SK105393A3 - N-sulphonyl-2-oxoindole derivatives, their preparation and their pharmaceutical agents with the content of those - 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

Technical field

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

BACKGROUND OF THE INVENTION

International Patent Application WO 91/01 306 discloses 2-oxoindole derivatives useful for the treatment of senile dementia. These compounds have the formula 1

wherein J ^is hydrogen, halogen, alkyl or alkoxy,

R 2 is hydrogen or lower alkyl,

R ₃ is alkyl, cycloalkylmethyl, benzodioxanylmethyl or optionally substituted benzyl;

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

In several patent applications, families of compounds with a non-peptidic structure that act on vasopressin and / or oxytocin receptors have recently been described. European applications EP 382 185 and EP 444 945, international application WO 91/05 549 and especially Japanese patent application JP 03/127732 can be mentioned in this regard. The latter document discloses indole-3-propionic acid derivatives of formula 2

where

R 12 is hydrogen, alkyl, alkenyl, phenylalkyl, tetrahydrofuryl, alkoxycarbonyl, alkoxycarbonylalkyl, carboxyalkyl or alkanoyl,

R '2 is hydrogen, hydroxyl, alkoxy, alkyl, phenylalkyl, phenylalkoxy or halogen,

R '' ₃ is hydrogen, alkoxy, free or substituted amino or an amino acid residue,

R ₁₄ is hydrogen, alkyl or phenylalkyl;

R '' ₅ is benzoyl, phenyl, alkyl, phenylalkenylcarbonyl, thienylcarbonyl, phenylsulfonyl, pyridylcarbonyl or imidazolylcarbonyl, wherein the phenyl and alkyl groups of R '. ₅ may be substituted.

These compounds are vasopressin antagonists.

US Patent 4,803,217 claims hapalindolinones obtained by fermentation that are vasopressin antagonists. These compounds have the formula 3

wherein R is H or Cl.

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

Vasopressin is a hormone known for its anti-diuretic and arterial pressure control activity. It stimulates several types of receptors, namely (V _1a , V 1) ^and V _2, and thus exerts cardiovascular, hepatic and antidiuretic effects, acts on platelet aggregation and on the central and peripheral nervous systems. Vasopressin receptor antagonists may affect regulation of central and peripheral circulation, especially coronary, renal and gastric circulation, as well as regulation of hydration and release of adrenocorticotropic hormone (ACTH). Non-peptidic vasopressin antagonists may advantageously replace vasopressin or analogues thereof in the treatment of diabetes insipidus; they can also be used in the treatment of enuresis and in the regulation of hemostasis; treatment of haemophilia and Von Willebrand syndrome, an antidote to platelet aggregating agents; Drug Investigation, 1990, 2 (Suppl. 5), 1-47. Vasopressin receptors, like oxytocin receptors, are also found in uterine smooth muscle. Oxytocin has a vasopressin-like peptide structure. Its receptors are also found in myoepithelial mammary gland cells and the central nervous system (Presse médicale, 1987, 16 (10), 481-485, J. Lab. Clin. Med., 1989, 114 (6), 617-632 and Pharmacol. Rev., 1991, 43 (1), 73-108). This hormone is active in childbirth, lactation and sexual behavior.

The compounds of the invention are therefore particularly suitable for the treatment of central and peripheral nervous system, cardiovascular, renal and gastric disorders and sexual behavior disorders in humans and animals.

SUMMARY OF THE INVENTION

The present invention provides compounds of formula I

(0th

where

R 1 and R ₂ independently represent hydrogen, hydroxy, C ₁ -C ₄ -haloalkoxy, halogen, C ₁ -C ₄ alkyl, trifluoromethyl, C ₁ -C ₄ -alkoxy, C 1 -C 4 -haloalkoxy,

C ₂ -C ₄ -oo-hydroxyalkoxy, οο-methoxyalkoxy, wherein alkyl is C ₂ -C ₄ , C ₂ -C ₄ -α-aminoalkoxy, which is free or substituted by one or two C ₁ -C ₄ alkyl,

C ₃ -C ₇ cycloalkoxy, cycloalkylmethoxy, wherein the cycloalkyl is C ₃ -C ₇ , phenoxy, benzyloxy, C 1 -C 4 alkylthio, phenylthio, nitro, amino, which are free or substituted by one or two C ₁ -C ₄ alkyl, cyano, C ₁ -C ₄ acyl, C ₁ -C ₄ acyloxy, C ₁ -C ₄ alkylsulfonamido, phenylsulfonamido, C ₁ -C ₄ alkylamido, C ₁ -C ₄ alkoxycarbonylamino, ureido, which are unsubstituted or substituted by phenyl or one or two C ₁ -C ₄ alkyl,

R ₃ and R ₄ independently represent C ₃ -C ₇ alkyl, C ₃ -C ₇ cycloalkyl, phenyl, benzyl, cycloalkylmethyl, wherein the cycloalkyl is C ₃ -C ₇ , or R ₃ and R ₄ together form - (CH ₂ ) p X ( CH ₂ ) g or R ₃ and R ₄ together with the carbon atom to which they are attached form an optionally fused, saturated or unsaturated ^C 3 ^-C 10 hydrocarbon ring which is unsubstituted or substituted by one or more groups or C ₃ -C ₅ spiroalkyl, or farther

C ₁ -C ₄ alkyl

Rt and R,

R c and R 2 independently have one of the meanings given above and R ₂ is located at the 4-position of the indole and forms a (CH ₂ ) _{3 group} with R ₃ independently represent hydrogen, halogen, C ₁ -C ₇ alkyl, trifluoromethyl, cyano, nitro, amino, which are free or substituted by one or two C 1 -C ₇ alkyl, hydroxyamino, hydroxy, carboxy, OR ₇ , SR _? , C ₁ -C ₇ acyl, C ₁ -C ₇ alkoxycarbonyl, phenoxycarbonyl, benzyloxycarbonyl, carbamoyl, substituted with R 18 and R 18 thiocarbamoyl which is free or substituted by one or two C ₁ -C ₇ alkyl, sulfamoyl, alkylsulfamoyl or dialkylsulfamoyl wherein alkyl is C 1 -C ₇ , SO ₂ R ' ₇ , alkyl is C 1 -C ₇ , COR' ₇ , CO-NHCH (R ₁₀ ) -COR ₁₂ ; optionally, alkylsulfonamido, wherein NR ₈ R ₉ ,

R * 6 ^a

R ¹

R ₇ is a phenyl group forming part of the substituent R ₅ and / or R 8, unsubstituted, monosubstituted or polysubstituted with C ₁ -C ₇ alkyl, trifluoromethyl, methoxy, halogen, sulfamoyl, alkylsulfoamoyl, wherein the alkyl is ¢ 6 -0.7, carboxy, alkoxycarbonyl wherein alkyl is C 1 -C ₇ acyloxy or imidazolyl,

R 8 is independently hydrogen, C ₁ -C ₇ alkyl which is unsubstituted or substituted with R ₁₆ , phenyl, pyridyl, methylpyridyl, piperidin-4-yl, methylpiperidin-4-yl, is hydroxy, cyano, carboxy which is free or esterified with C ₁ -C ₇ alkyl or benzyl, phenyl, pyridyl, methylpyridyl, amino, which is free or substituted with one or two C ₁ -C ₇ alkyl,

C ₁ -C ₇ alkyl, phenyl, benzyl, C ₃ -C ₇ cycloalkyl, C ₂ -C ₄ alkenyl, C ₁ -C ₇ -haloalkyl, C ₁ -C ₇ polyhaloalkyl, C ₁ -C ₇ acyl, C C ₁ -C ₆ -carboxyalkyl which is free or esterified with C 1 -C ₄ alkyl or benzyl, C ₂ -C ₇ -aminoalkyl, wherein the amino group is free, substituted with one or two C 1 -C ₄ alkyls or in in the form of ammonium ion,

R '7 is piperazin-1-yl which is unsubstituted or substituted in the 4-position by R ₇ , piperidino which is unsubstituted or substituted in the 4-position by R ¹¹ , azetidin-1-yl which is unsubstituted or substituted in the 3-position by R ' 7, a pyridyl group which is unsubstituted or substituted by methyl,

R ₇ is C ₁ -C ₄ alkyl, phenyl, benzyl, C ₁ -C ₄ acyl,

R 7 is R 7 or amino, which is free or carries a protecting group,

R g and R _g is hydrogen, C ₁ -C ₇ alkyl, phenyl or benzyl; R _g may also be C ₁ -C ₇ acyl, C ₁ -C ₇ thioacyl, cycloalkylcarbonyl wherein the cycloalkyl is C ₃ -C _7, cykloalkyltiokarbonyl, wherein the cycloalkyl is C ₃ -C _7, C ₄ -C ^ O ° - aminoacyl, C ₁ -C ₄ -00-hydroxyacyl, C ₁ -C ₄ -benzyloxyacyl, phenoxycarbonyl, thienocarbonyl, pyridylcarbonyl, methylpyridylcarbonyl, C 1 -C ₄ alkoxycarbonyl, benzoyl, phenacetyl, CO-CH (R ₁₀ ) -NR _{1] L} R _ιχ, CH (R ₁₀₎ CO ₂ R _11, (CH ₂₎ t ^C0R i2 'is C0 (CH _{2) t} COR _12> carbamoyl, unsubstituted or substituted by phenyl or by one or two C ₁ -C ₄ alkyls, m is 1 or, when R _{g is} halogen, C ₁ -C ₇ alkyl or C ₁ -C ₇ alkoxy may also be 2, 3 or (R _g ) _m may be m substituents with different meanings selected from halogen, C ₁ -C ₇ alkyl and C ₁ -C ₇ alkoxy, and p and q are integers the sum of which can range from 3 to 6, t is an integer which can range from 1 to 5 .

X is oxygen, sulfur or NR _13, ^R 10 ^E 7 ^{Example of water} / C ₁ -C ₄ alkyl or benzyl, ^R 11 ^{and R} 11 are independently hydrogen or a C - ^ - C 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 alkyl, ^R 13 j ^{e in} UIK ° C? -C ₄ alkyl, phenyl, benzyl, C ^ - C ₄ acyl, C 1 -C ₄ alkoxycarbonyl or carbamoyl which is unsubstituted or substituted by one or two C ₁ -C ₄ alkyl, and possible salts thereof.

': ·· ·· · - - * * * »- - - -v -' in ';

When a compound of the invention has one or more asymmetric carbons, the invention includes all optical isomers of the compound.

Salts of the compounds of the formula I according to the invention include salts with mineral or organic acids which allow suitable separation or crystallization of the compounds of the formula I, such as picric acid, oxalic acid or some optically active acids, for example mandelic acid or camphosulfonic acid and mineral or organic acids which they form physiologically acceptable salts such as hydrochloride, hydrobromide, sulfate, hydrogen sulfate, dihydrogen phosphate, maleate, fumartan or naphthalene-2-sulfonate.

Salts of the compounds of formula I also include salts with organic or mineral bases, for example alkali metal or alkaline earth metal salts such as sodium, potassium and calcium salts, and potassium salts or amine such as salts of arginine, lysine or any preferably sodium trometamol, or a physiologically acceptable amine.

According to the invention, halogen is an atom selected from fluorine, chlorine, bromine and iodine, preferably fluorine or chlorine. By amino protecting group is meant a group such as tert-butoxycarbonyl, benzyloxycarbonyl or benzyl.

According to the invention, the optionally fused, saturated or unsaturated ^C 3 ^-C hydrocarbon rings also means different hydrocarbon rings of monocyclic, dicyclic or tricyclic structure such as cyclobutane, cyclopentane, cyclohexane, cyclooctane, indan, hexahydroindane, adamantane, norbornane, nornornen, dihydrofenalén, tricyclo [5,2,1,0 ² ' ⁶ ] decane or tricyclo [5,2,1,0 ^{2, 6} ] dec-8-ene.

Compounds of formula I wherein the 5-position is indole and R ₂ is hydrogen are preferred.

ιΛ.Κ · * '

Compounds of formula I wherein R 6 is a chlorine atom or an ethoxy group at the 5-position of the indole and R ₂ is hydrogen are preferred.

Compounds of formula I wherein R ₃ and R ₄ together with the carbon to which they are attached form a C ₃ -C ₁₀ hydrocarbon ring are preferred; particularly preferred are compounds wherein R ₃ and R ₄ together with the carbon to which they are attached form cycloheptane, adamantane, tricyclo [5,2,1,0 "dec-8-ene, or cyclohexane, which is unsubstituted; or substituted with C ₃ -C ₅ spirocycloalkyl or with one or two C ₁ -C ₇ alkyl groups.

Compounds of formula I wherein R ₃ and R ₄ together with the carbon to which they are attached form a 4-piperidine or N-methyl-4-piperidine ring are also preferred.

The compounds of formula I, wherein _R5 and _Rg are methoxy, are preferred. Similarly preferred are compounds wherein Rg at the 2-position is methoxy and Rg at the 4-position is C ₁ -C ₄ acylamino, C ₁ -C ₄ dialkylureido or alkoxycarbonylalkylcarbamoyl, wherein the alkyl groups are C ₁ -C ₆ .

These abbreviations are used throughout the description and examples;

DCM dichloromethane ether Ethyl ether iso ether isopropyl BOC tert Me methyl MeO methoxy et ethyl pr propyl Pr isopropyl nPr n-propyl Bu butyl iBu isobutyl Bu t. butyl ph phenyl bz benzyl

... ..... 1. ··. ·, »Ívvuii'iv.

Ac acetyl

AcOEt ethyl acetate

AcOH acetic acid

MeOH methanol

EtOH ethanol

DMF dimethylformainide

THF tetrahydrofuran

DMSO dimethylsulfoxide

DIFEA diisopropylethylamine

TEA triethylamine

TFA trifluoroacetic acid

TMEDA tetramethylethylenediamine

mp mp saline saturated aqueous sodium chloride solution TLC thin layer chromatography

HPLC high pressure liquid chromatography aqueous hydrochloric acid dilute hydrochloric acid, about 1N

RT room temperature

The invention furthermore relates to a process for the preparation of the compounds according to the invention comprising the step of preparing a benzenesulphonyl halide of the formula III.

Hai-SC ^

(ΙΠ) where R'5, resp. R _VI has the meaning of either R ₅ or R ₆ given in formula I, or a precursor of the groups R ₅ and R 8, reacted with the 2-oxoindole disubstituted at the 3-position of formula II

wherein R'j. R ₂ has the meaning of either or _R2, defined for formula I, or a prodrug of R] _ and _R2 and _R3 and _R4 are as defined for Formula I, and either f where R ^{= R} and ⁹ R ¹ 2 'R ₂ R * 5 ^{= R} 5 * ^{and R} VI' R 4 *, the obtained compound of formula I is isolated,

- or, if any of the groups R 1, ^R 2, ^R 5 ^{and R} vi is a precursor of the groups R 12, R 2, R 5 and / or R 8, the compound obtained is subjected to post-treatment to prepare a compound of formula I by converting any of the groups R'2, R'5 and RVI ^to Rx, respectively. R ₂ , resp. R ₅ , resp. R _g .

