CA2107348A1 - N-sulfonyl-2-oxoindole derivatives having affinity for vasopressin and/or ocytocin receptors - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE

The invention relates to N-sulfonyl-2-oxoindole derivatives of formula (I) and their possible salts as well as their preparation and the pharmaceutical compositions in which they are present.
These compounds have an affinity for vasopressin and/or ocytocin receptors.

Description

2~73~

iv-~tLvcs~ h-cir ~

The present invention relates to N-sulfonyl-2-oxoindole derivatives, their S pr~paration and the pharmaceu~ical cosnposi~ions in which they are presen~.
International patent applica~ion WO 91/01 3C16 descTibes Z-oxoindole derivatives which are useful for the treatmen~ of senile dcmentia. These compounds have the fonm~la R"~

1~ O

COR"4 in which lR"1 is hyd~ogen, a halogen, an alkyl or an alkoxy;
- R"2 is hydrogen or a lower alkyl;
15 - 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 ocytocin20 receptors. European applications EP 382185 and EP 444 945, international application WO 91/05 549 and, more particularly, Japanese patent application JP
03/127732 can be cited in this respect. The latter describes indole-3-plopionic acid derivatives of the fonnula:

~ ~ R " ' l~ 4 :: 25 R " ' ~ ~ .
~, -21~73~

in which - R"'1 is hydrogen, an aikyl, an alk~nyl, a phcnylalkyi, a tetrahyd~ofuryl, a alkoxycarbonyl, an alkaxycarbonylalkyl, a carboxyalkyl or an alkanoyl;
- R"'2 is hydrogcn, a hydroxyl, an alkoxy, an allsyl, a phenylalkyl, a S phenylalkoxy or a halogcn;
- R"'3 is a hydrogen, an alkoxy, a ~ree or substituted amirlo group or an arnino acid residue;
- R"'4 is hydrogen, an alkyl or a phenylalkyl; and - R"'s is a benzoyl, a phenyl, an alkyl, a phenylalkenylcarbonyl, a thienylcarbonyl, ~ phenylsulfonyl, a pyridylcarbonyl or an imidazolylcar~onyl, it being possible ~or the phenyl and alkyl ~oups of the substituent R"'s to be substituted.
These compounds are vasopressin antagonists.
Patent US 4,8()3,217 clairns hapalindolinones obtained by fermentatinn, which are vasoprexsin antagonists. These compounds have the following fonnula:

CH2 ~ CH ~

~C,J~ J~; o CH3 in which R is H or Cl.
The N-sulfonyl-2-oxoindole derivatives accoIding to the present inve~ion have an ~ffinity for the vasopressin and ocytocin receptos~.
Vasopressin is a horrnone known for its antidiuretic effe~t and its eiYect in regulating the arterial pressure. It stimulates several types of receptols, namely V~ a, Vlb~ and V2, and thus exerts cardiovascular, hepatic, antidiuretic and platelet-aggregating effects and effccts on the central and peripheral nervous systems. Va~sopressin receptor antagonists can affect the regulation of the central and peripheral circulations, especially the coronary, renal and gastric circulatiuns, as well æ the regulation of hydration and the release of adrenocorticotrophic hormone (ACI H). Non-peptide agonists of vasopressin can advantageously 2~ar~3~8 r~placc vasopressill or its analt)gs in thc trcatnlcnt o~ ciiabctcs insipidus; thcy can also bc usccl in th~ trcatrncnt of ~nur~,sia and in ~hc rcgulation of hcmostasis;
treatm~nt of hcmophilia al1~1 of Von Willcbrand's synclrom, antidotc to platelet-aggrcgating agents; Dlllg ll~v~stigation, 1990, 2 (S~lppl. S), 1-47. Thc vasopr~ssin S reccptors, like thc ocytocin r~cepto~s, arc also found on thc smooth muscl~ of the utems. Ocytocin has a pepticic structure similar to that of vasopressin. Its receptors are also found on myoepith~lial cells of thc mammary gland and in the central nervous system (Presse médicale, 1987, l6 (l()), 481-4gS, J. Lab. Clin. Med., 1989, 114 (6), 617-632, and Phannacol. Rev., 1991, 43 (1), 73-108). This 10 hormone is involved in palturition, lactation and sexual behaviour.
Thus the compounds according to the invention are useful especially in the treatmeîlt of complaints of the ccntral and peripheral nervous systerns, the cardiovascular system~ ~he renal sphcre and the gastric sphere and in diso~ders of sexual behavior, ;n humans and animals.
The present invention relates to compounds of the formula R~
R ~ / JR
R2 ~,1. N ,L--O
SO
l 2 (I) - ¦--R5 (R6)m in which - Rl and R~ are each independently a hydrogen, a hydroxy, a Cl-C4~cl1-20 halogenoalkoxy, a halogen, a C1-C4-alkyl, a trifluoromethyl, a C1-C7-alkoxy, a C1-C4-polyhalogenoalkoxy, a C2-C4-~hydroxyalkoxy, an ~-methoxyalkoxy in which the alkyl is C2-C4, a C2-C4-~-aminoalkoxy which is free or substituted by one or two C1-C4-alkyls; a C3-C7-cycloalkyloxy; a cycloalkylmethoxy iD which the cycloalkyl is C3-C7; a phenoxy; a benzyloxy;
25 a C1-C4-alkylthio; a phens~lthio; a nitro; an amino which is free or substituted by one or two C1-C4-alkyls; a cyano; a C1-C4-acyl; a C1-C4-acyloxy; a .

2~ ~PI34~

Cl~C~_alk~lsul~onallli(lo; a phcn~lsulfonamido; a Cl-C4-~lkylamido; a Cl-C4-.1lk~ ycarbollylanlino; a urcido which is unsubstitutcd or substituted by a phcnyl or by OllC or two Cl-C4 alkyls;
- R3 an(l R4 ar~ cach indepcndcntly a (:1-C6-alkyl, a C3-C~-cycloalkyl, a 5 phcnyl, a bcnzyl, a cycloalkylmcthyl in which the cycloalkyl is C3-C7;
or - R3 and R4 ~ogether fonn ~ group ~(CH~)pX(CH~)q;
or - R3 and R4 together with thP carbon atom to which they are bonded, fonrl an 10 optionally fused, saturated or unsaturated C3-C1o hydrocarbon ring which is unsubstituted Ol substituted by one or mnre Cl-C7-alkyl groups Ol by a C3-Cs-spirocycloalkyl;
or else - R1 and R4 each have one of the above meanings and R2 is located in the 4-1~ position of the indole and fonns a group (CH ~)3 with R3;
- Rs and R6 are each independently a hydrogen, a halogen, a C1-C7-alkyl, a trifluoromethyl, a cyano, a nitro, an amino which is free or substituted by one or two C1-C7-alkyls; a hydroxyamino; a hydroxy; a carboxy; a group OR7; a group SR7; a C1-C7-acyl; a Cl-C7-alkoxycarbonyl; a phenoxycarbonyl; a 20 benzyloxycarbonyl; a carbamoyl substituted by groups R'6 and R'16; a thiocarbamoyl which is free or substituted by one or two Cl-C7-alkyls; a sulfamoyl; an alkylsulfamoyl or a dialkylsulfamoyl in which the alkyl is C1-C7;-a group SO2R'7; an alkylsulfonamido in which the alkyl is C1-C7; a group COR'7; a group NRgRg; a group CO-NH-CH(Rl~)-COR12; if 25 appropriate, the phenyl group forming part of the substitutent Rs and/or R6 can be unsubstituted or monosubstituted or polysubstituted by a C1-C7-alkyl, a trifluoromethyl, a methoxy, a halogen, a sulfamoyl, an alkylsulfamoyl in which the alkyl is Cl-C4, a carboxy, an alkoxycarbonyl in which the alkyl is C1-C7, a C1-C7-acyloxy or an imidazolyl;
30 - R'6 and R"6 are each independently hydrogen, a C1-C7 alkyl which is unsubstituted or substituted by R"'6, a phenyl, a pyridyl, a methylpyridyl, a piperidin-4-yl, a methylpiperidin-4-yl; or R'6 and R"6 form, with the nitrogen atom to which they are bonded, a heterocycle selected from piperazine and piperidine;

21(~73~

~ R"'6 is ~1 hyclro,Yy, a cy~no, a carl~o.Yy which is free or esterifi~d by a C1-C7-alks~l or by a bcnzyl; a phenyl; a pyridyl; a methylpyridyl; an amino whieh is free or substitutcd by onc ~r two C~ -C7-~lkyls;
- R7 is a Cl-C7-alkyl, a phenyl, a b~nzyl, a C3-C7-eyeloalkyl, a C2-C4-S alkenyl, a C1-C7-~1)-halogenoalkyl, a C1-C7-polyhalogenoalkyl, a Cl-C7~
acyl, a C1-C7-~-carboxyalkyl which is free or est(~rified by a Cl-C4-alkyl or by a benzyl, a C~-C7 ~-aminoalkyl in which the amino group is ~ree, substituted by one or two C1-C4-alkyls or in the folm of an ammonium ion;
- R'7 is a piperazin-1-yl group which is unsubstituted or subslituted in the 4-10 position by a group R"7, a piperidino group which is unsubstituted orsubstituted in the 4-position by a group R"'7, an a7etidin-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 C1-C4-alkyl, a phenyl, a benzyl, a C1-C4-acyl;
15 - R"'7 is R"~ or an amino which is free or carries a protecting group;
- R8 and R~ are each independently a hydrogen, a C1-C7-alkyl, a phenyl or a benzyl; Rg can also be a C1-C7-acyl, a Cl-C7-thioalkyl, a cycloalkylcarbonyl in which the cycloalkyl is C3-C7, a cysloalkylthiocarbonyl in which the cycloalkyl is C3-C7, a Cl-C4-~-aminoacyl, a (:1-C4-~-20 hydroxyacyl, a C1-C4-~-benzyloxyacyl, a phenoxycarbonyl, a thienocarbonyl, a pyridylcarbonyl, a methylpyridylcarbonyl, a C1-C4-alkoxycarbonyl, a benzoyl, a group C-CH(~10)-NR11R 11~ a group CH(R10)~23~11, a group (CH~)tCOR1~ a group CO(CH2)tCOR12, a carbarnoyl which is unsubstituted or substituted by a phenyl or one or two Cl-2S C4-alkyls, m is 1 or, when R6 is a halogen, a C1-C7-alkyl or a C1-C7-alkoxy, m can also be 2, 3 or 4 or else (R6)m can be m substituents having different meanings selected from halogen, C1-C7-alkyl or C1-C7-alkoxy;
p and 9 are each integers, it being possible for their sum to vary from 3 to 6;
30 - t is an integer which can vary from 1 to 5;
- X is oxygen, sulfur or a group NR13;
:: - R1o is hydrogen, a C1-C4-alkyl or a benzyl;
- R11 and R'11 are each independently hydrogen or a C1-C4-alkyl;

.
:

. : .

210 ~ 3 l~ g ~ R12 is a hydroxy, a Cl~Cd,~-alkoxy or an amino which is unsubs~ituted or substitutcd by one or lwo C1-C4 alkyls;
~ ~13 is hyd~ogen, a C1-C~-alkyl, a phenyl, a benzyl, a C1-C4-acyl, a C1-C4-alkoxycarbonyl or a c~rbamoyl which is unsubstituted or substituted by one or Stwo Cl-C4 alkyls;
as well as ~heir possible salts.
If a compound ascording to the invellt~on has one or more asymmetAc carbons, the invention ineludes all the optical isomers of this compound.
The salts of the compounds o~ formula (I) according to the present invention 10include ths)se with mineral or organic acids which permit a suitable SeparatiOD or ~ystalliza~ion of the compounds of ~ormula (I), such as picric acid, oxalic acid or an optically active acid, for example a mandelic acid s)s a camphoslllfonic acid, and mineral or organic acids which form physiologically acceptable salts sllch as the hydrochloride~ hydrobromide, sulfate, hydrogensul~ate, di-hydrogenphosphate, 15maleate, ~umarate or naphthalene-2-sulÇonate.
The salts of the compounds of fo~nula (I) also include the salts with or~9anic or mineral bases, for e~cample the salts of alkali rnetal or -alkaline ear~h 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, Iysine, 20or any physiologically aeceptable amine.
According to the present invention, halogen is understood as meaning an atom selected from fluorine, chlorine, bromins and iodine, preferably fluorine or chlorine. Amino-protecting group is understood as meaning a ~oup such as, for example, tert-butoxycarbonyl, ben~yloxycarbonyl or benzyl.
2SAccording to the present invention, optionally fused condensed9 saturated OI
unsatu~ated C3-C1o hydrocarbon ring is understood as meaning various hydrocarbon nngs with a monocyclic9 dicyclic or tricyclic structure, for example a cyclobutane, a cyclopentane, a cyclohexane, a cycloheptane, a cyclooctane9 an indane, a hexahydroindane, an adamantane, a norbornane, a norbornene, a 30dihydrophenalene, a tricyclo[S.2.1.02,6]decane or a tricyclo[5.2.1.02~6]dec-8-ene.
The cornpounds of formula (I) in which Rl is in the 5-position of the indole and R2 is hydrogen are preferred compounds.
The compounds of formula ~I) in which Rl is a chlorine atom or an ethoxy group in the 5-position of the indole and R2 is hydrogen are preferIed compounds.

2~73~8 Thc compounds of ~ormul~ (I) in which R3 an~l R4 togcthcr with thc carbon to which they are bonded, form a C3-Clo hy~lrocasbon ~ng are prefcrred compounds; particularly pr~ferrcd compounds ~rc thosc in which R3 and R4, together with the carbon to which they are bonded, ~orm a cyeloheptane, an S adamantane, a tricyclo[s.2.l.o2~6]dec-g-e~le s~r a cyclohexane which is unsubstihlted or substituted by a C3~ s-spirocycloalkyl or by one or two Cl-C7-alkyl ~oups.
l~e compounds of fonnula ~I~ in which lR3 and R4, together with the ca~bon ts~ wh;ch they are bondçd, form a pipencline-4 or N-methylpiperidille-4 ring arealso preferred.
The compounds of fonnula (~) in which Rs and R6 are each a methoxy are prefeIred compounds. Li!cewisi, the compounds in which Rs in the 2-position is amethoxy and R6 in the 4-position is a C1-C7-af~ylamino, a C1-C4-dialkyluseido or an alkoxycar~onylalkylcarbamoyl in which the alkyl groups are C1-C7 are preferred compound~.
rhe following abbreYiations are used in the description and in the examples.
DCM: dichloromethane Ether: ethyl ether Iso ether: isopropyl ether Boc: tert-butoxycarbonyl Me, MeO: methyl, mcthoxy Et: ethyl Pr, iPr, nPr: propyl, isopropyl, n-propyl Bu, iBu? tBu: butyl, isobutyl, ter~-butyl 2S Ph: phenyl Bz: benzyl Ac: acetyl AcOEt: ethyl acetate AcOH: acetic acid MeOH: methanol Etl:)H: ethanol ~; DMF: dimethylformamide THF: tetrahydrofuran DMSO: dimethyl sulfoxide ::
:

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DIPEA: diisopropylcthylaminc IEA: tricthylamine TF~: tAfluoroacetic acid TMEDA: tetr~nethylethylcncdi~mine s M.p.: melting point Salin~ solution: satu~ated aqueous sodium chloride solution TLC: thin layer chromatography HPLC: high pressure liquid cblomatography Aqueous hydrochloric acid: dilute hydrochloric acid~ about 1 N
RT: room temperature The present invention fu~her relates to the method of preparing the compounds accolding to the invention, characterized in that:
a benzenesulfonyl halide of the formula;
::
Hal~02~R~5 VI~ m ~:: in whlch R's and RVI are respectively either Rs and R6 as defined above for ~1)9 or plecursor groups of Rs and R6 is reacted with a 2-oxoindole disu~stituted in the: ~ :: : 3 position, of the fonnula:
20:

R' 7 ~ D`N -- (II) ~: : H
m~which R'l and~R'2 aro~respectivoly either R1 and R2 as defined above for (1~, or : precursor groups of 12 1 and R2, and R3 and R4 are as defined above for (1), 25~ - either, if R'1=R1, R'2=R2, R's-Rs and RVl=R6~ the r~sulting compound of formula (~ is isolated; ~
orj if any one of the groups R'1, R'2~ E~'s and RVI is respectively a precursor group of R1, R2,:: Rs and/or R6, the compound obtained is subjected to a subsequent treatment in order to prepare the compound of fonnula (1~ by ;~:
.

