful for the preparation of compounds in which this amino group is substituted by a group (CH2)t-COR1 2 In this case, a compound of the formula Hal-(CH 2 )t- COOAlk, in which Hal is a halide, for example bromine, and Alk is a C1-C 4 alkyl, is reacted with in the presence of cuprous chloride; if appropriate, the resulting ester is converted to the acid or an amide. The reaction of a lactone, such as butyrolactone or valerolactone, with a compound in which R' 5 is an amino can be used to prepare the compound in which R' 5

NHCO(CH

2 )tCO2H, where t 2 or 3.

In the same way, the compounds of formula in which R 5 is an amino group substituted by a group CH(R 1 0 )C0 2

R

11 are prepared by reacting a compound of the formula Hal-CH(R 10 )C0 2

R

1 1 with the corresponding compounds in which the substituent R' 5 is an amino.

A compound in which R 5 is an amino group substituted by an alkoxycarbonyl or a phenoxycarbonyl is prepared by reacting an alkyl or phenyl chloroformate with a compound in which the substituent R'5 is an amino.

A compound of formula in which R 5 is a ureido is prepared by reacting ammonia with a compound of formula in which R' 5 is an amino group substituted by a phenoxycarbonyl; a compound of formula in which R5 is N- S* phenylureido or N-alkylureido or N,N-dialkylureido in which the alkyl is C 1

-C

4 is prepared by reacting an aniline or a C 1

-C

4 -monoalkylamine or -dialkylamine with such a compound of formula A compound in which R 5 is a carbamoyl which is unsubstituted or 20 substituted by one or 2 alkyl groups is prepared by reacting an appropriate amine with a compound in which the substituent R'5 is an amino, in the presence of phosgene.

It is also possible to prepare a compound in which R 5 is an amino group substituted by an alkylcarbamoyl or by a phenylcarbamoyl by reacting an alkyl or 25 phenyl isocyanate with a compound in which the substituent R' 5 is an amino.

Furthermore, a compound in "-hich R5 is a sulfamoyl group which is unsubstituted or substituted by a C 1

C

4 -alkyl is prepared by reacting ammonia or an alkylamine with a compound in which R'5 is a halogenosulfonyl group.

The compounds of formula which are useful as precursors for the preparation of compounds of formula are included in formula and form part of the invention.

Among the compounds of formula the compounds of formulae (XII) and (XIII) below, which are useful for the preparation of other compounds of formula are preferred compounds according to the invention.

Thus one subject of the present invention consists of the compounds of the formula

R

3

R

2 4

N

SOU

2

OIX)

COOFI

in which RI, R 2

R

3

R

4 and R5~ are defined as indicated above for and its esters or salts.

to* 5 Another subject of the present invention consists of the compounds of the *formula

N

V Rs N02 in whc 142 RR n 5aedfnd sidctdaoefr() n hi sats were apropiate Ye aohe ubet fth reet nenin ositJo omondRf h forul R

R

R2 R4 R o-^

R

SO

2

(XI)

R

OH

in which R 1

R

2

R

3 R4 and R 5 are defined as indicated above for Another subject of the present invention consists of compounds of the formula HO R3

N

SO2 (XII)

R

(R6)m in which Rs, R4, R 5

R

6 and m are defined as indicated above for Yet another subject of the present invention consists of the compounds of the 10 formula

S

K

NH

0 I NN R2

SO

2 (XIII)

R

(R

6 )m in which R 1

R

2

R

5

R

6 and m are defined as indicated above for The affinity of the compounds according to the invention for the vasopressin receptors was determined in vitro by using the method described in C.J. Lynch et al., J. Biol. Chem., 1985, 260(5), 2844-2851. This method consists in studying the displacement of tritiated vasopressin bound to the V 1 sites of rat liver membranes.

The concentrations of the compounds according to the invention which inhibit the binding of tritiated vasopressin by 50% (IC 50 are low, ranging up to 10 7

M.

The affinity of the compounds according to the invention for the V 2 receptors was measured on a bovine kidney membrane preparation using a method adapted from P. Crause et al., Molecular and Cellular Endocrinology, 1982, 28, 529-541, and from F.L. Stassen et al., J. Pharmacol. Exp. Ther., 1982, 223, 50-54.

The compounds according to the invention inhibit the binding of tritiated 15 arginine-vasopressin to the receptors of the membrane preparation. The IC 5 0 values of the compounds according to the invention are low, ranging up to 10 9

M.

The activity of the compounds according to the invention as V 2 receptor antagonists was demonstrated by the adenylate cyclase activity assay performed by 20 a method adapted from M. Laburthe et al., Molecular Pharmacol., 1986, 29, 23-27.

A bovine kidney membrane preparation is used and each product is incubated for miumtes at 37C, by itself or in the presence of AVP (arginine-vasopressin) at a concentration of 3.10- 8 M. The cyclic AMP (cyclic adenosine monophosphate) produced is measured by radioimmunoassay. The concentration which causes a 50% inhibition (IC50) of the stimulation of adenylate cyclase induced by 3.10-8 M AVP is determined. The IC 5 0 values determined are of the order of 10 7

M,

ranging up to 10-8 M.

The activity of the compounds according to the invention, administered orally, as V 2 receptor agonists or antagonists is evaluated in hyperhydrated rats (OFA strain, Sprague-Dawley) treated with vasopressin.

Likewise, the affinity of the compounds according to the invention for the ocytocin receptors was determined in vitro by the displacement of a radioiodinated ocytocin analog bound to the receptors of a gestating rat mammary gland membrane preparation, using a technique similar to that described by J. Eland et al.

in Eur. J. Pharmacol., 1987, 147, 197-207. The IC 5 0 values of the compounds according to the invention reach 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 or ocytocin-dependent complaints, especially cardiovascular complaints such as hypertension, cardiac insufficiency or coronary vasospasm, in particular in smokers, cardiac ischemia, S hemostatic disorders, especially hemophilia, and Von Willebrand's syndrome; complaints of the central nervous system, for example cerebral edemas, depression, 20 anxiety, psychotic states and memory disorders; complaints of the renal system, such as renal vasospasm, necrosis of the renal cortex, hyponatremia and hypokalemia; and complaints of the gastric system, such as hepatocirrhosis, ulcers, the pathology of vomiting, for example nausea, travel sickness or else the Ssyndrome of inappropriate secretion of antidiuretic hormone (SIADH), diabetes 25 insipidus and enuresia. The compounds according to the invention can also be used in the treatment of disorders of sexual behavior; in women, the compounds according to the invention can be used for the treatment of dysmenorrhea or premature labor.

0 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 salts where appropriate, can be administered to animals and humans in unit forms of administration, mixed with conventional pharmaceutical carriers, for the prophylais or treatment of the above disorders or diseases. The 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 per day.

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 a 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 Ssucrose, a cellulose derivative or other appropriate substances or they can 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.

25 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 i 0antiseptics, 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 cacao 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 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 above or one of the pharmaceutically acceptable salts, the compositions of 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 further relates to pharmaceutical compositions containing several active principles in association, one of which is a compound according to the invention.

Thus, according to the present invention, it is possible to prepare pharmaceutical compositions containing a compound which is a VI receptor antagonist in association with a compound which acts on the renin-angiotensin system, such as a converting enzyme inhibitor, an angiotensin II antagonist or a renin inhibitor. They can also be associated for example with a peripheral vasodilator or a calcium inhibitor. Such compositions will be useful in particular in the treatment of hypertension or cardiac deficiency.

20 Preparation of 2-oxoindoles Preparation 1: 4,6-Dimethyl-3-spirocyclohexaneindol-2-one This compound is prepared according to Moore and Plant in J. Chem. Soc., 25 1951, 3475.

A mixture containing 15 ml of quinoline and 10 g of calcium oxide is refluxed under an inert atmosphere and 5 g of the 3,5-dimethylphenylhydrazide of cyclohexanecarboxylic acid (II, R' 1

R'

2

CH

3

CR

3

R

4 cyclohexane) are added over 30 minutes. The reaction medium is cooled and then poured into an ice/hydrochloric acid mixture. Extraction is carried out with ethyl acetate and the extract is washed with normal hydrochloric acid and with water until the washings are neutral, and then dried and concentrated under vacuum to give a brown solid.

Trituration in iso ether gives the expected compound.

M.p. 223'C.

The indol-2-one derivatives described in Table 1 below are obtained by following the same procedure and varying the starting hydrazide.

These compounds are purified by chromatography on a silica column using DCM as the eluent or by chromatography on an alumina column using DCM or iso ether as the eluent.

TABLE 1

R

3 RI -0 2 N N

H

R'

1 R'2 CR 3

R

4 M.p. 'C 5-C1 H cyclobutane 191 5-Cl H cyclopentane 189 5-Cl H cyclohexane 186 H H cyclohexane 123-124 3 H cyclohexane 164 3 0 H cyclohexane 226 6-C1 H cyclohexane 168

CF

3 0 H cyclohexane 164 6

H

5 0 H cyclohexane 160 Preparation 2: 10 The 3-spirocyclohexaneindol-2-one described in Table 1 above can also be obtained by alkylation of the indol-2-one using the method described below.

A solution of 30 g of indol-2-one in 900 ml of THF is kept at -40*C under a nitrogen atmosphere and 101 g of potassium tert-butylate are added. The temperature is allowed to rise to 0*C over 1 hour, the mixture is then cooled to and a solution of 52 g of 1,5-dibromopentane in 50 ml of THF is added dropwise.

After 30 minutes at -60'C, the temperature is allowed to rise to RT, 30 ml of water are then added and the solvent is evaporated off under reduced pressure. The residue is taken up in 500 ml of DCM and 200 ml of water, the insoluble material is then filtered off and the organic phase is separated off, washed with 100 ml of water, dried over magnesium sulfate and evaporated under vacuum. The residue is chromatographed on silica using a cyclohexane/ether mixture as the eluent to give the expected compound, which is recrystallized from heptane.

m 34 g.

M.p. 123-124'C.

A similar procedure can be applied starting from other indol-2-ones and other alkylating agents.

By way of example, among the starting compounds of formula (VII), chloroindol-2-one is described by Bright in J. Am. Chem. Soc., 1956, 79, 221, and by RajanBabu in J. Org. Chem., 1986, 51, 1704. 4-Chloroindol-2-one can be prepared from 2-chloro-6-nitrotoluene by the method described in J. Am. Chem.

Soc., 1956, 78, 221.

5-Methoxyindol-2-one is prepared from 4-methoxyaniline by the method described in J. Am. Chem. Soc., 1974, 96, 5512. In the same way, various indol- 2-ones are prepared from the appropriate aniline derivative.

Preparation 3: 5-Ethoxyindol-2-one A 3-Thiomethyl-5-ethoxyindol-2-one 23.6 g of ethyl thiomethylacetate in 60 ml of DCM are added to a solution, cooled to about -70*C, of 12.5 g of chlorine in 400 ml of DCM. After stirring for Sminutes at the same temperature, a solution of 4-ethoxyaniline (48.3 g) in 120 ml of DCM is added. The mixture is stirred for one hour at about 70*C, 39.3 ml of triethylamine are added and the resulting mixture is left to warm up to room temperature. 200 ml of water are added and the organic phase is decanted, dried 25 over magnesium sulfate and evaporated under reduced pressure. The residue is taken up in 500 ml of isopropanol and 20 ml of concentrated hydrochloric acid.

The mixture is stirred for about 16 hours at room temperature and filtered and the precipitate is separated off. The filtrate is concentrated under reduced pressure to give the expected product.