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 tert. potassium butylate.

The 2-oxoindoles (II) can be prepared by various methods. Some of these compounds are novel and form part of the invention.

Compounds (II) wherein R 1 and / or R ₂ is halogen and R ₃ and R ₄ together with the carbon to which they are attached form spirocyclobutane, spirocyclohexane or spirocycloheptane are known, for example, from DW Robertson et al., J. Med. Chem., 1987, 30 (5), 824-829. 5-chloro-3-spirocyclopentanindol-2-one is also described in U.S. Patent 3,947,451.

The Brunner reaction described in RF Moore and SGP Plant can be used to prepare compounds (II) when R ₃ and R ₄ are together or separately a hydrocarbon group. J. Chem. Soc., 1951, 3475-3478, which leads to the preparation of compounds (II) wherein CR ₃ R ₄ is cyclopentane or cyclohexane.

This reaction is carried out by cyclization of the phenylhydrazide derivative of formula IV

(IV) wherein R ' ₂ and R' ₂ are as defined in formula II and R 1 and R ₄ are as defined in formula I, for example by heating in the presence of calcium oxide and quinoline.

According to the same authors, the phenylhydrazide derivative IV is obtained by reacting a hydrazine derivative of the formula V

R

nh-nh ₂ (V) where R *! and R ' ₂ are as defined in formula II with an acid halide of formula VI

Hal-C-CR ₃ R ₄

Wherein R ₃ and R ₄ are as defined in formula I.

According to a particular embodiment, when R ₃ and R ₄ together with the carbon to which they are attached form a fused polycyclic hydrocarbon such as norborane or norbornene, the reaction is as described in J. Wolff et al.

performed by Tetrahedron,

1986, 42 (15), 4267-4272; First, a lithium salt of 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 cyclization is carried out by heating in a solvent such as naphthalene or prehenene (1,2,3,3). (4-tetramethylbenzene).

Compounds (II) wherein R 1 = R ₂ = H and CR ₃ R ₄ is adamantane are described in I. Fleming et al., J. Chem. Soc., Perkin Trans I, 1991, 3, 617-626. Compounds (II) wherein R ₃ and R ₄ together with the carbon atom to which they are attached form adamantane and R 1 and R ₂ are other than hydrogen are novel and form part of the invention. They can be prepared as described above.

The hydrazine derivatives (V) are known or are prepared by known methods. The same applies to acid halides (VI).

The 2-oxoindole, substituted in the 3-position (II), can also be prepared from the 2-oxoindole of formula VII

wherein R '1 and R' ₂ have the meaning given in formula II by various methods.

For example, the method described in AS Kende and JC Hodges, Synth. Commun., 1982, 12 (1), 1-10, involves the addition of an alkylating agent in a suitable solvent. To prepare compound (II) wherein R ₃ = R ₄ , the reaction is carried out at -75 ° C in THF in the presence of TMEDA by addition of an alkyl lithium such as butyllithium followed by a reaction with a halide of formula R ₃ Hal; if R ₃ and R _{4 are} different, the alkylation reaction can be carried out in two stages with two different alkylating agents of formulas R ₃ Hal and R ₄ Hal. For the preparation of compound (II) wherein R ₃ and R ₄ together form a group of formula - (CH ₂ ) _n -, where n ranges from 2 to 7, the reagent used is a compound of formula Z (CH ₂ ) _{n -} Z, wherein Z is an acceptor group such as halogen, preferably bromine or iodine, tosyloxy or mesyloxy.

Compounds of formula II wherein R ₃ and R ₄ are independently alkyl or phenyl are known. For example, DE 3,300,522 describes 5-alkoxy-3,3-dimethylindol-2-ones.

The compounds of formula II wherein R ₃ and R ₄ together with the carbon to which they are attached, form a C ₄ -C _g hydrocarbon ring substituted with one or more C ^ -Cyalkylovýrai groups or CJC ₅ spirocycloalkyl, are prepared in the same manner. These compounds are novel and form part of the invention.

To form a R _g and R ₄ together are - _(CH2) p X _{(CH2) q} _ wherein p, q and X are as defined for formula I, may be a 2-oxoindole, di-substituted in position 3, of formula II prepared from 2-oxoindole, unsubstituted at the 3-position (VII) by reaction with a compound of formula VIII z- (ch ₂ ) _p -x- (CH ₂ ) _q -z (VIII) wherein Z is as defined above and X, p and q are as defined above The reaction is carried out in the presence of an alcoholate, e.g. potassium butylate, in an anhydrous solvent such as THF.

When X is a nitrogen atom substituted with a C 1 -C 4 acyl, a C 1 -C ₄ alkoxycarbonyl or a C 1 -C ₄ alkylcarbamoyl, the substitution for X may be carried out either on the 2-oxoindole derivative (II) or on the final compound (I) ) a process starting from a compound wherein the nitrogen atom (X = NH) is not substituted.

Compounds (I) wherein X = NH are preferred according to the invention.

When X is a nitrogen atom substituted with a C ₁ -C ₄ alkoxycarbonyl, the first step is the preparation of compound II or I, wherein X is NH, which is then reacted with the appropriate chloroformate to the desired compound II or I. In the same manner C ₁ -C ₄ alkylisocyanate reacted with compound II or I wherein X = NH- to form the 2-oxoindole derivative (II) or compound I wherein X is a nitrogen atom substituted with an alkylcarbamoly. For the preparation of a compound of formula I wherein X is an acyl substituted nitrogen atom, the acid chloride or anhydride is reacted with a compound II or I wherein X = NH.

Compounds of formula II wherein R ₃ and R ₄ together with the carbon to which they are attached form a pyrrolidine N-alkylpyrrolidine, piperidine or N-alkylpiperidine ring are described in MJ Kornet,

J. Med. Chem., 1976, 19 (7), 892-899.

In particular, horsphilin of formula

MeO

is an alkaloid as described in 56 (23), 6527-6530.

in A. Jossang et al.,

J. Org. Chem., 1991,

Compounds of formula II wherein R ₃ and R ₄ together with the carbon to which they are attached form a group (CH 2) p X (CH ₂ ) q -, where p and q are integers the sum of which can range from 3 to 6 and X is oxygen, sulfur or NR ₁₃ , where R ₁₃ is C 1 -C 4 cyl, benzyl, C ₁ -C ₄ alkoxycarbonyl or carbamoyl, which is unsubstituted or substituted by one or two C ₁ -C ₄ alkyls, are new and form part of invention.

For the preparation of a compound of formula II wherein R ₃ and R ₄ together with the carbon to which they are attached form tricyclo [5,2,1,0 ² * ⁶ ] decane or tricyclo [5,2,1, O ² · ⁶ ] dec-8-ene, leaving a compound of formula VII ', respectively. the compound of formula VII

wherein Z is as defined above, to react with a compound of formula VII. Compounds (VIII ') and (VII) substituted with one or more C ₁ -C ₄ alkyl groups are used to prepare compounds (II) wherein said carbocycles are substituted.

For the preparation of a compound of formula II, wherein R ₃ and R ₄ together with the carbon to which they are attached form an indane or hexahydroindane, a compound of formula VIII 'and a compound of formula VIII', respectively, is left. the compound of formula VIII

Z-CH ₂ -t ^{5 R} ^> | (VNI) '

wherein Z is as defined in formula VIII, to react with compound VII. Compounds VIII 'and VIII, substituted with one or more C ₁ -C ₄ alkyl groups, are used to prepare compounds II wherein the indane or hexahydroindane is substituted.

The compounds of formula II, wherein R ₃ R ₄ together with the carbon to which they are attached, form a tricyclo [5,2, l, 0 ² * ^6] decane, tricyclo (5,2, l, ^2.6] dec-8 -en, indane or hexahydroindane, which are unsubstituted or substituted by one or two C 1 -C 6 alkyl, are novel and form part of the invention.

When both R ₃ and R _{4 are} phenyl, the procedure described in Helv. Chim. Acta, 1946, 29, 415-432.

The 2-oxoindole derivatives (VII) are known or are prepared by known methods. As an example, J. V. RajanBaba in J. Org. Chem., 1986, 51, 1704-1712.

Compounds of formula II which carry certain substituents R '1 and R' ₂ on the benzene ring ^are used as precursors for the preparation of compounds of formula II which carry other substituents R '1' and R ' ₂ For example, compounds (II) wherein R'' and / or R ' ₂ = H, may be nitrated with the usual reagents; they can also be acylated by reaction with an acyl chloride of formula RCOC1, where R is C ₁ -C ₄ alkyl, in the presence of a Lewis acid such as aluminum chloride, to prepare compound (II) wherein R 1 is amino, is prepared by catalytic hydrogenation of the compound (II) wherein R 1 is nitro and R ' ₂ is hydrogen.

Compounds of Formula II '

(Π) ’where

R 1 and R ₂ independently represent hydrogen, hydroxy, C ₁ -C ₄ -haloalkoxy, halogen, C ₁ -C ₄ alkyl, trifluoromethyl, C ₁ -C ₄ -alkoxy, C ₁ -C ₄ polyhaloalkoxy, C ₂ -C ₄ -hydroxyalkoxy, ω-methoxyalkoxy, wherein alkyl is C ₂ -C ₄ , C ₂ -C ₄ -aminoalkoxy which is free or substituted by one or two C ₁ -C ₄ alkyl,

C ₃ -C ₇ cycloalkoxy, cycloalkylmethoxy in which the cycloalkyl is C _{3 -C?} , phenoxy, benzyloxy, C ₁ -C ₄ alkylthio, phenylthio, nitro, amino, which are free or substituted by one or two C ₁ -C ₄ alkyl, cyano, C ₁ -C ₄ acyl, C ₁ -C ₄ acyloxy, C _1-C4 alkylsulfonamido, phenylsulfonamido, C ₁ -C ₄ alkylamido, C ₁ -C ₄ alkoxycarbonylamino, ureido, unsubstituted

C ₁ -C ₇ alkyl or substituted with phenyl or one or two C ₁ -C ₄ alkyl, and

R 8 and R ₄ together with the carbon to which they are attached form adamantane, indane or hexahydroindane which are unsubstituted or substituted by one or more groups,

- tricyklof5,2,1, O ² · ⁶ decane or a tricyclo [5,2, l, 0 ² * ^6] dec-8-ene which is substituted by or one or more C ₁ -C ₇ alkyl, or

- a C ₄ -C ₈ hydrocarbon ring substituted with one or more C 1 -C ₇ alkyl groups or C ₃ -C ₅ spirocycnesubstituted with a loalkyl, or

R 8 and R ₄ together form a group - (CH ₂ ) p X (CH ₂ ) g - wherein p and q are integers the sum of which may vary from 3 to 6 and X is oxygen, sulfur or NR ₁₃ where R ₁₃ is phenyl , benzyl, C ₁ -C ₄ acyl, C ₁ -C ₄ alkoxycarbonyl or carbamoyl which is unsubstituted or substituted by one or two C ₁ -C ₄ alkyl, provided that when CR ₃ R _{4 is} adamantane, they are R 1 and R ₂ other than hydrogen are novel and form part of the invention.

Compounds of formula III '

where:

R 1 -hydroxy, C ₁ -C ₄ -oo-haloalkoxy, halogen, C ₁ -C ₄ alkyl, trifluoromethyl, C ₁ -C ₇ alkoxy, C ₁ -C ₄ polyhaloalkoxy, C ₂ -C ₄ -, - hydroxyalkoxy, '-metoxyalkoxy, wherein the alkyl is a C ₂ ~ C _4, C ₂ -C ₄ -' 18 aminoalkoxy which is free or substituted by one or two C ₁ -C ₄ alkyl, C ₃ -C ₇ cycloalkoxy, cycloalkylmethoxy in which cycloalkyl is C ₃ -C ₇ , phenoxy, benzyloxy, C ₁ -C ₄ alkylthio, phenylthio, nitro, amino, which are free or substituted by one or two C ₁ -C ₄ alkyl, cyano, C ₁ -C ₄ acyl, C ₁ - C ₄ acyloxy, C ₁ -C ₄ alkylsulfonamido, phenylsulfonamido, C ₁ -C ₄ alkylamido, C ^ ¢ ₄ alkoxycarbonylamino or ureido which is unsubstituted or substituted by phenyl or by one or two C ^ C ₄ alkyl, and or R ₃ and R ₄ form together - (CH _{2) p} X _{CH2) q_; or R ₃ and R ₄ together with the carbon atom to which they are attached form an optionally fused, saturated or unsaturated ^C 3 ^"c 10 ^at hi ° ⁱⁿ ° Thanksgiving crust h, which is unsubstituted or substituted by one or more C ₁ -C ₄ alkyl groups or C ₁ -C ₄ spiroalkyl, and p and q are integers the sum of which can range from 3 to 6, t is an integer which can range from 1 to 5 .

X is oxygen, sulfur or a group R ₁₃ , ^R 13 ^hydrogen or C ₁ -C ₄ alkyl, phenyl, benzyl, C ₁ -C ₄ acyl, C ₁ -C ₄ alkoxycarbonyl or carbamoyl which is unsubstituted or substituted by one or two C ₁ -C ₄ alkyl, with the restriction that when R? is methoxy, is CR ₃ R ₄ other than 3-pyrrolidine which is unsubstituted or N-substituted by Cy-C ^ alkyl, and when R _x halogen is CR ₃ R ₄ other than pentane are novel and form part of the invention.

2a, 3,4,5-tetrahydrobenz [c, d] indol-2 (1H) -one of formula

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

Benzenesulfonyl halides (III) are known and are prepared by known methods. For example, 4-dimethylaminobenzenesulfonyl chloride is prepared according to CN Sukeník et al., J. Amer. . Chem. Soc., 1977, 99, 851-858. Generally speaking, benzenesulfonyl halides (III), wherein R ₅ is dimethylamino, are either new or are prepared by known methods; p-benzyloxybenzenesulfonyl chloride is prepared according to European patent application EP 229 566.

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

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

Haloalkoxybenzenesulfonyl chlorides can be prepared according to U.S. Patent No. 2,540,057.

Benzenesulfonyl halides of formula III '

SO 2 Cl

OAlk (ΙΠ) ¹

YR _V where

Alk is C ₁ -C ₇ alkyl,

Y is O or S and

R y 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 -oo-carboxyalkyl, esterified

C ₁ -C ₄ alkyl or benzyl are new and form part of the invention.

