NO180538B - N-sulfonyl-2-oxoindole derivatives having affinity for vasopressin and / or ocytocin receptors, pharmaceutical compositions containing them and intermediates in the preparation of the derivatives - Google Patents

Abstract

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

Description

The present invention relates to N-sulfonyl-2-oxo-indole derivatives, pharmaceutical mixtures containing them, optionally together with another active principle, and intermediate products in their preparation.

International patent application WO 91/01 306 describes 2-oxoindbl derivatives which can be used for the treatment of senile dementia. These compounds have the formula

where

R''i is hydrogen, a halogen, an alkyl or an alkoxy; R'' 2 is hydrogen or a lower alkyl;

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

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

Several patent applications have recently described families of compounds with a non-peptide structure that are active on the vasopressin and/or oxytocin receptors. European applications EP 382 185 and EP 444 945, international application WO 91/05 549, and more specifically, Japanese patent application JP 03/-127732, can be mentioned in this connection. The latter describes indole-3-propionic acid derivatives with the formula:

where

R'''i is hydrogen, an alkyl, an alkenyl, a phenylalkyl,

a tetrahydrofuryl, an alkoxycarbonyl, an alkoxycarbonylalkyl, a carboxyalkyl or an alkanoyl;

R'''2 is hydrogen, a hydroxyl, an alkoxy, an alkyl, a

phenylalkyl, a phenylalkoxy or a halogen,-

R' <1> '3 is a hydrogen, an alkoxy, a free or substituted amino group or an amino acid residue;

R'' '4 is hydrogen, an alkyl or a phenylalkyl; and

R'''s is a benzoyl, a phenyl, an alkyl, a phenylalkenylcarbonyl, a thienylcarbonyl, a phenylsulfonyl, a pyridylcarbonyl or an imidazolylcarbonyl, where it is possible that the phenyl and alkyl groups of the substituent R'''s

may be substituted.

These compounds are vasopressin antagonists.

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

where R is H or Cl.

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

Vasopressin is a hormone known for its antidiuretic effect and its effect in regulating arterial pressure. It stimulates several types of receptors, namely vi(via" vib) °9 V2" and thus has cardiovascular, hepatic, antidiuretic and platelet-aggregating effects and effects on the central and peripheral nervous system. Vasopressin receptor antagonists can affect the regulation of the central and peripheral circulations, especially the coronary, renal and gastric circulations, as well as the regulation of hydration and the release of adrenocorticotropic hormone (ACTH). Non-peptide vasopressin agonists may advantageously replace vasopressin or its analogs in the treatment of diabetes insipidus; they can also be used in the treatment of enuresis and in the regulation of hemostasis; treatment of hemophilia and of Von Willebrand's syndrome, antidotes to platelet aggregating agents; Drug Investigation, 1990, 2. (suppl. 5), 1-47. The vasopressin receptors, like the oxytocin receptors, are also found on the smooth muscle of the uterus. Ocytocin has a peptide structure similar to that of vasopressin. Its receptors are also found on myoepithelial cells in the mammary gland and in the central nervous system (Presse médicale, 1987, 1£ (10), 481-485, J. Lab. Clin. Med., 1989, 114 (6), 617-632, and Pharmacol. Rev., 1991, 43 (1), 73-108). This hormone is involved in childbirth, milk secretion and sexual behaviour.

The compounds according to this invention can thus be used in particular in the treatment of ailments in the central and peripheral nervous system, the cardiovascular system, in the kidney region and the stomach region, and in disorders of sexual behavior in humans and animals.

The present invention relates to compounds with the formulas

where

R x and R 2 are both independently hydrogen, hydroxy, C 1 -C 6 -halo alkoxy, halogen, C 1 -C 4 -alkyl, trifluoromethyl, C 1 -C 1 -alkoxy, C 1 -C -polyhalo alkoxy, C 2 -C 4 -co hydroxy alkoxy , (j-methoxyalkoxy where the alkyl is C2-C4, C2-C4-<g>>-aminoalkoxy which is free or substituted with one or two C^-C^-alkyls; C3-C7-cycloalkoxy,- cycloalkylmethoxy where the cycloalkyl is C3-C7; phenoxy; benzyloxy; C1-C4-alkylthio; phenylthio, nitro; amino which is free or substituted with one or two C1-C4-alkyls, - cyano; C1-C4-acyl;

C 1-4 -acyloxy; C 1-3 -alkyl sulfonamido, phenylsulfonamido, C 1-3 -alkylamido, C 1-C 6- alkoxycarbonylamino, ureido which is unsubstituted or substituted with a phenyl or with

one or two C₁-C₆ alkyls,-

R 3 and R 4 are both independently C 1 -C 4 -alkyl, C 3 -C 7 -cycloalkyl,

phenyl, benzyl, cycloalkylmethyl wherein the cycloalkyl is C3-C7; or

R 3 and R 4 together form a group - (CH 2 ) p X (CH 2 ) q - ; or

R3 and R4," together with the carbon atom to which they are attached, form an optionally fused, saturated or unsaturated C3~C10 hydrocarbon ring which is unsubstituted or substituted with one or more C1-C4 alkyl groups or with a

C3 - Cs- spirocycloalkyl,-

or also

Ri and R4 both have one of the above meanings, and R2 is placed in the 4-position of the indole and forms the group (CH2)3 with R3/-

R 5 and R 6 are both independently hydrogen, halogen, C 1 -C 1 alkyl, trifluoromethyl, cyano, nitro, amino which is free or substituted with one or two C 1 -C 6 alkyls, hydroxyamino; hydroxy; carboxy group 0R7; the group SR7; C1-C7 acyl; C 1-6 -Alkoxycarbonyl; phenoxycarbonyl;

benzyloxycarbonyl; carbamoyl substituted with the groups R's and R''s; thiocarbamoyl which is free or substituted with one or two C 1 -C 4 alkyls; sulfamoyl; alkylsulfamoyl or dialkylsulfamoyl wherein the alkyl is C 1 -C 1 ; the group S02R'7/- alkylsulfonamido where the alkyl is C^ C^ ; the group COR'7; the group NR 1 R 9 or the group CO-NH-CH(R 10 )-COR 12 ;

if appropriate, the phenyl group which forms part of the substituent R s and/or R 6 may be unsubstituted or monosubstituted or polysubstituted with C 1 -C 1 -alkyl, trifluoromethyl, methoxy, halogen, sulfamoyl, alkylsulfamoyl where the alkyl is C 1 -C 3 , carboxy, alkoxycarbonyl

wherein the alkyl is C 1 -C 4 , C 1 -C 4 -acyloxy or imidazolyl; R''s and R''6 are both independently hydrogen, Cx-C7 alkyl which is unsubstituted or substituted by R'''s, phenyl, pyridyl, methylpyridyl, piperidin-4-yl or methylpiperidin-4-yl;

R'''6 is hydroxy, cyano, carboxy which is free or esterified with a C 1 -C 4 alkyl or with a benzyl; phenyl;

pyridyl; methylpyridyl; amino which is free or substituted

with one or two C1-Gj alkyls;

R, is C 1 -C 7 -alkyl, phenyl, benzyl, C 3 -C 7 -cycloalkyl, C 2 -C 4 -alkenyl, C 1 -C -haloalkyl, C 1 -C -polyhaloalkyl, C 1 -C -acyl, C 1 -C -7 -aj-carboxyalkyl which is free or esterified with a Cx-^-alkyl or with a benzyl, C2-C7-oj-aminoalkyl where the amino group is free, substituted by one

or two C 1 -C 4 alkyls or in the form of an ammonium ion; R'7 is a piperazin-1-yl group which is unsubstituted or substituted in the 4-position with the group R'' 7I a piperidino group which is unsubstituted or substituted in the 4-position

with the group R'''7, an azetidin-1-yl group which is unsubstituted or substituted in the 3-position with the group R'''7/ a pyridyl group which is unsubstituted or substituted by a methyl;

R''7 is C1-C4-alkyl, phenyl, benzyl or C1-C4-acyl; R'"7 is R", or amino which is free or has a protecting group,-

R 8 and R 9 are both independently hydrogen, C 1 -C y alkyl, phenyl or benzyl; R9 can also be C!-C7-acyl, C1-C7-thioacyl, cycloalkylcarbonyl where cycloalkyl is C3-C7, cycloalkyl-thiocarbonyl where cycloalkyl is C3-C7, C1-^-w-aminoacyl, Cj-Q-co-hydroxyacyl , C1-Qj-u-benzyloxyacyl, phenoxycarbonyl, thienocarbonyl, pyridylcarbonyl, methylpyridyl-carbonyl, C1-C^-alkoxycarbonyl, benzoyl, phenacetyl, the group CO-CH (R10)-NRnR'u, the group CH (Rl0) C02Rllr the group ( CH2)tCORl2, the group CO (CH2)tC0Rl2, carbamoyl which is unsubstituted or substituted by a phenyl or

one or two C 1 -C 4 alkyls;

m is 1 or, when R 6 is halogen, C 1 -C 7 alkyl or C 1 -C 7 alkoxy, m may also be 2, 3 or 4, or (R 6 ) m may be m substituents having different meanings selected from halogen , C 1 -C 7 -alkyl and C 1 -C 7 -Alkoxy;

p and q are both whole numbers, where it is possible that the sum

can vary from 3 to 6;

t is an integer that can range from 1 to 5;

X is oxygen, sulfur or the group NR13;

R 10 is hydrogen, C 1 -C 6 alkyl or benzyl;

Rough. and R'u both independently are hydrogen or Cx-C4 alkyl; R 12 is hydroxy, C 1 -C 4 alkoxy or amino which is unsubstituted or substituted by one or two C 1 -C 4 alkyls; R13 is hydrogen, C1-C4-alkyl, phenyl, benzyl, C1-C4-acyl,

C1-C4-Alkoxycarbonyl or Carbamoyl which is unsubstituted

or substituted with one or two C1-C4 alkyls; provided that when R 3 is methyl, R 4 is methyl or ethyl and m = 1, R 6 is not methyl,

and its salts where appropriate.

If a compound according to this invention has one or more asymmetric carbon atoms, the invention shall include all the optical isomers of this compound.

The salts of the compounds of formula (I) according to the present invention include salts with mineral or organic acids which allow a suitable separation or crystallization of the compounds of formula (I), such as picric acid, oxalic acid or an optically active acid, e.g. a mandelic acid or a camphosulphonic acid, and mineral or oranic acids which form physiologically acceptable salts such as the hydrochloride, the hydrobromide, the sulphate, the hydrogen sulphate, the dihydrogen phosphate, the maleate, the fumarate or the naphthalene-2-sulphonate.

The salts of the compounds of formula (I) also include the salts with organic or mineral bases, e.g. the salts of alkali metals or alkaline earth metals, such as sodium, potassium and calcium salts, of which sodium and potassium salts are preferred, or with an amine such as trometamol, or also the salts of arginine, lysine or any physiologically acceptable amine.

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

According to the present invention, an optionally fused condensed, saturated or unsaturated C3-Cl0 hydrocarbon ring is to be understood to mean different hydrocarbon rings with a monocyclic, dicyclic or tricyclic structure, e.g. cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, indane, hexahydroindane, adamantane, norbornane, norbornene, dihydrophenalene, tricyclo [5.2 .1.02'6] decane or tricyclo-[5.2.1.0<2>'<6>]dec- the 8.

The compounds of formula (I) where Rx is a chlorine atom or an ethoxy group in the 5-position of the indole and R2 is hydrogen are preferred compounds.

The compounds of formula (I) where R 3 and R 4 , together with the carbon atom to which they are attached, form a C 3 -C 10 hydrocarbon ring are preferred compounds.

The compounds of formula (I) where R3 and R4, together with the carbon atom to which they are attached, form cyclohexane which is unsubstituted or substituted with one or two C-^-CY-alkyl group(s) or with C3-C5-spirocycloalkyl, cycloheptane, adamantane or tricyclo[5.2.1.02-6]dec-8-ene.

The compounds of formula (I) where R 3 and R 4 , together with the carbon atom to which they are attached, form a piperidine-4- or N-methylpiperidine-4-ring, are also preferred.

The compounds of formula (I) where R 5 and R 6 are both methoxy are preferred compounds. Similarly, the compounds where Rs in the 2-position is methoxy and R6 in the 4-position is C1-C7-acylamino, C1-C3-dialkylureido or alkoxycarbonylalkylcarbamoyl where the alkyl groups are C1-C1 are to be preferred compounds.