30 B 5-Ethoxyindol-2-one The above solid, in 1500 ml of ethanol, is dethiomethylated in the presence of 100 g of Raney nickel (80 to 100 m 2 per under reflux, for 3 hours, under a nitrogen atmosphere. The mixture is filtered on talc, the material on the filter is rinsed with 1000 ml of ethanol and the filtrate is concentrated under reduced pressure. 16 g of the expected product are isolated after recrystallization from toluene.

29 M.P. 156*C.

The following are isolated in the same manner starting from the cori-esponding anilines: 5-benzyloxyindol-2-one m.p. 152*C 5-n-propylindol-2-one m.p. 136*C 5-ethylindol-2-one m.p. 152*C 5-(2,2,2-trifluoroethoxy)indol-2-one m.p. =145*C The compounds of formula (ID) described below are obtained by following the technique described in Preparation 2 and varying the starting indol-2-one derivative and the alkylating reagent.

TABLE 2 R'

R

R'

2 N-

N

H

R1 I2CR 3

R

4 IM.P CI Alkylating reagent 3 0 cyclohexane cycloheptane 4,4-dimethyl cyclohexane 2-hexahydroindane 4,4-dimethyl cyclohexane 2-indane

C(CH

3 2

C(CH-

2

CH

3 2 C(n Pr)2 C(iBu) 2 186-189 202 180 223 202 228 160 156 158 164 Br(CH 2 5 Br Br(CH 2 6 Br

TSO(CH

2 2

C(CH

3 2

-(CH

2 2 OTs cis-1,2diiodomethylcyclohexane TsO (CH 2 2

C(CH

3 2

-(CH

2 2

-OTS

c,c'-dibromomethyl orthoxylene

CH

3 1

CH

3

CH

2

)I

nPrI iBul 4-Cl

H

N-methyl-4piperidine 4-tetrahydropyranne cyclc~hexane cyclohexane

C(CH

2

C

6

H

5 2 C(n-pentyl) 2 2,3-dihydro phenalene-2 4,4-diinethyl cyclohexane 4-spirocyclopentane cyclohexane cyclohexane N-tBu-4piperidine N-Bz-4piperidine N-phenyl-4piperidine 4,4-diethy t cyclohexane cyclohexane 4,4-dimethyl cyclohexane 260 223 215 162 206 142 154 202 151 165 188 300 132 163 178 Cl(CI1 2 2

N(CH

3

-(CH

2 2 C1

I(CH

2 2 0(CH 2 2 1 Br(CH 2 5 Br Br(CH 2 5 Br

C

6

H

5

CH

2 Br

CH

3

(CH

2 4 Br BrCH 2

CH

2 )Br

TSO(CH

2 2

C(CH

3 2

-(CH

2 2 OTs

CK(CH

2 2 OTs

(GH

2 2 0Ts Br(CH 2 5 Br

~(CH

2 2 Br

,.(CH

2 2 Br BzN

(CH

2 2 Br ll- (CH 2 2 C1 C6H-N

I-,(CH

2 2 C1 la CH2 SO 2 CH3

CH

2 O 2

CH

3 TsO(CH 2 2

C(C

2 H5)2

-(CH

2 2 OTs Br(CH 2 5 Br

TSO(CI{

2 2

C(CH

3 2

-(CH

2 2 OTs H cycloheptane 139 Br(CH 2 6 Br H 4,4-dimethyl 160 TsO(CH 2 2

C(CH

3 2 cyclohexane

-(CH

2 2 OTs 3

CH

2 O- H 4,4-dimethyl 164 ditto cyclohexane H H 4,4-dimethyl 169 ditto cyclohexane Preparation 4: 3-Spiroadamantaneindol-2--one This comnpound is prepared according to 1. Fleming et al., Tetrahedron Letters, 1982, 2053-2056, from 2-bromoaniline and adamantan-2-one.

Preparation 5-Chloro-3,3-diphenylindol-2-one This compound is prepared by the method described in Helv. Chim. Acta, 1946, 29, 415-431, by the reaction of benzene with 5-chioroisatin in the presence of aluminum chloride.

M.P. 281*C.

Preparation 6: 5-Nitro-3-spirocyclohexaneindol-2-one This compound is pitpared by the method described in J. Am. Chem. Soc., 1945, 67, 499, by the nitration of 3-spirocyclohexanindol-2-one.

M.P. =192*C.

5-Nitro-3-spiroadamantaneindol-2-one is prepared in the same manner starting from 3-spiroadamantaneindol-2-one.

M.P. 260*C.

5-Nitro-3-spiro(4,4-dimethyl)cyclohexaneindol-2-one is also prepared.

M.P. 195*C.

Preparation 7: 5-Aniino-3-spirocyclohexancindol-2-one This compound is prepared by the method described in J. Chem. Soc., 1951, 3475, by the reduction of 5-nitro-3-spirocyclohexaneindol-2-onc, prepared above.

M.p. 176C.

5-Amino-3-spiroadamantane is prepared in the same manner.

M.p. 245'C.

Preparation 8: 5-Fluoro-3-spirocyclohexaneindol-2-one A 5-Diazonium-3-spirocyclohexaneindol-2-one tetrafluoroborate A solution containing 4 g of 5-amino-3-spirocyclohexaneindol-2-one in 9.2 ml of 6 N hydrochloric acid is cooled to O0C and 2.27 g of sodium nitrite in 2.6 ml of water are added, followed by 2.54 g of sodium tetrafluoroborate in 9 ml of water. After stirring for 5 minutes, the precipitate is filtered off and washed with a solution of tetrafluoroborate, with 3 ml of methanol cooled to about O0C and then with 5 ml of ether. The salt obtained is dried under vacuum at RT in the presence of phosphorus pentoxide.

B 5-Fluoro-3-spirocyclohexaneindol-2-one 1 g of the compound obtained in step A is placed in 5 ml of xylene and heated at about 115"C for 2 hours. The mixture is cooled to RT, the precipitate is filtered off and rinsed with toluene and 0.1 g of active charcoal is added to the 20 filtrate. After filtration, the solvent is evaporated off under reduced pressure to give 0.45 g of the expected compound, which is recrystallized from pentane.

SO: M.p. 114'C.

Preparation 9: 25 5-Cyano-3-spirocyclohexaneindol-2-one 4.78 g of potassium cyanide and 4.95 g of cuprous cyanide are dissolved at RT in 40 ml of DMSO. The solution is cooled to about 15C and 4.15 g of the diazonium salt obtained in step A of the previous preparation are added.

After stirring for 30 minutes at RT, 100 ml of w-ter and 100 ml of ether are 30 added and the organic phase is then separated off, dried over magnesium sulfate and evaporated under reduced pressure. The residue is chromatographed on silica using a cyclohexane/ether mixture as the eluent to give the expected compound, which is recrystallized from heptane.

m 1.4 g.

M.p. 216*C.

Preparation 5-Chloro-3-spiroadamantaneindol-2-one 1 g of the p-chlorophenylhydrazide of adamantane-2-carboxylic acid is dissolved and 2.5 ml of a solution of n-butyllithium (1.6 M in hexane) are added at -40'C. After stirring for 5 minutes, the mixture is concentrated under vacuum with the temperature being kept below 30'C. 30 ml of 1,2,3,4-tetramethylbenzene are added and the mixture is refluxed for 1 hour. It is concentrated under reduced pressure, the residue is taken up in normal hydrochloric acid, extraction is carried out with ether and the extract is washed, dried and concentrated under vacuum.

The oil obtained is chromatographed on a silica column using DCM as the eluent to give 0.3 g of the expected product in the form of a wax, which is crystallized from iso ether.

M.p. 249*C.

Preparation 11: 5-Chloro-3-cyclohexyl-3-methylindol-2-one The method described in Synth. Commun., 1982, 12(1), 1-10, is used to prepare 5-chloro-3-cyclohexylindol-2-one as an intermediate, and the expected compound is then obtained by reaction with methyl iodide.

Preparation 12: 5-Acetyl-3-spirocyclohexaneindol-2-one 2.56 g of acetyl chloride and then 8.25 g of anhydrous aluminum chloride are added to a solution, cooled to 5*C, of 4 g of 3-spirocyclohexaneindol-2-one in 25 ml of 1,2-dichloroethane. The mixture is refluxed for 2 hours, the solvent is evaporated off under reduced pressure and the medium is hydrolyzed with 50 g of ice and extracted with ethyl acetate.

The organic phase is washed with water, dried over magnesium sulfate and then evaporated under reduced pressure. The residue is chromatographed on a 30 silica column using a mixture of heptane and ethyl ether as the eluent to give 3.6 g of the expected product.

M.p. 192C.

The benzenesulfonyl chlorides described in the Table below were prepared using the procedure described.

Cl

SO

2

OCH

3 Y RV M.p. "C S CH 3 0 CH 2 Bz O CH 2

CO

2 Et 89 0 (CH 2 3 Br 106-108 s Starting from the various 2-oxoindoles described above benzenesulfonyl chlorides, the compounds according to the prepared using the procedures reported in the Examples below.

and appropriate invention were EXAMPLE 1 5-Chloro-l-(2-methoxy-4-nitrobenzenesulfonyl)-3spirocyclohexaneindol-2-one A mixture containing 0.7 g of 5-chloro-3-spirocyclohexaneindol-2-one and 70 mg of sodium hydride in 7 ml of THF is stirred under nitrogen at RT for minutes. 0.7 g of 2-methoxy-4-nitrobenzenesulfonyl chloride is introduced and stirring is maintained at RT for 20 hours. The mixture is concentrated under 15 vacuum, the residue is taken up in 30 ml of water, extraction is carried out with ethyl acetate and the extract is washed with water and then dried and concentrated to give 1.1 g of the expected compound, which crystallizes from iso ether.

M.p. 188*C.

EXAMPLE 2 1-(4-Amino-2-methoxybenzenesulfonyl)-5-chloro-3spirocyclohexaneindol-2- one 0.8 g of the compound obtained in the previous Example is reduced with hydrogen under normal pressure at RT for 20 hours in 10 ml of acetic acid, in the presence of 30 mg of platinum oxide. The reaction medium is filtered, the filtrate is concentrated, the residue is taken up in a water/ethyl acetate mixture and the organic phase is washed with water, dried and concentrated. The yellow foam ,obtained is chromatographed on alumina using DCM as the eluent to give 0.2 g of the expected product.

M,p. 173C.

EXAMPLE 3 5-Chloro-l-[4-(2-methylphenylcarboxamido)-2methoxybenzenesulfonyl]-3-spirocyclohexaneindol-2-one A mixture containing 0.2 g of the compound prepared in the previous Example, 0.5 ml of triethylamine, 5 ml of DCM and 0.1 g of orthotoluoyl chloride is s rred at RT for 48 hours. It is concentrated under vacuum, the residue is taken up in a water/ether mixture and left to decant and the organic phase is washed with a saturated solution of sodium hydrogencarbonate and then with water, dried and concentrated under vacuum to give 250 mg of a solid, which is chromatographed on silica using DCM a: the eluent to give 0.1 g of the expected product.

20 M.p. 192*C.

EXAMPLE 4 6-Chloro-1-(2,4-dimethoxybenzenesulfonyl)-3-spirocyclohexaneindol- 2-one 25 A mixture containing 0.15 g of 6-chloro-3-spirocyclohexaneindol-2-one and 15 mg of sodium hydride in 2 ml of THF is stirred for 30 minutes at RT under nitrogen; 0.15 g of 2,4-dimethoxybenzenesulfonyl chloride is introduced and i" stirring is maintained at RT for 20 hours. The mixture is concentrated under vacuum, the residue is taken up in 30 ml of water and extracted with ethyl acetate and the extract is washed with water, dried and concentrated under vacuum. The product obtained is recrystallized from iso ether.

M.p. 147*C.

