DE4005969A1 - NEW TRISUBSTITUTED PYRROLE, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS - Google Patents

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

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

wherein
R¹ is hydrogen, an optionally acylated carbohydrate radical, a saturated or unsaturated, straight-chain or branched, unsubstituted or mono- or polysubstituted, preferably mono- to trisubstituted, substituted C₁-C₁₀ aliphatic radical,
wherein the substituents halogen, cyano, azido, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carboxy, alkoxycarbonyl, amidino, isothiocyanato, dimethylphosphonyl, optionally substituted C₂-C₇-cycloalkyl, optionally substituted aryl, optionally substituted hetaryl or a group of the formula

mean,
R² and R³ 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,
R⁴ 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 -OR⁷ or, -NR⁸R⁹, or the same meaning as R¹ with the exception of the meaning hydrogen,
R⁵ represents a carbocyclic or heterocyclic aromatic group,
R⁶ is hydrogen, alkyl, aryl, arylalkyl, hydroxyalkyl, haloalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, acylaminoalkyl, alkylsulfonylaminoalkyl, arylsulfonylaminoalkyl, mercaptoalkyl, alkylthioalkyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, alkylthio or alkylsulfonic acid;
R⁷ denotes 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,
R⁸ and R⁹ 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,
R¹⁰ and R¹¹ 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,
R¹² denotes alkyl or aryl,
X = NH or O,
Y = NH or S,
Z = NH, S or O and
W = amino, alkylamino, dialkylamino or alkylthio, with the condition that

• a) R⁴ is not the methyl group when R¹, R², R³, R⁶ Hydrogen and R⁵ 3-indolyl or (6-hydroxy) -3-indolyl or R¹, R², R³ are hydrogen, R⁶ methyl and R⁵ (2-methyl) -3- indolyl and R¹, R², R³ hydrogen, R⁶ phenyl and R⁵ (2- Phenyl) -3-indolyl means
• b) R⁴ is not the benzyl group when R¹, R², R³, R⁶ Is hydrogen, R⁵ 3-indolyl and
• c) R⁴ is not 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) Keneko, T; Wong, H; Okamoto, KT; Clardy, I., Tetrahedron Lett., 26 (34), 4015 (1985)

In the context of the invention means in all cases

Alkyl alone or in combination a straight-chain or branched C₁-C₇ alkyl group, such as methyl, ethyl, propyl, butyl, isobutyl, tert. Butyl, amyl, isoamyl, hexyl and heptyl, especially methyl, ethyl, propyl and butyl,
Alkoxy is a C₁-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 C₁-C₇ alkane carboxylic acid radical such as formyl, acetyl, propionyl, isopropionyl, butyryl, isobutyryl, pentanoyl, hexanoyl and heptanoyl, in particular formyl, acetyl, propionyl and butyryl,
Halogen fluorine, chlorine and bromine,
Aryl, alone or in combination, the phenyl group, which can optionally carry one or more, preferably 1-3, substituents, such as halogen, e.g. B. fluorine, chlorine, bromine, alkyl, hydroxy, alkoxy, benzyloxy, haloalkyl, nitro, amino, acylamino, 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 optionally contains a fused-on benzene ring, such as pyridyl, pyrimidyl, pyrazinyl, thienyl, oxazolyl, pyrazolyl, imidazolyl, tetrazolyl, thiazolyl, benzothienyl, benzothiazolyl, indolyl, benzimazylyl, benzimidazolyl, benzimidazolyl, benzimidazolyl, benzimidazolyl, benzimidazolyl, benzimidazolyl, benzimidazolyl, benzimidazolanyl especially imidazolyl, furanyl, thienyl, pyridyl, indolyl and benziminedazolyl; the substituted hetaryl radical carries one or more, preferably 1-3, substituents such as halogen, e.g. B. chlorine, bromine, fluorine, alkyl, hydroxy, alkoxy, haloalkyl, nitro, amino, acylamino, 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,
C₃-C₇-cycloalkyl cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, especially cyclopropyl, cyclopentyl and cyclohexyl; the optionally mono- or polysubstituted C₃-C₇ cycloalkyl usually carries 1-3 substituents from the group hydroxy or alkoxy.

The carbohydrate residue of R¹ means glucopyranosyl, manopyranosyl or ribofuranosyl, especially glucopyranosyl. The C₁-C₁₀ aliphatic radical of R¹ is preferably methyl, Ethyl, propyl, isopropyl, butyl, isobutyl, tert. Butyl, isoamyl, Isohexyl, n-hexyl, n-octyl, n-decyl, allyl, methallyl, Isopentenyl, n-hexenyl, n-decenyl, proparyl, butinyl, n-hexinyl, n-decinyl, especially methyl, ethyl, isobutyl, isohexyl, n-decyl, allyl, methallyl isopentenyl and propargyl.

Three to seven-membered rings, the R⁸ and R⁹ or R¹⁰ and R¹¹ together with the nitrogen to which they are attached are preferably the aziridine, the pyrrolidine and the piperidine ring, especially the pyrrolidine ring. The Heteroatoms that the rings can contain are nitrogen, Sulfur or oxygen. There are rings such as B. To understand piperazine, morpholine and thiomorpholine. Substituents the rings mentioned above are in particular C₁-C₃-alkyl and C₁-C₃ alkoxyl groups, such as. As methyl, ethyl or Propyl or methoxy, ethoxy or propoxy.

A carbocyclic aromatic group R⁵ is mono- or polycyclic, preferably phenyl or naphthyl, and unsubstituted or substituted, e.g. B. by one or more, preferably 1-3 substituents from the group of halogen, alkyl, hydroxy, Alkoxy, haloalkyl, nitro, amino, acylamino, 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-methoxyphenyl, 2- or 3-tri fluoromethylphenyl, 2-, 3- or 4-nitrophenyl, 3- or 4-aminophenyl, 4-methylthiophenyl, 4-methylsulfinylphenyl, 4-methylsulfonylphenyl and 1- or 2-naphthyl.

A heterocyclic aromatic group R⁵ can be a 5- or 6-membered heterocyclic aromatic group which if desired, contains a condensed benzene ring and is unsubstituted or substituted, e.g. B. with one or several, preferably 1-3 substituents from the group of Halogen, alkyl, hydroxy, alkoxy, haloalkyl, nitro, amino, Acylamino, mono- or dialkylamino, alkylthio, alkylsulfinyl and alkylsulfonyl. If the heterocyclic aromatic group 3-indolyl, this group can be one of the formula II  

be,
wherein R¹ ', R²', R³ 'and R⁶' have one of the meanings of R¹, R², R³ and R⁶ in formula I.

Examples of heterocyclic aromatic groups R⁵ are 2- or 3-thienyl, 3-benzothienyl, 1-methyl-2-pyrrolyl, 1-benzimidazolyl, 3-indolyl, 1- or 2-methyl-3-indolyl, 1-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-mercapto ethylthio) ethyl] -3-indolyl, 1- (1-phenylthioethyl) -3-indolyl, 1- [1- (carboxymethylthio) ethyl] -3-indolyl and 1-benzyl-3-indolyl, 1-indolyl, (3-dimethylaminomethyl) -1-indolyl, 1-indazolyl, 1-benzotriazolyl, 1-pyrrolyl, 1-imidazolyl, 1-triazolyl and 1-tetrazolyl.

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

• a) a compound of the general formula III, in which R¹, R², R³, R⁵ and R⁶ have the abovementioned meanings, with a compound of the general formula IV or IVa, R⁴-NH₂ (IV) or R⁴-NH₃⁺A ^- (IVa) in R⁴ the abovementioned meanings has 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 R¹, R², R³, R⁴ and R⁶ have the meanings given above, with a compound of the general formula VI, in which R² ', R³' and R⁶ 'have the meanings given above and "Hal", halogen, such as chlorine, bromine or iodine, or
• c) a compound of general formula V with a Alkali metal derivative one of the above converts heterocyclic groups, or
• d) in the case of a compound of the general formula I in which R¹ Hydrogen means nitrogen substituted, or
• e) in the case of a compound of the general formula I in which R⁴ Is hydrogen, corresponding to nitrogen, substituted,
• f) if desired, one in a compound of formula I. functionally converts existing reactive substituents 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 R¹, R², R³, R⁵ and R⁶ have the meanings given above and "M" denotes an alkali metal, with a concentrated mineral acid, or
• i) a compound of the general formula VIII, in which R¹, R², R³ and R⁶ have the abovementioned meanings with a compound of the general formula IX, R⁵-CH₂-COOH (IX) in which R⁵ has the abovementioned meanings.

Compounds of the general formula V can be prepared be by a compound of general formula VI in which R² ′, R³ ′ and R⁶ ′ have the same meaning as R², R³ and R⁶ in of formula V, with a compound of general Formula X,  

in which R⁴ has the meanings given above, implemented becomes.

Compounds of the general formula VII are from one compound of the general formula I, in which R⁴ is methyl or ethyl means obtainable by alkaline hydrolysis.

Compounds of the general formula VIII can in themselves be made in a known manner by using an indole general formula XI,

in which R¹, R², R³ and R⁶ have the meanings given above reacted with oxalyl chloride.

Compounds of the general formula X can be in themselves known manner with alkylation of 2,4-dibromomaleimide a compound of the general formula XII,

R⁴-Abg (XII)

in which R⁴ has the meanings given above and "Abg" has one Leaving group from the group of halogens, such as chlorine, bromine or Iodine or from the group of sulfonic acid esters such as tosylate, Mesylate or triflate means.  

The reaction of a compound of formula III with a compound of the formula IV or IVa is carried out in a manner known per se Way ¹) ²) ³) either by having the two reactants between 100 ° C and 250 ° C, preferably at 180 ° C for the reaction brings, or in an inert solvent such as pyridine, Methylene chloride, chloroform or dimethylformamide, with or without adding a tert. Nitrogen base such as triethylamine and at a temperature between room temperature and boiling temperature of the solvent used.

1) BW Larner, AT Peters, J. Chem. Soc., 680 (1952)
2) S. Ohki, T. Nayasaka, Chem. Pharm. Bull., 19, 545 (1971)
³) M. Aeberli, H. Erlenmeyer, Helv. Chim. Acta, 31, 470 (1948)

The Grignard reaction between a compound of formula V or X and one of formula VI can be in itself perform known manner, e.g. B. in an inert Solvents such as benzene, toluene, tetrahydrofuran or ether and at a temperature between room temperature and Reflux temperature of the reaction mixture. Conveniently is a compound of formula VI in situ starting from indole or a substituted indole and a suitable one Alkyl magnesium halide such as methyl magnesium bromide or iodide produced in a manner known per se.

Carrying out the reaction of a compound of formula V with the alkali metal derivative of one of the above heterocyclic aromatic groups are made 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 in situ from one of the aromatic mentioned above heterocyclic groups and an alkali metal hydride, preferably Sodium hydride generated.

The N substitution of a compound of formula I in which R¹ Hydrogen means, according to variant d) one can in itself for perform the N¹ substitution of indoles in a known manner. A hydroxyalkyl group R¹ can e.g. B. in a compound of Formula I in which R 1 is hydrogen can be introduced by that first such a compound in an alkali metal derivative, e.g. B. sodium derivative transferred using sodium hydride, and then the derivative obtained with a the hydroxyalkyl group generating agents, e.g. B. an alkylene oxide such as propylene oxide or treated with ethylene oxide. An alkoxyalkyl group R¹ can  by treating a compound of formula I in which R¹ Is hydrogen, with a suitable dialkyl acetal in Presence of an acid, e.g. B. p-toluenesulfonic acid at increased Introduce temperature. A compound of formula I, in which R¹ is hydrogen, with an alkyl, one Arylalkyl or a hetarylalkyl halide in the presence of a Base to a compound of formula I in which R¹ is alkyl or alkyl substituted by aryl or hetaryl will.

