WO1991013071A1

WO1991013071A1 - Novel trisubstituted pyrrols, process for their production and medicaments containing these compounds

Info

Publication number: WO1991013071A1
Application number: PCT/EP1991/000330
Authority: WO
Inventors: Christos Tsaklakidis; Michael Schultz; Rainer Haag; Werner Scheuer; Eberhard Russmann
Original assignee: Boehringer Mannheim Gmbh
Priority date: 1990-02-26
Filing date: 1991-02-22
Publication date: 1991-09-05
Also published as: DE4005969A1; AU7301191A

Abstract

Compounds of the formula (I) in which the substituents R?1 - R?6 have the significance set out in the claims, process for their production and medicaments containing these compounds for the treatment of immune and allergic diseases.

Description

New trisubstituted pyrroles, processes for their preparation and medicaments containing these compounds

The present invention relates to new trisubstituted pyrrole derivatives of the general formula I.

wherein

R ^{1 is} hydrogen, acyl, an optionally acylated carbohydrate radical, a saturated or unsaturated, straight-chain or branched, unsubstituted or mono- or polysubstituted, preferably mono- to trisubstituted, substituted C-2_-C ₁₀ aliphatic radical,

being the substituents

Halogen, cyano, azido, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carboxy, alkoxycarbonyl, amidino, isothiocyanato, dimethylphosphonyl, optionally substituted C3-C7-cycloalkyl, optionally substituted aryl, optionally substituted hetaryl or a group of the formula S, ^l ° Z

-OR ⁷ , -SR ⁷ , -X-S0 ₂ -R ¹² or -YCW

(a) (b) (c) Cd) ^■ (f) (g) mean

R ² and R ^{3 may be the} same or different and are hydrogen, halogen, alkyl, hydroxy, methylenedioxy, alkoxy, aryloxy, haloalkyl, nitro, amino, acylamino, monoalkyla ino, dialkylamino, acyloxy, carboxy, alkoxycarbonyl, alkylthio, alkylsulfinyl, alkylsulfonyl, Arylalkyloxy, aminocarbonyl, mono- or diaminocarbonyl or cyano,

R ^{4 is} a C ₃ -C 7 -cycloalkyl radical which is optionally substituted by hydroxyl or alkoxyl groups, an optionally substituted aryl radical, an optionally substituted hetaryl radical, cyano, amidino, aminocarbonylamino, a radical of the formula -OR ⁷ or,

-NR ⁸ R ⁹ , or has the same meaning as R ¹ with the exception of the meaning hydrogen,

R ^{5 represents} a carbocyclic or heterocyclic aromatic group,

R ^{6 is} hydrogen, alkyl, aryl, arylalkyl, hydroxyalkyl, haloalkyl, a inoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, acylaminoalkyl, alkylsulfonylaminoalkyl, arylsulfonyl-a inoalkyl, mercaptoalkyl, alkylthioalkyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkylsulfonyl, alkylthio;

R ^{7 is} hydrogen, a straight-chain or branched alkyl radical, an optionally substituted C3-C7-cycloalkyl radical, an arylalkyl radical, a hetarylalkyl radical, alkoxycarbonylalkyl, carboxyalkyl, aσyl, thioalkyl, mercaptoalkyl, hydroxyalkyl or alkoxyalkyl,

R ⁸ and R ^{9 can be the} same or different and denote hydrogen, alkyl, aryl, hetaryl or acyl, or together with the nitrogen can form a saturated or unsaturated three- to seven-membered ring which can also contain further heteroatoms and optionally substitute them is. R ¹⁰ and R ^{11 may be the} same or different and represent hydrogen, alkyl, aryl or hetaryl, or together with the nitrogen a three to seven

can form a membered ring which is optionally substituted and may contain further heteroatoms,

R ¹² denotes alkyl or aryl, X = NH or 0, Y = NH or SZ = NH, S or O and

W = amino, alkylamino, dialkylamino or alkylthio, with the condition that

a) R ⁴ does not mean the methyl group if R ¹ , R ² , R ³ , R ^{6 is} hydrogen and R ^{5 is} 3-indolyl or (6-hydroxy) -3-indolyl or R ¹ , R ² , R ^{3 is} hydrogen, R ⁶ denotes methyl and R ⁵ (2-methyl) -3-indolyl and R ¹ , R ² , R ^{3 are} hydrogen, R ^{6 is} phenyl and R ⁵ (2-phenyl) -3-indolyl,

b) R ⁴ does not mean the benzyl group when R ¹ , R ² , R ³ , R ^{6 is} hydrogen, R ^{5 is} 3-indolyl and

c) R ⁴ does not mean the benzyloxymethyl group,

as well as pharmacologically acceptable salts of acidic or basic compounds of the general formula I.

The connections excluded by "Disclaimer" are known from

to a) Steglich, W., Tetrahedron 44. (10), 2887 (1988) to b) Bergman I .; Pelcman, B, Tetrahedron Lett., 28 (38) 4441

(1987) to c) Kaneko, T; Wong, H; Okamoto, K.T. ; Clardy, I.,

Tetrahedron Lett., 2.6 (34), 4015 (1985)

In the context of the invention means in all cases

Alkyl alone or in combination a straight-chain or branched Ci-C-alkyl group, such as methyl, ethyl, propyl, butyl, isobutyl, tert. Butyl, amyl, isoamyl, Hexyl and heptyl, in particular methyl, ethyl, propyl and butyl,

Alkoxy is a C * --_- C5 alkoxy group, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert. Butoxy and pentoxy, especially methoxy, ethoxy, isopropoxy, butoxy and tert. Butoxy

Acyl is a straight-chain or branched Ci-C -alkanecarboxylic acid residue such as for yl, acetyl, propionyl, isopropionyl, butyryl, isobutyryl, pentanoyl, hexanoyl and heptanoyl, in particular formyl, acetyl, propionyl and butyryl or an aromatic or heteroaromatic acid residue, such as benzol and oxazoloyl,

Halogen fluorine, chlorine and bromine,

Aryl, alone or in combination, the phenyl group, which may optionally carry one or more, preferably 1-3, substituents, such as halogen, e.g. Fluorine, chlorine, bromine, alkyl, hydroxy, alkoxy, benzyloxy, haloalkyl, nitro, amino, aσylamino, mono- or dialkylamino, cyan, methylenedioxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkoxycarbonyl, aminocarbonyl, mono- or dialkylaminocarbonyl and Cyano.

Hetaryl is an aromatic 5- or 6-membered heterocyclic group which, if desired, contains a fused-on benzene ring, such as pyridyl, pyrimidyl, pyrazinyl, thienyl, oxazolyl, pyrazolyl, idazolyl, tetrazolyl, thiazolyl, benzothienyl, benzothiazolyl, indolyl, indolyl, benzim , Benzotriazolyl, Furanyl, in particular Imidazolyl, Furanyl, Thienyl, Pyridyl, Indolyl and Benzi idazolyl; the substituted hetaryl radical carries one or more, preferably 1-3, substituents such as halogen, e.g. Chlorine, bromine, fluorine, alkyl, hydroxy, alkoxy, haloalkyl, nitro, amino, acyla ino, mono- or dialkylamino and cyano,

Haloalkyl is an alkyl radical which carries one or more halogen atoms, such as chlorine, bromine or fluorine, the chloromethyl and trifluoromethyl radicals being preferred. C ₃ -C 7 cycloalkyl cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, in particular cyclopropyl, cyclopentyl and cyclohexyl; the optionally mono- or polysubstituted C3-C7 cycloalkyl radical generally bears 1-3 substituents from the group hydroxy or alkoxy.

The carbohydrate residue of R ¹ means glucopyranosyl, manopyranosyl or ribofuranosyl, in particular glucopyranosyl. The ^c l " ^c 10 aliphatic radical of R ¹ preferably denotes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert. Butyl, iso- ^" amyl, isohexyl, n-hexyl, n-octyl, n-Deσyl, allyl, Methallyl, isopentenyl, n-hexenyl, n-decenyl, proparyl, butinyl, n-hexinyl, n-decinyl, in particular methyl, ethyl, isobutyl, isohexyl, n-decyl, allyl, methallyl isopentenyl and propargyl.

Three- to seven-membered rings, which R ⁸ and R ⁹ or R ¹⁰ and R11 together with the nitrogen to which they are attached, are preferably the aziridine, pyrrolidine and piperidine rings, in particular the pyrrolidine ring. The heteroatoms that the rings can contain are nitrogen, sulfur or oxygen. This includes rings such as piperazine, morpholine and thiomorpholine. Substituents of the rings mentioned above are in particular C1-C ₃ alkyl and C1-C3 alkoxyl groups, such as methyl, ethyl or propyl or methoxy, ethoxy or propoxy.