EXAMPLE Acid fumarate of 5-chloro-l-[4-(3- Sdimethylaminopropoxy)benzenesulfonyl]-3-spirocyclohexaneindol-2-one A) 4-(3-Bromopropoxy)benzenesulfonyl chloride A mixture containing 23 g of sodium 4-hydroxybenzenesulfonate dihydrate, 7 g of potassium hydroxide pellets 30 ml of water, 50 ml of absolute ethanol, 40 g of 1,3-dibromopropane and 3.4 g of tetrabutylammonium hydrogensulfate is refluxed for 3 hours. The reaction medium is concentrated under vacuum, taken up in ethanol and concentrated once again. The residue is taken up in hot methanol. The insoluble material is filtered off, the filtrate is concentrated and the residue is triturated in ether to give 22.5 g of a white solid.

120 ml of phosphorus oxychloride and 16 g of phosphorus pentachloride are added to this solid and the mixture is stirred for 20 hours at RT and then refluxed for 1 hour. The reaction medium is concentrated under vacuum, the residue is then taken up in an ether/water mixture and the organic phase is decanted and washed with a saturated solution of sodium hydrogencarbonate. After drying and concentration, the expected product is obtained in the form of a yellow oil.

B) 1-[4-(3-Bromopropoxy)benzenesulfonyl]-5-chloro-3spirocyclohexaneindol-2-one A mixture containing 1.2 g of 5-chloro-3-spirocyclohexaneindol-2-one S, and 0.16 g of sodium hydride in 6 ml of THF is stirred at RT for 30 minutes under o 20 nitrogen. 1.6 g of 4-(3-bromopropoxy)benzenesulfonyl chloride are then added.

After 20 hours at RT, the reaction medium is concentrated under vacuum, the residue is taken up in a water/ethyl ether mixture and decanted and the organic phase is washed with water, dried and concentrated. The oil obtained is purified by chromatography on silica using iso ether as the eluent. The expected product is 25 obtained in the form of an oil, which crystallizes from iso ether.

m 1 g.

M.p. 123C.

SC) Acid fumarate of 5-chloro-1-[4-(3dimethylaminopropoxy)benzenesulfonyl]-3-spirocyclohexaneindol-2-one A mixture containing 0.5 g of the product obtained in the above step, 0.5 g of potassium iodide and 20 ml of a 33% solution of dimethyiamine in methanol is stirred at RT for 20 hours. The reaction medium is concentrated and taken up in ml of water and, after trituration, the insoluble material is separated off and treated with 10 ml of 3 N hydrochloric acid. A gum is formed which is dissolved in 30 ml of warm water, and the solution is filtered on paper and then rendered alkaline by the addition of 12 N sodium hydroxide, The insoluble material is extracted with ether and the extract is washed, dried anu then concentrated to give a yellow oil.

This is dissolved in 10 ml of acetone, and 0.1 g of fumaric acid is added to the hot solution.

The expected product precipitates at m 240 mg.

M.p. 168'C.

EXAMPLE 6 5-Chloro-l-(2,4-dimethoxybenzenesulfonyl)-3-spiroadamantaneindol-2one A mixture containing 0.2 g of 5-chloro-3-spiroadamantaneindol-2-one and 20 mg of sodium hydride in 3 ml of THF is stirred for 30 minutes at RT under a nitrogen atmosphere. 0.18 g of 2,4-dimethoxybenzenesulfonyl chloride is added and stirring is maintained at RT for 20 hours. The reaction medium is concentrated under vacuum, the residue is taken up in 30 ml of water and extracted with ether and the extract is washed with water, dried and concentrated under vacuum. The wax obtained crystallizes from 15 ml of iso ether.

m 240 mg.

20 M.p. 152-154'C.

t EXAMPLE 7 5-Chloro-l-(2,4-dimethoxybenzenesulf 3vylt-3-spirocycloheptaneindol- 2-one 0,0 0 25 A solution containing 0.156 g of potassium tert-butylate and 0.33 g of chloro-3-spirocycloheptaneindol-2-one in 15 ml of THF is cooled to -40*C under an inert atmosphere. The temperature is allowed to rise to about 10'C over 1 hour, the solution is then cooled to about -40*C, a solution of 0.335 g of 2,4-dimethox'ybenzenscforyl choride in 15 ml of THF is added dropwise and the mixture is stirred at RT for 2 hours. The solvent is evaporated off under reduced pressure and the residue is then taken up in 30 ml of DCM and 30 ml of water. The organic phase is separated olf, washed with 15 ml of water, dried over magnesium sulfate and evaporated under vacuum. The oil obtained is chromatographied on silica using a cyclohexane/DCM mixture as the eluent to give the expected compound, which recrystallizes from heptane.

m 0.51 g.

M.p. 135'C.

EXAMPLE 8 2,4-Dimethoxy-l-benzenesulfonyl-2a-methyl-2a,3,4,5-tetrahydrobenz[c, d]indol-2-one R 1 H, -R 2 -R3 -(CH 2 3

R

4

CH

3

R

5

R

6

OCH

3 2a,3,4,5-Tetrahydrobenz[c,d]indol-2-one is commercially available. With the temperature maintained at -40'C and under a nitrogen atmosphere, a solution containing 0.7 g of this compound and 1.36 g of potassium tert-butylate in 40 ml of anhydrous THF is prepared.

The temperature is allowed to rise to about O0C, the solution is then cooled to and a solution of 0.57 g of methyl iodide in 20 ml of THF is added; the medium is maintained at -10'C for 30 minutes, with stirring, and then cooled to about -40*C and a solution of 0.96 g of 2,4-dimethoxybenzenesulfonyl chloride in 10 ml of THF is added. After stirring for 16 hours at RT, the solvent is evaporated off under reduced pressure and the residue is taken up in 30 ml of DCM and 30 ml of water; the organic phase is separated off and then dried over magnesium sulfate and evaporated. The oil obtained is purified by chromatography on silica using a cyclohexane/DCM mixture as the eluent to give the expected product, which is recrystallized from a cyclohexane/AcOEt mixture (95/5; v/v).

160*C.

The compounds according to the invention collated in Table 3 below were prepared from the 2-oxoindoles described above by following the procedure described in the above Examples.

TABLE 3 *9%o so R1 R42

SO

2 2

(I)

(R

6 )m Unless indicated otherwise in the Table below R2 H and m 1.

Ex. RICR 3

R

4 R5(R 6 )m IM.P. C S

S

S S

S

S

S. 1 0 5-NO 2 11 5-Cl 12 5-cl 13 5-NH 2 14 5-CN 15 5-Cl 16 5-Cl 17 5-Cl 18 5-Cl 19 5-Cl 20 5-Cl 21 5-F 22 5-Cl 23 5-Cl CyClohxan cyclohexane

C(CH

3 2 cyciihexane c.yclohexane cyclohexane C(Pr) 2 indane-2 C(iBu) 2 N-methyl piperidine-4 C(Et) 2 cyclohexane 4-tetrahydropyranne 4,4-dimethyl cyclohexane 3-MeO 3-MeO 4-MeO 3-MeO 3-MeO 2-MeO 4-MeO 2-MeO 2-MeO 2-MeO 2-MeO 2-MeO 2-MeO 2-MeO 2-MeO 4-MeO 4-MeO

H

4-MeO 4-MeO 4-MeO 2,3,6-triMe 4-MeO 4-MeO 4-MeO 4-MeO 4-MeO 4-MeO 4-MeO 4-MeO 178 157 112 110 171 148 188 186 182 184 142 190 149 142 118 24 5-Cl 2-hexahydro- 2-MeO 4-MeO 89 indane 4-Cl cyclohexane 2-MeO 4-MeO 150 26 5-Cl cyclohexane 3-MeO 4-MeO 152 27 5-Cl cyclohexane 4-Me H 150 28 H cyclohexane 3-MeO 4-MeO 107 29 5-Me cyclohexane 3-MeO 4-MeO 171 5-MeO cyclohexane 3-MeO 4-MeO 124 31 5-Cl cyclohexane 2-MeO 4-MeO 149 32 5-Cl cyclohexane 4-Cl H 154 33 5-Cl cyclobutane 3-MeO 4-MeO 111 34 5-Cl cyclopentane 3-MeO 4-MeO 106 5-Cl cyclohexane 4-MeO 2-Cl 174 5-Cl cyclohexane 4-NO 2 H 172 37 5-Cl cyclohexane 4-CN H 198 38 5-Cl cyclohexane 4-MeO 2-NO 2 147 39 5-Cl cyclohexane 4-CF 3 H 139 5-Cl cyclohexane 4-CF 3 0 H 134 41 5-Cl cyclohexane 4-MeO 2-NH 2 150

C

C

CC..

C

.C

C

4-CH 3

R

2 =6-

CH

3 5-Cl 5-Cl

H

5-Cl cyclohexane cyclohexane cyclohexane cyclohexane cyclohexane cyclohexane cyclohexane

'C-

OH

3 adamantane 4,4-dimethyl cyclohexane cyclohexane cyclohexane cyclohexane cyclohexane cyclohexane 4-MeO 3-Me 4-iPr 2-CF 3 2-MeO 4-MeO 2-MeO 2-MeO 2-MeO 2-MeO 2-MeO 2-MeO 2-Me 2-CF 3

CH

2 0 2-MeO 2-MeO 4-BzO 2,6-iPr

H

cQ CO-NH

OH

3 OH1 3 C- 0O-NH

OH

3 4-CH 3 0CO 4-MeO 4-MeO 4-MeO 4-CH 3

SO

2

NH

CI

()CONH-4 5-F 5-CF 3

CH

2

O

Q- NH CO -4

CH

3 165 127 172 154 215 193 120 184 172 152 131 240 153 175 218 a.

a a a *aa.

a a a a a.

a. a

I

a.

57 58 59 61 62 64 65 66 67 68 69 70 71 72 73 5-Cl 5-Cl 5-BzO 5-BzO 5-Cl 5-Cl

H

5-CH 3

CO

5-Cl 5-Cl 5-H 2

)N

5-Cl 5-cl 5-nPr 5-Et() 5-Cl cyclohexane cyclohexane rcyqlohexane 4,4-dim ethyl cyclohexane cyclohexane cyclohexane

C(CH

2

C

6

H

5 2 cyclohexane C(n-pentYl) 2

C(CH

2

C

6

H

5 2 cyclohexane 4-spirocyclopentane cyclohexane cyclohexane N-tBu-4piperidine N-Bz-4piperidine 2-MeO 5-NH 2 S0 2 2-MeO 2-MeO 2-MeO 2-MeO 3-MeO 3-MeO 2-MeO 2-MeO 2-MeO 2-MeG 2-MeG 2-MeG 2-MeG 2-MeG O-CO-4 2,4-di MeG 4-MeG 4-MeO

CH

3 O- -CNH-4 0 CH3N JN -C-4 \-eG 4-MeG 4-MeG 4-MeG 4-MeG 4-MeG 4 -MeG 4-MeG 4-MeG 159 142 192 158 146 122 140 185 230 154 116 138 (0.25

H

2 0) 76

H

2 0O) 165 270 43 74 5-Cl N-phenyl-4- 2-MeO 4-MeO 163 piperidine 5-Cl cyclohexane 2-EtO 4-EtO 123 76 5-Cl /,2-MeO 4-McO 190 77 5-EtO 4,4-diethyl 2-MeO 4-MeO 129 cyclohexane 78 5-EtO cycloheptane 2-MeO 4-MeO 130 79 5-EtO cyclohexane 2-MeO 4-MeD 134 5-EtO 4,4-dimethyl 2-MeD 4-MeD 160 cyclohexane 5-Et 4,4-dimethyl 2-MeD 4-MeO 166 cyclohexane 82 5-EtO 4,4-dimethyl 2-MeD 4-NO 2 110 cyclohexane 83 5-EtO 4,4-dimethyl 2-MeD 4-NH 2 230 cyclohexane 84 5-NO 2 4,4-dimethyl 2-MeD 4-MeD 102 cyclohexane 5-NH 2 4,4-dimethyl 2-MeD 4-MeD 180 cyclohexane 86 5- 4,4-dimethyl 2-MeD 4-MeD 169

CFACH

9 )O cyclohexane I L L EXAMPLE 87 1-(2,4-Dimethoxybenzenesulfonyl)-3-(4,4-dimethylspirocyclohexane)-5hydroxyindol-2-one 3.51 g of the compound prepared in Example 60 are stirred at 50C for 1 hour, under a hydrogen atmosphere, with 0.5 g of 10% palladium-on-charcoal in 150 ml of ethanol. The catalyst is filtered off on talc, the material on the filter is rinsed with DCM and the filtrate is evaporated under reduced pressure to give 2.8 g of the expected compound, which is recrystallized from a cyclohexane/AcOEt mixture (90/10; v/v).