These compounds are prepared according to D. Hofmann et al., Liebigs Ann. Chem., 1982, 287-297. The benzene compounds bearing the R _v and O Alk substituents at the 1 and 3 positions are reacted at room temperature in a solvent such as DCM. Then the method of R. Passerini et al., Gazz. Chim. Ital., 1960, 90, 1277-89 and then neutralized, for example with an alkali metal carbonate and then reacted with a halide such as POCl ₃ to give the desired benzenesulfonyl halide.

Benzenesulfonyl halide (III) wherein the substituent R ₅ alkoxycarbonyl, phenoxycarbonyl, benzyloxycarbonyl, alkylthio, phenylthio, benzylthio or a group SR _7, wherein R ₇ is as defined for formula I, are prepared according to Col. Czechloslov. Chem. Commun. 1984, 49, 1184, from an aniline derivative substituted with the same R'5 group, which is obtained from the corresponding nitrated derivative.

Nitrobenzoic acid derivatives are known: the corresponding alkyl and phenyl esters are obtained from this acid by an appropriate esterification reaction.

Benzenesulfonyldihalides (III, R ' ₅ -SO ₂ Hal) are known or are prepared by known methods. For example, 2,4-dimethyloxybenzene-1,5-disulfonyldichloride is described in RJW Cremlyn, J. Chem. Soc. C, 1969, 1344.

Haloalkoxybenzenesulfonyl chlorides (III, R ' ₅ = <- haloalkoxy) are used to prepare compounds of the invention wherein R 5 is ω-aminoalkoxy which is unsubstituted or substituted with one or two alkyls, according to the equation

- O-Alk'-Hal + NHRgRg -> -OAlk '- NR _g Rg where Alk' is C 1 -C 4 alkyl.

For certain values of the substituents R, R _2, R ₅ and / or R _g may be the compound (I) of the invention prepared from a precursor of formula I 'which is substituted by R ^, R _2, ^R s and / or R _VI, called precursor R 1, R _2, R ₅ and / or R _g.

Further described is the preparation of compounds of formula I bearing R 1 and / or R 1 substituents; the same method is suitable for the preparation of compounds wherein the substituents R ₂ and / or R _g as defined as above for R and R _g.

The compounds (I) wherein R and / or R _G is hydroxy can be obtained by catalytic hydrogenation of a compound of formula I ', wherein R' i or R _'5 hydroxy, may be used to prepare the compounds (I), wherein R ₃ and / or R 6 is alkoxy, by reaction with an alkyl halide in the presence of a base such as an alkali or alkaline earth metal hydride or carbonate such as K ₂ CO ₃ or Cs ₂ CO ₃ in a solvent such as THF or DMF. Similarly, compounds of formula I where R and / or ^{R 3} and 5 °° -aminoalkyloxy, are prepared by the reaction of .omega.-chlóralkylamínu with compounds in which R '2. and / or R ₁₅ = OH; similarly compounds wherein R 1 and / or R 5 is ω-hydroxyalkoxy are prepared by reaction with a chloroalkylalcohol; in the particular case of the preparation of compound (I), wherein R 11 and / or R ₅ = O (CH ₂ ) ₂ OH, it is also possible to react the ethylene carbonate with the compound (I ') where R 14 and / or R ₁₄ = OH.

Compounds of formula I wherein R 1 and / or R 1 is acyloxy are prepared by reacting an acid halide or anhydride with compound (I ') wherein R 1' and / or R ' ₅ is hydroxy.

For the preparation of compounds of formula I wherein R ₃ and / or R ₅ is monoalkylamino or dialkylamino, compounds of formula I 'where R 1 -a and / or R ₅ is amino may be subjected to reductive alkylation. When R '2 and / or R' ₅ is amino, nitrosation may also be performed, for example in the presence of nitric acid or alkyl nitrite, to prepare compound (I) wherein R 1 and / or R ₅ is a diazonium salt; by reactions known to those skilled, the compounds (I) of the invention, R ₃ and / or _Rg is cyano, halogen or C - ^ - C ^ thioalkyl. Finally, compounds (I) wherein R 1 and / or R _g is one of the groups of formulas RCONH-, ROCONH-, RNHCONH- and RSO ₂ NH-, where R is C ₁ -C ₄ alkyl, can be prepared by conventional reactions. from compounds (I ') wherein R' i and / or R ' ₅ = NH ₂ .

Compounds of formula I 'where R 1' is phenoxycarbonyl can be used to prepare compounds - (I) wherein R ₅ is phenylcarbamoyl or alkylcarbamoyl, by reaction with aniline or alkylamine. A substituted aniline or an alkyl amine substituted on an alkyl can be used to prepare compounds of formula I wherein R ₅ is phenylcarbamoyl, respectively. alkylcarbamoyl, substituted on alkyl.

The compounds of formula I ', wherein R ₅ is benzyloxycarbonyl, may be used to prepare the compounds (I), wherein R ₅ is carboxy by catalytic hydrogenation. Treatment with a thionyl halide yields compounds of formula I wherein R ₅ is halocarbonyl. These compounds are used to prepare compounds of formula I wherein R ₅ is N-substituted carbamoyl by reaction with a substituted amine.

Compounds of formula I wherein R ₅ is COR ₇ are prepared from the corresponding compounds (I ') wherein R' ₅ is phenoxycarbonyl, by reaction with a substituted piperazine or azetidine.

Compound (I ') wherein R' ₅ is nitro may be used to prepare compound (I) wherein R 'is amino by catalytic hydrogenation, for example in the presence of platinum oxide; other compounds wherein the amino group is substituted may then be prepared using reactions known to those skilled in the art.

For example, if it is desired to prepare a compound (I) of the invention wherein R 5 is NR 8 R 8, where R 8 is optionally substituted benzoyl, benzoyl chloride, where phenyl carries the appropriate substituent, is reacted with I 'where R 1' is amino in the presence an amine such as triethylamine. For example, 4-chlorosulfonylbenzoyl chloride can be reacted to prepare compound I 'where R' ₅ is 4-chlorosulfonylbenzamido, whereby compound (I) wherein R ₅ is 4-sulfamoylbenzamido or 4-alkylsulfamoylbenzamido is obtained by reaction with ammonium. . C ₁ -C ₄ alkylamine.

In like manner, if desired, Compound (I), wherein R ₅ is a group NRgR _g, wherein R _g is Ο - ^ - ^ Ο- ογΙ, reacting the corresponding anhydride with a compound I ', wherein R'g the amino group in in the presence of an amine such as triethylamine.

In another preparative example, compound (I) wherein R ₅ is an alkylsulfonamido group is obtained by reacting an alkylsulfonyl halide with a compound I 'wherein R 1 is an amino group.

Compounds of formula I 'where R' ₅ is amino are also useful for the preparation of compounds wherein this amino group is substituted with (CH ₂ ) _t -COR _12. In this case, the compound of formula Hal- (CH ₂ ) _t -COOAlk, where Hal is a halide such as bromine, and Alk is C ₁ -C ₄ alkyl, reacted with compound (I ') in the presence of copper (I) chloride; the ester formed is converted to the acid or amide as necessary. By reacting a lactone such as butyrolactone or valerolactone with compound I ', where R' ₅ is an amino group, it can be used to prepare compound 'I' where R ' ₅ = NHCO (CH ₂ ) 4' CO 2 H where t = 2 or 3.

In the same way, compounds of formula I wherein R ₅ is an amino group substituted with CH (R ₁₀ ) CO ₂ R ₁₁ are prepared by reacting a compound of formula Hal-CH (R ₁₀ ) CO ₂ R ₁₁ with the corresponding compounds (I ') where R is ₅ is amino.

Compound (I) wherein R ₅ is amino substituted by alkoxycarbonylo or phenoxycarbonyl is prepared by reacting an alkyl or phenyl chloroformate with compound (I ') wherein R' ₅ is amino.

A compound of formula I wherein R ₅ is ureido is prepared by reacting ammonia with a compound of formula (I ') wherein R' ₅ is an amino group substituted with phenyloxycarbonyl; a compound of formula I wherein R ₅ is N-phenylureido or N-alkylureido wherein alkyl is C ₁ -C ₄ is prepared by reacting aniline or C ₁ -C ₄ amonoalkylamine or -dialkylamine with such a compound of formula I '.

Compound (I) wherein R ₅ is carbamoyl which is unsubstituted or substituted with one or two alkyl groups is prepared by reacting the corresponding amine with compound (I ') wherein R ₅ is amino, in the presence of phosgene.

It is also possible to prepare a compound (I) wherein R ₅ is an amino group substituted with an alkylcarbamoyl or phenylcarbamoyl by reacting an alkyl or phenyl isocyanate with a compound (I ') wherein R' ₅ is amino.

Further, compound (I), wherein R ₅ is a sulfamoyl group which is unsubstituted or substituted with C ₁ -C ₄ alkyl, is prepared by reacting ammonia or an alkylamine with a compound (I 5) wherein R 15 is a halosulfonyl group.

Compounds of formula I 'which are useful as prodrugs for the preparation of compounds of formula I are included in formula I and form part of the invention.

Among the compounds of the formula I according to the invention, the compounds of the formulas IX, X, XI, XII and XIII mentioned below which are suitable for the preparation of other compounds of the formula I are preferred.

Thus, one object of the invention is to provide compounds of formula IX

COOH wherein R 6, R ₂ , R ₃ , R ₄ and R ₅ have the meaning given in Formula I functional derivatives such as esters.

A further object of the invention are compounds of formula X and their compounds

(X) wherein R _1, R ₂ , R ₃ , R _4, and R ₅ have the meaning given in Formula I, optional salts.

Another object of the invention are compounds of formula XI and their compounds

(XI) wherein R, R _2, R _3, R ₄ and R ₅ are as defined for formula I.

A further object of the invention are compounds of formula XII

wherein R _3, R _4, R _5, and R _g are as defined for formula I.

A further object of the invention are compounds of formula XIII

wherein R 1, R ₂ , R ₅ , R 8a and r are as defined in Formula I.

The affinity of the compounds of the invention for vasopressin receptors was determined in vitro using the method described by CJ Lynch et al., J. Biol. Chem., 1985, 260 (5), 2844-2851. This method is based on the study of the release of tritiated vasopressin bound to rat liver V-membrane sites. The concentrations of the compounds of the invention inhibit the binding of tritiated vasopressin by 50% (IC _5Q) are low, typically up to 10 ^"7 M

The affinity of the compounds (I) of the invention for V ₂ receptors was measured on a bovine tunnel membrane preparation using a tailored method according to P. Craus et al., Molecular and Cellular Endocrinology, 1982, 28, 529-541 and FL Stassen et al. J. Pharmacol. Exp. Ther., 1982, 223, 50-54. The compounds of the invention inhibit the binding of tritiated arginine-vasopressin to the receptors of the membrane preparation. The IC ₅₀ values of the compounds of the invention are low with a size of up to 10 ⁹ M.

The activity of the compounds of the invention as V ₂ receptor antagonists has been demonstrated by the adenylate cyclase activity assay performed according to a modified method of M. Laburthe et al., Molecular Pharmacol., 1986, 29, 23-27. A bovine ladle membrane preparation is used and each product is incubated for 10 min. at 37 ° C alone or in the presence of 3.10 ^-8 M AVP (arginine-vasopressin). The production of cyclic AMP (cyclic adenosine monophosphate) is measured by radioimmunoassay. The concentration that causes 50% inhibition (IC 50) of adenylate cyclase stimulation induced by 3.10 ^-8 M AVP is determined. IC 50 values determined are of the order of 10 ^-7 M and reach up to 10 " ⁸ M.

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

Similarly, the affinity of the compounds (I) of the invention for oxytocin receptors is determined in vitro by the release of a radioactive iodo-labeled oxytocin analog bound to the rat mammary gland membrane preparation by a method similar to that described in J. Eland et al., Eur. J. Pharmacol.

197-207. The IC _5Q compounds of this invention achieve 10 ^"8 M.

The compounds of the invention are effective after administration by various routes, especially orally.

No signs of toxicity are observed with these compounds at pharmacologically effective doses.

in smokers, haemophilia and

The compounds according to the invention can therefore be used for the treatment or prevention of various vasopressin or oxytocin-dependent disorders, in particular cardiovascular disorders such as hypertension, cardiac insufficiency or coronary vasospasm, in particular cardiac ischemia, haemostatic disorders, in particular Von Willebrand's syndrome, central nervous system syndrome. , for example, cerebral edema, depression, anxiety, psychotic conditions and memory disorders, renal system disorders such as renal vasospasm, ladvian crust necrosis, hyponatraemia and hypokalaemia, and gastric disorders such as hepatocirhosis, ulcers, vomiting kinetics or nausea, for example nausea or nausea syndrome of inappropriate antidiuretic hormone secretion (SIADH) diabetes and enuresis. The compounds of the invention may also be used in the treatment of sexual behavior disorders; in women, the compounds of the invention may be used in dysmenorrhea or preterm labor.

The invention further provides pharmaceutical compositions comprising an effective dose of a compound of the invention, or a pharmaceutically acceptable salt thereof, and suitable carriers.

The carriers are selected according to the pharmaceutical form and the desired mode of administration.

In the pharmaceutical compositions of the invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical intratracheal, intranasal, transdermal or rectal administration, the active ingredients of Formula I or, as appropriate, their salt may be administered to animals and humans in unit dosage forms in admixture with conventional pharmaceuticals. carriers for the prophylaxis or treatment of said disorders or diseases. Appropriate unit dosage forms include oral administration forms such as tablets, gelatin capsules, powders, granules and solutions or suspensions for oral administration, sublingual, buccal, intratracheal or intranasal forms, subcutaneous, intramuscular or intravenous forms and rectal forms. For topical application, the compounds of the invention may be used in creams, ointments or lotions.

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

Each unit dose may contain 0.5 to 1000, preferably 1 to 500 mg, of the active ingredient in combination with a pharmaceutical carrier. This unit dose may be administered 1 to 5 times daily so that the daily dose is 0.5 to 5000, preferably 1 to 2500 mg.

When preparing a solid composition in the form of a tablet, the main active ingredient is mixed with a pharmaceutical vehicle such as gelatin, starch, lactose, magnesium stearate, talc, acacia and the like. The tablets may be coated with sucrose, a cellulose derivative or other suitable material or may be formulated so as to have a sustained or delayed activity and to provide a continuous release of a specified amount of the active ingredient.

The gelatin capsule preparation is obtained by mixing the active ingredient with a diluent and encapsulating the mixture in soft or hard gelatin capsules.