. . .

21~73'18 conversion of any one of thc grouys R'l, R'2, R's and RVl to R1, R2, Rs and R6, rcspectivcly.
The rcactioll is calr~ed out in an anhydrous solvent such as DMF or THF, in the presencc o~ a metal hydride such as~ for example, sodium hydnde, or in the presence of an alcoholate such as potassium tert-butylate.
The 2-oxoindoles (ll~ can be prepared using different procedures. Some of the~ compounds are novel and form part of the invention.
Compounds (II) in which E~ll and/or R'2 are a halogen and R3 and R4, together with the carbon So which they are bonded, fonn a spirocyclobutane, a spirocyclohexane or a spi~ocycloheptane are known, for example in D. W.
Robertson et al. J. Med. Chem., 1987, 30 ~5), 824 829. Also, 5-chloro-3-spirocyclopentaneindol-2-one is described in US Patent 3,94~,451.
To prepare the compounds ~II) in the case where ~3 and R4 are together or separately a hydrocarbon group, it is possible to use the Brur~er reaction desc~ibed by R.F. Moose and S.G.P. Plant in J. Chem. Soc., 1951, 3475-3478; which leads tothe preparation of compounds (Il) in which CR3R4 is a cyclopentane or a cyclohexane.
This reaction is carried out by cyclizing a phenylhydrazide derivative of the fonnula:

~ 2~LNH NH 1 1 ~H~

in which R'l and R'2 are as defined above for (II), and R3 and R4 have the meanings indicated above for (1), for example by heating in ~he presence of calcium oxide and quinoline.
~ccording to the same authors, the phenylhydrazide derivative (IV) is obtained by reacting a hydrazine derivative of the fonnula:
:~' N H~H2 : R' (V) 210 ~ 3 4 8 in which R'1 and IR'2 havc thc mcanings ;ndicated ab~vc for ~11), wi~h an acid halide of the fonnula:
H~ CR3R4 l l (VI) o in whieh R3 and R4 have the meanings indicated above fos ~1).
According to a particular embodiment, if R3 and R4 together with the carbon to which they are bonded, fonn a fused polyGyClic hydsocar~, for example norbornane or norbornene, the reaction is carried out by the method described by J. Wolff et al., Tetrahedron, 1986, ~ (15), 42~7-4272: first of all, a lithium salt of the compound (IV3 is prep~ed by reaction with a lithium rea~rlt such as n-butyllithium, in an inert solvent such as THF, at low temperature, and~hen the cyclization is effeeted by heating jD a solvent such as naphthalene or prehnitene (1,2,3,4-tetramethylbenzene).
The compounds (Il) in which R1= R2= H and CR3E~4 is adamantane are s describet in I. Fleming et al., J. Chem. Soc., Perkin Trans I, 1991, ~, 617-626.
Thus, the ~mpounds (I~ in which R3 and R4, together with the carbon atom to . ~ ~ whieh they are bonded, form an adamantane and R1 and R2 aIe other than hyd~ogen, are novel and form part of the invention. l'h~y can be prepared by themethod described above.
The hydrazine derivatives (V) are lcnows~ or are prepared by known rnethods.
The same applies to the acid halides (Vl).
A 2 ~oxoindole disubstituted in the 3-position (II) can also be prepared from a 2-oxoindole of the fonnula:

R2~ ~ (V
: ~ : 25 : H
:~ ~
in which R'l and R'2 are as defined above for (II), by using variou~ methods.
;: : For example, the method described by A.S. Kende and J.C. Hodges in Synth.
Commun., 1982, 12 (1), 1-10, involves the addition of an alkyla¢ing agent in an appropriate solvent. Thus, to prepare a compound (Il) in which R3 - , the ~ ~ reaction is carried out in THF at -75- C, in the presence of TMEDA, by addition of ::

2 1 ~

an alkyllithium such as butyllithium, followcd by rcaction with a halide of the fomlula R3Hal; if R3 and R4 are diffcrent, the alkylating reaction can be performed in two steps with 2 different alkyl halides of the formulae R3Hal and R4Hal. To p~epare a compound (Il) in which R3 and R4 together form a group of s th~ fomlula -(CH2)n-, in which n varies from 2 to 7, the reactant uscd is a compound of fonnula Z(CH2)rlZ, in which Z is an electroYI-accepting group such as a halogen, preferably bromine or iodine, a tosyloxy group or a mesyloxy group.
lhe compounds of fonnula (II) in which R3 and R4 are each independerltly an alkyl or a phenyl are known. ~or example, paten~ DB 3 300 522 des~ibes 5-0 alkoxy-3,3,-dimethylindol-2-ones.
Thc compounds of ~ormula (II) in which R3 and R4, together with the carbon to which they are bonded, form a C4-C8 hydroc~rbon ring substituted by one more C1-C7-alkyl groups or by a C3-Cs-spirocycloalkyl are prepared in the samc manner. ~ese compounds are novel and fonn part of the invention.
If R3 and R4 together fonn a ~(CH2)pX(CH~q_ ~oup, in which p, q and X
are as defined above for (I), a 2-oxoindole disubstituted in the 3-position, of fonnula (II~, can be prepared ~om a 2-oxoindole unsubs~ituted in the 3-position (VI~ by reaction with a compound of the fonnula:

Z~CH2)p-X~CH ~)q~Z (VIIr) in which Z is as defined above and X, p and q are as de~med above for (1). The ~eaction is carried out irl the presence of an alcoholate, for example potassium tert-butylate, in an anhydrous solvent such as, for example, THF.
If X is a nitrogen atom substituted by a C1-C4-acy1, a C1-C4-alkoxycarbonyl or a C1-C4-alkylcarbamoyl, the substitution on X can be effected either on the 2-oxoindole derivative (Il) or on the ~mal compound (I) starting from a compound in which the nitrogen atom (X = NH) is not substituted.
The compounds (I) in which X = NH a~e preferred compounds according to theinvention.
Thus, if X is a nitrogen atom substituted by a C1-C4-alkoxycarbonyl, the ~Irst step is to prepare a compound (Il) or (I) in which X is NEI, which is thenreacted with the appropriate chloroformate to give the desired compound (II) or (~).
In the same way, a Cl-C4-alkyl isocyanate is reacted with a compound (II) or (I) .

2~073~

in which X = NH to g~ve a 2-oxoindole dcrivativc (II) o~ a compound (I) in whichX is a nitrogen atom substituted by an alkylcarbamoyl. An acid chloride s)r an anhydride is reacted with a compound (Il) or (1~ in which X - N~ in order to prepare a compound of fonnula (I) in which X is a nitrogell atom substituted by an 5 acyl, The compounds (Il) in which R3 and R4 together with the ~bon to which they are bonded, ~onn a pyrrolidine, N-alkylpyrrolidine, pipendine or N-alky1piperidine ring are described by M. J. Komet in J. Med. C}lem., 1976, ~, (7), ~92-899.
In particular, the horsfiline of the formula:
~ Me Me O ~ ~

is an alkaloid described in A. Jossang et al., J. Org. Chem., 1991, ~6 (23)7 6527-~5 6530.
T~e compounds (Il) in which R3 and R4, together with the carbon to which they are bonded, fonn a group ~(CH2)pX(CH2)q~ in which p and q are integers whose sum can vaIy from 3 to 6 and X is oxy~n, sulfur or a ~oup NR13, R13 being a Cl-C4-acyl, a benzyl, a Cl-C4-alkoxycarbonyl or a carbamoyl which is 20 unsubstituted or substituted by one or two C1-C4 alkyls, are novel and fo~n part of the invention.
To prepare a compound of fonnula (I~) in which R3 and R4, together with the carbon to which they are bonded, form a tr~cyclo[S.2.1.O2~63decane or a tncyclo[5.2.1.O2~6]dee-8-ene, a compound of formula (VII') or a compound 25 ~" respectively, of the formulae .
Z H2~ Z~H

(VII)' (VII)"

210734~

in which Z is as ~cfin~d ~bove, is rcac~cd with a compound of formula (VII).
Cs)mpounds (Vll)' and (Vll)" substitutcd by onç or more Cl-C4-allcyl groups are used to prcpare compounds (Il) in which said carbocycles are substituted.
To prepare a compound (Il) in which R3 and ~, together with the carbon to s which they are ~onded, forrn a~ indane or a hexahydroindane, a compound ~VII~' or a compound (VIII)" respectively~ of the formulac ~H2~¦ Z~H2 Z~H~ Z~H

(~III)' (VIIl)~

o in which Z is defined as indicated above for (VII~, is reacted with a compound ~VII). Compounds (VIII)' and ~YIII)" substituted by one or mo~e Cl-C~-alkyl groups are used to prepare compounds (Ir) in which the indane or lhe hexahydroindane are substituted.
The compounds (Il) in which R3 and R~ together with the carbon to which they are bonded; folln a tricyclo[S.2.1.02~6]decane, a tricyclo~S.2.1.02~S~dec-8-~; ~ ene, an indane or a he~ahydroindane which are unsubstituted or substituted by one or more C1-C4-alkyls, are novel and ~orm part of the invention.
If R3 and R4 each are a phenyl, the method described iD E~elv. Chim. Acta, 1946, ~2. 415-432, can be used to prepare a compound (II).
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, ~, 1704-1712.
The compounds of formula (Il~ which carry certain substituents R'1 and R'2 on their benzene rnoiety are used as precursors for the preparation of compounds of 2s; Ionnula ~ which car~ other substituents R'1 and R'2. For example, the compounds (I~ in which R'1 and/or R'2 = H can be nitrated with the conventional reagents; they car~ also be acylated by reaction with an acid chlolide of formula RCOCI, in which R is a C1-C4-alkyl, in the presence of a Lewis acid such as alumimum chloride, in order to prepare a compound (II) in which R'1 and/or R'2 =30 COR. A compound (Il~ in which R'1 is an amino group is prepared by catalytic , .

~:, 7 3 ~ ~

hydrogcnation of a compound (Il) in which R'l is a nitro glOUp and R12 is hydrogcn.
The compounds of thc formula ~N l~

in which - R1 and R2 are each independen~ly a hydrogen, a hydr~xy, a C1--C4-~-halogenoalkoxy, a halogen, a Cl-C4-alkyl, a trifluoromethyl, a C1-C7~
alkoxy, a Cl-C4-polyhalogenoalkoxy, a C2-C4-~-hydroxyalko~cy, an ~-metho~yalkoxy in whif h the alkyl is C2-C4, a C2-C4-~-aminoalk~y whi~h is ~e or substituted by one or two C1-C4-alkyls, a C3-C7-cycloalkoxy, a cycloalkylmethoxy in which the cycloalkyl is c~q, a phenoxy, a benzyloxy, a Cl-C4-alkylth;o, a phenylthio, a nitro, an amino which is free o~ substituted by one or two Cl-C4 alkyls, a cyano~ a C1-C4-acyl, a C1~4-acylo~y, a C1-C4-alkylsulfonamido, a phenylsulfonamido, a Cl-C4-alkyla;nido, a Cl-~: C4-alkoxywbonylarnino or a ureido which is unsubstituted or substitlated by a phenyl or by one Ol two C1-C4-alkyls; and R3 and R4, together with the carbon to which they are bonded, form ~: 20 . an adamantane, an indane or a hexahydroindane which are unsubstituted or substituted by one or more C1-C7-alkyl groups, : . a tricyc~o[5.2.1.02~6]decane or a tlicyclo[5.2.1.02~6~dec-8-ene which are unsubstituted or substituted by oDe or more C1-C7-alkyl groups, or : 25 . a C4-C~ hydrocarbon ring substituted by one or more C~ alkyl groups or by a C3-Cs-spirocycloalkyl; or else R3 and R4 together form a group ~(CH2)p~X(CH2)q~ in which p and q are integers whose sum can vary ~om 3 to 6 and X is oxygen, sulfur or a ~oup NR139 R13 being a phenyl, a benzyl, a C1-C4-acyl, a C1-C4-alkoxycarbollyl ~or a carbamoyl which is unsubstituted or substituted by one or two C1-C4-alkyls, with the limitation that if CR3R4 is adamantane, R1 and R2 are other than hydrogen, :, .
, ,~ ' 12~73~8 a~e 3~0v~:1 and ~onr~ part of the invcntion.
The compounds of thc fonnula N (II)"
H
s in which - R1 is a hydroxy, a Cl-C4~ halogeDoalkoxy, a halogerl, a C1-C4-a~yl, a trifluorQmethyl, a C1-C7-alko~y, a C1-C~-polyhalagenoalkoxy, a C~-C4-CI~
-hydr~xyalkoxy, an ~o-methoxyallcoxy in which ~he alkyl is C2-( 4, a C2-C4-~3-amino~lkoxy which is ~ee or substituted by onc or two Cl-~4-alkyls, a C3 q-cycloalkoxy, a cycloalkylmethoxy in which ~he cycloalkyl is c3-q, a phenoxy, a ~nzylo~y, a C1~C4-alkylthio, a phenyl~hio, a nit~, an a3nino which is ~e or substituted ~y one or two Cl-~4-alkyls, a cyano, a C1-C4-acyl, a 3:1-C4-acyloxy, a Cl-C4-alkylsulfonamido, a phellylsulfollamido, a C~ -alkylamido, a C1-C4-alkoxycarbonylamino or a ureido which is unsubstituted or substituted by a phenyl or by vne or two C1-C~-alkyls;
- R3 and R4 tog~ther ~orm a group -(CH2)p X(CH2)q~; or - R3 and R4, together with the carbon to which they are bonded, foIm an optionally fused, saturated or unsaturated C3-C1o hydrocarbon nng which is ~: 20 unsubstituted or substitutcd by one or morc S~ C4-alkyl groups or by a C3-~: Cs-spirocycloalkyl;
- p and q are each an integer, it being possible for theîr sum to vary ~om 3 to 6;
X is oxygen, sul~r Ol a group NR13; and - R13 is hydrogen, a C1-C4-alkyl, a phenyl, a bcnzyl, a C1-C4-acyl, a C1-C4-25 allcoxycarbonyl or a carbamoyl which is unsubstituted or substituted by one or 2Cl-C4-alkyls, with the limitation that - if Rl is methoxy, CR3R4 is other than a pylTolidine-3 which is unsubstituted or N-substituted by a C1-C4-alkyl, and if R1 is a halogen, CR3R4 is other than a 30 pentane, ~: :
are novel and form part of the invention.