M.p. 220*C.

EXAMPLE 88 1-( 2 ,4-Dimethoxybenzenesulfonyl)-5-hydroxy-3-spirocyclohexaneindol- 2-one is prepared in the same manner starting from the 5-benzyloxy derivative described in Example 59.

M.p. 196C.

EXAMPLE 80 bis o: 1-(2,4-Dimethoxybenzenesulfonyl)-3-(4,4-dimethylspirocyclohexane)-5- 20 ethoxyindol-2-one This compound, already described in Example 80, can be prepared by another method starting from the homologous 5-hydroxy compound. 0.6 g of the compound prepared in Example 87 is stirred at RT for 16 hours, under an inert atmosphere, with 0.19 g of anhydrous potassium carbonate and 0.315 g of ethyl 25 iodide in 11 ml of DMF. The solvent is evaporated off under reduced pressure and ml of AcOEt and 30 ml of water are added. The organic phase is washed with water, dried over magnesium sulfate and then concentrated under reduced pressure.

0.45 g of the expected product is obtained by crystallization from cyclohexane.

M.p. 160'C.

The compounds described in Table 4 below are prepared in the same manner.

TABLE 4 e

S

EX. R1CR 3

R

4

R

5

R

6 M.p.*C 89 5-nPrO cyclohexane 2-MeO 4-MeO 139 90 5-nPrO 4,4-dimethyl 2-MeO 4-MeO 158 cyclohexane 91 5-iPrO 4,4-dimethyl 2-MeO 4-MeO 154 cyclohexane 92 C2 cyclohexane 2-MeO 4-MeO 155 EXAMPLE 93 5-Acetoxy-1-(2,4-dimethoxybenzenesulfonyl)-3-spirocyclohexaneindol- 2-one g of the compound prepared in Exampte 88, 2.5 ml of isopropeny. acetate and 0.165 g of potassium carbonate in 2.5 ml of toluene and 0.3 ml of DMF are heated at about 65*C for 15 hours. After cooling, 10 mnl of water and 15 ml of ethyl acetate are added and the organic phase is decanted, washed with water, dried over magnesium sulfate and concentrated under reduced pressure. 0.51 g of the expected compound, containing 0.5 mol of cyclohexane, is isolated by crystallization from a cyclohexane/ethyl acetate mixture.

M.p. 116*C.

EXAMPLE 94 1-(2,4-Dimethoxybenzenesulfonyl)-5-(2-hydroxyethoxy)-3spirocyclohexaneindol-2-one g of the compound prepared in Example 88, 0.5 g of ethylene carbonate and 0.272 g of anhydrous potassium carbonate in 1.25 ml of DMF are heated at about 70C for 40 hours. After cooling, 10 ml of water and 15 ml of ethyl acetate are added and the organic phase is decanted, washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The oily residue is chromatographed on a silica column using a cyclohexane/AcOEt mixture (70/30; v/v) as the eluent to give 0.5 g of the expected product, which is recrystallized from a heptane/DCM mixture.

M.p. 170C.

EXAMPLE 5-(2-Dimethylaminoethoxy)-l-(2,4-dimethoxybenzenesulfonyl)-3spirocyclohexaneindol-2-one 0.6 g of the compound prepared in Example 88 is heated at about 40'C for 16 20 hours, under an inert atmosphere, with 0.32 g of N,N-dimethyl(2chloroethylamine) and 1.76 g of cesium carbonate in 7.2 ml of acetone and 2.4 ml of DMF. The salts are filtered off and 20 ml of water and 20 ml of AcOEt are added to the filtrate. The organic phase is decanted, washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue is chromatographed on silica using a DCM/MeOH mixture v/v) as the eluent to **:give 0.6 g of the expected product, which is recrystallized from a cyclohexane/iso ether mixture.

M.p. 122*C.

EXAMPLE 96 5-Chloro-l-(2,4-dimethoxybenzenesulfonyl)-3-(spiropiperidine-4)indol- 2-one This reaction is performed according to T. Org. Chem., 1984, 49, 2795-2799.

0.75 g of 1-chloroethyl chloroformate is added at 0*C to a solution of 1.31 g of the compound described in Example .73 and 0.32 g of 1,8-bisdimethylaminonaphthalene in 22 ml of 1,2-dichloroethane. The mixture is refluxed for about 20 minutes and concentrated under reduced pressure to a volume of about 10 ml, and 22 ml of methanol are then added. After refluxing for minutes, the reaction medium is concentrated under reduced pressure and the residue is chromatographed on a silica column using a DCM/MeOH mixture (95/5; v/v) as the eluent. 1.16 g of the expected product are isolated and recrystallized from a mixture of cyclohexane and ethyl acetate.

M.p. 172C.

EXAMPLE 97 3-(N-Acetylspiropiperidine-4)-5-chloro-l-(2,4dimethoxybenzenesulfonyl)indol-2-one 0.086 ml of acetyl chloride is added to a solution, cooled to about '0C, of 0.35 g of the compound prepared in the previous Example and 0.23 ml of triethylamine in 5 ml of DCM. The mixture is stirred for one hour at 20'C, 5 ml of water are added, the organic phase is decanted, washed with water, dried over magnesium sulfate and concentrated under reduced pressure and the residue is chromatographed on a silica column using a DCM/MeOH mixture (99/1; v/v) as the eluent. 0.29 g of the expected product is isolated in the form of the hemihydrate.

20 M.p. 107*C.

EXAMPLE 98 5-Chloro-l-(2,4-dimethoxybenzenesulfonyl)-3-(Nmethoxycarbonylspiropiperidine-4)indol-2-one 25 This compound is prepared from the one obtained in Example 96 by reaction with methyl chloroformate.

147C.

EXAMPLE 99 1-(3,4-Dimethoxybenzenesulfonyl)-5-propionamido-3spirocyclohexaneindol-2-one A solution of 0.144 g of propionyl chloride in 3 ml of DCM is added to a solution, cooled to about 0*C, of 0.5 g of the compound described in Example 13 and 0.167 ml of triethylamine in 10 ml of DCM. The mixture is stirred for 2 hours at 20'C, 20 ml of water are then added and. the organic phase is decanted, washed with water, dried over magnesium sulfate and concentrated under reduced pressure. 0.5 g of 'the expected product is isolated after recrystallization from a heptane/AcOEt mixture (95/5; v/v).

M.p. 158*C.

EXAMPLE 100 1-(3,4-Dimethoxybenzenesulfonyl)-5-(N-methylureido)-3spirocyclohexaneindol-2-one 0.15 g of methyl isocyanate is added to a solution, cooled to about 0*C, of g of the compound described in Example 13 in 10 ml of DCM. After stirring for about 16 hours at RT, 20 ml of water are added and the organic phase is decanted, washed with water, dried over magnesium sulfate and concentrated under reduced pressure. 0.5 g of the expected product is isolated after recrystallization from a mixture of heptane and ethyl acetate.

M.p. 214'C.

The compound described in the following Example is prepared in the same manner.

Sfl.

EXAMPLE 101 1-(3,4-Dimethoxybenzenesulfonyl)-5-(N-phenylureido)-3- 20 spirocyclohexaneindol-2-one M.p. 124'C.

0. EXAMPLE 102 S0* 5-Dimethylamino-l-(2,4-dimethoxybenzenesulfonyl)-3- 25 spirocyclohexaneindol-2-one A mixture of 0.5 g of the compound described in Example 68 with 0.5 ml of a 35% solution of formaldehyde and 0.12 g of sodium cyanoborohydride in 5: ml of acetonitrile is stirred at RT, under a nitrogen atmosphere, and the pH is adjusted to about 6.5 with a few drops of acetic acid. After 48 hours at 20'C, the solvent is evaporated off under reduced pressure and 20 ml of an approximately 2 N aqueous solution of sodium hydroxide and 20 ml of DCM are added. The organic phase is decanted, washed with water and dried over magnesium sulfate and the solvent is evaporated off under reduced pressure. The residue is chromatographed on a silica column using a cyclohexane/ethyl acetate mixture (80/20; v/v) as the eluent. 0.27 g of the expected product is isolated.

SM.p. 167'C.

EXAMPLE 103 1-(2,4-Dimethoxybenzenesulfonyl)-5-ethylthio-3spirocyclohexaneindol-2-one This compound is preparcd according to J. Chem. Soc., Chem. Commun., 1980, 16, 756. A mixture of 2.95 g of diethyl disulfide and 0.386 g of isopentyl nitrite is heated to about 80*C, under an inert atmosphere, and 0.8 g of the compound prepared in Example 68 is added. The medium is stirred for one hour at and then concentrated under reduced pressure. The residue is chromatographed on a silica column using a DCM/cyclohexane mixture (80/20; v/v) as the eluent. The expected product is iso"ted after crystallization from cyclohexane.

M.p. 123C.

EXAMPLE 104 15 5-Chloro-l-[4-(dimethylaminomethylcarboxamido)-2methoxybenzenesulfonyl]-3-spirocyclohexaneindol-2-one A) 5-Chloro-l-[4-(chloromethylcarboxamido)-2methoxybenzenesulfonyl]-3-spirocyclohexaneindol-2-one S: 0.2 g of the compound prepared in Example 2 is placed in 4 ml of DCM 20 and 0.5 g of TEA at RT and 0.1 g of chloroacetyl chloride is added. After stirring for 20 hours at RT, the mixture is concentrated under vacuum. The concentrate is extracted with ethyl acetate, the extract is washed with water and a solution of sodium carbonate and the residue is then chromatographed on silica using a mixture of DCM and AcOEt as the eluent to give 0.15 g of the expected product.

B) 5-Chloro-1-[4-(dimethylaminomethylcarboxamido)-2methoxybenzenesulfonyl]-3-spirocyclohexaneindol-2-one The compound obtained in the previous step (150 mg) is stirred at RT for hours in 20 ml of a 33% solution of dimethylamine in ethanol. Extraction is carried out with AcOEt and the extract is washed with N sodium hydroxide and then water. The residue is chromatographed on silica using AcOEt as the eluent to give 0.025 g of the expected product.

M.p. 173C.

EXAMPLE 105 1-[4-(4-Sulfamoylphenylcarboxamido)-2-methoxybenzenesulfonyl]-5chloro-3-spirocyclohexaneindol- 2-one 4-Chlorosulfonylbenzoyl chloride is prepared according to Chem. Ber., 1941, 271.

0.2 g of the compound prepared in Example 2 is brought into contact with g of TEA in 5 ml of DCM; 0.13 g of 4-chlorosulfonylbenzoyl chloride is added and the mixture is stirred for 20 hours at RT. It is concentrated under vacuum, the concentrate is taken up in THF, and 10 ml of aqueous ammonia are added. Stirring is continued for a further 20 hours at RT and the mixture is concentrated under vacuum. The residue is extracted with ether and the extract is washed with water, dried over sodium sulfate and then chromatographed on silica using AcOEt as the eluent to give the expected product.