The preparation in syrup or elixir form or for administration in the form of drops may contain the active ingredient in combination with a sweetener, which is preferably non-caloric and methyl paraben and propyl paraben as antiseptics, as well as flavoring and coloring agents.

The water dispersible granules or powders may contain the active ingredient in admixture with dispersing or wetting agents or suspension stabilizers, such as polyvinylpyrrolidone, as well as sweetening or flavoring agents.

Rectal applications are carried out using suppositories which are prepared with binders melting at the rectal temperature, for example cocoa butter or polyethylene glycols.

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

The active ingredient may also be formulated into microcapsules, as appropriate, with one or more carriers or excipients.

In addition to the above products of Formula I or a pharmaceutically acceptable salt thereof, the compositions of the invention may contain other active ingredients that may be useful in the treatment of the above disorders or diseases.

Accordingly, the invention further provides pharmaceutical compositions comprising the combination of several active ingredients, one of which is a compound of the invention.

Accordingly, the present invention provides pharmaceutical compositions comprising a compound that is a receptor antagonist in conjunction with a compound that acts on a renin-angiotensin system such as a converting enzyme inhibitor, an angiotensin II antagonist, or a renin inhibitor. They may also be combined, for example, with a peripheral vasodilator or calcium inhibitor. Such compositions are particularly suitable for the treatment of hypertension or cardiac insufficiency.

Preparation of 2-oxoindoles

Preparation: 4,6-dimethyl-3-spirocyclohexanindol-2-one

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

A mixture containing 15 ml of quinoline and 10 g of calcium oxide is refluxed under an inert atmosphere for 30 min. 5 g of cyclohexanecarboxylic acid 3,5-dimethylphenylhydrazide (II, R'j, R'2 = CH ₃ , C 1 R 4 = cyclohexane) are added. The reaction mixture was cooled and then poured into ice / hydrochloric acid. Extraction is carried out with ethyl acetate and the extract is washed with normal hydrochloric acid and water until neutral and then dried and concentrated in vacuo to a brown solid. Trituration in iso ether yields the expected compound, mp 223 C.

Using the same procedure for varying the starting hydrazide, the indol-2-one derivatives shown in Table 1 are obtained.

These compounds are purified by silica column chromatography eluting with DMC or by column chromatography alumina eluting with DCM or iso ether.

Table 1

^R, 1 ^R 2 Cr ₃ ^R 4 mp 'C 5-C1 H cyclobutane 191 5-C1 H cyclopentane 189 5-C1 H cyclohexane 186 H H cyclohexane 123-124 _5-CH3 H cyclohexane 164 _5-CH3 H H cyclohexane 226 6-C1 H cyclohexane 168 cf ₃ o H cyclohexane 164 5-C ₆ H ₅ O H cyclohexane 160

Preparation 2

The 3-spirocyclohexanindol-2-one listed in Table 1 can also be obtained by alkylation of indol-2-one using the following procedure:

A solution of 30 g of indol-2-one in 900 ml of THF is maintained at -40 ° C under a nitrogen atmosphere and 101 g of tertiary is added. potassium butylate. The temperature is allowed to rise 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 room temperature, then 30 ml of water are added and the solvent is evaporated under reduced pressure. The residue is taken up in 500 ml of DCM and 200 ml of water, then the insoluble matter is filtered off and the organic phase is separated, washed with 100 ml of water, dried over magnesium sulphate and evaporated in vacuo. The residue is chromatographed on silica using cyclohexane / ether as eluent to give the expected compound which is recrystallized from heptane. Weight 34 g t. t. 123-124 C. C.

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

As an example of the starting compounds of formula VII, 5-chloroindol-2-one is described in Bright. J. Am. Chem. Soc., 1956, 79, 221, and in RajanBab, J. Org. Chem., 1986, 51, 1704,

4-Chloroindol-2-one can be prepared from 2-chloro-6-nitrotoluene as described in J. Am. Chem. Soc., 1956, 78, 221.

5-Methoxyindol-2-one was prepared from 4-methoxyaniline as described in J. Am. Chem. Soc., 1974, 96, 5512. Various indol-2-ones are prepared from the corresponding aniline derivative by the same procedure.

Preparation 3: 5-ethoxyindol-2-one

a) 3-thiomethyl-5-ethoxyindol-2-one

23.6 g of ethylthiomethyl acetate in 60 ml of DCM is added to the solution

12.5 g of chlorine in 400 ml of DCM, cooled to about -79 ° C. The mixture was stirred for 5 min. at the same temperature and a solution of 4-ethoxyaniline (48.3 g) in 120 mL of DCM was added. The mixture was stirred for 1 hour. at about 70 ° C, 39.3 ml of triethylamine are 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 about 16 hours. at room temperature and filtered and the precipitate collected. The filtrate is concentrated under reduced pressure to give the expected product.

b) 5-ethoxyindol-2-one

The above solid in 1500 mL of ethanol was methylated for 3 hours. under reflux in a nitrogen atmosphere in the presence of 100 g of Raney nickel (80 to 100 m ² / g). The mixture is filtered through talc, the filter material is washed with 1000 ml of ethanol and the filtrate is concentrated under reduced pressure. After recrystallization from toluene, 16 g of the expected product are isolated, mp 156 ° C.

The following compounds are obtained in the same way from the corresponding anilines:

5-Benzyloxyindol-2-one 1.1. = 152 ’C

5-n-Propylindol-2-one 1.1. = 136 ’C

5-ethylindol-2-one m.p. = 152 ’C

5- (2,2,2-Trifluoroethoxy) indol-2-one 1.1. = 145 ’C

By varying the starting indol-2-one derivative and the alkylating agent, the following compounds of formula II are obtained according to the procedure of Preparation 2:

Table 2

(Π)

R ' R2 ' CR3R4 M.P ° C alkylating agent 5-Cl H cyclohexane 186-189 Br (CH2) 5Br 5-Cl H cycloheptane 202 Br (CH2) 6 Br 5-Cl H 4,4-dimethyl cyclohexane 180 TsO (CH 2 Cl 2 (CH ₃ ) 2 - (CH 2 O ₃ ) 5-Cl H. 2-hexahydroindane 223 cis-1,2 dijódometylcyklohexán S-CH3 O H 4,4-dimethyl cyclohexane 202 TsO (CH 2) 2 C (CH ₃ ) 2 - (CH ₃ -Os) 5-Cl H 2-indan 228 α, α '- d dibromome 1 ortoxylene 5-Cl H 'C (CH ₃₎ 2 160 CH3I 5-Cl H ccch ₂ ch ₃ ) 2 156 CH3CH2 5-Cl H C (nPr) 2 158 NPRI 5-Cl H C (iBu) 2 164 iBul 5-Cl H N-methyl-4- piperidine 260 CI (CH 2) 2 N (CH ₃ ) - 5-Cl H 4-tetrahydro- pyran 223 I, (CH 2) 2 O (CH 2) 2, 4-Cl H cyclohexane 215 Br (CH2) 5Br 5-BzO H cyclohexane 162 Br (CH2) 5Br

Η 5-Cl 5-Cl H H H C (CH ₂ C ₆ H ₅ ) 2 C (n-pentyl) 2 2,3-dihydro-phenalen-2 205 '· 142 ·. « C ₆ H ₅ CH ₂ Br 'CH 3 (CH ₂ ) ₄ Br BrCH _? CH ₂ Br ób 5-BzO H 4,4-dimethyl 154 TsO (CH ₂ ) 2 C (CH 3) 2 - cyclohexane - (CHzhOTs 5-Cl H 4-spirocyclopentane 202 (CH ₂ ) ₂ OTs cyclohexane (CH ₂ ) ₂ OTs 5-nPr H cyclohexane 151 BrCCFI ^ Br 5-EtO H N-tBu-4- - (CH ₂ ) ₂ Br piperidine N-Bu (CH ₂ ) ₂ Bc 5-a H N-Bz-4- 165 (CH ₂ ) ₂ Br piperidine Bz-N? (CH ₂ ) ₂ Br 5-Cl H N-phenyl-4- 188 _x (CH ₂ ) ₂ Q piperidine ^G 6 H ₅ < ; 5-Cl. H -'on 300 CH ₂ OSO ₂ CH ₃ U ^ ^x ^ ^X 'CH ₂ OSO ₂ CH ₃ 5-EtO H 4,4-diethyl 132 TsOCCI ^ C ^ Hsh cyclohexane - (CH OTs 5-EtO H cyclohexane 163 Bt (CH2) 5Br 5-EtO ' H 4,4-dimethyl 178 TsOCCH ^ CC ^ H cyclohexane · - (CH OTs 5-EtO H cycloheptane 4,4-dimethyl 139 B ^ Br CH 5-Et H cyclohexane 160 TSOC ^ cccHsh- 5-CF3CH2O- H 4,4-dimethyl cyclohexane 164 - (CH OTs ditto H H 4,4-dimethyl 169 ditto cyclohexane

Preparation 4: 3-Spiroadamantanindol-2-one

This compound is prepared according to I. Fleming 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 was prepared as described in Helv. Chim. Acta, 1946, 29, 415-431, by reacting benzene with 5-chloroisatin in the presence of aluminum chloride, m.p. t. = 281 ’C.

Preparation 6: 5-nitro-3-spirocyclohexanindol-2-one

This compound was prepared according to the procedure described in J. Am. Chem. Soc., 1945, 67, 499, by nitration

3-spirocyclohexanindol-2-one, m.p. t. = 192 ’C.

5-Nitro-spiroadamantanindol-2-one was prepared in the same manner from 3-spiroadamantanindol-2-one, m.p. > 260 ’C.

Also prepared is 5-nitro-3-spiro (4,4-dimethyl) cyclohexanindol-2-one, m.p. t. 195 ’C.

Preparation 7: 5-amino-3-spirocyclohexaniridol-2-one

This compound was prepared as described in J. Chem. Soc., 1951, 3475, by reducing the above 5-nitro-3-spirocyclohexanindol-2-one, m.p. t. = 176 ’C.

5-Amino-3-spiroadamantane was prepared in the same manner. t. = 245 ’C.

Preparation 8: 5-fluoro-3-spirocyclohexan-2-one

a) 5-Diazoniuin-3-spirocyclohexanindol-2-ontetrafluoroborate

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

b) 5-fluoro-3-spirocyclohexanindol-2-one g of the compound obtained in step a) is placed in 5 ml of xylene for 2 hours. heats up to about 115 C. C. The mixture was cooled to room temperature, the precipitate was filtered off and washed with toluene, and 0.1 g of activated carbon was 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, m.p. t. = 114 ’C.

Preparation 9: 5-Cyano-3-spirocyclohexanindol-2-one

4.78 g of potassium cyanide and 4.95 g of copper cyanide are dissolved in 40 ml of DMSO at room temperature. The solution is cooled to about 15 ° C and 4.15 g of the diazonium salt obtained in the step is added

(a) previous preparation.

The mixture was stirred for 30 min. at room temperature, 100 ml of water and 100 ml of ether are added, then the organic phase is separated, dried over magnesium sulphate and evaporated under reduced pressure. The residue is chromatographed on silica using cyclohexane / ether as eluent to give the expected compound, which is recrystallized from heptane, 1.4 g, m.p. t. = 216 ’C.

Preparation 10: 5-Chloro-3-spiroadamantanindol-2-one ¹⁹ adamantane-2-carboxylic acid p-chlorophenylhydrazide was dissolved and 2.5 ml of n-butyllithium solution (1.6 M in hexane) was added at -40 ° C. ). The mixture was stirred for 5 min, concentrated in vacuo keeping the temperature below 30 C. 30 ml of 1,2,3,4-tetramethylbenzene was added and the mixture was stirred for 1 h. reflux. It is concentrated under reduced pressure, the residue is taken up in normal hydrochloric acid, extracted with ether and the extract is washed, dried and concentrated in vacuo. The oil obtained is chromatographed on a silica column using DCM as eluent; 0.3 g of the expected product is obtained in the form of a wax, which is recrystallized from iso ether, mp = 249 DEG.

Preparation 11: 5-chloro-3-cyclohexyl-3-methyliridol-2-one

To prepare 5-chloro-3-cyclohexylindol-2-one as an intermediate, the procedure described in Synth. Commun., 1982, 12 (1), 1-19 and the expected compound is then obtained by reaction with methyl iodide.

Preparation 12: 5-Acetyl-3-spirocyclohexan-2-one

2.56 g of acetyl chloride and then 8.25 g of anhydrous aluminum chloride are added to a solution, 4 g of 3-spirocyclohexanindol-2-one in 35 ml of 1,2-dichloroethane, cooled to 5 ° C. The mixture was stirred for 2 hours. reflux, the solvent was evaporated under reduced pressure and the mixture was hydrolyzed with 50 g of ice 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 to give 3.6 g of the expected product, m.p. t. = 192 ’C.

The benzenesulfonyl chlorides listed in the table are prepared as described below:

Cl

OCHYR _V

Y ry mp 'C with ch ₃ 85 0 CH ₂ Bz 95 0 CH ₂ CO ₂ Et 89 0 (Cfl ₂ ) ₃ Br 106-108

DETAILED DESCRIPTION OF THE INVENTION

Using the various aforementioned 2-oxoindoles and the corresponding benzenesulfonyl chlorides as starting materials, the compounds of the invention are prepared by the procedures described in the Examples.

Example 1

5-Chloro-1- (2-methoxy-4-nitrobenzenesulfonyl) -3-spirocyclohexane indol-2-one

A mixture containing 0.7 g of 5-chloro-3-spirocyclohexanindol-2-one and 70 mg of sodium hydride in 7 ml of THF was added for 30 min. Stir under nitrogen at room temperature. 0.7 g of 2-methoxy-4-nitrobenzenesulfonyl chloride are introduced and stirring is maintained at room temperature for 20 hours. The mixture is concentrated in vacuo, 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 iso ether, m.p. t. = 188 * C.

Example 2

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

0.8 g of the compound obtained in the previous example was added for 20 hours. It is reduced with hydrogen at normal pressure at room temperature in 10 ml of acetic acid in the presence of 30 mg of platinum oxide. The reaction mixture is filtered, the filtrate is concentrated, the residue is taken up in water / ethyl acetate and the organic phase is washed with water, dried and concentrated. The yellow foam obtained is chromatographed on alumina using DCM as eluent to give 0.2 g of the expected product, m.p. = 173 ’C.

