WO1991013070A1 - Novel trisubstituted maleinimides, process for their production and medicaments containing these compounds - Google Patents

Novel trisubstituted maleinimides, process for their production and medicaments containing these compounds Download PDF

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WO1991013070A1
WO1991013070A1 PCT/EP1991/000331 EP9100331W WO9113070A1 WO 1991013070 A1 WO1991013070 A1 WO 1991013070A1 EP 9100331 W EP9100331 W EP 9100331W WO 9113070 A1 WO9113070 A1 WO 9113070A1
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radical
optionally substituted
formula
alkyl
aryl
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PCT/EP1991/000331
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German (de)
French (fr)
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Michael Schultz
Christos Tsaklakidis
Rainer Haag
Werner Scheuer
Eberhard Russmann
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Boehringer Mannheim Gmbh
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
    • C07D473/32—Nitrogen atom
    • C07D473/34—Nitrogen atom attached in position 6, e.g. adenine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/40—Heterocyclic compounds containing purine ring systems with halogen atoms or perhalogeno-alkyl radicals directly attached in position 2 or 6

Definitions

  • the present invention relates to new trisubstituted derivatives of maleimide of the general formula I.
  • R1 is hydrogen, acyl, an optionally acylated carbohydrate radical, a saturated or unsaturated, straight-chain or branched, unsubstituted or mono- or polysubstituted, preferably mono- to trisubstituted, C 1 -C 4 -aliphatic radical,
  • R 2 and R 3 may be the same or different and are hydrogen, halogen, alkyl, hydroxy, alkoxy, aryloxy, arylalkyloxy, haloalkyl, nitro, amino, acylamino, monoalkylamino, dialkyla ino, acyloxy, carboxy, carboxamido, cyano, alkoxycar ⁇ bonyl, alkylthio, alkylsulfinyl, alkylsulfonyl or together methylenedioxy,
  • R 4 is a C 3 -C 7 -cycloalkyl radical which is optionally substituted by hydroxyl or alkoxyl groups, an optionally substituted aryl radical, an optionally substituted hetaryl radical, cyano, amidino, aminocarbonylamino, a radical of the formula -OR 7 or,
  • R 5 is an unsubstituted or substituted bicyclic heteroaromatic or a radical of the formula
  • R 6 is hydrogen, alkyl, aryl, arylalkyl, hydroxyalkyl, haloalkyl, a inoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, acylaminoalkyl, alkylsulfonylaminoalkyl, arylsulfonyl-a inoalkyl, mercaptoalkyl, alkylthioalkyl, carboxyalkyl, alkoxycarbonylalkyl, a inocarbonylalkylsulfonyl, alkylthio;
  • R 7 is hydrogen, a straight-chain or branched alkyl, alkenyl or alkynyl radical, an optionally substituted C 3 -C7 cycloalkyl radical, an optionally substituted aryl radical, an optionally substituted hetaryl radical (optionally hydrogenated or partially hydrogenated), an arylalkyl radical, one
  • R 8 and R 9 can be the same or different and denote 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 is still can contain further heteroato e and is optionally substituted,
  • R 10 denotes alkyl or aryl
  • R 11 and R 12 can be the same or different and represent hydrogen, alkyl, arylalkyl, aryl or hetaryl, or together with the nitrogen can form a three- to seven-membered ring which is optionally substituted and can contain further heteroatoms,
  • R 5 is not an aromatic monocyclic group of formula (c)
  • Alkyl alone or in combination a straight-chain or branched C ⁇ -C7-alkyl group such as methyl, ethyl, propyl, butyl, isobutyl, tert.
  • Alkenyl alone or in combination, a straight-chain or branched C 3 -C 7 alkenyl group such as allyl, methylallyl, isopentenyl, n-hexenyl, n-decenyl, in particular allyl,
  • Alkynyl alone or in combination a straight-chain or branched C 3 -C 7 -alkynyl group such as propargyl, butynyl, n-hexynyl, n-decynyl, in particular propargyl,
  • Alkoxy is a Ci-Cs-alkoxy group, such as methoxy, ethoxy,
  • Acyl alone or in combination is a straight-chain or branched C 1 -C 7 -alkanecarboxylic acid residue such as formyl, acetyl, propionyl, isopropionyl, butyryl, isobutyryl, pentanoyl, hexanoyl and heptanoyl, in particular formyl, acetyl, propionyl and butyryl or an aromatic or heteroaromatic, such as aromatic or heteroaromatic Benzoyl, picoloyl and oxazoloyl,
  • 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,
  • substituents such as halogen, alkyl, hydroxy, alkoxy, benzyloxy, haloalkyl, nitro, amino, acylamino, mono- or dialkylamino, cyano, methylenedioxy , Alkylthio, alkylsulfinyl, alkylsulfonyl, alkoxycarbonyl, aminocarbonyl, mono- or dialkylamin
  • 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, indolyl, benzim Benzotriazolyl, 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 chloromethyl and trifluoromethyl radicals being preferred. Halogen fluorine, chlorine or bromine,
  • the optionally mono- or polysubstituted C3-C7-cycloalkyl radical generally bears 1-3 substituents from the group hydroxy or alkoxy.
  • the carbohydrate residue of R 1 means glucopyranosyl, manopyranosyl or ribofuranosyl, in particular glucopyranosyl.
  • the c ⁇ l c 1 0 aliphatic group of R 1 is preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.
  • Three- to seven-membered rings which R 8 and R 9 or R 10 and R11 or R 13 and R 14 or R 16 and R 17 together with the nitrogen to which they are attached can be preferred ⁇ as the aziridine, pyrrolidine, pyrroline and piperidine ring, especially the pyrrolidine ring.
  • the hetero atoms which the rings can contain are nitrogen, sulfur or oxygen. This includes rings such as piperazine, morpholine and thiomorpholine.
  • Substituents of the rings mentioned above are in particular C1-C 3 alkyl and C1-C 3 alkoxyl groups, such as methyl, ethyl or propyl or methoxy, ethoxy or propoxy.
  • a bicyclic heteroaromatic R 5 (each having 1-3 heteroatoms) consists of two 5- or 6-membered aromatic groups which are fused together and which are unsubstituted or substituted, for example 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.
  • bicyclic heteroaromatics R 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, and also 4-aza -1-benzimidazolyl and 7-aza-l-indolyl.
  • R 1 , R 2 , R 3 , R 5 and R 6 have the meanings given above, with a compound of the general formula III or purple.
  • R 4 has the meanings given above and "A ⁇ " denotes an acid anion such as chloride, bromide, carbonate, sulfate or acetate, or
  • R 1 , R 2 , R 3 , R 5 and R 6 have the meanings given above and "M" denotes an alkali metal, brings about a reaction with a concentrated mineral acid, or a compound of the general formula VIII,
  • R 2 , R 3 and R 6 have the meanings given above and "shark” means halogen such as chlorine, bromine or iodine.
  • Organometallic compounds of the general formula V where R 5 is an aliphatic radical of the definition given above, can be prepared in a manner known per se by metalation of compounds of the general formula XII,
  • R 4 has the meanings given above and "Abg" denotes a leaving group from the group of the halogens, such as chlorine, bromine or iodine, or from the group of the sulfonic acid esters, such as tosylate, mesylate or triflate.
  • halogens such as chlorine, bromine or iodine
  • sulfonic acid esters such as tosylate, mesylate or triflate.
  • reaction of a compound of the formula II with a compound of the formula III or lilac is carried out in a manner known per se 1) 2 ) 3 ) either by mixing the two reaction partners between 100 ° C. and 250 ° C., preferably at 180 "C brings to reaction, or in an inert solvent such as pyridine, methylene chloride, chloroform or dimethylformamide, with or without the addition of a tertiary nitrogen base such as triethylamine and a temperature between room temperature and the boiling point of the solvent used.
  • an inert solvent such as pyridine, methylene chloride, chloroform or dimethylformamide
  • the Grignard reaction to a compound of general formula IV between a compound of formula X and one of formula XI can be carried out in a manner known per se, e.g. in an inert solvent such as benzene, toluene, tetrahydrofuran or ether and at a temperature between room temperature and the reflux temperature of the reaction mixture.
  • a compound of the formula XI is expediently prepared in situ from indole or a substituted indole and a suitable alkylmagnesium halide, such as methylmagnesium bromide or iodide, in a manner known per se.
  • the reaction of a compound of formula IV with an alkali metal derivative of formula V is carried out according to conventional methods in an inert solvent such as tetrahydrofuran, ether or dimethylformamide and at a temperature between room temperature and the reflux temperature of the reaction mixture, preferably at 50 ° C.
  • the alkali metal derivative is preferably generated in situ by deprotonation of a compound of formula VI with an alkali metal hydride, preferably sodium hydride.
  • reaction of a compound of formula IV with a compound of 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.
  • a suitable solvent such as methanol, ethanol, pyridine, dimethylformamide, tetrahydrofuran or ether
  • a suitable auxiliary base such as tertiary amines
  • a hydroxyalkyl group R 1 can, for example, be introduced into a compound of the formula I in which R 1 is hydrogen by first converting such a compound into an alkali metal derivative, for example sodium derivative by means of sodium hydride, and then the derivative obtained with a treated the hydroxyalkyl group generating agents, for example an alkylene oxide such as propylene oxide or ethylene oxide.
  • An alkoxyalkyl group R 1 can be introduced by treating a compound of the formula I in which R 1 is hydrogen with a suitable dialkylacetal in the presence of an acid, for example p-toluenesulfonic acid, at elevated temperature. Furthermore, a compound of the formula I in which R 1 is hydrogen can be reacted with an alkyl, an arylalkyl or a hetarylalkyl halide in the presence of a base to give a compound of the formula I in which R 1 is alkyl or alkyl substituted by aryl or hetaryl , are implemented.
  • the variant N) substitution of a compound of the formula I in which R 4 is hydrogen can be carried out in a manner known per se for the N 1 substitution of maleimides, for example a compound of the formula I in which R 4 is hydrogen, in an inert solvent such as dimethyl formamide by means of a base from the group of alkali metal carbonates or hydroxides, such as potassium carbonate or sodium hydroxide, into the corresponding alkali metal derivative, such as potassium or sodium derivative, and convert this as desired i) with an alkyl, arylalkyl or hetarylalkyl halide to give a compound of the formula I in which R 4 is alkyl or alkyl substituted by aryl or hetaryl, or
  • an alkyl halide containing an oxirane ring such as epichlorohydrin
  • an alkyl halide containing an oxirane ring such as epichlorohydrin
  • R 4 is an alkyl radical substituted by an oxirane ring
  • alcohols or mercaptans to give compounds of the formula I in which R 4 is an alkyl radical which is disubstituted by two of the groups hydroxyl, alkoxy, monoalkylamino, dialkylamino and alkylthio.
  • the functional conversions of compounds of the formula I to variant g) can be carried out in a manner known per se. For example, one can reduce a nitro group to the amino group and then alkylate or acylate the latter.
  • An aminoalkyl group can be alkylated, acylated or sulfonylated.
  • An alkylthio or alkylthioalkyl group can be oxidized to the alkylsulfinyl or alkylsulfinylalkyl group and the latter, if desired, to the alkylsulfonyl or alkylsulfonylalkyl group.
  • An alkoxycarbonylalkyl group can be saponified to form the carboxyalkyl group and the latter can then be amidated or transesterified.
  • An alkoxyalkyl group can be converted into an alkylthioalkyl or arylthioalkyl group using an alkanethiol or thiophenol.
  • An azidoalkyl group can be converted into an aminoalkyl group by catalytic hydrogenation and the latter in turn can be subjected to functional modifications.
  • an aminoalkyl group can be converted into an isothiocyanatoalkyl group using l, l'-thiocarbonyldiimidazole.
  • An alkylcarbonyloxyalkyl group can be saponified to give the hydroxyalkyl group and the latter can be converted into a haloalkyl or an alkylsulfonyloxyalkyl group in a manner known per se.
  • a hydroxyalkyl group can also be converted to an aminoalkylaminoalkyl group by treatment with trifluoromethanesulfonic anhydride followed by reaction with a suitable diiaoalkane.
  • An alkylsulfonyloxyalkyl group can, for example, be converted into a mono-, di- or trialkylaminoalkyl group by means of a mono-, di- or trialkyla in, into a cyanoalkyl group using an alkali metal cyanide, into an alkylthioalkyl group using an alkali metal alkane thiolate, or into an acylthioalkyl group using an alkali metal thioacylate.
  • a cyanoalkyl group can be converted into an amidinoalkyl group by means of ammonia, an acylthioalkyl group into a mercaptoalkyl group by means of aqueous ammonia, and a benzyloxy-aryl group into a hydroxy-aryl group by hydrogenolysis.
  • the conversion of an acidic compound of the formula I into a pharmaceutically acceptable salt according to variant h) can be carried out in a manner known per se by treatment with a suitable base.
  • suitable salts are those which are derived from an inorganic base, for example sodium, potassium or calcium salts, or from an organic base, such as ethylenediamine or mono- or diethanolamine.
  • the conversion of a basic compound of the formula I into a pharmaceutically usable salt can be accomplished by treatment with a suitable acid in a manner known per se.
  • Suitable Salts are those which are derived from an inorganic acid, for example hydrochlorides, hydrobromides, phosphates or sulfates, or from an organic acid, for example acetates, citrates, fumarates, tartrates, maleates, methanesulfonates or p-toluenesulfonates.
  • a compound of the formula II is prepared from a compound of the formula VII in a manner known per se (W. Steglich, Tetrahedron, 44. (10), 2887).
  • a concentrated alkali metal solution such as sodium hydroxide solution or potassium hydroxide solution
  • an alcohol such as methanol, ethanol or propanol
  • the reaction of a compound of formula VIII with a compound of formula IX is preferably carried out in an inert solvent such as methylene chloride, dichloroethane or ether with the addition of an acid-binding agent, suitably a tertiary amine such as a trialkylamine, e.g. Triethyl- in and at a temperature between -30 * C and 40 * C, preferably at room temperature.
  • an indole of the general formula XIV with oxalyl chloride to give a compound of the formula VIII takes place in a manner known per se in an inert solvent such as methylene chloride, diethyl ether or dimethylformamide and at a temperature between -20 ° C. and the reflux temperature of the reaction mixture, preferably at O ' C.
  • the resulting compound of formula VIII can be isolated as such, or reacted in situ with a compound of formula IX to a compound of formula II.
  • the alkylation of 3,4-dibromomaleimide with a compound of formula XV 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 O'C and reflux temperature of the solvent used in the alkali metal derivative and this is reacted with an alkylating agent of formula XV.
  • a base such as sodium or potassium hydroxide, sodium or potassium alcoholate, sodium or potassium carbonate or hydride
  • an inert solvent such as Methanol, ethanol, ether, tetrahydrofuran or dimethylformamide
  • the compounds of general formula I according to the invention can also contain asymmetric carbon atoms.
  • the invention therefore also relates to diastereomers, racemates and the optically active forms of the compounds of the general formula I according to the invention. If diastereomers are obtained in the synthesis of the compounds according to the invention, these can be separated in the corresponding racemates by column chromatography.
  • optically active compounds can be prepared from their racemic mixtures by methods known per se.
  • Basic or acidic racemic mixtures can e.g. are split into their optically active forms via their diastereomeric salts.
  • racemate resolution e.g. Tartaric acid, malic acid, camphoric acid, camphorsulfonic acid, dibenzoyltartaric acid, cinchonin, phenethylain, brucine or quinine can be used.
  • Neutral racemic mixtures can be separated chromatographically into the optically active forms on chiral phases.
  • Compounds of the general formula I furthermore inhibit the degradation of basophilic granulocytes and are therefore suitable for the medicinal treatment or prophylaxis of allergic diseases.
  • the maleimides of the formula I and their salts can be used as medicaments, for example in the form of pharmaceutical preparations which can be administered orally, for example in the form of tablets, dragées, hard or soft gelatin capsules, solutions, emulsions or suspensions. They can also be administered rectally, for example in the form of suppositories, or parenterally, for example in the form of injection solutions.
  • these compounds can be processed in therapeutically inert inorganic and organic carriers.
  • Examples of such carriers for tablets, dragées and hard gelatin capsules are lactose, corn starch or derivatives thereof talc, stearic acid or its salts.
  • Suitable carriers for the production of solutions and syrups are water, polyols, sucrose, invert sugar and glucose.
  • Suitable carriers for injection solutions are water, alcohols, polyols, glycerol and vegetable oils.
  • Suitable carriers for suppositories are vegetable or hardened oils. Waxes, fats and semi-liquid polyols.
  • the pharmaceutical preparations can also contain preservatives, solvents, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavoring agents, salts for changing the osmotic pressure, buffers, coating agents or antioxidants, and, if appropriate, other therapeutic agents.
  • the maleimides of the formula I and their salts can be used in the treatment or prophylaxis of diseases, especially inflammatory, allergic or immunological diseases. Dosage can vary widely, but is generally in the range of about 5 to 500 mg / day for oral administration to adults, although the latter may be increased if necessary. The daily dose can be administered in a single dose or in multiple doses. The following connections are preferred for the purposes of the registration:
  • the aqueous phase is extracted with ethyl acetate, the combined phases are dried and evaporated down i.Vac. to dry up.
  • the residue is taken up in 10 ml of trifluoroacetic acid and left at room temperature for 2 hours. You narrow i.Vak. one, takes up the residue twice in toluene and distills the solvent in each case i.Vak.