M.p. 238-242*C after recrystallization from AcOEt.

EXAMPLE 106 1-[4-(3-Sulfamoylphenylcarboxamido)-2-methoxybenzenesulfonyl]-5- S"chloro-3-spirocyclohexaneindol-2-one A) 3-Chlorosulfonylbenzoyl chloride 20 This compound is prepared according to patent US 3 290 370. 11 g of chlorosulfonic acid are heated to 60*C and 8 g of phenylchloroform are added dropwise. After heating for 2 hours at 130'C, the mixture is distilled to give 1 g of the expected product.

B.p. 120-125*C under 0.5 mm Hg.

*l B) 1-[4-(3-Sulfamoylphenylcarboxamido)-2-methoxybenzenesulfonyl]- 5-chloro-3-spirocyclohexaneindol-2-one 210 mg of the compound prepared in Example 2 are placed in 10 ml of DCM with 220 mg of the compound obtained in the previous step and 200 mg of TEA, the mixture is stirred overnight and the solvents are then evaporated off under vacuum. The residue is taken up in 20 ml of THF and 20 ml of aqueous ammonia and the mixture is stirred for 6 hours at RT. The solvents are driven off under vacuum and the residue is then taken up in AcOEt and water. Extraction is carried out with AcOEt and the extract is washed with water and then chromatographed on silica using an AcOEt/cyclohexane mixture (50/50; v/v) as the eluent to give the expected product.

M.p. 176*C.

EXAMPLE 107 1-[4-(2-Carboxyphenylcarboxamido)-2-methoxybenzenesulfonyl]-5chloro-3-spirocyclohexaneindol-2-one The preparation is carried out according to J. Heterocycl. Chem., 1974, 997-1000.

A mixture containing 0.2 g of the compound prepared in Example 2 with ml of TEA and 160 mg of phthalic anhydride is stirred at 60'C for 3 hours. It is concentrated under vacuum and treated with normal hydrochloric acid. The precipitate formed is filtered off and treated with a 10% solution of sodium carbonate; a precipitate forms again, the aqueous phase is decanted and the precipitate is treated with 10% AcOH. The precipitate is filtered off and then washed with 10% AcOH followed by isopropyl ether and recrystallized from iso ether to give the expected product.

m= 0.150 g.

M.p. 157-158*C.

S: EXAMPLE 108 20 1-[4-(Benzyloxymethylcarboxamido)-2-methoxybenzenesulfonyl]-5chloro-3-spirocyclohexaneindol-2-one This compound is prepared by the procedure described in Example 3 by reacting benzyloxyacetyl chloride with the compound prepared in Example 2.

M.p. 143*C after recrystallization from iso ether.

EXAMPLE 109 5-Chloro-1-[4-(hydroxymethylcarboxamido)-2methoxybenzenesulfonyl]-3-spirocyclohexaneindol-2-one This compound is obtained by hydrogenating the compound prepared in the previous Example, under the pressure of a water column, in the presence of palladium-on-charcoal in an EtOH/AcOEt mixture.

M.p. 202'C.

EXAMPLE 110 5-Chloro-l-[4-(imidazol-l-ylphenylcarboxamido)-2methoxybenzenesulfonyl]-3-spirocyclopentaneindol-2-one A) Ethyl ester of 4-(imidazol-l-yl)benzoic acid A mixture containing 35 g of 4-fluorobenzoyl chloride in 50 ml of 100 ethanol is refluxed for 15 minutes. 35 g of the ethyl ester of 4-fluorobenzoic acid obtained are mixed with 22 g of imidazole and 61 g of potassium carbonate in ml of DMSO. The mixture is heated for 18 hours at 120-130'C and 500 ml of iced water are then added. A precipitate forms and the expected product crystallizes from iso ether.

M.p. 98*C.

B) Imidazol-1-ylbenzoyl chloride g of the ester obtained in step A are refluxed for 2 hours in 20 ml of water and 20 ml of sodium hydroxide solution. The reaction medium is washed with ether and then acidified (pH 2) with concentrated hydrochloric acid. The precipitate formed is filtered off and then washed with iso ether. 5 g of the acid obtained are brought to the reflux temperature in 35 ml of thionyl chloride. The precipitate formed is filtered off and then washed with iso ether to give the expected acid chloride.

M.p. 243'C.

"20 C) 5-Chloro-1-[4-(imidazol-l-ylphenylcarboxamido)-2methoxybenzenesulfonyl]-3-spirocyclopentaneindol-2-one A mixture containing 210 mg of the compound prepared in Example 2 and 200 mg of the acid chloride prepared in step B in 10 ml of DCM and 1.5 ml of S. TEA is stirred at RT for 1 h and then refluxed for 3 hours. The reaction medium is 25 extracted with DCM and then washed with water and an aqueous solution of sodium hydroxide. After evaporation of the solvents, the residue is chromatographed on silica using a DCM/ methanol mixture as the eluent. The expected product is recrystallized from iso ether.

m 0.010 g.

M.p. 145C.

EXAMPLE 111 5-Chloro-l-[2-methoxy-4-(phenoxycarboxamido)benzenesulfonyl]-3spirocyclohexaneindol-2-one This compound is prepared by reacting phenyl chloroformate with the compound prepared in Example 2.

M.p. 209C after recrystallization from iso ether.

EXAMPLE 112 5-Chloro-l-[4-(N-methylureido)-2-methoxybenzenesulfonyl]-3spirocyclohexaneindol-2-one 140 mg of the compound obtained in the previous Example are mixed with ml of ethanol, 5 ml of DCM and 5 ml of a 33% solution of methylamine in ethanol. After one hour at RT, the solvents are driven off and the residue is then chromatographed on silica using a DCM/MeOH mixture as the eluent. The product obtained is recrystallized from iso ether.

M.p. 254'C.

EXAMPLE 113 5-Chloro-l-(2-methoxy-4-ureidobenzenesulfonyl)-3- 15 spirocyclohexaneindol-2-one A mixture containing 200 mg of the compound prepared in Example 111 with 5 ml of 20% aqueous ammonia, 5 ml of ethanol and 5 ml of DCM is stirred for 1 hour at RT. After filtration of the reaction medium and evaporation of the solvents, the expected product is crystallized from iso ether.

20 M.p. 228'C.

EXAMPLE 114 5--Chloro-l-[4-(N-o-tolylureido)-2-methoxybenzenesulfonyl]-3spirocyclohexaneindol-2-one 25 A mixture containing 250 mg of the compoud prepared in Example 2, S• ml of xylene and 80 mg of orthotoluyl isocyanate is refluxed for 18 hours. A white precipitate forms and is filtered off. The reaction medium is extracted with ether and the extract is washed with water and then chromatographed on silica using a DCM/MeOH mixture as the eluent. The expected product crystallizes from iso ether.

M.p. 182*C.

EXAMPLE 115 Benzyl 4-(5-methoxy-2-oxo-3-spirocyclohexaneindol-1-yl)sulfonyl- 3-methoxybenzoate mg of sodium hydride are poured in small portions into a mixture containing 500 mg of 3-spirocyclohexane-5-methoxyindol-2-one in 50 ml of THF. After 30 minutes at RT, 800 mg of benzyl 3-methoxy-4-chlorosulfonylbenzoate chloride are added and the mixture is stirred for 2 hours at RT. The medium is concentrated and taken up in AcOEt and the mixture is washed with water, dried over sodium sulfate and concentrated. The residue is chromatographed on silica using DCM as the eluent.

NMR (at 250 MHz in DMSO): 1.2-1.8 ppm 10H: cyclohexyl 3.6 ppm and 3.8 ppm 2 x 3H: 2x OCH 3 5.4 ppm 2H C0 2 -CH2-C 6

H

6.8-8.2 ppm 11H: aromatic protons EXAMPLE 116 S 15 4 3 -Spirocyclohexane-5-methoxy-2-oxoindol-1-yl)sulfonyl-3methoxybenzoic acid 600 mg of the compound prepared in the previous Example are placed in 50 ml of AcOEt and hydrogenated at RT and atmospheric pressure in the presence of 140 mg of palladium-on-charcoal to give 310 mg of the expected acid, which 20 is recrystallized from a hexane/ ethanol mixture (70/30; v/v).

M.p. 210*C.

EXAMPLE 117 5-Chloro-1-[4-(N-(ethoxycarbonylmethyl)carbamoyl)-2- 25 methoxybenzenesulfonyl]-3-spirocyclohexaneindol-2-one 450 mg of ethyl glycinate hydrochloride in 20 nig of sodium methylate are 57 placed in methanol. 200 mg of the compound described in Example6. in 50 ml of DCM are added and the mixture is stirred at RT for 48 hours. It is extracted with DCM and the extract is washed with water, dried, concentrated and then chromatographed on silica using DCM/McOH (99.5/0.5; v/v) as the eluent.

M.p. 164'C.

EXAMPLE 118 1-(4-Carbamoyl-2-methoxybenzenesulfonyl)-5-chloro-3spirocyclohexaneindol-2- ne 57/ 300 mg of the compound described in Example.4 are mixed with 5 ml of aqueous ammonia, 10 ml of ethanol and 10 ml of DCM. After 1 hour at RT, the mixture is concentrated and extracted with DCM and the extract is washed with water, dried, concentrated and then chromatographed on silica using DCM/MeOH (99/1; v/v) as the eluent to give 109 mg of the expected product.

M.p. 160'C.

EXAMPLE 119 5-Chloro-1-[2-methoxy-4-(N-(2-methoxycarbonylethyl)carbamoylbenzenesulfonyl)]-3-spirocyclohexaneindol-2-one A mixture comprising 320 mg of the compound described in Example.

and 2 g of methyl aminobispropionate in 30 ml of tetramethylbenzene is refluxed for 30 minutes. It is extracted with AcOEt and the extract is washed with a 1 N solution of hydrochloric acid, dried over sodium sulfate and concentrated. The 15 residue is chromatographed on silica using DCM/MeOH (99/1; v/v) as the eluent to give 100 mg of the expected product.

SM.p. 147C.

EXAMPLE 120 20 1-[4-(3-(N-Boc)aminoazetidin-l-ylcarbonyl)-2methoxybenzenesulfonyl]-5-chloro-3-spirocyclohexaneindol-2-one A mixture containing 300 mg of the compound prepared in Example6G;, 900 mg of 3-(N-Boc)aminoazetidine, 1 ml of triethylamine, 10 ml of DCM and 10 ml of methanol is stirred at RT for 1 hour. It is concentrated and extracted with So: 25 ethyl acetate and the extract is washed with a 1 N solution of hydrochloric acid, dried over sodium sulfate and concentrated. The expected product is obtained after chromatography on silica using DCM/MeOH (99/1; v/v) as the eluent.

M.p. 136C.

EXAMPLE 121 1-[4-(3-Aminoazetidin-l-ylcarbonyl)-2-methoxybenzenesulfonyl]-5chloro-3-spirocyclohexaneindol-2-one A mixture containing 160 mg of the compound prepared in the previous Example and 3 ml of TFA in 10 ml of DCM is stirred for 30 minutes at RT. The reaction medium is concentrated and crystallized from iso ether and the crystals are filtered off and dried. The product obtained is dissolved in 10 ml of water and then ml of 1 N sodium hydroxide; the solution is extracted with DCM and the extract is washed with water, dried over sodium sulfate and concentrated. The expected product is obtained after chromatography on silica using DCM/MeOH (96/4; v/v) as the eluent.

M.p. 145C.