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

DCM : dichloromethane

Ether : ethyl ether

Isoether : isopropyl ether

Boe : tert-butoxycarbonyl

Me, MeO : methyl, mtoxy

Et : ethyl

Pr, iPr, nPr : propyl, isopropyl, n-propyl

Bu, iBu, tBu: butyl, isobutyl, tert-butyl

Ph: phenyl

Ac: acetyl

AcOEt : ethyl acetate

AcOH : acetic acid

MeOH: methanol

EtOH: ethanol

DMF : dimethylformamide

THF: tetrahydrofuran

DMSO: dimethyl sulfoxide

DIPEA : diisopropylethylamine

TEA : triethylamine

TFA: trifluoroacetic acid

TMEDA : tetramethylethylenediamine

Temp. : melting point

Salt solution : saturated aqueous sodium chloride solution TLC : thin layer chromatography

HPLC : high pressure liquid chromatography

Aqueous hydrochloric acid: diluted hydrochloric acid, approx. IN

RT : room temperature

The compounds according to this invention can be prepared by:

a benzenesulfonyl halide of the formula:

where R's and RVI are respectively either Rs and R6 as defined above for (I), or precursor groups for R5 and R6 are reacted with a 2-oxoindole disubstituted in the 3-position, with the formula:

where R'x and R'2 are respectively either Rx and R2 as defined above for (I), or precursor groups for Rx and R2, and R3 and R4 are as defined above for (I),

either, if R'i=Ri/ R'2=R2, R'5=R5 and RVI=R6( the

resulting compound of formula (I) isolated;

or, if any of the groups R' lt R' 2, R' 5

and Rvj: are respectively a precursor group for Rlf R2, Rs and/or R6, the obtained compound is subjected to a subsequent treatment to prepare the compound of formula (I) by transformation of any of the groups

R'1; R'2f R's and Rv! to R1 respectively; R2/ R5 and R6.

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

The 2-oxoindoles (II) can be prepared using different methods. Some of these compounds with formula (II) as defined later are new and form part of this content.

The compounds (II) where R'x and/or R'2 are halogen and R3 and R4, together with the carbon atom to which they are attached, form a spirocyclobutane, a spirocyclohexane or a spirocycloheptane, are described e.g. in D.W. Robertson et al., J. Med. Chem., 1987, 30(5), 824-829. Also, 5-chloro-3-spirocyclopentane-indol-2-one is described in US patent 3,947,451.

For the preparation of the compounds (II) in the case where R 3 and R 4 together or separately are a hydrocarbon group, it is possible to use the Brunner reaction described by R.F. Moore and S.G.P. Plant in J. Chem. Soc, 1951, 3475-3478, leading to the preparation of the compounds (II) where CR 3 R 4 is a cyclopentane or a cyclohexane.

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

where R'i and R'2 are as defined for (II), and R3 and R4 have the meanings stated above for (I), e.g. by heating in the presence of calcium oxide and quinoline.

According to the same authors, the phenylhydrazide derivative (IV) is prepared by reacting a hydrazine derivative of the formula: where R'x and R'2 have the meaning given above for (II), with an acid halide of the formula:

where R3 and R4 have the meaning indicated above for (I).

According to a particular embodiment, if R3 and R4, together with the carbon atom to which they are attached, form a co-fused polycyclic hydrocarbon, e.g. norbornane or norbornene, the reaction is carried out by the method described by J. Wolff et al., Tetrahedron, 1986, 42 (15), 4267-4272: first of all, a lithium salt of the compound (IV) is prepared by reaction with a lithium reagent such as n- butyllithium, in an inert solvent such as THF, at low temperature, and then the cyclization is carried out by heating in a solvent such as naphthalene or prenitene (1,2,3,4-tetramethylbenzene).

The compounds (II) where R1=R2=H and CR3R4 is adamantane are described in I. Fleming et al., J. Chem. Soc, Perkin Trans I, 1991, 3, 617-626. The compounds (II) where R3 and R4, together with the carbon atom to which they are attached, form an adamantane and Rx and R2 are different from hydrogen, are thus new and form part of this invention. They can be produced by the method described above.

Are the hydrazine derivatives (V) known or are they prepared by known methods? The same applies to the acid halides (IV).

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

where R<1>! and R' 2 is as defined above for (II), using different methods.

E.g. will the procedure described by A.S. Kende and J.C. Hodges in Synth. Commun., 1982, 12 (1), 1-10, comprise the addition of an alkylating agent in a suitable solvent. Thus, to prepare a compound (II) where R3=R4, the reaction is carried out in THF at -75°C, in the presence of TMEDA, by adding an alkyllithium such as butyllithium, followed by reaction with a halide of the formula R3Hal / if R3 and R4 are different, the alkylation reaction can be carried out in two steps with two different alkyl halides of the formula R3Hal and R4Hal. For the preparation of a compound (II) where R3 and R4 together form a group of the formula -(CH2)n-, where n varies from 2 to 7, the reactant used will be a compound of the formula Z(CH2)nZ, where Z is an electron-accepting end group such as e.g. a halogen, preferably bromine or iodine, a tosyloxy group or a mesyloxy group.

The compounds of formula (II) where R 3 and R 4 are both independently alkyl or phenyl will be known. E.g. will patent DE 3 300 522 describe 5-Alkoxy-3,3-dimethylindol-2-ones.

The compounds of formula (II) where R3 and R4, together with the carbon atom to which they are attached, form a C4-C8 hydrocarbon ring substituted with one or more Cx-Cy alkyl groups or with a C3-C5 spirocycloalkyl, be produced in the same way. These compounds are new and form part of this invention.

If R3 and R4 together form a - (CH2)pX(CH2)q group, where p, q and X are as defined above for (I), a 2-oxoindole disubstituted in the 3-position, with the formula (II) , is prepared from a 2-oxoindole unsubstituted in the 3-position (VII) by reaction with a compound of the formula:

where Z is as defined above and X, p and q are as defined above for (I). The reaction is carried out in the presence of an alcoholate, e.g. potassium tert-butylate, in an anhydrous solvent such as, for example, THF.

If X is a nitrogen atom substituted with C1-C4-acyl, C1-C4-alkoxycarbonyl or C1-d-alkylcarbamoyl, the substitution on X can be carried out either on the 2-oxoindole derivative (II) or on the final compound (I) with starting from a compound where the nitrogen atom (X=NH) is not substituted.

The compounds (I) where X=NH are preferred compounds according to this invention.

If X is a nitrogen atom substituted with Cx-C4-Alkoxy - carbonyl, the first step will thus be to prepare a compound (II) or (I) where X is NH, and which is then reacted with the appropriate chloroformate to give the desired compound (II) or (I). In the same way, a Cx-C4 alkyl isocyanate is reacted with a compound (II) or (I) where X=NH to form a 2-oxoindole derivative (II), or a compound (I) where X is a nitrogen atom substituted with alkylcarbamoyl. An acid chloride or an anhydride is reacted with a compound (II) or (I) where X=NH to produce a compound of formula (I) where X is a nitrogen atom substituted by acyl.

The compounds (II) in which R3 and R4, together with the carbon atom to which they are attached, form a pyrrolidine, N-alkylpyrrolidine, piperidine or N-alkylpiperidine ring are described by M.J. The grain in J. Med. Chem., 1976, 19_, (7), 892-899.

In particular, the horsfile is with the formula:

an alkaloid described in A. Jossang et al., J. Org. Chem., 1991, 56 (23), 6527-6530.

The compounds (II) where R3 and R4, together with the carbon atom to which they are attached, form the group - (CH2)pX(CH2)q- where p and q are whole numbers with a sum that can vary from 3 to 6, and X is oxygen, sulfur or the group NR13, where R13 is Cx-C4-acyl, benzyl, C1-Cj-alkoxycarbonyl or carbamoyl which is unsubstituted or substituted by one or two C1-C4 alkyls, are new and form part of this invention.

For the preparation of a compound of formula (II) where R3 and R4, together with the carbon atom to which they are attached, form tricyclo[5.2.1.02-6]decane or tricyclo[5.2.1.02'6]dec-8- one, becomes a compound with the formula (VII)' or with the formula (VII)'' respectively, with the formulas

wherein Z is as defined above, reacted with a compound of formula (VII). The compounds (VII)' and (VII)'' substituted with one or more C1-C4 alkyl groups are used to prepare the compounds (II) where said carbocycles are substituted. For the preparation of a compound (II) where R3 and R4, together with the carbon atom to which they are attached, form an indane or a hexahydroindane, respectively a compound (VIII) ' or a compound (VIII) '', with the formulas

where Z is defined as above for (VIII), reacted with a compound (VII). Compounds (VIII)' and (VIII)''

substituted with one or more Cx-Qj alkyl groups, is used for the preparation of the compounds (II) where the indane or hexahydroindane is substituted.

The compounds (II) where R3 and R4, together with the carbon atom to which they are attached, form a tricyclo [5 .2 .1.02,6] decane, a tricyclo [5 .2 .1.02,6] dek-8-ene, an indane or a hexahydroindane unsubstituted or substituted with one or more C 1 -C 4 alkyls are novel and form part of this invention.

If R3 and R4 are both phenyl, the method described in Heiv. Chim. Acta, 1946, 29., 415-432, is used for the preparation of a compound (II).

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

The compounds of formula (II) which have certain substituents R'i and R,2 on their benzene group are used as precursors for the preparation of compounds of formula (II) which carry other substituents R'x and R'2. E.g. will the compounds (II) where R'i and/or R'2=H, be nitrated with the conventional reagents; they can also be acylated by reaction with an acid chloride of the formula RCOC1, where R is C1-C4 alkyl, in the presence of a Lewis acid such as aluminum chloride, to produce a compound (II) where R'x and/or R'2 =C0R. A compound (II) where R'x is an amino group is prepared by catalytic hydrogenation of a compound (II) where R'x is a nitro group and R'2 is hydrogen.

The compounds with the formula

where

R x and R 2 are both independently hydrogen, hydroxy, C 1 -C 4 -co-halo alkoxy, halogen, C 1 -C 4 -alkyl, trifluoromethyl, C x -C 7 - alkoxy, C 1 -C 4 -polyhalo alkoxy, C 2 -C 4 -w-hydroxy alkoxy, w- methoxyalkyloxy where the alkylene is C2-C4, C2-C4-cj-amino alkoxy which is free or substituted with one or two C1-Cj-alkyls, C3-C7-cycloalkyloxy, cycloalkylmethoxy where the cycloalkylene is C3-C7; phenoxy, benzyloxy, Cx-C4-alkyl-thio, phenylthio, nitro, amino which is free or substituted with one or two C1-d-alkyls, cyano, C1-Qj-acyl, C^^-acyloxy, Cl-Q, -alkyl sulfonamido, phenyl sulfonamido, Cx-C^-alkylamido, Cx-C^-alkoxycarbonylamino or ureido which is unsubstituted or substituted with a phenyl or with

one or two C 1-6 alkyls; and

R3 and R4, together with the carbon atom to which they are attached,

forms

an adamantane,

an indane or a hexahydroindane which is unsubstituted or substituted with one or more C 1 -C 1 -alkyl groups,

tricyclo [5.2.1.02'6] decane or tricyclo [5 .2 .l.2,6] -

dec-8-ene which is unsubstituted or substituted with one or more C 1 -C 4 -alkyl groups, or

a C4-C8 hydrocarbon ring substituted with one or more Cx-Gj alkyl groups or with a C3-C8 spirocycloalkyl; or also

R3 and R4 together form the group - (CH2)P-X(CH2)q- where

p and q are whole numbers with a sum that can vary from 3 to 6, and X is oxygen, sulfur or the group NR 13 , where R 13 is phenyl, benzyl, C 1 -C 4 -acyl, C 1 -C 6 -alkyloxycarbonyl or carbamoyl which is unsubstituted or substituted with one or two C 1 -C alkyls,

with the proviso that if CR3R4 is adamantane, Rx and R2 must be different from hydrogen,

are new and form part of this invention. The compounds with the formula

where

Rx is hydroxy, Cx-Q-w-halogeno alkoxy, halogen, ^-C^-alkyl, trifluoromethyl, Cx-C7-alkoxy, C1-C^-polyhalo- alkoxy, C2-C4-co-hydroxy alkoxy, co-methoxy alkoxy where the alkyl is C2-C4, C2-C4-6-aminoalkoxy which is free or substituted with one or two C1-C4-alkyls, C3-C7-cyclo-alkoxy, cycloalkylmethoxy where the cycloalkyl is C3-C7, phenoxy, benzyloxy, Ci- C 1 -alkylthio, phenylthio, nitro, amino which is free or substituted with one or two C 2 -C 4 alkyls, cyano, C 1 -C 3 -acyl, C 1 -C 4 -acyloxy, C 1 -C 4 -alkylsulfonamido, phenylsulfonamido, C 1 -C 4 -alkylamido, C 1 -C 4 - alkoxycarbonylamino or ureido which is unsubstituted or substituted with phenyl or with one or

two C 1 -C 4 alkyls;