Example 3

5-chloro-1- [4- (2-methylphenylcarboxamido) -2-methoxybenzenesulfonyl] -3-spirocyclohexanindol-2-one

A mixture containing 0.2 g of the compound prepared in the previous example, 0.5 ml of triethylamine, 5 ml of DCM and 0.1 g of o-toluoyl chloride was stirred for 48 hours. at room temperature. It is concentrated in vacuo, the residue is taken up in water / ether and allowed to decant and the organic phase is washed with saturated sodium bicarbonate solution and then with water, dried and concentrated in vacuo to give 250 mg of a solid which is chromatographed on silica using DCM as eluent to give 0.1 g of the expected product, m.p. t. = 192 ’C.

Example 4

6-chloro-1- (2,4-dimethoxybenzenesulfonyl) -3-spirocyclohexanindol-2-one

A mixture containing 0.15 g of 6-chloro-3-spirocyclohexanindol-2-one and 15 mg of sodium hydride in 2 ml of THF was added for 30 min. stirred under nitrogen at room temperature; 0.15 g of 2,4-dimethoxybenzenesulfonyl chloride was added and 20 hours. stirring is continued at room temperature. The mixture is concentrated in vacuo, 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 in vacuo. The product obtained is recrystallized from iso ether, m.p. t. Melting point = 147 DEG.

Example 5

5-Chloro-1- [4-dimethylaminopropoxy) -benzenesulfonyl] -3-spirocyclohexanindol-2-one acid fumarate

a) 4- (3-bromopropoxy) benzenesulfonyl chloride

The mixture containing 23 g of sodium 4-hydroxybenzenesulfonate dihydrate, 7 g of potassium hydroxide cubes (85%), 30 ml of water, 50 ml of absolute ethanol, 40 g of 1,3-dibromopropane and 3.4 g of tetrabutylammonium hydrogen sulphate was added for 3 hours. reflux. The reaction mixture is concentrated in vacuo, taken up in ethanol and concentrated again. The residue was taken up in hot methanol. The insoluble material was filtered off, the filtrate was concentrated and the residue was triturated in ether to give 22.5 g of a white solid. To this solid was added 120 mL of phosphorus oxychloride and 16 g of phosphorus pentoxide, and the mixture was stirred for 20 h. at room temperature and then at room temperature for 1 hour. reflux. The reaction mixture is concentrated in vacuo, the residue is then taken up in ether / water and the organic phase is decanted and washed with saturated sodium bicarbonate solution. 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-spirocyclohexanindol-2-one

A mixture containing 1.2 g of 5-chloro-3-spirocyclohexanindol-2-one and 0.16 g of sodium hydride in 6 ml of THF was added for 30 min. Stir under nitrogen. 1.6 g of 4- (3-bromopropoxy) benzenesulfonyl chloride are then added.

After 20 hrs. at room temperature, the reaction mixture is concentrated in vacuo, the residue is taken up in water / ethyl ether and decanted, and the organic phase is washed with water, dried and concentrated. The oil obtained is purified by chromatography on silica using an isoether as eluent. The expected product is obtained in the form of an oil which crystallizes from iso ether; weight 1 g, t. t. = 123 “C.

c) 5-Chloro-1 '[4-dimethylaminopropoxy) -benzenesulfonyl] -3-spirocyclohexanindol-2-one acid fumarate

The mixture containing 0.5 g of the product obtained in the preceding step, 0.5 g of potassium iodide and 20 ml of a 33% solution of dimethylamine in methanol is stirred for 20 hours. at room temperature. The reaction mixture is concentrated and taken up in 10 ml of water and then, after trituration, the insoluble material is separated and 10 ml of 3N hydrochloric acid are added. A resin is formed which is dissolved in 30 ml of warm water, filtered through paper and then made alkaline by addition of 12N sodium hydroxide. The insoluble material was extracted with ether and the extract was washed, dried and then concentrated to give a yellow oil. This was dissolved in 10 ml of acetone and 0.1 g of fumaric acid was added to the hot solution. The expected product precipitates at 20 ° C; weight 240 mg, t. t. = 168 ’C.

Example 6

5-Chloro-1- (2,4-dimethoxybenzenesulfonyl) -3-spiroadamantanindole

-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 was added for 30 min. Stir at room temperature under a nitrogen atmosphere. 0.18 g of 2,4-dimethoxybenzenesulfonyl chloride is added and stirring is continued at room temperature for 20 hours. The reaction mixture is concentrated in vacuo, the residue is taken up in 30 ml of water and extracted with ether and the extract is washed with water, dried and concentrated in vacuo. The wax obtained is crystallized from 15 ml of iso ether; weight 240 mg, t. t. = 152,154 ’C.

Example 7

5-chloro-l- (2,4-dimethoxybenzenesulfonyl) -3-spirocykloheptánindol-2-όη

A solution containing 0.156 g of tert. potassium butylate and 0.33 g of 5-chloro-3-spirocycloheptanindol-2-one in 15 ml of THF are cooled to -40 ° C in an inert atmosphere. The temperature is left for 1 h. The solution is cooled to about -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 for 1 hour. at room temperature. 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 in vacuo. The oil obtained is chromatographed on silica using cyclohexane / DCM as eluent to give the expected compound which is recrystallized from heptane; weight 0.51 g, t. t. = 135 ’C.

Example 8

2,4-dimethoxy-1-benzenesulfonyl-2a-methyl-2a, 3,4,5-tetrahydrobenz [c, d] indol-2-one (I: R _x = H, -R ₂ ^R 3 = - (CH ₂ ) ₃ _, R ₄ = CH ₃ , R 8 = R 8 = OCH ₃ )

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 is prepared containing 0.7 g of this compound and 1.36 g of tert. of potassium butylate in 40 ml of anhydrous THF.

The temperature is allowed to rise to about 0 ° C, then the solution is cooled to -60 ° C and a solution of 0.57 g of methyl iodide in 20 ml of THF is added; the mixture is kept under stirring for 30 min. to -10 ° C and then cooled to about -40 ° C and g of 2,4-dimethoxybenzenesulfonyl chloride in 10 mL of THF is added.

solution 0.96 The mixture is stirred for 1 h. at room temperature, the solvent is evaporated off under reduced pressure and the residue is taken up in 30 ml of DCM and 30 ml of water; the organic phase is separated and then dried over magnesium sulphate and evaporated. The oil obtained is purified by chromatography on silica using cyclohexane / DCM as eluent to give the expected product which is recrystallized from cyclohexane / AcOEt (95/5, v / v; mp = 160 ° C).

The compounds listed in Table 3 were prepared from the above 2-oxoindoles by the procedures described in the above Examples. Unless otherwise indicated (*), R ₂ = H and m = 1.

Table 3

Unless otherwise stated, (*) R ₂ = H and m = 1.

Ex. ^R i CR3R4 R 5 (RO) m M.p. * C 9 5-Cl C (C ₆ H ₅ ) 2 3-MCO 4-MeO 178 10 5-NO2 cyclohexane . 3-MeO 4-MeO ¹ 157 11 5-Cl cyclohexane 4-MeO H 112 12 5-a C _(CH3) 2 3-MeO 4-MeO 110 13 _5-NH2 cyclohexane 3-MeO 4-MeO 171 14 5-CN cyclohexane 2-MeO 4-MCO 148 15 5-a cyclohexane 4-MCO 2,3,6-trim 188 16 5-a C (Pr) 2 2-MeO 4-MCO 186 17 5-a indan-2 2-MeO 4-MeO 182 18 5-a C (iBu) 2 N-methyl- 2-MeO 4-MCO 184 19 5-a piperidin-4 2-MCO 4-MeO 142 20 • 5-a. C (Et) 2 2-MeO 4-MeO 190 21 5-F cyclohexane 2-MeO 4-MeO 149 22 5-a 4-tetrahydro- pyran 2-MeO 4-MCO 142 23 5-a 4,4-dimethyl cyclohexane 2-MeO 4-MeO 118

24 5-C1 2-hexahydro- indane 2-MCO 4-MCO 89 25 4-C1 cyclohexane 2-MCO 4-MCO 150 26 5-Cl cyclohexane 3-MCO 4-MeO 152 27 5-Cl cyclohexane 4-Me H 150 28 Η cyclohexane 3-MCO 4-MCO 107 29 5-Me cyclohexane 3-MeO 4-MCO 171 30 5-MCO cyclohexane 3-MCO 4-MCO 124 31 5-Cl cyclohexane 2-MCO 4-MCO 149 32 5-Cl cyclohexane 4-a H 154 33 5-Cl cyclobutane 3-MCO 4-MeO 111 34 5-a cyclopentane 3-MeO 4-MCO 106 35 5-a cyclohexane 4-MCO 2-a 174 36 5-a cyclohexane 4-NO2 H 172 37, 5-a cyclohexane 4-CN H 198 Λ * · 38 5-Cl cyclohexane 4-MCO 2-NO2 147 39 5-Cl cyclohexane 4-CF3 H 139 40 5-a cyclohexane 4-CF3O H 134 41 5-a cyclohexane 4-MCO 2-NH ₂ 150

42 _4-CH3 cyclohexane 4-MeO 2-MCO 165 * R 2 = 6- ch ₃ 43 5-C1 cyclohexane 3-Me 4-BzO 127 44 5-C1 cyclohexane 4-iPr 2,6-iPr 172 45 5-C1 cyclohexane 2-CF ₃ H «« 154 46 5-a cyclohexane 2-MCO 'CO-NH- 215 ch ₃ ch ₃ 47 5-a cyclohexane 4-MCO y -CO-NH- 193 48 5-a cyclohexane 2-MCO ch ₃ 4-O ₃ OCO 120 49 5-a fO 2-MeO 4-MeO 184 50 H CH adamantane 2-MeO 4-MCO 172 51 5-MCO 4,4-dimethyl 2-MeO 4-MeO 152 52 5-a cyclohexane cyclohexane 2-MCO 4-CH ₃ SO ₂ NH 131 53 5 _r a cyclohexane 2-MCO and y-m 240. -. [Y-CONH-4] and 54 5-a cyclohexane 2-Me 5-F 153 55 5-a cyclohexane 2-CF _3- ch ₂ o 5-CF ₃ CH ₂ O 175 56 5-a cyclohexane 2-MCO From the "W-NHCO-4 218 ch ₃

57 5-C1 cyclohexane 2-MCO y-O-CCM 165 58 5-Cl cyclohexane 5-NH ₂ 2,4-Dimco 270 SCB 59 5-BzO cyclohexane 2-MCO 4-MCO 159 60 5-BzO 4,4-dimethyl cyclohexane 2-MeO 4-MeO. 142 61 5-Cl : cyclohexane 2-MCO ch ₃ o - (-) - c-nh ^ 0 192 62 5-Cl cyclohexane 2-MCO P ~ \ CH, N, N-C-4 158 64 H CCCHfcČfiHjh 3-MeO 4-MCO 146 65 5-CH3 CO cyclohexane 3-MCO 4-MCO 122 66 5-Cl C (n-pcntyl) 2 2-MCO 4-MCO 140 67 5-Cl CCCH ₂ C ₆ H ₅ ) 2 2-MCO 4-MCO 185 68 5-H ₂ N cyclohexane 2-MeO 4-MCO 230 69 5-Cl 4-spirocycle 2-MCO 4-MeO 154 pentane ..70 ‘ 5-Cl cyclohexane 2-MCO 5-MeO 116 71 5-nPr cyclohexane 2-MCO 4-MCO 138 72 5-EtO N-Bu-4 2-MeO 4-MCO 95 piperidine (0:25 H ₂ O) 73 5-Cl N-Bz-4- 2-MCO 4-MCO 76 piperidine (0-5 H ₂ O)

74 75 5-Cl 5-C1 N-phenyl-4- piperidine cyclohexane 2-MeO 2-EtO 4-MeO 4-EtO 163 123 76 5-C1 2-MeO 4-MCO Λ 190 77 5-EtO 4,4-diethyl cyclohexane 2-MeO '  4-M.cÓ • 129 78 5-EtO cycloheptane 2-MCO 4-MCO 130 79 5-EtO cyclohexane 2-MCO 4-MeO 134 80 81 5-EtO 5-ei 4,4-dimethyl cyclohexane 4,4-dimethyl cyclohexane 2-MCO 2-MCO 4-MeO 4-MeO 160 166 82 5-EtO 4,4-dimethyl cyclohexane 2-MeO 4-NO2 110 83 5-EtO 4,4-dimethyl cyclohexane 2-MCO _4-NH2 230 84 5-NO2 · » 4,4-dimethyl cyclohexane 2-MeO 4-MCO 102 85 • 5-NH 2 4,4-dimethyl cyclohexane 2-MCO 4-MCO 180 86 5 CF3CH7O 4,4-dimethyl cyclohexane 2-MeO 4-MCO 169

Example 87

1- (2,4-dimetoxybenzénsulfony1) -3- (4,4-dimetylspirocyklohexán) -5-hydroxyindole-2-one

3.51 g of the compound prepared in Example 60 was stirred for 1 hour. in a hydrogen atmosphere at 50 ° C with 0.5 g of 10% palladium on charcoal in 150 ml of ethanol. The catalyst is filtered off through talc, the filter residue is washed with DCM and the filtrate is evaporated under reduced pressure to give 2.8 g of the expected compound which is recrystallized from cyclohexane / AcOEt (90/10, v / v), tt = 220 [ ^deg.] C.

Example 88

1- (2,4-Dimethoxybenzenesulfonyl) -5-hydroxy-3-spirocyclohexaindol-2-one was prepared in the same manner from the 5-benzyloxy derivative described in Example 59, m.p. t. = 196 ’C.

Example 80a

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

This compound, already described in Example 80, can be prepared by another method starting from a homologous 5-hydroxy compound, 0.6 g of the compound prepared in Example 87 is stirred for 16 hours. at room temperature 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 was evaporated under reduced pressure and 39 ml of AcOEt and 30 ml of water were added. The organic phase is washed with water, dried over magnesium sulphate and then concentrated under reduced pressure. Recrystallization from cyclohexane yields 0.45 g of the expected product; t. t. = 160 ’C.

The compounds listed in Table 4 were prepared in the same manner.

Table 4

pr. ^R 1 ^Cr 3 ^R 4 ^R 5 ^R 6 mp 'C 89 5-N pro cyclohexane 2-MeO 4-MeO 139 90 5-N pro 4,4-dimethyl cyclohexane 2-MeO 4-MeO 159 91 5-iPrO 4,4-dimethyl cyclohexane 2-MeO 4-MeO 154 92 CH ₂ -0 cyclohexane 2-MeO 4-MeO 155

Example 93

5-acetoxy-l- (2,4-dimethoxybenzenesulfonyl) -3-spirocyklohexaindol-2-one

0.5 g of the compound prepared in Example 88, 2.5 ml of isopropyl acetate and 0.165 g of potassium carbonate in 2.5 ml of toluene and 0.3 ml of DMF were stirred for 15 hours. heated at about 65 ° C. 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 cyclohexane, is isolated by crystallization from cyclohexane / ethyl acetate, m.p. t. = 110 C.