EXAMPLE 122 5-Ethoxy-1- [4-(3-dimethylaminopropoxy)-3methoxybenzenesulfonyl]-3-spirocyclohexaneindol-2-one hydrochloride A) 5-Ethoxy-l-[4-(3-bromopropoxy)-3-methoxybenzenesulfonyl]-3spirocyclohexaneindol-2-one A mixture containing 0.5 g of 5-ethoxy-3-spirocyclohexaneindol-2-one, ml of THF and 0.07 g of sodium hydride is stirred at 20'C for 15 minutes, 1.65 g of 4 -(3-bromopropoxy)-3-methoxybenzenesulfonyl chloride are then added and the resulting mixture is stirred for 20 hours at RT. It is concentrated under vacuum and extracted with ether and the extract is washed with water and then a solution of sodium carbonate. The expecter product crystallizes from pentane and is then recrystallized from iso ether.

SMp. 114-118*C.

S' B) 5-Ethoxy-1-[4-(3-dimethylaminopropoxy)-3methoxybenzenesulfonyl]-3-spirocyclohexaneindol-2-one hydrochloride The compound obtained in the previous step is mixed with 7.5 g of a 33% solution of dimethylamine in ethanol and placed in 10 ml of THF. After stirring for 25 3 hours, the mixture is concentrated under vacuum and taken up in 10 ml of w"aer and the resulting mixture is extracted with ether. The ether phase is treated with ml of 2 N hydrochloric acid, after which solid potassium carbonate is added to render the solution alkaline to pH 9. The oil which precipitates is extracted with DCM. The expected product crystallizes from ether.

M.p. 135-138'C.

EXAMPLE 123 1-[4-Aminosulfonamido-2-methoxybenzenesulfony]-5-chloro-3spirocyclohexaneindol-2-one 0.3 g of the compound prepared in Example 2 is placed in 4 ml of DCM in the presence of 0.5 g of TEA, and 0.3 g of aminosulfonyl chloride, prepared according to Chem. Ber., 1958, 91, 1339-1341, is added. After stirring for 2 days at RT, the medium is concentrated under vacuum and extracted with ether and the extract is washed with water. After drying, the residue is chromatographed on silica using DCM and then AcOEt as the eluent to give the expected product, which crystallizes from ether.

M.p. 205-208*C.

EXAMPLES 124 and 125 l-( 4 -Dimethylamino-2-methoxybenzenesulfonyl)-5-methoxy-3spirocyclohexaneindol-2-one and l-(4-methylamino-2methoxybenzenesulfonyl)-5-methoxy-3-spirocyclohexaneindol-2-one 500 mg of l-(4-amino-2-methoxybenzenesulfonyl)-5-methoxy-3spirocyclohexaneindol-2-one are mixed with 1 ml of a 37% aqueous solution of formaldehyde, 10 ml of acetonitrile and 430 mg of sodium cyanoborohydride, and 0.12 ml of acetic acid is then added. The temperature of the medium rises and the medium is cooled in an ice bath. Two products of different polarity are formed in succession. 1 ml of an aqueous solution of formaldehyde, 300 mg of sodium cyanoborohydride and 0.12 ml of acetic acid are added to the medium. The mixture is stirred for 1 and a half hours, poured into iced water and then extracted 20 with AcOEt. The extract is washed with water, dried and concentrated to give 2 products, which are separated by chromatography on silica using DCM/AcOEt (98/2; v/v) as the eluent.

M.p. 210'C (Ex. 124).

M.p. 170C (Ex. 125).

TABLE

R

**R2 S(i) Unless indicated otherwise, the substituent R6 is in the 4-position and m 1.

Ex R R 2

R

5 R6M.P.CT 126 cl H 2-MeO -CN- 210 127 Cl H 2-MeO me- CN- 192 M oO C O N

H

2-MeO CONH- 128 CI H 2M 188 11 Cl H 2-MeO /146

CONH-

:130 0l HM-e HCNH23 133 ci HHCONH- Me *131 Cl H 2-MeO 2CCOH2- 147

COH

135

C

136 137 138 139 Cl Cl MeO Mco 2-MeO 2-MeO 2-MeO 2-MeO

CONH-

CONH-

CONH-

CONH-

Me *4 *4 S 4 4 4.4 4444 *.44 4444 4 4 4 4

V

*4 44 4 4

S

4 *44* .44.

4*S4 4* 44

S

4 44 4**4

S

S

.4.4 4.44 *4 4* *4

CONH-

iPr 7/ pcONH- 180 189 176 245 194 141 140 225 161 209 140 Cl 141 Cl 142 143 144 C,

H

MeO H MeO H 2-McO 2-MoO Me q CONH- 2-MoO MoOCH 2

CONH-

2-McO tBuCH 2

CONH-

145 DtO Hf 2-McO "NH 223 Me 146 DtO H 2-MeO Me N-HCN- 136 Me IICH- 147 Cl H 2-Meo Me COH26 Me~ 148 CH 3 0 H 2-MeO Me NCH 190 Me/

-OII

Me 149 EtO H 2-MeO 192 Me :::150 EtO H 2-MeO Me160

N-CONH-

Et I:.151 DtO H 2-MeQ Et 168 Et~'N-CONH- 152 DtO H 2-MeG Me c OH 137 Pr 153 Cl H 2-McO MCN- No 157 154 CI H 2-MeO me -(CH 2 2 -NHCO- 163 Me 15:5 CI H 2-McO M'\N-O 192

N-O

n "71W 61 156 cl Hf 2-McO Me N-S2 231 Mc 2 157 Cl H 2-McO H 106 158 Cl H 2-McO 226 Me-N \N-SO 2 159 Cl H 2-MeO MeOCONH-HO 117 Bz 160 MeO H 2-MeO 0 2 N- 188 161 Cl H 2-MeO BzOCO- NMR 162 Cl H 2-Mo 215

NHCO-

iPr 163 Mo H 2-MoO NH 2 188 164 MeO H 2-MeO MoO- 172 *165 Mo H 2-MeO /162 16 *e -e 198 168 MoO 6 -MeO 2-MeO MoO- 183 62 169 Eto Hi 2-MeOUO 150 170 EtO I-I 2-MoO BzOCO- 135 171 EtO H 2-McO HIOOC- NMR 172 EDO H 2-McO MeNHfCO- 239 173 EtO H 2-McG 5-MeG 131 174 EDO H 3-MeO MeG- 127 175 EtO H 2-MeG me 167 176 DtO H 3-MeG Me-i-e 130 *177 EtO H 2-MeG 195

NHCO-

*178 EtO H 2-MeO /168 179 EtO H 2-MeG N 2 0 160 180 DtO H 2-Me MeG 176 181 EtO H 3-MeG CH 2

=CH-CH

2 O- 130 182 CF 3 0 H 2-MeG MeG 127 63 183 EtO H 2-MeO Me, 171 Me 184 DtO H 2-MoO EtGCOCH 2 NHGO- 203 185 EtO H 2-NfeO /181 186 EDO H 2-MeO 4,5-di-McO 136 187 EtO H 2-Me 4-MeO, 5-Cl 129 188 DtO H 2-MeG- zN -HO 8 189 EtO H 2-MeO HO(CH 2 2 -NHCO- 157 190 EtO H 2- H 117 5 Me *191 EtO H 2-0e 212 S Me\

,HCI

:192 EtO H 2-MoO /181 s CONH- 193 DtO H MeO- Et206

~:CH-CONH-

Et 194 EDO H 2-McO BzOCOCH 2 NHCO NMR 195 DtO H 2-MeO me 144 Me 64 196 DtO H 2-MeO 0 152 197 EtO H 2-McO Et NC 148 Et 198 EtO H 2-MeO lEt 128 Et /N-CS 199 EtO H 2-MeO CN-CH 2 NH-CO- 232 200 EDO H 2-MeO EtO 2

C-CH

2 -N-CGO- NMR Go*201 EDO H 2-McO HO 2

C-CH

2 NH-CO- 137 0 a@ O',.202 DO H 2-MeO H~t 2 NCO-NH0- 19640 203 EtO H 2-MeO 145 O H CO-NH- 21 208 EtO H 2-MeO Et CH-CON- 138 EtI Me 209 EtO H 2-MeO EtQ-CO-CH 2 O- 160 The NMR spectra are run in DMSO at 200 Mffz.

NMR of Example 161: 1.3-1.8 ppm 1OH cyclohexyl ppm: 3H: OCH 3 5.3 ppm: 2H: O-CH 2

C

6

H

7.2-8.2 ppm: 11H -,aromatic protons NMR of Example 171: 1.15 ppm: 3H: GCl 3 1.19-2 ppm 10Hl cyclohexyl, 3.6 ppm 3H: OCH 3 4 ppm 2H: OCH 2

-CH

3 6.7-8.2 ppm 6H aromatic protons NMR of Example 200: 0.00.. 1-2.2 ppmn: 16H cyclohexyl 2CH 3 3 ppm 3H NCH 3 :20 4-4.4 ppm 6H1: aromatic protons 0. 6.8-8.2 ppmn 6H :aromatic protons A resolution of the signals is observed; this is associated with the amide isomerism.

EXAMPLE 210 1-(4-Bcnzyloxy-2-methoxybenzenesulfonyl)-5-ethoxy- 3 spirocyclohexaneindol-24-onf.

A) Potassium 4-benzyloxy-2-methoxybenzenesulfonate This preparation is carried out according to K. Hofmann et al., Liebigs Ann.

Chem., 1982, 282-297.

10.5 g of 4 -benzyloxy-2-methoxybenzene are mixed at 5C with 30 ml of DCM, and 8 ml of trimethylsilyl chlorosulfonate in 30 ml of DCM are added over 15 minutes at a temperature between 5 and 10*C; after stirring for 15 minutes, 50 g of ice are added. The mixture is washed with ethyl ether, treated with potassium hydrogencarbonate and then concentrated under vacuum. After drying, the residue is taken up in 150 ml of methanol. The insoluble material is filtered off at the boil and the expected compound then crystallizes at M.p. 300*C.

The structure of the compound is confirmed by analysis of the NMR spectrum.

m' o"f B) 4-Benzyloxy-2-methoxybenzenesulfonyl chloride 15 2.8 g of the compound prepared in the previous Example are mixed with ml of POC1 3 and the mixture is refluxed for 3 hours. It is concentrated under vacuum, treated with 20 g of ice and extracted with ethyl ether and the extract is i* washed with 30 ml of N sodium hydroxide and then water. The medium is S* concentrated and the oil obtained is then triturated in 30 ml of iso ether. The expected product (0.7 g) crystallizes.

M.p. C) 1-(4-Benzyloxy-2-methoxybenzenesulfonyl)-5-ethoxy-3spirocyclohexaneindol-2-one 25 This compound is prepared by the usual procedure. It crystallizes from iso o: ether.

M.p. 135'C.

The structure of the compound is verified by analysis of the NMR spectrum in 2 dimensions (NOESY: Nuclear Overhauser Effect Spectroscopy).

The compound of the next Example is subsequently prepared by debenzylation.

EXAMPLE 211 5-Ethoxy-l-(4-hydroxy-2-methoxybenzenesulfonyl)-3spirocyclohexaneindol-2-one SM.p. 209'C.