2a,3,4,5-Tetrahydrobenz[c,d]indol 2(1H)-one of the fonnula ~ ' .

2107~

is commercially available; its derivatives are known OI are prepared by k~ow~
methods.
S The ber~enesulfonyl halides (II~) are known and are prep~ed by known me~hods. Thus, ~r example, 4-dimethylaminobenzene~ulfonyl chloride is prepared according to C.N. Sukenik et al., J. Amer. Chem. Soc., 1977, 99~ 851-858. More generally, the benzenesulfonyl halides (1l1) in which the substituent Rs is a din~ethylamino group are knowsl or are prepared by known methods; p-berlzyloxybenzenesulfonyl chloride is prcpared according tv ~uropean patent application EP 229 566.
The alkoxybenze~esulfonyl chloride is prepared ~om the ~odium ;: aLlcoxybcnzenesulfonate, which is itself prepared by reacting an alkyl halide with sodium hydroxybenzenesulfonate.
2~4-Dimetho~ybcnzenesulfonyl chloride is prepared according to J. Am.
Chem. Soc., 1952, 74, 2û08.
The halogenoalkoxybenzenesulfonyl chlorides can be prepared according to paterlt US 2 540 057.
The benzenesulfonyl halides of the formula ~Alk YRV
:": ~: : : ::
in which Alk is a C~ alkyl;
25: - Y is O or S; and : - ~

:. .

21~7~ 1~
l7 ~ RV is a C1-5~7-alkYl, a C3-C7-cycloalkyl, a (:2-C4-alkcnyl, a C1~C7-~-halogcnoalkyL a C1-C7-polyhalogcnoalkyl, a bcn~yl, a Cl C7-acyl or a Cl-C7-~-carboxyalkyl esterified by a Cl-C4-alkyl or by a bcnzyl, are novel and form part of the invention.
S lllese compounds are preparf d according to O. Hofmann et al. in Liebigs Ann. Chem., 1982, 287-297. Benzene compounds carrying the subseituents YRV
and OAlk iD the 1- and 3-positions are reacted with trimethylsilyl chlorosulfonaSe in a solvent such as OCM, at RT. ll~e 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 allcali metal carbonate, and then by reaction with a hali~e such asPOCl3 to give the desired benzenesulfonyl halide.
The benzenesulfonyl halides ~ in which the substituent R's is an alko~ycarbonyl, a phenoxycarbonyl, a benzyloxycarbonyl, an alkylthio, a phenylthio~ a benzylthio or a group SR7, R7 being as defined for ~I), are prepared accordiYlg to Col. ~zechoslov. Chem. Commun., 1984, 49, 1184, from an aniline derivative substituted by the same grouping R'5, said aniline derivative itself being obtained ~om the colTesponding nitrated derivative.
The nitroberlzoic acid derivatives are known; the corresponding alkyl and phenyl estPrs are obtained by subjecting this acid to an appropnate esterification reactioD.
The benzenedisulfonyl dihalides (III, R's = S02Hal) are known or are prepared by known methods. For example, 2,4-dimethoxybenzene-1,5-disulfonyl dichloride is descnbed in R.J.W. Cremlyn, J. Chem. Soc. C, 1969,1344.
The halogenoalk~xybenzenesulfonyl chlorides (III, R's = o~-halogenoalkoxy) are used to prepare compounds according to the invention in which the substituent R5 is an ~-aminoalkoxy which is unsubstituted or substituted by one or two alkyls, according to the following equation:

-O-Alk'-Hal + NHR~Rg --> -OAlk'-NRgRg 3~
in which Alk' is a Cl-C4-alkyl.
For certain meanings of the substituents Rl, R2, Rs and/or Rs, the compounds (1~ according to the invention can be prepared from a precllrsor of for nula (I)' substituted by a group R'l, R'2, R's and/or RVI~ called a precursor group of R1, R2, Rs and/or R6 21~07~8 ~hc dcscription wtlich follows dcscribcs the p~cparatiorl of the cornpounds of formula (I) carrying substitucnts Rl an~Vor Rs; thc same mcthods apply to the preparation of the compounds in which the substituents R2 and/or R6 are defmed as indicated for R1 and Rs.
S I~e compounds (1) in which Rl and/or R5 a~e a hydroxy can ~e obtained by the catalytic hydrogenation of a compound of fonnula (I)' in which R'l and/or R'$
are a benzyloxy, for cxample irl the preseDce of palladium-on-charcoal.
The c~mpounds (I)' in which R'l and/or E~'s are a hydroxy c~n be used to prepare compounds (I3 in which R1 and/or Rs 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 aikaline earth metal carbonate like K2C03 or Cs~CO3, in a solvent such as THF orI)MF. ~ikewise, the compounds of formula (I) in which Rl an(Vor Rs aIe an ~-aminoalkyl~7~y are prepared by reacting an ~-chloroalkylamine wi~h the compounds in which R'1 and/or R's = OH; similarly, the sompounds in which Rl and/or Rs aN an ~-hydroxyalkoxy are preparcd by reaction with a chloroalkyl alcohol; in the particul~r case of the preparation of a compound (I) in which Rlandlor Rs = O(CH2)20E~, it is also possible to react ethylene carbonate with a compolmd ~1)' in which R'l and/or R'5 = OH.
The compounds of foDnula (I) in which R1 and/or Rs are an acyloxy are obtained by reacting an acid halide or an anhydride with a compound (~' in whichR'1 and/or R'S are a hydroxy.
To prepare compounds of formula (I) in which R~ Vor R5 are a monoalkylamino or a dialkylamino, the compounds of fonnula (1~' in which R'l and/or R's are an amino can undergo reductive alkylation. If R'l and/or R's are an amino, it is also possible to perform a nitrosation, for example in the presence of nitrous acid or an alkyl nitrite, to prepare a compo~md (I) in which Rl and/or Rs are a diazonium salt; reactions krlown to those skilled in the art then afford the compounds (I) according to the invention in which Rl and/or Rs are a cyano, a halogeno or a Cl-C4-thioalkyl. Finally, compounds (1) in which Rl and/or Rs are 3û one of the groups of the forrnulae RCONH-, ROCONH-, RNEICONH- and RSO2NH-, in which R is a C1-C4-alkyl, can be prepared by conventional reactions starting ~om compounds (I)' in which R'l and/or R's = NH2 The compounds of formula (I)' in which the substituent R'S is a phenoxycarbonyl can be used to obtain the compounds (I) in which Rs 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 2ln73~s used to obtain compounds of formula (I) in which Rs is a phcnylcarbamoyl or, rcspcctivcly, an alkylcarbamoyl substitutcd on thc alkyl.
The compoun~s of formula (I)' in which R'5 is a ben~yloxycarbonyl can bc uscd to obtain thc compounds (~) in which Rs is a carboxy by catalytic S hydrogenation. Reaction with a thionyl halidc givcs the compounds of ~onnula (I) in which RS is a balogenocarbonyl. Such compounds arc used to prepare compounds of formula (I) in which Ks is an N-substituted carbamoyl by reactior with a substituted amine.
The eompounds of formula (I) in which Rs is a group COR"7 are prepared from corresponding compounds (1~' in which R~5 is a phenoxycarbonyl by reaction with a substituted piperazine or azetidine.
A compound (1~' in which K~5 is a nitro group can be used to obtain a compound ~1) in which R5 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 thoseskilled in the art.
For example, if it is desired to obtain a compound (1~ accolding to the invention in which Rs is a group NR~3Rg, Rg being an optionally substituted ber~oyl, the henzoyl chloride in which the phenyl carries ~he appropriate substituent is reacted with a compound (1)' in which R's is an amino group, in the presence of an amine such as triethylamine. For example, 4-chlorosulfonylbenzoylchloride can be reacted in order to prepare a compound (~' in which R's is a 4-chlorosulforlylbenz3mido group, after which a compound (I) in which the substituent Rs is a 4-sulfamoylbenzamido group or a 4-alkylsulfamoylbenzamido group is obtained by reaction with ammonia or a Cl-C4-alkylamine respectively.
In the same way, if it is desired to prepare a compound (I) in which Rs is a group NRgR~, Rg being a Cl-C7-acyl, the appropriate anhydride is reacted with a compound (I)' in which R's is an amino group, in the presence oP an amine suchas triethylamine.
Ln another preparative example, a compound (I) in which Rs is an alkylsulfonamido gr~up is obtained by reacting an alkylsulfonyl halide with a compound (1~' in which R's is an amino group.
The compounds of fonnula (I)' in which R's is an amino group are also useful for the preparation of compounds in which this amino group is substitutedby a group (CH2)t-COR12. In this case, a compound of the formula Hal-(CH2~t-~ COOAlk, in which Hal is a halide, for example bromine, and Alk is a Cl-C4-21073 ~

alkyl, is rcacted with (I)~ in thc presenc~ of cuprous chloridc; if appropriate, the r~sulting cstcr is convertccl io thc acid or an amide. The reaction of a lactonc, such as butyrolactone or valcrolactonc, with a compoun~l (I)~ in which ~'5 is an amino can be used to pr~pare thc compound (I)' in which R'5 = NHCO~CH2)tCOzH, 5 whcre t = 2 or 3.
ln the same way, the compounds of formula ([) in which Rs is an amino grollp substituted by a group CH(R1o)CO2R1 1 are prepared by reacting a compound of the formula Hal-CH(Rlo)C02Rll with the corresponding compolmds (I)' in which the substituent R's is an amino.
A compound (13 in which R5 is an amino group substituted ~y an alkoxycarbonyl or a phenoxycarbonyl is prepared by reacting an alkyl or phenyl chlorofonnate with a compound (1~' in which the substituent R's is an amino.
A compound of formula ~1) in which Rs is a ureido is prepared by reacting ammonia with a compound of fonnula (I)' in which R'5 iS an amino ~oup substituted by a phenoxycarbonyl; a compound of fonnula (13 in which ~5 is N-phenylureido or N-alkylureido or N,N-dialkylureido in which the alkyl is C1-~4 is prepared by reacting an aniline or a C1-C4-monoalkylamine or -dialkylamine with such a compound of fonnula (I)'.
A compound (I) in which R5 is a carbamoyl which is unsubstituted or substituted by one or 2 alkyl groups is prepared by reacting an appropriate amine with a compound (1~' in which the substituent R'5 is an amino, in ~he presence of phosgene.
It is also possible to prepare a compound (I) in which Rs is an amino group substituted by an alkylcarbamoyl or by a phenylcarbamoyl by reacting an alkyl orphenyl isocyanate with a compound (1)' in which the substituent R's is an amino.Furthermore, a compound (I) in which Rs is a sul~amoyl ~oup which is unsubstituted or substituted by a Cl-C4-alkyl is prepared by reacting ammonia oran alkylamine with a compound (I~' in which R's is a halogenosul~onyl ~çroup.
The compounds of formula (I)' which are useful as precursors for the preparation of compounds of formuîa (1) are included in fonnula (1) aDd form part of the invention.
Among the compounds of formula (I), the compounds of formulae (IX), (X), (XI), (XII) and (XIII) below, which are useful for the preparation of other compounds of formula (1~, are preferred compounds according to the invention.
Thus one subject of the prcsent invention consists of the compounds of the formula 2~3~8 ~1 N

S~ (LX) s COOH

i~ which ~1~ R2, R3, R4 and Rs are defined as indicated above for (1), and theirfimctional derivatives such as their esters.
S Another subject of ~he present invention consists of the compounds of the formula R2 ~ O
- ~ S O 2 in which Rl, R2, R3, R4 and Rs are defined as indicated a~ove for ~I), and their10 salts where appropriate.
Yet ~other subject of the present invention consists of compoul~ds of tbe folmula .

~::

:~ :
:~ :

2 ~ O r j~ 3 !1 ~

R~ oR4 ~0~

~¦- R~;

OH
in which R~, R2,, R3, R4 and Rs are defimed as indicated above for (I).
Another sub~ect of the present invention consists of compounds of the S ~onnula \ ,'-'` ~ R

: S2 (XIl) ~,~--R5 (R6)m jD which R3, E24, Rs, R6 and m are de~med as indicated above for (I).
Yet another subject of the present invention consists of the compounds of the 10 fonnula :: : :

~3 ~7~

1~ 1 ~ ` Ni~l 2 ~Jr /~

S 0~ ~XIIl) ~R6~m in which R1~ R2, R5, R~ and m are defined as inclicated above for (1~.
The affinity of the compounds according to the invention for the vasopressin S receptors was determined in vitro by using the method d~ scribed in C.J. Lyllch et al., J. BioL Chem., 19.85, 260(5), 2B44-2851. This method consists in studyiDg the displacement of tritiated vasopressin bound to the Vl sites of rat liver memb~anes.
The concentr~tions of the compounds accarding to thc is~vention which inhibit the binding of tritiated vasopressin by 50% (ICso) are low, rangillg up to 10-7 M.
The affinity of the compounds (I) according to the invention for the V2 receptors was measured on a bovine kidney membrane preparation using a method adapted ~m P. Crause et al., Molecular and Cellular E~ndocrinolo~y, 1982, 28, 529-541, and ~om F.L. Stassen et al., J. Phannacol. Exp. ll~er., 1982, ~3, 50-54.
The compounds according to the invention inhibit the binding of tritiated arginine-vasopressi~ to the receptors of the membrane preparation. The ICs~
values of the compounds according to the invention are low, ranging up to 10-9 The activity of the compounds according to the invention as V2 receptor antagonists was demonstrated by the adenylate cyclase activity assay peronned by a method adapted from M. I~burthe et al., Molecular Pharmacol., 1986, 29, 23-27.A bovine kidney membrane preparation is used and each product is incubated ~or ~: 10 minutes at 37-C, by itself or in the presenee of AVP (arginine-vasopressin) at a concentration of 3.10-8 M. The cyclic AMP (çyclic adenosine monophosphate) produced is measured by radioimmunoassay. 7'he concentration which causes a 50~o inhibition (ICSo) of the stimulation of adenylate cyclase induced by 3.10-8:: M AVP is detenDined. The ICso values detennined are of the order of 10-7 M, rangirlg up to 10-8 M.