R3 and R4 together form the group - (CH2) P-X (CH2) q-; or R3 and R4, together with the carbon atom to which they are attached,

forms an optionally fused, saturated or unsaturated C3-C10 hydrocarbon ring which is unsubstituted or substituted with one or more C1-C4 alkyl groups or with

C3-C5 spirocycloalkyl;

p and q are both integers, where it is possible that their

sum can vary from 3 to 6;

X is oxygen, sulfur or the group NR13; and R 13 is hydrogen, C 1 -C 4 alkyl, phenyl, benzyl, C 1 -C 4 acyl,

C 1 -C 7 -Alkoxycarbonyl or carbamoyl which is unsubstituted or substituted with one or two C 1 -C 4 alkyls,

with the limitation that

if Rx is methoxy, CR3R4 shall be different from a pyrrolidine-3 which is unsubstituted or N-substituted with C1-C6 alkyl, and if Rx is halogen, CR3R4 shall be different from pentane,

are new and form part of this invention. 2a,3,4,5-tetrahydrobenz[c,d]indol-2(1H)-one with the formula

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

The benzenesulfonyl halides (III) are known and can be prepared by known methods. Thus, e.g. 4-Dimethyl-aminobenzenesulfonyl chloride prepared according to C.N. Sukenik et al., J. Amer. Chem. Soc, 1977, 99, 851-858. More generally, the benzenesulfonyl halides (III) where the substituent Rs is a dimethylamino group will be known or can be prepared by known methods, p-benzyloxybenzenesulfonyl chloride is prepared according to European patent application EP 229 566.

Alkoxybenzenesulfonyl chloride is produced from the sodium alkoxybenzenesulfonate, which itself is produced by reacting an alkyl halide with sodium hydroxybenzenesulfonate.

2,4-dimethoxybenzenesulfonyl chloride is prepared according to J. Am. Chem. Soc, 1952, 74.2008.

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

The benzenesulfonyl halides with the formula

where

Alk is Cx-C7-alkyl,-

Y is 0 or S; and

Rv is C 1 -C 7 alkyl, C 3 -C 7 cycloalkyl, C 2 -C 4 alkenyl, C 1 -C 7 -haloalkyl, C 1 -C 7 -polyhaloalkyl, benzyl, C 1 -C 7 acyl or C 1 -C 7 -w -carboxyalkyl esterified with C-^- C^-

alkyl or with benzyl,

are new and form part of this invention.

These compounds are prepared according to D. Hofmann et al. in Liebig's Ann. Chem., 1982, 287-297. Benzene compounds with the substituents YRV and OAlk in the 1- and 3-positions are reacted with trimethylsilylchlorosulfonate in a solvent such as DCM, at RT. The method of R. Passerini et al. in Gaza. Chim. Ital., 1960, 90, 1277-89, is then applied, and this is followed by neutralization, e.g. with alkali metal carbonate, and then by reaction with a halide such as POCl3, forming the desired benzenesulfonyl halide.

The benzenesulfonyl halides (III) where the substituent R's is alkoxycarbonyl, phenoxycarbonyl, benzyloxycarbonyl, alkylthio, phenylthio, benzylthio or the group SR7, where R7 is as defined for (I), are prepared according to Col. Czechoslovak. Chem. Commun., 1984, 49, 1184, from an aniline derivative substituted with the same grouping R's, where said aniline derivative is itself prepared from the corresponding nitrated derivative.

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

The benzenedisulfonyl dihalides (III, R's=SO 2 Hal) are known or can be prepared by known methods. E.g. is 2,4-dimethoxybenzene-1,5-disulfonyl dichloride described in R.J.W. Kremlin, J. Chem. Soc. C, 1969, 1344.

The haloalkoxybenzenesulfonyl chlorides (III, R's=co-halogenalkoxy) are used to prepare compounds according to this invention, where the substituent Rs is co-aminoalkoxy which is unsubstituted or substituted with one or two alkyls, according to the following equation:

where Alk' is C 1 -C 4 -alkyl.

For certain meanings of the substituents R 1 R 2 , R 1 and/or R 6 , the compounds (I) according to this invention can be prepared from a precursor of the formula (I)' substituted with the group R' 1 R' 2 ; R's and/or RVI, called a precursor group for Rlf R2, Rs and/or R6.

The description that follows describes the preparation of the compounds of formula (I) which have substituents Rx and/or R5; the same methods apply to the preparation of the compounds where the substituents R2 and/or Rs are defined as indicated for Ri and Rs.

The compounds (I) where Rx and/or Rs are hydroxy can be prepared by catalytic hydrogenation of a compound of formula (I)', where R 1 and/or R' 5 is benzyloxy, e.g. in the presence of palladium-on-charcoal.

The compounds (I) where R'x and/or R's are hydroxy can be used to prepare the compounds (I) where Rx and/or Rs are alkoxy by reaction with an alkyl halide in the presence of a base, such as a metal hydride or an alkali metal - or alkaline earth metal carbonate such as K2C03 or Cs2C03, in a solvent such as THF or DMF. In a similar way, the compounds of formula (I) where Rx and/or R5 are w-aminoalkyloxy can be prepared by reacting a w-chloroalkylamine with the compounds where R'x and/or R's=OH; in a similar way, the compounds where Rx and/or Rs are ω-hydroxyalkyloxy can be prepared by reaction with a chloroalkyl alcohol; in the special case of producing a compound (I) where Rx and/or Rs=0(CH2) 20H, it is also possible to react ethylene carbonate with a compound (I) where R'x and/or R's=OH.

The compounds of formula (I) where Rx and/or Rs are acyloxy can be prepared by reacting an acid halide or anhydride with a compound (I) where R'x and/or R's are hydroxy.

For the preparation of compounds of formula (I) where Rx and/or R5 is monoalkylamino or dialkylamino, the compounds of formula (I) where R'x and/or R'5 are amino can undergo reductive alkylation. If R'x and/or R's are amino, it is also possible to carry out a nitrosation, e.g. in the presence of nitric acid or an alkyl nitrite, to produce a compound (I) where Rx and/or Rs is a diazonium salt,* reactions known to those skilled in the art then give the compounds (I) according to this invention where Rx and/ or R 5 is cyano, halogen or C 1 -C 4 -thioalkyl. Finally, the compounds (I) where Rx and/or R5 is one of the groups of formula RCONH-, ROCONH-, RNHCONH- and RS02NH-, where R is Cx-C^-alkyl, can be prepared by conventional reaction starting from the compounds (I ) ' where R'x and/or R'S=NH2. "The compounds of formula (I)" where the substituent R'5 is phenoxycarbonyl, can be used to prepare the compounds (I) where Rs is phenylcarbamoyl or alkylcarbamoyl, by reaction with an aniline or an alkylamine. A substituted aniline or an alkylamine substituted on the alkylene can be used to prepare compounds of formula (I) where R5 is respectively phenylcarbamoyl or an alkylcarbamoyl' substituted on the alkylene. The compounds of formula (I) where R's is benzyloxycarbonyl can be used to prepare the compounds (I) where Rs is carboxy by catalytic hydrogenation. Reaction with a thionyl halide gives the compounds of formula (I) where Rs is a halocarbonyl. Such compounds are used to prepare compounds of formula (I) where Rs is N-substituted carbamoyl by reaction with a substituted amine. The compounds of formula (I) where Rs is the group COR''7 are prepared from corresponding compounds (I)' where R's is phenoxycarbonyl, by reaction with a substituted piperazine or azetidine. A compound (I) where R's is a nitro group can be used to prepare a compound (I) where Rs is an amino group by catalytic hydrogenation, e.g. in the presence of platinum oxide; other compounds where the amino group is substituted can then be prepared using reactions well known to those skilled in the art. If, for example, it is desired to prepare a compound (I) according to this invention where Rs is the group NR8R9, where R9 is optionally substituted benzoyl, the benzoyl chloride where phenyl has the appropriate substituent is reacted with a compound (I)' where R'5 is an amino group, in the presence of an amine such as triethylamine. For example, 4-chlorosulfonylbenzoyl chloride can be reacted to prepare the compound (I) ' where R's is a 4-chlorosulfonylbenzamido group, after which a compound (I) is prepared where the substituent Rs is a 4-sulfamoylbenzamido group or a 4-alkyl sulfamoylbenzamido group, by reaction with ammonia or a d-CV respectively alkylamine. In the same way, if it is desired to prepare a compound (I) where Rs is the group NR8RS, where R9 is Cx-Cy-acyl, the appropriate anhydride is reacted with a compound (I) ' where R's is e n amino group, in the presence of an amine such as triethylamine. In another preparative example, a compound (I) where R5 is an alkylsulfonamido group is prepared by reacting an alkylsulfonyl halide with a compound (I) where R's is an amino group. The compounds of formula (I) where R's is an amino group can also be used for the preparation of compounds where this amino group is substituted with the group (CH2)t-COR12. In this case, a compound with the formula Hal-(CH2)t-COOAlk is reacted, where Hal is a halide, e.g. bromine, and Alk is C 1 -C 4 alkyl, with (I) ' in the presence of cupric (I) chloride; if appropriate, the resulting ester is converted to the acid or an amide. The reaction of a lactone, such as butyrolactone or valero-lactone, with a compound (I) 'where R's is amino, can be used to prepare the compound (I)' where R'5=NHCO-(CH2)tCO2H, where t=2 or 3. In the same way, the compounds of formula (I) where Rs is an amino group substituted with the group CH(R10)CO2Rn are prepared by reacting a compound of the formula Hal-CH (R10)CO2Rn with the corresponding compounds (I) ' where the substituent R'5 is amino. A compound (I) in which R5 is an amino group substituted with alkoxycarbonyl or phenoxycarbonyl is prepared by reacting an alkyl or phenyl chloroformate with a compound (I) in which the substituent R'5 is amino. A compound of the formula (I) where R 5 is ureido is prepared by reacting ammonia with a compound of the formula (I) ' where R's is an amino group substituted with phenoxycarbonyl; a compound of formula (I) where Rs is N-phenylureido or N-alkylureido or N,N-dialkylureido where the alkyl is C1-C2, is prepared by reacting an aniline or a C1-CV monoalkylamine or -dialkylamine with such a compound - ;else with formula (I)'. A compound (I) where R5 is carbamoyl which is unsubstituted or substituted with one or two alkyl groups is produced by reacting an appropriate amine with a compound (I) where the substituent R'5 is amino, i presence of phosgene. It is also possible to prepare a compound (I) where R5 is an amino group substituted with alkylcarbamoyl or with phenylcarbamoyl by reacting an alkyl or phenyl isocyanate with a compound (I) where the substituent R's is amino. Furthermore, a compound (I) is prepared where Rs is a sulphamoyl group which is unsubstituted or substituted with C x -C4 alkyl, by reacting ammonia or an alkylamine with a compound (I) ' where R's is a halosulfonyl group. The compounds of formula (I) which can be used as precursors for the production of compounds of formula (I) are included in formula (I) and form part of this invention. Among the compounds of formula (I), the compounds of formulas (IX), (X), (XI), (XII) and (XIII) below, which can be used for the preparation of other compounds of formula (I), are preferred compounds according to this invention. ;An object of the present invention ;thus consists of the compounds of the formula ;where R 1 R 2 , R 3 / R 4 and R s are defined as indicated above for (I), and their functional derivatives such as their esters. Another object of the present invention consists of the compounds of the formula ;wherein R1# R2I R3< R4 and Rs are defined as indicated above for (1), and their salts where appropriate. Another object of the present invention consists of compounds of the formula where Rx, R2, R3, R4 and Rs are defined as indicated above for (I). ;Another object of the present invention consists of compounds of the formula ;;where R 3 , R 4 , R s > R 6 and m are defined as indicated above for (I). Another object of the present invention consists of the compounds of the formula where R1# R2f Rs, Rs and m are defined as indicated above for (I). The affinity of the compounds of this invention for the vasopressin receptors was determined in vitro using the method described in C.J. Lynch et al., J. Biol. Chem., 1985, 260(5), 2844-2851. This method consists in studying the displacement of tritiated vasopressin bound to the Vx sites in rat liver membranes. The concentrations of the compounds according to this invention which inhibit the binding of tritiated vasopressin by 50% (ICS0) are low, in the range up to 10"<7> M. The affinity of the compounds (I) according to this invention for the V2 receptors was measured on a bovine kidney membrane preparation using a method adapted from P. Crause et al., Molecular and Cellular Endocrinology, 1982, 28, 529-541, and from F. L. Stassen et al., J. Pharmacol. Exp. Ther., 1982, 223, 50-54. The compounds according to this invention inhibit the binding of tritiated arginine-vasopressin to the receptors in the membrane preparation. The ICS0 values for the compounds according to this invention are low, in the range up to 10"<9> M. ;The activity of the compounds according to this invention as V2 receptor antagonists, was demonstrated by the adenylate cyclase activity determination which was carried out by a method adapted from M. Laburthe et al., Molecular Pharmacol., 1986, 29, 23-27. A bovine kidney membrane preparation is used, and each product is incubated for 10 min. at 37°C by itself or in the presence of AVP (arginine vasopressin), at a concentration of 3.10"<8> M. The produced cyclic AMP (cyclic adenosine monophosphate) is measured by radioimmunoassay. The concentration is determined which causes 50% inhibition (ICS0) of the stimulation of adenylate cyclase induced by 3.10"<8> M AVP. The IC50 values determined are of the order of 10"<7> M, in the range down to 10'<8> M. The activity of the compounds of this invention, administered orally, as V2 receptor agonists or antagonists, is evaluated in hyperhydrated rats (OFA strain, Sprague-Dawley) treated with vasopressin. In the same way, the affinity of the compounds (I) according to the invention to the oxytocin receptors was determined in vitro by calculation of a radioiodinated oxytocin analogue bound to the receptors in a mammary gland membrane preparation from a pregnant rat, using by a technique similar to that described by J. Eland et al. in Eur. J. Pharmacol., 1987, 147, 197-207. The ICS0 values for the compounds of this invention come down to 10"<8> M. The affinity of the compounds to the vasopressin receptors (V-^ and V2) and to the oxytocin (Oc) receptors was determined in vitro as previously described. The results (ICS0) for some representative compounds are given in the following table. ;Dose of adenylate cyclase activity ;- •*