Claims (16)

1. A compound of the formula N (R6)m in which -R 1 and R 2 are each independently a hydrogen, a hydroxy, a Cl-C 4 -co- a halogen, a C 1 -C 4 -alkyl, a trifluoromethyl, a C-7 alkoxy, a Cl-C 4 -polyhalogenoalkoxy, a C2-C 4 -o-hydroxyalkoxy, an co- methoxyalkoxy in which the alkyl is C-,-C 4 a C 2 -C 4 -co-aminoalkoxy which is free or substituted by one or two Cl-C 4 -alkyls, a C3-C 7 -cycloalkoxy; a cycloalkylmethoxy in which the cycloalkyl is C 3 -C 7 a phenoxy; a benzyloxy; a Cl-C 4 -alkylthio; a phenylthio; a nitro; an amino which is free or substituted by one or two Cl-C 4 -alkyls; a cyano; a Cl-C 4 -acyl; a Cl-C 4 -acyloxy; a Cl-C 4 -alkylsulfonamido; a phenylsuffonamido; a Cl-C 4 -alkylamido; a j C 4 -alkoxycarbonylamino; a ureido which is unsubstituted or substituted by a phenyl or by one or two Cl-C 4 -alkyls; R 3 and R4. are each independently a C 1 -C 6 -alkyl, a C 3 -C 7 -cycloalkyl, a phenyl, a benzyl, a cycloalkylmethyl in which the cycloalkyl is C 3 -C 7 or R 3 and R(4 together form a group -(CH,2)pX(CH2)q-; or R 3 and R 4 together with the carbon to which they are bonded, form an optionally fused, saturated or unsaturated C 3 -Cl 0 hydrocarbon ring which is unsubstituted or substituted by one or more Cl-C 7 -alkyl groups or by a C 3 C 5 -spirocycloalkyl; or else R 1 and R 4 each have one of the meanings indicated above and R 2 is located in the 4-position of the indole and forms a group (CH2) 3 with R 3 R 5 and R 6 are each independently a hydrogen, a halogen, a C 1 -C 7 -alkyl, a trifluoromethyl, a cyano, a nitro, an amino which is free or substituted by one or two C 1 -C 7 -alkyls; a hydroxyamino; a hydroxy; a carboxy; a group OR 7 a group SR 7 a C 1 -C 7 -acyl; a C 1 -C 7 -alkoxycarbonyl; a phenoxycarbonyl; a benzyloxycarbonyl; a carbamoyl substituted by groups R' 6 and R" 6 a thiocarbamoyl which is free or substituted by one or two C 1 -C 7 -alkyls; a sulfamoyl; an alkylsulfamoyl or dialkylsulfamoyl in which the alkyl is C 1 -C 7 a group SO 2 R' 7 an alkylsulfonamido in which the alkyl is C 1 -C 7 a group COR' 7 a group NR 8 R 9 or a group CO-NH-CH(R 10 )-COR 1 2 if appropriate, the phenyl group forming part of the substituent R 5 and/or R 6 can be unsubstituted or monosubstituted or polysubstituted by a C 1 -C 7 -alkyl, a trifluoromethyl, a methoxy, a halogen, a sulfamoyl, an alkylsulfamoyl in which the alkyl is C 1 -C 7 a carboxy, an alkoxycarbonyl in which the alkyl is C 1 -C 7 a C 1 -C 7 -acyloxy or an imidazolyl; R' 6 and R" 6 are each independently hydrogen, a C 1 -C 7 -alkyl which is unsubstituted or substituted by R"' 6 a phenyl, a pyridyl, a methylpyridyl, a piperidin-4-yl or a methylpiperidin-4-yl; R"' 6 is a hydroxy, a cyano, a carboxy which is free or esterified by a C1-C7- alkyl or by a benzyl, a phenyl, a pyridyl, a methylpyridyl, an amino which is free or substituted by one or two C 1 -C 7 -alkyls; R 7 is a C 1 -C 7 -alkyl, a phenyl, a benzyl, a C 3 -C 7 -cycloalkyl, a C2-C4- alkenyl, a C 1 -C 7 halogenoalkyl, a C 1 -C 7 -polyhalogenoalkyl, a C1-C7- acyl, a C 1 -C 7 -a-carboxyalkyl which is free or esterified by a C 1 -C 4 -alkyl or by a benzyl, a C2-C 7 -w-aminoalkyl in which the amino group is free, substituted by one or two C 1 -C 4 -alkyls or in the form of an ammonium ion; R' 7 is a piperazin-1-yl group which is unsubstituted or substituted in the 4- position by a group R" 7 a piperidino group which is unsubstituted or substituted in the 4-position by a group R"' 7 an azetidin-1-yl group which is unsubstituted or substituted in the 3-position by a group R"' 7 a pyridyl group which is unsubstituted or substituted by a methyl; R" 7 is a C 1 -C 4 -alkyl, a phenyl, a benzyl or a C 1 -C 4 -acyl; R"' 7 is R" 7 or an amino which is free or carries a protecting group; 69 R 8 and R 9 are each independently a hydrogen, a C1-C 7 -alkyl, a phenyl or a benzyl; R 9 can also be a C 1 -C 7 -acyl, a C 1 -C 7 -thioacyl, a cycloalkylcarbonyl in which the cycloalkyl is C 3 -C 7 a cycloalkylthiocarbonyl in which the cycloalkyl is C 3 -C 7 a C 1 -C 4 -co-aminoacyl, a C 1 -C 4 -co-hydroxyacyl, a C 1 C4-o-benzyloxyacyl, a phenoxycarbonyl, a thienocarbonyl, a pyridylcarbonyl, a methylpyridylcarbonyl, a C 1 -C 4 -alkoxycarb.onyl, a benzoyl, a phenacetyl, a group CO-CH(R 1 0 )-NR 1 1 R' 1 1 a group CH(R 1 0 )C0 2 R 11 a group (CH 2 )tCOR1 2 a group CO(CH2)tCOR1 2 a carbamoyl which is unsubstituted or substituted by a phenyl or by one or two C 1 -C 4 alkyls; m is 1 or, if R 6 is a halogen, a C1-C 7 -alkyl or a C 1 -C 7 -alkoxy, m can also be 2, 3 or 4, or else (R 6 )m can be m substituents having different meanings selected from halogen, C 1 -C 7 -alkyl and C 1 -C 7 -alkoxy; p and q are each an integer, it being possible for their sum to vary from 3 to 6; t is an integer which can vary from 1 to X is oxygen, sulfur or a group NR 13 R- R 10 is hydrogen, a C 1 -C 4 -alkyl or a benzyl; R 11 and R' 1 1 are each independently hydrogen or a C 1 -C 4 -alkyl; R 12 is a hydroxy, a C 1 -C 4 -alkoxy or an amino which is unsubstituted or substituted by one or two C 1 -C 4 -alkyls; R 13 is hydrogen, a C 1 -C 4 -alkyl, a phenyl, a benzyl, a C 1 -C 4 -acyl, a C1-C4- alkoxycarbonyl or a carbamoyl which is unsubstituted or substituted by one or two C 1 -C 4 -alkyls; and its salts where appropriate.

2. A compound of formula according to claim 1 wherein R 1 is a chlorine atom or an ethoxy group in the 5-position of the indole and R 2 is hydrogen.

3. A compound of formula according to claim 1 wherein R 3 and R 4 together with the carbon to which they are bonded, form a C 3 -C 1 0 hydrocarbon ring.

4. A compound of formula according to claim 1 wherein R 3 and R 4 together with the carbon to which they are bonded, form a cyclohexane which is unsubstituted or substituted by one or two C 1 -C 7 -alkyl groups or by a C3-CS~ spirocycloalkyl, a cycloheptane, an adamantane or a tricyclo[5.2.1.0 2 6 ]dc-8- ene. A compound of formula wherein R 3 and R 4 together with the carbon to which they are bonded, form a piperidine-4 or N-methylpiperidine-4 ring.

6. A compound of formula according to claim 1 wherein R 5 and R 6 are each a methoxy.

7. A compound of formula according to claim 1 wherein R 5 in the 2- position is a methoxy and R 6 in the 4-position is a C 1 -C 7 -acylamino, a C1-C 4 dialkylureido or an alkoxycarbonylalkylcarbamoyl in which the alkyl groups are C1-C7-

8. A compound of formula according to claim 1 wherein R 1 is in the position and R 2 is hydrogen.

9. A compound according to claim 1 of the formula R1 R R 3 R2 O °so-o N so 2 (ix) COOH in which R 1 R 2 R 3 R 4 and R 5 are defined as indicated above for in claim 1, ~and its f u tional derivative. ester5 or sq 'f. 15 10. A compound according to claim 1 of the formula i" R 1 R 3 R 2 R4 SO 2 (X) N 2 R NH2 in which R 1 R 2 R 3 R4 and R 5 are defined as indicated above for in claim 1, and its salts where appropriate.

11. A compound according to claim 1 of the formula RR 3 R2-- R4 SO 2 S(XI) 5 OH .in which R 1 R 2 R 3 R 4 and R 5 are defined as indicated above for in claim 1.

12. A compound according to claim 1 of the formula HO: HO R3 NOR4 -4 S0 2 (XII) 10 (R6)m in which R 3 R 4 R 5 R 6 and m are defined as indicated above for in claim 1.

13. A compound according to claim 1 of the formula SO 2 (xII) (R 6 )m in which R 1 R 2 R 5 R 6 and m are defined as indicated above for in claim 1.

14. A method of preparing a compound according to claim 1, characterized 5 in that: "a benzenesulfonyl halide of the formula *.R Hal-SO- 2 (R m in which R' 5 and RVI are respectively either R 5 and R 6 as defined above for or precursor groups of R 5 and R 6 is reacted with a 2-oxoindoe disubstituted in the 3-position, of the formula R' 2 N (II) H in which R' 1 and R' 2 are respectively either R 1 and R2 as defined for or precursor groups of R 1 and R 2 and R 3 and R 4 are as defined above for and either, if R' 1 R 1 R' 2 R 2 R' 5 R 5 and RVI R 6 the resulting compound of formula is isolated; or, if any one of the groups R'I, R' 2 R' 5 and RVI is respectively a precursor group of R 1 R 2 R 5 and/or R 6 the compound obtained is subjected to a subsequent treatment in order to prepare the compound of formula by conversion of any one of the groups R t 1 R' 2 R' 5 and RVI to R1, R 2 R 5 and R 6 respectively. A compound of the formula N H(I) in which RI and R 2 are each independently a hydrogen, a hydroxy, a jC-O halogenoalkoxy, a halogen, a Cl-C 4 -alkyl, a trifluoromethyl, a C-7 alkoxy, a Cl-C 4 -polyhalogenoalkoxy, a C 2 -C 4 -co-hydroxyalkoxy, an a)- methoxyalkoxy in which the alkyl is C 2 -C 4 a C 2 -C 4 -ow-aminoalkoxy which is free or substituted by one or two Cl-C 4 -alkyls, a C 3 -C 7 -cycloalkoxy, a 15 cycloalkylmethoxy in which the cycloalkyl is C 3 -C 7 a phenoxy, a benzyloxy, 15 Cl-C 4 -alkylthio, a phenylthio, a nitro, an amino which is free or substituted by one or two Cl-C 4 -alkyls, a cyano, a Cl-C 4 -acyl, a CI-C 4 -acyloxy, a Cl-C 4 -alkylsulfonamido, a phenylsulfonamido, a Cl-C 4 -alkylamido, a Cl- 0 OV.C 4 -alkoxycarbonylamino or a ureido which is unsubstituted or substituted by a 0 a. phenyl or by one or two Cl-C 4 -alkyls; and .20 R 3 and R 4 together with the carbon to which they are bonded, form an adamantane, an indane or a hexahydroindane which are unsubstituted or substituted by one or more Cl-C 7 -alkyl groups, a tricyclo[5.2.1.0 2 6 ]decane or a tricyclo[5.2.1.0 2 6 ]dec-8-ene which are unsubstituted or substituted by one or more Cl-C 7 -alkyl groups, or a C 4 -C8 hydrocarbon ring substituted by one or more CI-C 7 -alkyl groups or by a C 3 -C 5 -spirocycloalkyl; or else R 3 and R4. together form a group -(CH2)p-X(CH2)q- in which p and q are integers whose sum can vary from 3 to 6 and X is oxygen, sulfur or a group NR 13 R 1 3 being a phenyl, a benzyl, a Cl- C 4 -acyl, a Cl-C 4 -alkoxycarbonyl or a carbamoyl which is unsubstituted or substituted by one or two C1-C4- alkyis, with the limitation that if CR 3 R 4 is adamantane, R 1 and R 2 are other than hydrogen.