Example 94

1- (2,4-Dimethoxybenzenesulfonyl) -5- (2-hydroxyethoxy) -3-spirocyklohexaindol-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 were added for 40 hours. heats at about 70 C. 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 oily residue is chromatographed on a silica column using cyclohexane / AcOEt (70/30, v / v) as eluent to give 0.5 g of the expected product, which is recrystallized from heptane / DCM; t. t. = 170 ’C.

Example 95

5- (2-dimethylaminoethoxy) -1- (2,4-dimethoxybenzenesulfonyl) -3-spirocyclohexaindol-2-one

0.6 g of the compound prepared in Example 88 was heated for 16 hours. in an inert atmosphere at about 40 ° C with 0.32 g of N, N-dimethyl- (2-chloroethylamine) and 1.72 g of cesium carbonate in 7.2 ml of acetone and 2.4 ml of DMF. The salts were filtered off and 20 ml of water and 20 ml of AcOEt were added to the filtrate. The organic phase is decanted, washed with water, dried over magnesium sulphate and concentrated under reduced pressure. The residue is chromatographed on silica using DCM / MeOH (9/1, v / v) as eluent to give 0.6 g of the expected product, which is recrystallized from cyclohexane / iso ether; t. t. = 122 ’C.

Example 96

5-chloro-l- (2,4-Dimethoxybenzenesulfonyl) -3- (4-spiropiperidine) indol-2-one

This reaction is carried out according to J. Org. Chem., 1984, 49,

2795-2799. At 0 ° C, 0.75 g of 1-chloroethyl chloroformate is added 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 about 20 min. It is refluxed and concentrated under reduced pressure to a volume of about 10 ml and then 22 ml of methanol are added. The mixture was refluxed for 50 min, the reaction mixture was concentrated under reduced pressure, and the residue was chromatographed on a silica column using DCM / MeOH (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, m.p. t. = 172 ’C.

Example 97

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

0.086 g of acetyl chloride is added to a solution of 0.35 g of the compound prepared in the previous example and 0.23 ml of triethylamine in 5 ml of DCM, cooled to about 0 ° C. The mixture was stirred for 1 hour. at 20 ° C, 5 ml of water are added, the organic phase is decanted, washed with water, dried over magnesium sulphate and concentrated under reduced pressure and the residue is chromatographed on a silica column using DCM / MeOH / 99/1, v / v) as eluent. 0.29 g of the expected product is isolated in the form of the hemihydrate, m.p. = 107 ’C.

Example 98

5-chloro-l- (2,4-Dimethoxybenzenesulfonyl) -3- (N-4-metoxykarbonylspiropiperidín) indol-2-one

This compound was prepared from the compound prepared in Example 96 by reaction with methyl chloroformate, m.p. t. = 147 ’C.

Example 99

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

A solution of 0.144 g of propionyl chloride in 3 ml of DCM is added to a solution of 0.5 g of the compound described in Example 13 and 0.167 ml of triethylamine in 10 ml of DCM, cooled to about 0 C. The mixture is stirred for 2 hours. at 20 ° C, then 20 ml of water are added and the organic phase is decanted, washed with water, dried over magnesium sulphate and concentrated under reduced pressure. 0.5 g of the expected product is isolated after recrystallization from heptane / AcOEt (95/5, v / v). t. = 158 ’C.

Example 100

1- (3,4-Dimethoxybenzenesulfonyl) -5- (N-ureido) -3-spirocyclohexaneindol-2-one

0.15 g of methyl isocyanate is added to a solution of 0.5 g of the compound described in Example 13 in 10 ml of DCM, cooled to about 0 ° C. The mixture is stirred for about 16 hours. at room temperature, 20 ml of water are added and the organic phase is decanted, 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. t. = 214 ’C.

Example 101

1- (3,4-dimethoxybenzenesulfonyl) -5- (N-phenylureido) -3-spirocyclohexanindol-2-one was prepared in the same manner as used in Example 100, m.p. t. = 124 ’C.

Example 102

5-dimethylamino-l- (2,4-dimethoxybenzenesulfonyl) -3-spirocyclohexaneindol-2-one

A mixture of 0.5 g of the compound described in Example 68 with 0.5 ml of a 35% formaldehyde solution and 0.12 g of sodium cyanoborohydride in 10 ml of acetonitrile is stirred under a nitrogen atmosphere at room temperature and the pH is adjusted to about 6.5 with a few drops acid octo55 egg. After 48 hrs. at 20 ° C the solvent was evaporated under reduced pressure and 20 ml of approximately 2N aqueous sodium hydroxide solution and 20 ml of DCM were added. The organic phase is decanted, 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 cyclohexane / ethyl acetate (80/20, v / v) as eluent. 0.27 g of the expected product is isolated, m.p. t. = 167 ’C.

Example 103

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

This compound was prepared according to J. Chem. Soc., Chem. Commun., 1980, 16, 756. A mixture of 2.95 g of diethyldisulfide and 0.386 g of isopentyl nitrite is heated to about 80 ° C under an inert atmosphere and 0.8 g of the compound prepared in Example 68 is added. at 80 ° C and then concentrated under reduced pressure. The residue is chromatographed on a silica column using DCM / cyclohexane (80/20, v / v) as eluent. The expected product is isolated after crystallization from cyclohexane, m.p. t. = 123 ’C.

Example 104

5-chloro-l- [4- (dimetylaminometylkarboxamido) -2-methoxybenzenesulfonyl] -3-spirocyclohexaneindol-2-one

a) 5-chloro-1- [4- (chloromethylcarboxamido) -2-methoxybenzenesulfonyl] -3-spirocyclohexanindol-2-one

0.2 g of the compound prepared in Example 2 is taken up in 4 ml of DCM and 0.5 g of TEA and 0.1 g of chloroacetyl chloride are added. The mixture was stirred for 20 hours. at room temperature, then concentrated in vacuo. The concentrate was extracted with ethyl acetate, the extract was washed with water and sodium carbonate solution and the residue was then chromatographed on silica using a mixture of DCM and AcOEt as eluent; 0.15 g of the expected product is obtained.

b) 5-chloro-1- [4- (dimethylaminomethylcarboxamido) -2-methoxybenzene-sulfonyl] -3-spirocyclohexanindol-2-one

The compound prepared in the previous step (150 mg) was stirred for 20 h. at room temperature in 20 ml of a 33% solution of dimethylamine in ethanol. Extraction of AcOEt is performed and the extract is washed with 1N sodium hydroxide and then with water. The residue is chromatographed on silica using AcOEt as eluent to give 0.025 g of the expected product, m.p. t. = 173 ° C.

Example 105 1- (4- (4-Sulfamoylphenylcarboxamido) -2-methoxybenzenesulfonyl) -5-chloro-3-spirocyclohexanindol-2-one

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

0.2 g of the compound prepared in Example 2 was contacted 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 room temperature. It is concentrated in vacuo, the concentrate is taken up in THF and 10 ml of aqueous ammonia are added. Stirring is continued for 20 hours. at room temperature and the mixture was concentrated in vacuo. The residue is extracted with ether and the extract is washed with water, dried over sodium sulphate and then chromatographed on silica using AcOEt as eluent to give the expected product; t. t. = 238-242 ’C after recrystallization from AcOEt.

Example 106

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

(a) 3-chlorosulfonylbenzoyl chloride

This compound is prepared according to U.S. Pat. No. 3,290,370. 11 g of chlorosulfonic acid are heated to 60 DEG C. and 8 g of phenyl chloroform are added dropwise. The mixture was heated for 2 hours. at 130 ° C, the mixture is distilled to give 1 g of the expected product; boiling point 120 - 125 ° C at 0.5 mm Hg.

b) 1- [4- (3-sulfamoylphenylcarboxamido) -2-methoxybenzenesulfonyl] -5-chloro-3-spirocyclohexanindol-2-one

210 mg of the compound prepared in Example 2 are placed in 10 ml of DCM with 220 mg of the compound obtained in the previous step and 200 mg of TEA, the mixture is stirred overnight and then the solvents are evaporated off under vacuum. The residue was taken up in 20 ml THF and 20 ml aqueous ammonia and stirred for 6 hours. at room temperature. The solvents were evaporated in vacuo and the residue was then taken up in AcOEt and water. AcOEt extraction is performed and the extract is washed with water and then chromatographed on silica using AcOEt / cyclohexane (50/50, v / v) as eluent to give the expected product, m.p. t. = 176 ’C.

Example 107

1- [4- (2-carboxyphenylcarboxamido) -2-methoxybenzenesulfonyl] -5-chloro-3-spirocyclohexanindol-2-one

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

A mixture containing 0.2 g of TEA and 160 mg of phthalic anhydride was added under vacuum and 1 N precipitate was filtered off and sodium; re-filtered, re-formed, added with 0.5 ml. Concentrated sodium carbonate formed; decant and filter to precipitate and wash with 10% and recrystallize from the isoether prepared in Example 2, stirred for 3 hours. at 60 ’C. hydrochloric acid, add 10% solution and add 10% solution precipitate, aqueous phase with% AcOH. The precipitate is formed

AcOH and then isopropyl ether to the expected product; mass

0.150 g, m.p. t. = 157-158 ° C.

Example 108

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

This compound was prepared as described in Example 3, by reacting benzyloxyacetyl chloride with the compound prepared in Example 2, m.p. t. = 143 ’C after iso-ether recrystallization.

Example 109

5-chloro-1- (4- (hydroxymethylcarboxamido) -2-methoxybenzenesulfonyl) -3-spirocyclohexanindol-2-one

This compound is obtained by hydrogenating the compound prepared in the previous example under a water column pressure in the presence of 5% palladium on carbon in EtOH / AcOEt, m.p. t. =

202 ’C.

Example 110

5-chloro-1- [4- (imidazol-1-ylphenylcarboxamido) -2-methoxybenzenesulfonyl] -3-spirocyclohexanindol-2-one

(a) 4- (imidazol-1-yl) benzoic acid ethyl ester

A mixture containing 35 g of 4-fluorobenzoyl chloride in 50 ml of 100% ethanol was added for 15 min. reflux. 35 g of the obtained 4-fluorobenzoic acid ethyl ester are mixed with 22 g of imidazole and 61 g of potassium carbonate in 35 ml of DMSO. The mixture was heated for 18 h. to 120-130 ° C and then add 500 ml of ice water. A precipitate formed and the expected product crystallized from iso ether, m.p. t. = 98 ’C.

b) Imidazol-1-ylbenzoyl chloride g of the ester obtained in step a) for 2 hours. reflux in 20 ml of water and 20 ml of sodium hydroxide solution. The reaction mixture was washed with ether and then acidified (pH = 2) with concentrated hydrochloric acid. The precipitate formed is filtered off and then washed with iso ether. 5 g of the acid obtained are introduced in 35 ml of thionyl chloride at reflux temperature. The precipitate formed is filtered off and then washed with iso ether to give the expected acid chloride, m.p. t. = 234 ’C.

c) 5-chloro-1- [4- (imidazol-1-ylphenylcarboxamido) -2-methoxybenzenesulfonyl] -3-spirocyclopentanindol-2-one

A mixture containing 210 mg of the compound prepared in Example 2 and 200 mg of the acyl chloride prepared in step b) in 10 ml of DCM and 1.5 ml of TEA was stirred for 1 hour. Stir at room temperature and then for 3 hours. reflux. The reaction mixture was extracted with DCM and then washed with water and aqueous sodium hydroxide solution. After evaporation of the solvents, the residue is chromatographed on silica using DCM / methanol as eluent. The expected product is recrystallized from iso ether; weight 0.010 g, t. t. = 145 ’C.

Example 111

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

This compound is prepared by reacting phenyl chloroformate with the compound prepared in Example 2; t. t. = 209 ’C after recrystallization from isoether.

Example 112

5-Chloro-1- [4- (N-methylureido) -2-methoxybenzenesulfonyl-3-spirocyclohexanindol-2-one

140 mg of the compound obtained in the previous example are mixed with 5 ml of ethanol, 5 ml of DCM and 5 ml of a 3% solution of methylamine in ethanol. After 1 hour the solvents were evaporated at room temperature and the residue was then chromatographed on silica using DCM / MeOH as eluent. The product obtained is recrystallized from iso ether, m.p. t. = 254 ’C.

Example 113

5-Chloro-1- (2-methoxy-4-ureidobenzenesulfonyl-3-spirocyclohexanindol-3-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 was added for 1 hour. Stir at room temperature. After filtering the reaction mixture and evaporating the solvents, the expected product is recrystallized from iso ether, m.p. t. = 228 ’C.

Example 114

5-Chloro-1- 14 - (N-o-tolylureido) -2-methoxybenzenesulfonyl] -3-spirocyclohexanindol-2-one

A mixture containing 250 mg of the compound prepared in Example 2, 10 ml of xylene and 80 mg of o-toluyl isocyanate was stirred for 18 hours. reflux. A white precipitate formed and was filtered off. The reaction mixture was extracted with ether and the extract was washed with water and then chromatographed on silica using DCM / MeOH as eluent. The expected product crystallizes from iso ether, m.p. t. = 182 ’C.

Example 115

Benzyl-4- (5-methoxy-2-oxo-spirocyclohexanindol-1-yl) sulfonyl

The 3-methoxybenzoate mg of sodium hydride is poured in small portions into a mixture containing 500 mg of 3-spirocyclohexane-5-methoxyindol-2-one in 50 ml of THF. After 30 min. 800 mg of benzyl 3-methoxy-4-chlorosulfonylbenzoate chloride is added at room temperature and the mixture is stirred for 2 hours. at room temperature. The mixture 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 3 H: 2 x OCH3

5.4 ppm: 2 H: CO ₂ -CH ₂ -C ₆ H ₅

6.8 - 8.2 ppm: 11 H: 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 are placed in 50 ml of AcOEt and hydrogenated at room temperature and atmospheric pressure in the presence of 140 mg of palladium on carbon; 310 mg of the expected acid is obtained, which is recrystallized from hexane / ethanol (70/30, v / v), m.p. t. = 210 “C.

Example 117

5-Chloro-1- [4- (N-ethoxycarbonylmethyl) carbamoyl-2-methoxybenzenesulfonyl] -3-spirocyclohexanindol-2-one

450 mg of ethyl glycinate hydrochloride in 20 mg of sodium methylate is poured into methanol. 200 mg of the compound described in Example 60 in 50 ml of DCM are added and the mixture is stirred for 48 hours. at room temperature. DCM is extracted 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, m.p. t. = 164 ’C.