The compounds were tested as described above, but on rat membrane instead of bovine kidney membrane.

Compound according to Example 23: IC50 = 6.7 10"<7>M

31: ICS0<=> 7.6 10"7M

150: ICS0 = 4.7 10"<8>M

The antagonistic activity against the V2 receptors of the compound according to Example 150 has been evaluated in rats under water-overweight as mentioned above.

Rats were given 10 mg/kg or 20 mg/kg per os of the compound and vasopressin; the volume of their urine output was compared to rats given only vasopressin: after 2 hours, diuresis was extended (X4) for rats given the compound.

The compounds according to this invention are active after administration in various ways, especially orally.

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

The compounds according to this invention can thus be used in the treatment or prevention of various vasopressin-dependent or oxytocin-dependent disorders, especially cardiovascular disorders such as hypertension, heart failure or coronary vasospasm, especially in smokers, cardiac ischemia, hemostatic disorders, especially hemophilia and Von Willebrand's syndrome; disorders of the central nervous system, e.g. cerebral edema, depression, anxiety, psychotic states, and memory disorders; disorders of the renal system, such as renal vasospasm, necrosis of the renal cortex, hyponatremia and hypokalemia; and disorders of the stomach system, such as hepatocirrhosis, stomach ulcers, the pathology of vomiting, e.g. nausea, motion sickness or also the syndrome of unsatisfactory secretion of anti-diuretic hormone (SIADH), diabetes insipidus and enuresis. The compounds according to this invention can also be used in the treatment of disorders of sexual behaviour; in women, the compounds according to the invention can be used for the treatment of dysmenorrhoea or premature labour.

The present invention further relates to pharmaceutical compositions containing an effective dose of a compound according to this invention, or a pharmaceutically acceptable salt, and suitable excipients.

Said excipients are selected according to the pharmaceutical form and the desired method of administration.

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

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

Each unit dose may contain from 0.5 to 1000 mg, preferably from 1 to 500 mg, of active ingredients in combination with a pharmaceutical carrier. This unit dose can be administered 1 to 5 times daily, thus administering a daily dosage of 0.5 to 5000 mg, preferably 1 to 2500 mg.

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

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

A preparation in the form of a syrup or elixir or for administration in the form of drops, may 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 agent and a suitable colour.

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

Rectal administration is carried out using suppositories which are made with binders which melt at rectal temperature, e.g. cocoa butter or polyethylene glycols.

Parenteral administration is carried out using aqueous suspensions, isotonic salt solutions or sterile and injectable solutions containing pharmacologically compatible dispersants and/or wetting agents, e.g. propylene glycol or butylene glycol.

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

In addition to the products with formula (I) above or one of the pharmaceutically acceptable salts, the mixtures according to the present invention may contain other active principles that can be used in the treatment of disorders or diseases more indicated above.

Thus, the present invention also relates to pharmaceutical mixtures containing several active principles that work together, one of which is a compound according to this invention.

According to the present invention, it is thus possible to prepare pharmaceutical mixtures containing a compound which is a V1 receptor antagonist, together with a compound which acts on the renin-angiotensin system, such as a converting enzyme inhibitor, an angiotensin-II antagonist or a renin -inhibitor. They can also be associated e.g. with a peripheral vasodilator or a calcium inhibitor. Such mixtures can be used in particular in the treatment of hypertension or heart failure.

Preparation of 2-oxoindoles

Preparation 1:

4,6-Dimethyl-3-spirocyclohexaneindol-2-one

This compound is prepared according to Moore and Plant in J. Chem. Soc, 1951, 3475.

A mixture containing 15 ml of quinoline and 10 g of calcium oxide is heated at reflux under an internal atmosphere, and 5 g of the 3,5-dimethylphenylhydrazide of the cyclohexanecarboxylic acid (II, R'x, R'2 = CH3, CR3R4 = cyclohexane) is added over 30 my. The reaction medium is cooled and then poured into an ice/hydrochloric acid mixture. Extraction is performed with ethyl acetate, and the extract is washed with normal hydrochloric acid and with water until the washings are neutral, then dried and concentrated under vacuum to give a brown solid. Trituration in isoether gives the expected compound.

Sm.p. = 223°C.

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

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

Preparation 2:

The 3-spirocyclohexaneindol-2-one described in Table 1 above can also be prepared by alkylating indol-2-one using the method described below.

A solution of 30 g of indol-2-one in 900 ml of THF is maintained

-40°C under a nitrogen atmosphere and 101 g of potassium tert-butylate are added. The temperature is allowed to rise to 0°C within 1 hour, the mixture is then cooled to -60°C, and a solution of 52 g of 1,5-dibromopentane in 50 ml of THF is added dropwise. After 30 min. at -60°C, the temperature is allowed to rise to RT, then 30 ml of water are added, and the solvent is evaporated off under reduced pressure. The residue is taken up in 500 ml of DCM and 200 ml of water, then the insoluble material is filtered off, and the organic

ice phase is separated, washed with 100 ml of water, dried over magnesium sulphate and evaporated under vacuum. The residue is chromatographed on silica using a cyclohexane/ether mixture as eluent to give the expected compound, which recrystallizes from heptane.

m = 34 g.

Sm.p. = 123-124°C.

A similar method can be used by starting with other indol-2-ones and other alkylating agents.

Among the starting compounds with formula (VII) is, for example, 5-chloroindol-2-one described by Bright in J. Am. Chem. Soc, 1956, 79, 221, and by RajanBabu in J. Org. Chem., 1986, 51, 1704. 4-chloroindol-2-one can be prepared from 2-chloro-6-nitrotoluene by the method described in J. Am. Chem. Soc, 1956, 78, 221.

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

Preparation 3:

5-Ethoxyindol-2-one

A - 3-Thiomethyl-5-ethoxyindol-2-one

23.6 g of ethyl thiomethyl acetate in 60 ml of DCM are added to a solution, cooled to approx. -70°C, of 12.5 g chlorine in 400 ml DCM. After stirring for 5 min. at the same temperature, a solution of 4-ethoxyaniline (48.3 g) in 120 ml of DCM is added. The mixture is stirred for 1 hour at approx. 70°C, 39.3 ml of triethylamine is added, and the resulting mixture is allowed to warm to room temperature. 200 ml of water are added, and the organic phase is decanted, dried over magnesium sulphate and evaporated under reduced pressure. The residue is taken up in 500 ml of isopropanol and 20 ml of concentrated hydrochloric acid. The mixture is stirred for approx. 16 hours at room temperature and filtered, and the precipitate separated. The filtrate is concentrated under reduced pressure to give the expected product.

B - 5-Ethoxyindole-2-ori

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

Sm.p. = 156°C.

The following are isolated in the same way starting from the corresponding anilines: 5-benzyloxyindol-2-one m.p. = 152°C 5-n-propylindol-2-one m.p. = 136°C 5-ethylindol-2-one m.p. = 152°C 5-(2,2,2-trifluoroethoxy)indol-2-one m.p. = 145°C

The compounds with formula (II) described below are prepared by following the technique described in Preparation 2 and by varying the starting indol-2-one derivative and the alkylation reagent.

Preparation 4:

3-Spiroadamantanindol-2-one

This compound is prepared according to I. Flemming et al., Tetrahedron Letters, 1982, 2053-2056, from 2-bromoaniline and adamantan-2-one.

Preparation 5:

5-Chloro-3,3-diphenylindol-2-one

This compound is produced by the method described in Heiv. Chim. Acta, 1946, 29, 415-431, by reaction of benzene with 5-chloroisatin in the presence of aluminum chloride.

Sm.p. = 281°C.

Preparation 6:

5-Nitro-3-spirocyclohexaneindol-2-one

This compound is prepared by the method described in J. Am. Chem. Soc, 1945, 67, 499, by nitration of 3-sp i ro cyclohexaneindo1-2-one.

Sm.p. = 192°C.

5-Nitro-3-spiroadamantanindol-2-one is prepared in the same way starting from 3-spiroadamantaninol-2-one.

Sm.p. > 260°C.

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

Sm.p. = 195°C.

Preparation 7:

5-Amino-3-spirocyclohexaneindol-2-one

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

Sm.p. = 176°C.

5-Amino-3-spiroadamantane is prepared in the same way. Sm.p. = 245°C.

Preparation 8:

5-Fluoro-3-spirocyclohexaneindol-2-one

A - 5-Diazonium-3-spirocyclohexaneindol-2-one tetrafluoroborate

A solution containing 4 g of 5-amino-3-spirocyclohexanindol-2-one in 9.2 ml of 6 N hydrochloric acid is cooled to 0°C, and 2.27 g of sodium nitrite in 2.6 ml of water is added, followed by of 2.54 g of sodium tetrafluoroborate in 9 ml of water. After stirring for 5 min., the precipitate is filtered off and washed with a 5% solution of tetrafluoroborate, with 3 ml of methanol cooled to approx. 0°C and then with 5 ml of ether. The prepared salt is dried under vacuum at RT in the presence of phosphorus pentoxide.

B - 5-Fluoro-3-spirocyclohexaneindol-2-one

1 g of the compound prepared in step A is placed in 5 ml of xylene and heated at approx. 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 activated carbon is added to the filtrate. After filtration, the solvent is evaporated off under reduced pressure to give 0.45 g of the expected compound, which is recrystallized from pentane.

Sm.p. 114°C.

Preparation 9:

5-Cyano-3-spirocyclohexaneindol-2-one

4.78 g of potassium cyanide and 4.95 g of cupric (I) cyanide are dissolved at RT in 40 ml of DMSO. The solution is cooled to approx. 15°C and 4.15 g of the diazonium salt prepared in step A in the previous preparation are added.

After stirring for 30 min. at RT, 100 ml of water and 100 ml of ether are added, and the organic phase is separated, dried over magnesium sulphate and evaporated under reduced pressure. The residue is chromatographed on silica using a cyclohexane/ether mixture as eluent, and gives the expected compound, which is recrystallized from heptane.

m = 1.4 g.

Sm.p. = 216°C.

Preparation 10:

5-chloro-3-spiroadamantanindol-2-one

1 g of the p-chlorophenylhydrazide of adamantane-2-carboxylic acid is dissolved, and 2.5 ml of a solution of n-butyllithium (1.6 M in hexane) is added at -40°C. After stirring for 5 min., the mixture is concentrated under vacuum while keeping the temperature below 30°C. 30 ml of 1,2,3,4-tetramethylbenzene are added, and the mixture is heated under reflux for 1 hour. It is concentrated under reduced pressure, the residue is taken up in normal hydrochloric acid, extraction is carried out with ether, and the extract is washed, dried and concentrated under vacuum. The produced oil is chromatographed on a silica column using DCM as eluent, and gives 0.3 g of the expected product in the form of a wax, which is recrystallized from isoether.

Sm.p. = 249°C.

Preparation 11:

5-Chloro-3-cyclohexy1-3-methylindol-2-one

The procedure described in Synt. 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 prepared 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 ml of 1,2-dichloroethane. The mixture is heated under reflux for 2 hours, the solvent is evaporated off under reduced pressure, and the medium is hydrolysed with 50 g.^s and extracted with ethyl acetate.

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

Sm.p. = 192°C.

The benzenesulfonyl chlorides described in the table below were prepared using the method described.

Starting from the various 2-oxoindoles described above and appropriate benzenesulfonyl chlorides, the compounds according to the invention were prepared using the methods reproduced in the examples below.

EXAMPLE 1

5-Chloro-i-(2-methoxy-4-nitrobenzenesulfonyl)-3-spirocyclohexane-indol-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 min. 0.7 g of 2-methoxy-4-nitro-benzenesulfonyl chloride is introduced, and the stirring is maintained at RT for 20 hours. The mixture is concentrated under vacuum, the residue is taken up in 30 ml of water, extracted with ethyl acetate, and the extract is washed with water and then dried and concentrated to give 1.1 g of the expected compound which crystallizes from isoether.

Sm.p. = 188°C.

EXAMPLE 2

1-(4-Amino-2-methoxybenzenesulfonyl)-5-chloro-3-spirocyclohexane-indol-2-one

0.8 g of the compound prepared in the previous example is reduced with hydrogen under normal pressure at RT for 20 hours in 10 ml of acetic acid, in the presence of 30 mg of platinum oxide. The reaction medium is filtered, the filtrate is concentrated, the residue is taken up in a water/ethyl acetate mixture, and the organic phase is washed with water, dried and concentrated. The yellow foam produced is chromatographed on alumina using DCM as eluent, and yields 0.2 g of the expected product.

Sm.p. = 173°C.

EXAMPLE 3

5- Chloro-1-[4-(2-methylphenylcarboxamido)-2-methoxybenzenesulfonyl]-3-spirocyclohexaneindol-2-one

A mixture containing 0.2 g of the compound prepared in the preceding example, 0.5 ml of triethylamine, 5 ml of DCM and 0.1 g of orthotoluene chloride is stirred at RT for 48 hours. It is concentrated under vacuum, the residue is taken up in a water/ether mixture and allowed to decant, and the organic phase is washed with a saturated solution of sodium bicarbonate and then with water, dried and concentrated under vacuum to give 250 mg of a solid which is chromatographed on silica using DCM as eluent, yielding 0.1 g of the expected product.

Sm.p. = 192°C.

EXAMPLE 4

6- Chloro-1-(2,4-dimethoxybenzenesulfonyl)-3-spirocyclohexane-indol-2-one

A mixture containing 0.15 g of 6-chloro-3-spirocyclohexaneindol-2-one and 15 mg of sodium hydride in 2 ml of THF is stirred for 30 min at RT under nitrogen; 0.15 g of 2,4-dimethoxybenzenesulfonyl chloride is introduced and the stirring is maintained at RT for 20 hours. The mixture is concentrated under vacuum, the residue is taken up in 30 ml of water and extracted with ethyl acetate, and the extract is washed with water, dried and concentrated under vacuum. The product produced is recrystallized from isoether.

Sm.p. = 147°C.

EXAMPLE 5

Acid fumarate of 5-chloro-1-[4-(3-dimethylaminopropoxy)benzenesulfonyl]-3-spirocyclohexaneindol-2-one

A) 4-(3-Bromopropoxy)benzenesulfonyl chloride

A mixture containing 23 g of sodium 4-hydroxybenzenesulfonate dihydrate, 7 g of potassium hydroxide pellets (85%), 30 ml of water, 50 ml of absolute ethanol, 40 g of 1,3-dibromopropane and 3,4 tetrabutylammonium hydrogen sulfate is heated at reflux for 3 hours. The reaction medium is concentrated under vacuum, taken up in ethanol and concentrated again. The residue is taken up in hot methanol. The insoluble material is filtered off, the filtrate is concentrated, and the residue is triturated with ether to give 22.5 g of a white solid. 120 ml of phosphorus oxychloride and 16 g of phosphorus pentachloride are added to this solid, and the mixture is stirred for 20 hours at RT, and then heated under reflux for 1 hour. The reaction medium is concentrated under vacuum, the residue is then taken up in an ether/water mixture, and the organic phase is decanted and washed with a saturated solution of sodium bicarbonate. After drying and concentration, the expected product is obtained in the form of a yellow oil.

B) 1-[4-(3-Bromopropoxy)benzenesulfonyl]-5-chloro-3-spirocyclohexanindo1-2-one

A mixture containing 1.2 g of 5-chloro-3-spirocyclohexaneindol-2-one and 0.16 g of sodium hydride in 6 ml of THF is stirred at RT for 30 min under nitrogen. 1.6 g of 4-(3-bromopropoxy)benzenesulfonyl chloride is 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 produced oil is purified by chromatography on silica using isoether as eluent. The expected product is obtained in the form of an oil, which crystallizes from isoether.

m = 1 g.

Sm.p. = 123°C.

C) Acid fumarate of 5-chloro-1-[4-(3-dimethylaminopropoxy)-benzenesulfonyl]-3-spirocyclohexaneindo1-2-one

A mixture containing 0.5 g of the product prepared in the above step, 0.5 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 concentrated and taken up in 10 ml of water, and after rubbing, the insoluble material is separated and treated with 10 ml of 3 N hydrochloric acid. A gum is formed which is dissolved in 30 ml of hot water, and the solution is filtered on paper and then made alkaline by the addition of 12 N sodium hydroxide. The insoluble material is extracted with ether, and the extract is washed, dried and then concentrated to give a yellow oil. This is dissolved in 10 ml of acetone, and 0.1 g of fumaric acid is added to the hot solution.

The expected product precipitates at 20°C.

m = 240 mg.

Sm.p. = 168°C.

EXAMPLE 6

5-Chloro-1-(2,4-dimethoxybenzenesulfonyl)-3-spiroadamantanindol-2-one

A mixture containing 0.2 g of 5-chloro-3-spiroadamantanindol-2-one. and 20 mg of sodium hydride in 3 ml of THF, stirred for 30 min at RT under a nitrogen atmosphere. 0.18 g of 2,4-dimethoxybenzenesulfonyl chloride is added, and stirring is continued at RT for 20 hours. The reaction medium is concentrated under vacuum, the residue is taken up in 30 ml of water and extracted with ether, and the extract is washed with water, dried and concentrated under vacuum. The wax produced is crystallized from 15 ml of isoether.

m = 240 mg.

Sm.p. 152-154°C.

EXAMPLE 7

5-Chloro-1-(2,4-dimethoxybenzenesulfonyl)-3-spirocycloheptane-indol-2-one

A solution containing 0.156 g of potassium tert-butylate and 0.33 g of 5-chloro-3-spirocycloheptanindol-2-one in 15 ml of THF is cooled to -40°C under an inert atmosphere. The temperature can rise to approx. 10°C over 1 hour, the solution is then cooled to approx. -40°C, a solution of 0.335 g of 2,4-dimethoxybenzenesulfonyl chloride in 15 ml of THF is added dropwise, and the mixture is stirred at RT for 2 h. The solvent is evaporated under reduced pressure, and the residue is then taken up in 30 ml of DCM and 30 ml of water. The organic phase is separated, washed with 15 ml of water, dried over magnesium sulphate and evaporated under vacuum. The oil produced is chromatographed on silica using a cyclohexane/DCM mixture as eluent to give the expected compound, which is recrystallized from heptane.

m = 0.51 g.

Sm.p. = 135°C.

EXAMPLE 8

2,4-Dimethoxy-1-benzenesulfonyl-2a-methyl-2a,3,4,5-tetrahydro-benz [c,d]indol-2-one (I: Rx = H, -R2-R3 = -( CH2)3-, R4 = CH3, Rs = Rs = 0CH3)

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

The temperature can rise to approx. 0°C, the solution is then cooled to -60°C, and a solution of 0.57 g of methyl iodide in 20 ml of THF is added; the medium is kept at -10°C for 30 min. while stirring, and then cool to approx. -40°C, and a solution of 0.96 g of 2,4-dimethoxybenzenesulfonyl chloride in 10 ml of THF is added. After stirring for 16 hours at RT, the solvent is evaporated under reduced pressure, and the residue is taken up in 30 ml of DCM and 30 ml of water, the organic phase is separated and then dried over magnesium sulfate and evaporated. The oil produced is purified by chromatography on silica using a cyclohexane/DCM mixture as eluent to give the expected product, which is recrystallized from a cyclohexane/AcOEt mixture (95/5; v/v).

Sm.p. = 160°C.

The compounds according to this invention compiled in Table 3 below were prepared from the 2-oxinodoles described above by following the method described in the examples above.

EXAMPLE 87

1-(2,4-Dimethoskybenzenesulfonyl)-3-(4,4-dimethylspirocyclohexane)-5-hydroxyindol-2-one

3.51 g of the compound prepared in Example 60 is stirred at 50°C for 1 hour under a hydrogen atmosphere with 0.5 g of 10% palladium-on-charcoal in 150 ml of ethanol. The catalyst is filtered off on talc, the material on the filter is rinsed with DCM, and the filtrate is evaporated under reduced pressure, yielding 2.8 g of the expected compound which is recrystallized from a cyclohexane/AcOEt mixture (90/10; v/v).

Sm.p. = 220°C.

EXAMPLE 88

1-(2,4-Dimethoxybenzenesulfonyl)-5-hydroxy-3-spirocyclohexane-indol-2-one is prepared in the same way by starting with the 5-benzyloxy derivative described in Example 59.

Sm.p. = 196°C.

EXAMPLE 80 bis

1-(2,4-Dimethoxybenzenesulfonyl)-3-(4,4-dimethylspirocyclohexane)-5-ethoxyindol-2-one

This compound, already described in example 80, can be prepared by another method starting from the homologous 5-hydroxy compound. 0.6 g of the compound prepared in example 87 is stirred at RT for 16 hours under an inert atmosphere with 0.19 g of anhydrous potassium carbonate and 0.315 g of ethyl iodide in 11 ml of DMF. The solvent is evaporated 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 sulphate and then concentrated under reduced pressure.

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

Sm.p. = 160°C.

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

EXAMPLE 93

5-Acetoxy-1-(2,4-dimethoxybenzenesulfonyl)-3-spirocyclohexane-indol-2-one

0.5 g of the compound prepared in Example 88, 2.5 ml of isopropenyl acetate and 0.165 g of potassium carbonate in 2.5 ml of toluene and 0.3 ml of DMF, are heated for approx. 65°C for 15 hours. After cooling, 10 ml of water and 15 ml of ethyl acetate are added, and the organic phase is decanted, washed with water, dried over magnesium sulphate and concentrated under reduced pressure. 0.51 g of the expected compound, containing 0.5 mol of cyclo-

hexane, is isolated by crystallization from a cyclohexane/ethyl acetate mixture.

Sm.p. = 116°C.

EXAMPLE 94

1-(2,4-Dimethoxybenzenesulfonyl)-5-(2-hydroxyethoxy)-3-spiro-cyclohexaneindol-2-one

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, is heated at approx. 70°C for 40 hours. After cooling, 10 ml of water and 15 ml of ethyl acetate are added, and the organic phase is decanted, washed with water, dried over magnesium sulphate and concentrated under reduced pressure. The oil residue is chromatographed on a silica column using a cyclohexane/AcOEt mixture (70/30; v/v) as eluent, giving 0.5 g of the expected product, which is recrystallized from a heptane/DCM mixture.