2~ ~10 7 3 !i 8 Thc activity of the ~ompo~lnds according to the in~cntion, administered orally, ~s V~ rcc~ptor agonists or antagonists is ~valuated in hypcrhydratcd rats (OFA strain, SpraKuc~ awlcy) trcated with vasoprcssin.
Lik~wis~, the affinity of th~ c~mpounds (I) according t~ thc invcnti~n for the S ocytocin rcceptors was dctcrmin~d in vitro by the displacemcnt of a radioiodinated ocytocin analog bound to thc r~ccptors of a gCSt~tiDg rat mamma~y gland membrane preparation, using a tcchnique similar to that described by J. lEland et al.
in Eur. 3. Pharmacol., 1987, 147, 197-207. The ICso values of the compounds according to the invention reach 10-8 M.
The compounds accûrding to the invention ar~ active aftsr 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 15 or prevention of Yarious vasopressin-dependent or ocytocin-dependent complaints, especially cardiovascular complaints such as hypertension, cardiac insufficiency or coronary vasospasm, in particular in smokers, cardiac ischemia,hemostatic disorders, especially hemophilia, and Vsn Willebrand's syndrome;
complaints of the central nervous system, for sxarnple cerebral edemas, depression, 20 anxiety, psychotic states and memory disorders; complaints of the renal system, such as renal vasospasm, necrosis of the renal co~tex, hyponatremia and hypokalemia; and complaints of the gastric system, such as hepatocirrhosis, ulcers, the pathology of vomiting, for ~xample nausea, travel siclcness or else the syndrome of inappropriate secretion of antidiuretic hormone (SIA.DH), diabetes 25 insipidus andl 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 dysmeno~hea or premature labor.
The present invention further relatcs to pharmaceutical compositions 30 containing an effective dose of a compound according to the invention, or of a phannaceuti~lly acceptable salt, and suitable excipients.
Said excipients are chosen according to the pharmaceutical fonn and the desired mode of administration.
~~ the pharmaceutical compositions of the present invention for oral, 35 sublingual, subcutaneous, intramuscular, intravenous, topical, intratracheal,mtranasal, transdermal or rectal administration, the active principles of fo~mula (I) ~J~73~8 abo~c, or thcir salts where appropnate, ccm bc administe~cc~ to animals and humans in unit forms of adlllinistr~tion, mixcd with c(~nvcntional pharmaccutical ~rriers, for thc prophylaxis or treatmcnt of the above clisordcrs or diseascs. Thc appropriate unit folms of administration include fonns for oral administration, such as tablets, S gela~in capsules, powders, granules and solutions or suspensions to be taken orally, forms for sublingual, buccal, intratracheal or in~ranasal administration, fonns fc~r subcutaneous, intramuscular or intravenous administration and for3ns ~or rectal administration. For topical application, the compounds accordin~s to the invention can be used in creams, ointments or lotions.
To obtain the desired prophylactic or therapeutic effect, thc dose of active principle can vary between 0.01 and 50 mg per kg of body weight per day.
Each unit dose can contain f~om a.s 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 adrninister a daily dosag~ of 0.5 to 5~0 mg, preferably 1 to 2500 mg.
If a solid composition in the ~orm of tablets is prepared, the main active ingredlent is mixed with a pharmaceutical vehicle such as gelatin, starch, lactose, magnesilJm stearate, talc, gum arabic or ~he like. The tablets can be coated with sucrose, a cellulose deriva~ive or other appropriate substances or they can be treated so as to have a prolonged or delayed actiYity and so as to release a predetennined amount of active principle continuously.
A preparation in the ~onn of gelatin capsules is obtained by mixing the active ingredient with a diluent and pouring the resulting mixture into soft or hard gelatin capsules.
A preparation in the fonn of a SyIup or elixir or for administration in the form of drops can contain the active ingredient in combination with a sweetener,which is preferably calorie-free, and methylparaben and propylparaben as antiseptics, as well as with a flavoring and an appropnate color.
Water-dispersible granules or powdels can contain the active ingredient mixed with dispersallts 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 pha~nacologically 2~ 073~8 compatiblc dispcrsants and~or wctting agcnts, for example ptopylene glycol or butyl~nc glycol.
Thc a~tivc principlc can also be fonnula~cd as microcapsules, if appropriate with one or more carriers or additives.
S Apart f~om the products of fonnula (I) above or one of the ph~ma~utically acceptable sal~s, the compositions of the present invention can contain other ac~ive principles which may be useful in the treatment of the disorde~s or diseases indicated above.
Thus the present invention fu~her relat~s to pharmaceutical compositions containing several active prineiples in association, one of which is a compound accoIding to the in~ention.
Thus, according to the present inv~ntion~ it is possible to prepare pharmaceutlcal compositions containing a compound which i5 a V1 ~eceptor antagonist in assaciation with a compound which acts on the renin angiotensin system, such as a converting enzyme inhibitor, an angiotensin ~ antagonist OT a renin inhibitor. They can also be associated for example with a periph~ral vasodilator or a calcium inhibitor. Such compositions will ~e uscful in paIticular in the treatment of hypertension or cardiac deficiency.

~0 Preparationof2- xQindoles Preparation 1:

4,6-Dimethyl-3-spirocyclohexaneindol-2-one This compound is prepared accordiDg to M~le and Plant in J. Chem. Soc., 1951, 3475.
A mixture containing 15 ml of quinoline and 10 g of calcium o~ide is refluxed under an ineIt atmosphere and S g of the 3,5-dimethylphenylhydrazide ofcyclohexanecarboxylic acid (Il, R'l~ R'2 = CH3, CR3R4 = cyclohexane) are added over 30 minutes. The reaction medium is cooled and then poured into an ice/~ydrochloric acid mixture. Extraction is carried out with ethyl acetate and the extract is washed with nolmal hydrochlolic acid and with water until the washings are neutral, and then dried and concentrated under vacuum to gi~e a brown solid.Trituration in iso ether gives the expected cornpound.
M.p. = 223-C.
3S The indol-2-one delivatives desclibed in Table 1 below are obtained by following the same procedure and varying the starting hydrazide.

.

~7 2~L073~8 Thesc compounds arc purificd by chromatography on a silica column using DCM as thc cluent or hy chromatography on an alumina column using DCM or iso cttlcr as thc clucnt.

S TABLE I

r-- ll4 ~ _ . ~ ~
R'1 R'2C~3~4 M p. C
_ ~ ~.

5-CI Hcyclobutane 191 5-CI Hcyclopentane 189 S-CI Hcyclohexane 186 H Hcyclohexane 123 124 5-CH3 Hcyclohexane 164 S-CE130 Hcyclohexane 226 6-CI Hcyclohexane 16$
CF30 Hcyclohexane 164 Hcyclohexane __160 Preparation 2:
10The 3-spirocyclohexaneindol-2-one described in Table 1 above can also be obtained by aikylation of the indol-2-one using the method described below.
A soiution of 30 g of indol-Z-one in 900 ml of THF is kept at -40-C under a nitrogen atmosphere and 1û1 g of potassium tert-butylate are addcd. The tempe-rature is allowed to rise to O-C over 1 hour, the mixture is then cooled to -60-C
15and a solution of 52 g of 1,5-dibromopentane in 50 ml of THF is added dropwise.
~fter 30 minutes at -60C, 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 mi of DCM and ~no ml of water, the insoluble materialis thcn filtered off and the organic phase is separated off, washed with 100 ml of 20 water, dried over magnesium sulfate and evaporatcd under vacuum. The residue is .~ ~
~:

' '' 2~ 2:L~73~8 chromatographccl on silica using a cyclohcYanc/ethcr rnixturc as thc clucnt to give thc cxpectc~ compound, which is rccrystallizcd from heptallc.
m=34g.
M.p. = 1~3-~24'C.
S A similar procedure can be applied star~ing from other indol-2-ones and other alkylating agents.
By way of example, among the starting compounds of fonnula (VII), S
chloroindoi-2--one is described by Bright in j. ~n. ~hem. Soc., 1~56, 79, 221, and by RajanE~abu in J. Org. Chem., 1986, 51, 1704. 4-Chloroindol-2-s~ne can be prepared from 2-chloro-6-nitrotoluene by the method desc~bed in J. Am. Chem.
Soc., 1956, 78, 221.
S-Methoxyindol-2-one is prepared from 4-rnethoxyaniline by the method described in J. Am. Chem. Soc., 1974, 96, 5512. ~ the same way, various indol-2-ones are prepared from the appropriate aniline derivative.
Preparatjon 3:
S-Ethoxyindol-2-one A - 3-Thiornethyl-5-ethoxyindol-2-one 23.6 g slf ethyl thiomethylacetate in 6() 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 S
minutes at the same temperature, a solution of 4-ethoxyanilin~ ~48.3 g) in 120 ml of DCM is added. The mixture is stirred for one hour at about 70C, 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 over magnesium sul~ate and evaporated under reduced pressure. llle residue is takerl up in S00 ml of isopropano~ and 2û 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 filtlate is concentrated under reduced pressure to ~; give the expected product.
B - S-Ethoxyindol-2-one Ihe above solid, in 1500 ml of ethanol, is dethiomethylated in the presence of 100 g of Raney nickel ~80 to 100 m2 per g), under reflux, for 3 hours, under a ;` ~ nitrogen atmosphere. The mixture is filtered on talc, the mateIial on the filter is rinsed with lM00 ml of ethanol and the filtrate is concentrated under reduced 3S pressure. 16 g of the expected product are isolated after recrystaliization from toluene.
' '9 2~7~

M.p. = lS6'C.
Thc following arc isolcltcd in thc samc manner star~ing from ~he corrcsponding anilillcs:
S-bcnzyloxyindol-2-onc m.p. - 152-C
S S-n-propylindol-2-onc m.p. = 136-C
S-eshylindol-2-one m.p. = 152-C
5-(2,2,2-trifluoroethoxy)indol-2-one m.p. = 145-C
The compounds of fonnula (Il) describrd below are obtained by following the technique described in Preparation ~ and varying the starting indol-2~one 10 derivative and the alkylating reagent.

R'~ L R (II) H
: 15 ~ ~ -. _ ~: : R~1 R~2 CR3R4 M.p C Alkylating reagent ~ . . .. _ , .
: S-CI E [cyclohexane 186-189Br~CH2)s Br S-CI Hcycloheptane 202Br(CH2)6Br 5-Cl H4,4-dimethyl 180TSo(cH2)2c(cH3)2 cyclohexane -(CH2)2oTs S-CI : H2-hexahydroindane 223 cis~1,2-diiodomethylcyclohexane ~ S-CH30 H4,4-dimethyl 202TsO (CH2)2C(CH3)2-: : cyclohexane -(CH2)2-oTs : : 5-Cl H~-indane 228a,a'-dibromomethyl :: : ~ : orthoxylene :S-CI H` C(CH3)7 160 CH3I
S-CI HC(CH ~CH3)2 156 CH3CH2I
:: S-CI HC(n Pr) ~ 158 nPrI
S-CI HC(iBu~ ~ 164 iBuI

.

.

2~073~8 S-CI HN-mcthyl-4- 260Cl(CEI232N(CH3?-pipcridine -(CH2) S-CI H4-tctrahydro - 2231(CH2)20~CH2)2 pyrannc 4-Cl Hcyclohexane 215Br(CH2)sBr S-BzO Hcyclohcxane 162Br(CE~2)5B~

H HC(CH2C6Hs)2 206C6HsCE~2Br 5-CI HC(n-pentyl3~ 142CH3(cH2)~Br 5-Cl H2,3-dihydro _ phenalene-2 ~/J\~
5-13zO H4,4-dimethyl 1$4TsO(CH2 )2C(CH3)2-cyclohexane (~H2)2OTs 5-CI H4-spirocyclopent~ne 202 ~ (CH2)2OTs cyclohexane (~2~2OTs 5-nPr Hcyclohexane 151Bl(CH2~5Br 5-EtO HN-tBu-4- _/ (CH2)2Br . . ...................... tBu~ \
: plpendme (CH2)2Br 5-CI HN-Bz-4- 165/ (CH2)2Br piperidine Bz ~
(CH2)2Br S-CI HN-phenyl-4- 188 / ( ~: ~ pipendine (CH2)2cl S-CI H\C ~ l 300~ CH20S02CH

~ ~ :
S~EtO H4,4-diethy5 132TSo(cH2)2c(c2H5)2 I : cyclohexane -(CH2)2oTs ~;~ : S-EtO Hcyclohexane 163Br(CH2)sBr 5 -EtO H4,4-dimethyl 17~TSo(cH2)2c(cH3)2 cyclohexane -(CH2)2oTs 31 21073~

~-EsO ~l cycl~h~pt~ne 139 13r(CH?)~r S-Et }I ~,4-clirncthyl I fi()TsO(CH2)2~(CH3)2~
cyclohcx~nc -(~H2)~0Ts 5-CF3CH~0- ~1 4,4--~in~cthyl 164 ditto cyclohexane H H 4,4-dilllcthyl 169 di~to cyclohcxane _ _ ~_ ____ E~e~:
3-Spiroadamantaneindol-2-one This compound is prepared according to 1. Fleming et al., Tetrahedron S Letters, 198'', ?053-''056, from 2-bromoaniline and adamantan-2-one.

Preparation 5:
5-Chloto- 3,3-diphenylindol-?-one This compound is prepared by the method described in Helv. (:him. Acta, 1946, 79, 41S-431, by the reaction of benzene with 5-chloroisatin in the presence of aluminum chloride.
M.p. = 281-C.

S-Nitro-3-spirocyclohexaneindol-2-one This compound is prepared by the method described in J. Am. Chem. Soc., 1945, 67~ 499, by the nitration of 3-spirocyclohexaneindol-2-one.
M.p. = 19?-C.
5-Nitro-3-spiroadamantaneindol-2-one is prepared in the same manner starting from 3-spiroadamantaneindol-2-one.
M.p. > 260''C.
5-I~itro-3-spiro(4,4-dimethyl)cyclohexaneindol-2-one is also prepared.
M.p. = 195C.
::
_reparation 7:
S-Amino-3-spirocyclohexaneindol-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-one, prepared abovc.

3~ 21~3~

~ p.- 17~5C~.
5-Amino-3- spiroadamantanc is prcparccl in ~hc samc rmanner.
~.p. = 245-C.

S Preparaeion 8:
S-Fiuoro-3-spirocyclohexaneindol-2-one A - S-~iazonium-3-spirocyclohexaneindol-2-onP tetrafluoroborate A solution containing 4 g of S-amino-3-spirocyelohexaneindol-2~one in 9.2 ml of 6 N hydrochloric acid is cooled ~o O-C and 2.27 g of sodium nitrite in 2.6 ml of water are added, fi~llowed by 2.54 g of sodium tetrafluoroborate in 9 ml of water. After stirring for S minutes, the precipitate is filtered off and washed with a 5% solution of tetrafluoroborate, with 3 ml of methanol cnoled to about 0-C and then with S ml of ether. The salt obtained is dried under vacuum at RT in the presence of phosphorus pentoxide.
lS
B- S-Fluoro-3~spirocyclohexaneindol-~-one 1 g of the compound obtai~led in s~ep 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 filtrate. After filtration, the solvent is evaporated off under reduced pressure ~o give 0.45 g of the expected compound, which is recrystallized from pentane.
~.p.= 114~

Preparation 9:
S-~yano-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 15-C and 4.15 g of the diazonium salt obtained in step A of the previous preparation are added.
After stirnng for 30 minutes at RT, 100 ml of water and 100 ml of ether are added and the organic phase is then separated off, dried over magnesium sulfate and evaporaeed under reduced pressure. The residue is chromatographed on silica using a cyclohexas~e/ether mixture as the eluent to give the expected compound~
which is recrystallized from heptane.
rn = 1.4 g.
~I.p. = 216-C.