  • the crude product is taken up in ethyl acetate, the organic phase is washed with water, dried and the residue after concentration i.Vak. purified by column chromatography on silica gel (mobile phase: dichloromethane). Obtained 0:11 g of l-methyl-3-butyl-4- (3-indolyl) maleimide, mp. 156- 158 C. ⁇
  • the trisubstituted maleimides described in the patent application influence the proliferation and / or the function of human lymphocytes.
  • a comparison of the concentration in the different test systems necessary for half-maximum inhibition shows the selectivity of the tested substances
  • Peripheral human blood is mixed with heparin (Lique in, Röche, Switzerland; 2500 IU / 100 ml blood) and diluted with the same volume of PBS without calcium and magnesium (Boehringer Mannheim, Mannheim).
  • the diluted blood is centrifuged for 10 minutes at 800 xg and at room temperature to separate platelets in the serum.
  • the cell precipitate is resuspended in the original volume and 30 ml of this is carefully pipetted onto 20 ml of lymphocyte separation medium (Boehringer Mannheim, Mannheim) in 50 ml Falcon centrifuge tubes (type 2070, Becton Dickinson, New Jersey).
  • the ' PBL are pipetted off from the separation layer and washed once with completed RPMI 1640 (RPMI 1640 from Boehringer Mannheim, Mannheim; additives: 10% by volume inactivated fetal calf serum, 2 mmol glutamine, 1 % BME vitamins, 10,000 IU penicillin and 10 mg streptomycin per 1 1 medium; all from Boehringer Mannheim, Mannheim).
  • the PBL are adjusted to 1 x 10 6 cells / ml.
  • 200 / ul of the PBL cell suspension (2 x 10 5 PBL) are pipetted into 0.25 ⁇ g / ml PWM (pokeweed mitogen, Boehringer Mannheim, Mannheim) in flat-bottom microtiter plates. After adding the substances to be tested, the mixture is incubated for 48 hours (37 ° C., 5% CO 2 , 95% relative atmospheric humidity). 18 hours before the end of the incubation, radiothymidine is added and, after the cells have been harvested, the radioactivity incorporated is determined. As described above, the IC 50 is calculated from these values.
  • 2 x 10 5 PBL are incubated in 200 / ul complemented RPMI 1640 medium with 0.2 / u / ml PWM in microtiter plates at 37 ° C, 5% C0 and 95% relative humidity for nine days.
  • the culture supernatant is then harvested and the concentration of human IgG is determined from this using an ELISA method.
  • TGI Tumor growth inhibition test
  • a chemically-induced (methylcholanthrene A) mouse fibrosarcom cell line is propagated at weekly intervals.
  • the cells are washed twice and adjusted to a cell density of 5 ⁇ 10 4 cells / ml in the above culture medium. 200 / ul of this cell suspension are added to the wells of a microtiter plate and incubated with the compounds to be tested for 48 hours at 37 ° C., 5% CO and 95% relative atmospheric humidity. Radiothymidine is added three hours before the incubation period expires and the amount of radioactivity incorporated is determined after harvesting. The test was evaluated as described above.
  • Table 1 summarizes the IC 50 values for seven examples from the patent application.
  • General cytotoxic or cytolytic compounds inhibit both the allogen-induced, the mitogen-induced and the spontaneous proliferation of eukaryotic at comparable concentrations. It can be seen from Table 1 that for half maximal inhibition of proliferation in most cases different concentrations are absolutely necessary. It is particularly striking, however, that concentrations which are sometimes more than 100 times lower than those necessary for inhibiting spontaneous tumor cell proliferation are sufficient for half-maximal inhibition of immunoglobulin synthesis.
  • IC 50 values are given in / ug / ml.
  • MLR mixed lymphocyte culture
  • PWK pokeweed-mitogen-induced lymphocyte proliferation
  • TGI tumor growth inhibition test
  • IgG PWM-induced IgG synthesis

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Abstract

Compounds of formula (I) in which the substituents R1 - R6 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

Neue trisubstituierte Maleini ide, Verfahren zur ihrer Herstellung sowie Arzneimittel, die diese Verbindungen enthalten New trisubstituted maleinides, processes for making them, and drugs containing these compounds
Die vorliegende Erfindung betrifft neue trisubstituierte Derivate des Maleinimids der allgemeinen Formel IThe present invention relates to new trisubstituted derivatives of maleimide of the general formula I.
Figure imgf000003_0001
worin
Figure imgf000003_0001
wherein
R1 Wasserstoff, Acyl, einen gegebenenfalls acylierten Kohlen- hydratrest, einen gesättigten oder ungesättigten, geradkettigen oder verzweigten, unsubstituierten oder ein- oder mehrfach, bevorzugt ein- bis dreifach substituierten C^-Cio aliphatischen Rest bedeutet,R1 is hydrogen, acyl, an optionally acylated carbohydrate radical, a saturated or unsaturated, straight-chain or branched, unsubstituted or mono- or polysubstituted, preferably mono- to trisubstituted, C 1 -C 4 -aliphatic radical,
wobei die Substituentenbeing the substituents
Halogen, Cyano, Azido, Alkylsulfinyl, Alkylsulfonyl, Arylsul- fonyl, Carboxy, Alkoxycarbonyl, Carboxamido, Amidino, Isothio- cyanato, Dimethylphosphonyl, C3-C7-Cycloalkyl, gegebenenfalls substituiert, Aryl, gegebenenfalls substituiert, Hetaryl, gegebenenfalls substituiert, oder eine Gruppe der FormelHalogen, cyano, azido, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carboxy, alkoxycarbonyl, carboxamido, amidino, isothiocyanato, dimethylphosphonyl, C 3 -C 7 -cycloalkyl, optionally substituted, aryl, optionally substituted, hetaryl, optionally substituted, or one Group of the formula
^R8 RII Z^ R8 R II Z
-0R7, -S(0)nR7, -N , -X-S02-R10 -C-N , od. -Y- O VRl2-0R 7 , -S (0) n R 7 , -N, -X-S0 2 -R 10 -CN, or. -Y- O V Rl2
(a) (b) (c) (d) (e) (f)(a) (b) (c) (d) (e) (f)
bedeuten, R2 und R3 gleich oder verschieden sein können und Wasserstoff, Halogen, Alkyl, Hydroxy, Alkoxy, Aryloxy, Arylalkyloxy, Haloalkyl, Nitro, A ino, Acylamino, Monoalkylamino, Dial- kyla ino, Acyloxy, Carboxy, Carboxamido, Cyano, Alkoxycar¬ bonyl, Alkylthio, Alkylsulfinyl, Alkylsulfonyl oder gemeinsam Methylendioxy bedeuten,mean, R 2 and R 3 may be the same or different and are hydrogen, halogen, alkyl, hydroxy, alkoxy, aryloxy, arylalkyloxy, haloalkyl, nitro, amino, acylamino, monoalkylamino, dialkyla ino, acyloxy, carboxy, carboxamido, cyano, alkoxycar ¬ bonyl, alkylthio, alkylsulfinyl, alkylsulfonyl or together methylenedioxy,
R4 einen gegebenenfalls durch Hydroxy- oder Alkoxylgruppen substituierten C3-C7-Cyloalkylrest, einen gegebenenfalls substituierten Arylrest, einen gegebenenfalls substi¬ tuierten Hetarylrest, Cyano, Amidino, Aminocarbonylamino, einen Rest der Formel -OR7 oder,R 4 is a C 3 -C 7 -cycloalkyl radical which is optionally substituted by hydroxyl or alkoxyl groups, an optionally substituted aryl radical, an optionally substituted hetaryl radical, cyano, amidino, aminocarbonylamino, a radical of the formula -OR 7 or,
-NR8R9 bedeutet, oder die gleiche Bedeutung wie R1 be¬ sitzt,-NR 8 R 9 , or has the same meaning as R 1 ,
R5 einen unsubstituierten oder substituierten bicyclischen Heteroaromaten oder einen Rest der FormelR 5 is an unsubstituted or substituted bicyclic heteroaromatic or a radical of the formula
33
//
-OR7, -S(0)nR7, -N-OR 7 , -S (0) n R 7 , -N
\\
R9R9
(a) (b) (c)(a) (b) (c)
OR13 R16 ZOR 13 R 16 Z
/ / II/ / II
-N , -N-N od. Y-C-W-N, -N-N or Y-C-W
\ I \\ I \
R14 R15 R17 R 14 R 15 R 17
(g) (n) (f) bedeutet, oder die gleiche Bedeutung wie R1 mit der Ausnahme der Bedeutung "Kohlenhydratrest" besitzt,(g) (n) (f) means, or has the same meaning as R 1 with the exception of the meaning "carbohydrate residue",
R6 Wasserstoff, Alkyl, Aryl, Arylalkyl, Hydroxyalkyl, Halo- alkyl, A inoalkyl, Monoalkylaminoalkyl, Dialkylaminoalkyl, Acylaminoalkyl, Alkylsulfonylaminoalkyl, Arylsulfonyl- a inoalkyl, Mercaptoalkyl, Alkylthioalkyl, Carboxyalkyl, Alkoxycarbonylalkyl, A inocarbonylalkyl, Alkylthio oder Alkylsulfinyl;R 6 is hydrogen, alkyl, aryl, arylalkyl, hydroxyalkyl, haloalkyl, a inoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, acylaminoalkyl, alkylsulfonylaminoalkyl, arylsulfonyl-a inoalkyl, mercaptoalkyl, alkylthioalkyl, carboxyalkyl, alkoxycarbonylalkyl, a inocarbonylalkylsulfonyl, alkylthio;
R7 Wasserstoff, einen geradkettigen oder verzweigten Alkyl—, Alkenyl- oder Alkinylrest, einen gegebenenfalls substituierten C3-C7-Cycloalkylrest, einen gegebenenfalls substituierten Arylrest, einen gegebenenfalls substituierten Hetarylrest (gegebenenfalls hydriert oder teilhydriert) , einen Arylalkylrest, einenR 7 is hydrogen, a straight-chain or branched alkyl, alkenyl or alkynyl radical, an optionally substituted C 3 -C7 cycloalkyl radical, an optionally substituted aryl radical, an optionally substituted hetaryl radical (optionally hydrogenated or partially hydrogenated), an arylalkyl radical, one
Hetarylalkylrest, Alkoxycarbonylalkyl, Carboxyalkyl, Acyl, Alkylthioalkyl, Mercaptoalkyl, Hydroxyalkyl oder Alkoxyalkyl bedeutet,Is hetarylalkyl, alkoxycarbonylalkyl, carboxyalkyl, acyl, alkylthioalkyl, mercaptoalkyl, hydroxyalkyl or alkoxyalkyl,
R8 und R9 gleich oder verschieden sein können und Wasserstoff, Alkyl, Aryl, Hetaryl, Arylalkyl, Hetarylalkyl oder Acyl, Alkyl-oder Arylsulfonyl bedeuten, oder zusammen mit dem Stickstoff einen gesättigten oder ungesättigten drei-bis siebengliedrigen Ring bilden können, der noch weitere Heteroato e enthalten kann und gegebenenfalls substituiert ist,R 8 and R 9 can be the same or different and denote 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 is still can contain further heteroato e and is optionally substituted,
R10 Alkyl oder Aryl bedeutet,R 10 denotes alkyl or aryl,
R11 und R12 gleich oder verschieden sein können und Wasser¬ stoff, Alkyl, Arylalkyl, Aryl oder Hetaryl bedeuten, oder zusammen mit dem Stickstoff einen drei- bis siebengliedri¬ gen Ring bilden können, der gegebenenfalls substituiert ist und weitere Heteroatome enthalten kann,R 11 and R 12 can be the same or different and represent hydrogen, alkyl, arylalkyl, aryl or hetaryl, or together with the nitrogen can form a three- to seven-membered ring which is optionally substituted and can contain further heteroatoms,
R13, R14, R15, R16 und R17 gleich oder verschieden sein können und Acyl bedeuten oder die gleiche Bedeutung wie R11 und R12 besitzen, n = 0, 1 oder 2, X = NH oder O, Y = NH oder S z = NH, S oder 0 und w = Amino, Alkylamino, Dialkylamino oder Alkylthio bedeutet, mit der Bedingung, daßR 13 , R 14 , R 15 , R 16 and R 17 can be the same or different and mean acyl or have the same meaning as R 11 and R 12 , n = 0, 1 or 2, X = NH or O, Y = NH or S z = NH, S or 0 and w = amino, alkylamino, dialkylamino or alkylthio, with the condition that
R5 nicht eine aromatische monocyclische Gruppe der Formel (c) istR 5 is not an aromatic monocyclic group of formula (c)
sowie pharmakologisch unbedenkliche Salze von sauren oder basi¬ schen Verbindungen der allgemeinen Formel I.as well as pharmacologically acceptable salts of acidic or basic compounds of the general formula I.
Verbindungen mit R5 = aromatische monocyclische Gruppen der Formel (c) sind im EP-A-328,026 beschrieben bzw. von der all¬ gemeinen Formel umfaßt.Compounds with R 5 = aromatic monocyclic groups of the formula (c) are described in EP-A-328,026 or encompassed by the general formula.
Im Rahmen der Erfindung bedeutet in allen FällenIn the context of the invention means in all cases
Alkyl allein oder in Kombination eine geradkettige oder verzweigte Cχ-C7-Alkylgruppe, wie Methyl, Ethyl, Propyl, Butyl, Isobutyl, tert. Butyl, Amyl, Isoamyl, Hexyl und Heptyl, insbesondere Methyl, Ethyl, iso- Propyl und Butyl,Alkyl alone or in combination a straight-chain or branched Cχ-C7-alkyl group, such as methyl, ethyl, propyl, butyl, isobutyl, tert. Butyl, amyl, isoamyl, hexyl and heptyl, especially methyl, ethyl, iso-propyl and butyl,
Alkenyl allein oder in Kombination eine geradkettige oder verzweigte C3-C7-Alkenylgruppe wie Allyl, Methyl- allyl, Isopentenyl, n-Hexenyl, n-Decenyl, insbeson¬ dere Allyl,Alkenyl, alone or in combination, a straight-chain or branched C 3 -C 7 alkenyl group such as allyl, methylallyl, isopentenyl, n-hexenyl, n-decenyl, in particular allyl,
Alkinyl allein oder in Kombination eine geradkettige oder verzweigte C3-C7-Alkinylgruppe wie Propargyl, Butinyl, n-Hexinyl, n-Decinyl, insbesondere Propar¬ gyl,Alkynyl alone or in combination a straight-chain or branched C 3 -C 7 -alkynyl group such as propargyl, butynyl, n-hexynyl, n-decynyl, in particular propargyl,
Alkoxy eine Ci-Cs-Alkoxygruppe, wie Methoxy, Ethoxy,Alkoxy is a Ci-Cs-alkoxy group, such as methoxy, ethoxy,
Propoxy, Isopropoxy, Butoxy, Isobutoxy, tert. Butoxy und Pentoxy, insbesondere Methoxy, Ethoxy, Isopro- poxy, Butoxy und tert. Butoxy,Propoxy, isopropoxy, butoxy, isobutoxy, tert. Butoxy and pentoxy, especially methoxy, ethoxy, isopropoxy, butoxy and tert. Butoxy,
Acyl allein oder in Kombination einen geradkettigen oder verzweigten Cι-C7-Alkancarbonsäurerest wie Formyl, Acetyl, Propionyl, Isopropionyl, Butyryl, Isobutyryl, Pentanoyl, Hexanoyl und Heptanoyl insbesondere For¬ myl, Acetyl, Propionyl und Butyryl oder einen aromatischen oder heteroaromatischen Säurerest, wie Benzoyl, Picoloyl und Oxazoloyl,Acyl alone or in combination is a straight-chain or branched C 1 -C 7 -alkanecarboxylic acid residue such as formyl, acetyl, propionyl, isopropionyl, butyryl, isobutyryl, pentanoyl, hexanoyl and heptanoyl, in particular formyl, acetyl, propionyl and butyryl or an aromatic or heteroaromatic, such as aromatic or heteroaromatic Benzoyl, picoloyl and oxazoloyl,
Aryl allein oder in Kombination die Phenylgruppe, die gegebenenfalls einen oder mehrere, vorzugsweise 1-3 Substituenten tragen kann, wie Halogen, Alkyl, Hydroxy, Alkoxy, Benzyloxy, Haloalkyl, Nitro, A ino, Acylamino, Mono- oder Dialkylamino, Cyano, Methylendioxy, Alkylthio, Alkylsulfinyl, Alkylsulfo- nyl, Alkoxycarbonyl, Aminocarbonyl, Mono- oder Dial- kylaminocarbonyl,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 eine aromatische 5- oder 6-gliedrige heterocyclische Gruppe, die gewünschtenfalls einen ankondensierten Benzolring enthält, wie Pyridyl, Pyrimidyl, Pyra- zinyl, Thienyl, Oxazolyl, Pyrazolyl, Imidazolyl, Tetrazolyl, Thiazolyl, Benzothienyl, Benzothiazolyl, Indolyl, Benzimidazolyl, Indazolyl, Benzotriazolyl, Furanyl, insbesondere Imidazolyl, Furanyl, Thienyl, Pyridyl, Indolyl und Benzimidazolyl; der substi¬ tuierte Hetarylrest trägt einen oder mehrere, vor¬ zugsweise 1-3 Substituenten wie Halogen, Alkyl, Hydroxy, Alkoxy, Haloalkyl, Nitro, Amino, Acylamino, Mono- oder Dialkylamino und 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, indolyl, benzim Benzotriazolyl, 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 einen Alkylrest, der ein oder mehrere Halogenatome trägt, wobei die Reste Chlormethyl und Trifluormethyl bevorzugt sind. Halogen Fluor, Chlor oder Brom,Haloalkyl is an alkyl radical which carries one or more halogen atoms, the chloromethyl and trifluoromethyl radicals being preferred. Halogen fluorine, chlorine or bromine,
C3-C7-Cycloal yl Cyclopropyl, Cyclobutyl, Cyclopentyl, Cyclo- hexyl, Cycloheptyl, insbesondere Cyclopropyl, Cyclo¬ pentyl und Cyclohexyl; der gegebenenfalls ein- oder mehrfach substituierte C3-C7-Cycloalkylrest trägt in der Regel 1-3 Substituenten aus der Gruppe Hydroxy oder Alkoxy.C 3 -C 7 cycloal yl cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, in particular cyclopropyl, cyclopentyl and cyclohexyl; the optionally mono- or polysubstituted C3-C7-cycloalkyl radical generally bears 1-3 substituents from the group hydroxy or alkoxy.
Der Kohlenhydratrest von R1 bedeutet Glucopyranosyl, Mano- pyranosyl oder Ribofuranosyl, insbesondere Glucopyranosyl. Der c l~c10 aliphatische Rest von R1 bedeutet vorzugsweise Methyl, Ethyl, Propyl, Isopropyl, Butyl, Isobutyl, tert. Butyl, Iso- a yl, Isohexyl, n-Hexyl, n-Octyl, n-Decyl, Allyl, Methallyl, Isopentenyl, n-Hexenyl, n-Decenyl, Propargyl, Butinyl, n- Hexinyl, n-Decinyl, insbesondere Methyl, Ethyl, Isobutyl, Iso¬ hexyl, n-Decyl, Allyl, Methallyl, Isopentenyl und Propargyl.The carbohydrate residue of R 1 means glucopyranosyl, manopyranosyl or ribofuranosyl, in particular glucopyranosyl. The c ~ l c 1 0 aliphatic group of R 1 is preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert. Butyl, iso-a yl, isohexyl, n-hexyl, n-octyl, n-decyl, allyl, methallyl, isopentenyl, n-hexenyl, n-decenyl, propargyl, butynyl, n-hexynyl, n-decynyl, especially methyl, Ethyl, isobutyl, isohexyl, n-decyl, allyl, methallyl, isopentenyl and propargyl.
Drei- bis siebengliedrige Ringe, die R8 und R9 bzw. R10 und R11 bzw. R13 und R14 bzw. R16 und R17 zusammen mit dem Stick¬ stoff, an dem sie gebunden sind, bilden können, sind vorzugs¬ weise der Aziridin-, der Pyrrolidin-, der Pyrrolin- und der Piperidinring, insbesondere der Pyrrolidinring. Die Hetero¬ atome, die die Ringe enthalten können, sind Stickstoff, Schwe¬ fel oder Sauerstoff. Es sind hierunter Ringe wie z.B. Piperazin, Morpholin und Thiomorpholin zu verstehen. Substi¬ tuenten der vorstehend genannten Ringe sind insbesondere C1-C3 Alkyl und C1-C3 Alkoxylgruppen, wie z.B. Methyl, Ethyl oder Propyl oder Methoxy, Ethoxy oder Propoxy.Three- to seven-membered rings which R 8 and R 9 or R 10 and R11 or R 13 and R 14 or R 16 and R 17 together with the nitrogen to which they are attached can be preferred ¬ as the aziridine, pyrrolidine, pyrroline and piperidine ring, especially the pyrrolidine ring. The hetero atoms which the rings can contain are nitrogen, sulfur or oxygen. This includes rings such as piperazine, morpholine and thiomorpholine. Substituents of the rings mentioned above are in particular C1-C 3 alkyl and C1-C 3 alkoxyl groups, such as methyl, ethyl or propyl or methoxy, ethoxy or propoxy.
Ein bicyclischer Heteroaromat R5 (mit jeweils 1-3 Heteroato- men) besteht aus zwei miteinander kondensierten 5- oder 6- gliedrigen aromatischen Gruppen, die unsubstituiert oder sub¬ stituiert sind, z.B. mit einem oder mehreren, vorzugsweise 1-3 Substituenten aus der Gruppe von Halogen, Alkyl, Hydroxy, Alkoxy, Haloalkyl, Nitro, Amino, Acylamino, Mono- und Dialkyl¬ amino, Mercapto, Alkylthio, Alkylsulfinyl und Alkylsulfonyl. Beispiele von bicyclischen Heteroaromaten R sind Purinreste wie Purinyl, 9-Xanthinyl, 9-Guanyl, 9-Adenyl, 6-Mercapto-9- adenyl, 6-Chlor-9-purinyl und 6-Hydroxy-9-purinyl, ferner 4- Aza-1-benzimidazolyl und 7-Aza-l-indolyl.A bicyclic heteroaromatic R 5 (each having 1-3 heteroatoms) consists of two 5- or 6-membered aromatic groups which are fused together and which are unsubstituted or substituted, for example 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 R 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, and also 4-aza -1-benzimidazolyl and 7-aza-l-indolyl.
Die erfindungsgemäßen Verbindungen der allgemeinen Formel I können dargestellt werden, indem manThe compounds of general formula I according to the invention can be prepared by:
a) eine Verbindung der allgemeinen Formel II,a) a compound of the general formula II,
Figure imgf000009_0001
Figure imgf000009_0001
in der R1, R2, R3, R5 und R6 die oben genannten Bedeutungen besitzen, mit einer Verbindung der allgemeinen Formel III oder lila.in which R 1 , R 2 , R 3 , R 5 and R 6 have the meanings given above, with a compound of the general formula III or purple.
R4-NH2 (III) oder R4-NH3+A- (lila)R 4 -NH 2 (III) or R 4 -NH 3 + A- (purple)
in der R4 die oben genannten Bedeutungen besitzt und "A~" ein Säureanion wie Chlorid, Bromid, Carbonat, Sulfat oder Acetat bedeutet, umsetzt, oder in which R 4 has the meanings given above and "A ~" denotes an acid anion such as chloride, bromide, carbonate, sulfate or acetate, or
b) eine Verbindung der allgemeinen Formel IV,b) a compound of the general formula IV,
Figure imgf000010_0001
Figure imgf000010_0001
in der R1, R2, R3, R4 und R6 die oben genannten Bedeutungen besitzen, mit einer Verbindung der allgemeinen Formel V,in which R 1 , R 2 , R 3 , R 4 and R 6 have the meanings given above, with a compound of the general formula V,
M-R5 (V)MR 5 (V)
in der R5, die oben genannte Bedeutung besitzt und "M" ein Alkalimetall bedeutet, umsetzt, oderin the R5, which has the meaning given above and "M" denotes an alkali metal, or
c) im speziellen Fall, wenn R5 einen aliphatischen Rest der oben genannten Definition bedeutet, eine Verbindung der Formel IV mit einem metallorganischen Derivat der allge¬ meinen Formel V, in der "M" ein Metall wie Lithium oder Kupfer bedeutet, umsetzt, oderc) in the special case when R 5 is an aliphatic radical of the above definition, a compound of the formula IV is reacted with an organometallic derivative of the general formula V in which "M" is a metal such as lithium or copper, or
d) eine Verbindung der allgemeinen Formel VI,d) a compound of the general formula VI,
H-R5 (VI)HR 5 (VI)
wobei R5 einen Rest der Formel (a) , (b) mit n = 0, (c) , (g) oder (h) bedeutet, mit einer Verbindung der allgemei¬ nen Formel IV umsetzt, oder e) eine Verbindung der allgemeinen Formel I, in der R1 Wasserstoff bedeutet, den Stickstoff entsprechend substi¬ tuiert, oderwherein R 5 is a radical of the formula (a), (b) with n = 0, (c), (g) or (h), with a compound of the general formula IV, or e) a compound of the general formula I in which R 1 is hydrogen, the nitrogen is substituted accordingly, or
f) eine Verbindung der allgemeinen Formel I, in der R4 Wasserstoff ist, den Stickstoff entsprechend, substi¬ tuiert,f) a compound of the general formula I in which R 4 is hydrogen is substituted for the nitrogen,
g) erwünschtenfalls einen in einer Verbindung der Formel I vorhandenen reaktiven Substituenten funktionell umwandelt undg) if desired, functionally converts a reactive substituent present in a compound of the formula I and
h) erwünschtenfalls eine saure bzw. basische Verbindung der allgemeinen Formel I mit einer Base bzw. Säure in ein pharmazeutisch verwendbares Salz überführt.h) if desired, converting an acidic or basic compound of the general formula I with a base or acid into a pharmaceutically usable salt.
Verbindungen der allgemeinen Formel II können dargestellt werden, indem man entwederCompounds of general formula II can be prepared by either
eine Verbindung der allgemeinen Formel VII,a compound of the general formula VII,
Figure imgf000011_0001
in der R1, R2, R3, R5 und R6 die oben genannten Bedeutungen besitzen und "M" ein Alkalimetall bedeutet, mit einer konzen¬ trierten Mineralsäure zur Reaktion bringt, oder eine Verbindung der allgemeinen Formel VIII,
Figure imgf000011_0001
in which R 1 , R 2 , R 3 , R 5 and R 6 have the meanings given above and "M" denotes an alkali metal, brings about a reaction with a concentrated mineral acid, or a compound of the general formula VIII,
Figure imgf000012_0001
Figure imgf000012_0001
in der R1, R2, R3 und R6 die oben genannten Bedeutungen be¬ sitzen mit einer Verbindung der allgemeinen Formel IX,in which R 1 , R 2 , R 3 and R 6 have the meanings given above with a compound of the general formula IX,
R5-CH -COOH (IX)R 5 -CH -COOH (IX)
in der R5 die oben genannten Bedeutungen besitzt,in which R 5 has the meanings given above,
umsetzt.implements.
Verbindungen der allgemeinen Formel IV können hergestellt werden, indem eine Verbindung der allgemeinen Formel X,Compounds of the general formula IV can be prepared by a compound of the general formula X,
Figure imgf000012_0002
Figure imgf000012_0002
in der R4 die oben genannte Bedeutung besitzt, mit einer Ver- bindung der allgemeinen Formel XI,in which R 4 has the meaning given above, with a binding of the general formula XI,
Figure imgf000013_0001
Figure imgf000013_0001
in der R2, R3 und R6 die obengenannten Bedeutungen besitzen und "Hai" Halogen wie Chlor, Brom oder Jod bedeutet, umsetzt.in which R 2 , R 3 and R 6 have the meanings given above and "shark" means halogen such as chlorine, bromine or iodine.
Metallorganische Verbindungen der allgemeinen Formel V, wobei R5 einen aliphatischen Rest der oben angegebenen Definition bedeutet, lassen sich in an sich bekannter Weise durch Metallierung von Verbindungen der allgemeinen Formel XII,Organometallic compounds of the general formula V, where R 5 is an aliphatic radical of the definition given above, can be prepared in a manner known per se by metalation of compounds of the general formula XII,
Figure imgf000013_0002
Figure imgf000013_0002
mit beispielsweise Lithium oder durch Ummetallierung einer Verbindung der allgemeinen Formel XIII,with, for example, lithium or by transmetallation of a compound of the general formula XIII,
Li-R5 (XIII)Li-R 5 (XIII)
mit Kupferhalogeniden oder durch Deprotonierung CH-acider Verbindungen der Formel VI mit starken Basen wie Alkyl-Lithium oder Alkalihydriden gewinnen (s. z.B. Houben-Weyl, Methoden der Organischen Chemie, Bde. 13: "Metallorganische Verbindungen", Georg Thieme Verlag, Stuttgart 1970-1984) . Verbindungen der allgemeinen Formel VII sind aus einer Ver¬ bindung der allgemeinen Formel I, in der R4 Methyl oder Ethyl bedeutet, durch alkalische Hydrolyse erhältlich.with copper halides or by deprotonation of CH-acidic compounds of the formula VI with strong bases such as alkyl lithium or alkali hydrides (see, for example, Houben-Weyl, Methods of Organic Chemistry, Vol. 13: "Organometallic Compounds", Georg Thieme Verlag, Stuttgart 1970-1984 ). Compounds of the general formula VII can be obtained from a compound of the general formula I in which R 4 is methyl or ethyl by alkaline hydrolysis.
Verbindungen der allgemeinen Formel VIII können in an sich bekannter Weise hergestellt werden, indem man ein Indol der allgemeinen Formel XIV,Compounds of the general formula VIII can be prepared in a manner known per se by adding an indole of the general formula XIV,
Figure imgf000014_0001
Figure imgf000014_0001
in der R1, R2, R3 und R6 die oben genannten Bedeutungen be¬ sitzen, mit Oxalylchlorid umsetzt.in which R 1 , R 2 , R 3 and R 6 have the meanings given above, reacted with oxalyl chloride.
Verbindungen der allgemeinen Formel X lassen sich in an sich bekannter Weise durch Alkylierung von 3,4-Dibrommaleinimid mit einer Verbindung der allgemeinen Formel XV,Compounds of the general formula X can be prepared in a manner known per se by alkylation of 3,4-dibromomaleimide with a compound of the general formula XV,
R4-Abg (XV)R 4 Abg (XV)
in der R4 die oben genannten Bedeutungen besitzt und "Abg" eine Abgangsgruppe aus der Gruppe der Halogene, wie Chlor, Brom oder Jod oder aus der Gruppe der Sulfonsäureester wie Tosylat, Mesylat oder Triflat bedeutet.in which R 4 has the meanings given above and "Abg" denotes a leaving group from the group of the halogens, such as chlorine, bromine or iodine, or from the group of the sulfonic acid esters, such as tosylate, mesylate or triflate.
Die Umsetzung einer Verbindung der Formel II mit einer Ver¬ bindung der Formel III oder lila erfolgt in an sich bekannter Weise l)2)3) entweder dadurch, daß man die beiden Reaktions¬ partner zwischen 100*C und 250βC, bevorzugt bei 180"C zur Reak¬ tion bringt, oder in einem inerten Lösungsmittel wie Pyridin, Methylenchlorid, Chloroform oder Dimethylformamid, mit oder ohne Zusatz einer tert. Stickstoffbase wie Triethylamin und bei einer Temperatur zwischen Raumtemperatur und Siedetemperatur des verwendeten Lösungsmittels.The reaction of a compound of the formula II with a compound of the formula III or lilac is carried out in a manner known per se 1) 2 ) 3 ) either by mixing the two reaction partners between 100 ° C. and 250 ° C., preferably at 180 "C brings to reaction, or in an inert solvent such as pyridine, methylene chloride, chloroform or dimethylformamide, with or without the addition of a tertiary nitrogen base such as triethylamine and a temperature between room temperature and the boiling point of the solvent used.
1) B.W. Larner, A.T. Peters, J. Chem. Soc. , 680 (1952) 1 ) BW Larner, AT Peters, J. Chem. Soc. , 680 (1952)
2) S. Ohki, T. Nayasaka, Chem. Phar . Bull., 19., 545 (1971) 2 ) S. Ohki, T. Nayasaka, Chem. Phar. Bull., 19, 545 (1971)
3) M. Aeberli, H. Erlenmeyer, Helv. chim. Aσta, .31, 70 (1948) 3 ) M. Aeberli, H. Erlenmeyer, Helv. Chim. Aσta, .31, 70 (1948)
Die Grignard-Reaktion zu einer Verbindung der allgemeinen Formel IV zwischen einer Verbindung der Formel X und einer solchen der Formel XI kann man in an sich bekannter Weise durchführen, z.B. in einem inerten Lösungsmittel wie Benzol, Toluol, Tetrahydrofuran oder Ether und bei einer Temperatur zwischen Raumtemperatur und Rückflußtemperatur des Reaktions¬ gemisches. Zweckmäßigerweise wird eine Verbindung der Formel XI in situ ausgehend von Indol oder einem substituierten Indol und einem geeigneten Alkylmagnesiumhalogenid, wie Methylmagnesium- bro id oder -jodid in an sich bekannter Weise hergestellt.The Grignard reaction to a compound of general formula IV between a compound of formula X and one of formula XI can be carried out in a manner known per se, e.g. in an inert solvent such as benzene, toluene, tetrahydrofuran or ether and at a temperature between room temperature and the reflux temperature of the reaction mixture. A compound of the formula XI is expediently prepared in situ from indole or a substituted indole and a suitable alkylmagnesium halide, such as methylmagnesium bromide or iodide, in a manner known per se.
Die Umsetzung einer Verbindung der Formel IV mit einem Alkali¬ metallderivat der Formel V erfolgt nach herkömmlichen Methoden in einem inerten Lösungsmittel wie Tetrahydrofuran, Ether oder Dimethylformamid und bei einer Temperatur zwischen Raumtempera¬ tur und Rückflußtemperatur des Reaktionsgemisches, vorzugweise bei 50*C. Das Alkalimetallderivat wird dabei vorzugsweise in situ durch Deprotonierung einer Verbindung der Formel VI mit einem Alkalimetallhydrid, vorzugsweise Natriumhydrid, erzeugt.The reaction of a compound of formula IV with an alkali metal derivative of formula V is carried out according to conventional methods in an inert solvent such as tetrahydrofuran, ether or dimethylformamide and at a temperature between room temperature and the reflux temperature of the reaction mixture, preferably at 50 ° C. The alkali metal derivative is preferably generated in situ by deprotonation of a compound of formula VI with an alkali metal hydride, preferably sodium hydride.
Im speziellen Fall der Umsetzung einer Verbindung der Formel IV mit einer metallorganischen Verbindung der Formel V wird diese zunächst in situ in einem inerten Lösungsmittel wie Tetrahydro¬ furan oder Ether unter Schutzgas bei einer Temperatur zwischen -70*C und 0"C erzeugt, bevor man eine Verbindung der Formel IV unter den üblichen Bedingungen des Arbeitens mit metallorgani¬ schen Reagenzien hinzufügt (s. z.B. Houben-Weyl, Methoden der Organischen Chemie, Bde. 13: "Metallorganische Verbindungen", Georg Thieme Verlag, Stuttgart 1970-1984) . Die Reaktion einer Verbindung der Formel IV mit einer Verbin¬ dung der Formel VI erfolgt in einem geeigneten Lösungsmittel wie Methanol, Ethanol, Pyridin, Dimethylformamid, Tetrahydro¬ furan oder Ether ohne oder mit Zusatz einer geeigneten Hilfs¬ base wie tertiärer Amine bei Temperaturen zwischen Raumtemperatur und Rückflußtemperatur des Reaktionsgemisches. U.U. kann auf ein Lösungsmittel auch verzichtet werden. Die Komponente der Formel VI dient dann sowohl als Lösungsmittel für eine Verbindung der Formel IV, als auch als Reaktionspart¬ ner.In the special case of reacting a compound of formula IV with an organometallic compound of formula V, this is first generated in situ in an inert solvent such as tetrahydrofuran or ether under a protective gas at a temperature between -70 ° C. and 0 ° C. before adds a compound of formula IV under the usual conditions of working with organometallic reagents (see, for example, Houben-Weyl, Methods of Organic Chemistry, Vol. 13: "Organometallic Compounds", Georg Thieme Verlag, Stuttgart 1970-1984). The reaction of a compound of formula IV with a compound of 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 the formula VI then serves both as a solvent for a compound of the formula IV and as a reaction partner.
Die N-Substitution einer Verbindung der Formel I, in der R Wasserstoff bedeutet, nach Variante e) kann man in an sich für die ^-Substitution von Indolen bekannter Weise durchführen. Eine Hydroxyalkylgruppe R1 kann z.B. in eine Verbindung der Formel I, in der R1 Wasserstoff ist, dadurch eingeführt werden, daß man zuerst eine solche Verbindung in ein Alkalimetall¬ derivat, z.B. Natriumderivat mittels Natriumhydrid, überführt, und dann das erhaltene Derivat mit einem die Hydroxyalkylgruppe erzeugende Mittel, z.B. einem Alkylenoxid, wie Propylenoxid oder Ethylenoxid behandelt. Eine Alkoxyalkylgruppe R1 kann man durch Behandlung einer Verbindung der Formel I, in der R1 Wasserstoff ist, mit einem geeigneten Dialkylacetal in Gegen¬ wart einer Säure, z.B. p-Toluolsulfonsäure bei erhöhter Tempe¬ ratur einführen. Weiter kann eine Verbindung der Formel I, in der R1 Wasserstoff bedeutet, mit einem Alkyl-, einem Arylalkyl- oder einem Hetarylalkylhalogenid in Gegenwart einer Base zu einer Verbindung der Formel I, in der R1 Alkyl oder durch Aryl oder Hetaryl substituiertes Alkyl bedeutet, umgesetzt werden. Die N- Substitution einer Verbindung der Formel I, in der R4 Wasserstoff bedeutet, nach Variante f) kann man in an sich bekannter Weise für die N1-Substitution von Maleinimiden durch¬ führen z.B. kann man eine Verbindung der Formel I, in der R4 Wasserstoff ist, in einem inerten Lösungsmittel wie Dimethyl¬ formamid mittels einer Base aus der Gruppe der Alkalimetall- carbonate oder -hydroxide, wie Kaliu carbonat oder Natrium¬ hydroxid in das entsprechende Alkalimetallderivat, wie Kalium¬ oder Natriumderivat überführen, und dieses nach Wunsch i) mit einem Alkyl-, Arylalkyl- oder Hetarylalkylhalogenid zu einer Verbindung der Formel I, in der R4 Alkyl oder durch Aryl oder Hetaryl substituiertes Alkyl bedeutet, umsetzen, oderThe N-substitution of a compound of formula I, in which R is hydrogen, according to variant e) can be carried out in a manner known per se for the ^ substitution of indoles. A hydroxyalkyl group R 1 can, for example, be introduced into a compound of the formula I in which R 1 is hydrogen by first converting such a compound into an alkali metal derivative, for example sodium derivative by means of sodium hydride, and then the derivative obtained with a treated the hydroxyalkyl group generating agents, for example an alkylene oxide such as propylene oxide or ethylene oxide. An alkoxyalkyl group R 1 can be introduced by treating a compound of the formula I in which R 1 is hydrogen with a suitable dialkylacetal in the presence of an acid, for example p-toluenesulfonic acid, at elevated temperature. Furthermore, a compound of the formula I in which R 1 is hydrogen can be reacted with an alkyl, an arylalkyl or a hetarylalkyl halide in the presence of a base to give a compound of the formula I in which R 1 is alkyl or alkyl substituted by aryl or hetaryl , are implemented. The variant N) substitution of a compound of the formula I in which R 4 is hydrogen can be carried out in a manner known per se for the N 1 substitution of maleimides, for example a compound of the formula I in which R 4 is hydrogen, in an inert solvent such as dimethyl formamide by means of a base from the group of alkali metal carbonates or hydroxides, such as potassium carbonate or sodium hydroxide, into the corresponding alkali metal derivative, such as potassium or sodium derivative, and convert this as desired i) with an alkyl, arylalkyl or hetarylalkyl halide to give a compound of the formula I in which R 4 is alkyl or alkyl substituted by aryl or hetaryl, or
ii) mit einem Alkylhalogenid, das einen Oxiranring enthält, wie z.B. Epichlorhydrin zu einer Zwischenverbindung der Formel I, in der R4 einen durch einen Oxiranring substituierten Alkylrest bedeutet, umsetzen, und nach Öffnung des Oxiranringes mit z.B. Mineralsäuren, Ammoniak, Mono- oder Dialkylaminen, Alkoholen oder Merkaptanen zu Verbindungen der Formel I, in der R4 einen durch zwei der Gruppen Hydroxy, Alkoxy, Monoalkylamino, Dial¬ kylamino und Alkylthio disubstituierten Alkylrest bedeutet, gelangen.ii) with an alkyl halide containing an oxirane ring, such as epichlorohydrin to an intermediate compound of the formula I in which R 4 is an alkyl radical substituted by an oxirane ring, and after opening the oxirane ring with, for example, mineral acids, ammonia, mono- or dialkylamines , Alcohols or mercaptans to give compounds of the formula I in which R 4 is an alkyl radical which is disubstituted by two of the groups hydroxyl, alkoxy, monoalkylamino, dialkylamino and alkylthio.
Die funktioneilen Umwandlungen von Verbindungen der Formel I nach Variante g) lassen sich in an sich bekannter Weise durch¬ führen. Z.B. kann man eine Nitrogruppe zur Aminogruppe reduzie¬ ren und letztere dann alkylieren oder acylieren. Eine Aminoalkylgruppe kann alkyliert, acyliert oder sulfonyliert werden. Eine Alkylthio- oder Alkylthioalkylgruppe kann man zur Alkylsulfinyl- bzw. Alkylsulfinylalkylgruppe und letztere gewünschtenfalls zur Alkylsulfonyl- bzw. Alkylsulfonylalkyl- gruppe oxidieren. Eine Alkoxycarbonylalkylgruppe kann zur Carboxyalkylgruppe verseift werden und letztere dann amidiert oder umgeestert werden. Eine Alkoxyalkylgruppe kann man zu einer Alkylthioalkyl- oder Arylthioalkylgruppe mittels eines Alkanthiols oder Thiophenols umsetzen. Eine Azidoalkylgruppe kann durch katalytische Hydrierung in eine Aminoalkylgruppe übergeführt und letztere wiederum funktioneilen Modifikationen unterworfen werden. Z.B. kann man eine Aminoalkylgruppe mittels l,l'-Thiocarbonyldiimidazol in eine Isothiocyanatoalkylgruppe umwandeln. Ferner kann man eine Aminoalkylgruppe in eine Alkylgruppe überführen, die durch einen Rest der Formel (f) substituiert ist, indem man sie, für den Fall, daß Y=NH, Z=NH und W=Amino bedeutet, mittels 3,5-Dimethylpyrazo-l-Carboxamidin umsetzt, oder für den Fall, daß Y=NH, Z=NH und W=Alkylthio bedeutet, mittels eines Dialkyl-N-cyandithioiminocarbonats umsetzt. Eine Alkylcarbonyloxyalkylgruppe kann man zur Hydroxyalkyl¬ gruppe verseifen und letztere in an sich bekannter Weise in eine Haloalkyl- oder eine Alkylsulfonyloxyalkylgruppe über¬ führen. Eine Hydroxyalkylgruppe kann man auch in eine Amino- alkylaminoalkylgruppe überführen durch Behandlung mit Trifluormethansulfonsäureanhydrid gefolgt durch Reaktion mit einem geeigneten Dia inoalkan überführen.The functional conversions of compounds of the formula I to variant g) can be carried out in a manner known per se. For example, one can reduce a nitro group to the amino group and then alkylate or acylate the latter. An aminoalkyl group can be alkylated, acylated or sulfonylated. An alkylthio or alkylthioalkyl group can be oxidized to the alkylsulfinyl or alkylsulfinylalkyl group and the latter, if desired, to the alkylsulfonyl or alkylsulfonylalkyl group. An alkoxycarbonylalkyl group can be saponified to form the carboxyalkyl group and the latter can then be amidated or transesterified. An alkoxyalkyl group can be converted into an alkylthioalkyl or arylthioalkyl group using an alkanethiol or thiophenol. An azidoalkyl group can be converted into an aminoalkyl group by catalytic hydrogenation and the latter in turn can be subjected to functional modifications. For example, an aminoalkyl group can be converted into an isothiocyanatoalkyl group using l, l'-thiocarbonyldiimidazole. It is also possible to convert an aminoalkyl group into an alkyl group which is substituted by a radical of the formula (f) by, in the case where Y = NH, Z = NH and W = amino, by means of 3,5-dimethylpyrazo -l-carboxamidine, or if Y = NH, Z = NH and W = alkylthio, by means of a dialkyl-N-cyano-dithioiminocarbonate. An alkylcarbonyloxyalkyl group can be saponified to give the hydroxyalkyl group and the latter can be converted into a haloalkyl or an alkylsulfonyloxyalkyl group in a manner known per se. A hydroxyalkyl group can also be converted to an aminoalkylaminoalkyl group by treatment with trifluoromethanesulfonic anhydride followed by reaction with a suitable diiaoalkane.
Eine Alkylsulfonyloxyalkylgruppe kann beispielsweise in eine Mono-, Di- bzw. Trialkylaminoalkylgruppe mittels eines Mono-, Di- bzw. Trialkyla in, in eine Cyanalkylgruppe mittels eines Alkalimetallcyanids, in eine Alkylthioalkylgruppe mittels eines Alkalimetallalkanthiolats, oder in eine Acylthioalkylgruppe mittels eines Alkalimetallthioacylats umgewandelt werden.An alkylsulfonyloxyalkyl group can, for example, be converted into a mono-, di- or trialkylaminoalkyl group by means of a mono-, di- or trialkyla in, into a cyanoalkyl group using an alkali metal cyanide, into an alkylthioalkyl group using an alkali metal alkane thiolate, or into an acylthioalkyl group using an alkali metal thioacylate.
Eine Alkylsulfonyloxyalkylgruppe kann man auch mittels Thio- harnstoff in eine Alkylgruppe, die durch einen Rest der Formel (f) , in der Y=_, Z=NH und W=Amino ist, substituiert ist, um¬ wandeln.An alkylsulfonyloxyalkyl group can also be converted by means of thiourea into an alkyl group which is substituted by a radical of the formula (f) in which Y = _, Z = NH and W = amino.
Ferner läßt sich eine Cyanalkylgruppe in eine Amidinoalkyl- gruppe mittels Ammoniak, eine Acylthioalkylgruppe in eine Mercaptoalkylgruppe mittels wässrigem Ammoniak, sowie eine Benzyloxy-arylgruppe in eine Hydroxy-arylgruppe durch Hydro- genolyse umwandeln.Furthermore, a cyanoalkyl group can be converted into an amidinoalkyl group by means of ammonia, an acylthioalkyl group into a mercaptoalkyl group by means of aqueous ammonia, and a benzyloxy-aryl group into a hydroxy-aryl group by hydrogenolysis.
Selbstverständlich haben die obigen Umwandlungen lediglich bei¬ spielhaften Charakter und es können andere dem Fachmann be¬ kannte Modifikationen durchgeführt werden.Of course, the above conversions are only exemplary and other modifications known to those skilled in the art can be made.
Die Überführung einer sauren Verbindung der Formel I in ein pharmazeutisch verwendbares Salz nach Variante h) kann durch Behandlung mit einer geeigneten Base in an sich bekannter Weise durchgeführt werden. Geeignete Salze sind solche die von einer anorganischen Base, z.B. Natrium-, Kalium- oder Calciumsalze, oder von einer organischen Base, wie Aethylendiamin oder Mono- oder Diäthanolamin, abgeleitet sind. Die Umwandlung einer basischen Verbindung der Formel I in ein pharmazeutisch ver¬ wendbares Salz kann durch Behandlung mit einer geeigneten Säure in an sich bekannter Weise bewerkstelligt werden. Geeignete Salze sind solche, die von einer anorganischen Säure, z.B. Hydrochloride, Hydrobromide, Phosphate oder Sulfate, oder von einer organischen Säure, z.B. Acetate, Citrate, Fumarate, Tartrate, Maleate, Methansulfonate oder p-Toluolsulfonate, abgeleitet sind.The conversion of an acidic compound of the formula I into a pharmaceutically acceptable salt according to variant h) can be carried out in a manner known per se by treatment with a suitable base. Suitable salts are those which are derived from an inorganic base, for example sodium, potassium or calcium salts, or from an organic base, such as ethylenediamine or mono- or diethanolamine. The conversion of a basic compound of the formula I into a pharmaceutically usable salt can be accomplished by treatment with a suitable acid in a manner known per se. Suitable Salts are those which are derived from an inorganic acid, for example hydrochlorides, hydrobromides, phosphates or sulfates, or from an organic acid, for example acetates, citrates, fumarates, tartrates, maleates, methanesulfonates or p-toluenesulfonates.
Die Herstellung einer Verbindung der Formel II aus einer Ver¬ bindung der Formel VII erfolgt in an sich bekannter Weise (W. Steglich, Tetrahedron, 44. (10), 2887). Z.B. kann man eine Verbindung der allgemeinen Formel I, in der R4 Methyl oder Ethyl bedeutet, mittels einer konzentrierten Alkalilauge wie Natronlauge oder Kalilauge, allein oder in Kombination mit einem Alkohol, wie Methanol, Ethanol oder Propanol, und bei einer Temperatur zwischen Raumtemperatur und Rückflußtemperatur des Reaktionsgemisches in eine Verbindung der Formel VII über¬ führen, und diese mit einer halbkonzentrierten Mineralsäure wie Salzsäure oder Schwefelsäure behandeln.A compound of the formula II is prepared from a compound of the formula VII in a manner known per se (W. Steglich, Tetrahedron, 44. (10), 2887). For example, you can a compound of general formula I, in which R 4 is methyl or ethyl, by means of a concentrated alkali metal solution such as sodium hydroxide solution or potassium hydroxide solution, alone or in combination with an alcohol such as methanol, ethanol or propanol, and at a temperature between room temperature and Transfer the reflux temperature of the reaction mixture into a compound of formula VII and treat it with a semi-concentrated mineral acid such as hydrochloric acid or sulfuric acid.
Die Reaktion einer Verbindung der Formel VIII mit einer Ver¬ bindung der Formel IX führt man vorzugsweise in einem inerten Lösungsmittel wie Methylenchlorid, Dichlorethan oder Ether unter Zusatz eines Säure-bindenden Mittels, zweckmässigerweise einem tertiären Amin, wie einem Trialkylamin, z.B. Triethyl- a in und bei einer Temperatur zwischen -30*C und 40*C, vorzugs¬ weise bei Raumtemperatur durch. Die Umsetzung eines Indols der allgemeinen Formel XIV mit Oxalylchlorid zu einer Verbindung der Formel VIII erfolgt in an sich bekannter Weise in einem inerten Lösungsmittel wie Methylenchlorid, Diethylether oder Dimethylformamid und bei einer Temperatur zwischen -20*C und Rückflußtemperatur des Reaktionsgemisches, vorzugsweise bei O'C. Die resultierende Verbindung der Formel VIII kann als solche isoliert werden, oder in situ mit einer Verbindung der Formel IX zu einer Verbindung der Formel II umgesetzt werden.The reaction of a compound of formula VIII with a compound of formula IX is preferably carried out in an inert solvent such as methylene chloride, dichloroethane or ether with the addition of an acid-binding agent, suitably a tertiary amine such as a trialkylamine, e.g. Triethyl- in and at a temperature between -30 * C and 40 * C, preferably at room temperature. The reaction of an indole of the general formula XIV with oxalyl chloride to give a compound of the formula VIII takes place in a manner known per se in an inert solvent such as methylene chloride, diethyl ether or dimethylformamide and at a temperature between -20 ° C. and the reflux temperature of the reaction mixture, preferably at O ' C. The resulting compound of formula VIII can be isolated as such, or reacted in situ with a compound of formula IX to a compound of formula II.
Die Alkylierung von 3,4-Dibrommaleinimid mit einer Verbindung der Formel XV wird in an sich bekannter Weise durchgeführt, daß man 3,4-Dibrommaleinimid mittels einer Base wie Natrium- oder Kaliumhydroxid, Natrium- oder Kaliumalkoholat, Natrium- oder Kaliumcarbonat oder -hydrid in einem inerten Lösungsmittel wie Methanol, Ethanol, Ether, Tetrahydrofuran oder Dimethylformamid und bei einer Temperatur zwischen etwa O'C und Rück¬ flußtemperatur des verwendeten Lösungsmittels in das Alkali¬ metallderivat überführt und dieses mit einem Alkylierungsmittel der Formel XV umsetzt.The alkylation of 3,4-dibromomaleimide with a compound of formula XV 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 O'C and reflux temperature of the solvent used in the alkali metal derivative and this is reacted with an alkylating agent of formula XV.
Die erfindungsgemäßen Verbindungen der allgemeinen Formel I können auch asymmetrische Kohlenstoffatome enthalten.The compounds of general formula I according to the invention can also contain asymmetric carbon atoms.
Gegenstand der Erfindung sind daher auch Diastereomere, Racema- te und die optisch aktiven Formen der erfindungsgemäßen Verbin¬ dungen der allgemeinen Formel I. Fallen Diastereomere bei der Synthese der erfindungsgemäßen Verbindungen an, so können diese durch Säulenchromatographie in den entsprechenden Racematen getrennt werden.The invention therefore also relates to diastereomers, racemates and the optically active forms of the compounds of the general formula I according to the invention. If diastereomers are obtained in the synthesis of the compounds according to the invention, these can be separated in the corresponding racemates by column chromatography.
Die optisch aktiven Verbindungen können aus ihren racemischen Mischungen nach an sich bekannten Methoden hergestellt werden.The optically active compounds can be prepared from their racemic mixtures by methods known per se.
Basische oder saure racemische Mischungen können z.B. über ihre diastereomeren Salze in die optisch aktiven Formen gespalten werden. Zur Racematspaltung können z.B. Weinsäure, Apfelsäure, Camphersäure, Camphersulfonsäure, DibenzoylWeinsäure, Cincho- nin, Phenethyla in, Brucin oder Chinin eingesetzt werden.Basic or acidic racemic mixtures can e.g. are split into their optically active forms via their diastereomeric salts. For racemate resolution e.g. Tartaric acid, malic acid, camphoric acid, camphorsulfonic acid, dibenzoyltartaric acid, cinchonin, phenethylain, brucine or quinine can be used.
Neutrale racemische Gemische lassen sich in die optisch aktiven Formen an chiralen Phasen chromatographisch trennen.Neutral racemic mixtures can be separated chromatographically into the optically active forms on chiral phases.
überraschenderweise wurde nun gefunden, daß Verbindungen der allgemeinen Formel I die Proliferation stimulierter humaner Milzzellen hemmen. Sie können daher in der Behandlung von Immunkrankheiten oder zu Organtransplantationen eingesetzt werden.Surprisingly, it has now been found that compounds of the general formula I inhibit the proliferation of stimulated human spleen cells. They can therefore be used in the treatment of immune diseases or for organ transplants.
Verbindungen der allgemeinen Formel I hemmen ferner die Degra- nulation basophiler Granulozyten und eigenen sich daher zur medikamentösen Behandlung oder Prophylaxe von allergischen Erkrankungen. Die Maleinimide der Formel I und ihre Salze können als Medika¬ mente verwendet werden, z.B. in Form von pharmazeutischen Präparaten, die man oral, z.B. in Form von Tabletten, Dragees, Hart- oder Weichgelatinekapseln, Lösungen, Emulsionen oder Suspensionen, verabreichen kann. Sie können auch rektal, z.B. in Form von Suppositorien, oder parenteral, z.B. in Form von Injektionslösungen verabreicht werden. Für die Herstellung von pharmazeutischen Präparaten können diese Verbindungen in thera¬ peutisch inerten anorganischen und organischen Träger verar¬ beitet werden. Beispiele von solchen Trägern für Tabletten, Dragees und Hartgelatinekapseln sind Lactose, Maisstärke oder Derivate davon Talk, Stearinsäure oder dessen Salze. Geeignete Träger für die Herstellung von Lösungen und Sirupen sind Was¬ ser, Polyole, Saccharose, Invertzucker und Glucose. Geeignete Träger für Injektionslösungen sind Wasser, Alkohole, Polyole, Glycerol und pflanzliche Oele. Geeignete Träger für Supposito¬ rien sind pflanzliche oder gehärtete öle. Wachse, Fette und halbflüssige Polyole.Compounds of the general formula I furthermore inhibit the degradation of basophilic granulocytes and are therefore suitable for the medicinal treatment or prophylaxis of allergic diseases. The maleimides of the formula I and their salts can be used as medicaments, for example in the form of pharmaceutical preparations which can be administered orally, for example in the form of tablets, dragées, hard or soft gelatin capsules, solutions, emulsions or suspensions. They can also be administered rectally, for example in the form of suppositories, or parenterally, for example in the form of injection solutions. For the production of pharmaceutical preparations, these compounds can be processed in therapeutically inert inorganic and organic carriers. Examples of such carriers for tablets, dragées and hard gelatin capsules are lactose, corn starch or derivatives thereof talc, stearic acid or its salts. Suitable carriers for the production of solutions and syrups are water, polyols, sucrose, invert sugar and glucose. Suitable carriers for injection solutions are water, alcohols, polyols, glycerol and vegetable oils. Suitable carriers for suppositories are vegetable or hardened oils. Waxes, fats and semi-liquid polyols.
Die pharmazeutischen Präparate können auch Konservierungs¬ mittel, Lösungsmittel, Stabilisierungsmittel, Netzmittel, Emul¬ giermittel, Süßstoffe, Farbstoffe, Geschmacksmittel, Salze zur Veränderung des osmotischen Druckes, Puffer, Überzugsmittel oder Antioxidantien, sowie gegebenenfalls andere therapeutische Wirkstoffe enthalten.The pharmaceutical preparations can also contain preservatives, solvents, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavoring agents, salts for changing the osmotic pressure, buffers, coating agents or antioxidants, and, if appropriate, other therapeutic agents.
Wie weiter oben angegeben können die Maleinimide der Formel I und ihre Salze in der Behandlung oder Prophylaxe von Krankhei¬ ten, speziell von inflammatorischen, allergischen oder immuno¬ logischen Krankheiten verwendet werden. Die Dosierung kann in weiten Bereichen variieren, liegt jedoch im allgemeinen bei oraler Verabreichung an Erwachsene im Bereich von etwa 5 bis 500 mg/Tag, obwohl letzterer Wert, falls nötig, erhöht werden kann. Die tägliche Dosis kann in einer Einzeldosis oder in mehreren Dosen verabreicht werden. Im Sinne der Anmeldung sind folgende Verbindungen bevorzugt:As indicated above, the maleimides of the formula I and their salts can be used in the treatment or prophylaxis of diseases, especially inflammatory, allergic or immunological diseases. Dosage can vary widely, but is generally in the range of about 5 to 500 mg / day for oral administration to adults, although the latter may be increased if necessary. The daily dose can be administered in a single dose or in multiple doses. The following connections are preferred for the purposes of the registration:
BV 1. l-Methyl-3-isobutyloxy-4-(l-(3-aminopropyl)-5,6- dichlor-3-indolyl)- aleinimidBV 1. l-methyl-3-isobutyloxy-4- (l- (3-aminopropyl) -5,6-dichloro-3-indolyl) aleinimide
2. l-Propyl-3-hydroxy-4-(1-(2-hydroxypropyl)-5-chlor-3- indolyl)-maleinimid2. l-Propyl-3-hydroxy-4- (1- (2-hydroxypropyl) -5-chloro-3-indolyl) maleimide
3. l-Ethyl-3-cyclohexyloxy-4-(1-dimethylaminocarbonyl- methyl-4,5-dichlor-3-indolyl)-maleinimid3. l-ethyl-3-cyclohexyloxy-4- (1-dimethylaminocarbonylmethyl-4,5-dichloro-3-indolyl) maleimide
4. l-Isopropyl-3-(4-fluorphenyloxy)-4-(l-pyrrolidinyl- carbonylmethyl-5-fluor-3-indolyl)-maleinimid4. l-Isopropyl-3- (4-fluorophenyloxy) -4- (l-pyrrolidinylcarbonylmethyl-5-fluoro-3-indolyl) maleimide
5. l-Isopentyl-3-(4-methoxyphenyloxy)-4-(1-methylsulfinyl- propyl-5-hydroxy-3-indolyl)-maleinimid5. l-Isopentyl-3- (4-methoxyphenyloxy) -4- (1-methylsulfinyl-propyl-5-hydroxy-3-indolyl) maleimide
6. l-Cyclohexyl-3-(4-pyridinyloxy)-4-(1-methylsulfonyl- propyl-5-methoxy-3-indolyl)-maleinimid6. l-Cyclohexyl-3- (4-pyridinyloxy) -4- (1-methylsulfonylpropyl-5-methoxy-3-indolyl) maleimide
7. l-Cyclopropyl-3-methoxycarbonylethyloxy-4-(1- methylcarbonylethyl-5-nitro-3-indolyl)-maleinimid7. l-Cyclopropyl-3-methoxycarbonylethyloxy-4- (1-methylcarbonylethyl-5-nitro-3-indolyl) maleimide
8. l-Cyclopentyl-3-methylcarbonylmethyloxy-4-(l-allyl-5- amino-3-indolyl)-maleinimid8. l-Cyclopentyl-3-methylcarbonylmethyloxy-4- (l-allyl-5-amino-3-indolyl) maleimide
9. l-Butyl-3-hydroxyethyloxy-4-(l-isohexyl-5-carbonyl-3- indolyl)-maleinimid9. l-Butyl-3-hydroxyethyloxy-4- (l-isohexyl-5-carbonyl-3-indolyl) maleimide
10. l-Benzyl-3-methoxyethyloxy-4-(1-dimethylphosphonyl- methyl-5-ethylamino-3-indolyl)-maleinimid10. l-Benzyl-3-methoxyethyloxy-4- (1-dimethylphosphonylmethyl-5-ethylamino-3-indolyl) maleimide
11. 1-Tert.-butyl-3-methylsulfinyl-4-(l-methyl-5- ethyloxycarbonyl-3-indolyl)-maleinimid 12. l-Octyl-3-methylsulfonyl-4-(l-methyl-5-carboxy-3- indolyl)-maleinimid11. 1-tert-butyl-3-methylsulfinyl-4- (l-methyl-5-ethyloxycarbonyl-3-indolyl) maleimide 12. l-Octyl-3-methylsulfonyl-4- (l-methyl-5-carboxy-3-indolyl) maleimide
13. 1-(4-Trifluormethyl-phenyl)-3-(N-butyl-N-methyl)-amino- 4-(1-(3-hydroxypropyl)-5-methylthio-3-indolyl)- maleinimid13. 1- (4-Trifluoromethyl-phenyl) -3- (N-butyl-N-methyl) -amino- 4- (1- (3-hydroxypropyl) -5-methylthio-3-indolyl) maleimide
14. l-(4-Hydroxycyclohexyl)-3-(l-pyrrolidinyl)-4-(l-(3- guanidino-propyl)-5-methylsulfinyl-3-indolyl)- maleinimid14. l- (4-Hydroxycyclohexyl) -3- (l-pyrrolidinyl) -4- (l- (3-guanidino-propyl) -5-methylsulfinyl-3-indolyl) maleimide
15. 1-(4-Methoxycyclohexyl)-3-hydroxyamino-4-(l-ethyl-5- methy1sulfonyl-3-indolyl)-maleinimid15. 1- (4-Methoxycyclohexyl) -3-hydroxyamino-4- (l-ethyl-5-methylsulfonyl-3-indolyl) maleimide
16. l-(4-Pyridinyl)-3-methoxyamino-4-(l-(2-methoxyethyl)-5- pentanoylamino-3-indolyl)-maleinimid16. 1- (4-pyridinyl) -3-methoxyamino-4- (1- (2-methoxyethyl) -5-pentanoylamino-3-indolyl) maleimide
17. l-Cyanomethyl-3-hydrazino-4-(l-(2-carboxyethyl)-3- indolyl)-maleinimid17. l-Cyanomethyl-3-hydrazino-4- (l- (2-carboxyethyl) -3-indolyl) maleimide
18. l-Amidinomethyl-3-acetyl-4-(l-methyloxycarbonylethyl-3- indolyl)-maleinimid18. l-Amidinomethyl-3-acetyl-4- (l-methyloxycarbonylethyl-3-indolyl) maleimide
19. l-Ethyloxycarbonylmethyl-3-pentyloxy-4-(1-ß-D-gluco- pyranosyl-3-indolyl)-maleinimid19. l-Ethyloxycarbonylmethyl-3-pentyloxy-4- (1-β-D-glucopyranosyl-3-indolyl) maleimide
20. l-(2-Ureidoethyl)-3-octyloxy-4-(l- -D-mannopyranosyl-3- indolyl)-maleinimid20. 1- (2-ureidoethyl) -3-octyloxy-4- (1-- D-mannopyranosyl-3-indolyl) maleimide
21. l-(5-Methoxypentyl)-3-isopropyl-4-(5-dimethylamino-3- indolyl)-maleinimid21. 1- (5-methoxypentyl ) -3-isopropyl-4- (5-dimethylamino-3-indolyl) maleimide
22. 1-(5-Hydroxypentyl)-3-methyl-4-(3-indolyl)-maleinimid22. 1- (5-hydroxypentyl) -3-methyl-4- (3-indolyl) maleimide
23. l-(3-Dimethylaminopropyl)-3-cyclohexyl-4-(3-indolyl)- maleinimid 24. l-Benzyl-4-(l-(3-azidopropyl)-3-indolyl)-maleinimid23. l- (3-Dimethylaminopropyl) -3-cyclohexyl-4- (3-indolyl) maleimide 24. l-Benzyl-4- (l- (3-azidopropyl) -3-indolyl) maleimide
25. 4-(1-(2-Cyanoethyl)-3-indolyl)-maleinimid25. 4- (1- (2-Cyanoethyl) -3-indolyl) maleimide
26. l-Acetamido-3-(9-xanthinyl)-4-(l-(2-fluorethyl)-3- indolyl)-maleinimid26. l-Acetamido-3- (9-xanthine) -4- (l- (2-fluoroethyl) -3-indolyl) maleimide
27. l-(4-Fluorphenyl)-3-(9-guanyl)-4-(3-indolyl)- maleinimid27. l- (4-fluorophenyl) -3- (9-guanyl) -4- (3-indolyl) maleimide
28. l-(4-Methoxyphenyl)-3-(9-adenyl)-4-(5-fluor-3-indolyl)- maleinimid28. 1- (4-methoxyphenyl) -3- (9-adenyl) -4- (5-fluoro-3-indolyl) maleimide
29. 1-(3,4-Dichlorphenyl)-3-(6-mercapto-9-purinyl)-4-(3- indolyl)-maleinimid29. 1- (3,4-dichlorophenyl) -3- (6-mercapto-9-purinyl) -4- (3-indolyl) maleimide
30. l-Cyano-3-(9-purinyl)-4-(5-cyano-3-indolyl)-maleinimid30. l-cyano-3- (9-purinyl) -4- (5-cyano-3-indolyl) maleimide
31. l-(5-Hydroxypentyl)-3-ethyloxy-4-(3-indolyl)- maleinimid31. 1- (5-hydroxypentyl) -3-ethyloxy-4- (3-indolyl) maleimide
32. l-Isopropyl-3-dimethylamino-4-(5-carboxamido-3- indolyl)-maleinimid32. l-isopropyl-3-dimethylamino-4- (5-carboxamido-3-indolyl) maleimide
33. l-Isopropyl-3-butyloxy-4-(l-acetyl-3-indolyl)- maleinimid33. l-Isopropyl-3-butyloxy-4- (l-acetyl-3-indolyl) maleimide
34. l-Ethinyl-3-isopropyloxy-4-(3-indolyl)-maleinimid34. l-Ethynyl-3-isopropyloxy-4- (3-indolyl) maleimide
35. l-Ethyl-3-ethyloxy-4-(l-(2-ureidoethyl)-3-indolyl)- maleinimid35. l-ethyl-3-ethyloxy-4- (l- (2-ureidoethyl) -3-indolyl) maleimide
36. l-Ethyl-3-ethyloxy-4-(1-(2-guanidinoethyl)-3-indolyl)- maleinimid36. l-ethyl-3-ethyloxy-4- (1- (2-guanidinoethyl) -3-indolyl) maleimide
37. l-Cyclopropyl-3-(6-mercapto-9-purinyl)-4-(3-indolyl)- maleinimid 38. l-Methyl-3-(6-acetamido-9-purinyl)-4-(l-acetamido-3- indolyl)-maleinimid37. l-Cyclopropyl-3- (6-mercapto-9-purinyl) -4- (3-indolyl) maleimide 38. l-Methyl-3- (6-acetamido-9-purinyl) -4- (l-acetamido-3-indolyl) maleimide
39. l-Butyl-3-(6-methyl-9-purinyl)-4-(3-indolyl)- maleinimid39. l-Butyl-3- (6-methyl-9-purinyl) -4- (3-indolyl) maleimide
40. l-Methyl-3-N-hydroxy-N-methylamino-4-(3-indolyl)- maleinimid40. l-Methyl-3-N-hydroxy-N-methylamino-4- (3-indolyl) maleinimide
41. l-Methyl-3-(1-(2,2-dimethyl)-hydrazino-4-(3-indolyl)- maleinimid41. l-Methyl-3- (1- (2,2-dimethyl) hydrazino-4- (3-indolyl) maleimide
42. l-Methyl-3-acetyl-4-(3-indolyl)-maleinimid42. l-Methyl-3-acetyl-4- (3-indolyl) maleimide
43. l-Methyl-3-phenylsulfinyl-4-(3-indolyl)-maleinimid43. l-methyl-3-phenylsulfinyl-4- (3-indolyl) maleimide
44. l-Methyl-3-phenylsulfonyl-4-(3-indolyl)-maleinimid44. l-Methyl-3-phenylsulfonyl-4- (3-indolyl) maleimide
45. l-Ethyl-3-methyloxy-4-(l-(2-bromethyl)-3-indolyl)- maleinimid45. l-Ethyl-3-methyloxy-4- (l- (2-bromoethyl) -3-indolyl) maleimide
46. l-Methyl-3-methyloxy-4-(1-(2-methylaminoethyl)-3- indolyl-maleinimid46. l-Methyl-3-methyloxy-4- (1- (2-methylaminoethyl) -3-indolyl-maleimide
47. l-Methyl-3-methyloxy-4-(1-(2-hydroxyethyloxymethyl)-3- indolyl)-maleinimid47. l-Methyl-3-methyloxy-4- (1- (2-hydroxyethyloxymethyl) -3-indolyl) maleimide
48. l-Methyl-3-ethyloxy-4-(l-(2-methylsulfinylethyl)-3- indolyl)-maleinimid48. l-Methyl-3-ethyloxy-4- (l- (2-methylsulfinylethyl) -3-indolyl) maleimide
49. l-Methyl-3-ethyloxy-4-(1-(2- ethylsulfonylethyl)-3- indolyl)-maleinimid49. l-Methyl-3-ethyloxy-4- (1- (2-ethylsulfonylethyl) -3-indolyl) maleimide
50. l-Methyl-3-butyl-4-(l-(2-thiocyanatoethyl)-2-methyl-3- indolyl)-maleinimid50. l-Methyl-3-butyl-4- (l- (2-thiocyanatoethyl) -2-methyl-3-indolyl) maleimide
51. l-Methyl-3-(N-(2-pyrrolidonyl)-4-(3-indolyl)- maleinimid 52. l-Methyl-3-aminocarbonylamino-4-(3-indolyl) -maleinimid, Fp. 210°C.51. l-Methyl-3- (N- (2-pyrrolidonyl) -4- (3-indolyl) maleimide 52. l-Methyl-3-aminocarbonylamino-4- (3-indolyl) maleimide, mp. 210 ° C.
53. l-Methyl-3-amidinothio-4-(3-indolyl) -maleinimid, Fp. 168βC.53. l-methyl-3-amidinothio-4- (3-indolyl) maleimide, mp. 168 β C.
54. l-Methyl-3-(N-methyl-2-diazolylthio) -4-(3-indolyl) - maleinimid, Fp. 224βC.54. l-methyl-3- (N-methyl-2-diazolylthio) -4- (3-indolyl) maleimide, mp. 224 β C.
55. 3-Phenyloxy-4-(3-indolyl) -maleinimid, Fp. 237βC.55. 3-phenyloxy-4- (3-indolyl) maleimide, mp. 237 β C.
56. l-Methyl-3-phenyloxy-4-(l-methyl-3-indolyl) -maleinimid, Fp. 190"C.56. l-Methyl-3-phenyloxy-4- (l-methyl-3-indolyl) maleimide, mp. 190 "C.
Beispiel 1example 1
l-Methyl-3-phenylthio-4-(3-indolyl) -maleinimidl-methyl-3-phenylthio-4- (3-indolyl) maleimide
a) Zu einer Suspension von 67 mg (2.7 mmol) 97proz. NaH in 10 ml abs. Dimethylformamid tropft man bei Raumtemperatur 0.28 ml (2.7 mmol) Thiophenol. Man rührt den Ansatz 30 min und fügt dann eine Lösung von l g (2.5 mmol) l-Methyl-3- brom-4-(1-(tert.-butyloxycarbonyl)-3-indolyl) -maleinimid langsam hinzu. Die Reaktionsmischung wird bei Raumtempera¬ tur gerührt und dünnschichtchromatographisch verfolgt. Nach 1.5 h wird die Lösung i.Vak. eingeengt, der Rückstand in Ethylacetat aufgenommen und die organische Phase mehr¬ mals mit Wasser extrahiert. Nach Trocknen und Einengen der organischen Phase wird das Rohprodukt durch Säulenchroma¬ tographie an Kieselgel gereinigt (Laufmittel: Ethyl- acetat/Heptan = 1:5).a) To a suspension of 67 mg (2.7 mmol) 97 percent. NaH in 10 ml abs. Dimethylformamide is added dropwise at room temperature to 0.28 ml (2.7 mmol) of thiophenol. The mixture is stirred for 30 min and then a solution of 1 g (2.5 mmol) of l-methyl-3-bromo-4- (1- (tert-butyloxycarbonyl) -3-indolyl) -maleimide is slowly added. The reaction mixture is stirred at room temperature and followed by thin layer chromatography. After 1.5 h the solution is evaporated. concentrated, the residue taken up in ethyl acetate and the organic phase extracted several times with water. After drying and concentrating the organic phase, the crude product is purified by column chromatography on silica gel (mobile phase: ethyl acetate / heptane = 1: 5).
Man erhält 0.7 g l-Methyl-3-phenylthio-4-(l-(tert.-butyl¬ oxycarbonyl) -3-indolyl)-maleinimid vom Fp. 138-141βC.0.7 g of l-methyl-3-phenylthio-4- (l- (tert-butyl-oxycarbonyl) -3-indolyl) -maleimide of mp 138-141 β C. are obtained.
b) l g des Produktes la) werden in 15 ml Trifluoressigsäure gelöst und 30 min bei Raumtemperatur gerührt. Die Lösung wird dann i.Vak. eingeengt und der Rückstand aus Ether/Isohexan kristallisiert. Man erhält 0.72 g 1-Methyl- 3-phenylthio-4-(3-indolyl)-maleinimid vom Fp. 225βC.b) lg of product la) are dissolved in 15 ml of trifluoroacetic acid and stirred for 30 min at room temperature. The solution is then i.Vak. concentrated and the residue from Ether / isohexane crystallized. This gives 0.72 g of 1-methyl-3-phenylthio-4- (3-indolyl) maleimide, mp. 225 C. β
Analog zum Beispiel 1 wurden hergestellt:The following were prepared analogously to Example 1:
1.1 1-Methyl-3-methoxy-4-(3-indolyl)-maleinimid, Fp. 162- 164βC.1.1 1-methyl-3-methoxy-4- (3-indolyl) maleimide, m.p. 162-164 β C.
1.2 l-Methyl-3-ethoxy-4-(3-indolyl)-maleinimid, Fp. 175βC.1.2 l-methyl-3-ethoxy-4- (3-indolyl) maleimide, mp. 175 β C.
1.3 l-Methyl-3-phenyloxy-4-(3-indolyl)-maleinimid, Fp. 202- 205"C.1.3 l-methyl-3-phenyloxy-4- (3-indolyl) maleimide, m.p. 202-205 "C.
1.4 l-Methyl-3-(4-pyridinyl)-thio-4-(3-indolyl)-maleinimid , Fp. 190-192βC.1.4 l-methyl-3- (4-pyridinyl) thio-4- (3-indolyl) maleimide, mp. 190-192 β C.
1.5 l-Methyl-3-(2-4,5-dihydro-thiazolyl)-thio-4-(3-indolyl)- aleinimid, Fp. 134-136βC.1.5 l-methyl-3- (2-4,5-dihydro-thiazolyl) thio-4- (3-indolyl) aleinimide, mp. 134-136 β C.
1.6 l-Methyl-3-dimethylamino-4-(3-indolyl)-maleinimid, Fp. 90'C (Zers.) .1.6 l-Methyl-3-dimethylamino-4- (3-indolyl) maleimide, mp 90'C (dec.).
1.7 l-Methyl-3-(l-piperidinyl)-4-(3-indolyl)-maleinimid, Fp. 248'C.1.7 l-Methyl-3- (l-piperidinyl) -4- (3-indolyl) maleimide, mp 248'C.
1.8 l-Methyl-3-phenylamino-4-(3-indolyl)-maleinimid, Fp. 232-1.8 l-methyl-3-phenylamino-4- (3-indolyl) maleimide, mp. 232-
235βC.235 β C.
1.9 l-Methyl-3-(4-trifluormethyl-phenylamino)-4-(3-indolyl)- maleinimid, Fp. 219-221'C.1.9 l-Methyl-3- (4-trifluoromethyl-phenylamino) -4- (3-indolyl) maleimide, m.p. 219-221'C.
1.10 l-Methyl-3-(1-(4-diphenyl-methyl)-piperazinyl)-4-(3- indolyl)-maleinimid, Fp. 228-230βC.1.10 l-methyl-3- (1- (4-diphenyl-methyl) -piperazinyl) -4- (3-indolyl) -maleimide, mp. 228-230 β C.
1.11 l-Methyl-3-(N-phenylacetamido-4-(3-indolyl)-maleinimid, Fp. 110βC (Zers.) .1.11 l-methyl-3- (N-phenylacetamido-4- (3-indolyl) -maleimide, mp. 110 β C (dec.).
1.12 l-Methyl-3-(N-benzylaraino)-4-(3-indolyl)-maleinimid, Fp. 172-174βC. 1.13 l-Methyl-3-(N-phenyl-4-(3-phenyl-5-methyl-isoxazoloyl) )- amino-4-(3-indolyl)-maleinimid, Fp. >250βC.1.12 l-methyl-3- (N-benzylaraino) -4- (3-indolyl) maleimide, mp 172-174 β C. 1.13 l-methyl-3- (N-phenyl-4- (3-phenyl-5-methyl-isoxazoloyl)) - amino-4- (3-indolyl) -maleimide, mp.> 250 β C.
1.14 l-Methyl-3-methylamino-4-(3-indolyl)-maleinimid, Fp. 255°C.1.14 l-methyl-3-methylamino-4- (3-indolyl) maleimide, mp. 255 ° C.
1.15 l-Methyl-3-(N-ethoxycabonylmethyl)-amino-4-(3-indolyl)- maleinimid, Fp. 220-225βC.1.15 l-methyl-3- (N-ethoxycabonylmethyl) amino-4- (3-indolyl) maleimide, mp. 220-225 β C.
1.16 l-Methyl-3-bis-(ethoxycarbonyl)-methyl-4-(3-indolyl)- maleinimid, Fp. 47*C.1.16 l-methyl-3-bis (ethoxycarbonyl) methyl-4- (3-indolyl) maleimide, mp. 47 * C.
1.17 l-Methyl-3-(4-aza-l-benzimidazolyl)-4-(3-indolyl)- maleinimid, Fp. 230-235"C.1.17 l-methyl-3- (4-aza-l-benzimidazolyl) -4- (3-indolyl) maleimide, mp 230-235 "C.
1.18 l-Methyl-3-(6-chlor-9-purinyl)-4-(3-indolyl)-maleinimid, Fp. >250°C.1.18 l-Methyl-3- (6-chloro-9-purinyl) -4- (3-indolyl) -maleimide, mp> 250 ° C.
1.19 l-Methyl-3-(6-amino-9-purinyl)-4-(3-indolyl)-maleinimid, Fp. >250"C.1.19 l-methyl-3- (6-amino-9-purinyl) -4- (3-indolyl) -maleimide, mp> 250 "C.
1.20 l-Methyl-3-(7-aza-l-indolyl)-4-(3-indolyl)-maleinimid, Fp. 150°C (Zers.).1.20 l-methyl-3- (7-aza-l-indolyl) -4- (3-indolyl) maleimide, mp. 150 ° C (dec.).
Beispiel 2Example 2
l-Methyl-3-butyl-4-(3-indolγl)-maleinimidl-methyl-3-butyl-4- (3-indolγl) maleimide
In einen ausgeflammten 100 ml Dreihalskolben gibt man 0.5 g (2.64 mmol) Cul. Man flammt mehrmals aus und läßt im Stick¬ stoff-Strom abkühlen. Nachdem man 15 ml abs. Tetrahydrofuran hinzugefügt hat, kühlt man den Ansatz auf -40'C ab. Man gibt 5.28 mmol Butyllithium in Hexan langsam mit Hilfe einer Einweg¬ spritze hinzu und rührt die Mischung für 20 min bei -40*C. Nachdem man die Cupratlösung auf -66*C abgekühlt hat, fügt man eine Lösung von 0.72 g (1.77 mmol) l-Methyl-3-brom-4-(l-(tert.- butyloxycarbonyl)-3-indolyl)-maleinimid in 10 ml abs. Tetra¬ hydrofuran tropfenweise innerhalb von 30 min hinzu. Man rührt den Ansatz 1.5 h, läßt ihn langsam auf -40 ' C erwärmen und gibt 0.68 ml Nitrobenzol hinzu (R.K. Olsen et al., J.Org.Chem. 47, 4605 (1982)). Der Ansatz wird langsam auf Raumtemperatur erwärmt und dann in 125 ml 3 N HCl gegossen. Man extrahiert die wässrige Phase mit Ethylacetat, trocknet die vereinigten Phasen und engt i.Vak. zur Trockne ein. Der Rück¬ stand wird in 10 ml Trifluoressigsaure aufgenommen und 2 h bei Raumtemperatur belassen. Man engt i.Vak. ein, nimmt den Rück¬ stand zweimal in Toluol auf und destilliert das Lösungsmittel jeweils i.Vak.. Das Rohprodukt wird in Ethylacetat aufgenommen, die organische Phase mit Wasser gewaschen, getrocknet und der Rückstand nach Einengen i.Vak. säulenchromatographisch an Kieselgel (Laufmittel: Dichlormethan) gereinigt. Man erhält 0.11 g l-Methyl-3-butyl-4-(3-indolyl)-maleinimid vom Fp. 156- 158βC.0.5 g (2.64 mmol) of cul are placed in a flamed 100 ml three-necked flask. It is flamed out several times and allowed to cool in the nitrogen stream. After 15 ml of abs. Tetrahydrofuran added, the mixture is cooled to -40'C. 5.28 mmol of butyllithium in hexane are slowly added using a disposable syringe and the mixture is stirred for 20 min at -40 ° C. After the cuprate solution has been cooled to -66 * C, a solution of 0.72 g (1.77 mmol) of l-methyl-3-bromo-4- (l- (tert.- butyloxycarbonyl) -3-indolyl) maleimide in 10 ml abs. Tetrahydrofuran is added dropwise within 30 min. The mixture is stirred for 1.5 h, slowly allowed to warm to -40 ° C. and 0.68 ml of nitrobenzene is added (RK Olsen et al., J.Org.Chem. 47, 4605 (1982)). The mixture is slowly warmed to room temperature and then poured into 125 ml of 3N HCl. The aqueous phase is extracted with ethyl acetate, the combined phases are dried and evaporated down i.Vac. to dry up. The residue is taken up in 10 ml of trifluoroacetic acid and left at room temperature for 2 hours. You narrow i.Vak. one, takes up the residue twice in toluene and distills the solvent in each case i.Vak. The crude product is taken up in ethyl acetate, the organic phase is washed with water, dried and the residue after concentration i.Vak. purified by column chromatography on silica gel (mobile phase: dichloromethane). Obtained 0:11 g of l-methyl-3-butyl-4- (3-indolyl) maleimide, mp. 156- 158 C. β
Beispiel 3Example 3
l-Methyl-3-amino-4-(3-indolyl)-maleinimidl-methyl-3-amino-4- (3-indolyl) maleimide
a) Die Lösung von 6 g (15 mmol) l-Methyl-3-brom-4-(l-(tert.- butyloxycarbonyl)-3-indolyl)-maleinimid in 150 ml methano¬ lischem Ammoniak und 10 ml Dimethylformamid wird 4 h am Rückfluß erhitzt. Dann wird die Reaktionsmischung abge¬ kühlt, der ausgefallene Niederschlag abgesaugt, nacheinan¬ der mit wenig Methanol und Ether gewaschen und i.Vak. getrocknet. Man erhält 3.1 g l-Methyl-3-amino-4-( (l-tert.- butyloxycarbonyl)-3-indolyl)-maleinimid vom Fp. 182βC.a) The solution of 6 g (15 mmol) of l-methyl-3-bromo-4- (l- (tert-butyloxycarbonyl) -3-indolyl) -maleimide in 150 ml of methanolic ammonia and 10 ml of dimethylformamide becomes 4 h heated at reflux. The reaction mixture is then cooled, the precipitate which has separated out is filtered off with suction, washed in succession with a little methanol and ether and in vacuo. dried. This gives 3.1 g of l-methyl-3-amino-4- ((l-tert-butyloxycarbonyl) -3-indolyl) maleimide, mp. 182 C. β
b) 350 mg (1.02 mmol) der Verbindung 3a) werden 20 min auf 220'C erhitzt. Der abgekühlte Kolbeninhalt wird mit 5 ml Methanol gerührt, der Niederschlag abgesaugt, mit Ether gewaschen und im Hochvakuum getrocknet. Man erhält 200 mg l-Methyl-3-amino-4-(3-indolyl)-maleinimid vom Fp. 190βC (Zers.) . Beispiel 4b) 350 mg (1.02 mmol) of compound 3a) are heated to 220'C for 20 min. The cooled contents of the flask are stirred with 5 ml of methanol, the precipitate is filtered off with suction, washed with ether and dried under high vacuum. This gives 200 mg of l-methyl-3-amino-4- (3-indolyl) maleimide, mp. 190 β C (dec.). Example 4
l-Methyl-3-acetamido-4-(3-indolyl)-maleinimidl-methyl-3-acetamido-4- (3-indolyl) maleimide
a) Die Lösung von 340 mg (1 mmol) der Verbindung 3a) in 5 ml Acetanhydrid wird 12 h bei 70"C erhitzt. Anschließend wird die Reaktionslösung mit 20 ml Wasser versetzt und die wäßrige Mischung mit Methylenchlorid extrahiert. Nach Trocknen der organischen Phase über Natriumsulfat und Abziehen des Lösungsmittels wird der Rückstand säulenchro- matographisch gereinigt (Laufmittel: Ethylacetat/Isohexan 1:1). Man erhält 300 mg l-Methyl-3-acetylamino-4-( i¬ tert,-butyloxycarbonyl)-3-indolyl)-maleinimid vom Fp. 155- 160βC (Zers.).a) The solution of 340 mg (1 mmol) of compound 3a) in 5 ml of acetic anhydride is heated for 12 h at 70 ° C. Then the reaction solution is mixed with 20 ml of water and the aqueous mixture is extracted with methylene chloride. After drying the organic phase The residue is purified by column chromatography over sodium sulfate and stripping off the solvent (mobile phase: ethyl acetate / isohexane 1: 1), giving 300 mg of l-methyl-3-acetylamino-4- (i-tert, -butyloxycarbonyl) -3-indolyl ) Maleimide of mp 155-160 β C (dec.).
b) 250 mg der Verbindung 4a) werden 20 min auf 180βC erhitzt. Der abgekühlte Kolbeninhalt wird mit 10 ml Ether gerührt, der Niederschlag abgesaugt und i.Vak. getrocknet. Man erhält 180 mg l-Methyl-3-acetylamino-4-(3-indolyl)- maleinimid vom Fp. >250*C.b) 250 mg of compound 4a) are heated to 180 ° C. for 20 min. The cooled contents of the flask are stirred with 10 ml of ether, the precipitate is suction filtered and i.Vac. dried. 180 mg of l-methyl-3-acetylamino-4- (3-indolyl) maleinimide, mp> 250 ° C., are obtained.
Beispiel 5Example 5
l-Methyl-3-(4-trifluormethyl-anilino)-4-(l-acetyl-3-indolyl _ - maleinimidl-methyl-3- (4-trifluoromethyl-anilino) -4- (l-acetyl-3-indolyl_ - maleimide
Die Lösung von 425 mg (1,1 mmol) l-Methyl-3-(4-trifluormethyl- anilino)-4-(3-indolyl)-maleinimid in 5 ml Acetanhydrid wird 1.5 h bei 120*C erhitzt. Anschließend wird die Reaktionslösung zur Trockne eingedampft, der Rückstand in 10 ml Ethylacetat aufge¬ nommen und die organische Lösung mit gesätt. Natriumhydrogen- carbonat-Lösung gewaschen. Nach Trocknen der organischen Phase über Natriumsulfat und Abziehen des Lösungsmittels wird das Rohprodukt säulenchromatographisch gereinigt (Laufmittel: Ethylacetat/Isohexan 1:3). Man erhält 320 mg l-Methyl-3-(4- trifluormethyl-anilino) -4-(1-acetyl-3-indolyl)-maleinimid vom Fp. 212-215βC. Pharmakoloσischer TestberichtThe solution of 425 mg (1.1 mmol) l-methyl-3- (4-trifluoromethyl-anilino) -4- (3-indolyl) -maleimide in 5 ml acetic anhydride is heated at 120 ° C. for 1.5 h. The reaction solution is then evaporated to dryness, the residue is taken up in 10 ml of ethyl acetate and the organic solution is saturated with sat. Washed sodium hydrogen carbonate solution. After the organic phase has been dried over sodium sulfate and the solvent has been stripped off, the crude product is purified by column chromatography (mobile phase: ethyl acetate / isohexane 1: 3). 320 mg of l-methyl-3- (4-trifluoromethyl-anilino) -4- (1-acetyl-3-indolyl) maleimide of mp 212-215 β C. are obtained. Pharmacological test report
Die in der Patentanmeldung beschriebenen trisubstituierten Maleinimide beeinflussen die Proliferation und/oder die Funktion humaner Lymphozyten. Ein Vergleich der für eine halb¬ maximale Hemmung notwendigen Konzentration in den verschiedenen Testsystemen zeigt die Selektivität der geprüften SubstanzenThe trisubstituted maleimides described in the patent application influence the proliferation and / or the function of human lymphocytes. A comparison of the concentration in the different test systems necessary for half-maximum inhibition shows the selectivity of the tested substances
METHODIK:METHODOLOGY:
Präparation von peripheren humanen Leukozyten (PBL :Preparation of peripheral human leukocytes (PBL:
Peripheres Humanblut wird mit Heparin (Lique in, Röche, Switzerland; 2500 IU/100 ml Blut) versetzt und mit dem gleichen Volumen PBS ohne Calcium und Magnesium (Boehringer Mannheim, Mannheim) verdünnt. Das verdünnte Blut wird 10 Minuten bei 800 x g und bei Raumtemperatur zentrifugiert, um Blutplättchen im Serum abzutrennen. Der Zellniederschlag wird im ursprüng¬ lichen Volumen resuspendiert und davon 30 ml auf 20 ml Lymphozyten-Trennmedium (Boehringer Mannheim, Mannheim) in 50 ml Falcon-Zentrifugenröhrchen (Typ 2070, Becton Dickinson, New Jersey) vorsichtig aufpipettiert. Nach Zentrifugation ( 30 Minuten bei 400 x g, Zimmertemperatur) werden die' PBL von der Trennschicht abpipettiert und einmal mit komplettiertem RPMI 1640 gewaschen (RPMI 1640 von Boehringer Mannheim, Mannheim; Zusätze: 10 Vol. % inaktiviertes fötales Kälberserum, 2 mmol Glutamin, 1 % BME-Vitamine, 10.000 IU-Penicillin und 10 mg Streptomycin per 1 1 Medium; alles von Boehringer Mannheim, Mannheim) . Die PBL werden eingestellt auf 1 x 106-Zellen/ml.Peripheral human blood is mixed with heparin (Lique in, Röche, Switzerland; 2500 IU / 100 ml blood) and diluted with the same volume of PBS without calcium and magnesium (Boehringer Mannheim, Mannheim). The diluted blood is centrifuged for 10 minutes at 800 xg and at room temperature to separate platelets in the serum. The cell precipitate is resuspended in the original volume and 30 ml of this is carefully pipetted onto 20 ml of lymphocyte separation medium (Boehringer Mannheim, Mannheim) in 50 ml Falcon centrifuge tubes (type 2070, Becton Dickinson, New Jersey). After centrifugation (30 minutes at 400 xg, room temperature), the ' PBL are pipetted off from the separation layer and washed once with completed RPMI 1640 (RPMI 1640 from Boehringer Mannheim, Mannheim; additives: 10% by volume inactivated fetal calf serum, 2 mmol glutamine, 1 % BME vitamins, 10,000 IU penicillin and 10 mg streptomycin per 1 1 medium; all from Boehringer Mannheim, Mannheim). The PBL are adjusted to 1 x 10 6 cells / ml.
Gemischte Lvmphozvtenkultur (MLR)Mixed culture (MLR)
1 x 105 PBL in 100 /ul RPMI 16 0-Kulturmedium wird mit der gleichen Menge PBL eines anderen Blutspenders in Nunklon-Mikro- titerplatten gemischt. Dazu werden die zu testenden Ver¬ bindungen abgestuft zugegeben. Die allogene Reaktion der Zellen wird nach sechstägiger Inkubation anhand von eingebautem Radio- thy idin (18-stündiger Puls) gemessen. Für jede geprüfte Konzentration wird die prozentuale Hemmung durch den Vergleich mit der Lösungsmittelkontrolle bestimmt. Aus den konzentra¬ tionsabhängigen Hemmwerten wird sodann die in den Tabellen angegebene IC 50 interpoliert. Mitocreninduzierte Zeilproliferation (PWM)1 x 10 5 PBL in 100 / ul RPMI 16 0 culture medium is mixed with the same amount of PBL from another blood donor in Nunklon microtiter plates. For this purpose, the compounds to be tested are added in stages. The allogeneic response of the cells is measured after six days of incubation using built-in radio thyroid (18-hour pulse). The percentage inhibition for each concentration tested is determined by comparison with the solvent control. The IC 50 specified in the tables is then interpolated from the concentration-dependent inhibition values. Mitocrine-induced cell proliferation (PWM)
200 /ul der PBL-Zellsuspension (2 x 105 PBL) werden mit 0,2 /ug/ml PWM (pokeweed mitogen, Boehringer Mannheim, Mannheim) in Flachboden-Mikrotiterplatten einpipettiert. Nach Zugabe der zu testenden Substanzen wird der Ansatz über 48 Stunden inkubiert (37° C, 5 % C02, 95 % relative Luft¬ feuchtigkeit) . 18 Stunden vor Beendigung der Inkubation wird Radiothymidin zugesetzt und nach dem Ernten der Zellen die eingebaute Radioaktivität bestimmt. Aus diesen Werten wird, wie oben beschrieben, die IC 50 berechnet.200 / ul of the PBL cell suspension (2 x 10 5 PBL) are pipetted into 0.25 µg / ml PWM (pokeweed mitogen, Boehringer Mannheim, Mannheim) in flat-bottom microtiter plates. After adding the substances to be tested, the mixture is incubated for 48 hours (37 ° C., 5% CO 2 , 95% relative atmospheric humidity). 18 hours before the end of the incubation, radiothymidine is added and, after the cells have been harvested, the radioactivity incorporated is determined. As described above, the IC 50 is calculated from these values.
Mitoσeninduzierte Immunσlobulinsynthese durch Leukozyten (IqG)Mitoσen-induced immunoglobulin synthesis by leukocytes (IqG)
2 x 105 PBL werden in 200 /ul komplementiertem RPMI 1640-Medium mit 0,2 /u/ml PWM in Mikrotiterplatten bei 37° C, 5 % C0 und 95 % relative Luftfeuchtigkeit über neun Tage inkubiert. Dann wird der Kulturüberstand geerntet und daraus über ein ELISA- Verfahren die Konzentration an humanem IgG bestimmt.2 x 10 5 PBL are incubated in 200 / ul complemented RPMI 1640 medium with 0.2 / u / ml PWM in microtiter plates at 37 ° C, 5% C0 and 95% relative humidity for nine days. The culture supernatant is then harvested and the concentration of human IgG is determined from this using an ELISA method.
Tumorwachstum-Inhibitionstest (TGI)Tumor growth inhibition test (TGI)
Eine chemisch-induzierte (Methylcholanthren A) Mäuse- fibrosarcom-Zellinie wird in wöchentlichen Abständen propa¬ giert. Für einen In-vitro-Test werden die Zellen zweimal gewaschen und in dem o. a. Kulturmedium auf eine Zelldichte von 5 x lθ4 Zellen/ml eingestellt. 200 /ul dieser Zellsuspension werden in die Vertiefungen einer Mikrotiterplatte gegeben und mit den zu testenden Verbindungen über 48 Stunden bei 37° C, 5 % C0 und 95 % relativer Luftfeuchtigkeit inkubiert. Drei Stunden vor Ablauf der Inkubationszeit wird Radiothymidin zugegeben und nach dem Ernten die Menge eingebauter Radio¬ aktivität bestimmt. Die Auswertung des Versuches erfolgte wie oben beschrieben.A chemically-induced (methylcholanthrene A) mouse fibrosarcom cell line is propagated at weekly intervals. For an in vitro test, the cells are washed twice and adjusted to a cell density of 5 × 10 4 cells / ml in the above culture medium. 200 / ul of this cell suspension are added to the wells of a microtiter plate and incubated with the compounds to be tested for 48 hours at 37 ° C., 5% CO and 95% relative atmospheric humidity. Radiothymidine is added three hours before the incubation period expires and the amount of radioactivity incorporated is determined after harvesting. The test was evaluated as described above.
ErgebnisseResults
In der Tabelle 1 sind die IC 50-Werte für sieben Beispiele aus der Patentanmeldung zusammengefaßt. Allgemein zytotoxisch wirkende oder zytolytische Verbindungen hemmen sowohl die Allogen-induzierte, die Mitogen-induzierte als auch die spontane Proliferation eukaryotischer bei vergleichbaren Konzentrationen. Aus Tabelle l ist zu entnehmen, daß für eine halbmaximale Hemmung der Proliferation in den meisten Fällen durchaus unterschiedliche Konzentrationen notwendig sind. Besonders auffallend ist jedoch, daß für eine halbmaximale Hemmung der Immunglobulinsynthese Konzentrationen ausreichen, die zum Teil mehr als Faktor 100 niedriger liegen als die für eine Hemmung der spontanen Tumorzellenproliferation notwendige.Table 1 summarizes the IC 50 values for seven examples from the patent application. General cytotoxic or cytolytic compounds inhibit both the allogen-induced, the mitogen-induced and the spontaneous proliferation of eukaryotic at comparable concentrations. It can be seen from Table 1 that for half maximal inhibition of proliferation in most cases different concentrations are absolutely necessary. It is particularly striking, however, that concentrations which are sometimes more than 100 times lower than those necessary for inhibiting spontaneous tumor cell proliferation are sufficient for half-maximal inhibition of immunoglobulin synthesis.
Tabelle 1Table 1
Immunpharmakologische In-vitro-Wirkung von trisubstituierten Maleinimiden an humanen Leukozyten und murinen Tumorzellen. Angegeben sind IC 50-Werte in /ug/ml.Immunopharmacological in-vitro effects of trisubstituted maleimides on human leukocytes and murine tumor cells. IC 50 values are given in / ug / ml.
Figure imgf000033_0001
Figure imgf000033_0001
MLR: Gemischte Lymphozytenkultur; PWK: pokeweed-mitogen- induzierte Lymphozytenproliferation; TGI: Tumorwachtums- inhibitionstest; IgG: PWM-induzierte IgG-Synthese; n.d. nicht gemessen (Methodenbeschreibung siehe Text) MLR: mixed lymphocyte culture; PWK: pokeweed-mitogen-induced lymphocyte proliferation; TGI: tumor growth inhibition test; IgG: PWM-induced IgG synthesis; n.d. not measured (method description see text)

Claims

Patentansprüche Claims
Verbindungen der Formel ICompounds of formula I.
Figure imgf000034_0001
worin
Figure imgf000034_0001
wherein
Rl Wasserstoff, Acyl, einen gegebenenfalls acylierten Kohlen- hydratrest, einen gesättigten oder ungesättigten, geradkettigen oder verzweigten, unsubstituierten oder ein- oder mehrfach substituierten Cτ_-Cιo aliphatischen Rest bedeutet,R1 is hydrogen, acyl, an optionally acylated carbohydrate residue, a saturated or unsaturated, straight-chain or branched, unsubstituted or mono- or polysubstituted Cτ_-Cιo aliphatic residue,
wobei die Substituentenbeing the substituents
Halogen, Cyano, Azido, Alkylsulfinyl, Alkylsulfonyl, Arylsul- fonyl, Carboxy, Alkoxycarbonyl, Carboxamido, Amidino, Isothio- cyanato, Dimethylphosphonyl, C3-C7-Cycloalkyl, gegebenenfalls substituiert, Aryl, gegebenenfalls substituiert, Hetaryl, gegebenenfalls substituiert, oder eine Gruppe der FormelHalogen, 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 the formula
Figure imgf000034_0002
Figure imgf000034_0002
bedeuten,mean,
R2 und R3 gleich oder verschieden sein können und Wasserstoff, Halogen, Alkyl, Hydroxy, Alkoxy, Aryloxy, Arylalkyloxy, Haloalkyl, Nitro, Amino, Acylamino, Monoalkylamino, Dial- kyla ino, Acyloxy, Carboxy, Carboxamido, Cyano, Alkoxycar¬ bonyl, Alkylthio, Alkylsulfinyl, Alkylsulfonyl oder gemeinsam Methylendioxy bedeuten,R 2 and R 3 can be the same or different and represent hydrogen, halogen, alkyl, hydroxy, alkoxy, aryloxy, arylalkyloxy, haloalkyl, nitro, amino, acylamino, monoalkylamino, dial- kyla ino, acyloxy, carboxy, carboxamido, cyano, alkoxycarbonyl, alkylthio, alkylsulfinyl, alkylsulfonyl or together methylenedioxy,
R4 einen gegebenenfalls durch Hydroxy- oder Alkoxylgruppen substituierten C3-C7-Cyloalkylrest, einen gegebenenfalls substituierten Arylrest, einen gegebenenfalls substi¬ tuierten Hetarylrest, Cyano, Amidino, Aminocarbonylamino, einen Rest der Formel -OR7 oder,R 4 is a C 3 -C 7 -cycloalkyl radical which is optionally substituted by hydroxyl or alkoxyl groups, an optionally substituted aryl radical, an optionally substituted hetaryl radical, cyano, amidino, aminocarbonylamino, a radical of the formula -OR 7 or,
-NR8R9 bedeutet, oder die gleiche Bedeutung wie l be¬ sitzt,-NR 8 R 9 means, or has the same meaning as 1,
R5 einen unsubstituierten oder substituierten bicyclischen Heteroaromaten oder einen Rest der FormelR 5 is an unsubstituted or substituted bicyclic heteroaromatic or a radical of the formula
RBRB
//
OR7 , -S (0) : n*7 , -NOR 7 , -S (0) : n * 7 , -N
(a) (b) (c)(a) (b) (c)
O 13 R16O 13 R 16
Figure imgf000035_0001
Figure imgf000035_0001
(g) (h) (f)(g) (h) (f)
bedeutet, oder die gleiche Bedeutung wie Rl mit der Ausnahme der Bedeutung "Kohlenhydratrest" besitzt ,means or has the same meaning as Rl with the exception of the meaning "carbohydrate residue",
R6 Wasserstoff , Alkyl , Aryl , Arylalkyl , Hydroxyalkyl , Halo¬ alkyl , Aminoalkyl , Monoalkylaminoalkyl , Dialkylaminoalkyl, Acyl aminoalkyl , Alkylsulf onylaminoalkyl , Arylsulfonyl- aminoalkyl , Mercaptoalkyl , Alkyl thioalkyl , Carboxyalkyl , Alkoxycarbonylalkyl, Aminocarbonylalkyl, Alkylthio oder Alkylsulfinyl;R 6 is hydrogen, alkyl, aryl, arylalkyl, hydroxyalkyl, haloalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, acylaminoalkyl, alkylsulfonylaminoalkyl, arylsulfonylaminoalkyl, mercaptoalkyl, alkylthioalkyl, carboxyalkyl, Alkoxycarbonylalkyl, aminocarbonylalkyl, alkylthio or alkylsulfinyl;
R7 Wasserstoff, einen geradkettigen oder verzweigten Alkyl-, Alkenyl- oder Alkinylrest, einen gegebenenfalls substituierten C3-C7-Cycloalkylrest, einen gegebenenfalls substituierten Arylrest, einen gegebenenfalls substituierten Hetarylrest (gegebenenfalls hydriert oder teilhydriert) , einen Arylalkylrest, einen Hetarylalkylrest, Alkoxycarbonylalkyl, Carboxyalkyl, Acyl,R 7 is hydrogen, a straight-chain or branched alkyl, alkenyl or alkynyl radical, an optionally substituted C3-C7-cycloalkyl radical, an optionally substituted aryl radical, an optionally substituted hetaryl radical (optionally hydrogenated or partially hydrogenated), an arylalkyl radical, a hetarylalkyl radical, alkoxycarbonylalkyl, carboxyalkyl Acyl
Alkylthioalkyl, Mercaptoalkyl, Hydroxyalkyl oder Alkoxyalkyl bedeutet,Means alkylthioalkyl, mercaptoalkyl, hydroxyalkyl or alkoxyalkyl,
R8 und R9 gleich oder verschieden sein können und Wasserstoff, Alkyl, Aryl, Hetaryl, Arylalkyl, Hetarylalkyl oder Acyl, Alkyl-oder Arylsulfonyl bedeuten, oder zusammen mit dem Stickstoff einen gesättigten oder ungesättigten drei-bis siebengliedrigen Ring bilden können, der noch weitere Heteroatome enthalten kann und gegebenenfalls substituiert ist,R 8 and R 9 can be the same or different and denote 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 is still can contain further heteroatoms and is optionally substituted,
Rl° Alkyl oder Aryl bedeutet,R 1 denotes alkyl or aryl,
RH und Ri2 gleich oder verschieden sein können und Wasser¬ stoff, Alkyl, Arylalkyl, Aryl oder Hetaryl bedeuten, oder zusammen mit dem Stickstoff einen drei- bis siebengliedrigen Ring bilden können, der gegebenenfalls substituiert ist und weitere Heteroatome enthalten kann,RH and R i2 can be the same or different and represent hydrogen, alkyl, arylalkyl, aryl or hetaryl, or together with the nitrogen can form a three to seven-membered ring which is optionally substituted and can contain further heteroatoms,
13/ R14; 15f R16 un(ä 17 gleich oder verschieden sein können und Acyl bedeuten oder die gleiche Bedeutung wie R11 und !2 besitzen. n = 0, 1 oder 2, X - NH oder 0, Y = NH oder S Z = NH, S oder 0 und13 / R 14 ; 15 f R 16 un ( ä 17 can be the same or different and mean acyl or have the same meaning as R 11 and! 2. n = 0, 1 or 2, X - NH or 0, Y = NH or SZ = NH, S or 0 and
W = Amino, Alkyla ino, Dialkylamino oder Alkylthio bedeutet, mit der Bedingung, daßW = amino, alkyla ino, dialkylamino or alkylthio, with the condition that
R5 nicht eine aromatische monocyclische Gruppe der Formel (c) istR5 is not an aromatic monocyclic group of formula (c)
sowie deren pharmakologisch unbedenkliche Salze.and their pharmacologically acceptable salts.
2. Verfahren zur Herstellung von Verbindungen der Formel I2. Process for the preparation of compounds of formula I.
Figure imgf000037_0001
Figure imgf000037_0001
worinwherein
Rl Wasserstoff, Acyl, einen gegebenenfalls acylierten Kohlen- hydratrest, einen gesättigten oder ungesättigten, geradkettigen oder verzweigten, unsubstituierten oder ein- oder mehrfach substituierten CI-CIQ aliphatischen Rest bedeutet.R1 is hydrogen, acyl, an optionally acylated carbohydrate residue, a saturated or unsaturated, straight-chain or branched, unsubstituted or mono- or polysubstituted CI-CIQ aliphatic residue.
wobei die Substituentenbeing the substituents
Halogen, Cyano, Azido, Alkylsulfinyl, Alkylsulfonyl, Arylsul- fonyl, Carboxy, Alkoxycarbonyl, Carboxamido, Amidino, Isothio- cyanato, Dimethylphosphonyl, C3-C7-Cycloalkyl, gegebenenfalls substituiert, Aryl, gegebenenfalls substituiert, Hetaryl, gegebenenfalls substituiert, oder eine Gruppe der Formel -OR7, -S(0)nR7, -
Figure imgf000038_0001
Halogen, cyano, azido, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carboxy, alkoxycarbonyl, carboxamido, amidino, isothiocyanato, dimethylphosphonyl, C 3 -C 7 -cycloalkyl, optionally substituted, aryl, optionally substituted, hetaryl, optionally substituted, or one Group of the formula -OR 7 , -S (0) n R 7 , -
Figure imgf000038_0001
(a) (b) (C) (d) (e) (f)(a) (b) (C) (d) (e) (f)
bedeuten,mean,
R2 und R3 gleich oder verschieden sein können und Wasserstoff, Halogen, Alkyl, Hydroxy, Alkoxy, Aryloxy, Arylalkyloxy, Haloalkyl, Nitro, Amino, Acylamino, Monoalkylamino, Dial¬ kylamino, Acyloxy, Carboxy, Carboxamido, Cyano, Alkoxycar¬ bonyl, Alkylthio, Alkylsulfinyl, Alkylsulfonyl oder gemeinsam Methylendioxy bedeuten,R 2 and R 3 can be the same or different and are hydrogen, halogen, alkyl, hydroxy, alkoxy, aryloxy, arylalkyloxy, haloalkyl, nitro, amino, acylamino, monoalkylamino, dial¬ kylamino, acyloxy, carboxy, carboxamido, cyano, alkoxycarbonyl , Alkylthio, alkylsulfinyl, alkylsulfonyl or together methylenedioxy,
R4 einen gegebenenfalls durch Hydroxy- oder Alkoxylgruppen substituierten C3-C7-Cyloalkylrest, einen gegebenenfalls substituierten Arylrest, einen gegebenenfalls substi¬ tuierten Hetarylrest, Cyano, Amidino, Aminocarbonylamino, einen Rest der Formel -OR7 oder,R 4 is a C 3 -C 7 -cycloalkyl radical which is optionally substituted by hydroxyl or alkoxyl groups, an optionally substituted aryl radical, an optionally substituted hetaryl radical, cyano, amidino, aminocarbonylamino, a radical of the formula -OR 7 or,
-NR8R9 bedeutet, oder die gleiche Bedeutung wie Rl be¬ sitzt,-NR 8 R 9 , or has the same meaning as Rl,
R5 einen unsubstituierten oder substituierten bicyclischen R 5 is an unsubstituted or substituted bicyclic
Heteroaromaten oder einen Rest der FormelHeteroaromatics or a radical of the formula
R8 R 8
//
-OR7, -S(0)nR7, -N-OR 7 , -S (0) n R 7 , -N
\\
R9 R 9
(a) (b) (c)(a) (b) (c)
Figure imgf000039_0001
Figure imgf000039_0001
(g) (h) (f) (g) (h) (f)
bedeutet, oder die gleiche Bedeutung wie l mit der Ausnahme der Bedeutung "Kohlenhydratrest" besitzt,means, or has the same meaning as l with the exception of the meaning "carbohydrate residue",
R6 Wasserstoff, Alkyl, Aryl, Arylalkyl, Hydroxyalkyl, Halo¬ alkyl, Aminoalkyl, Monoalkylaminoalkyl, Dialkylaminoalkyl, Acylaminoalkyl, Alkylsulfonylaminoalkyl, Arylsulfonyl- aminoalkyl, Mercaptoalkyl, Alkylthioalkyl, Carboxyalkyl, Alkoxycarbonylalkyl, Aminocarbonylalkyl, Alkylthio oder Alkylsulfinyl;R 6 is hydrogen, alkyl, aryl, arylalkyl, hydroxyalkyl, haloalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, acylaminoalkyl, alkylsulfonylaminoalkyl, arylsulfonylaminoalkyl, mercaptoalkyl, alkylthioalkyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, alkylthio or alkylthio or alkylthio or alkylthio or
R7 Wasserstoff, einen geradkettigen oder verzweigten Alkyl-, Alkenyl- oder Alkinylrest, einen gegebenenfalls substituierten C3-C7-Cycloalkylrest, einen gegebenenfalls substituierten Arylrest, einen gegebenenfalls substituierten Hetarylrest (gegebenenfalls hydriert oder teilhydriert) , einen Arylalkylrest, einen Hetarylalkylrest, Alkoxycarbonylalkyl, Carboxyalkyl, Acyl, Alkylthioalkyl, Mercaptoalkyl, Hydroxyalkyl oder Alkoxyalkyl bedeutet,R 7 is hydrogen, a straight-chain or branched alkyl, alkenyl or alkynyl radical, an optionally substituted C 3 -C 7 cycloalkyl radical, an optionally substituted aryl radical, an optionally substituted hetaryl radical (optionally hydrogenated or partially hydrogenated), an arylalkyl radical, a hetarylalkyl radical, alkoxycarbonylalkyl , Carboxyalkyl, acyl, Means alkylthioalkyl, mercaptoalkyl, hydroxyalkyl or alkoxyalkyl,
R8 und R9 gleich oder verschieden sein können und Wasserstoff, Alkyl, Aryl, Hetaryl, Arylalkyl, Hetarylalkyl oder Acyl, Alkyl-oder Arylsulfonyl bedeuten, oder zusammen mit dem Stickstoff einen gesättigten oder ungesättigten drei-bis siebengliedrigen Ring bilden können, der noch weitere Heteroatome enthalten kann und gegebenenfalls substituiert ist,R 8 and R 9 can be the same or different and denote 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 is still can contain further heteroatoms and is optionally substituted,
Rl° Alkyl oder Aryl bedeutet,R 1 denotes alkyl or aryl,
RH und Ri2 gleich oder verschieden sein können und Wasser¬ stoff, Alkyl, Arylalkyl, Aryl oder Hetaryl bedeuten, oder zusammen mit dem Stickstoff einen drei- bis siebengliedrigen Ring bilden können, der gegebenenfalls substituiert ist und weitere Heteroatome enthalten kann,RH and R i2 can be the same or different and represent hydrogen, alkyl, arylalkyl, aryl or hetaryl, or together with the nitrogen can form a three to seven-membered ring which is optionally substituted and can contain further heteroatoms,
Ri3, Rl , Rl5, Rl6 und R17 gleich oder verschieden sein können und Acyl bedeuten oder die gleiche Bedeutung wie R11 und R12 besitzen,R i3 , Rl, Rl 5 , Rl 6 and R 17 can be the same or different and mean acyl or have the same meaning as R 11 and R 12,
n = 0, 1 oder 2, X = NH oder 0, Y = NH oder S Z = NH, S oder 0 undn = 0, 1 or 2, X = NH or 0, Y = NH or S Z = NH, S or 0 and
W = Amino, Alkylamino, Dialkylamino oder Alkylthio bedeutet, mit der Bedingung, daßW = amino, alkylamino, dialkylamino or alkylthio, with the condition that
R5 nicht eine aromatische monocyclische Gruppe der Formel (c) ist. sowie deren pharmakologisch unbedenkliche Salze, dadurch gekennzeichnet, daß man in an sich bekannter WeiseR 5 is not an aromatic monocyclic group of formula (c). and their pharmacologically acceptable salts, characterized in that in a manner known per se
a) eine Verbindung der allgemeinen Formel II,a) a compound of the general formula II,
Figure imgf000041_0001
Figure imgf000041_0001
in der Rl, R2, R3, R5 und R6 die oben genannten Bedeutungen besitzen, mit einer Verbindung der allgemeinen Formel III oder lila.in which R 1, R 2 , R 3 , R 5 and R 6 have the meanings given above, with a compound of the general formula III or purple.
R4-NH2 (III) oder R4-NH3 +A_ (lila)R 4 -NH 2 (III) or R 4 -NH 3 + A _ (purple)
in der R4 die oben genannten Bedeutungen besitzt und "A~" ein Säureanion wie Chlorid, Bromid, Carbonat, Sulfat oder Acetat bedeutet, umsetzt, oder in which R 4 has the meanings given above and "A ~" denotes an acid anion such as chloride, bromide, carbonate, sulfate or acetate, or
b) eine Verbindung der allgemeinen Formel IV,b) a compound of the general formula IV,
Figure imgf000042_0001
Figure imgf000042_0001
in der Rx, R2, R3, R4 und R6 die oben genannten Bedeutungen besitzen, mit einer Verbindung der allgemeinen Formel V,in which R x , R 2 , R 3 , R 4 and R 6 have the meanings given above, with a compound of the general formula V,
X-R5 (V)XR 5 (V)
in der R5 die oben angegebene Bedeutung besitzt und X Wasser¬ stoff, ein Alkalimetall oder Kupfer bedeutet, umsetzt,in which R 5 has the meaning given above and X denotes hydrogen, an alkali metal or copper,
und anschließend gegebenenfalls erhaltene Verbindungen der Formel I in andere Verbindungen der Formel I überführt und ge- wünschtenfalls die erhaltenen Verbindungen in pharmakologisch unbedenkliche Salze überführt.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. Arzneimittel, enthaltend eine Verbindung gemäß Anspruch 1 neben üblichen Träger- und Hilfsstoffen.3. Medicament containing a compound according to claim 1 in addition to conventional carriers and auxiliaries.
4. Verwendung von Verbindungen gemäß Anspruch 1 zur Her¬ stellung von Arzneimitteln zur Behandlung von Immuner¬ krankungen oder allergischen Erkrankungen. 4. Use of compounds according to claim 1 for the manufacture of medicaments for the treatment of immune diseases or allergic diseases.
PCT/EP1991/000331 1990-02-26 1991-02-22 Novel trisubstituted maleinimides, process for their production and medicaments containing these compounds WO1991013070A1 (en)

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US5405864A (en) * 1993-10-15 1995-04-11 Syntex (U.S.A.) Inc. Chemotherapeutic maleimides
US5481003A (en) * 1994-06-22 1996-01-02 Eli Lilly And Company Protein kinase C inhibitors
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US7855203B2 (en) 2000-12-08 2010-12-21 Ortho-Mcneil-Janssen Pharmaceuticals, Inc. Indazolyl-substituted pyrroline compounds as kinase inhibitors
US8114901B2 (en) 2002-07-12 2012-02-14 Eli Lilly And Company Crystalline 2,5-dione-3-(1-methyl-1H-indol-3-yl)-4-[1-(pyridin-2-ylmethyl)piperidin-4-yl]-1H-indol-3-yl]-1H-pyrrole mono-hydrochloride
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US8304425B2 (en) 2007-06-22 2012-11-06 Arqule, Inc. Pyrrolidinone, pyrrolidine-2,5-dione, pyrrolidine and thiosuccinimide derivatives, compositions and methods for treatment of cancer
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US5559228A (en) * 1995-03-30 1996-09-24 Eli Lilly And Company Synthesis of bisindolylmaleimides
WO2000006564A1 (en) * 1998-07-30 2000-02-10 Japan Tobacco Inc. Disubstituted maleimide compounds and medicinal utilization thereof
US6800621B2 (en) 1998-11-27 2004-10-05 Shionogi & Co., Ltd. Imidazo[4,5-b]-pyridiniummethyl-containing cephem compounds having broad antibacterial spectrum activity
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US6518263B1 (en) 1998-11-27 2003-02-11 Shionogi & Co., Ltd. Imidazo[4,5-b]pyridiniummethyl-containing cephem compounds having broad antibacterial spectrum
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US7220774B2 (en) 2000-11-07 2007-05-22 Novartis Ag Indolylmaleimide derivatives
US7825124B2 (en) 2000-11-07 2010-11-02 Rainer Albert Indolylmaleimide derivatives
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