Sm.p. = 170°C.

EXAMPLE 95

5-(2-Dimethylaminoethoxy)-1-(2,4-dimethoxybenzenesulfonyl)-3-spirocyclohexaneindol-2-one

0.6 g of the compound prepared in Example 88 is heated to approx. 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 of acetone and 2.4 ml of DMF. The salts are filtered off and 20 ml of water and 20 ml of AcOEt are added to the filtrate. The organic phase is decanted off, washed with water, dried over magnesium sulphate and concentrated under reduced pressure. The residue is chromatographed on silica using a DCM/MeOH mixture (9/1; v/v) as eluent to give 0.6 g of the expected product which is recrystallized from a cyclohexane/isoether mixture.

Sm.p. = 122°C.

EXAMPLE 96

5-Chloro-1-(2,4-dimethoxybenzenesulfonyl)-3-(spiropiperidin-4)-indol-2-one

This reaction is carried out according to J. Org. Chem., 1984, 49, 2795-2799. 0.75 g of 1-chloroethyl chloroformate is added at 0°C to a solution of 1.31 g of the compound described in Example 73, and 0.32 g of 1,8-bis-dimethylaminonaphthalene in 22 ml of 1,2-dichloroethane . The mixture is heated under reflux for approx. 20 minutes and concentrated under reduced pressure to a volume of approx. 10 ml, and 22 ml of methanol are then added. After heating under reflux for 50 minutes, the reaction medium is concentrated under reduced pressure and the residue is chromatographed on a silica column using a DCM/MeOH mixture (95/5; v/v) as eluent. 1.16 g of the expected product is isolated and recrystallized from a mixture of cyclohexane and ethyl acetate.

Sm.p. = 172°C.

EXAMPLE 97

3-(N-Acetylspiropiperidin-4)-5-chloro-1-(2,4-dimethoxybenzenesulfonyl)indol-2-one

0.086 ml of acetyl chloride is added to a solution cooled to approx. 0°C of 0.35 g of the compound prepared in the preceding example and 0.23 ml of triethylamine in 5 ml of DCM. The mixture is stirred for 1 hour at 20°C, 5 ml of water is added, the organic phase is decanted off, washed with water, dried over magnesium sulfate and concentrated under reduced pressure, and the residue is chromatographed on a silica column using a DCM/MeOH mixture ( 99/1; v/v) as eluent. 0.29 g of the expected product is isolated in the form of the hemihydrate.

Sm.p. = 107°C.

EXAMPLE 98

5-Chloro-1-(2,4-dimethoxybenzenesulfonyl)-3-(N-methoxycarbonyl-spiropiperidin-4)indol-2-one

This compound is prepared from that which was prepared in example 96 by reaction with methyl chloroformate.

Sm.p. = 147°C.

EXAMPLE 99

1-(3,4-Dimethoxybenzenesulfonyl)-5-propionamido-3-spirocyclohexaneindole - 2 - one

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

Sm.p. = 158°C.

EXAMPLE 100

1-(3,4-Dimethoxybenzenesulfonyl)-5-(N-methylureido)-3-spiro-cyclohexaneindol-2-one

0.15 g of methyl isocyanate is added to a solution cooled to approx. 0°C of 0.5 g of the compound described in Example 13, in 10 ml of DCM. After stirring for approx. 16 hours at RT, 20 ml of water are added, and the organic phase is decanted off, washed with water, dried over magnesium sulphate and concentrated under reduced pressure. 0.5 g of the expected product is isolated after recrystallization from a mixture of heptane and ethyl acetate.

Sm.p. = 214°C.

The compound described in the following example is produced in the same way.

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EXAMPLE 101

1-(3,4-Dimethoxybenzenesulfonyl)-5-(N-phenylureido)-3-spiro-cyclohexaneindol-2-one

Sm.p. = 124°C.

EXAMPLE 102

5-Dimethylamino-1-(2,4-dimethoxybenzenesulfonyl)-3-spirocyclohexaneindole - 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 approx. 6.5 with a few drops of acetic acid. After 48 hours at 20°C, the solvent is evaporated off under reduced pressure, and 20 ml of an approx. 2 N aqueous solution of sodium hydroxide and 20 ml of DCM are added. The organic phase is decanted off, washed with water and dried over magnesium sulphate, and the solvent is evaporated off under reduced pressure. The residue is chromatographed on a silica column using a cyclohexane/ethyl acetate mixture (80/20; v/v) as eluent. 0.27 g of the expected product is isolated.

Sm.p. = 167°C.

EXAMPLE 103

1-(2,4-Dimethoxybenzenesulfonyl)-5-ethylthio-3-spirocyclohexane-indol-2-one

This compound is prepared according to J. Chem. Soc. Chem. Commun., 1980, 16, 756. A mixture of 2.95 g of diethyl disulfide and 0.386 g of isopentyl nitrite is heated to approx. 80°C under an inert atmosphere, and 0.8 g of the compound prepared in Example 68 is added. The medium is stirred for 1 hour at 80°C and then concentrated under reduced pressure. The residue is chromatographed on a silica column using a DCM/cyclohexane mixture (80/20; v/v) as eluent. The expected product is isolated after crystallization from cyclohexane.

Sm.p. = 1.3°C.

EXAMPLE 104

5-Chloro-1-[4-(dimethylaminomethylcarboxamido)-2-methoxybenzenesulfonyl]-3-spirocyclohexaneindol-2-one

A) 5-Chloro-1-[4-(chloromethylcarboxamido)-2-methoxybenzenesulfonyl]-3-spirocyclohexaneindol-2-one

0.2 g of the compound prepared in example 2 is placed in 4 ml of DCM and 0.5 TEA at RT, and 0.1 g of chloroacetyl chloride is added. After stirring for 20 hours at RT, the mixture is concentrated under vacuum. The concentrate is extracted with ethyl acetate, the extract is washed with water and a solution of sodium carbonate, and the residue is then chromatographed on silica using a mixture of DCM and AcOEt as eluent, giving 0.15 g of the expected product.

B) 5-Chloro-1-[4-(dimethylaminomethylcarboxamido)-2-methoxy-benzenesulfonyl]-3-spirocyclohexaneindol-2-one

The compound prepared 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 chromatographed on silica using AcOEt as eluent, and yields 0.025 g of the expected product.

Sm.p. = 173°C.

EXAMPLE 105

1-[4-(4-Sulfamoylphenylcarboxamido)-2-methoxybenzenesulfonyl]-5-chloro-3-spirocyclohexaneindol-2-one

4-Chlorosulfonylbenzoyl chloride is prepared according to Chem. Ber., 1941, 271.

0.2 g of the compound prepared in Example 2 is brought into contact with 0.5 g of TEA in 5 ml of DCM; 0.13 g of 4-chlorosulfonylbenzoyl chloride is added, and the mixture is stirred for 20 hours at RT. It is concentrated under vacuum, the concentrate is taken up in THF, and 10 ml of aqueous ammonia is added. Stirring is continued for a further 20 hours at RT, and the mixture is concentrated under vacuum. The residue is extracted with ether, and the extract is washed with water, dried over sodium sulfate and then chromatographed on silica using AcOEt as eluent, forming the expected product.

SM.p. = 238-242°C after recrystallization from AcOEt.

EXAMPLE 106

1-[4-(3-Sulfamoylphenylcarboxamido)-2-methoxybenzenesulfonyl]-5-chloro-3-spirocyclohexaneindol-2-one

A) 3-Chlorosulfonylbenzoyl chloride

This compound is prepared according to US patent 3,290,370. 11 g of chlorosulfonic acid is heated to 60°C, and 8 g of phenylchloroform is added dropwise. After heating for 2 hours at 130°C, the mixture is distilled to give 1 g of the expected product.

K.p. = 120-125°C below 0.5 mm Hg.

B) 1-[4-(3-Sulfamoylphenylcarboxamido)-2-methoxybenzenesulfonyl]-5-chloro-3-spirocyclohexaneindol-2-one

210 mg of the compound prepared in Example 2 is placed in 10 ml of DCM with 220 mg of the compound prepared in the previous step and 200 mg of TEA, the mixture is stirred overnight, and the solvents are then evaporated under vacuum. The residue is taken up in 20 ml of THF and 20 ml of aqueous ammonia, and the mixture is stirred for 6 hours at RT. The solvents are driven off under vacuum, and the remainder is then taken up in AcOEt and water. Extraction is carried out with AcOEt, and the extract is washed with water and then chromatographed on silica using an AcOEt/cyclohexane mixture (50/50; v/v) as eluent, giving the expected product.

Sm.p. = 176°C.

EXAMPLE 107

1- [4-(2-Carboxyphenylcarboxamido)-2-methoxybenzenesulfonyl]-5-chloro-3-spirocyclohexaneindol-2-one

The preparation is carried out according to J. Heterocycl. Chem., 1974, 997-1000.

A mixture containing 0.2 g of the compound prepared in example 2 with 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 treated with normal hydrochloric acid. The precipitate formed is filtered off and treated with a 10% solution of sodium carbonate; a precipitate forms again, the aqueous phase is decanted off, and the precipitate is treated with 10% AcOH. The precipitate is filtered off and then washed with 10% AcOH, followed by isopropyl ether and recrystallized from isoether to give the expected product.

m = 0.150 g.

Sm.p. = 157-158°C.

EXAMPLE 108

1-[4-(Benzyloxymethylcarboxamido)-2-methoxybenzenesulfonyl]-5-chloro-3-spirocyclohexaneindol-2-one

This compound is prepared by the method described in example 3 by reacting benzyloxyacetyl chloride with the compound prepared in example 2.

Sm.p. = 143°C after recrystallization from isoether.

EXAMPLE 109

5-Chloro-1-[4-(hydroxymethylcarboxamido)-2-methoxybenzenesulfonyl]-3-spirocyclohexaneindol-2-one

This compound is prepared by hydrogenating the compound prepared in the previous example, under the pressure of a water column, in the presence of 5% palladium-on-charcoal in an EtOH/AcOEt mixture.

Sm.p. = 202°C.

EXAMPLE 110

5-Chloro-1-[4-(imidazol-1-ylphenylcarboxamido)-2-methoxybenzenesulfonyl]-3-spirocyclopentandindo1-2-one

A) Ethyl ester of 4-(imidazol-1-yl)benzoic acid

A mixture containing 35 g of 4-fluorobenzoyl chloride in 50 ml of 100% ethanol is heated under reflux for 15 min. 35 g of the obtained ethyl ester of 4-fluorobenzoic acid are mixed with 22 g of imidazole and 61 g of potassium carbonate in 35 ml of DMSO. The mixture is heated for 18 hours at 120-130°C, and 500 ml of ice water is then added. A precipitate forms, and the expected product is crystallized from isoether.

Sm.p. = 98°C.

B) Imidazol-1-ylbenzoyl chloride

5 g of the ester prepared in step A is heated under reflux for 2 hours in 20 ml of water and 20 ml of sodium hydroxide solution. The reaction medium is washed with ether and then acidified (pH 2) with concentrated hydrochloric acid. The precipitate formed is filtered off and then washed with isoether. 5 g of the prepared acid are brought to reflux temperature in 35 ml of thionyl chloride. The precipitate formed is filtered off and then washed with isoether to form the expected acid chloride.

Sm.p. = 243°C.

C) 5-Chloro-1-[4-(imidazol-1-ylphenylcarboxamido)-2-methoxy-benzenesulfonyl]-3-spirocyclopentanindol-2-one

A mixture containing 210 mg of the compound prepared in Example 2 and 200 mg of the acid chloride prepared in Step B in 10 mL DCM and 1.5 mL TEA is stirred at RT for 1 hour and then heated at reflux for 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 chromatographed on silica using a DCM/methanol mixture as eluent. The expected product is recrystallized from isoether.

m = 0.010 g.

Sm.p. = 145°C.

EXAMPLE 111

5-Chloro-1-[2-methoxy-4-(phenoxycarboxamido)benzenesulfonyl]-3-spirocyclohexaneindol-2-one

The compound is prepared by reacting phenylchloroformate with the compound prepared in example 2.

Sm.p. = 209°C after recrystallization from isoether.