16. A compound of the formula R R3 1N4 N (II)" H in which R 1 is a hydroxy, a C 1 -C 4 -o-halogenoalkoxy, a halogen, a C1-C 4 -alkyl, a trifluoromethyl, a C1-C 7 -alkoxy, a C 1 -C4-polyhalogenoalkoxy, a C 2 -C 4 -hydroxyalkoxy, an o-methoxyalkoxy in which the alkyl is C 2 -C 4 a C2-C4- o-aminoalkoxy which is free or substituted by one or two C 1 -C 4 -alkyls, a C 3 -C 7 -cycloalkoxy, a cycloalkylmethoxy in which the cycloalkyl is C 3 -C 7 a *see phenoxy, a benzyloxy, a C 1 -C 4 -alkylthio, a phenylthio, a nitro, an amino which is free or substituted by one or two C1-C 4 -alkyls, a cyano, a C1-C4- 15 acyl, a C 1 -C4-acyloxy, a C1-C 4 -alkylsulfonamido, a phenylsulfonamido, a C 1 -C 4 -alkylamido, a C 1 -C 4 -alkoxycarbonylamino or a ureido which is unsubstituted or substituted by a phenyl or by one or two C 1 -C 4 -alkyls; R 3 and R4 together form a group -(CH2)pX(CH2)q-; or 20 R 3 and R 4 together with the carbon to which they are bonded, form an optionally fused, saturated or unsaturated C 3 -C 10 hydrocarbon ring which is unsubstituted or substituted by one or more C 1 -C 7 -alkyl groups or by a C 3 C 5 -spirocycloalkyl; p and q are each an integer, it being possible for their sum to vary from 3 to 6; X is oxygen, sulfur or a group NR 13 and R 13 is hydrogen, a C 1 -C 4 -alkyl, a phenyl, a benzyl, a C1-C 4 -acyl, a C1-C4- alkoxycarbonyl or a carbamoyl which is unsubstituted or substituted by one or two C 1 -C 4 -alkyls, with the limitation that if R 1 is methoxy, CR 3 R 4 is other than a pyrrolidine-3 which is unsubstituted or N-substituted by a C 1 -C 4 -alkyl, and if R 1 is a halogen, CR 3 R 4 is other than a pentane. A (Z 17. A compound according to claim 16 in which R1 is ethoxy. 75

18. Pharmaceutical composition in which a compound according to any one of claims 1 to 8 is present as the active principle.

19. Pharmaceutical composition in which a compound according to any one of claims 1 to 8 is present in association with another active principle. Compounds of the formula methods for their preparation or pharmaceutical compositions containing them, substantially as hereinbefore described with reference to the Examples. *ea* DATED this 17th day of July, 1995 15 ElfSanofi By Its Patent Attorneys DAVIES COLLISON CAVE *S g* 950717,p\opc\dab,35043.spc,75 1NTINAAONIAN brX2.MXIt rEpOWA' nPCTFR 93/00093o PCT/FR 93/00093 A. CLASSIFICATION OF SUBJECT MATTER Int. C1 5.C07D209/96; A61K31/40; C07D209/90; C07D491/10; S C07D471/10; C07D403/12; C07D409/12; C07D209/34 According to International Patent Classification (IPC) or to both national classification and IPC B. FIELDS SEARCHED Minimum documentation searched (classification system followed by classification symbols) Int. C1. 5 CO7D Documentation searched other than minimum documentation to the extent that such documents are included in the fields searched Electronic data base consulted during the international search (name of data base and, where practicable, scierch terms used) C. DOCUMENTS CONSIDERED TO BE RELEVANT Category* Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No. X CHEMICAL ABSTRACTS, Vol. 77, 1 1972, Columbus, Ohio, US; abstract No. 114172c, NATSUME, MITSUTAKA ET AL. 'Formation of 3-cyano-1, 4-dihydroquinolines and their conversion to indole derivatives.' page 429; RN 36797-34-9 and RN 36797-35-0 (2H-Indole-2-one, 3-ethyl-i, 3-dihidro-3-methyl-1((4-methylphenyl) sulfonyl)- and 2H-Indol-2-one, 1,3-dihidro-3, 3-dimethyl- 1-((4-methylphenyl) sulfonyl)- 'Chem. Pharm. Bull. 1972, 20(7), 1595-8' A US,A, 3838167 (ELI LILLY AND COMPANY) 1,19 24 September 1974 column 1-2; column 6, lines 42-44* A EP, A, 0429685 (TAIHO PHARMACEUTICAL COMPANY, LTD.) 1 June 1991 see claims Further documents are listed in the continuation of Box C. See patent family annex. S Special categories of cited documents: laterdocumentpublishedaftertheinternational filingdateorpriority date and not in confict with the application but cited to understand document defining the general state of the art which is not considered the principle or theory underlying the invention to be of particular relevance prinple r heoy th invention earlier document but publ hed on or after theinternational filing date document of particular relevance: the claimed invention cannot be considered novel or cannot be considered to involve an inventive document which may throw doubts on priority claim(s) or which is step when the document is taken alone cited to establish the publication date of another citation or other special reason (as specified) documett of particular relevance; the claimed invention cannot be document referring to an oral disclosure, use, exhibition or other considered to involve an inventive step when the document is means combined with oneor more other such documents, such combination means being obvious to a person skilled in the art document published prior to the international filing date but later than bg o s to a se n te a the priority date claimed document member of the same patent family Date of the actual completion of the international search Date of mailing of the international search report April 1993 (20.04.93) 11 May 1993 (11.05.93) Name and mailing address of the ISA/ Authorized officer European Pantent Office Facsimile No. Telephone No. Form PCT/ISA/210 tsecond sheet) (July 1992) ANNEX TO THE INTERNATIONAL SEARCH REPORT ON INTERNATIONAL PATENT APPLICATION NO. FR 93000~93 SA 70247 This annex fists the patent family members relating to the patent documents cited in the above-mentioned international search report. Thbe members are as contained in the European Patent Office EDP file on The European Patent Office is in no way liable for these particulars whiich are metely given for the purpose of information. 20/04/93 Patent n&,cuet Publication Patent family Publication cited in search report date member(s) date US-A-3838167 24-09-74 None EP-A-0429685 05-06-91 AU-B- 617621 28-11-91 AU-A- 6032190 22-02-91 WO-A- 9101306 07-02-91 For mom~ details about this annex see Official Journal of the European Patent Office, No. 12/82 RAPORT DE RECHERCHE INTERNATIONALE Demands lnternational. No PCT/FR 93/00093 L CLASSEMVENT DE L'INVENTION (si plusiours symboles do classification on: applicables, 1os idlquer tous) 7 Solon la classification Internationzale des brevets (allI) ou Alas foda solon Is classification national@ at It CIE CIB 5 1707D209/96; A61K31/40; CO7D209/90; C07D491/1O '7D471/10; C070403/12; C070409/12; C070209/34 U. DOMAINES SUR LESQUELS LA RECHERCHE A PORTE Documentation minimal. consultho 8 Documentation consultbe autre quo Ia documentation minimal. dabs I& mosure o0 ds tols documsnts foot partio des domaines sur squels I& rechierche a portif

131. DOCUMENTS CONSIDERES COMM PERTINENTS' 0 Caidgorie oIdentification des documents citts, avec Indication, Ai nkcesealre0 2 No. des revendications des passages pertinente 13vsis1 x CHEMICAL ABSTRACTS, vol. 77, 1 1972, Columbus, Ohio, US; abstract no. 114172c, NATSUME, MITSUTAKA ET AL. 'Formation of 3-cyano-1,4-dihydroquinolines and their conversion to indole derivatives.' page 429; RN 36797-34-9 et RN 36797-35-0 2H-Indo le-2-one, 3-ethyl-i ,3-di hidro-3-methyl-l( 4-methylphenyllsulfonyl)- et 2H-Indol-2-o ne, 1,3-dihidro-3,3-dimethyl-l-(( 4-methyiphenyl) sulfonyl)- 'Chem. Pharm. Bull. 1972, 20(7), 1595-8' A US,A,3 838 167 (ELI LILLY AND COMPANY) 1,19 24 Septembre 1974 *colonne 1-2; colonne 6, ligne 42-44* oCatigories spkdales do documents ltk: 1 IT' document utthrieur publib postbleuremtnt i la date de dkpdt A doumet dflnssat Iita gdnml o I tehniuenonInternational ou A. Is date ds prioriti at n'appartnanantpe 'A conricu m mnt p~faisit iulret p e Itien qe Ao I'ktat doa technique pertinent, mals citl pour compred= con~kr*coma prtiulltemet prtientIs prlncipe ou It thboris constituant labia.e l'lnvntion E' document antdrleur, mals pubild AIa date do ddt intens- 'XI document partiwuliroment petnet Ilntion revendl- tionil ou apris Cle date ith no peut 6tre considirke comma nouvell. ou comma LV document pouvant later un doute sur une revostdlcation do Impliquant une activittiInventive prioritt ou dt6 pour d~terminer I& date do publication d'une document partilatlirement pertinent; V'invention reven- autre citation ou pour une ralson spkclale (tellsqu'indiqude) elquie no pout ftre considiria comma Impliquant ntin document so r~ftrnt J. m. divulgation orale, A un usage, A activit6 Inventive lorsqus lId document est associb A un ou ntin exposition ou taus autres moyans 1usleurs autrts documents ds meme nature, ctue combl- document publIA avant la. date do dkpct Internationul, male Xelon ktant Wvdente pour tine pomon.e du mitier. postbrlwrement Atla date do prioritt revendlqute 'A document qul hit partr. do Ia memo fameille de brevets IV. CERTIFICATION Date A laquelle I& rechierche Internationale a 6t6 effectivoment acbevie Date d'e-xpedtion du priksent rapport do recherche Internationale Administration chiants e20rcerh AV I 1993nal Sliatre du fonctionnaire atrs OFFICE EUROPEEN DES BREVETS VAN BIJLEN H. lsawhlairo PCT/LSA210 idoda hille) (Julwe IM)S PCT/FR 93/00093 Deande Intuanazioale No m. (U DJM4SONIES ME 4 lDES RENSEINEMINTS INDIQUES SUIR LA Caa6go *Idomifiajion des doaamuits dtks, U aec Indkiflon, mi mscenare INo. des revndicSnomls mgotdes psur-es Pwamts" I visim s A EP,A,O 429 685 (TAIHO PHARMACEUTICAL1 COMPANY, LTD.) Juin 1991 voir revendications Fammm PcrJLsAJnio ow miUmmmik Iod*na Ill ANNEXE AU RAPPORT DE RECHERCHE INTERNATIONALE RELATIF A LA DEMANDE INTERNATIONALE NO. FR 9300093 SA 70247 La prisentc annexe indique les mneonhes dc In famnille de brevets relatifs aux documents brevets citis dans le rapport de recherche internationale vise ci-desmu. Lesdits membres sont contenus au fielder informatique de I'Ofice europien des brevets i la date du Les renseignements fournis wont donnis a titre indicatif et nWengagent pas la rtsponsabiliti dc I'Office europ~n des brevets 20/04/93 Document brevet cit6 Date de Membre(s) deI Date de au rapport de recherche publication famille de breve4s publication US-A-3838167 24-09-74 Aucun EP-A-0429685 05-06-91 AU-B- 617621 28-11-91 AU-A- 6032190 22-02-91 WO-A- 9101306 07-02-91 0 Pour tout renseignement concernant ctte annexe voir Journal Officiel de I'Office europn des brevets, No.12/82