33 21Q73~8 Prc~p~j~
S--Chloro-3-spiroacl~n~antanein(lol--~-onc 1 g of the p-chlorophenylhy~rclzidc of adamantanc-2-carboxylic acid is dissolvcd ancl 2.5 ml of a solution of n-buty!lithium (1.6 M in hexane) are added at 5 -40DC. After stirring for S minutes, the mixture is concentratcd under vacuum with the temperature bcing kep~ below 3()^C. 30 ml of 1,2,3,4-tetramethylbcnzene are added and ~he mixture is refluxed for 1 hour. It is concentrated under reduced pressure, the residlle is taken up in normal hydrochloric acid, extraction is carried ou~ with ether and the extract ;s washed, dried ansl conccntsated under vacuum.
10 The oil obtained is chromatographed on a silica column using l)CM as the eluent to give û.3 g of the expected product in the fonn of a wax, which is crystallized from iso ether.
M.p. = ~49~C.

Pre~aration 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 35 25 ml of 1,2-dichloroethane. The mixture is refluxed for 2 hours, the solvent isevaporated off under reduced pressure and the medium is hydrolyzed with 50 g of ice and e~tracted with ethyl acetate.
The organic phase is washed with water, dried over magnesium sulfate and then evaporated under reduced pressure. The residue is chrornatographed 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. = 192-C.
The benzenesulfonyl chlorides described in the Table below were prepared using the procedure described.

:~

3~
2:~07~

~Z

~,J
Y R~,~
_ Y RV M.p. C
, . ~ . _ O CH2CO2Et 89 O (CH-2)3Br Starting from the various 2-oxoindoles described above and appropriate : S benzenesulfonyl chlorides, the compounds according to the invention were prepared using the procedures reported in the Examples below.

EXAMPL~ 1 S-Chloro-1-(2-methoxy-4-nitrobenzenesulfonyl)-3-spirocyclohexaneindol-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 30 minutes. 0.7 g of 2-metboxy-4-nitrobenzenesulfonyl chloride is introduced and stirsing is maintained at RT for 20 hou~s. The mixture is concentrated under 15: ~ ~ vacuum, the residue is taken up in 30 ml of water, extraction is calIied 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 ~om iso ether.
M.p. = 18~-C.

20 ~ ~ E~AMPLE2 1-(4-Amino-2-methoxybenzenesulfonyl)-5-chloro-3-:: spirocyclohexaneindol-2-one ~ ~.

3s ~ 3 ~ ~

0.8 g of thc compouncl obtaincd in thc prrvious Exarnplc is reduccd with hydrogcn un(lcr normal prcssurc at RT for 20 hours in 10 ml of acetic acid, in the prescncc of 30 mg of platinum oxide. The rcaction medium is filtcred, thc filtrate is conccntratcd, thc residuc is takcn up in a watcr/ethyl acetatc mixture and the S organic phas~ is washed with water, dned and concentrated. Thc yellow foam obtained is chromatographed on alumina using DCM as the eluent to give 0.2 g of the expected product.
M.p. = 173-C.

S-Chloro- 1-[4-(2-methylphenylcarboxamido~-2-methoxybenzenesulfonyl]-3-spi~cyclohexaneindol-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 orthotollloyl chloride 15 is stirred at RT for 48 hours. It is concentrated undcr vacuum, the residue is taken up in a water/ether mixture and le~t 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 as the eluent to give ().1 g of the expected product :~ 20 M.p. = 192-C.

6-Chloro-1-(2,4-dimethoxybenzenesulfonyl)-3-spirocyclohexaneindol-2-one A mixtuIe 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 undernitrogen; 0.15 g of ~,4-dimethoxybenzenesulfonyl chloride is introduced and stsning is maintained at RT for 20 hou~s. The mixture is concentrated under vacuum, the residue is taken up in 30 ml of water and extracted with ethyl acetate 30 and the extract is washed with water, dried and concentrated under ~acuum. Ihe product obtained is recrystallized from iso ether.
M.p. = 147-C.

EXA~PLE 5 Acid fumarate of S-chloro-1-[4-(3-dimethylaminopropoxy)benzenesulfonyll-3-spirocyclohexaneindol-2~one 36 21~73 A) 4-(3-Bromopropoxy)bcnzcncsulfonyl chloridc A mixturc containing 23 g of sodiLIm 4-hydroxybcnzcncsulfonate dihydratc, 7 g of potassi~lm hydroxidc pcll~ts (85%), 30 ml of watcr, 50 ml of absolute cthanol, ~0 g of l,3-dibromopropanc alld 3.4 g of t~trabutylammoslium S hyclrogensulfatc is rcfluxed fi)r 3 hours. Thc reaction medium is concentratcdunder vacuum, taken up in cthanol and concentrated once again. Thc residue is taken up in hot mcthanoi. The insoluble material is filtFred of~, thc filtrate is conc~ntrated and the residue is triturated in ether to give 22.5 g of a white solid.
120 ml of phosphoms oxychloride and 16 g of phosphorus pentachloride are added 10 to this solid and the mixture is stirred for 20 hours at RT and then refluxed ~or 1 hour. The reaction medium is concentrated under vacuum, the residuc is then taken up in an etherlwater mixture and the organic phase is decanted and washed with asaturated solution of sodium hydrogencarbonate. After drying and concentration, the expected product is obtained in the ~onn o~ a yellow oil.
B) 1-~4-(3-Bromopropoxy)berlzenesulfonyl]-5-chloro-3-spirocyclohexaneindol -2-one A mixture containing 1.2 g of S-chloro-3-spirocyclohexaneindol-2-one and 0.16 g of sodium hydride in 6 ml of TlHEi is stirred at RT for 30 minutes under 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 fonn of an oil, which crystallizes from iso ether.
~n=lg.
M.p. = 123-C.

~; C) Acid fumarate of S-chloro-1-[4-~3-30 dimethylaminopropoxy)benzenesulfonyl]-3-spirocyclohexaneindol-2-one A mixture containing O.S g of the product obtained in the aboYe step, O.S g of potassium iodide and 20 ml of a 33% solution of dimethylamine in methanol is stirred at RT for 20 hours. The reaction medium is concent~ated and taken up in 10 ml of water and, after trituration, the insoluble material is separated off and treated 35 with 10 ml of 3 N hydrochloric acid. A gum is formed which is dissolved in 30 ml of wann water, and the solution is filtered on paper and then rendered alkaline by 2~073~

thc addi~ion of 1 N sodium hydroxide. Thc insolub3c matcrial is cxtractcd with cthcr and the cxtract is washcd, (Iricd an(l thcn conccn~ratcd to give a yellow oil.
This is dissolvecl in 10 ml of acctonc, and 0.1 g of fumaric acid is ild(iccl to thc hot SOlUtiOII.
S The expected product precipitatcs at 20-C.
m = 240 mg.
M.p. = 16BC.

5-Chloro-1-(2,4-dimethoxybenzenesulfQrlyl)-3-spiroadamalltaneindol-2-one A mixh3re containing 0.2 g of 5-chloro-3-spiroadamantaneindol-2-one and 20 mg of sodium hydnde in 3 ml of THF is stirred for 30 minutes at RT under a nitrogen atmospllere. 0.18 g of 2,4~dimethoxybenzenesulfonyl chloride is addedand 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 etherand the extract is washed with water, dried and concentrated urlder vacuum The wax obtained crystallizes from 15 ml of iso ether.
m=240mg.
M.p. = 152-154-C.

5-Chloro-1-(2,4-dimethoxybenzenesulfonyl)-3-spirocycloheptaneindol-2- one A solution containing 0.156 g of potassium tert-butylate and 0 33 g of 5-chloro-3-spirocycloheptaneindol-2-one in lS ml of THF is cooled to -40-C un-der an inert atmosphere. The temperature is allowed to rise to about 10-C over 1hour, the solution is then cooled to about -40-C, a solution of 0.335 g of 2,4-di-methoxybenzenesulfonyl chloride in 15 ml of THF is added dropwise and the 3 0 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. I~e organic phase is separated off, washed with 15 ml of water, dried over magnesiumsulfate and evaporated under vacuum. The oil obtained is evaporated under va-cuum using a cyclohexane/DCM mixture as the eluent to give the expected com-pound, which recrystallizes from heptane.

m - 0.51 g.
M.p. = 13S-C.

E~CAMPLB 8 2,4-Dimethoxy-1-benzenesulfonyl-2a-methyl-2a,3,4,5-tetrahydrobenz[c, d]indol-2-one (I: R1 = H, -R2-R3 = -(CH2)3-, R4 = CH3, R5 = R6 = OCH3~
2a,3,4,5-Te~rahydrobenz[c,d]indol-2-ollc 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 mllû of anhydrous ~F is prepared.
The temperature is allowed to rise to about ()-C, the solution is then cooled to-60C and a solution of 0.57 g of msthyl iodide in 20 ml of THF is added; the medium is maintained at -10C for 30 minutes, with stirring, and then cooled to about -40-C and a solution of 0.96 g of 2,4-dimethoxybenzenesulfonyl chloride in10 ml of THF is added. After stirnng 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 mlof water; the organic phase is scp~rated off and then dried over magnesium sulfate and evaporated. The oil obtained is purified by chromatog~aphy on silica using acyclohexane/DCM mixture as the eluent to give the expected product, which is recrystallized from a cyclohexane/AcOEt mix~ure (9S/S; v/v).
M.p. = 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.

R~ r f R4 R2~ O

b ~
(R6)m :, 21~73~8 Unless indicated othcrwise in thc Table bclow (~), R2 = H ancl m - 1 ~ _ _ _._.~m ~ _ ~_ ~__ Ex. Rl CR3~4 R5 (~6)m M.p. ~C
~ _~ _ ~
9 S-CI C(C6Hs)2 3-MeO 4~ eO 178 10 5-N02 cyclohexane 3-MeO 4-MeO 157 11 S-CI cyclohexane 4-MeO H 112 12 S-CI C(CH3)2 3-MeO 4-MeO 110 13 5-NH2 cyclohexane 3-MeO 4-MeO 171 14 S-CN cyclohexane 2-MeO 4-MeO 148 S-CI cyclohexane 4-MeO2,3,6-triMe 188 6 S-CI C(Pr)2 2-MeO 4-MeO 186 : 17 S-CI indane-2 2-MeO 4-MeO 182 18 5-CI C(iBu)2 2-MeO 4-MeO 184 19 5-CI N-rncthyl 2-MeO 4-MeO 142 plperidlne-4 : ~ 20 S-CI C(Et)2 2-MeO 4-MeO 190 2t S-F cyclohexane 2-MeO 4-MeO 149 22 5-CI 4-tetrahydro 2-MeO 4-MeO 142 pyranne 23 S-CI 4,4-dimethyl 2-~leO 4-MeO 118 cyclohexane `:

: :

2~ 073~
'~() 24 S-CI2-heYahy~lro 2 -McO 4-McO 89 25 4 -CIcyclohc,Y.Illc 2-~fcO 4-McO 150 26 5-CIcyclohcxane 3-MeO 4-MeO 152 27 5-CIcyclohcxane 4-Me ff 150 28 Hcyclohexa~e 3-MeO 4-MeO 107 29 5-Mecyclohexane 3-MeO 4-MeO 171 30 S-MeOcyclohexane 3-Me t) 4-MeO 124 31 S-CIcyclohexane 2-MeO 4-MeO 149 32 5-CIcyclohexane 4-CI H 154 33 S-CIcyclobutane 3-MeO 4-MeO 111 34 5-CIcyclopentane 3-MeO 4-MeO lO6 5-CIcyclohexane 4-MeO 2-CI 174 36 S-CIcyclohexane 4-N02 H 172 37 S-CIcyclohexane 4-CN H 198 38 5-CIcyclohexane 4-MeO 2-N02 147 39 S-CIcyclohexane 4-CF3 H 139 5-CIcyclohexane 4-CF30 H 134 41 5-CIcyclohexane 4-MeO 2-NH2 150 41 ~1~73~3 42 ~-CE13 cyclohcxane 4-MeO 2-McO 165 ~ R~ fi-43 S-CI cyclohexanc 3-Mc 4-BzO 127 44 S-CI cyclohexane 4-iPr 2,6-iPr 172 S-CI cyclohexane 2-CF3 H 154 46 S-CI cyclohexane 2-MeO CH~ C}13 215 47 S-CI cyclohexane 4-MeO /~co~ 193 4B S-CI cyclohexane 2 MeO 4-CE~3OCO 120 49 S-CI c~ 2-MeO 4-MeO 184 H adamantane 2-MeO 4~MeO 172 51S-MeO 4,4-dimethyl2-MeO 4-MeO 152 cyclohexane 52 5-CI cyclohexane2-MeO 4-CH3SO2NH 131 S3 S-CI cyclohexane2-MeO ~ ~ 240 ~CONH

54 5-CI cyclohexane2-Me S-F lS3 S5 S-CI cyclohexane2CC23O-5-CF3CH2O 175 56 S-CI cyclohexane2-MeO /~N~Co 218 C~13 ' "' .

2~07~8 ~2 57 5-CIcyclohexane 2-MeO /~ ~ ~o 165 `~
58 5-CI cyclohcxane S-soH22_2,4-~li MeO 270 595-BzOcyclohcxalle 2-MeO 4- MeO 15~

60S-BzO 4,4-dimethyl 2-MeO 4-MeO 142 cyclohexane 61 5-CI cyclohexane 2-MeO cll3o~c 192 o 62 5-CI cyclohexane 2-MeOC}~3 N~JN -~ 158 64 H C(CH2C6~5)2 3-MeO 4-MeO 146 655-CH3COcyc!ohexane 3-MeO 4-MeO 122 66 S-CI C(n-pentyl)2 2-MeO 4-MeO 140 67 5-CI C(CH2C6H5)2 2-MeO 4-MeO 185 685-H2N cyclohexane 2-MeO 4-MeO 230 69 5-CI 4-spirocyclo- 2-MeO 4-MeO 154 : pentane 70 5-CI cyclohexane 2-MeO 5-MeO 116 ~715-nPrcyclohexane 2-MeO 4-MeO 138 72S-EtO N-tBu-4- 2-MeO 4-MeO 95 pipendino (o22s) 73 5-CI N-Bz-4- 2-MeO 4-MeO 76 ~:~ pipel~dine (0 5 ~3 21073~

74 5-CIN-phcnyl-~- 2-McC) 4-McO 163 piperidinc S-CI~yclohcxanc 2-EtO 4-EtO :123 76 S-CI ~ C ~ 2-Me(:) 4-McO 190 77 S-EtO4,4-diethyl 2-McO 4-MeO 129 cyclohexanc 78 5-Etocycloheptane 2-MeO 4~MeO 130 79 5-EtOcyclohexane 2-MeO 4-MeO 134 8û S-EtO4,4-dimethyl 2-MeC) 4-MeO 160 cyclohexane 81 5-Et4,4-dimethyl 2-MeO 4-MeO 166 cyclohexane : : :
82 S-EtO4,4-dimetbyl 2-MeO 4-NC)2 110 cyclohexane ~;:
~: 83 S-EtO4,4-dimethyl 2-MeO 4-NH2 230 ~: cyclohexane : :
: : 84 5-NO24~4-dimethyl 2-MeO 4-MeO 102 : cyclohexane :85 5-NH24,4-dimethyl 2-MeO 4-MeO lB0 cyclohexane ~ :
~ 86 ~; 5-4,4-dimethyl 2-MeO 4-MeO 169 1~ CF~CH~Ocyclohexane _ __ ,, . . ., _ 21 073 ~8 ~s~

1-(2,~~Dinlctho,Yybcllzcllcxulfonyl)- 3-(4,4-~imcthylspirocyciohc;~sane)-5-hydro~yindol-2-onc 3.51 g of thc cs)mpollnd prcparcd in Examplc 60 are stirrctl at 50C for 1 S hour, under a hydrogcn atmospherc, with 0.5 g of 10% pall~dium-oll-charcoal in150 ml of cthanol. The catalyst is filtered off on talc, the material on the filter i5 rinsed with DCM and the filtrate is evaporated undcr reduced pressure to give 2.8 g of the expected eompound, which is recrystallized from a cyclohexane/AcOEt mixture ~90/1û; v/v).
M.p. = 22û-C.