EXAMPLE 112

5-Chloro-1-[4-(N-methylureido)-2-methoxybenzenesulfonyl]-3-spiro-cyclohexaneindol-2-one

140 mg of the compound prepared in the previous example are mixed with 5 ml of ethanol, 5 ml of DCM and 5 ml of a 33% solution of methylamine in ethanol. After 1 hour at RT, the solvents are driven off and the residue is then chromatographed on silica using a DCM/MeOH mixture as eluent. The product produced is recrystallized from isoether.

Sm.p. = 254°C.

EXAMPLE 113

5-Chloro-1-(2-methoxy-4-ureidobenzenesulfonyl)-3-spirocyclohexaneindole - 2 - one

A mixture containing 200 mg of the compound prepared in Example 111 with 5 ml of 20% aqueous ammonia, 5 ml of ethanol and 5 ml of DCM is stirred for 1 hour at RT. After filtering the reaction medium and evaporating the solvents, the expected product is crystallized from isoether.

Sm.p. = 228°C.

EXAMPLE 114

5-Chloro-1-[4-(N-o-tolylureido)-2-methoxybenzenesulfonyl]-3-spirocyclohexaneindol-2-one

A mixture containing 250 mg of the compound prepared in Example 2, 10 ml of xylene and 80 mg of orthotoluene isocyanate is heated under reflux for 18 hours. A white precipitate forms which 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 eluent. The expected product is crystallized from isoether.

Sm.p. = 182°C.

EXAMPLE 115

Benzyl-4-(5-methoxy-2-oxo-3-spirocyclohexaneindol-1-yl)-sulfonyl-3-methoxybenzoate 60 mg of sodium hydride sodium hydride is poured in small portions into a mixture containing 500 mg of 3-spirocyclohexane-5- methoxyindol-2-one in 50 mL THF. After 30 min. at RT, 800 mg of benzyl-3-methoxy-4-chlorosulfonylbenzoate chloride are added, and the mixture is stirred for 2 hours at RT. The medium is concentrated and taken up in AcOEt, and the mixture is washed with water, dried over sodium sulfate and concentrated. The residue is chromatographed on silica using DCM as eluent.

NMR (at 250 MHz in DMSO):

1.2-1.8 ppm : 10H : cyclohexyl

3.6 ppm and 3.8 ppm: 2 x 3H .- 2 x OCH3

5.4 ppm: 2H : CO 2 -CH 2 -C 6 H 5

6.8-8.2 ppm : 11H : aromatic protons

EXAMPLE 116

4-(3-Spirocyclohexane-5-methoxy-2-oxoindol-1-yl)sulfonyl-3-methoxybenzoic acid

600 mg of the compound prepared in the previous example is placed in 50 mL of AcOEt and hydrogenated at RT and atmospheric pressure in the presence of 140 mg of palladium-on-charcoal to give 310 mg of the expected acid, which is recrystallized from a hexane/ethanol mixture ( 70/30) v/v).

Sm.p. = 210°C.

EXAMPLE 117

5- Chloro-1- [4- (N-(ethoxycarbonylmethyl)carbamoyl)-2-methoxy-benzenesulfonyl]-3-spirocyclohexaneindol-2-one

450 mg of ethyl glycinate hydrochloride in 20 mg of sodium methylate, placed in methanol. 200 mg of the compound described in Example 57, in 50 ml of DCM, is added and the mixture is stirred at RT for 48 hours. It is extracted with DCM, and the extract is washed with water, dried, concentrated and then chromatographed on silica using DCM/MeOH (99.5/0.5; v/v) as eluent.

Sm.p. = 164°C.

EXAMPLE 118

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

300 mg of the compound described in example 57 are mixed with 5 ml of 30% aqueous ammonia, 10 ml of ethanol and 10 ml of DCM. After 1 h at RT, the mixture is concentrated and extracted with DCM, and the extract is washed with water, dried, concentrated and then chromatographed on silica using DCM/- MeOH (99/1, v/v) as eluent, giving 109 mg of the expected product.

Sm.p. = 160°C.

EXAMPLE 119

5-Chloro-1-[2-methoxy-4-(N-(2-methoxycarbonylethyl)carbamoyl-benzenesulfonyl)]-3-spirocyclohexaneindol-2-one

A mixture comprising 320 mg of the compound described in example 57 and 2 g of methylaminobispropionate in 30 ml of tetramethylbenzene is heated under reflux for 30 min. 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 DCM/MeOH (99/1, v/v) as eluent, and gives 100 mg of the expected product.

Sm.p. = 147°C.

EXAMPLE 120

1-[4-(3-(N-Boc)aminoacetidin-1-ylcarbonyl)-2-methoxybenzenesulfonyl]-5-chloro-3-spirocyclohexaneindol-2-one

A mixture containing 300 mg of the compound prepared in Example 57, 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 ethyl acetate, and the extract is washed with 1 N solution of hydrochloric acid, dried over sodium sulfate and concentrated. The expected product is obtained after chromatography on silica, using DCM/MeOH (99/1, v/v) as eluent.

Sm.p. = 136°C.

EXAMPLE 121

1-[4-(3-Aminoazetidin-1-ylcarbonyl)-2-methoxybenzenesulfonyl]-5-chloro-3-spirocyclohexaneindol-2-one

A mixture containing 160 mg of the compound prepared in the previous example and 3 ml of TFA in 10 ml of DCM is stirred for 30 min. at RT. The reaction medium is concentrated and crystallized from isoether, and the crystals are filtered off and dried. The prepared product is dissolved in 10 ml of water and then in 10 ml of 1 N sodium hydroxide; the solution is extracted with DCM, and the extract is washed with water, dried over sodium sulfate and concentrated. The expected product is obtained after chromatography on silica, using DCM/MeOH (96/4, v/v) as eluent.

Sm.p. = 145°C.

EXAMPLE 122

5-Ethoxy-1-[4-(3-dimethylaminopropoxy)-3-methoxybenzenesulfonyl]-3-spirocyclohexaneindol-2-one hydrochloride A) 5-Ethoxy-1-[4-(3-bromopropoxy)-3-methoxybenzenesulfonyl ]-3-spirocyclohexaneindol-2-one

A mixture containing 0.5 g of 5-ethoxy-3-spiro-cyclohexaneindol-2-one, 5 ml of THF and 0.07 g of sodium hydride is stirred at 20°C for 15 min., 1.65 g of 4- (3-Bromopropoxy)-3-methoxybenzenesulfonyl chloride is then added and the resulting mixture is stirred for 20 hours at RT. It is concentrated under vacuum and extracted with ether, and the extract is washed with water and then a 10% solution of sodium carbonate. The expected product is crystallized from pentane and then recrystallized from isoether.

Sm.p. = 114-118°C.

B) 5-Ethoxy-1-[4-(3-dimethylaminopropoxy)-3-methoxybenzenesulfonyl]-3-spirocyclohexaneindol-2-one hydrochloride

The compound prepared 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 3 hours, the mixture is concentrated under vacuum and taken up in 10 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 make the solution alkaline to pH 9. The oil that precipitates is extracted with DCM. The expected product is crystallized from ether.

Sm.p. = 135-138°C.

EXAMPLE 123

1-[4-Aminosulfonamido-2-methoxybenzenesulfonyl]-5-chloro-3-spiro-cyclohexaneindole - 2 - one

0.3 g of the compound prepared in example 2 is placed in 4 ml of DCM in the presence of 0.5 g of TEA, and 0.3 g of aminosulfonyl chloride, prepared according to Chem. Ber., 1958, 1339-1341. After stirring for 2 days at RT, the medium is concentrated under vacuum and extracted with ether, and the extract is washed with water. After drying, the residue is chromatographed on silica, using DCM and then AcOEt as eluent, to give the expected product, which is crystallized from ether.

Sm.p. = 205-208°C.

EXAMPLES 124 and 125

1-(4-Dimethylamino-2-methoxybenzenesulfonyl)-5-methoxy-3-spiro-cyclohexaneindole-2-one and 1-(4-methylamino-2-methoxybenzenesulfonyl)-5-methoxy-3-spirocyclohexaneindole-2 -on

500 mg of 1-(4-amino-2-methoxybenzenesulfonyl)-5-methoxy-3-spirocyclohexaneindol-2-one are mixed with 1 ml of a 37% aqueous solution of formaldehyde, 10 ml of acetonitrile and 430 mg of sodium cyanoborohydride, and 0, 12 ml of acetic acid is then added. The temperature of the medium rises, and the medium is then cooled in an ice bath. Two products of different polarity are formed in sequence. 1 ml of an aqueous solution of formaldehyde, 300 mg of sodium cyanoborohydride and 0.12 ml of acetic acid are added to the medium. The mixture is stirred for 1.5 hours, poured into ice water and then extracted with AcOEt. The extract is washed with water, dried and concentrated to form two products

which are separated by chromatography on silica, using DCM/AcOEt (98/2, v/v) as eluent.

Sm.p. = 210°C (ex. 124).

Sm.p. = 170°C (ex. 125) .

The NMR spectra are run in DMSO at 200 MHz.

NMR of Example 161:

1.3-1.8 ppm : 10H : cyclohexyl 3.5 ppm : 3H : OCH3

5.3 ppm : 2H : 0-CH2-C6Hs 7.8-8.2 ppm : 11H : aromatic protons

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:

1-2.2 ppm : 16H : cyclohexyl + 2CH3

3 ppm : 3H : NCH3

4-4.4 ppm : 6H : aromatic protons 6.8- 8.2 ppm : 6H : aromatic protons

A resolution of the signals is observed; this is put in context with the amide isomerism.

EXAMPLE 210

1-(4-Benzyloxy-2-methoxybenzenesulfonyl)-5-ethoxy-3-spiro-cyclohexaneindole - 2 - one

A) Potassium 4-benzyloxy-2-methoxybenzenesulfonate

This preparation is carried out according to K. Hofmann et al., Liebigs Ann. Chem., 1982, 282-297.

10.5 g of 4-benzyloxy-2-methoxybenzene are mixed at 5°C with 30 ml of DCM, and 8 ml of trimethylsilylchlorosulfonate in 30 ml of DCM are added over 15 min. at a temperature between 5 and 10°C; after stirring for 15 min. add 50 g of ice. The mixture is washed with ethyl ether, treated with potassium bicarbonate and then concentrated under vacuum. After drying, the residue is taken up in 150 ml of methanol. The insoluble material is filtered off at the boiling point, and the expected compound then crystallizes at 5°C.

Sm.p. > 300°C.

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

B) 4-Benzyloxy-2-methoxybenzenesulfonyl chloride

2.8 g of the compound prepared in the previous example are mixed with 30 ml of POCl 3 , and the mixture is heated at reflux for 3 hours. It is concentrated under vacuum, treated with 20 g of ice and extracted with ethyl ether, and the extract is washed with 30 ral of normal sodium hydroxide and then water. The medium is concentrated, and the produced oil is then rubbed into 30 ml of isoether. The expected product (0.7 g) crystallizes.

Sm.p. = 95°C.

C) 1-(4-Benzyloxy-2-methoxybenzenesulfonyl)-5-ethoxy-3-spirocyclohexaneindol-2-one

This compound is prepared by the usual method. It crystallizes from isoethers.

Sm.p. = 135°C.

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

The compound in the next example is then prepared by debenzylation.

EXAMPLE 211

5-Ethoxy-1-(4-hydroxy-2-methoxybenzenesulfonyl)-3-spirocyclohexaneindole - 2 - one

Sm.p. = 209°C.