Example 118

1- (4-Carbamoyl-2-methoxybenzenesulfonyl) -5-chloro-3-spirocyclo62 hexanindol-2-one

300 mg of the compound, 30% aqueous ammonia, washed with water at room temperature, dried, mixed with DCM / MeOH of the expected product described in Example 60, with 5 ml of 10 ml of ethanol and 10 ml of DCM. After 1 hour when the mixture is concentrated and extracted with DCM and the extract is concentrated and chromatographed on silica using pou (99/1, v / v) as eluent; 109 mg t is obtained. t. = 160 ’C.

Example 119

5-chloro-l- [2-methoxy-4- (N- (2-methoxycarbonylethyl) karbamoylbenzénsulfonyl)] - 3-spirocyclohexaneindol-2-one

A mixture of 320 mg of the compound described in Example 60 and 2 g of methyl aminobispropionate in 30 ml of tetraraethylbenzene was added for 30 min. reflux. Extraction with AcOEt is carried out and the extract is washed with 1N hydrochloric acid solution, dried over sodium sulphate and concentrated. The residue is chromatographed on silica using DCM / MeOH (99/1, v / v) as eluent to give 100 mg of the expected product, m.p. t. = 147 ’C.

Example 120 1- [4- (3- (N-Boc) aminoazetidin-1-ylcarbamoyl) -2-methoxybenzenesulfonyl] -5-chloro-3-spirocyclohexanindol-2-one

A mixture containing 300 mg of the compound prepared in Example 60, 900 mg of 3- (N-Boc) aminoazetidine, 1 ml of triethylamine, 10 ml of DCM and 10 ml of methanol was added for 1 hour. Stir at room temperature. It is then concentrated and extracted with ethyl acetate and the extract is washed with 1N hydrochloric acid solution, dried over sodium sulphate and concentrated. The expected product is obtained after chromatography on silica using DCM / MeOH (99/1, v / v) as eluent, m.p. t. = 136 ’C.

63 Example 121

1- [4- (3-aminoazetidine-l-ylcarbamoyl) -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 THF in 10 ml of DCM was added for 30 min. Stir at room temperature. The reaction mixture is concentrated, allowed to crystallize from iso ether and the crystals are filtered off and dried. The product obtained is dissolved in 10 ml of water and then 10 ml of 1N sodium hydroxide; the solution was extracted with DCM and the extract was 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, m.p. t. = 145 ’C.

Example 122

5-ethoxy-l- (4- {3-dimethylamino-propoxy) -2-methoxybenzenesulfonyl]

3-spirocyclohexaneindol-2-one hydrochloride

(a) 5-ethoxy-1- [4- (3-bromopropoxy) -3-methoxybenzenesulfonyl] -3-spirocyclohexanindol-2-one

A mixture containing 0.5 g of 5-ethoxy-3-spirocyclohexanindol-2-one, 5 ml of THF and 0.07 g of sodium hydride was added for 15 min. stir at 20 C. 1.65 g of 4- (3-bromopropoxy) -3-methoxybenzenesulfonyl chloride are then added and the mixture is stirred for 20 hours. at room temperature. Concentrate in vacuo and extract with ether and wash the extract with water and then with 10% sodium carbonate solution. The expected product crystallizes from pentane and is then recrystallized from iso ether; t. = 114-118 C. C.

b) 5-ethoxy-1- [4- (3-dimethylaminopropoxy) -3-methoxybenzenesulfonyl] -3-spirocyclohexanindol-2-one hydrochloride

The compound obtained in the preceding step is mixed with

7.5 g of a 33% solution of dimethylamine in ethanol and added to 10 ml of THF.

«.vt3

The mixture was stirred for 3 hours, then concentrated in vacuo and taken up in 10 ml of water and extracted with ether. The ether phase is mixed with 20 ml of 2N hydrochloric acid, then solid potassium carbonate is added to basify the solution to pH 9. The oil which precipitates is extracted with DCM. The expected product crystallizes from ether, m.p. t. = 135-138 C. C.

Example 123

1- [4-amino sulfonamide-2-methoxybenzenesulfonyl] -5-chloro-3-spirocyclohexaneindol-2-one

0.3 g of the compound prepared in Example 2 is mixed with 4 ml of DCM in the presence of 0.5 g of TEA and 0.3 g of aminosulfonyl chloride prepared according to Chem. Ber., 1958, 91, 1339-1341. The mixture was stirred at room temperature for 2 days, then concentrated in vacuo and extracted with ether, and the extract was washed with water. After drying, the residue is chromatographed on silica using DCM and then AcOEt as eluent to give the expected product, which crystallizes from ether, m.p. t. = 205 - 208 ’C.

Examples 124 and 125

1- [4-dimethylamino-2-methoxybenzenesulfonyl] -5-methoxy-3-spirocyclohexanindol-2-one and 1- [4-methylamino-2-methoxybenzenesulfonyl] -5-methoxy-3-spirocyclohexanindol-2-one

500 mg of 1- (4-amino-2-methoxybenzenesulfonyl) -5-methoxy-3-spirocyclohexanindol-2-one are mixed with 1 ml of 37% aqueous formaldehyde solution, 10 ml of acetonitrile and 430 mg of sodium cyanoborohydride, and then 0, 0 is added. 12 ml acetic acid. The temperature of the mixture rises and the mixture is cooled in an ice bath. Gradually, two products with different polarities are formed. 1 ml of aqueous formaldehyde solution, 300 mg of sodium cyanoborohydride and 0.12 ml of acetic acid are added to the mixture. The mixture was stirred for 1 1/2 hours, poured into ice water and then extracted with AcOEt. The extract was washed with water, dried and concentrated to give 2 products which were separated by chromatography on silica using DCM / AcOEt (98/2, v / v) as eluent, m.p. t. = 210 ’C (Ex 124), 170’ C (Ex 125).

Table 5

(D

Unless otherwise stated, the substituent Rg is in the 4-position and m = 1.

* 6

ex ri R 2 R 5 R6 M.p. 'C 126 Cl H 2-MCO \ ^ CONH 210 127 and H 2-MCO ^{Me0 in} Z ^ ^C0NH 192 2-MeO / V-CONH- 128 Cl H 188 129 Cl H 2-MCO / V-CONH- 146 OMe 130 and H 2-MeO 'J V-ch ₂ conh-R 190 131 Cl H 2-MeO / V-CONH- 147 \ = ^ OCOCHj 132 ^with Cl H 2-MeO CH3CONH- 230 • 2-MeO Me 133 Cl H <1 V-CONH- 205 Me 134 and H 2-MeO HO2C (CH2) 2 205 CONH-

180

189

135 Cl H H 136 Cl H 2-MeO 137 Cl H 2-MeO 138 MeO H 2-MeO 139 MeO H 2-MeO 140 Cl H 2-MeO 141 Cl • · H 2-MeO 142 Cl H 2-MeO 143 MeO H 2-MeO 144 MeO H 2-MeO

176

245

194

141

140

225

161

209

145 EtO H 2-MeO / V-CONH- 223 146 EtO H 2-MeO t Me / N-CH ₂ COH-Me ^Z 136 147 Cl H 2-MeO Me ···· ^X N-CO-NH- Me ^Z 226 148 ch ₃ o H 2-MeO Me ^X N-COH- Me ^Z 190 149 EtO H 2-MeO Me 2 N-CONH- Me ^Z 192 150 EtO H 2-MeO Me / N-CONH-Et ^Z 160 151 EtO H 2-MeO Et N-CONH- Et ⁷ 168 152 EtO k · H 2-MeO Me N-CONH- Pr ⁷ 137 153 Cl H 2-MeO \ - € O- 157 154 Cl H 2-MeO Me ✓ N- (CH ₂ ) ₂ -NHCOMe ^Z 163 155 Cl H 2-MeO Me _x N-CO-Me ^Z 192

156 Cl H 2-MeO Mc, Ν-SOnMe ^{x 2} 231 157 C1 H 2-MeO H 106 158 Cl H 2-MeO f ~ \ Mc-N ••• / N-SO2-., 226 159 Cl H 2-MeO MCOC HC-NHCO- bz 117 160 MeO H 2-MeO O ₂ N- 188 161 Cl H 2-MeO BzOCO- NMR 162 and H 2-MeO NHCO- 215 163 MeO H 2-MeO nh ₂ - 188 164 MeO H 2-MeO MeO 172 165 MeO H 2-MeO 162 166 · * MeO H 2-MeO / Y-NHCO- 198 167 EtO H 2-MeO h ₂ n- 177 168 MeO 6-MeO 2-MeO MeO 183

169 ΕίΟ H 2-MeO ΓΥ nhco- Mc 150 170 EtO H 2-MCO BzOCO- 135 171 EtO H 2-MCO ......... HÓOC- ' NMR 172 EtO H 2-MeO MeNHCO- 239 173 EtO H 2-MeO 5-MCO 131 174 EtO H 3-MCO McO- 127 175 EtO H 2-MeO Me. N- Me 167 176 EtO H 3-MeO 4,5-MeO 130 177 EtO H 2-MCO Vnhco- \ IE 195 178 EtO · » H 2-MCO 0-CH ₂ NHCO- 168 179 EtO H 2-MCO n ₂ 0 160 180 EtO H 2-Me MCO 176 181 EtO H 3-MeO ch ₂ = ch-ch ₂ o- 130 182 cf ₃ o H 2-MeO MeO . 127

183 EtO H 2-MeO Me / ČHNHCO- Me 171 184 EtO H 2-MeO EtOCOCH ₂ NHCO- 203 185 EtO H 2-MeO f / - v O-CO-NH- 181 186 EtO H 2-MeO 4,5-MeO 136 187 EtO H 2-Me 4-MeO, 5-Cl 129 188 EtO H 2-MCO N-Bz NHCO- 188 189 EtO H 2-MeO HO (CH2) 2-NHCO- 157 190 EtO H 2 H 117 MeOCO 191 EtO H 2-MeO Me N- (CH ₂ ) 3 -O- Me ^z 212 , HCl 192 EtO H 2-MeO n CONH- 181 about 193 • · EtO H MeO Et-CH-CONH-Et ⁷ 206 194 EtO H 2-MeO BzOCOCH ₂ NHCO NMR 195 EtO H 2-MeO Me 144 C The N-CO- Me

196 EtO H 2-MeO y _O co- 152 197 EtO H 2-MeO Et ^. N-COEt ^z 148 198 EtO H 2-MeO ^Et \. C-CS - Et ^z 128 199 EtO H 2-MeO cn-ch ₂ nh-co- 232 200 EtO H 2-MeO EtO ₂ C-CH ₂ -N-CO- NMR Me 201 EtO H 2-MeO HO2C-CH2-NH-CO 137 202 Cl H 2-MeO (Et ^ N-CO-NH- 194 203 EtO H 2-MeO ^ -CONH- 214 204 EtO H 2-MeO H ₂ N (CH 2) ₃ O- 136-140 205 EtO H 2-MeO + (CH ₃ ) ₃ N (CH ₂ ) ₃ O- I- 145-150 206 C ₆ H ₅ O H 2-MeO 4-MeO 130 207 EtO H 2-MeO CS-NH- 210

208 EtO H 2-MeO ^Et x CH-CO NEt 2 Me 138 209 EtO H 2-MCO EtO-CO-CH ₂ O- 160

NMR spectra were measured in DMSO at 200 MHz.

NMR in Example 161:

1.3-1.8 ppm: 10H: cyclohexyl

3.5 ppm: 3 H: OCH ₃

5.3 ppm: H 2 O-CH ₂ -C ₆ H ₅

7.2 - 8.2 ppm: 11 H: aromatic protons

NMR in Example 171:

1.15 ppm: 3 H: CH ₃

1.19-2 ppm: 10H: cyclohexyl

3.6 ppm: 3 H: OCH ₃ ppm: 2 H: OCH ₂ -CH ₃

6.7 - 8.2 ppm: 6 H: aromatic protons

NMR in Example 200:

1-2.2 ppm: 16 H: cyclohexyl + 2CH ₃ 3 ppm: 3 H: NCH ₃

4-4.4 ppm: 6 H: aromatic protons

6.8 - 8.2 ppm: 6 H: aromatic protons

Signal degradation is observed; is associated with the amide isomerism.

74 Example 210

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

(a) Potassium 4-benzyloxy-2-methoxybenzenesulfonate

This compound is prepared according to K. Hofmann et al., Liebigs Ann. Chem., 1982, 282-297.

10.5 g of 4-benzyloxy-2-methoxybenzene were mixed with 30 ml of DCM at 5 ° C and over 15 min. 8 ml of trimethylsilyl chlorosulfonate in 30 ml of DCM are added at a temperature between 5 and 10 ° C; The mixture was stirred for 15 min. 50 g of ice are added. The mixture was washed with ethyl ether, potassium bicarbonate was added and the mixture was concentrated in vacuo. After drying, the residue is taken up in 150 ml of methanol. The insoluble matter is filtered off under boiling and the expected compound crystallizes at 5 ° C, m.p. t. > 300 ’C. The structure of the compound is confirmed by spectra

NMR.

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 stirred for 3 hours. reflux. Concentrate in vacuo, add 20 g of ice, extract with ethyl ether and wash the extract with 30 ml of 1N sodium hydroxide and then with water. The mixture was concentrated and the resulting oil was then triturated in 30 mL of iso ether. The expected product crystallizes (0.7 g), mp = 95 ° C.

c) 1- (4-Benzyloxy-2-methoxybenzenesulfonyl) -5-ethoxy-3-spirocyclohexanindol-2-one

This compound is prepared by a conventional procedure. Crystallized from iso ether, m.p. t. = 135 ’C. The structure of the compound is verified by NMR spectrum analysis in 2 dimensions (NOESY: Nuclear Overhauser Effect Spectroscopes).

75 Example 211

5-ethoxy-l- (4-hydroxy-2-methoxybenzenesulfonyl) -3-spirocyclohexaneindol-2-one

This compound is prepared by debenzylation of the compound prepared in the previous example, m.p. t. =

209 ’C.