1 -(2,4-Dimethoxybenzenesulfonyl)-5-hydroxy-3-spirocyclohexaneindol-2-one is prepared in the same manner starting from the S-benzyloxy derivative 15 described in Example 59.
M.p. = L96-C.

EXAMPLE 80 bis (2,4-Dimethoxybenzenesulfonyl)-3 -(4,4 -dirnethylspir~cyclohexane~-5-20 ethoxyindol-2-one This compound, already describèd in Example 80, can be prepared by another methorl starting from the homologous 5-hydroxy compound. 0.6 g of the compound prepared in Example 87 is sti~red at RT for 16 hou~s, 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 30 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 ~om cyclohexane.
M.p. = 160-C.
The compounds described in Table 4 below are prepared in the same manner.

:

.

21073~3 rAst E 4 s }:~ _ R5 R6 M.p.'C
. _ _ .
89 S-nPrO cyclohexane 2-MeO 4-MeO 139 S-nPrO 4,4-dimethyl 2-MeO 4-MeO 158 ; cyclohexane 91 5 iPrO 4,4-dimethyl 2-MeO 4-MeO 154 cyclohexane _ ~ . cyclohexane 2-MeO 4-McO 155 - :

5-Acetoxy- 1 -(2,4-dimethoxybenzenesulfonyl)-3-spirocyclohexaneindol-2-one 0.5 g of the compound prepa~d in Example 88, 2.5 ml of isopropenyl acetate 10 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. Afler 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 sùl~ate and concentrats~d under reduced pressure. 0.51 g of the expected compound, containing 0.5 mol of cyclohexane, is isolated by 15 crysiallization from a cyclohcxane/ethyl ace~ate mixture.

:::
~ .

46 21073~

M.p. = 116-C.

EXAMPLE 9~
1 -~2,4-Dimethoxybf~nzcncsulfonyl)-5-(2-hydroxyethoxy~-3-spirocyclohcxaneindol~2-onc 0.5 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 arc heated at about 7QC ~or 40 hours. After cooling, 10 ml of water and 15 rnl of ethyl acetate are added and the organic phase is decantsd, washed with wa~er, dried over magnesium sulfate and concentrated wlder reduced pressure. The oily residue is chromatographed on a silica column using a cyGlohexane/AcOEt mixture (70/30;
v/v) as the eluent to give 0.5 g of ~he expected product, which is recrystallized from a heptane/DCM mixture.
M.p. = 170-C.
lS

5-(2-Dimethylaminoethoxy)-1-(2,4-dimethoxybenzenesulfonyl)-3-spirocyclohexaneindol-2-one 0.6 g of the compound prepared in Example 88 is heated at about 40-C for 16 hours, under an inert atmosphere, with 0.32 g of N,N-dimethyl(2-chloroethylamine~ and 1.76 g of cesium carbonate in 7.2 ml s)f acetone and 2.4 ml j ~ of DMF. lhe 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 (9/1; v/v) as the eluent to give 0.6 g of the expected product, which is recrystallized f~om a cyclohexane/iso ether mi~ture.
M.p. = 122~C.

5-Chloro-1-(2,4-dimethoxybenzenesulfonyl)-3-~spiropiperidine-4)indol-2-one This reaction is perfonned according to J. Org. Chem., 1984, 49, 2795-2799.
0.75 g of 1-chloroethyl chlorofonnate is added at 0-C to a solution of 1.31 g of the compound descnbed in Example 73 and 0.32 g of 1,8-bis-dimethylaminonaphthalene in 22 ml of 1,2-dichloroethane. The mixture is . .

L~ 7 2 ~ 4 refluxcd for about ~0 n~inutcs ancl conc~ntratcd undcr rcducc~l prcssurc to a volume of about 10 ml, and ~2 nll of mcthanol arc ~hen adclcd. Aftcr rcfluxing for 50 minutes, thc rcaction mcclium is conccntrat~d unclcr rcduccd pressure and theresidllc is chromatographcd Oll a silica column using a 13CM/MeO~I mixture (95/5;
S v/v) as the cluent. 1.16 g of the expccted product arc isolatecl and recrystallized from a mixturc of cyclohcxane anci ethyl acetate M.p. = 172-C.

3~ Acetylspiropiperidine-4)-S-chloro-1-(2,4-dimethoxybenzenesulfonyl)indol-2-one 0.086 ml of acetyl chloride is a;dded to a solution, cooled to about 0'C, of 0.35 g of the compound prepared in the previous Example and 0.23 ml of triethylamine in S ml of DCM. The mixture is st~rred for one hour at 20-C, 5 ml o 15 water are added, the organic phase is decanted, washed with water, dried overmagnesium sulfate and concentra~ed 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 fonn of the hemihydrate.
M.p. = 107-C.

5-Chloro-1-(2,4-dimethoxybenzenesulfonyl)-3-(N-methoxycarbonylspiropiperidine -4)indol -2-one ~is compound is prepared from the one obtained in F,xample 96 by reaction with methyl chloroformate.
M.p. = 147-C.

~XAMPLE 99 1-(3,4-Dimethoxybenzenesulfonyl)-5-propionamido-3-spirocyclohexaneindol-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 35 at 20GC, 20 ml of water are then added and the organic phase is decanted, washed with water, driod over magnesium sulfate and concentrated under r~duced 48 2~73~8 pressure. 0.5 ~ of thc e:~pectecl produet is isolate(l after reerystalliz~tion from a hcptan~/AeOE~t mi;Yture (95/5; v/v).
M.p. = 158-C.

S E~5AMPLE 100 I -(3~4-Oimethoxybenzencsulfollyl)-S-~N-mcthylllrcido)-3-spirocyclohcxaneirldol-2-one 0.15 g of methyl isocyanate is added to a solution, cooled to about O~C, of 0.5 g of the compound described in Example 13 in lO ml of DCM. After stirring 10 for about 16 hours at Rr, 20 ml of water are added and the organic phase is decanted, washed with watcr, dried over magnesium sulfa~e 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 descnbed in the following Example is prepared in the same manner.

(3,4-Dimethoxybenzenesulfonyl)-S-(N-phenylur~ido)-3-20 spirocyclohexaneindol-2-one M.p. = 124~C.
:

5-Dimethylamino-1-(2~4-dimethoxyben7enesulfonyl)-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 10 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~, the 30 solvent is evapora~ed 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 o~er 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 3s (80!20; v/v) as the eluent. 0.27 g of the expected product is isolated.
M.p. = 167-C.

21073~8 ~9 1-( ,4-l)imethoxybcnzcncsulfonyl)-5-cthylthio-3-spirocyclohcxaneindol-2-onc This compo~lnd is p~ep~red according to J. Chem. Soc., Chem. Commun., 1980, 16, 756. A mixturc of 2.95 g of diethyl disulfide ancl 0.386 g o~ isopcntyl nitnte is heated to about 80~C, under an inert atmosphcrc, and 0.8 g of the compound prepared in Example 68 is added. The medium is stirred for one hour at ~O-C and then concentrated under reduced pressure. The residue is chromatographed on a silica column using a DCM/cyclohexane mixture (80/20;
lQ v/v) as the eluent. Ihe expected product is isolated after crystallization from cyclohexane.
M.p. = 123-C.

5-Chloro-l-f4-(dimethylamillomethylcarboxamido)-2-methoxybenzenesul~onyl]~3-spirocyclohexaneindol-2-one A) S-Chloro~1-[4-(chloromethylcarboxamido)-2-methoxybenzcnesulfonyl] -3-spirocyclohexaneindol-2-one 0.2 g of thç compound prepared in Example 2 is placed in 4 ml of DCM
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 con-~entrate is ` extracted with ethyl acetate~ the extract is washed with water and a solution of sodium carbonate and the residue is thcn chromatographed on silica using a mixture of DCM and AcOEt as the eluent to give 0.15 g of the expected product.
B) S-hloro-1-[4-(dimethylaminomethylcarboxamido)-2-methoxybenzenesul~onyl]-3-spirocyclohexaneindol-2-one The compound obtained in the previous step (150 mg) is stirred at RT for 20 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 chIomato~raphed on silica using AcOEt as the eluent to give 0.025 g of the expected product.
; M.p. = 173-C.
~, ~

. - .

21 0 rl 3 ~ g s(~

I- ~4-(4--Sulfamoylphcnylcarbo,Yamido)-2-mcthoxybellzcncsul~nyl] -5-chloro-3-spirocyclohcxaneindol -2-one 4-Chlorosul~nylbcnzoyl chloridc is prepared according to Chem. Ber., 1~41, 271.
0.2 g of thc compound prepared in Example 2 is brought into contact with 0.5 g of TEA in 5 ml of DCM; 0.13 g of 4-chlorosulfonyibenzoyl chlorid~ is added and the mi~sture is stirred for 20 hou~ at RT. It is concen~rated under vacuum, the concentrate is taken up in THF, and 10 ml of aquf~-ous ammonia are added. Stirring is continued for a fur~her ~0 hours at RT and the mixture is concentrated under vacuum. ~he residue is extracted with ether and the extract is washed with water, dried over sodium sulfate and then chromatographed on silica using AcOEt ~s the eluent to give the expected product.
M.p. - 238-242~C after recrystallization from AcOEt.

1-[4-(3-Sulfamoylphenylcarboxamido)-2-methoxybellzenesulfonyl~-5-chloro-3-spirocyclohexaneindol-2-one A) 3-Chlorosulfonylbenzoyl cllloride 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, ~he mixture is distilled to give 1 g of thé expected product.
B.p. = 120-125-C under 0.5 mm Hg.
; 25 B) 1-[4-(3-Sulfamoylphenylcarboxamido)-2-methoxybenzenesulfonyl]-5-chloro-3-spiIocyclohexaneindol -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 evaporat d 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 dAven offunder vacuum and the residue is then taken up in AcOEt and water. Extraction is carried out with AcOEt and the ex~ract 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.

~:
, .

5, 2:3 07~

p. = 176~.

l-[4-(2-Carboxyphc1lylcarboxamiclo)-~-methoxybenzenesulf'onyl~~S-S chloro-3-spirocyclohexaneindol-2-one The preparation is carricd out aceording to J. Hetcrocycl. Chem., 1974, 997-100û.
A mixture containing 0.2 g of the compound prepared in Lxample 2, with 0.5 ml of TEA and 160 mg of phthalic anhydride is stirred at 60-C for 3 hours. It is concentrated under vacuum and trsated 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 e~hcr and recrystallized ~om iso ether to give the expected product.
m=O.lSOg, M.p. = 157-158-C.

EXAMPLE lU8 1-[4-(Benzyloxymethylcarboxamido~-~-methoxybenzenesulfonyl]-S-chloro-3-spirocyclohexaneindol-2-one This compound is prepared by the procedure described in Example 3 by reacting bènzyloxyacetyl chloride with the compound prepared in Example 2.
M.p. = 143~C after recrystallizativn from iso ether.

5-Chloro-1-[4-(hydroxymethylcarboxamido)-2-methoxybenzenesulfonyl]-3-spirocyclohexaneindol-2-one This compound is obtained by hydrogenating the compound prepared in 3 0 ~ the previous Example, under the pressure of a water column, in the presence of 5%
palladium-on-charcoal in an EtOH/AcOEt mixture.
M.p. = 202~C.

5-Chloro-1-[4-(imidazol-l-ylphenylcarboxamido)-2-methoxybenzenesulfonyl]-3-spi~cyclopentaneindol-2-one , . .

5~ 2~73~8 A) Ethyl cstcr of ~-(imidazol~ yl)hcnzoic acid A mixturc containing 35 ~ of 4-fluorob~nzoyl chlori~c in S() ml of lr)O
cth~nol is rcfluxcd for IS rninutcs. 35 g of thc cthyl cst~r of 4-fluorob~nzoic acid obtaincd are mixcd with 22 g of imidazolc and 61 g of potassium carbonate in 35 S ml of DMSO. Thc rnixture is heatcd for 18 hours at 120-130C and SOO ml of iccd water are then addcd. A prccipitat~ fo~s and the cxpccted product crystallizes fiom iso ether.
M.p. ~ 98-C.

lQ B) Lmidazol-1-ylbenzoyl chloride S 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 hydrochlonc acid. The precipitate ~ormed is filtered of~ and then washed with iso ether. S g of the acid obtained are brought to the reflux temperature in 35 ml of thionyl chloride. Theprecipitate formed is filtered off and then washed with iso ether to give the expected acid chloride.
M.p. = 243-C.

C) S-Chloro-1-[4-(imidazol-1-ylphenylcarboxamido)-2-methoxybenzenesulfonyl]-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 stcp B in 10 ml of DCM and 1.S ml of TEA is stirred at RT for 1 h and then refluxed ~or 3 hours. The reaction medium is extracted with DCM and then washed with water and an aqueous solution of sodium hydroxide. After evaporation of the solvents, the residue is c~romatographed on silica using a DCM/ methanol mixture as the eluent. I~e expected product is recrystalli7ed from iso ether.
m=O.OlOg.
M.p. = 14S-C.

S-Chloro-1-[2-methoxy-4-(phenoxycarboxamido)benzenesulfonyl]-3-spirocyclohexaneindol-2-one This compound is prepared by reacting phenyl chloroformate with the ~ ~ compound prepared in Example 2.
:~:

53 2 1 ~

M.p. = 2()9-C aftcr recrystallization from iso cthcr.

EX~MPLE 112 S-Chloro-1-[4-(N-methylur~ido)-2-m~thoxybenzencsulfonyll-3-5 spi~ocyclohexaneindol-2-one 140 ~g of th~ compouncl obtained in ~he prcvious Examplc arc mixed with ~` S ml of ethanol, S ml of DCM an~l S ml of a 33% solution of methylamine in ethanol. After one hour at RT, the solvents arc driven off and the residue is tben chromatographed on silica using a I)CM/MeOH mixture as the ellJent. Thc product obtained is recrystallized f~om iso ether.
M.p. = 254C.