The N substitution of a compound of formula I in which R⁴ Hydrogen means, according to variant e) one can in itself perform known manner for the N¹ substitution of maleimides e.g. B. can be a compound of formula I, in which R⁴ 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 transfer sodium derivative, and this as desired

• i) with an alkyl, arylalkyl or hetarylalkyl halide a compound of formula I in which R⁴ is alkyl or by aryl or hetaryl means substituted alkyl, implement, or
• ii) with an alkyl halide containing an oxirane ring, such as e.g. B. epichlorohydrin to an intermediate compound of formula I, in the R⁴ an alkyl radical substituted by an oxirane ring means implement, and after opening the oxirane ring with z. B. Mineral acids, ammonia, mono- or dialkylamines, alcohols or mercaptans to compounds of the formula I in which R⁴ is one by two of the groups hydroxy, alkoxy, monoalkylamino, dialkylamino and alkylthio means disubstituted alkyl radical, reach.

The functional conversions of compounds of formula I. variant f) can be carried out in a manner known per se. For example, a nitro group can be reduced to an amino group and then alkylate or acylate the latter. A Aminoalkyl group can be alkylated, acylated or sulfonylated will. An alkylthio or alkylthioalkyl group can be used for Alkylsulfinyl or alkylsulfinylalkyl group and the latter if desired to the alkylsulfonyl or alkylsulfonylalkyl group oxidize. An alkoxycarbonylalkyl group can be used Carboxyalkyl group are saponified and the latter then amidated or be transesterified. An alkoxyalkyl group can be added  an alkylthioalkyl or arylthioalkyl group by means of a Implement alkanethiols or thiophenols. An azidoalkyl group can be catalytically hydrogenated into an aminoalkyl group transferred and the latter in turn functional modifications be subjected. For example, one can use an aminoalkyl group 1,1'-thiocarbonyldiimidazole in an isothiocyanate alkyl group convert. You can also an aminoalkyl group in a Convert alkyl group which is represented by a radical of formula (g) is substituted by, in the event that Y = NH, Z = NH and W = amino, by means of 3,5-dimethylpyrazo-1-carboxamidine implements, or in the event that Y = NH, Z = NH and W = alkylthio means by means of a dialkyl-N-cyandithioiminocarbonate implements.

An alkylcarbonyloxyalkyl group can be added to the hydroxyalkyl group saponify and the latter in a manner known per se convert a haloalkyl or an alkylsulfonyloxyalkyl group. A hydroxyalkyl group can also be converted into an aminoalkylaminoalkyl group convict by treatment with Trifluoromethanesulfonic anhydride followed by reaction with transfer to a suitable diaminoalkane.

For example, an alkylsulfonyloxyalkyl group can be incorporated into a Mono-, di- or trialkylaminoalkyl group by means of a mono-, Di- or trialkylamine, in a cyanoalkyl group by means of a Alkali metal cyanide, into an alkylthioalkyl group by means of a Alkali metal alkanethiolate, or into an acylthioalkyl group be converted using an alkali metal thioacylate.

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

Furthermore, a cyanoalkyl group can be converted into an amidinoalkyl group by means of ammonia, an acylthioalkyl group into a Mercaptoalkylgruppe using aqueous ammonia, and a Benzyloxy aryl group into a hydroxy aryl group by hydrogenolysis convert.

Of course, the above conversions are exemplary only Character and others known to those skilled in the art Modifications are carried out.

The conversion of an acidic compound of formula I into a pharmaceutically acceptable salt according to variant g) can by Treatment with a suitable base in a manner known per se be performed. Suitable salts are those from one inorganic base, e.g. B. sodium, potassium or calcium salts,  or from an organic base, such as ethylenediamine or mono- or diethanolamine. The conversion of a basic compound of formula I into a pharmaceutically usable Salt can be treated with an appropriate acid be accomplished in a manner known per se. Suitable Salts are those derived from an inorganic acid, e.g. B. Hydrochloride, hydrobromide, phosphate or sulfate, or from an organic acid, e.g. B. acetates, citrates, fumarates, Tartrates, maleates, methanesulfonates or p-toluenesulfonates, are derived.

The preparation of a compound of formula III from a Compound of formula VII is carried out in a manner known per se (W. Steglich, Tetrahedron, 44 (10), 2887). For example, one can Compound of the general formula I, in which R⁴ is methyl or Ethyl means by means of a concentrated alkali 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 reflux temperature of the reaction mixture in a compound of formula VII transfer, and this with a semi-concentrated mineral acid treat like 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 Solvents such as methylene chloride, dichloroethane or ether with the addition of an acid-binding agent, expediently a tertiary amine such as a trialkylamine, e.g. B. triethylamine and at a temperature between -30 ° C and 40 ° C, preferably at room temperature. Implementation of an indole general formula XI with oxalychloride to a compound of Formula VIII is carried out in a manner known per se in an inert manner Solvents such as methylene chloride, diethyl ether or dimethylformamide and at a temperature between -20 ° C and reflux temperature of the reaction mixture, preferably at 0 ° C. The resulting compound of formula VIII can be isolated as such be, or in situ with a compound of formula IX be converted into a compound of formula III.

The alkylation of 3,4-dibromomaleimide with one compound of the formula XII is carried out in a manner known per se, that 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 dimethylformamide  and at a temperature between about 0 ° C and reflux temperature of the solvent used in the Alkali metal derivative transferred and this with an alkylating agent of 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 invention Compounds of the general formula I. Incorporate diastereomers the synthesis of the compounds according to the invention this by column chromatography in the corresponding Racemates are separated.

The optically active compounds can from their racemic Mixtures are prepared by methods known per se.

Basic or acidic racemic mixtures can e.g. B. about their cleaved diastereomeric salts into the optically active forms will. For resolution, z. B. tartaric acid, malic acid, Camphoric acid, camphor sulfonic acid, dibenzoyl tartaric acid, Cinchonine, phenethylamine, brucine or quinine are used will.

Neutral racemic mixtures can be integrated into the optically active ones Chromatically separate shapes on chiral phases.

Compounds of the general formula I, in which R⁴ is hydrogen means have been described as protein kinase inhibitors (EP-A 03 28 026).

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

Surprisingly, it has now been found that compounds of general formula I, in which R⁴ the above Has meanings, the proliferation of stimulated human Inhibit spleen cells much more and more selectively than that literature-known compounds of formula I, in which R⁴ Means hydrogen. Therefore, the ones claimed here Compounds of general formula I in a special way Therapy of immune diseases and organ transplants suitable.  

Compounds of the general formula I also inhibit the Degranulation of basophil granulocytes, therefore, they can occur in the therapy of allergic diseases find application.

The superior effect of the present compounds can be seen e.g. B. demonstrate that the inhibition of Thymidine incorporation into the DNA of stimulated human spleen cells certainly.

The pyrroles of formula I and their salts can be used as medication are used, e.g. B. in the form of pharmaceutical preparations, which one takes orally, e.g. B. in the form of tablets, drag'es, hard or Soft gelatin capsules, solutions, emulsions or suspensions, can administer. You can also rectally, e.g. B. in the form of Suppositories, or parenterally, e.g. B. in the form of injection solutions be administered. For the manufacture of pharmaceutical Preparations can use these compounds in therapeutically inert inorganic and organic carriers processed will. Examples of such carriers for tablets, drag'es and hard gelatin capsules are lactose, corn starch or derivatives of which 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, colors, flavorings, salts for Change in osmotic pressure, buffer, coating agent or antioxidants, and optionally other therapeutic Contain active ingredients.

As indicated above, the pyrroles of formula I and their salts in the treatment or prophylaxis of diseases especially inflammatory or immunological diseases be used. The dosage can vary widely however, is generally due to oral administration Adults range from about 5 to 500 mg / day, though the latter value can be increased if necessary. The daily Dose can be administered in a single dose or in multiple doses will.  

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

• BV
  1. 1- (3- (1-pyrrolidino) -2-hydroxypropyl) -3,4-bis (3-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- (ethoxycarbonyl methyl) -3-indolyl) maleimide; Mp 156 ° C.
• 5. 1- (1-hydroxy-cyclohex-4-yl) -3,4-bis- (3-indolyl) - maleimide; Mp 142 ° (dec.)
• 6. 1-Methyl-3- (5,6-dimethoxy-3-indolyl) -4- (3-indolyl) maleimide
• 7. 1-Methyl-3- (5,6-dichloro-3-indolyl) -4- (3-indolyl) maleimide
• 8. 1-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. 1-ethyl-3- (5-fluoro-3-indolyl) -4- (3-indolyl) maleimide
• 11. 1-methyl-3-5-hydroxy-3-indolyl) -4- (3-indolyl) maleimide
• 12. 1-methyl-3,4-bis (5-hydroxy-3-indolyl) maleimide
• 13. 1-butyl-3,4-bis (5-hydroxy-3-indolyl) maleimide
• 14. 1-Propyl-3- (5-benzyloxy-3-indolyl) -4- (5-trifluoromethyl-3-indolyl) ma-linimide
• 15. 1-Methyl-3- (5-trifluoromethyl-3-indolyl) -4- (2-methyl-3-indolyl) malei-nimide
• 16. 1-n-Pentyl-3- (5-nitro-3-indolyl) -4- (2-methyl-3-indolyl) maleimide  
• 17. 1-methyl-3,4-bis (5-nitro-3-indolyl) maleimide
• 18. 1-methyl-3,4-bis (5-amino-3-indolyl) maleimide
• 19. 1-Methyl-3- (5-amino-3-indolyl) -4- (4-chloro-3-indolyl) maleimide
• 20. 1-Methyl-3- (5-amino-3-indolyl) -4- (3-indolyl) maleimide
• 21. 1-Methyl-3- (5-acetylamino-3-indolyl) -4- (3-indolyl) maleimide
• 22. 1-Methyl-3- (5-methylamino-3-indolyl) -4- (5-dimethyl amino-3-indolyl) maleimide
• 23. 1-Methyl-3- (5-acetyloxy-3-indolyl) -4- (5-trifluoromethyl) maleimide
• 24. 1-Cyclopentyl- (5-carboxy-3-indolyl) -4- (3-indolyl) maleimide
• 25. 1-Methyl-3,4-bis (5-ethoxycarbonyl-3-indolyl) maleimide
• 26. 1-Methyl-3- (5-ethoxycarbonyl-3-indolyl) -4- (3-indolyl) maleimide
• 27. 1-Methyl-3- (5-ethoxycarbonyl-3-indolyl) -4- (5,6-dichloro-3-indolyl) ma-linimide
• 28. 1-ethyl-3- (5-methylthio-3-indolyl) -4- (3-indolyl) maleimide
• 29. 1-methyl-3- (1- (3-amino) propyl-5-methylthio-3-indolyl) - 4- (5-methylthio-3-indolyl) maleimide
• 30. 1-ethyl-3- (5-methylsulfinyl-3-indolyl) -4- (3-indolyl) maleimide
• 31. 1-Ethyl-3- (5-methylsulfonyl-3-indolyl) -4- (3-indolyl) maleimide
• 32. 1-Methyl-3,4-bis (5-methylthio-3-indolyl) maleimide  
• 33. 1-Methyl-3,4-bis (5-methylsulfinyl-3-indolyl) maleimide
• 34. 1-Methyl-3,4- (1- (2-hydroxy) propyl-5-methylsulfinyl-3-indolyl) maleimide
• 35. 1-Propionylamino-3- (1-dimethylaminocarbonylmethyl-3-indolyl) -4- (3-in-dolyl) maleimide
• 36. 1-Acetyloxy-3- (1- (1-pyrrolidino) carbonylmethyl-3-indolyl) -4- (3-indolyl) maleimide
• 37. 1-Methyl-3- (1- (3-hydroxy) propyl-3-indolyl) -4- (3-indolyl) maleimide
• 38. 1-Methyl-3- (1- (3-methylsulfonyloxy) propyl-3-indolyl) -4- (3-indolyl) maleimide
• 39. 1-Cyclopropyl-3- (1- (prop-2-en-1-yl) -3-indolyl) -4- (3-indolyl) maleimide
• 40. 1-tert-Butyl-3- (1- (4-methyl) pentyl-3-indolyl) -4- (3-indolyl) maleimide
• 41. 1- (3,4-Methylenedioxy) phenyl-3,4-bis (3-indolyl) maleimide
• 42. 1-Methyl-3- (1-dimethylphosphinylmethyl-3-indolyl) -4- (3-indolyl) maleimide
• 43. 1-Propyl-3- (5,6-dichloro-3-indolyl) -4- (2-chlorophenyl) maleimide
• 44. 1-Methyl-3- (4,5-dichloro-3-indolyl) -4- (2,4-dichlorophenyl) maleimide
• 45. 1-Ethyl-3- (5-fluoro-indolyl) -4- (4-fluorophenyl) maleimide
• 46. 1-Methyl-3- (5-hydroxy-3-indolyl) -4- (2-methoxyphenyl) maleimide
• 47. 1-Methyl-3- (5-hydroxy-3-indolyl) -4- (3,4-methylenedioxyphenyl) maleimide  
• 48. 1-Methyl-3- (5-methoxy-3-indolyl) -4- (phenyl) maleimide
• 49. 1-n-Butyl-3- (5,6-dimethoxy-3-indolyl) -4- (2,4-dimethoxyphenyl) maleimide
• 50. 1-Propyl-3- (5-trifluoromethyl-3-indolyl) -4- (3,4-methylene-dioxyphenyl) maleimide
• 51. 1- (3-Methylhexyl) -3- (3-indolyl) -4- (2-trifluoromethylphenyl) maleimide
• 52. 1-Cyclopentyl-3- (5-nitro-3-indolyl) -4- (2-chlorophenyl) maleimide
• 53. 1-n-Butyl-3- (3-indolyl) -4- (4-dimethylaminophenyl) maleimide
• 54. 1-Cyclopropyl-3- (5-methylamino-3-indolyl) -4- (1-naphthyl) maleimide
• 55. 1-Isopropyl-3- (1-β-D-glucopyranoside-3-indolyl) -4- (3-indolyl) maleimide
• 56. 1-n-Pentyl-3- (5-nitro-3-indolyl) -4- (2-nitrophenyl) maleimide
• 57. 1-Methyl-3- (5-methyl-3-indolyl) -4- (2,4-dimethylphenyl) maleimide
• 58. 1-Methyl-3- (5-chloro-3-indolyl) -4- (4-hydroxyphenyl) maleimide
• 59. 1-n-Hexyl-3- (5,6-dimethoxy-3-indolyl) -4- (4-methylthiophenyl) maleimide
• 60. 1-n-Hexyl-3- (5,6-dimethoxy-3-indolyl) -4- (4-methylsulfonylphenyl) maleimide
• 61. 1-n-Hexyl-3- (5,6-dimethoxy-3-indolyl) -4- (4-methylsulfinyl) phenyl) m-aleinimide
• 62. 1-Hydroxy-3- (3-indolyl) -4- (3-bromophenyl) maleimide
• 63. 1-Amidino-3- (3-indolyl) -4- (2,5-dimethylphenyl) maleimide  
• 64. 1-Cyclopropyl-3- (1-methyl-3-indolyl) -4- (4-aminophenyl) maleimide
• 65. 1-n-Butyl-3- (1- (3-hydroxypropyl) -3-indolyl) -4- (2,3,6-trichlorophenyl) maleimide
• 66. 1-n-Heptyl-3- (1- (3-guanidinopropyl) -3-indolyl) -4- (2,6-dichlorophenyl) maleimide
• 67. 1-Methyl-3- (1-ethyl-3-indolyl) -4- (1-benzimidazolyl) maleimide
• 68. 1-Cyclopentyl-3- (1- (methoxyethyl) -3-indolyl) -4- (1-indolyl) -maleinimi-d
• 69. 1-isobutyl-3- (1- (1-methoxyethyl) -3-indolyl) -4- (3-thienyl) maleimide-
• 70. 1-Methyl-3- (1- (3-aminopropyl) -3-aminopropyl) -3-indolyl) -4- (2-furyl) maleimide
• 71. 1- (3-Phenylthio-propyl) -3- (1-methyl-3-indolyl) -4- (2-methyl-3-indolyl -) - maleimide
• 72. 1- (2-Dimethylaminoethyl) -3- (1- (2,3-epoxypropyl) -3-indolyl) -4- (3-indo-lyl) -maleimide
• 73. 1- (2-Dimethylaminoethyl) -3- (1- (2-hydroxy-3-dimethylamino propyl) -3 - indolyl) -4- (3-indolyl) maleimide
• 74. 1-Isopropyl-3- (1-dimethylaminomethyl-3-indolyl) -4- (2-benzothienyl) -m-aleinimide
• 75. 1-Methyl-3- (1-ethyl-3-indolyl) -4- (2-methylthio-3-indolyl) maleimide-
• 76. 1-Methyl-3 (1-ethyl-3-indolyl) -4- (2-methylsulfinyl) -3-indolyl) maleimide
• 77. 1-Methyl-3 (1-ethyl-3-indolyl) -4- (2-methylsulfonyl) -3-indolyl) maleimide
• 78. 1-Cyclohexyl-3,4-bis (2-phenyl-3-indolyl) maleimide  
• 79. 1-Methyl-3- (1- (9-carboxy-nonyl) -3-indolyl) -4- (3-indolyl) maleimide
• 80. 1-Neopentyl-3- (1- (2-carboxy-ethyl) -3-indolyl) -4- (1-methyl-3-pyrrolyl -) - maleimide
• 81. 1-Methyl-3- (1- (2-hydroxy-3-azido-propyl) -3-indolyl) -4- (1- (1,2,4-triazolyl)) maleinimide
• 82. 1-Methyl-3- (1- (2-aziridino) methyl-3-indolyl) -4- (1- (1,2,4-triazolyl) maleimide
• 83. 1-Isopropyl-3- (3-indolyl) -4- (1-tetrazolyl) maleimide
• 84. 1-Ethyl-3- (1- (2-methyl-propyl) -3-indolyl) -4- (5-methoxy-2-benzofurany-l) -maleimide
• 85. 1- (1-adamantyl) -3,4-bis (3-indolyl) maleimide; Mp 148 ° C.

Example 1 1- (1-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) of alanine ethyl ester hydrochloride were 4 hours heated to 180 ° C.

The cooled melt was then treated with a 1/1 Water / ether mixture added, the ether phase separated and dried over sodium sulfate. After removing the ether the residue was made up of a little ethyl acetate recrystallized. 1.4 g of 1- (1-ethoxycarbonylethyl) -3,4-bis (3-indolyl) maleimide were obtained m.p. 238 ° C.

The following were prepared analogously to Example 1:

• 1.1 1-cyanomethyl-3,4-bis (3-indolyl) maleimide; Mp 196 ° C.
• 1.2 1-ethyl-3,4-bis (3-indolyl) maleimide; Mp 240-242 ° C.
• 1.3 1-butyl-3,4-bis (3-indolyl) maleimide; Mp 193 ° C.
• 1.4 1-cyclohexyl-3,4-bis (3-indolyl) maleimide; Mp 170 ° C.

Example 2 1- (2-propen-1-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) allylamine and 10 ml triethylamine in 50 ml dry dimethylformamide was refluxed for 4 hours heated. The reaction mixture was then in vacuo Evaporated to dryness, the residue in methylene chloride added and the methylene chloride solution with 0.1 N hydrochloric acid shaken. After drying the methylene chloride phase over Sodium sulfate and stripping off the solvent Crystallized residue from toluene. 0.9 g of 1- (2- Propen-1-yl) -3,4-bis (3-indolyl) maleimide, mp 214 ° C.  

The following were prepared analogously to Example 2:

• 2.1 1- (3-ethoxycarbonylpropyl) -3,4-bis (3-indolyl) maleimide; Mp 178 ° C.
• 2.2 1- (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 1-carboxymethyl-3,4-bis (3-indolyl) maleimide; Mp 252 ° C.
• 2.5 1-aminocarbonylmethyl-3,4-bis (3-indolyl) maleimide; Mp 236 ° C.
• 2.6 1- (1,4-dimethylpent-1-yl) -3,4-bis (3-indolyl) maleimide; Mp 132 ° C.
• 2.7 1-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 1- (1-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 1- (carboxy-3-methylthio-prop-1-yl) -3,4-bis (3-indolyl) maleimide; Mp 186 ° C.
• 2.17 1-cyclopropyl-3,4-bis (3-indolyl) maleimide; Mp 224 ° C.
• 218. 1- (3-quinuclidino) -3,4-bis (3-indolyl) maleimide; Mp 236 ° C.
• 2.19 1- (10-carboxydecyl) -3,4-bis (3-indolyl) maleimide; Mp 124 ° C.
• 2.20 1-hydroxy-3,4-bis (3-indolyl) maleimide; Mp 192 ° C.
• 2.21 1-aminocarbonylamino-3,4-bis (3-indolyl) maleimide; Mp 138 ° C.
• 2.22 1-isopropyl-3,4-bis (3-indolyl) maleimide; Mp 138 ° C.
• 2.23 1- (2-glucopyranosyl) -3,4-bis (3-indolyl) maleimide; Mp 167 ° C.
• 2.24 1- (4-dimethylaminophenyl) -3,4-bis (3-indolyl) maleimide; Mp <250 ° C.
• 2.25 1- (2,3-dihydroxypropyl) -3,4-bis (3-indolyl) maleimide; Mp 125 ° C.

Example 3 1-Methyl-3- (1- (2-hydroxy-3- (1-pyrrolidino) propyl) -3-indolyl) -4- (3-i-ndolyl) maleimide

• 3.1. 10.2 g (0.03 mol) of 1-methyl-3,4-bis (3-indolyl) maleimide (W. Steglich) are dissolved in 90 ml of dry dimethylformamide. The solution is cooled to 0 ° C. and 0.72 g (0.03 mol) sodium hydride is added. The reaction mixture is stirred for a further 10 min at 0 ° C. and 6 ml of epichlorohydrin are then added. The mixture is then heated at 50 ° C. for 1 hour, then cooled and mixed with saturated ammonium chloride solution. The aqueous solution is extracted 3 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
  • 3.1.a) 3.9 g of 1-methyl-3- (1- (2,3-epoxypropyl)) - 3-indolyl) -4- (3-indolyl) -maleinimi-d and
  • 3.1.b) 3.2 g of 1-methyl-3,4-bis (1- (2,3-epoxypropyl)) -3-indolyl) maleimide
• 3.2. The solution of 2.3 g (5.8 mmol) of compound 3.1a) and 4 ml Pyrrolidine in 100 ml of ethanol is refluxed for 1 hour heated. Then the solvent and the Excess pyrrolidine removed in vacuo and the 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-inolyl) maleimide mp 86 ° C.

The following were produced analogously to example 3.1:

• 3.1.1 1-methyl-3- (1- (3-bromopropyl) -3-indolyl) -4- (3-indolyl) maleimide; Mp 199 ° C.
• 3.1.2 1-methyl-3- (1- (ethoxycarbonylmethyl) -3-indolyl) -4- (3-indolyl) maleimide; Mp 215 ° C.
• 3.1.3 1-methyl-3,4-bis (1- (ethoxycarbonylmethyl) -3-indolyl) maleimide; Mp 148 ° C.
• 3.1.4 1-methyl-3- (1- (carboxymethyl) -3-indolyl) -4- (3-indolyl) maleimide; Mp 201 ° C.
• 3.1.5 1-methyl-3,4-bis (1- (carboxymethyl) -3-indolyl) maleimide; Mp 99 ° C.

Analogously to Example 3.2), compound 3.1b) and pyrrolidine are obtained
1-methyl-3,4-bis- (1- (2-hydroxy-3- (1-pyrrolidino) propyl-3-indolyl) -m-aleinimide; mp 78-80 ° C.

Example 4 1-methyl-3- (1- (2-hydroxy-3-azido) propyl) -3-indolyl-4- (3-indolyl) ma-linimide

The solution of 234 mg (3.6 mmol) sodium azide and 470 mg (1.2 mmol) the compound 3.1.a) in 10 ml DMF was 4 hours Heated to 80 ° C. Then the reaction mixture with 50 ml Water was added and the aqueous solution 3 times with ether extracted. After drying the combined ether extracts and stripping the solvent became the residue purified by column chromatography. Eluent: Ethyl acetate / isohexane = 1/1. 300 mg of 1- Methyl 3- (1- (2-hydroxy-3-azido) propyl) -3-indolyl) -4- (3-indolyl) maleimide mp 90 ° C (dec.).

Example 5 1-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 to the solution of 1.1 ml at 45 ° C. (15 mmol) ethyl bromide in 5 ml abs. Tetrahydrofuran. To complete dissolution of the magnesium is added a solution of 1.95 g (15 mmol) 2-methyl-indole in 40 ml abs. Tetrahydrofuran added and the reaction mixture is stirred for 30 min at 45 ° C. Then a solution of 3 g is added dropwise (7.4 mmol) 1-methyl-3-bromo-4- (1- (tert-butyloxycarbonyl) -3-indolyl) maleimide (M. Brenner et al., Tetrahydron 44, 2887 (1988)) in 40 ml abs. Tetrahydrofuran too, heated then the reaction mixture was refluxed for 2 h and acidified with 20% citric acid. After diluting the Reaction solution with 50 ml of water becomes the aqueous solution extracted with ethyl acetate, the organic phase dried over sodium sulfate and the solvent deducted. After purification of the column chromatography Crude product on silica gel (eluent: Ethyl acetate / n-heptane = 1/5) gives 1.28 g of 1- Methyl 3- (1- (tert-butyloxycarbonyl) -3-indolyl) -4- (2- methyl-3-indolyl) maleimide, mp 139-142 ° C (dec.).  
• b) 1.28 g of product 5a) in 10 ml Trifluoroacetic acid dissolved and 15 min at room temperature touched. The solution is then i. Vac. restricted and the Residue chromatographed on silica gel (eluent: Ethyl acetate / isohexane 1/2). 0.57 g of 1- Methyl 3- (2-methyl-3-indolyl) -4- (3-indolyl) maleimide from Mp 235-240 ° C (dec.).

The following were prepared analogously to Example 5:

• 5.1 1-methyl-3- (5-chloro-3-indolyl) -4- (3-indolyl) maleimide; Mp 164 ° C.
• 5.2 1-methyl-3- (5-methoxy-3-indolyl) -4- (3-indolyl) maleimide; Mp 272 ° C.
• 5.3 1-methyl-3- (6-chloro-3-indolyl) -4- (3-indolyl) maleimide; Mp 130 ° C.

Example 6 1-amino-3,4-bis (3-indolyl) maleimide

1 g (2.26 mmol) of 1- (tert-butyloxycarbonyl) amino-3,4-bis (3-indolyl) maleimide (Mp. 198 ° C), produced analogously to Example 2 is dissolved in 150 ml of methanolic hydrochloric acid. Man If the solution is stirred for 4 hours at room temperature, it is concentrated then i. Vac. and takes the residue in ethyl acetate on. The organic solution is saturated with sodium bicarbonate solution washed and dried over sodium sulfate. After removing the solvent, the residue purified by column chromatography. 0.61 g of 1-amino 3,4-bis (3-indolyl) maleimide, mp 290-292 ° C.  

Example 7 1-acetylamino-3,4-bis (3-indolyl) maleimide

The suspension of 342 mg (1 mmol) of the compound of the example 6 and 0.12 ml of acetic anhydride in 5 ml of ethyl acetate stirred for one hour at 30 ° C so that a solution is formed. The Solution is then a further 5 hours at room temperature touched. The resulting reaction product is suctioned off and washed with a little ethyl acetate. 0.2 g is obtained pure 1-acetylamino-3,4-bis (3-indolyl) maleimide of mp. 194 ° C.

Analogously to Example 7, 1-hydroxy-3,4-bis (3-indolyl) maleimide is obtained (see above) and acetic anhydride 1- Acetyloxy-3,4-bis (3-indolyl) maleimide, mp 204 ° C

Example 8 1-methyl- (1- (2,3-dihydroxy) propyl-3-indolyl) maleimide

To the suspension of 240 mg (10 mmol) sodium hydride in 30 ml Section. Dimethylformamide is added dropwise to a solution at room temperature 3.4 g (10 mmol) of 1-methyl-3,4-bis (3-indolyl) maleimide. The reaction mixture is then left to stir for 45 min. then heat it to 50 ° C and add 2.9 g (10 mmol) Solectal tosylate in 10 ml abs. Dimethylformamide. Then you leave stirring the reaction mixture for 3 hours at 50 ° C, it cools and add 50 ml sat. Ammonium chloride solution. The aqueous solution is extracted with methylene chloride, which Dried methylene chloride phase over sodium sulfate and that Solvent i. Vac. deducted. The residue is in 50 ml Dissolved acetone and treated the solution with 10 ml of 6N hydrochloric acid. After 30 min, the reaction solution is evaporated and chromatograph the residue on silica gel (mobile solvent: Ethyl acetate). 1.2 g of 1-methyl-3- (1- (2,3- dihydroxy) propyl-3-indolyl) -4- (3-indolyl) maleimide, mp. 117-120 ° C.

The following was prepared analogously to Example 8:

• 8.1 1-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 1-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 ° C the solution of 3.4 ml (45 mmol) Ethyl bromide in 10 ml abs. Tetrahydrofuran. To complete dissolution of the magnesium one adds the solution of Add 6.6 g (45 mmol) of 5-methoxyindole in 30 ml of toluene and leave then stir the reaction mixture at 45 ° C for one hour. Then the solution of 2.69 g (10 mmol) of 1- Add methyl 3,4-bis-dibromomaleimide in 50 ml toluene and leave stir the reaction solution at reflux for one hour. After that acidify the mixture with 20 percent. Citric acid, separates the organic phase, the aqueous solution extracted with Ethyl acetate and dries the combined organic Phases over sodium sulfate. After removing the solvent the residue is chromatographed on silica gel (mobile solvent: Ethyl acetate / isohexane = 1/2). 2.82 g of 1- Methyl 3,4-bis (5-methoxy-3-indolyl) maleimide, mp 286 ° C.

The following were prepared analogously to Example 9:

• 9.1 1-methyl-3,4-bis (5-chloro-3-indolyl) maleimide; Mp 2908 ° C.
• 9.2 1-methyl-3,4-bis (6-chloro-3-indolyl)) maleimide; Mp 279 ° C.

Example 10 1-methyl-3- (1-benzimidazolyl) -4- (3-indolyl) maleimide

To the suspension of 240 mg (10 mmol) sodium hydride in 10 ml Section. Tetrahydrofuran is added dropwise at room temperature to 1.18 g (10 mmol) Benzimidazole in 40 ml abs. Tetrahydrofuran. Subsequently the reaction mixture is stirred for 15 min at room temperature and then adds 4.05 g (10 mmol) of 1-methyl-3-bromo-4- (1-tert.- butyloxycarbonyl) -3-indolyl) maleimide (see Example 5a). The reaction mixture is then stirred for a further one Hour, then add 100 ml sat. Ammonium chloride solution, the tetrahydrofuran evaporates, shakes the aqueous solution 3 times with ethyl acetate and dried the combined organic extracts over sodium sulfate. To Removing the solvent, the residue is heated to Stop the gas evolution to 160 ° C, cools down and chromatographs the contents of the flask on silica gel (mobile solvent: Ethyl acetate / isohexane = 2/1). 0.52 g of 1- Methyl 3- (1-benzimidazolyl) -4- (3-indolyl) maleimide, mp.

The following were prepared analogously to Example 10:

• 10.1 1-methyl-3- (1-benzotriazolyl) -4- (3-indolyl) maleimide; Mp 254 ° C.
• 10.2 1-methyl-3- (1-imidazolyl) -4- (3-indolyl) maleimide; Mp 290 ° C.
• 10.3 1-methyl-3- (3-indolyl) -4- (1-indolyl) maleimide; Mp 189 ° C.
• 10.4 1-methyl-3- (1-indazolyl) -4- (3-indolyl) maleimide; Mp 301 ° C.
• 10.5 1-methyl-3- (3-dimethylaminomethyl) -1-indolyl) -4- (3-indolyl) maleimide; Mp 156 ° C.

Claims (7)

1. Compounds of formula I. wherein
R¹ is hydrogen, an optionally acylated colohydrate residue, a saturated or unsaturated, straight-chain or branched, unsubstituted or mono- or polysubstituted substituted C₁-C₁₀ aliphatic radical,
wherein the substituents halogen, cyano, azido, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carboxy, alkoxycarbonyl, amidino, isothiocyanato, dimethylphosphonyl, optionally substituted C₂-C₇-cycloalkyl, optionally substituted aryl, optionally substituted hetaryl or a group of the formula mean,
R² and R³ 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,
R⁴ 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 -OR⁷ or, -NR⁸R⁹, or the same meaning as R¹ with the exception of the meaning hydrogen,
R⁵ represents a carbocyclic or heterocyclic aromatic group,
R⁶ is hydrogen, alkyl, aryl, arylalkyl, hydroxyalkyl, haloalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, acylaminoalkyl, alkylsulfonylaminoalkyl, arylsulfonylaminoalkyl, mercaptoalkyl, alkylthioalkyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, alkylthio or alkylsulfonic acid;
R⁷ denotes 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,
R⁸ and R⁹ 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,
R¹⁰ and R¹¹ 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,
R¹² denotes alkyl or aryl,
X = NH or O,
Y = NH or S,
Z = NH, S or O and
W = amino, alkylamino, dialkylamino or alkylthio, with the condition that

• a) R⁴ is not the methyl group if R¹, R², R³, R⁶ are hydrogen and R⁵ 3-indolyl or (6-hydroxy) -3-indolyl or R¹, R², R³ are hydrogen, R⁶ methyl and R⁵ (2-methyl) - 3-indolyl and R¹, R², R³ is hydrogen, R⁶ phenyl and R⁵ (2-phenyl) -3-indolyl,
• b) R⁴ is not the benzyl group when R¹, R², R³, R⁶ is hydrogen, R⁵ is 3-indolyl and
• c) R⁴ is not the benzyloxymethyl group,

and their pharmacologically acceptable salts. 2. Process for the preparation of compounds of formula I. wherein
R¹ is hydrogen, an optionally acylated colohydrate residue, a saturated or unsaturated, straight-chain or branched, unsubstituted or mono- or polysubstituted substituted C₁-C₁₀ aliphatic radical,
wherein the substituents halogen, cyano, azido, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carboxy, alkoxycarbonyl, amidino, isothiocyanato, dimethylphosphonyl, optionally substituted C₂-C₇-cycloalkyl, optionally substituted aryl, optionally substituted hetaryl or a group of the formula mean,
R² and R³ 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,
R⁴ 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 -OR⁷ or, -NR⁸R⁹, or the same meaning as R¹ with the exception of the meaning hydrogen,
R⁵ represents a carbocyclic or heterocyclic aromatic group,
R⁶ is hydrogen, alkyl, aryl, arylalkyl, hydroxyalkyl, haloalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, acylaminoalkyl, alkylsulfonylaminoalkyl, arylsulfonylaminoalkyl, mercaptoalkyl, alkylthioalkyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, alkylthio or alkylsulfonic acid;
R⁷ denotes 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,
R⁸ and R⁹ 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,
R¹⁰ and R¹¹ 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,
R¹² denotes alkyl or aryl,
X = NH or O,
Y = NH or S,
Z = NH, S or O and
W = amino, alkylamino, dialkylamino or alkylthio, with the condition that

• a) R⁴ is not the methyl group if R¹, R², R³, R⁶ are hydrogen and R⁵ 3-indolyl or (6-hydroxy) -3-indolyl or R¹, R², R³ are hydrogen, R⁶ methyl and R⁵ (2-methyl) - 3-indolyl and R¹, R², R³ is hydrogen, R⁶ phenyl and R⁵ (2-phenyl) -3-indolyl,
• b) R⁴ is not the benzyl group when R¹, R², R³, R⁶ is hydrogen, R⁵ is 3-indolyl and
• c) R⁴ is not the benzyloxymethyl group,

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

• a) a compound of the general formula III, in which R¹, R², R³, R⁵ and R⁶ have the abovementioned meanings, with a compound of the general formula IV or IVa, R⁴-NH₂ (IV) or R⁴-NH₃⁺A ^- (IVa) in R⁴ the abovementioned meanings has 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 R¹, R², R³, R⁴ and R⁶ have the meanings given above, with a compound of the general formula VI, in which R² ', R³' and R⁶ 'have the meanings given above and "Hal", 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,

and then optionally obtained compounds of Formula I converted into other compounds of formula I and if desired the compounds obtained in pharmacological harmless salts transferred.   3. Medicament containing a compound according to claim 1 in addition to the usual carriers and auxiliaries. 4. Use of compounds according to claim 1 for the preparation of medicines for the treatment of immune diseases or allergic diseases.