A carbocyclic aromatic group R ⁵ is mono- or polycyclic, preferably phenyl or naphthyl, and unsubstituted or substituted, for example by one or more, preferably 1-3, substituents from the group consisting of halogen, alkyl, hydroxy, alkoxy, haloalkyl and nitro , Amino, Aσyla ino, mono- or dialkylamino, alkylthio, alkylsulfinyl and alkylsulfonyl. Examples of such carbocyclic aromatic groups are phenyl, 2-, 3- or 4-chlorophenyl, 3-bromophenyl, 2- or 3-methylphenyl, 2,5-dimethylphenyl, 4-methoxypheny1, 2- or 3-trifluoromethylphenyl, 2-, 3- or 4-nitrophenyl, 3- or 4-aminophenyl, 4-methylthiophenyl, 4-methylsulfinylphenyl, 4-methylsulfonylphenyl and 1- or 2-naphthyl.

A heterocyclic aromatic group R ⁵ can be a 5- or 6-membered heterocyclic aromatic group which, if desired, contains a fused-on benzene ring and is unsubstituted or substituted, for example with one or more, preferably 1-3, substituents from the group consisting of halogen, alkyl, Hydroxy, alkoxy, haloalkyl, nitro, amino, acylamino, mono- or dialkylamino, alkylthio, alkylsulfinyl and alkylsulfonyl. If the heterocyclic aromatic group is 3-indolyl, this group can be one of the formula II

his,

wherein R ¹ ', R ² ', R ³ 'and R ⁶ ' have one of the meanings of R ¹ , R ² , R ³ and R ⁶ in formula I.

Examples of heterocyclic aromatic groups R ⁵ are 2- or 3-thienyl, 3-benzothienyl, l-methyl-2-pyrrolyl, 1-benzimidazolyl, 3-indolyl, 1- or 2-methyl-3-indolyl, l-methoxymethyl- 3-indolyl, 1- (1-methoxyethyl) -3-indolyl, 1- (2-hydroxypropyl) -3-indolyl, 1- (4-hydroxybutyl) -3-indolyl, 1- [1- (2-hydroxyethylthio) ethyl] -3-indolyl, 1- [1- (2-mercaptoethylthio) ethyl] -3-indolyl, l- (l-phenylthioethyl) -3-indolyl, l- [l- (carboxymethylthio) ethyl] -3-indolyl and 1-benzyl-3-indolyl, 1-indolyl ,. (3-dimethylaminomethyl) -1-indolyl, 1-indazolyl, 1-benzotriazolyl, 1-pyrrolyl, 1-imidazolyl, 1-triazolyi and 1-tetrazolyl.

The compounds of general formula I according to the invention can be prepared by:

a) a compound of the general formula III,

in which R ¹ , R ² , R ³ , R ⁵ and R ^{6 have} the meanings given above, with a compound of the general formula IV or IVa,

R -NH ₂ (IV) or R ⁴ -NH ₃ ⁺ A ^_ (IVa)

in which R ^{4 has} the meanings given above and "A ~" means an acid anion such as chloride, bromide, carbonate, sulfate or acetate, or

b) in the event that a compound of the general formula V,

in which R ¹ , R ² , R ³ , R ⁴ and R ^{6 have} the meanings given above, with a compound of the general formula VI,

in which R ', R ³ ' and R ⁶ 'have the meanings given above and "shark", halogen, such as chlorine, bromine or iodine, or

c) reacting a compound of the general formula V with an alkali metal derivative of one of the heterocyclic groups mentioned above, or

d) in a compound of the general formula I in which R ^{1 is} hydrogen, the nitrogen is substituted accordingly, or

e) in the case of a compound of the general formula I in which R ^{4 is} hydrogen, the nitrogen is substituted accordingly. f) if desired, functionally converts a reactive substituent present in a compound of formula I and

g) if desired, converting an acidic or basic compound of the general formula I with a base or acid into a pharmaceutically usable salt.

Compounds of the general formula III can be prepared by

h) a compound of the general formula VII,

in which R ¹ , R ² , R ³ , R ⁵ and R ^{6 have} the meanings given above and "M" denotes an alkali metal, brings about a reaction with a concentrated mineral acid, or

i) a compound of the general formula VIII,

(VIII)

in which R ¹ , R ² , R ³ and R ^{6 have} the meanings given above with a compound of the general formula IX,

R ⁵ -CH ₂ -COOH (IX)

in which R ^{5 has} the meanings given above,

implements. ^*

Compounds of the general formula V can be prepared by a compound of the general formula VI in which R ² ', R ³ ' and R ⁶ 'have the same meaning as R ² , R ³ and R ⁶ in the formula V Compound of the general formula X,

in which R ^{4 has} the meanings given above, is implemented.

Compounds of the general formula VII can be obtained from a compound of the general formula I in which R ^{4 is} methyl or ethyl by alkaline hydrolysis.

Compounds of the general formula VIII can be prepared in a manner known per se by adding an indole of the general formula XI,

in which R ¹ , R ² , R ³ and R ^{6 have} the meanings given above and reacted with oxalyl chloride.

Compounds of the general formula X can be prepared in a manner known per se by alkylation of 3,4-dibromomaleimide with a compound of the general formula XII,

R -Agg (XII)

in which R ^{4 has} the meanings given above and "Abg" denotes a leaving group from the group of the halogens, such as chlorine, bromine or iodine, or from the group of the sulfonic acid esters, such as tosylate, mesylate or triflate.

The reaction of a compound of formula III with a compound of the formula Ver¬ IV or IVa is carried out in manner known per se!) ²⁾ ³⁾ either by reacting the two partner Reaktions¬ C and 250 ^* C, preferably between 100 ^* at 180 ° C brings to reaction, or in an inert solvent such as pyridine, methylene chloride, chloroform or dimethylformamide, with or without the addition of a tert. Nitrogen base such as triethylamine and at a temperature between room temperature and the boiling point of the solvent used.

!) B.W. Larner, A.T. Peters, J. Chem. Soc. , 680 (1952)

² ) S. Ohki, T. Nayasaka, Chem. Pharm. Bull., 19, 545 (1971)

³ ) M. Aeberli, H. Erlenmeyer, Helv. Chim. Aσta, H, 470 (1948)

The Grignard reaction between a compound of formula V or X and that of formula VI can be carried out in a manner known per se, for example in an inert manner Solvents such as benzene, toluene, tetrahydrofuran or ether and at a temperature between room temperature and the reflux temperature of the reaction mixture. A compound of the formula VI is expediently prepared in situ from indole or a substituted indole and a suitable alkylmagnesium halide, such as methylmagnesium bromide or iodide, in a manner known per se.

The reaction of a compound of formula V with the alkali metal derivative of one of the above-mentioned heterocyclic aromatic groups is carried out according to conventional methods in an inert solvent such as tetrahydrofuran, ether or dimethylformamide and at a temperature between room temperature and the reflux temperature of the reaction mixture , preferably at 50 ° C. The alkali metal derivative used is preferably generated in situ from one of the aromatic heterocyclic groups mentioned above and an alkali metal hydride, preferably sodium hydride.

The N-substitution of a compound of formula I, in which R ^{1 is} hydrogen, according to variant d) can be carried out in a manner known per se for the N - ^ - substitution of indoles. A hydroxyalkyl group R ¹ can, for example, be introduced into a compound of the formula I in which R ^{1 is} hydrogen by first converting such a compound into an alkali metal derivative, for example sodium derivative by means of sodium hydride, and then the derivative obtained with a treated the hydroxyalkyl group generating agents, for example an alkylene oxide such as propylene oxide or ethylene oxide. An alkoxyalkyl group R ¹ can

by treating a compound of formula I in which R ^{1 is} hydrogen with a suitable dialkyl acetal in the presence of an acid, for example p-toluenesulfonic acid, at an elevated temperature. Furthermore, a compound of the formula I in which R ^{1 is} hydrogen can be reacted with an alkyl, an arylalkyl or a hetarylalkyl halide in the presence of a base to give a compound of the formula I in which R ^{1 is} alkyl or alkyl substituted by aryl or hetaryl , are implemented. The N substitution of a compound of the formula I in which R ^{4 is} hydrogen, according to variant e), can be carried out in a manner known per se for the N ¹ substitution of maleimides, for example a compound of the formula I in which R ^{4 is} hydrogen, in an inert solvent such as dimethylformamide by means of a base from the group of alkali metal carbonates or hydroxides, such as potassium carbonate or sodium hydroxide, into the corresponding alkali metal derivative, such as potassium or sodium derivative, and convert this as desired

i) with an alkyl, arylalkyl or hetarylalkyl halide to give a compound of the formula I in which R ^{4 is} alkyl or alkyl substituted by aryl or hetaryl, or

ii) with an alkyl halide containing an oxirane ring, such as epichlorohydrin to an intermediate compound of the formula I in which R ^{4 is} an alkyl radical substituted by an oxirane ring, and after opening the oxirane ring with, for example, mineral acids, ammonia, mono- or dialkylamines , Alcohols or mercaptans to give compounds of the formula I in which R ^{4 is} an alkyl radical which is disubstituted by two of the groups hydroxyl, alkoxy, monoalkylamino, dialkylamino and alkylthio.