EXAMPLE~ 113 S-Chloro-1-(2-methoxy-4-ureidobenzenesulfonyl)-3-spirocyclohexaneindol-2-one A mixture containing 200 mg of the compound prepared in Example 111 with S 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 thesolvents, the expected product is crystallized ~om iso ether.
M.p. = 228-C.

lEXAMPLE 114 S-Chloro-1-[4-(N-o-tolylureido)-2-methoxy]-3-spirocyclohexaneindol-2-one A mixture containing 250 mg of the compound prepared in Example 2, 10 ml of xylene and 80 mg of orthotoluyl isocyanate is refluxed for 18 hours. A white precipitate fonns 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.

Benzyl 4-(5-methoxy-2-oxo-3-spirocyclohexaneindol-1-yl)sulfonyl-3-methoxybenzoate 5~ 2~73`1~

6() nlg of so~lium hy~ri(lc ~rc poured in small portions into ;~ mixtur~
containing 500 mg of 3-spirocyclohcx~nc-5 mcthocyindol-2-onc in 5() ml o~
THF. Aflcr 30 minutcs a~ RT, 8()0 mg of b~nzyl 3-mcthoxy-4-chlorosulfonyl-benzoatc chloride arc added and the nlixture is stirrcd for 2 hours at RT. Tbe S mcdium is concen~ratcd and taken up in AcOEt and the mixturc is washcd with water, dned over sodium sulfate and concentratcd. The resi(lue is chromatographed on silica using DCM as thc elucnt.
NM~ (at 250 M[Hz in DMSO):
l.2-1.8 ppm: 10H: cyclohe~yl 3.6 ppm and 3.8 ppm: 2 x 3H: 2 x VCH3 5.4 ppm: 2H: CO2-CH2-C6Hs 6.8-8.2 ppm: 11H: aromatic protons E~AMPLE 116 4-(3-Spiroeyclohexane-5-methoxy-2-oxoindol-1-yl)sulfonyl-3-methoxybenzoic 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 presencc of 140 mg of palladium-on-charcoal to give 310 mg of the expected acid, which is recrystallized from a hexane/ ~thanol mixture (70/30; v/v).
M.p. - 210-C.

5-Chloro-1-[4-(N-(ethoxycarbonylmethyl)carbamoyl)-2-me~hoxy]-3-spirocyclohexaneindol-2-one 450 mg of ethyl glycinate hydrochloride in 20 mg of sodium methylate are placed in methanol. 200 mg of the compound described in Example 60 in Sû ml of DCM are added and the mixture is stirred at RT for 48 hours. It is cxtracted with DCM and the extract is washed with water, dried, concentrated and then chlomatographed on silica using DCM/MeOH (99.5/0.5; v/v) as the eluent.
M.p. = 164-C.

1 -(4-Carbamoyl-2-methoxybenzenesulfonyl)-5-chloro-3-spirocyclohexaDeindol-2-one ;

5~ 2 lO73~1g 30() m~ ot the compound dcscribcd in E~xample G0 arc mixed with 5 ml of 30% aqucous ammonia, 10 ml of cthanol and 10 ml of DCM. Aftcr 1 hour at RT, thc mixture is conc~ntr~tcd ~md cxtsact~l with DCM and the cxtract is washed with water, dned, concentra~ed an(l thcn chromatographed on silica USillg DCM/McOH
(99/1; v/v) as the eluent to givc 109 mg of thc cxpectcd product.
M.p. = 160~C.

5-Chloro-1-[2-methoxy-4-(N-(2~methoxycarbonylethyl~carbamoyl)~-3-spirocyclohexaneindol-2-one A mixture comprising 320 mg of the compound described in Example 60 and 2 g of methyl aminobispropionate in 3û 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 residue is chromatographed on silica using DCh~eOH (99/1; v/v~ as the eluent to give 100 mg of the expected product.
M.p. = 147-C.

1-[4-(3-(N-Boc)aminoazetidin-1-ylcarbonyl)-2-methoxybenzenesulfonyl]-S-chloro-3-spirocyclohexaneindol-2-one A mixture containing 300 mg of the compound prepared in E~sample 60, 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 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 chrornatography on silica using DCM/MeOH (99/1; v/v) as the eluent.
M.p. = 136-C.

1-[4-(3-Aminoazetidin-1-ylcarbonyl~-2-methoxybenzenesulfonyl]-5-chloro-3-spirocyclohexaneindol-2-one A~mlxture containing 160 mg of the compound prepared in the previous xample and 3 ml of TFA in 10 ml of DCM is stirred for 31) minutes at RT. The 35 ~ ~ reaction medium is concentrated and crystallized from iso ether and the crystals are flltered off~and dried. The product obtained is dissolved in 10 ml of water and then .: .
: :

~6 21~7~

I() ml o~ I N sodillm hyclro,~ide; thc SOIutiOll iS c~tractcd with DCM ansJ thc c.l~tract is washcd with wcltcr, clric(l ovcr so(iium sulfatc and concelltratccl. Thc cxpcct~i product is obt~nllccl aftcr chrom~tography Oll silica using DCM/McOH
(96/4; v/v) as the clucnt.
S M.p.- 14SC.

S-Fthoxy-1-[4-(3-dimethylaminopropoxy)-3-methoxybenzenesulfonyl~-3-spirocyclohexaneindol-2-one hydrochloride A) S-Ethoxy-1-[4-(3-hromopropoxy)-3-methoxybenzellesulfonyl~-3-spirocyclohexaneindol-2-one A mixture containing 0.5 g of S-ethoxy-3-spirocyelohexaneindol~2 one, S ml of THF and 0.07 g of sodium hydride is stirred at 20'3C for lS minutes, 1.65 g of 4-(3-bromopropoxy)-3-methoxybenzenesulfonyl chloride are then added and ~he resulting mixture is stirred for 20 hours at Rl'. It is concentrated under vacuullI
and exsracted with etheF and ~he extract is washed with wa~er and then a 10%
solution of sedium carbonate. The expected product crystallizes from pentane andis then r~crystallized from iso eth~r.
M.p. = 114-118~C.
B) S-Ethoxy-1-[4-(3-dimethylaminopIopoxy)-3-methoxybenzenesulfonyl~-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 2S 3 hours, the mixture is concentrated under vacuum and taken up in 1() ml of water and the resulting mixture is extracted with ether. The ether phase is treated with 20 ml of 2 N hydrochloric acid, after which solid potassium carbonate is added to render the solution alkaline to pH 9. The oil whieh precipitates is extracted with DCM. The expected product crystallizes from ether.
M.p. = 135~138-C.

EXAMPL~ 123 1-[4-Aminosulfonamido-2-methoxybenzenesulfony]-S-ehloro-3-spirocyclohexaneindol-2-one 0.3 g of the compound prepared in Example 2 is placed in 4 ml of DCM in the presence of O.S g of TEA, and 0.3 g of aminosulfonyl chloride, prepared 21073~

accordin~ to Chem. Ber.~ 1958, 91~ 1339-1341~ is a(ldcd. Aftcr stirring for 2 days at RT, the mcdium is conccntnatcd undcr vacuum and cxtracted with ether and the c~ract is washed with watcr. After drying, thc rcsidue is chromatographcd on silica using DCM alld thcn AcOFt as thc clucnt to give thc cxpccted product~
S which crystallizes from ethcr.
M.p. = 205-208C.

E~fAMPLES 124 and 125 1 -(4-Dimethylamino-2-methoxybenzenesulfonyl)-5-methoxy-3-10 spirocyclohexalleindol-2-one and 1-(4-methylamino-2-metho~ybenzenesulfonyl)-5-methoxy-3-spirocyclohexaneindol-2-one 50~ mg of 1-(4-amino-2-methoxybenzenesulfonyl)-5-methoxy-3-spirocyclohexaneindol-2-one are mixed with 1 ml o~ a 37% aqueous solution of formaldehyde, 10 ml of ace~onitrile and 430 mg of sodiunn cyanoborohyd~ide, and 15 û.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 fonnaldehyde, 300 mg of sodium cyanoborohydride and 0.12 rnl of acetic acid are added to the medium. The mlxture is stilred for 1 and a half hours, poured into iced water and then extracted 20 with AcOFt. ~e extract is washed with water, dried and roncelltrated to give 2 products, which are separated by chromatography on silica using DCM/AcOEt (98i2; Viv) as the eluent.
M.p. = 210-C (Ex. 124).
M.p. = 170-C (Ex. 125).
:~ TABLE 5 S 2 (I) :
~ R6 :

, . ~ .

5~ 2~073~8 Unless indicatcd othcrwis~, th~ substitucnt R6 is in thc 4-position ~n~l m = 1.
... _.. _ ~ ,, Ex R1 R2 R5 R6 M.p. C
~ . . ~ . .
126 Cl H 2-MeO~N--~ 210 127 Cl H 2-MeOMeO~CON 192 2-MeO /~ CON~I -12~ Cl H ~CF3 188 129 Cl H 2-MeO/<~CONH - 146 ;~ OMe ; 130 Cl H 2--MeO /~CH2CONH 190 Me 131 Cl H 2--MeO /~-CONH- 147 132 Cl H 2-MeOCH3CONH- 230 2--MeO Me 33 ~ Cl H ~/~ CONN- ~S

134 Cl H 2-MeOHO2C(CH2)2- 2ûS
CONH-:
: :

S~ 2~073~

135 Cl H H ~ ~ ~ 180 137 ~Cl H~ 2-MeO ~ C~N~-138 MeO H2-MeO /~MCONH- 245 139 MGO H2-MeO ~CONII-140 Cl H~ 2-MGO I /~CON~

141 Cl H2-MeO Me~ 140 142 Cl H2-MeO Me ~CONH 225 MGO H2 MeO ~lGocH2coNH- 161 144 ~MeO H2-MeO tBuCH2CONH- 209 ' ~,o 21~73 ~3 145 1 ~tO ~ 2-M~0 <~ CON~- 223 Me 146 EtO H 2-MeO Mc \ 136 , N~fl2CONH

147 Cl H 2-MeO Me \ 226 / N-CONH-Me 148 CH30 H 2-MeO Me \ 190 / N-CONH-: ~ 149 EtO H 2-MeO Me \ 192 / N-CC)NH
Me 150 EtO H 2-MeC) Me ~ 160 Et/ N-C~NH-151 EtO H 2-MeO N-CONH- 168 : Et /
~: 152 EtO H 2-MeQ Me \ 137 : : ~ / N-CONH-, Pr :~ : 153 Cl H 2-MeO /~\ 157 MeCONH \ N~

:154~: Cl ~ H 2-MeO \ N~CH2)2-NHC 163 : ~ Me i55 Cl H 2-MeO Me\ 192 ~ .
::~: :: ~ :
:

::~ ` ~ :

, fi' 21 ~73 ~ ~

156 Cl H 2-McO M~N so 231 157 Cl H 2-McO H ~.06 158 Cl H 2-MeO /~ 226 Me -N\ JN -S 2 ~

159 Cl H 2-M[eO Bz' 117 160 MeO H 2-MeO 2~- 188 161 Cl H 2-MeO BzOCO- NMR

162 ~ Cl H ~ 2-MeO ~ ~Nl~CO~

163 MeO H 2-MeO NH2- 188 164 MeO H 2-MeO MeO- 172 165 MeO H 2-MeO /~o-CO- 162 166 ~ McO H 2-McO ~NHCO 198 167 EtO H 2-MeO ~I2N- 177 168 ~ MeO ~6-MeO 2-MeO MeO- lB3 6~ 21~73~8 169 EtO H 2-McO /\r~- NHCO- 15() = Mc 170 EtO H 2-MeO BzOCO- 135 171 EtO H 2-MeO HOOC- NMR

172 3EtO H 2-MeO MeNHCO~ 239 173 EtO H 2-MeO S-MeO 131 174 EtO H 3-MeO MeO- 127 175 EtO H 2-MeO / 167 Me 176 EtO H 3-MeO 4,5-di-MeC) 130 177 EtO H 2-P~eO\/r \~ NHco- 195 ~e 178 EtC) H 2--MeO/~\~cH2 NHCO 168 179 EtO H 2-MeO N20 160 180 EtO H 2-Me MeO 176 181 EtO H 3-McOCH2=cH-cH2o- 130 182 CF30 H 2-MeO MeO 127 ::

~)3 21Q73~8 183 EIO ~ 2 MCO M~; 171 CHN H CO
184 EtO H 2~MCO EtOCOCH~NHCO 203 185 EtO H 2-MCO /~O~O-NH- 181 186 EtO H 2 MeO 4 5-d;-MCO 136 187 EtO H 2 Me 4-MeO 5-Cl 188 EtO H 2-MCO B~ N NHCO- 188 189 EtO H 2 M~O HO(C~2)2-NHCO 157 190 EtO H 2- H

MeOCO
191 EtO H 2-MeO Me\ 212 N~CH2)3~ -~; ~ HCl 192 EtO H 2-MeO '~lLcoNH-193 EtO H MeO- Et \

CH~ONH-Et 194 EtO H 2-MeO BzOCOCH2NHCO
NMR
l 95 ~M

.

fi~ ~lO~f3~8 196 EtO H 2-MeO ~>~.OCO- 152 197 EtO H 2-McO Et / N~O 148 198 EtO H 2-MeO \ N~S 128 199 EtO H 2-MeO CN CH2NH-CO- 232 200 EtO H 2-MeO EtO2C~H2~O NMR

201 EtO H 2-l!~eO H02C-C~I2NH-CO- 137 202 Cl H 2-MeO ~Et)2N-CO-NH 194 203 EtO H 2-MeO C}CONH- 214 204 EtO H 2-MeO H2N(CH2)3O- 136-140 205 EtO ~ 2-MeO~H3)3N(CH2)3o- 145-~50 206 C6HsO H 2-MeO 4-MeO 130 : 207 E~O H 2-MeO O- CS~H- 210 ; ~ ~ 208 DO H 2-McO `CH CON- 138 :

~: :

fiS 21073~

Thc NMR spectra arc run in DMSO at 200 MHz.

NMR of Examplc 161:
1.3-1.8 ppm: 10H: cyclohexyl 3.5 ppm: 3H: OCH3 5.3 ppm: 2H: O-cH2-c6Hs 7.2-8.2 ppm: 1 lH: aromatic proeons NMR of Example 171:
1.15 ppm: 3H: CH3 1~19-2 ppm: 10H: cyclohexyl 3.6 ppm: 3H: OCH3 4 ppm: 2H; OCH2-CH3 6.7-8.2 ppm: 6H: aromatic protons ;

NMR of Example 200:
2.2 ppm: 16H: cyclohexyl + 2CH3 3 ppm: 3H: NCE~3 4-4.4 ppm: 6H: aromatic prots3ns 6.8-8.2 ppm: 6H: aromatic protons A resolution of the signals is observed; this is associated with the amide : : isomerism.
EXAMPLF 21() 1-(4-Benzyloxy-2-methoxybenzençsulfonyl)-5-ethoxy-3-:spirocyclohexaneindol-2-one A) Potassium 4-benzyloxy-2 methoxybenzenesulfonate 3U This preparation is carried out according to K. Ho~ann et al., Liebigs Ann.
Chem., 1982, 282-297.
10.5 g of 4-benzyloxy-2-methoxybenzene are mixed at 5-C with 30 ml of DCM, and 8 ml of tnmethylsilyl chlorosulfonate in 30 ml of DCM are added over 15 minutes at a temperahlre between 5 and 10~C; after stirring for 15 minutes, 50 g ; :
-~ .

()6 2 1 ~ 7 J !l ~

of icc are a(ldcd. Thc mixtllrc is washed with ethyl cthcr, treated with potassium hy(lrogcllcarbollatc ~nd thCIl conccntr~tc(l un(ler vacuum. After dryillg, the rcsidue is takcn up in lS0 ml of mcthanol. Thc insolublc matcrial is filtercd off ~t thc boil and the c~pecte~l compound thcn crystallizes at 5-C.
M.p. ~ 300-C.
The st~ucture of thc compound is con~irmed by analysis of the NMR
spectrum.

B) 4-Benzyloxy-2-methoxybenzellesulfonyl chloridc 2.8 g of the compound prepared in the previous Example are mixed with 30 ml of POCl3 and the mixture is r~fluxed for 3 bours. It is concentrated under vacuum, treated with 20 g of ice and extracted with ethyl ether and the extract is washed with 30 ml of N sodium hydroxide and then water. The medium is concentrated and the oil obtained is then triturated in 30 ml of iso ether. The expected product (0.7 g) crystallizes.
M.p.=95~C.

C) 1-(4-Benzyloxy-2-methoxybenzenesulfonyl)-5-ethoxy-3-spirocyclohexaneindol-2-one l'his compound is prepared by the usual procedure. It crystallizes from iso ether.
M.p. = 135-C.
~e structure of the compound is verified by analysis of the NMR spectmm in 2 dimensions (NOESY: Nuclear Overhauser lEf~ect Spectroscopy).
The compound of the next Example is subsequently prepared by debenzylation.

5-Ethoxy-1 -(4-hydroxy-2-methoxybenzenesulfonyl)-3-spirocyclohexaneindol-2-one M.p. = 209-C.

Claims

1. A compound of the formula (I) in which - R1 and R2 are each independently a hydrogen, a hydroxy, a C1-C4-.omega.-halogenoalkoxy, a halogen, a C1-C4-alkyl, a trifluoromethyl, a C1-C7-alkoxy, a C1-C4-polyhalogenoalkoxy, a C2-C4-.omega.-hydroxyalkoxy, an .omega.-methoxyalkoxy in which the alkyl is C2-C4, a C2-C4-.omega.-aminoalkoxy which is free or substituted by one or two C1-C4-alkyls, a C3-C7-cycloalkoxy; a cycloalkylmethoxy in which the cycloalkyl is C3-C7; a phenoxy; a benzyloxy;
a C1-C4-alkylthio; a phenylthio; a nitro; an amino which is free or substituted by one or two C1-C4-alkyls; a cyano; a C1-C4-acyl; a C1-C4-acyloxy; a C1-C4-alkylsulfonamido; a phenylsulfonamido; a C1-C4-alkylamido; a C1-C4-alkoxycarbonylamino; a ureido which is unsubstituted or substituted by a phenyl or by one or two C1-C4-alkyls;
- R3 and R4 are each independently a C1-C6-alkyl, a C3-C7-cycloalkyl, a phenyl, a benzyl, a cycloalkylmethyl in which the cycloalkyl is C3-C7;
or - R3 and R4 together form a group -(CH2)pX(CH2)q-;
or - R3 and R4, together with the carbon to which they are bonded, form an optionally fused, saturated or unsaturated C3-C10 hydrocarbon ring which is unsubstituted or substituted by one or more C1-C7-alkyl groups or by a C3-C5-spirocycloalkyl;
or else - R1 and R4 each have one of the meanings indicated above and R2 is located in the 4-position of the indole and forms a group (CH2)3 with R3;
- R5 and R6 arc each independently a hydrogen, a halogen, a C1-C7-alkyl, a trifluoromethyl, a cyano, a nitro, an amino which is free or substituted by one or two C1-C7-alkyls; a hydroxyamino; a hydroxy; a carboxy; a group OR7; a group SR7; a C1-C7-acyl; a C1-C7-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 C1-C7-alkyls; a sulfamoyl, an alkylsulfamoyl or dialkylsulfamoyl in which the alkyl is C1-C7;
a group SO2R'7; an alkylsulfonamido in which the alkyl is C1-C7; a group COR'7; a group NR8R9 or a group CO-NH-CH(R10)-COR12; if appropriate, the phenyl group forming part of the substituent R5 and/or R6 can be unsubstituted or monosubstituted or polysubstituted by a C1-C7-alkyl, a trifluoromethyl, a methoxy, a halogen, a sulfamoyl, an alkylsulfamoyl in which the alkyl is C1-C7, a carboxy, an alkoxycarbonyl in which the alkyl is C1-C7, a C1-C7-acyloxy or an imidazolyl;
- R'6 and R"6 are each independently hydrogen, a C1-C7-alkyl which is unsubstituted or substituted by R'''6, a phenyl, a pyridyl, a methylpyridyl, a piperidin-4-yl or a methylpiperidin-4-yl; or R'6 and R"6 form, with the nitrogen atom to which they are bonded, a heterocycle selected from piperazine or piperidine;
- 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 C1-C7-alkyls;
- R7 is a C1-C7-alkyl, a phenyl, a benzyl, a C3-C7-cycloalkyl, a C2-C4-alkenyl, a C1-C7-.omega.-halogenoalkyl, a C1-C7-polyhalogenoalkyl, a C1-C7-acyl, a C1-C7-.omega.-carboxyalkyl which is free or esterified by a C1-C4-alkyl or by a benzyl, a C2-C7-.omega.-aminoalkyl in which the amino group is free, substituted by one or two C1-C4-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 C1-C4-alkyl, a phenyl, a benzyl or a C1-C4-acyl;
- R'''7 is R"7 or an amino which is free or carries a protecting group;

- R8 and R9 are each independently a hydrogen, a C1-C7-alkyl, a phenyl or a benzyl; R9 canl also be a C1-C7-acyl, a C1-C7-thioalkyl, a cycloalkylcarbonyl in which the cycloalkyl is C3-C7, a cycloalkylthiocarbonyl in which the cycloalkyl is C3-C7, a C1-C4-.omega.-aminoacyl, a C1-C4-.omega.-hydroxyacyl, a C1-C4-.omega.-benzyloxyacyl, a phenoxycarbonyl, a thienocarbonyl, a pyridylcarbonyl, a methylpyridylcarbonyl, a C1-C4-alkoxycarbonyl, a benzoyl, a group CO-CH(R10)-NR11R'11, a group CH(R10)CO2R11, a group (CH2)tCOR12, a group CO(CH2)tCOR12, a carbamoyl which is unsubstituted or substituted by a phenyl or by one or two C1-C4 alkyls;
- m is 1 or, if R6 is a halogen, a C1-C7-alkyl or a C1-C7-alkoxy, m can also b 2, 3 or 4, or else (R6)m can be m substituents having different meanings selected from halogen, C1-C7-alkyl and C1-C7-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 5;
- X is oxygen, sulfur or a group NR13;
- R10 is hydrogen, a C1-C4-alkyl or a benzyl;
- R11 and R'11 are each independently hydrogen or a C1-C4-alkyl;
- R12 is a hydroxy, a C1-C4-alkoxy or an amino which is unsubstituted or substituted by one or two C1-C4-alkyls;
- R13 is hydrogen, a C1-C4-alkyl, a phenyl, a benzyl, a C1-C4-acyl, a C1-C4-alkoxycarbonyl or a carbamoyl which is unsubstituted or substituted by one or two C1-C4-alkyls;
and its salts where appropriate.
2. A compound of formula (I) according to claim 1 wherein R1 is a chlorine atom or an ethoxy group in the 5-position of the indole and R2 is hydrogen.
3. A compound of formula (I) according to claim 1 wherein R3 and R4, togetber with the carbon to which they are bonded, form a C3-C10 hydrocarbon ring.
4. A compound of formula (I) according to claim 1 wherein R3 and R4, together with the carbon to which they are bonded, form a cyclohexane which is unsubstituted or substituted by one or two C1-C7-alkyl groups or by a C3-C5-spirocycloalkyl, a cycloheptane, an adamantane or a tricyclo[5.2.1.02.6]dec-8-ene.
5. compound of fnrmula (I) wherein R3 and R4, together with the carbon to which they are bonded, form a piperidine-4 or N-methylpiperidine-4 ring.

6. A compound of formula (I) according to claim 1 wherein R5 and R6 are each a methoxy.
7. A compound of formula (I) according to claim 1 wherein R5 in the 2-position is a methoxy and R6 in the 4-position is a C1-C7-acylamino, a C1-C4-dialkylureido or an alkoxycarbonylalkylcarbamoyl in which the alkyl groups are C1-C7.
8. A compound of formula (I) according to claim 1 wherein R1 is in the 5-position and R2 is hydrogen.
9. A compound according to claim 1 of the formula (IX) in which R1, R2, R3, R4 and R5 are defined as indicated above for (1) in claim 1, and its functional derivatives.
10. A compound according to claim 1 of the formula (X) in which R1, R2, R3, R4 and R5 as defined as indicated above for (1) in claim 1,and its salts where appropriate.
11. A compound according to claim 1 of the formula (XI) in which R1, R2, R3, R4 and R5 are defined as indicated above for (I) in claim 1.
12. A compound according to claim 1 of the formula (XII) in which R3, R4, R5, R6 and m are defined as indicated above for (I) in claim 1.13. A compound according to claim 1 of the formula (XIII) in which R1, R2, R5, R6 and m are defined as indicated above for (1) in claim 1.14. A method of preparing a compound (I) according to claim 1, characterized in that:
a benzenesulfonyl halide of the formula (III) in which R'5 and RVI are respectively either R5 and R6 as defined above for (I), or precursor groups of R5 and R6, is reacted with a 2-oxoindole disubstituted in the 3-position, of the formula (II) in which R'1 and R'2 are respectively either R1 and R2 as defined for (I), or precursor groups of R1 and R2, and R3 and R4 are as defined above for (I); and - either, if R'1 = R1, R'2 = R2, R'5 = R5 and RVI = R6, the resulting compound of formula (I) is isolated;
- or, if any one of the groups R'1, R'2, R'5 and RVI is respectively a precursor group of R1, R2, R5 and/or R6, the compound obtained is subjected to a subsequent treatment in order to prepare the compound of formula (I) by conversion of any one of the groups R'1, R'2, R'5 and RVI to R1, R2, R5 and R6 respectively.
15. A compound of the formula (II)' in which - R1 and R2 are each independently a hydrogen, a hydroxy, a C1-C4-.omega.-halogenoalkoxy, a halogen, a C1-C4-alkyl, a trifluoromethyl, a C1-C7-alkoxy, a C1-C4-polyhalogenoalkoxy, a C2-C4-.omega.-hydroxyalkoxy, an .omega.-methoxyalkoxy in which the alkyl is C2-C4, a C2-C4-.omega.-aminoalkoxy which is free or substituted by one or two C1-C4-alkyls, a C3-C7-cycloalkoxy, a cycloalkylmethoxy in which the cycloalkyl is C3-C7, a phenoxy, a benzyloxy, a C1-C4-alkylthio, a phenylthio, a nitro, an amino which is free or substituted by one or two C1-C4-alkyls, a cyano, a C1-C4-acyl, a C1-C4-acyloxy, a C1-C4-alkylsulfonamido, a phenylsulfonamido, a C1-C4-alkylamido, a C1-C4-alkoxycarbonylamino or a ureido which is unsubstituted or substituted by a phenyl or by one or two C1-C4-alkyls; and - R3 and R4, 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 C1-C7-alkyl groups, a tricyclo[5.2.1.02.6]decane or a tricyclo[5.2.1.02.6]dec-8-ene which are unsubstituted or substituted by one or more C1-C7-alkyl groups, or a C4-C8 hydrocarbon ring substituted by one or more C1-C7-alkyl groups or by a C3-C5-spirocycloalkyl; or else - R3 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 NR13, R13 being a phenyl, a benzyl, a C1-C4-acyl, a C1-C4-alkoxycarbonyl or a carbamoyl which is unsubstituted or substituted by one or two C1-C4-alkyls, with the limitation that if CR3R4 is adamantane, R1 and R2 are other than hydrogen.
16. A compound of the formula (II)"

in which - R1 is a hydroxy, a C1-C4-.omega.-halogenoalkoxy, a halogen, a C1-C4-alkyl, a trifluoromethyl, a C1-C7-alkoxy, a C1-C4-polyhalogenoalkoxy, a C2-C4--hydroxyalkoxy, an .omega.-methoxyalkoxy in which the alkyl is C2-C4, a C2-C4-.omega.-aminoalkoxy which is free or substituted by one or two C1-C4-alkyls, a C3-C7-cycloalkoxy, a cycloalkylmethoxy in which the cycloalkyl is C3-C7, a phenoxy, a benzyloxy, a C1-C4-alkylthio, a phenylthio, a nitro, an amino which is free or substituted by one or two C1-C4-alkyls, a cyano, a C1-C4-acyl, a C1-C4-acyloxy, a C1-C4-alkylsulfonamido, a phenylsulfonamido, a C1-C4-alkylamido, a C1-C4-alkoxycarbonylamino or a ureido which is unsubstituted or substituted by a phenyl or by one or two C1-C4-alkyls;
- R3 and R4 together form a group -(CH2)pX(CH2)q-;
or - R3 and R4, together with the carbon to which they are bonded, form an optionally fused, saturated or unsaturated C3-C10 hydrocarbon ring which is unsubstituted or substituted by one or more C1-C7-alkyl groups or by a C3-C5-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 NR13; and - R13 is hydrogen, a C1-C4-alkyl, a phenyl, a benzyl, a C1-C4-acyl, a C1-C4-alkoxycarbonyl or a carbamoyl which is unsubstituted or substituted by one or two C1-C4-alkyls, with the limitation that - if R1 is methoxy, CR3R4 is other than a pyrrolidine-3 which is unsubstituted or N-substituted by a C1-C4-alkyl, and if R1 is a halogen, CR3R4 is other than a pentane.
17. A compound according to claim 16 in which R1 is ethoxy.

18. A compound of the formula (III)' in which - Alk is a C1-C7-alkyl;
- Y is O or S; and - RV is a C1-C7-alkyl, a C3-C7-cycloalkyl, a C2-C4-alkenyl, a C1-C7-.omega.-halogenoalkyl, a C1-C7-polyhalogenoalkyl, a benzyl, a C1-C7-acyl or a C1-C7-.omega.-carboxyalkyl esterified by a C1-C4-alkyl or by a benzyl.
19. Pharmaceutical composition in which a compound according to any one of claims 1 to 8 is present as the active principle.
20. Pharmaceutical composition in which a compound according to any one of claims 1 to 8 is present in association with another active principle.