Claims (20)

A compound of formula I and R ₂ independently represent hydrogen, hydroxy, C ₃ -C ₄ -haloalkoxy, halogen, C ₁ -C ₄ alkyl, trifluoromethyl, C ₁ -C ₇ alkoxy, C ₁ -C ₄ polyhaloalkoxy, C ₂ -C ₄ -? - hydroxyalkoxy,? -Methoxyalkoxy, wherein the alkyl is C ₂ -C ₄ , C ₂ -C ₄ -aminoalkoxy, which is free or substituted by one or two C 1 -C ₄ alkyl, C ₃ -C ₇ cycloalkoxy, cycloalkylmethoxy, wherein the cycloalkyl is C ₃ -C ₇ , phenoxy, benzyloxy, C ₁ -C ₄ alkylthio, phenylthio, nitro, amino, which are free or substituted by one or two C ₁ -C ₄ alkyl, cyano, C ₁ -C ₄ acyl, C ₁ -C ₄ acyloxy, C ₁ -C ₄ alkylsulfonamido, phenylsulfonamido, C ₁ -C ₄ alkylamido, C ₁ -C ₄ alkoxycarbonylamino, ureido, which are unsubstituted or substituted by phenyl or by one or two C ₁ -C ₄ alkyl, 1mi, R ₃ and R ₄ independently represent C 1 -C ₇ alkyl, C ₃ -C ₇ cycloalkyl, phenyl, benzyl, cycloalkylmethyl, wherein the cycloalkyl is C ₃ -C ₇ , or R ₃ and R ₄ together form - (CH ₂ ) p X ( CH ₂ ) g or R ₃ and R ₄ together with the carbon atom to which they are attached form an optionally fused, saturated or unsaturated C 3 -C 10 hydrocarbon ring which is unsubstituted or substituted by one or more ^C 1 ^-C 4 alkyl groups or C ₃ -C ₅ spiroalkyl, or further R 1 and R ₄ independently have one of the meanings given above and R ₂ is located at the 4-position of the indole and forms the (CH ₂ ) _{3 group} with ^r 3 ' R ₅ and R _g is hydrogen, halogen, C ₁ ~ C ₇ alkyl, trifluoromethyl, cyano, nitro, amino which is free or substituted by one or two C ₁ -C ₇ alkyl, hydroxyamino, hydroxy, carboxy, a group 0R ₇ , a group SR _7, C Cyacyl, C? -C ₇ alkoxycarbonyl, phenoxycarbonyl, benzyloxycarbonyl, carbamoyl, substituted with groups R _g and R _6, thiocarbamoyl which is free or substituted by one or two C ₁ -C ₇ alkyl, sulfamoyl, alkylsulfamoyl or dialkylsulfamoyl wherein alkyl is C ₁ -C ₇ , SO ₂ R ' ₇ , alkylsulfonamido wherein alkyl is COR' ₇ , NR _g R ₉ , CO-NHCH (R ₁₀ ) -COR ₁₂ ; as needed is phenyl, forming part of the substituent R and / or R, is unsubstituted, monosubstituted or polysubstituted C ₁ -C ₇ alkyl, trifluoromethyl, methoxy, halogen, sulfamoyl, alkylsulfoamoylom, wherein the alkyl, carboxy, alkoxycarbonyl, wherein the alkyl acyloxy or imidazolyl, R ₁₆ and R 8 are independently hydrogen, C ₁ -C ₇ alkyl, which is unsubstituted or substituted with R ₁₆ , phenyl, pyridyl, methylpyridyl, piperidin-4-yl, methylpiperidin-4-yl R ₁₈ is hydroxy, cyano, carboxy, which are free or esterified with C ₁ -C ₇ alkyl or benzyl, phenyl, pyridyl, methylpyridyl, amino, which are free or substituted with one or two C ₁ -C ₇ alkyl, R ₇ is C ₁ -C ₇ alkyl, phenyl, benzyl, C ₃ -C ₇ cycloalkyl, C ₂ -C ₄ alkenyl, C ₁ -C ₇ haloalkyl, C ₁ -C ₇ polyhaloalkyl, C ₁ -C _{7 7} acyl, C ₁ -C ₇ - ° o-carboxyalkyl which is free or esterified by C ₁ -C ₄ alkyl or benzyl, C2 "C ₇ -« - amino alkyl, wherein the amino group is free, substituted by one or two C1-C4-alkyl or ammonium ion, R '7 is piperazin-1-yl which is unsubstituted or substituted in the 4-position by R ₇ , piperidino which is unsubstituted or substituted in the 4-position by R ₇ ', azetidin-1-yl which: is unsubstituted or substituted in the 3-position by R ' ₇ , a pyridyl group which is unsubstituted or substituted by methyl, R ₇ is C ₁ -C ₄ alkyl, phenyl, benzyl, C ₁ -C ₄ acyl, R ₇ is R ₇ or amino, which is free or carries a protecting group, R g and R _g is hydrogen, C ₁ -C ₇ alkyl, phenyl or benzyl; R _g may also be a C? -C? Acyl, C - ^ - C-ytioacyl, cycloalkylcarbonyl wherein the cycloalkyl is C ₃ -C _7, cykloalkyltiokarbonyl, wherein the cycloalkyl is C ₃ ~ C _7, C ₁ -C ₄ - »- aminoacyl, C ₁ -C ₄ -οο-hydroxyacyl, C ₁ -C ₄ -oo-benzyloxyacyl, phenoxycarbonyl, tienokarbonyl, pyridylcarbonyl, metylpyridylkarbonyl, ^{C "C4} alkoxycarbonyl benzoyl, CO-CH (R ₁₀₎ NR R n, CH (R ₁₀ ) CO ₂ R ₁₁ , (CH ₂ ) _t COR ₁₂ , CO (CH ₂ ) _t COR ₁₂ , carbamoyl which is unsubstituted or substituted by phenyl or by one or two C ₁ -C ₄ alkyl , m is 1 or, when R _g, halo, C ₁ ~ C ₇ alkyl or C? -C ₇ alkoxy, m can also be 2, 3 or (R _{6) m} can be m substituents with different meanings selected from halogen , C 1 -C ₇ alkyl and C ₁ -C ₇ alkoxy, p and q are integers the sum of which can range from 3 to 6, t is an integer which can range from 1 to 5, X is oxygen, sulfur or NR _13, ^R 10 3 ^θ C ₁ -C ₄ alkyl or benzyl, ^R 11 ^{and R} ll ^means by independent hydrogen or C ₁ -C ₄ 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 alkyl, ^R 13 ^{is hydrogen} 3 'and ^{c-c, and} 4 The alkyl, phenyl, benzyl, C ₁ ~ C ₄ acyl, C 1 -C ₄ alkoxycarbonyl or carbamoyl which is unsubstituted or substituted by one or two C 1 -C 4 alkyl, and possible salts thereof. A compound of formula I according to claim 1, wherein R 1 is a chlorine atom or an ethoxy group at the 6-position of the indole and R ₂ is hydrogen. A compound of formula I according to claim 1, wherein R ₃ and R ₄ together with the carbon to which they are attached form a C ₃ -C 10 hydrocarbon ring. A compound of formula I according to claim 1, wherein R ₃ and R ₄ together with the carbon to which they are attached form cyclohexane which is unsubstituted or substituted by one or two C 1 -C ₇ alkyl groups or C ₃ -C ₅ spirocycloalkyl, cycloheptane , adamantane and tricyclo [5,2, l, 0 ^{2 '6)} dec-8-ene A compound of formula I, wherein R ₃ and R ₄ together with the carbon to which they are attached form a 4-piperidine or N-methyl-4-piperidine ring. A compound of formula I according to claim 1, wherein R _g and R _g are both methoxy. 7. A compound of formula I according to claim 1, wherein R _g at position 2 is methoxy and _Rg is in the 4-C - ^ - Cyacylamino, C ₁ -C ₄ dialkylureido, but will _£ alkoxycarbonylalkylcarbamoyl in which the alkyl groups are C-C _7th A compound of formula I according to claim 1, wherein R 1 is R 1. is in position 6 and R ₂ is hydrogen. A compound according to claim 1 of formula IX S0 ₂ CK) COOH wherein R 1, R ₂ , R ₃ , R ₄ and R ₅ are as defined in Formula 1 and functional derivatives thereof. in the claim 10. The compound of claim 1 of formula X (X) wherein R _{2 l of} R, R _3, R ₄ and R ₅ are as defined for formula I, and optionally the salts thereof. of claim 1 A compound according to claim 1 of formula XI wherein R ₃ , R ₂ , R ₃ , R ₄ and R ₅ are as defined in the formula First in the claim A compound according to claim 1 of formula XII m (ΧΠ) wherein R _3, R _4, R _5, and R _g are as defined for formula I in claim 1. 13. The compound of Claim 1 of formula XIII (ΧΠΙ) wherein R _lr R _2, R _5, R _g and m are as defined for Formula I in Claim 1 Process for the preparation of a compound of formula I according to claim 1, characterized in that the benzenesulphonyl halide of formula III Hal-SO ₂ ( ^R Vm m (ΙΠ) where R ' ₅ and R _{VI respectively} have the meaning of either Rg or Rg shown in Formula I, or a precursor of the Rg and Rg groups, reacted with the 2-oxoindole disubstituted in position 3, of formula II (Π) wherein R '2 »respectively. R ₂ is as defined, either R. and R ₂ in the formula I, or a precursor of R ₃ and R ₂ and R ₃ and R ₄ are as defined for formula I, and either when R ' ₃ ⁼ R ^ t ^R 12 ⁼ R 2 * R * 5 ^{= R} 5 ^R 6 ^{= R} 6 ⁹ , the obtained compound of formula I is isolated, - or, when R 'i which any of R, R _2, R'g and R _VI, a precursor of the group R _x, R _2, R and / or R, the obtained compound is subjected to the subsequent treatment in order to prepare a compound of formula I, converting ktoréhokoívek from the groups R ' _{1 #} R' ₂ / ^R 's ^{and R} vi ^{to the} group R _x , respectively. R ₂ , resp. Rg, respectively. Rg. A compound of formula II '(II) ¹ wherein R and R ₂ are independently hydrogen, hydroxy, C ₁ -C ₄ - »- haloalkoxy, halogen, C ₁ ~ C ₄ alkyl, trifluoromethyl, C ^ -Cyalkoxy, C? -C? Polyhaloalkoxy, C ₂ -C ₄ - 'J-hydroxyalkoxy,' -metoxyalkoxy, wherein the alkyl is a C ₂ -C _4, C ₂ -C ₄ -oo-aminoalkoxy which is free or substituted by one or two C ₁ -C ₄ alkyl, C ₃ -C ₇ cycloalkoxy, cycloalkylmethoxy, wherein the cycloalkyl is C ₃ -C _7, phenoxy, benzyloxy, _C1-C4 alkylthio, phenylthio, nitro, amino which is free or substituted by one or two C ₁ -C ₄ alkyl, cyano, C -C ₄ acyl, C ₃ -C ₄ acyloxy, C ₁ -C ₄ alkylsulfonamido, phenylsulfonamido, C ₁ -C ₄ alkylamido, C ₁ -C ₄ alkoxycarbonylamino, ureido, which are unsubstituted or substituted by phenyl or by one or two C ₁ -C ₄ alkyl, R ₃ and R ₄ together with the carbon to which they are attached form adamantane, indane or hexahydroindane which are unsubstituted or substituted by one C ₁ -C ₇ alkyl group, tricyclo (5.2.1.0.2 / ⁶ ) decane or tricyclo [5,2, l, 0 ^{2 '6]} dec-8-ene which or substituted by one or more of the unsubstituted or more C ₁ -C ₇ alkyl groups; C ₄ -C _g hydrocarbon ring or substituted by one or R ₃ and R ₄ together form a group - (CH ₂ ) p X (CH ₂ ) g - where p and q are integers the sum of which may vary from 3 to 6, and X is oxygen, sulfur or NR ₁₃ where R ₁₃ is phenyl, benzyl, C ₁ -C ₄ acyl, C ₁ -C ₄ alkoxycarbonyl or carbamoyl which is unsubstituted or substituted with one or two C ₁ -C ₄ alkyl, provided that when C ₃ R _{4 is} adamantane, they are R 1 and R ₂ other than hydrogen. A compound of formula II ', ^R 3 H (Π) wherein is hydroxy, C ₁ -C ₄ -oo-haloalkoxy, halogen, C ₁ -C ₄ alkyl, trifluoromethyl, C ₁ -C ₇ alkoxy, C ₁ -C ₄ polyhaloalkoxy, C ₂ -C ₄ - °° -hydroxyalkoxy, n metoxyalkoxy, wherein the alkyl is a ^C 2 ^-C 4 ° ^C 2 ^-C 4 and ^m and ^{-00- NOA} ° p xy which is free or substituted by one or two C ₁ -C ₄ alkyl, C ₃ -C ₇ cycloalkoxy, cycloalkylmethoxy in which the cycloalkyl is C _{3 -C?} , phenoxy, benzyloxy, C ₁ -C ₄ alkylthio, phenylthio, nitro, amino, which are free or substituted by one or two C ₁ -C ₄ alkyl, cyano, C ₁ -C ₄ acyl, C ₁ -C ₄ acyloxy, C C ₁ -C ₄ alkylsulfonamido, phenylsulfonamido, C ₁ -C ₄ alkylamido, C ₁ -C ₄ alkoxycarbonylamino, ureido, which are unsubstituted or substituted by phenyl or one or two C ₁ -C ₄ alkyl, R ₃ and R ₄ together form - (CH ₂ ) _p X (CH ₂ ) q -, or R ₃ and R ₄ together with the carbon to which they are attached form an optionally fused, saturated or unsaturated ^C 3 ^-C 10 hydrocarbon ring which is unsubstituted or substituted by one or more C 1 -C ₆ -alkyl groups or C ₃ -C ₅ spirocycloalkyl , p and q are integers whose sum can range from 3 to 6, X is oxygen, sulfur or NR ₁₃ ^R 13 and C ₁ -C ₄ alkyl, _R phenyl, benzyl, C ₁ -C ₄ acyl, _C-L-C4 alkoxycarbonyl, or carbamoyl, unsubstituted or substituted by one or two C C ₁ -C ₄ alkyl, with the restriction that when R 1 is methoxy, Cr ₃ R _{4 is} other than 3-pyrrolidine, which is unsubstituted or N-substituted with C 1 -C 4 alkyl, and when R 1 is halogen, C 1 -C 4 is C 1 -C 4 alkyl; ₃ R ₄ other than pentane. A compound according to claim 16, wherein R 1 is ethoxy. A compound of formula _II 'with ₂ ci OAlk YRi (ΙΠ) · where Alk is C ₁ -C ₇ alkyl, Y is O or Sa R y is C ₁ -C ₇ alkyl, C ₃ -C ₇ cycloalkyl, C ₂ -C ₄ alkenyl, Cj-Cy-w-haloalkyl, C-Cy-polyhaloalkyl, benzyl, C ₁ -C * _7-acyl, or C ₁ -C ₇ - '- carboxy-esterified C 1 -C ₄ alkyl or benzyl. » 19. A pharmaceutical composition comprising as active ingredient a compound according to any one of claims 1 to 8. 20. A pharmaceutical composition comprising a compound according to any one of claims 1 to 8 in association with a active ingredient.