WO1991013070A1 - Nouveaux maleinimides trisubstitues, leur procede de fabrication, et medicaments renfermant ces composes - Google Patents

Nouveaux maleinimides trisubstitues, leur procede de fabrication, et medicaments renfermant ces composes 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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Prior art keywords
radical
optionally substituted
formula
alkyl
aryl
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PCT/EP1991/000331
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German (de)
English (en)
Inventor
Michael Schultz
Christos Tsaklakidis
Rainer Haag
Werner Scheuer
Eberhard Russmann
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Boehringer Mannheim Gmbh
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Publication of WO1991013070A1 publication Critical patent/WO1991013070A1/fr

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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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  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Composé de formule (I) dans laquelle les substituants R1-R6 ont la signification indiquée dans les revendications, leur procédé de fabrication, et médicaments renfermant ces composés, pour le traitement d'immuno-maladies et de maladies allergiques.
PCT/EP1991/000331 1990-02-26 1991-02-22 Nouveaux maleinimides trisubstitues, leur procede de fabrication, et medicaments renfermant ces composes WO1991013070A1 (fr)

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DEP4005970.7 1990-02-26
DE19904005970 DE4005970A1 (de) 1990-02-26 1990-02-26 Neue trisubstituierte maleinimide, verfahren zu ihrer herstellung sowie arzneimittel, die diese verbindungen enthalten

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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
US5491242A (en) * 1994-06-22 1996-02-13 Eli Lilly And Company Protein kinase C inhibitors
US5541347A (en) * 1993-12-07 1996-07-30 Eli Lilly And Company Synthesis of bisindolylmaleimides
US5552396A (en) * 1993-12-07 1996-09-03 Eli Lilly And Company Protein kinase c inhibitors
US5559228A (en) * 1995-03-30 1996-09-24 Eli Lilly And Company Synthesis of bisindolylmaleimides
US5614647A (en) * 1993-12-07 1997-03-25 Eli Lilly And Company Intermediates for the synthesis of bisindolylmaleimides
US5661173A (en) * 1993-12-23 1997-08-26 Eli Lilly And Company Protein kinase C inhibitors
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US5723456A (en) * 1993-12-07 1998-03-03 Eli Lilly & Company Therapeutic treatment for cardiovascular diseases
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WO2000006564A1 (fr) * 1998-07-30 2000-02-10 Japan Tobacco Inc. Composes de maleimide disubstitues et utilisation en medecine de ces derniers
WO2000032606A1 (fr) * 1998-11-27 2000-06-08 Shionogi & Co., Ltd. COMPOSÉS DE CÉPHÈME À BASE D'IMIDAZO[4,5-b]PYRIDINIUMMÉTHYLE À LARGE SPECTRE ANTIBACTÉRIEN
WO2001074771A1 (fr) * 2000-04-04 2001-10-11 Smithkline Beecham P.L.C. Derives de pyrrole-2, 5-dione destines au traitement du diabete
EP1224932A1 (fr) * 1999-08-20 2002-07-24 Sagami Chemical Research Center Medicaments inhibant la mort cellulaire
US6645970B2 (en) 2000-11-07 2003-11-11 Novartis Ag Indolylmaleimide derivatives
US7713969B2 (en) 2005-02-09 2010-05-11 Arqule, Inc. Compositions and methods for treatment of cancer
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CN101348482B (zh) * 2008-08-04 2012-05-09 东华大学 3-酰胺基-4-吲哚马来酰亚胺化合物及其制备方法和应用
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US8513292B2 (en) 2007-06-22 2013-08-20 Arqule, Inc. Compositions and methods for the treatment of cancer
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US5621098A (en) * 1993-12-07 1997-04-15 Eli Lilly And Company Process for preparing bis-indolyl macrocycles
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US5843935A (en) * 1993-12-07 1998-12-01 Eli Lilly And Company Protein kinase C inhibitors
US5739322A (en) * 1993-12-07 1998-04-14 Eli Lilly And Company Process for preparing BIS-indolyl macrocycles
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US5665877A (en) * 1993-12-07 1997-09-09 Eli Lilly And Company Synthesis of bisindolylmaleimides
US6057440A (en) * 1993-12-07 2000-05-02 Eli Lilly And Company Process for preparing bis-indoly macrocycles
US5674862A (en) * 1993-12-07 1997-10-07 Eli Lilly And Company Methods of treating diabetic mellitus and its complications
US5696108A (en) * 1993-12-07 1997-12-09 Eli Lilly And Company Protein kinase C inhibitors
US5698578A (en) * 1993-12-07 1997-12-16 Eli Lilly And Company Protein kinase C inhibitors
US5719175A (en) * 1993-12-07 1998-02-17 Eli Lilly And Company Protein kinase C inhibitors
US5723456A (en) * 1993-12-07 1998-03-03 Eli Lilly & Company Therapeutic treatment for cardiovascular diseases
US5672618A (en) * 1993-12-23 1997-09-30 Eli Lilly And Company Protein kinase C inhibitors
US5661173A (en) * 1993-12-23 1997-08-26 Eli Lilly And Company Protein kinase C inhibitors
US5491242A (en) * 1994-06-22 1996-02-13 Eli Lilly And Company Protein kinase C inhibitors
US5481003A (en) * 1994-06-22 1996-01-02 Eli Lilly And Company Protein kinase C inhibitors
US5559228A (en) * 1995-03-30 1996-09-24 Eli Lilly And Company Synthesis of bisindolylmaleimides
WO2000006564A1 (fr) * 1998-07-30 2000-02-10 Japan Tobacco Inc. Composes de maleimide disubstitues et utilisation en medecine de ces derniers
US6800621B2 (en) 1998-11-27 2004-10-05 Shionogi & Co., