DE4005970A1 - NEW TRISUBSTITUTED MALEINIMIDES, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS - Google Patents

Abstract

Compounds of 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 or allergic diseases.

Description

The present invention relates to new trisubstituted Derivatives of maleimide of the general formula I

in which 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, carboxamido, amidino, isothiocyanato, dimethylphosphonyl, C₃-C₇-cycloalkyl, optionally substituted, aryl, optionally substituted, hetaryl, optionally substituted, or a group of formula

mean,
R² and R³ may be the same or different and are hydrogen, halogen, alkyl, hydroxy, alkoxy, aryloxy, arylalkyloxy, haloalkyl, nitro, amino, acylamino, monoalkylamino, dialkylamino, acyloxy, carboxy, carboxamido, cyano, alkoxycarbonyl, alkylthio, alkylsulfinyl, alkylsulfonyl or together mean methylenedioxy,
R⁴ is a C₃-C₇-cycloalkyl radical which is optionally substituted by hydroxyl or alkoxy groups, an optionally substituted aryl radical, an optionally substituted hetaryl radical, cyano, amidino, aminocarbonylamino, a radical of the formula -OR, or,
-NR⁸R⁹ means, or has the same meaning as R¹,
R⁵ is an unsubstituted or substituted bicyclic heteroaromatic or a radical of the formula

means, or has the same meaning as R¹ with the exception of the meaning "carbohydrate residue",
R⁶ is hydrogen, alkyl, aryl, arylalkyl, hydroxyalkyl, haloalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, acylaminoalkyl, alkylsulfonylaminoalkyl, arylsulfonylaminoalkyl, mercaptoalkyl, alkylthioalkyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, alkylthio or alkylthio or alkylthio or
R⁷ is hydrogen, a straight-chain or branched alkyl, alkenyl or alkynyl radical, an optionally substituted C₃-C₇cycloalkyl radical, an optionally substituted aryl radical, an optionally substituted hetaryl radical (optionally hydrogenated or partially hydrogenated), an arylalkyl radical, a hetarylalkyl radical, alkoxycarbonylalkyl, carboxyalkyl, Means acyl, alkylthioalkyl, mercaptoalkyl, hydroxyalkyl or alkoxyalkyl,
R⁸ and R⁹ can be the same or different and are hydrogen, alkyl, aryl, hetaryl, arylalkyl, hetarylalkyl or acyl, alkyl or arylsulfonyl, or together with the nitrogen can form a saturated or unsaturated three- to seven-membered ring which can also form further heteroatoms can contain and is optionally substituted,
R¹⁰ denotes alkyl or aryl,
R¹¹ and R¹² may be the same or different and denote hydrogen, alkyl, arylalkyl, 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,
R¹³, R¹⁴, R¹⁵, R¹⁶ and R¹⁷ can be identical or different and mean acyl or have the same meaning as R¹¹ and R¹²,
n = 0, 1 or 2,
Y = NH or O,
Y = NH or S,
Z = NH, S or O and
W = amino, alkylamino, dialkylamino or alkylthio, with the condition that
R⁵ is not an aromatic monocyclic group of formula (c)
as well as pharmacologically acceptable salts of acidic or basic compounds of the general formula I.

Compounds with R⁵ = aromatic monocyclic groups of Formula (c) are described in EP-A-3 28 026 or of the general Formula includes.