Claims (19)

1. Connection, characterized by the formula where Rx and R2 are both independently hydrogen, hydroxy, C^ C^- u- haloalkoxy, halogen, Cx-C4-alkyl, trifluoromethyl, Cx-C7-alkoxy, Cx-Cj-polyhalogenalkoxy, C2 - C4-co-hydroxy - alkoxy, co-methoxyalkoxy where the alkyl is C2-C4, C2-C4-co -aminoalkoxy which is free or substituted with one or two C 1 -C 4 alkyls; C3-C7 cycloalkyloxy, cycloalkylmethoxy where the cycloalkylene is C3-C7; phenoxy; benzyloxy; C 1 -C 4 -alkylthioj ^phenylthio, nitro,- amino which is free or substituted by one or two C 1 -C 6 -alkyls,- cyano; C 1 -C 4 acyl; Cx-Cj acyloxy; Cx-C4-alkyl sulfonamido, phenylsulfonamido, C1-4-alkylamido, C1-C4-alk0xycarbonylarrri.no, ureido which is unsubstituted or substituted with a phenyl or with one or two Cx-Q-alk<y>les ; R3 and R4 both independently are Cx-Cg-alkyl, C3-C7-cycloalkyl, phenyl, benzyl, cycloalkylmethyl wherein the cycloalkyl is C3-C7; or R 3 and R 4 together form a group - (CH 2 ) p X (CH 2 ) q -; or R3 and R4, together with the carbon atom to which they are attached, form an optionally fused, saturated or unsaturated C3-Cl0 hydrocarbon ring which is unsubstituted or substituted with one or more Ci-Cy alkyl groups or with a C3-Cs spirocycloalkyl; or also Rx and R4 both have one of the above meanings, and R2 is placed in the 4-position of the indole and forms the group (CH2)3 with R3; R s and R 6 are both independently hydrogen, halogen, C 1 -C 7 - alkyl, trifluoromethyl, cyano, nitro, amino which is free or substituted with one or two C 1 -C 1 alkyl er, hydroxyamino; hydroxy; carboxy; the group 0R7; the group SR7; C 1 -C y acyl; C 1 -C 6 -Alkoxycarbonyl; f enoxycarbonyl; benzyloxycarbonylcarbamoyl substituted with the groups R'6 and R''6; thiocarbamoyl which is free or substituted with one or two C 1 -C 7 alkyls; sulfamoyl; alkylsulfamoyl or dialkylsulfamoyl wherein the alkyl is C1-C1; the group S02R'7; alkylsulfonamido wherein the alkyl is C1-C1; the group COR'7; the group NR 8 R 9 or the group CO-NH-CH(R 10 )-COR 12 ; if appropriate, the phenyl group which forms part of the substituent Rs and/or Rs can be unsubstituted or monosubstituted or polysubstituted with Cx-C, -alkyl, trifluoromethyl, methoxy, halogen, sulfamoyl, alkylsulfamoyl where the alkyl is Cx-C7, carboxy, alkoxycarbonyl wherein the alkyl is Cx-C7, CVCy-acyloxy or imidazolyl; R'6 and R<f>% are both independently hydrogen, C 1 -C 1 -alkyl which is unsubstituted or substituted by R'''s, phenyl, pyridyl, methylpyridyl, piperidin-4-yl or methylpiperidin-4- howl; R'"6 is hydroxy, cyano, carboxy which is free or esterified with a Cx-Cy alkyl or with a benzyl; phenyl, -pyridyl; methylpyridyl; amino which is free or substituted with one or two C 1 -C 4 -alkyls,- R 7 is C 1 -C 1 -alkyl, phenyl, benzyl, C 3 -C 7 -cycloalkyl, C 2 - C 4 -alkenyl, C 1 -C 2 -haloalkyl, C 1 -C 7 -polyhaloalkyl, C 1 -C 7 -acyl, C 1 -C 7 -carboxyalkyl which is free or esterified with a C 1 -C 4 -alkyl or with a benzyl , C2-C7-co-aminoalkyl where the amino group is free, substituted by one or two C^-Q alkyls or in the form of an ammonium ion, -R'7 is a piperazin-1-yl group which is unsubstituted or substituted in 4-position with the group R''7#© a piperidino group which is unsubstituted or substituted in the 4-position with the group R'''7, an azetidin-1-yl group which is unsubstituted or substituted in the 3-position with the group R'' a pyridyl group which is unsubstituted or substituted with a methyl; R' S is C 1 -C 4 alkyl, phenyl, benzyl or C 1 -d -acyl; R' ' '7 is R' '7 or amino which is free or has a be- shooting group; R 8 and R 9 are both independently hydrogen, C 1 -C 1 -alkyl, phenyl or benzyl; R9 can also be Ci-C^-acyl, Cx-C^-thioacyl, cycloalkylcarbonyl where cycloalkyl is C3-C7, cycloalkyl-thiocarbonyl where cycloalkyl is C3-C7, Cx-C^-co-aminoacyl, Ci-^-co -hydroxyacyl, Ci-^-w-benzyloxyacyl, f enoxycarbonyl, thienocarbonyl, pyridylcarbonyl, methylpyridyl-carbonyl, CVC^-alkoxycarbonyl, benzoyl, phenacetyl, the group CO-CH (Rl0) -NRnR 'X1, the group CH (R10) C02Ru, the group (CH 2 ) tCOR 12 , the group CO (CH 2 ) tCOR 1 2 , carbamoyl which is unsubstituted or substituted with a phenyl or a. or two C1-C4 alkyls,- m is 1 or, when R 6 is halogen, C 1 -C 1 -alkyl or C 1 -C 7 - alkoxy, m may also be 2, 3 or 4, or (R 6 )ffi may be<*>m-substituents having different meanings selected from halogen, C 1 -C 1 -alkyl and C 1 -C 1 -alkyl, -p and g are both whole numbers, where it is possible that the sum can vary from 3 to 6; t is an integer that can range from 1 to 5; X is oxygen, sulfur or the group NR13; R 10 is hydrogen, C 1 -C 4 alkyl or benzyl; Rn °9 R'ii both independently are hydrogen or Cx - C4 - alkyl; R 12 is hydroxy, C 1 -C 4 alkoxy or amino which is unsub substituted or substituted with one or two C 1-6 alkyls; R13 is hydrogen, C1-C4 alkyl, phenyl, benzyl, C1-C4 acyl, C 1 -C 6 -Alkoxycarbonyl or carbamoyl which is unsubstituted or substituted by one or two C 1 -C 4 alkyls, -provided that when R 3 is methyl, R 4 is methyl or ethyl and m = 1, R s is not methyl, and its salts where appropriate. 2. Compound with formula (I) according to claim 1, characterized in that Rx is a chlorine atom or an ethoxy group in the 5-position of the indole, and R2 is hydrogen. 3. Compound with formula (I) according to claim 1, characterized in that R3 and R4, together with the carbon atom to which they are bound, form a C3-C10 hydrocarbon ring. 4. Compound with formula (I) according to claim 1, characterized in that R3 and R4, together with the carbon atom to which they are bound, form cyclohexane which is unsubstituted or substituted with one or two Cx-Cy alkyl groups or with C3-Cs spirocycloalkyl, cycloheptane, adamantane or tricyclo[5.2.1.02-6]dec-8-ene. 5. Compound with formula (I) according to claim 1, characterized in that R3 and R4, together with the carbon atom to which they are bound, form a piperidine-4- or N-methylpiperidine-4-ring. 6. Compound with formula (I) according to claim 1, characterized in that R5 and R6 are both methoxy. 7. Compound with formula (I) according to claim 1, characterized in that Rs in the 2-position is methoxy and R6 in the 4-position is Cx-Cy-acylamino, C1-C4-dialkyl-ureido or alkoxycarbonylalkylcarbamoyl, where the alkyl groups are Q1 - C?. 8. Compound with formula (I) according to claim 1, characterized in that Rj is in the 5-position, and R2 is hydrogen. 9. Connection according to claim 1, characterized by the formula where Rx, R2, R3, R4 and R5 are defined as stated above for (I) in claim 1, and its functional derivatives. 10. Connection according to claim 1, characterized by the formula where Rlf R2, R3, R4 and R5 are defined as stated above for (I) in claim 1, and its salts where appropriate. 11. Connection according to claim 1, characterized by the formula where RX/ R2, R3, R4 and R5 are defined as stated above for (I) in claim 1. 12. Connection according to claim 1, characterized by the formula where R3, R4, Rs, R6 and m are defined as stated above for (I) in claim 1. 13. Connection according to claim 1, characterized by the formula where Rl7 R2, Rs, R6 and m are defined as stated above for (I) in claim 1. 14. Connection, characterized by the formula where Rx and R2 are both independently hydrogen, hydroxy, C1-C4-co- haloalkoxy, halogen, C1-C4-alkyl, trifluoromethyl, Cx-C7-alkoxy, Cx-C3-polyhalogenalkoxy, C2-C4-w-hydroxyalkoxy, co-methoxyalkoxy where the alkyl is C2-C4, C2-C4-cj -aminoalkoxy which is free or substituted with one or two Cx-C4-alkyl is, C3-C7-cycloalkyloxy, cycloalkylmethoxy where the cycloalkyl is C3-C7, phenoxy, benzyloxy, Cx-Cj-alkyl-thio, phenylthio, nitro, amino as is free or substituted with one or two Ci-Cj alkyls, cyano, Cx-C^-acyl, Cx-Cj-acyloxy, Cx-C4-alkylsulfonamido, phenyl sulfonamido, Cx-C4-alkylamido, Cj-C 3-Alkoxycarbonylamino or ureido which is unsubstituted or substituted with a phenyl or with one or two C 1 -C 4 alkyls; and R3 and R4, together with the carbon atom to which they are attached, forms adamantane, indane or hexahydroindane which is unsubstituted or substituted with one or more Ci-CValkyl groups, tricyclo [5.2.1.02-6] decane or tricyclo [5.2 .1.0<26>] - dec-8-ene which is unsubstituted or substituted with one or more Ci-Cy alkyl groups, or a C4-Ca hydrocarbon ring substituted with one or several C 1 -C 4 -alkyl groups or with C 3 -C 8 -spirocycloalkyl; or also R3 and R4 together form the group - (CH2) p-X (CH2) q-, where p and q are whole numbers with a sum that can vary from 3 to 6, and X is oxygen, sulfur or the group NR13, where R13 is phenyl, benzyl, C1-C4-acyl, C1-C4- alkoxycarbonyl or carbamoyl which is unsubstituted or substituted with one or two C 1 -C 4 alkyls, with the restriction that if CR3R4 is adamantane, Rx <p>g R2 must be different from hydrogen. 15. Connection, characterized by the formula where Rx is hydroxy, Cx-Q-co-halogenoalkyl, halogen, ^- C^- alkyl, trifluoromethyl, C 1 -C 1 -alkyloxy, C 1 -C 4 -polyhalo-alkyloxy, C 2 -C 4 -w-hydroxyalkyloxy, w-methoxyalkyloxy where the alkyl is C 2 -C 4 , C 2 -C 4 -amino alkoxy which is free or substituted with one or two Cx-^-alkyls, C3-C7-cyclo-alkyloxy, cycloalkylmethoxy where the cycloalkyl is C3-C7, phenoxy, benzyloxy, Cx-Cj-alkylthio, phenylthio, nitro, amino which is free or substituted with one or two Cx-C4-alkyls, cyano, Cx-C4-acyl, Cx-C^-acyloxy, Cx-C4-alkyl sulfonamido, phenyl sulfonamido, Cx-d-alkylamido, Cx-C^-alkoxycarbonylamino or ureido which is unsubstituted or substituted by phenyl or by one or two C 1 -C 4 alkyls; R3 and R4 together form the group - (CH2) p-X (CH2)q-,- or R3 and R4, together with the carbon atom to which they are attached, forms an optionally condensed, saturated or unsaturated C3-C10 hydrocarbon ring which is unsubstituted or substituted with one or more Cx-C4-alkyl groups or with C3-Cs-spirocycloalkyl; p and q are both integers, where it is possible that their sum can vary from 3 to 6; X is oxygen, sulfur or the group NR13,- and R13 is hydrogen, Cx-C4-alkyl, phenyl, benzyl, C1-C4-acyl, Cx-C4-Alkoxycarbonyl or carbamoyl which is unsubstituted or substituted with one or two Cx-C4-alkyls, with the limitation that if Rx is methoxy, CR3R4 must be different from 3-pyrrolidine which is unsubstituted or N-substituted with Cx-C4 alkyl, and if Rx is halogen, CR3R4 must be different from pentane. 16. Connection according to claim 15, characterized in that Rj is ethoxy. 17. Compound, characterized by the formula where Alk is C 1 -C 7 alkyl; Y is 0 or S; and Rv is Cx-C7-alkyl, C3-C7-cycloalkyl, C2-C4-alkenyl, Cx-C7- w-haloalkyl, C1-C7-polyhaloalkyl, benzyl, C-^-C-,-acyl or (VCVaj-carboxyalkyl esterified with Cx-C7-alkyl or with benzyl. 18. Pharmaceutical mixture, characterized in that a compound according to any one of claims 1 to 8 is present as the active principle. 19. Pharmaceutical mixture, characterized in that a compound according to any one of claims 1 to 8 is present together with another active principle.