The functional conversions of compounds of the formula I according to variant f) can be carried out in a manner known per se. For example, one can reduce a nitro group to the amino group and then alkylate or acylate the latter. An aminoalkyl group can be alkylated, acylated or sulfonylated. An alkylthio or alkylthioalkyl group can be oxidized to the alkylsulfinyl or alkylsulfinylalkyl group and the latter, if desired, to the alkylsulfonyl or alkylsulfonylalkyl group. An alkoxycarbonylalkyl group can be saponified to form the carboxyalkyl group and the latter can then be amidated or transesterified. An alkoxyalkyl group can be added

an alkylthioalkyl or arylthioalkyl group using an alkanethiol or thiophenol. An azidoalkyl group can be catalytically hydrogenated into an aminoalkyl group transferred and the latter in turn subjected to functional modifications. For example, an aminoalkyl group can be converted into an isothiocyanatoalkyl group using l, l'-thiocarbonyldiimidazole. Furthermore, an aminoalkyl group can be converted into an alkyl group which is substituted by a radical of the formula (g) by, in the case where Y = NH, Z = NH and W = amino, by means of 3,5-dimethylpyrazo -l-carboxamidine, or if Y = NH, Z = NH and W = alkylthio, by means of a dialkyl-N-cyano-dithioiminocarbonate.

An alkylcarbonyloxyalkyl group can be saponified to give the hydroxyalkyl group and the latter can be converted into a haloalkyl or an alkylsulfonyloxyalkyl group in a manner known per se. A hydroxyalkyl group can also be converted to an aminoalkylaminoalkyl group by treatment with trifluoromethanesulfonic anhydride followed by reaction with a suitable diaminoalkane.

An alkylsulfonyloxyalkyl group can, for example, be converted into a mono-, di- or trialkylaminoalkyl group using a mono-, di- or trialkylamine, into a cyanoalkyl group using an alkali metal cyanide, into an alkylthioalkyl group using an alkali metal alkane thiolate, or into an acylthioalkyl group using an alkali metal thioacylate.

An alkylsulfonyloxyalkyl group can also be converted by means of thiourea into an alkyl group which is substituted by a radical of the formula (g) in which Y = S, Z = NH and W = amino.

Furthermore, a cyanoalkyl group in a Amidinoalkyl- can group by means of ammonia, a Acylthioalkylgruppe in a mercaptoalkyl group by means of aqueous ammonia ^• and a benzyloxy-aryl group in a hydroxy aryl group genolyse by hydro- convert.

Of course, the above conversions are only exemplary and other modifications known to those skilled in the art can be made.

The conversion of an acidic compound of the formula I into a pharmaceutically acceptable salt according to variant g) can be carried out by Treatment with a suitable base can be carried out in a manner known per se. Suitable salts are those derived from an inorganic base, for example sodium, potassium or calcium salts,

or derived from an organic base such as ethylenediamine or mono- or diethanolamine. The conversion of a basic compound of the formula I into a pharmaceutically usable salt can be accomplished by treatment with a suitable acid in a manner known per se. Suitable salts are those derived from an inorganic acid, e.g. Hydrochlorides, hydrobromides, phosphates or sulfates, or from an organic acid, e.g. Acetates, citrates, fu arates, tartrates, maleates, methanesulfonates or p-toluenesulfonates are derived.

A compound of formula III is prepared from a compound of formula VII in a manner known per se

(W. Steglich, Tetrahedron, .44. (10), 2887). For example, you can a compound of general formula I, in which R ^{4 is} methyl or ethyl, by means of a concentrated alkali metal solution such as sodium hydroxide solution or potassium hydroxide solution, alone or in combination with an alcohol such as methanol, ethanol or propanol, and at a temperature between room temperature and convert the reflux temperature of the reaction mixture into a compound of formula VII, and treat it with a semi-concentrated mineral acid such as hydrochloric acid or sulfuric acid.

The reaction of a compound of formula VIII with a compound of formula IX is preferably carried out in an inert solvent such as methylene chloride, dichloroethane or ether with the addition of an acid-binding agent, suitably a tertiary amine such as a trialkylamine, for example triethylamine and at a temperature between -30 * C and 40 * C, preferably at room temperature. The reaction of an indole of the general formula XI with oxalyl chloride to give a compound of the formula VIII takes place in a manner known per se in an inert solvent such as methylene chloride, diethyl ether or diethyl formamide and at a temperature between -20 ° C. and the reflux temperature of the reaction mixture , preferably at 0 "C. The resulting compound of formula VIII can be isolated as such or reacted in situ with a compound of formula IX to a compound of formula III.

The alkylation of 3,4-dibromomaleimide with a compound of the formula XII is carried out in a manner known per se, by using 3,4-dibromomaleimide using a base such as sodium or potassium hydroxide, sodium or potassium alcoholate, sodium or potassium carbonate or Hydride in an inert solvent such as methanol, ethanol, ether, tetrahydrofuran or diethyl

formamide and at a temperature between about 0 ° C. and the reflux temperature of the solvent used in the alkali metal derivative and this is reacted with an alkylating agent of the formula XII.

The compounds of general formula I according to the invention can also contain asymmetric carbon atoms.

The invention therefore also relates to diastereomers, racemates and the optically active forms of the compounds of the general formula I according to the invention. If diastereomers are obtained in the synthesis of the compounds according to the invention, they can be separated into the corresponding racemates by column chromatography.

The optically active compounds can be prepared from their racemic mixtures by methods known per se.

Basic or acidic racemic mixtures can e.g. are split into their optically active forms via their diastereomeric salts. For racemate resolution e.g. Tartaric acid, malic acid, camphoric acid, camphor sulfonic acid, dibenzoyl tartaric acid, cinchonine, phenethylamine, brucine or quinine can be used.

Neutral racemic mixtures can be separated chromatographically into the optically active forms on chiral phases. Compounds of the general formula I in which R ^{4 is} hydrogen have been described as protein kinase inhibitors (EP-A-0328026).

They inhibit cell proliferation and can be used in the treatment of immune diseases or organ transplants.

Surprisingly, it has now been found that compounds of the general formula I in which R ^{4 has} the meanings mentioned above inhibit the proliferation of stimulated human spleen cells much more and more selectively than the literature-known compounds of the formula I in which R ^{4 is} hydrogen. The compounds of the general formula I claimed here are therefore particularly suitable for the therapy of immune diseases and for organ transplants.

Compounds of the general formula I also inhibit the degranulation of basophil granulocytes, which is why they can be used in the therapy of allergic diseases.

The superior activity of the present compounds can be seen e.g. by demonstrating that the inhibition of thymidine incorporation into the DNA of stimulated human spleen lines is determined.

The pyrroles of the formula I and their salts can be used as medicaments, for example in the form of pharmaceutical preparations which can be administered orally, for example in the form of tablets, dragées, hard or soft gelatin capsules, solutions, emulsions or suspensions. They can also be administered rectally, for example in the form of suppositories, or parenterally, for example in the form of injection solutions. For the production of pharmaceutical preparations, these compounds can be processed in therapeutically inert inorganic and organic carriers. Examples of such carriers for tablets, dragées and hard gelatin capsules are lactose, corn starch or derivatives thereof talc, stearic acid or its salts. Suitable carriers for the production of solutions and syrups are water, polyols, sucrose, invert sugar and glucose. Suitable carriers for injection solutions are water, alcohols, polyols, glycerol and vegetable oils. Suitable carriers for suppositories are vegetable or hardened oils, waxes, fats and semi-liquid polyols.

The pharmaceutical preparations can also contain preservatives, solvents, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavoring agents, salts for changing the osmotic pressure, buffers, coating agents or antioxidants, and, if appropriate, other therapeutic agents.

As indicated above, the pyrroles of formula I and their salts can be used in the treatment or prophylaxis of diseases, especially inflammatory or immunological diseases. The dosage can vary widely, but is generally in the range of about 5 to 500 mg / day for oral administration to adults, although the latter value can be increased if necessary. The daily dose can be administered in a single dose or in several doses.

The following connections are preferred for the purposes of the registration:

BV 1. l- (3- (l-pyrrolidino) -2-hydroxypropyl) -s ^ -bis - ^ - indolyl) -maleimide; Mp 135 "C.

2. 1- (3- (1-pyrrolidino) -2-hydroxypropyl) -3,4-bis- (1- (3- (1-pyrrolidino) -2-hydroxypropyl) -3-indolyl) - maleimide; Mp 82 * C.

3. 1- (ethoxycarbonylmethyl) -3,4-bis - (- 3-indolyl) maleimide; Mp 224'C.

4. 1- (ethoxycarbonylmethyl) -3,4-bis- (1- (ethoxycarbonylmethyl) -3-indolyl) maleimide; Mp 156 * c.

5. l- (l-hydroxy-cyclohex-4-yl) -3,4-bis- (3-indolyl) aleinimide; Mp 142 ° (dec.) 6. l-Methyl-3- (5,6-dimethoxy-3-indolyl) -4- (3-indolyl) maleimide

7. l-Methyl-3- (5,6-dichloro-3-indolyl) -4- (3-indolyl) aleinimide

8. l-Propyl-3,4-bis (5-chloro-3-indolyl) maleimide

9. 1-Methyl-3- ( ^' 4,5-dichloro-3-indolyl) -4- (5,6-dichloro-3-indolyl) maleimide

10. l-Ethyl-3- (5-fluoro-3-indolyl) -4- (3-indolyl) maleimide

11. l-Methyl-3- (5-hydroxy-3-indolyl) -4- (3-indolyl) aleinimide

12. l-Methyl-3,4-bis (5-hydroxy-3-indolyl) maleimide

13. l-butyl-3,4-bis (5-hydroxy-3-indolyl) maleimide-

14. l-Propyl-3- (5-benzyloxy-3-indolyl) -4- (5-trifluoromethyl-3-indolyl) maleimide

15. l-Methyl-3- (5-trifluoromethyl-3-indolyl) -4- (2-methyl-3-indolyl) maleimide

^'16 . In-pentyl-3- (5-nitro-3-indolyl) -4- (2-methyl-3-indolyl) maleimide

17. l-Methyl-3,4-bis (5-nitro-3-indolyl) maleimide

18. l-Methyl-3,4-bis (5-amino-3-indolyl) maleimide

19. l-Methyl-3- (5-amino-3-indolyl) -4- (4-chloro-3-indolyl) maleimide

20. l-Methyl-3- (5-amino-3-indolyl) -4- (3-indolyl) maleimide 21. i-Methyl-3- (5-acetylamino-3-indolyl) -4- (3-indolyl) maleimide

22. l-Methyl-3- (5-methylamino-3-indolyl) -4- (5-dimethylamino-3-indolyl) maleimide

23. l-Methyl-3- (5-acetyloxy-3-indolyl) -4- (5-trifluoromethyl-maleinimide

24. l-Cyclopentyl- (5-carboxy-3-indolyl) -4- (3-indolyl) maleimide

25. l-Methyl-3,4-bis (5-ethoxycarbonyl-3-indolyl) maleimide

26. l-Methyl-3- (5-ethoxycarbonyl-3-indolyl) -4- (3-indolyl) maleimide

27. l-Methyl-3- (5-ethoxycarbonyl-3-indolyl) -4- (5,6-dichloro-3-indolyl) maleimide

28. l-Ethyl-3- (5-methylthio-3-indolyl) -4- (3-indolyl) maleimide

29. l-Methyl-3- (l- (3-amino) propyl-5-methylthio-3-indolyl) -4- (5-methylthio-3-indolyl) maleimide

30. l-ethyl-3- (5-methylsulfinyl-3-indolyl) -4- (3-indolyl) maleimide

31. l-Ethyl-3- (5-methylsulfonyl-3-indolyl) -4- (3-indolyl) maleimide

32. l-Methyl-3,4-bis (5-methylthio-3-indolyl) maleimide

33. l-Methyl-3,4-bis (5-methylsulfinyl-3-indolyl) maleinimide 34. l-Methyl-3,4-bis (1- (2-hydroxy) propyl-5-methylsulfinyl-3-indolyl) maleimide

35. l-Propionylamino-3- (l-dimethylaminocarbonylmethyl-3-indolyl) -4- (3-indolyl) maleimide

36. l-Acetyloxy-3- (l- (l-pyrrolidino) carbonylmethyl-3-indolyl) -4- (3-indolyl) maleimide

37. l-Methyl-3- (l- (3-hydroxy) propyl-3-indolyl) -4- (3-indolyl) maleimide

38. l-Methyl-3- (1- (3-methylsulfonyloxy) propyl-3-indolyl) -4- (3-indolyl) maleimide

39. l-Cyclopropyl-3- (l- (prop-2-en-l-yl) -3-indolyl) -4- (3-indolyl) maleimide

40. l-tert-butyl-3- (I- (4-methyl) -pentyl-3-indolyl) -4- (3-. Indolyl) -maleimide

41. 1- (3,4-Methylenedioxy) phenyl-3,4-bis (3-indolyl) maleinimide

42. l-Methyl-3- (l-dimethylphosphinylmethyl-3-indolyl) -4- (3-indolyl) maleimide

43. l-Propyl-3- (5,6-dichloro-3-indolyl) -4- (2-chlorophenyl) maleimide

44. l-Methyl-3- (4,5-dichloro-3-indolyl) -4- (2,4-dichlorophenyl) maleimide

45. l-Ethyl-3- (5-fluoro-indolyl) -4- (4-fluorophenyl) maleimide

46. l-Methyl-3- (5-hydroxy-3-indolyl) -4- (2-methoxyphenyl) maleimide 47. l-Methyl-3- (5-hydroxy-3-indolyl) -4- (3,4-methylenedioxyphenyl) maleimide

48. l-Methyl-3- (5-methoxy-3-indolyl) -4- (phenyl) maleimide

49. l-n-butyl-3- (5,6-dimethoxy-3-indolyl) -4- (2,4-dimethoxyphenyl) maleimide

50 .. l-propyl-3- (5-trifluoromethyl-3-indolyl) -4- (3,4-methylene-dioxyphenyl) maleimide

51. 1- (3-Methylhexyl) -3- (3-indolyl) -4- (2-trifluoromethylphenyl) maleimide

52. l-Cyclopentyl-3- (5-nitro-3-indolyl) -4- (2-chlorophenyl) maleimide

53. 1-n-Butyl-3- (3-indolyl) -4- (4-dimethylaminophenyl) maleimide

54. l-Cyclopropyl-3- (5-methylamino-3-indolyl) -4- (lr-naphthyl) maleimide

55. l-Isopropyl-3- (l-β-D-glucopyranoside-3-indolyl) -4- (3-indolyl) maleimide

56. 1-n-Pentyl-3- (5-nitro-3-indolyl) -4- (2-nitrophenyl) maleimide

57. l-Methyl-3- (5-methyl-3-indolyl) -4- (2,4-dimethylphenyl) ■ maleimide

58. l-Methyl-3- (5-chloro-3-indolyl) -4- (4-hydroxyphenyl) aleinimide

59. In-hexyl-3- (5,6-dimethoxy-3-indolyl) -4- (4-methylthiophenyl) maleimide 60. In-hexyl-3- (5,6-dimethoxy-3-indolyl) -4- (4-methylsulfonylphenyl) maleimide

61. l-n-Hexyl-3- (5,6-dimethoxy-3-indolyl) -4- (4-methylsulfinyl) phenyl) maleimide

62. l-Hydroxy-3- (3-indolyl) -4- (3-bromophenyl) maleimide

63. l-Amidino-3- (3-indolyl) -4- (2,5-dimethylphenyl) maleimide

64. l-Cyclopropyl-3- (1-methyl-3-indolyl) -4- (4-aminophenyl) maleimide

65. l-n-butyl-3- (l- (3-hydroxypropyl) -3-indolyl) -4- (2,3,6-trichlorophenyl) maleimide

66. l-n-heptyl-3- (1- (3-guanidinopropyl) -3-indolyl) -4- (2,6-dichlorophenyl) maleimide

67. l-Methyl-3- (l-ethyl-3-indolyl) -4- (1-benzimidazolyl) maleimide

68. l-Cyclopentyl-3- (l- (methoxyethyl) -3-indolyl) -4- (l-indolyl) maleimide

69. l-isobutyl-3- (l- (l-methoxyethyl) -3-indolyl) -4- (3-thienyl) maleimide

70. l-Methyl-3- (1- (3-aminopropyl) -3-indolyl) -4- (2-furyl) maleimide

71. 1- (3-Phenylthio-propyl) -3- (l-methyl-3-indolyl) -4- (2-methyl-3-indolyl) maleimide

72. 1- (2-Dimethylaminoethyl) -3- (1- (2,3-epoxypropyl) -3-indolyl) -4- (3-indolyl) maleimide 73. ι- (2-Dimethylaminoethyl) -3- (1- (2-hydroxy-3-dimethylamino-propyl) -3-indolyl) -4- (3-indolyl) -maleimide

74. l-Isopropyl-3- (l-dimethylaminomethyl-3-indolyl) -4- (2-benzothienyl) maleimide

75. l-Methyl-3- (l-ethyl-3-indolyl) -4- (2-methylthio-3-indolyl) maleimide

76. l-Methyl-3- (l-ethyl-3-indolyl) -4- (2-methylsulfinyl) -3- ^' indolyl) maleimide

77. l-Methyl-3- (l-ethyl-3-indolyl) -4- (2-methylsulfonyl-3-indolyl) maleimide

78. l-Cyclohexyl-3,4-bis (2-phenyl-3-indolyl) maleimide

79. l-Methyl-3- (1- (9-carboxy-nonyl) -3-indolyl) -4- (3-indolyl) maleimide

80. l-Neopentyl-3- (1- (2-carboxy-ethyl) -3-indolyl) -4- (1-methyl-3-pyrrolyl) maleimide

81. l-Methyl-3- (l- (2-hydroxy-3-azido-propyl) -3-indolyl) -4- (l- (l, 2,4-triazolyl)) maleimide

82. l-Methyl-3- (l- (2-aziridino) methyl-3-indolyl) -4- (1- (1,2,4-triazolyl) maleimide

83. l-Isopropyl-3- (3-indolyl) -4- (1-tetrazolyl) maleimide

8th . l-ethyl-3- (1- (2-methyl-propyl) -3-indolyl) -4- (5-methoxy-2-benzofuranyl) maleimide

85. 1- (1-adamantyl) -3,4-bis (3-indolyl) maleimide; Mp 148 * c. 86. l-Methyl-3- (l- (2-dimethylaminoeτ_hyl) -3-indolyl) -4- (3-indolyl) -maleimide, mp. 123 ° c

87. l-methyl-3,4-bis- (1- (2-dimethylaminoethyl) -3-indolyl) maleinimide, mp. 160 ^* C.

88. l-Methyl-3- (1- (4- (3,5-dimethylisoxazolyl) -3-indolyl)) ■ 4- (3-indolyl) maleimide, m.p. 258'C.

89. l-Methyl-3,4-bis- (1- (4- (3,5-dimethylisoxazoloyl) -3-indolyl)) maleimide, mp 248'C.

90. l-methyl-3- (1- (4- (3-phenyl-5-methylisoxazoloyl) -3-indolyl)) -4- (3-indolyl) -maleimide, mp. 214 ^β C.

91. 1- (3-hydroxypropyl) -3,4-bis- (l-methyl-3-indolyl) maleimide, mp 105 ° C.

92. l-Methyl-3- (l- (β-D-ribofuranosyl) -3-indolyl) -4- (3-indolyl) -maleimide, mp. 130 * C (dec.).

93. l-Cyclohexyl-3,4-bis (1- (3-hydroxypropyl) -3-indolyl) maleimide, m.p. 114 * C.

94. l-Cyclohexyl-3- (l- (3-hydroxypropyl) -3-indolyl) -4- (3-indolyl) maleimide, mp. 176 * C.

95. l-Cyclohexyl-3- (l ₇ methyl-3-indolyl) -4- (l- (3-hydroxypropyl) -3-indolyl) -maleimide, mp. 164 * C.

96. l-Methyl-3,4-bis- (1- (2-carbamoylethyl) -3-indolyl) maleimide, mp. 153 * C.

97. l-Methyl-3- (1- (2-carbamoylethyl) -3-indolyl-4- (3-indolyl) -maleimide, mp. 230 * C.

98. l-Cyclohexyl-3- (1- (2-carbamoylethyl) -3-indolyl-4- (3-indolyl) maleimide, mp. 188 "C. 99. l-Cyclohexyl-3,4-bis (1- (2-carbamoylethyl) -3-indolyl) maleimide, mp 229 ° C.

100. l-Cyclohexyl-3- (1- (3-mercaptopropyl) -3-indolyl) -4- (3-indolyl) maleimide, mp. 222 ° C.

101. l-Methyl-3- (l-methyl-3-indolyl) -4- (3-indolyl) -malein¬ imide, mp. 211'C.

102. l-Cyclohexyl-3,4-bis- (1- (2,3-dihydroxypropyl) -3-indolyl) -4- (3-indolyl) -maleimide, mp. 224 * C.

103. l-Cyclohexyl-3- (l-methyl-3-indolyl) -4- (3-indolyl) maleimide, m.p. 170'C.

104. l-Methyl-3- (l-methyl-3-indolyl) -4- (l- (3-amidinothiopropyl) -3-indolyl) maleimide, mp. 238 * C.

105. l-methyl-3- (l- (3-methylaminopropyl) -3-indolyl) -4- (3-indolyl) maleimide hydrochloride, mp 218 ^• C.

106. l-Methyl-3- (l- (3-dimethylaminopropyl) -3-indolyl) -4- (3-indolyl) maleimide hydrochloride, mp. 170 * C.

107. l-Cyclohexyl-3- (1- (3-amidinothiopropyl) -3-indolyl-4- (3-indolyl) -maleimide, mp. 137 * C.

108. l-Methyl-3- (l-carbamoylmethyl-3-indolyl) -4- (3-indolyl) ^■ maleimide, mp. 198 'C.

109. l-Methyl-3,4-bis- (l-carbamoylmethyl-3-indolyl) maleinimide, mp> 25 ° C.

110. l-Acetylamino-3,4-bis (3-indolyl) maleimide, mp. 194 * C.

111. l-phenyl-3,4-bis (l- (3-hydroxy-3- (l-pyrrolidino) propyl) maleimide, m.p. 163 ^β C. 112. l-Methyl-3- (3-indolyl) -4- (l- (2,3-dihydroxy-propyl) -3-indolyl) maleimide, m.p. 90'C

113. l-Methyl-3,4-bis (1- (2,3-dihydroxy-propyl) -3-indolyl) maleimide, mp. 105 ° C

114. l- (l-Adamantyl) -3,4-bis- (l- (2,3-dihydroxy-propyl) -3-indolyl) maleimide, mp. 138 ^β C.

115. 1- (1-Adamamtyl) -3- (3-indolyl) -4- (l- (2,3-dihydroxy-propyl) -3-indolyl) maleimide, mp. 148 * C.

116. l-Methyl-3- (3-indolyl) -4- (1- (3-azido-propyl) -3-indolyl) maleimide, mp. 190 "C (dec.).

117. 1- (3,4,5-Trimethoxyphenyl) -3, -bis- (3-indolyl) maleimide, mp> 250 * C.

118. 1- (2,4-dimethoxyphenyl) -3,4-bis- (3-indolyl) -malein¬ imide, mp.> 250 * C.

119. 1- (4-Hydroxyphenyl) -3,4-bis (3-indolyl) maleimide, mp> 250 * C.

120. l- (2-methoxyphenyl) -3, -bis- (3-indolyl) maleimide, mp> 250 * C.

121. l-Methyl-3- (l-allyl-3-indolyl) -4- (l- (3-amidinothio-propyl) -3-indolyl) -maleimide, mp. 146 * C.

122. 1- (4-Formylamino-butyl) -3,4-bis (3-indolyl) -maleimide, m.p. 110'C (dec.).

123. l-Methyl-3- (3-indolyl) -4- (l- (3-amidinothio-propyl) -3-indolyl) maleimide, m.p. 160'C.

124. l-Methyl-3,4-bis- (1- (3-amidinothio-propyl) -3-indolyl) maleimide, mp.> 250 * C. 125. 1- (2-thiazolyl) -3,4-bis- (3-indolyl) maleimide, mp> 250 ^β C.

126. l- (2- (l, l-dimethoxy) ethyl) -3,4-bis- (3-indolyl) aleinimide, mp. 223 ^β C.

127. 1- (2-mercaptoethyl) -3,4-bis (3-indolyl) maleimide, mp. 180'C (dec.).

128. l-methyl-3,4-bis- (l-hydroxypropyl-3-indolyl) -malein¬ imide, mp. 173 "C.

129. l-Methyl-3- (3-indolyl) -4- (1-hydroxypropy1-3-indolyl) maleimide, mp. 208'C.

example 1

l- (l-ethoxycarbonylethyl) -3, 4-bis (3-indolyl) maleimide

1.6 g (4.9 mmol) of 3,4-bis (3-indolyl) maleic anhydride (W. Steglich et al., Angew. Chem. Int. Ed., 19., 459, (1980)) and 1.17 g (10 mmol) alanine ethyl ester hydrochloride were heated to 180 * C for 4 hours.

The cooled melt was then taken up in a 1/1 water / ether mixture, the ether phase was separated off and dried over sodium sulfate. After the ether had been stripped off, the residue was recrystallized from a little ethyl acetate. 1.4 g of 1- (1-ethoxycarbonylethyl) -3,4-bis (3-indolyl) -maleimide, mp 238'C, were obtained. The following were prepared analogously to Example 1:

1.1 l-cyanomethyl-3,4-bis (3-indolyl) maleimide; Mp. 196 "C.

1.2 l-ethyl-3,4-bis (3-indolyl) maleimide; Mp 240-242'C.

1.3 l-butyl-3,4-bis (3-indolyl) maleimide; Mp. 193 * C.

1.4 l-cyclohexyl-3,4-bis (3-indolyl) maleimide; Mp 170'C.

Example 2

l- (2-propen-l-yl) -3, 4-bis (3-indolyl) maleimide

The solution of 1.64 g (5 mmol) of 3,4-bis (3-indolyl) maleic anhydride, 0.2 g (5 mmol) of allylamine and 10 ml of triethylamine in 50 ml of dry dimethylformamide was heated under reflux for 4 hours. The reaction mixture was then evaporated to dryness in vacuo, the residue was taken up in methylene chloride and the methylene chloride solution was shaken with 0.1 N hydrochloric acid. After the methylene chloride phase had been dried over sodium sulfate and the solvent had been stripped off, the residue was recrystallized from toluene. 0.9 g of l- (2-propen-1-yl) -3,4-bis (3-indolyl) -maleimide of mp 214'C was obtained.

The following were prepared analogously to Example 2:

2.1 1- (3-ethoxycarbonylpropyl) -3,4-bis (3-indolyl) maleimide; Mp 178'C.

2.2 l- (2-ethoxycarbonylethyl) -3,4-bis (3-indolyl) maleimide; Mp 194 * c. 2.3 1- (2-propin-1-yl) -3,4-bis (3-indolyl) maleimide; Mp 170'C.

2.4 l-carboxymethyl-3,4-bis (3-indolyl) maleimide; Mp 252 "C.

2.5 l-aminocarbonylmethyl-3,4-bis (3-indolyl) maleimide; Mp. 236 "C.

2.6 l- (1,4-dimethylpent-l-yl) -3,4-bis (3-indolyl) maleimide; Mp 132'C.

2.7 l-phenyl-3,4-bis (3-indolyl) maleimide; Mp 293'C.

2.8 1- (2- (4-morpholino) ethyl) -3,4-bis (3-indolyl) maleimide; Mp 168'C.

2.9 1- (4-chlorophenyl) -3,4-bis (3-indolyl) maleimide; Mp 265'C (dec.).

2.10 1- (4-methylphenyl) -3,4-bis (3-indolyl) maleimide; Mp> 280 * C.

2.11 1- (4-methoxyphenyl) -3,4-bis (3-indolyl) maleimide; Mp> 270'C ,.

2.12 1- (3,4-dichlorophenyl) -3,4-bis (3-indolyl) maleimide; Mp 134 * c.

2.13 1- (4-pyridinyl) -3,4-bis (3-indolyl) maleimide; Mp 287'C.

2.14 l- (l-piperidino) -3,4-bis (3-indolyl) maleimide; Mp 220'C.

2.15 1- (5-hydroxypentyl) -3,4-bis (3-indolyl) maleimide; Mp 180 * C. 2.16 l- (carboxy-3-methylthio-prop-l-yl) -3,4-bis (3-indolyl) maleinimide; Mp 186'C.

2.17 l-cyclopropyl-3,4-bis (3-indolyl) maleimide; Mp 224 ° C.

2.18 l- (3-quinuclidino) -3,4-bis (3-indolyl) maleimide; Mp 236 ° C.

2.19 Ι- (IO-carboxydecyl) -3,4-bis (3-indolyl) maleimide; Mp 124 "C.

2.20 l-hydroxy-3,4-bis (3-indolyl) maleimide; Mp 192'C

2.21 l-aminocarbonylamino-3,4-bis (3-indolyl) maleimide; Mp. 138 ^β C

2.22 l-isopropyl-3,4-bis (3-indolyl) maleimide; Mp. 138 ^β C

2.23 l- (2-glucopyranosyl) -3,4-bis (3-indolyl) maleimide; Mp 167'C

2.24 l- (4-dimethylaminophenyl) -3,4-bis (3-indolyl) maleimide; Mp> 250 ^β C

2.25 l- (2,3-dihydroxypropyl) -3,4-bis (3-indolyl) maleimide; Mp 125 * c

Example 3

l-methyl-3- (l- (2-hydroxy-3- (l-pyrrolidino) propyl) -3-indolyl) - 4- (3-indole l) -maleimide

3.1. 10.2 g (0.03 mol) of l-methyl-3,4-bis- (3-indolyl) -maleimide (W. Steglich) are dissolved in 90 ml of dry dimethylformamide. The solution is cooled to 0 ^β C and mixed with 0.72 g (0.03 mol) sodium hydride. The reaction mixture is stirred for a further 10 min at 0 ^° C. and 6 ml of epichlorohydrin are then added. Then you heat the Mixture at 50 ^* C for 1 hour, then cools it and mixed with saturated ammonium chloride solution. The aqueous solution is extracted three times with ethyl acetate and the combined organic phases are dried over sodium sulfate. After the solvent has been stripped off, the residue is purified by column chromatography. You get

3.La) 3.9 g of l-methyl-3- (l- (2,3-epoxypropyl)) -3-indolyl) - 4- (3-indolyl) -maleimide and

- 3.1.b) 3.2 g l-methyl-3,4-bis- (l- (2,3-epoxypropyl)) -3-indolyl) aleinimide

3.2. The solution of 2.3 g (5.8 mmol) of compound 3.1a) and 4 ml of pyrrolidine in 100 ml of ethanol is refluxed for 1 hour. The solvent and the excess of pyrrolidine are then stripped off in vacuo and the residue is purified by column chromatography. Mobile phase: ethyl acetate. 2.2 g of 1-methyl-3- (1- (2-hydroxy-3- (1-pyrrolidino)) propyl) -3-indolyl) -4- (3-indolyl) -maleimide of mp 86 are obtained * C.

The following were produced in analogy to example 3.1:

3.1.1 l-methyl-3- (1- (3-bromopropyl) -3-indolyl) -4- (3-indolyl) maleimide; Mp 199 * c.

3.1.2 l-methyl-3- (1- (ethoxycarbonylmethyl) -3-indolyl) -4- (3-indolyl) maleimide; Mp 215 ^,, C.

3.1.3 l-methyl-3,4-bis- (1- (ethoxycarbonylmethyl) -3-indolyl) maleinimide; Mp 148 * c.

3.1.4 l-methyl-3- (1- (carboxymethyl) -3-indolyl) -4- (3-indolyl) maleimide; Mp. 201 ^β C. 3.1.5 l-methyl-3,4-bis (1- (carboxymethyl) -3-indolyl) maleinimide; Mp 99'C.

Analogously to Example 3.2), compound 3.1b) and pyrrolidine are obtained

l-methyl-3,4-bis- (l- (2-hydroxy-3- (1-pyrrolidino) propyl-3-indolyl) maleimide; mp 78-80 ^β C.

Example 4

l-methyl-3- (1- (2-hydroxy-3-azido-propyl) -3-indolyl-4- (3-indolyl) maleimide

The solution of 234 mg (3.6 mmol) sodium azide and 470 mg (1.2 mmol) of compound 3.La) in 10 ml DMF was heated for 4 hours at 80'C. The reaction mixture was then mixed with 50 ml of water and the aqueous solution extracted 3 times with ether. After the combined ether extracts had dried and the solvent had been stripped off, the residue was purified by column chromatography. Mobile phase: ethyl acetate / isohexane = 1/1. 300 mg of 1-methyl-3- (1- (2-hydroxy-3-azido) -propyl) -3-indolyl) -4- (3-indolyl) -maleimide of mp 90 ° C. (dec.) Were obtained. .

Example 5

l-methyl-3- (2-methyl-3-indolyl) -4- (3-indolyl) maleimide

a) To 0.36 g (14.8 mmol) magnesium shavings in 10 ml abs.

Tetrahydrofuran is added dropwise at 45 ^° C. to the solution of 1.1 ml (15 mmol) of ethyl bromide in 5 ml of abs. Tetrahydrofuran. After the magnesium has completely dissolved, a solution of 1.95 g (15 mmol) of 2-methyl-indole in 40 ml of abs is added. Add tetrahydrofuran and stir the reaction mixture 30 min at 45 ^° C. Then a solution of 3 g (7.4 mmol) of l-methyl-3-bromo-4- (l- (tert-butyloxycarbonyl) -3-indolyl) -maleinimide (M. Brenner et al ., Tetrahydron 44., 2887 (1988)) in 40 ml abs. Tetrahydrofuran, then the reaction mixture is heated under reflux for a further 2 h and acidified with 20% citric acid. After the reaction solution has been diluted with 50 ml of water, the aqueous solution is extracted with ethyl acetate, the organic phase is dried over sodium sulfate and the solvent is stripped off. After purification of the crude product by column chromatography on silica gel (mobile phase:

Ethyl acetate / n-heptane = 1/5) gives 1.28 g _l - methyl-3- (l- (tert-butyloxycarbonyl) -3-indolyl) -4- (2-methyl-3-indolyl) maleimide of mp . 139-142 ° C (dec.)

b) 1.28 g of product 5a) are in 10 ml

Trifluoroacetic acid dissolved and stirred for 15 min at room temperature. The solution is then i.Vak. concentrated and the residue chromatographed on silica gel (mobile phase: ethyl acetate / isohexane 1/2). 0.57 g of 1-methyl-3- (2-methyl-3-indolyl) -4- (3-indolyl) maleimide of mp 235-240'C (dec.) Is obtained.

The following were prepared analogously to Example 5:

5.1 l-methyl-3- (5-chloro-3-indolyl) -4- (3-indolyl) maleimide; Mp 164 ° C

5.2 l-methyl-3- (5-methoxy-3-indolyl) -4- (3-indolyl) maleimide; Mp 272'C

5.3 l-methyl-3- (6-chloro-3-indolyl) -4- (3-indolyl) maleimide; Mp 130 * C Example 6

l-amino-3,4-bis (3-indolyl) maleimide

1 g (2.26 mmol) 1- (tert-butyloxycarbonyl) amino-3,4-bis (3-indolyl) maleimide (mp. 198 ^* C), prepared analogously to Example 2, is in 150 ml of methanolic hydrochloric acid solved. The solution is allowed to stir for 4 hours at room temperature, then evaporated down i.Vac. and takes up the residue in ethyl acetate. The organic solution is washed with saturated sodium bicarbonate solution and dried over sodium sulfate. After the solvent has been stripped off, the residue is purified by column chromatography. 0.61 g of 1-amino- ^' 3,4-bis- (3-indolyl) maleimide of mp 290-292 * C is obtained.

Example 7

l-acetylamino-3,4-bis (3-indolyl) maleimide

The suspension of 342 mg (1 mmol) of the compound of Example 6 and 0:12 ml of acetic anhydride in 5 ml of ethyl acetate is stirred for one hour at 30 ^* C, so that a solution is formed. The solution is then stirred for a further 5 hours at room temperature. The reaction product which has precipitated is filtered off with suction and washed with a little ethyl acetate. 0.2 g of pure l-acetylamino-3,4-bis (3-indolyl) maleimide, mp. 194 * C, is obtained.

Analogously to Example 7, 1-hydroxy-3,4-bis (3-indolyl) maleimide (see above) and acetic anhydride 1-acetyloxy-3,4-bis (3-indolyl) maleimide from Mp. 204'C Example 8

l-methyl- (l- (2,3-dihydroxy) propyl-3-indolyl) maleimide

To the suspension of 240 mg (10 mmol) sodium hydride in 30 ml abs. Dimethylformamide is added dropwise to a solution of 3.4 g (10 mmol) of 1-methyl-3,4-bis (3-indolyl) maleimide at room temperature. Then allowed the reaction mixture to stir for 45 min, then heated to 50 ^* C and treated with 2.9 g (10 mmol) Solektaltosylat in 10 ml abs. Dimethylformamide. The reaction mixture is then left to stir at 50 ° C. for a further 3 hours and is then cooled

and add 50 ml sat. Ammonium chloride solution. The aqueous solution is extracted with methylene chloride, the methylene chloride phase is dried over sodium sulfate and the solvent is in vacuo. deducted. The residue is dissolved in 50 ml of acetone and the solution is treated with 10 ml of 6N hydrochloric acid. After 30 min, the reaction solution is evaporated and the residue is chroographed on silica gel (mobile phase: ethyl acetate). 1.2 g of l-methyl-3- (l- (2,3-dihydroxy) propyl-3-indolyl) -4- (3-indolyl) -maleimide of mp 117-120'C are obtained.

The following was prepared analogously to Example 8:

8.1 l-methyl-3,4-bis- (1- (2,3-dihydroxy) propyl-3-indolyl) maleimide; Mp 110'C.

8.2 1- (1-piperidino) -3- (1- (2,3-dihydroxypropyl) -3-indolyl) -4- (3-indolyl) maleimide; Mp 146'C

Example 9

l-methyl-3 -4-bis- (5-methoxy-3-indolyl) maleimide

To 1.08 g (45 mmol) magnesium shavings in 20 ml abs. Tetrahydrofuran is added dropwise at 45 ml abs ^β C the solution of 3.4 ml (45 mmol) of ethyl bromide in Fig.10. Tetrahydrofuran. After the magnesium has completely dissolved, add the solution of Add 6.6 g (45 mmol) of 5-methoxyindole in 30 ml of toluene and then allow the reaction mixture to stir at 45'C for one hour. Then the solution of 2.69 g (10 mmol) of 1-methyl-3,4-bis-dibromomaleimide in 50 ml of toluene is added dropwise and the reaction solution is stirred for one hour under reflux. Then you acidify the mixture with 20 percent. Citric acid, separates the organic phase, extracts the aqueous solution with ethyl acetate and dries the combined organic phases over sodium sulfate. After the solvent has been stripped off, the residue is chromatographed on silica gel (mobile phase: ethyl acetate / isohexane = 1/2). 2.82 g of 1-methyl-3,4-bis (5-methoxy-3-indolyl) maleimide, mp 286'C, are obtained.

The following were prepared analogously to Example 9:

9.1 l-methyl-3,4-bis (5-chloro-3-indolyl) maleimide; Mp: 2908'C

9.2 l-methyl-3,4-bis (6-chloro-3-indolyl) maleimide; Mp 279 * c.

Example 10

l-methyl-3-.1-benzimidazolyl, -4- (3-indolyl) maleimide

To the suspension of 240 mg (10 mmol) sodium hydride in 10 ml abs. Tetrahydrofuran is added dropwise at room temperature to 1.18 g (10 mmol) of benzimidazole in 40 ml of abs. Tetrahydrofuran. The reaction mixture is then stirred for 15 min at room temperature and 4.05 g (10 mmol) of l-methyl-3-bromo-4- (l-tert-butyloxycarbonyl) -3-indolyl) -maleinimide (see Example 5a) are then added . The reaction mixture is then stirred for a further hour, after which 100 ml of sat.

Ammonium chloride solution, the tetrahydrofuran evaporates, the aqueous solution is shaken three times with ethyl acetate and the combined organic extracts are dried over sodium sulfate. To Withdrawing the solvent, the residue is heated to 160 ^° C. until gas evolution ceases, the mixture is cooled and the contents of the flask are chromatographed on silica gel (mobile phase: ethyl acetate / isohexane = 2/1). 0.52 g of 1-methyl-3- (l-benzimidazolyl) -4- (3-indolyl) -maleimide of mp.

The following were prepared analogously to Example 10:

10.1 l-methyl-3- (1-benzotriazolyl) -4- (3-indolyl) maleimide; Mp 254'C.

10.2 l-methyl-3- (l-imidazolyl) -4- (3-indolyl) maleimide; Mp 290'C.

10.3 l-methyl-3- (3-indolyl) -4- (1-indolyl) maleimide; Mp. 189 ^β C.

10.4 l-methyl-3- (l-indazolyl) -4- (3-indolyl) maleimide; Mp 301'C.

10.5 l-methyl-3- (3-dimethylaminomethyl) -1-indolyl) -4- (3-indolyl) maleimide; Mp. 156 ^β C.

Pharmacological test report

The trisubstituted pyrroles described in the patent application influence the proliferation and / or the function of human lymphocytes. A comparison of the concentration in the various test systems necessary for half-maximum inhibition shows the selectivity of the tested substances.

METHODOLOGY:

Preparation of peripheral human leukocytes fPBL):

Peripheral human blood is mixed with heparin (Liquemin, Röche, Switzerland; 2500 IU / 100 ml blood) and diluted with the same volume of PBS without calcium and magnesium (Boehringer Mannheim, Mannheim). The diluted blood is centrifuged for 10 minutes at 800 xg and at room temperature to separate platelets in the serum. The cell precipitate is resuspended in the original volume and 30 ml of this is carefully pipetted onto 20 ml of lymphocyte separation medium (Boehringer Mannheim, Mannheim) in 50 ml Falcon centrifuge tubes (type 2070, Becton Dickinson, New Jersey). After centrifugation (30 minutes at 400 xg, room temperature), the PBL are pipetted off from the separation layer and washed once with completed RPMI 1640 (RPMI 1640 from Boehringer Mannheim, Mannheim; additives: 10% by volume of inactivated fetal calf serum, 2 mmol of glutamine, 1% BME vitamins, 10,000 IU penicillin and 10 mg streptomycin per 1 1 medium; all from Boehringer Mannheim, Mannheim). The PBL are adjusted to 1 x 10 ⁶ cells / ml.

Mixed Lvmphocyte Culture (MLR)

1 x 10 ⁵ PBL in 100 / ul RPMI 1640 culture medium is mixed with the same amount of PBL from another blood donor in Nunklon microtiter plates. For this purpose, the compounds to be tested are added in stages. The allogeneic reaction of the cells is measured after six days of incubation using built-in radio-thymidine (18-hour pulse). The percentage inhibition for each concentration tested is determined by comparison with the solvent control. The IC 50 specified in the tables is then interpolated from the concentration-dependent inhibition values. Mitooeninduced cell proliferation (PWM)

200 / ul of the PBL cell suspension (2 x 10 ⁵ PBL) are pipetted into 0.25 µg / ml PWM (pokeweed mitogen, Boehringer Mannheim, Mannheim) in flat-bottom microtiter plates. After adding the substances to be tested, the mixture is incubated for 48 hours (37 ° C., 5% CO ₂ , 95% relative atmospheric humidity). 18 hours before the end of the incubation, radiothymidine is added and, after the rows have been harvested, the built-in radioactivity is determined. As described above, the IC 50 is calculated from these values.

Mitoqen-induced immunoglobulin synthesis by leukocytes (IσG)

2 x 10 ⁵ PBL are incubated in 200 / ul complemented RPMI 1640 medium with 0.2 / u / ml PWM in microtiter plates at 37 ° C, 5% CO2 and 95% relative humidity for nine days. The culture supernatant is then harvested and the concentration of human IgG is determined from this using an ELISA method.

Tumor growth inhibition test (TGI)

A chemically-induced (methylcholanthrene A) mouse. fibrosarcom cell line is propagated at weekly intervals. For an in vitro test, the cells are washed twice and adjusted to a cell density of 5 × 10 ⁴ cells / ml in the above culture medium. 200 ul of this cell suspension are added to the wells of a microtiter plate and incubated with the compounds to be tested for 48 hours at 37 ° C., 5% CO ₂ and 95% relative atmospheric humidity. Radiothymidine is added three hours before the incubation period expires and the amount of radioactivity incorporated is determined after harvesting. The test was evaluated as described above.

Results

Table 1 summarizes the IC 50 values for six examples from the patent application. General cytotoxic or cytolytic compounds inhibit both the allogen-induced, the mitogen-induced and the spontaneous proliferation of eukaryotic at comparable concentrations. It can be seen from Table 1 that for a half-maximal inhibition of proliferation in Examples BV 5 and BV 85 quite different concentrations are necessary. It is particularly striking, however, that concentrations are sufficient for a half-maximum inhibition of immunoglobulin synthesis, some of which are more than a factor of 100 lower than those necessary for inhibiting spontaneous tumor cell proliferation.

Table 1

Immunopharmacological in-vitro effects of trisubstituted pyrroles on human leukocytes and murine tumor cells. IC 50 values are given in / µg / ml.

MLR: mixed lymphocyte culture; PWK: pokeweed-mitogen-induced Lyphocyte proliferation; TGI: tumor growth inhibition test; IgG: PWM-induced IgG synthesis; n.d. not measured (method description see text)

Claims

1. Compounds of formula I.

wherein

R ^{1 is} hydrogen, acyl, an optionally acylated carbohydrate residue, a saturated or unsaturated, straight-chain or branched, unsubstituted or mono- or polysubstituted

aliphatic residue means

being the substituents

Halogen, cyano, azido, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carboxy, alkoxycarbonyl, amidino, isothiocyanato, dimethylphosphonyl, optionally substituted C3-C7-cycloalkyl, optionally substituted aryl, optionally substituted hetaryl or a group of the formula

- ^O R ⁷ , - _SR 7, _ "

( ^a ) (b)

)

mean,

R ² and R ^{3 can be the} same or different and are hydrogen, halogen, alkyl, hydroxy, methylenedioxy, alkoxy, aryloxy, haloalkyl, nitro, amino, acylamino, monoalkylamino, dialkylamino, acyloxy, carboxy, alkoxycarbonyl, alkylthio, Are alkylsulfinyl, alkylsulfonyl, arylalkyloxy, aminocarbonyl, mono- or diaminocarbonyl or cyano,

R ^{5 represents} a carbocyclic or heterocyclic aromatic group,

R ^{6 is} hydrogen, alkyl, aryl, arylalkyl, hydroxyalkyl, haloalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, acylaminoalkyl, alkylsulfonylaminoalkyl, arylsulfonylaminoalkyl, mercaptoalkyl, alkylthioalkyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, alkylthio or alkylthio or alkylthio or alkylthio or

R ^{7 represents} hydrogen, a straight-chain or branched alkyl radical, an optionally substituted C3-C7 cycloalkyl radical, an arylalkyl radical, a hetarylalkyl radical, alkoxycarbonylalkyl, carboxyalkyl, acyl, thioalkyl, mercaptoalkyl, hydroxyalkyl or alkoxyalkyl,

R ⁸ and R ^{9 can be the} same or different and denote hydrogen, alkyl, aryl, hetaryl or acyl, or together with the nitrogen can form a saturated or unsaturated three- to seven-membered ring which can also contain further heteroatoms and is optionally substituted,

R ¹⁰ and R ¹ - ^{1 can be the} same or different and mean hydrogen, alkyl, aryl or hetaryl, or together with the nitrogen a three- to seven-membered group Can form a ring which is optionally substituted and can contain further heteroatoms,

R ¹² denotes alkyl or aryl, X = NH or 0, Y = NH or SZ = NH, S or 0 and

W = amino, alkylamino, dialkylamino or alkylthio, with the condition that

c) R ⁴ does not mean the benzyloxymethyl group,

and their pharmacologically acceptable salts.

2. Process for the preparation of compounds of formula I.

(I)

wherein

R ^{1 is} hydrogen, acyl, an optionally acylated carbohydrate residue, a saturated or unsaturated, straight-chain or branched, unsubstituted or mono- or polysubstituted C 1 -C 8 aliphatic residue,

being the substituents

Halogen, cyano, azido, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carboxy, alkoxycarbonyl, amidino, isothiocyanato, dimethylphosphonyl, optionally substituted C ₃ -C ₇ cycloalkyl, optionally substituted aryl, optionally substituted hetaryl or a group of the formula

-OR ⁷ , -SR ⁷ ,

^(a) < ^b >

mean

R ² and R ^{3 may be the} same or different and are hydrogen, halogen, alkyl, hydroxy, methylenedioxy, alkoxy, aryloxy, haloalkyl, nitro, amino, acylamino, monoalkylamino, dialkylamino, acyloxy, carboxy, alkoxycarbonyl, alkylthio, alkylsulfinyl, alkylsulfonyl, arylalkyloxy , Aminocarbonyl, mono- or diaminocarbonyl or cyano,

R ^{4 is} a C3-C7-cycloalkyl radical optionally substituted by hydroxyl or alkoxyl groups, an optionally substituted aryl radical, an optionally substituted hetaryl radical, cyano, amidino, aminocarbonylamino, a radical of the formula -OR ⁷ or. -NR ⁸ R ⁹ , or has the same meaning as R ¹ with the exception of the meaning hydrogen,

R ^{5 represents} a carbocyclic or heterocyclic aromatic group,

R ^{6 is} hydrogen, alkyl, aryl, arylalkyl, hydroxyalkyl, haloalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, acylaminoalkyl, alkylsulfonylaminoalkyl, arylsulfonyl-a inoalkyl, mercaptoalkyl, alkylthioalkyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkylsulfonyl or alkylthio;

R ¹⁰ and R ^{11 may be the} same or different and denote hydrogen, alkyl, aryl or hetaryl, or together with the nitrogen may form a three to seven-membered ring which is optionally substituted and may contain further heteroatoms,

R ¹² denotes alkyl or aryl,

X = NH or 0,

Y = NH or S

Z = NH, S or 0 and W - amino, alkylamino, dialkylamino or alkylthio means, with the condition that

c) R ⁴ does not mean the benzyloxymethyl group,

and their pharmacologically acceptable salts, characterized in that in a manner known per se

a) a compound of the general formula III,

R -NH ₂ (IV) or R -NH ₃ + A- (IVa)

in which R ^{4 has} the meanings given above and "A ~" means an acid anion such as chloride, bromide, carbonate, sulfate or acetate, or b) in the event that a compound of the general formula V,

in which R ² ', R ³ ' and R ⁶ 'have the meanings given above and "shark", halogen, such as chlorine, bromine or iodine, or

c) a compound of general formula V with a

Alkali metal derivative of one of the heterocyclic groups mentioned above,

and subsequently optionally obtained compounds of the formula I are converted into other compounds of the formula I and, if desired, the compounds obtained are converted into pharmacologically acceptable salts.

3. Medicament containing a compound according to claim 1 in addition to conventional carriers and auxiliaries.

4. Use of compounds according to claim 1 for the manufacture of medicaments for the treatment of immune diseases or allergic diseases.