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, isopropyl and butyl,
Alkenyl alone or in combination a straight-chain or branched C₃-C₇ alkenyl group such as allyl, methylallyl, isopentenyl, n-hexenyl, n-decenyl, in particular allyl,
Alkynyl alone or in combination a straight-chain or branched C₃-C₇alkynyl group such as propargyl, butynyl, n-hexynyl, n-decynyl, in particular propargyl,
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 alone or in combination a straight-chain or branched C₁-C₇ alkane carboxylic acid residue such as formyl, acetyl, propionyl, isopropionyl, butyryl, isobutyryl, pentanoyl, hexanoyl and heptanoyl, in particular formyl, acetyl, propionyl and butyryl,
Aryl, alone or in combination, the phenyl group, which can optionally carry one or more, preferably 1-3, substituents, such as halogen, alkyl, hydroxy, alkoxy, benzyloxy, haloalkyl, nitro, amino, acylamino, mono- or dialkylamino, cyano, methylenedioxy, Alkylthio, alkylsulfinyl, alkylsulfonyl, alkoxycarbonyl, aminocarbonyl, mono- or dialkylaminocarbonyl,
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, imidazolyl, tetrazolyl, thiazolyl, benzothienyl, benzothiazolyl, indolyl, benzotriazolidolyl, benzimiazolylol Furanyl, especially imidazolyl, furanyl, thienyl, pyridyl, indolyl and benzimidazolyl; the substituted hetaryl radical carries one or more, preferably 1-3, substituents such as halogen, alkyl, hydroxy, alkoxy, haloalkyl, nitro, amino, acylamino, mono- or dialkylamino and cyano,
Haloalkyl is an alkyl radical which carries one or more halogen atoms, the radicals chloromethyl and trifluoromethyl being preferred,
Halogen fluorine, chlorine or bromine,
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, propargyl, butinyl, n- Hexynyl, n-decynyl, 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 or R¹³ and R¹⁴ or R¹⁶ and R¹⁷ together with the nitrogen, to which they are bound can form are preferred the aziridine, the pyrrolidine, the pyrroline and the Piperidine ring, especially the pyrrolidine ring. The heteroatoms, the rings can contain 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 bicyclic heteroaromatic R⁵ (with 1-3 heteroatoms each) consists of two 5- or 6- condensed together membered aromatic groups which are unsubstituted or substituted are, e.g. B. with one or more, preferably 1-3 Substituents from the group of halogen, alkyl, hydroxy, Alkoxy, haloalkyl, nitro, amino, acylamino, mono- and dialkylamino,  Mercapto, alkylthio, alkylsulfinyl and alkylsulfonyl.

Examples of bicyclic heteroaromatics R⁵ are purine residues such as purinyl, 9-xanthine, 9-guanyl, 9-adenyl, 6-mercapto-9- adenyl, 6-chloro-9-purinyl and 6-hydroxy-9-purinyl, also 4- Aza-1-benzimidazolyl and 7-aza-1-indolyl.

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

• a) a compound of general formula II in which R¹, R², R³, R⁵ and R⁶ have the abovementioned meanings, with a compound of the general formula III or IIIaR⁴-NH₂ (III) or R⁴-NH₃⁺A ^- (IIIa) in which R⁴ has the abovementioned meanings and "A ^- " means an acid anion such as chloride, bromide, carbonate, sulfate or acetate, or
• b) a compound of the general formula IV in which R¹, R², R³, R⁴ and R⁶ have the abovementioned meanings, with a compound of the general formula VM-R⁵ (V) in which R⁵ has the abovementioned meaning and "M" denotes an alkali metal, or
• c) in the special case when R⁵ is an aliphatic radical of Above definition means a connection of the Formula IV with an organometallic derivative of the general Formula V, in which "M" is a metal such as lithium or Copper means, implements, or
• d) a compound of the general formula VI H-R⁵ (VI) where R⁵ is a radical of the formula (a), (b) with n = 0, (c), (g) or (h) means with a compound of the general Formula IV implements, or
• e) a compound of general formula I in which R¹ Hydrogen means that nitrogen is substituted accordingly, or
• f) a compound of general formula I in which R⁴ Hydrogen is substituted, corresponding to nitrogen,
• g) if desired, one in a compound of formula I. functionally converts existing reactive substituents and
• h) if desired, an acidic or basic compound of general formula I with a base or acid in a transferred pharmaceutically usable salt.

Compounds of general formula II can be prepared by either
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
a compound of general formula VIII

in which R¹, R², R³ and R⁶ have the meanings given above with a compound of general formula IX

R⁵-CH₂-COOH (IX)

in which R⁵ has the meanings given above,
implements.

Compounds of the general formula IV can be prepared by using a compound of the general formula X

in which R⁴ has the meaning given above, with a compound of the general formula XI

in which R², R³ and R⁶ have the meanings given above and "Hal" means halogen such as chlorine, bromine or iodine.

Organometallic compounds of the general formula V, where R⁵ is an aliphatic radical of the definition given above means can be carried out in a manner known per se Metallation of compounds of general formula XII

Hal-R⁵ (XII)

with, for example, lithium or by metal remodeling Compound of the general formula XIII

Li-R⁵ (XIII)

with copper halides or by deprotonation CH-acidic Compounds of formula VI with strong bases such as alkyl lithium or alkali hydrides (see e.g. Houben-Weyl, methods of Organic Chemistry, Vol. 13: "Organometallic Compounds", Georg Thieme Verlag, Stuttgart 1970-1984).

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 XIV

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 3,4-dibromomaleimide a compound of general formula XV

R⁴-Abg (XV)

in which R⁴ has the meanings given above and "Abg" means 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.

1) (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. Acta, 31, 470 [1948])

The reaction of a compound of formula II with a compound of formula III or IIIa is carried out in a manner known per se ¹) ²) ³) either by reacting the two reactants between 100 ° C and 250 ° C, preferably at 180 ° C, or in an inert solvent such as pyridine, methylene chloride, chloroform or dimethylformamide, with or without addition one tert. Nitrogen base such as triethylamine and at a temperature between room temperature and the boiling point of the solvent used.

The Grignard reaction to a compound of the general Formula IV between a compound of formula X and one those of the formula XI can be used in a manner known per se perform, e.g. B. in an inert solvent such as benzene, Toluene, tetrahydrofuran or ether and at one temperature between room temperature and reflux temperature of the reaction mixture. A compound of the formula XI in situ starting from indole or a substituted indole and a suitable alkyl magnesium halide, such as methyl magnesium bromide or iodide prepared in a manner known per se.

The reaction of a compound of formula IV with an alkali metal derivative Formula V is based on 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 is preferably in situ by deprotonating a compound of formula VI with an alkali metal hydride, preferably sodium hydride.

In the special case of the implementation of a compound of formula IV with an organometallic compound of the formula V, this is initially in situ in an inert solvent such as tetrahydrofuran or ether under protective gas at a temperature between -70 ° C and 0 ° C generated before using a compound of formula IV under the usual conditions of working with organometallic Adds reagents (see e.g. Houben-Weyl, Methods der Organic Chemistry, Vol. 13: "Organometallic Compounds", Georg Thieme Verlag, Stuttgart 1970-1984).

The reaction of a compound of formula IV with a compound of the formula VI is carried out in a suitable solvent such as methanol, ethanol, pyridine, dimethylformamide, tetrahydrofuran or ether without or with the addition of a suitable auxiliary base such as tertiary amines at temperatures between Room temperature and reflux temperature of the reaction mixture. Under certain circumstances, a solvent can also be dispensed with. The Component of formula IV then serves both as a solvent for a compound of formula IV, as well as a reactant.

The N substitution of a compound of formula I in which R¹ Hydrogen means, according to variant e) 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 the presence an acid, e.g. B. p-toluenesulfonic acid at elevated temperature introduce. Furthermore, a compound of formula I, in the R¹ is hydrogen, with an alkyl, an arylalkyl or a hetarylalkyl halide in the presence of a base a compound of formula I in which R¹ is alkyl or aryl or hetaryl is substituted alkyl. The N substitution of a compound of formula I in which R⁴ Hydrogen means, according to variant f) one can in itself perform in a 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 bond 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 g) 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 isothiocyanatoalkyl group convert. You can also an aminoalkyl group in a Convey alkyl group, which is represented by a radical of formula (f) 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 (f) 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 usable salt according to variant h) can by Treatment with a suitable base in a manner known per se be performed. Suitable salts are those of a 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 II from a compound 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 using 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 convert the reaction mixture into a compound of formula VII, and this with a semi-concentrated mineral acid like Treat hydrochloric acid or sulfuric acid.

The reaction of a compound of formula VIII with a compound Formula IX is preferably carried out with 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 XIV with oxalyl chloride to form a compound Formula VIII is carried out in a manner known per se in one inert 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 used as  such are isolated, or in situ with a compound of Formula IX can be converted into a compound of formula II.

The alkylation of 3,4-dibromomaleimide with one compound Formula XV is carried out in a manner known per se that to 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 Formula XV implements.

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

The invention therefore also relates to diastereomers and racemates and the optically active forms of the compounds of the invention of general formula I. Are diastereomers in the Synthesis of the compounds according to the invention, they can by column chromatography in the corresponding racemates be 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 can be used.

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

Surprisingly, it has now been found that compounds of general formula I the proliferation of stimulated human Inhibit spleen cells. You can therefore in the treatment of Immune diseases or organ transplants.  

Compounds of the general formula I also inhibit degranulation basophilic granulocytes and are therefore suitable for drug treatment or prophylaxis of allergic Diseases.

The maleimides of formula I and their salts can be used as medication are used, e.g. B. in the form of pharmaceutical Preparations to be taken orally, e.g. B. in the form of tablets, drages, 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 are administered. For the production 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 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, colors, flavorings, salts for Change in osmotic pressure, buffer, coating agent or antioxidants, and optionally other therapeutic Contain active ingredients.

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

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

• BV 1. 1-methyl-3-isobutyloxy-4- (1- (3-aminopropyl) -5,6-dichloro-3-indolyl) maleimide,
• 2. 1-propyl-3-hydroxy-4- (1- (2-hydroxypropyl) -5-chloro-3- indolyl) maleimide,
• 3. 1-ethyl-3-cyclohexyloxy-4- (1-dimethylaminocarbonyl- methyl-4,5-dichloro-3-indolyl) maleimide,
• 4. 1-isopropyl-3- (4-fluorophenyloxy) -4- (1-pyrrolidinyl- carbonylmethyl-5-fluoro-3-indolyl) maleimide,
• 5. 1-isopentyl-3- (4-methoxyphenyloxy) -4- (1-methylsulfinyl- propyl-5-hydroxy-3-indolyl) maleimide,
• 6. 1-Cyclohexyl-3- (4-pyridinyloxy) -4- (1-methylsulfonyl- propyl-5-methoxy-3-indolyl) maleimide,
• 7. 1-Cyclopropyl-3-methoxycarbonylethyloxy-4- (1- methylcarbonylethyl-5-nitro-3-indolyl) maleimide,
• 8. 1-Cyclopentyl-3-methylcarbonylmethyloxy-4- (1-allyl-5- amino-3-indolyl) maleimide,
• 9. 1-butyl-3-hydroxyethyloxy-4- (1-isohexyl-5-carbonyl-3- indolyl) maleimide,
• 10. 1-benzyl-3-methoxyethyloxy-4- (1-dimethylphosphonyl- methyl-5-ethylamino-3-indolyl) maleimide,
• 11. 1-tert-butyl-3-methylsulfinyl-4- (1-methyl-5- ethyloxycarbonyl-3-indolyl) maleimide,
• 12. 1-octyl-3-methylsulfonyl-4- (1-methyl-5-carboxy-3- indolyl) maleimide,
• 13. 1- (4-trifluoromethyl-phenyl) -3- (N-butyl-N-methyl) -amino- 4- (1- (3-hydroxypropyl) -5-methylthio-3-indolyl) - maleimide,
• 14. 1- (4-Hydroxycyclohexyl) -3- (1-pyrrolidinyl) -4- (1- (3- guanidino-propyl) -5-methylsulfinyl-3-indolyl) - maleimide,
• 15. 1- (4-methoxycyclohexyl) -3-hydroxyamino-4- (1-ethyl-5- methylsulfonyl-3-indolyl) maleimide,  
• 16. 1- (4-pyridinyl) -3-methoxyamino-4- (1- (2-methoxyethyl) -5- pentanoylamino-3-indolyl) maleimide,
• 17. 1-cyanomethyl-3-hydrazino-4- (1- (2-carboxyethyl) -3- indolyl) maleimide,
• 18. 1-amidinomethyl-3-acetyl-4- (1-methyloxycarbonylethyl-3- indolyl) maleimide,
• 19. 1-ethyloxycarbonylmethyl-3-pentyloxy-4- (1-β-D-gluco- pyranosyl-3-indolyl) maleimide,
• 20. 1- (2-ureidoethyl) -3-octyloxy-4- (1- -D-mannopyranosyl-3- indolyl) maleimide,
• 21. 1- (5-methoxypentyl) -3-isopropyl-4- (5-dimethylamino-3- indolyl) maleimide,
• 22. 1- (5-hydroxypentyl) -3-methyl-4- (3-indolyl) maleimide,
• 23. 1- (3-dimethylaminopropyl) -3-cyclohexyl-4- (3-indolyl) - maleimide,
• 24. 1-benzyl-4- (1- (3-azidopropyl) -3-indolyl) maleimide,
• 25. 4- (1- (2-cyanoethyl) -3-indolyl) maleimide,
• 26. 1-Acetamido-3- (9-xanthine) -4- (1- (2-fluoroethyl) -3- indolyl) maleimide,
• 27. 1- (4-fluorophenyl) -3- (9-guanyl) -4- (3-indolyl) - maleimide,
• 28. 1- (4-methoxyphenyl) -3- (9-adenyl) -4- (5-fluoro-3-indolyl) - maleimide,
• 29. 1- (3,4-dichlorophenyl) -3- (6-mercapto-9-purinyl) -4- (3- indolyl) maleimide,
• 30. 1-cyano-3- (9-purinyl) -4- (5-cyano-3-indolyl) maleimide,
• 31. 1- (5-hydroxypentyl) -3-ethyloxy-4- (3-indolyl) - maleimide,
• 32. 1-isopropyl-3-dimethylamino-4- (5-carboxamido-3- indolyl) maleimide,
• 33. 1-isopropyl-3-butyloxy-4- (1-acetyl-3-indolyl) - maleimide,  
• 34. 1-ethynyl-3-isopropyloxy-4- (3-indolyl) maleimide,
• 35. 1-ethyl-3-ethyloxy-4- (1- (2-ureidoethyl) -3-indolyl) - maleimide,
• 36. 1-ethyl-3-ethyloxy-4- (1- (2-guanidinoethyl) -3-indolyl) - maleimide,
• 37. 1-Cyclopropyl-3- (6-mercapto-9-purinyl) -4- (3-indolyl) - maleimide,
• 38. 1-methyl-3- (6-acetamido-9-purinyl) -4- (1-acetamido-3- indolyl) maleimide,
• 39. 1-butyl-3- (6-methyl-9-purinyl) -4- (3-indolyl) - maleimide,
• 40. 1-methyl-3-N-hydroxy-N-methylamino-4- (3-indolyl) - maleimide,
• 41. 1-Methyl-3- (1- (2,2-dimethyl) hydrazino-4- (3-indolyl) - maleimide,
• 42. 1-methyl-3-acetyl-4- (3-indolyl) maleimide,
• 43. 1-methyl-3-phenylsulfinyl-4- (3-indolyl) maleimide,
• 44. 1-methyl-3-phenylsulfonyl-4- (3-indolyl) maleimide,
• 45. 1-ethyl-3-methyloxy-4- (1- (2-bromethyl) -3-indolyl) - maleimide,
• 46. 1-methyl-3-methyloxy-4- (1- (2-methylaminoethyl) -3- indolyl maleinimide,
• 47. 1-methyl-3-methyloxy-4- (1- (2-hydroxyethyloxymethyl) -3- indolyl) maleimide,
• 48. 1-methyl-3-ethyloxy-4- (1- (2-methylsulfinylethyl) -3- indolyl) maleimide,
• 49. 1-methyl-3-ethyloxy-4- (1- (2-methylsulfonylethyl) -3- indolyl) maleimide,
• 50. 1-methyl-3-butyl-4- (1- (2-thiocyanatoethyl) -2-methyl-3- indolyl) maleimide,
• 51. 1-Methyl-3- (N- (2-pyrrolidonyl) -4- (3-indolyl) - maleimide.

Example 1 1-methyl-3-phenylthio-4- (3-indolyl) maleimide

a) To a suspension of 67 mg (2.7 mmol) 97 percent. NaH in 10 ml Section. Dimethylformamide is added dropwise at room temperature 0.28 ml (2.7 mmol) thiophenol. The mixture is stirred for 30 min and then adds a solution of 1 g (2.5 mmol) of 1-methyl-3- bromo-4- (1- (tert-butyloxycarbonyl) -3-indolyl) maleimide slowly add. The reaction mixture is at room temperature stirred and followed by thin layer chromatography. After 1.5 h the solution is i. Vac. concentrated, the residue taken up in ethyl acetate and the organic phase several times extracted with water. After drying and concentrating the organic phase, the crude product by column chromatography purified on silica gel (eluent: ethyl acetate / heptane = 1: 5).

0.7 g of 1-methyl-3-phenylthio-4- (1-tert-butyloxycarbonyl) - 3-indolyl) maleimide, mp 138-141 ° C.

b) 1 g of product 1a) in 15 ml of trifluoroacetic acid dissolved and stirred for 30 min at room temperature. The solution then i. Vac. concentrated and the residue from Ether / isohexane crystallized. 0.72 g of 1-methyl 3-phenylthio-4- (3-indolyl) maleimide, mp 225 ° C.

The following were prepared analogously to Example 1:

• 1.1 1-methyl-3-methoxy-4- (3-indolyl) maleimide, mp 162- 164 ° C.
• 1.2 1-Methyl-3-ethoxy-4- (3-indolyl) maleimide, mp 175 ° C.
• 1.3 1-methyl-3-phenyloxy-4- (3-indolyl) maleimide, mp. 202- 205 ° C.
• 1.4 1-methyl-3- (4-pyridinyl) thio-4- (3-indolyl) maleimide, Mp 190-192 ° C.
• 1.5 1-methyl-3- (2-4,5-dihydro-thiazolyl) thio-4- (3-indolyl) - maleimide, mp 134-136 ° C.
• 1.6 1-methyl-3-dimethylamino-4- (3-indolyl) maleimide, mp. 90 ° C (dec.).  
• 1.7 1-Methyl-3- (1-piperidinyl) -4- (3-indolyl) -maleimide, mp. 248 ° C.
• 1.8 1-methyl-3-phenylamino-4- (3-indolyl) maleimide, mp. 232- 235 ° C.
• 1.9 1-methyl-3- (4-trifluoromethyl-phenylamino) -4- (3-indolyl) - maleimide, mp 219-221 ° C.
• 1.10 1-methyl-3- (1- (4-diphenyl-methyl) -piperazinyl) -4- (3- indolyl) maleimide, mp 228-230 ° C.
• 1.11 1-methyl-3- (N-phenylacetamido-4- (3-indolyl) maleimide, Mp 110 ° C (dec.).
• 1.12 1-Methyl-3- (N-benzylamino) -4- (3-indolyl) maleimide, mp. 172-174 ° C.
• 1.13 1-Methyl-3- (N-phenyl-4- (3-phenyl-5-methyl-isoxazoloyl)) - amino-4- (3-indolyl) maleimide, mp <250 ° C.
• 1.14 1-methyl-3-methylamino-4- (3-indolyl) maleimide, mp. 255 ° C.
• 1.15 1-Methyl-3- (N-ethoxycabonylmethyl) amino-4- (3-indolyl) - maleimide, mp 220-225 ° C.
• 1.16 1-methyl-3-bis (ethoxycarbonyl) methyl-4- (3-indolyl) - maleimide, mp 47 ° C.
• 1.17 1-methyl-3- (4-aza-1-benzimidazolyl) -4- (3-indolyl) - maleimide, mp 230-235 ° C.
• 1.18 1-methyl-3- (6-chloro-9-purinyl) -4- (3-indolyl) maleimide, Mp <250 ° C.
• 1.19 1-methyl-3- (6-amino-9-purinyl) -4- (3-indolyl) maleimide, Mp <250 ° C.
• 1.20 1-Methyl-3- (7-aza-1-indolyl) -4- (3-indolyl) maleimide, mp. 150 ° C (dec.).

Example 2 1-methyl-3-butyl-4- (3-indolyl) maleimide

0.5 g is added to a flamed 100 ml three-necked flask (2.64 mmol) CuI. Flame several times and leave in nitrogen Cool electricity. After 15 ml of abs. Tetrahydrofuran added, the mixture is cooled to -40 ° C. You give 5.28 mmol butyllithium in hexane slowly using a disposable syringe add and stir the mixture for 20 min at -40 ° C. After you have cooled the cuprate solution to -66 ° C, you add a solution of 0.72 g (1.77 mmol) of 1-methyl-3-bromo-4- (1- (tert.- butyloxycarbonyl) -3-indolyl) maleimide in 10 ml abs. Tetrahydrofuran added dropwise within 30 min.

The mixture is stirred for 1.5 h and slowly allowed to warm to -40 ° C and adds 0.68 ml nitrobenzene (R.K. Olsen et al., J. Org. Chem. 47, 4605 (1982)). The approach is slowly starting Warmed to room temperature and then poured into 125 ml of 3N HCl. Man extracts the aqueous phase with ethyl acetate, dries the united phases and narrow i. Vac. to dry up. The residue is taken up in 10 ml of trifluoroacetic acid and at 2 h Leave room temperature. One constricts i. Vac. one, takes the backlog twice in toluene and the solvent distilled each i. Vac. The crude product is taken up in ethyl acetate, the organic phase washed with water, dried and the Residue after concentration i. Vac. column chromatography Silica gel (eluent: dichloromethane) cleaned. You get 0.11 g of 1-methyl-3-butyl-4- (3-indolyl) maleimide, mp. 156- 158 ° C.

Example 3 1-methyl-3-amino-4- (3-indolyl) maleimide

a) The solution of 6 g (15 mmol) of 1-methyl-3-bromo-4- (1-tert.- butyloxycarbonyl) -3-indolyl) maleimide in 150 ml methanolic Ammonia and 10 ml of dimethylformamide is 4 h on Heated to reflux. Then the reaction mixture is cooled the precipitate is suctioned off, one after the other washed with a little methanol and ether and i. Vac. dried. 3.1 g of 1-methyl-3-amino-4 - ((1-tert.- butyloxycarbonyl) -3-indolyl) maleimide, mp. 182 ° C.  

b) 350 mg (1.02 mmol) of compound 3a) are on for 20 min Heated at 220 ° C. The cooled flask content is 5 ml Methanol stirred, the precipitate suctioned off with ether washed and dried in a high vacuum. 200 mg are obtained 1-Methyl-3-amino-4- (3-indolyl) maleimide, mp 190 ° C. (Dec.).

Example 4 1-methyl-3-acetamido-4- (3-indolyl) maleimide

a) The solution of 340 mg (1 mmol) of compound 3a) in 5 ml Acetic anhydride is heated at 70 ° C for 12 h. Then will the reaction solution with 20 ml of water and the aqueous mixture extracted with methylene chloride. To Drying the organic phase over sodium sulfate and The solvent is stripped off by column chromatography cleaned (eluent: ethyl acetate / isohexane 1: 1). 300 mg of 1-methyl-3-acetylamino-4 - ((1- tert-butyloxycarbonyl) -3-indolyl) maleimide, mp 155- 160 ° C (dec.).

b) 250 mg of compound 4a) are heated to 180 ° C. for 20 min. The cooled flask contents are stirred with 10 ml ether, the precipitate is suctioned off and i. Vac. dried. Man receives 180 mg of 1-methyl-3-acetylamino-4- (3-indolyl) - maleimide of mp <250 ° C.

Example 5 1-methyl-3- (4-trifluoromethyl-anilino) -4- (1-acetyl-3-indolyl) - maleimide

The solution of 425 mg (1.1 mmol) of 1-methyl-3- (4-trifluoromethyl- anilino) -4- (3-indolyl) maleimide in 5 ml acetic anhydride is 1.5 h heated at 120 ° C. The reaction solution then becomes Evaporated to dryness, the residue taken up in 10 ml of ethyl acetate and the organic solution with sat. Sodium hydrogen carbonate Solution washed. After drying the organic phase over sodium sulfate and stripping off the solvent Crude product purified by column chromatography (eluent: Ethyl acetate / isohexane 1: 3). 320 mg of 1-methyl-3- (4- trifluoromethyl-anilino) -4- (1-acetyl-3-indolyl) maleimide from Mp 212-215 ° C.

Claims (4)

1. Compounds of formula I. wherein R¹ is hydrogen, an optionally acylated carbohydrate radical, a saturated or unsaturated, straight-chain or branched, unsubstituted or mono- or polysubstituted C₁-C₁₀ aliphatic radical,
wherein the substituents halogen, cyano, azido, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carboxy, alkoxycarbonyl, carboxamido, amidino, isothiocyanato, dimethylphosphonyl, C₃-C₇-cycloalkyl, optionally substituted, aryl, optionally substituted, hetaryl, optionally substituted, or a group of formula mean,
R² and R³ may be the same or different and are hydrogen, halogen, alkyl, hydroxy, alkoxy, aryloxy, arylalkyloxy, haloalkyl, nitro, amino, acylamino, monoalkylamino, dialkylamino, acyloxy, carboxy, carboxymido, cyano, alkoxycarbonyl, alkylthio, alkylsulfinyl, alkylsulfonyl or together mean methylenedioxy,
R⁴ is a C₃-C₇-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 -OR⁷ or,
-NR⁸R⁹ means, or has the same meaning as R¹,
R⁵ is an unsubstituted or substituted bicyclic heteroaromatic or a radical of the formula means, or has the same meaning as R¹ with the exception of the meaning "carbohydrate residue",
R⁶ is hydrogen, alkyl, aryl, arylalkyl, hydroxyalkyl, haloalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, acylaminoalkyl, alkylsulfonylaminoalkyl, arylsulfonylaminoalkyl, mercaptoalkyl, alkylthioalkyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, alkylthio or alkylsulfonic acid;
R⁷ is hydrogen, a straight-chain or branched alkyl, alkenyl or alkynyl radical, an optionally substituted C₃-C₇cycloalkyl radical, an optionally substituted aryl radical, an optionally substituted hetaryl radical (optionally hydrogenated or partially hydrogenated), an arylalkyl radical, a hetarylalkyl radical, alkoxycarbonylalkyl, carboxyalkyl, Means acyl, alkylthioalkyl, mercaptoalkyl, hydroxyalkyl or alkoxyalkyl,
R⁸ and R⁹ can be the same or different and are hydrogen, alkyl, aryl, hetaryl, arylalkyl, hetarylalkyl or acyl, alkyl or arylsulfonyl, or together with the nitrogen can form a saturated or unsaturated three- to seven-membered ring which can also form further heteroatoms can contain and is optionally substituted,
R¹⁰ denotes alkyl or aryl,
R¹¹ and R¹² may be the same or different and denote hydrogen, alkyl, arylalkyl, 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,
R¹³, R¹⁴, R¹⁵, R¹⁶ and R¹⁷ can be identical or different and mean acyl or have the same meaning as R¹¹ and R¹²,
n = 0, 1 or 2,
X = NH or O,
Y = NH or S,
Z = NH, S or O and
W = amino, alkylamino, dialkylamino or alkylthio, with the condition that
R⁵ is not an aromatic monocyclic group of formula (c)
and their pharmacologically acceptable salts. 2. Process for the preparation of compounds of formula I. wherein R¹ is hydrogen, an optionally acylated carbohydrate radical, a saturated or unsaturated, straight-chain or branched, unsubstituted or mono- or polysubstituted C₁-C₁₀ aliphatic radical,
wherein the substituents halogen, cyano, azido, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carboxy, alkoxycarbonyl, carboxamido, amidino, isothiocyanato, dimethylphosphonyl, C₃-C₇-cycloalkyl, optionally substituted, aryl, optionally substituted, hetaryl, optionally substituted, or a group of formula mean,
R² and R³ may be the same or different and are hydrogen, halogen, alkyl, hydroxy, alkoxy, aryloxy, arylalkyloxy, haloalkyl, nitro, amino, acylamino, monoalkylamino, dialkylamino, acyloxy, carboxy, carboxamido, cyano, alkoxycarbonyl, alkylthio, alkylsulfinyl, alkysulfonyl or together mean methylenedioxy,
R⁴ is a C₃-C₇-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 -OR⁷ or,
-NR⁸R⁹ means, or has the same meaning as R¹,
R⁵ is an unsubstituted or substituted bicyclic heteroaromatic or a radical of the formula means, or has the same meaning as R¹ with the exception of the meaning "carbohydrate residue",
R⁶ is hydrogen, alkyl, aryl, arylalkyl, hydroxyalkyl, haloalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, acylaminoalkyl, alkylsulfonylaminoalkyl, arylsulfonylaminoalkyl, mercaptoalkyl, alkylthioalkyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, alkylthio or alkylsulfonic acid;
R⁷ is hydrogen, a straight-chain or branched alkyl, alkenyl or alkynyl radical, an optionally substituted C₃-C₇cycloalkyl radical, an optionally substituted aryl radical, an optionally substituted hetaryl radical (optionally hydrogenated or partially hydrogenated), an arylalkyl radical, a hetarylalkyl radical, alkoxycarbonylalkyl, carboxyalkyl, Means acyl, alkylthioalkyl, mercaptoalkyl, hydroxyalkyl or alkoxyalkyl,
R⁸ and R⁹ can be the same or different and are hydrogen, alkyl, aryl, hetaryl, arylalkyl, hetarylalkyl or acyl, alkyl or arylsulfonyl, or together with the nitrogen can form a saturated or unsaturated three- to seven-membered ring which can also form further heteroatoms can contain and is optionally substituted,
R¹⁰ denotes alkyl or aryl,
R¹¹ and R¹² may be the same or different and denote hydrogen, alkyl, arylalkyl, 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,
R¹³, R¹⁴, R¹⁵, R¹⁶ and R¹⁷ can be identical or different and mean acyl or have the same meaning as R¹¹ and R¹²,
n = 0, 1 or 2,
X = NH or O,
Y = NH or S,
Z = NH, S or O and
W = amino, alkylamino, dialkylamino or alkylthio, with the condition that
R⁵ is not an aromatic monocyclic group of the formula (c),
as well as their pharmacologically acceptable salts, characterized in that in a manner known per se

• a) a compound of general formula II in which R¹, R², R³, R⁵ and R⁶ have the abovementioned meanings, with a compound of the general formula III or IIIa, R⁴-NH₂ (III) or R⁴-NH₃⁺A ^- (IIIa) in R⁴ the abovementioned meanings has and "A ^- " means an acid anion such as chloride, bromide, carbonate, sulfate or acetate, or
• b) a compound of the general formula IV in which R¹, R², R³, R⁴ and R⁶ have the meanings given above, with a compound of the general formula VX-R⁵ (V) in which R⁵ has the meaning given above and X is hydrogen, in alkali metal or copper,
  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 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.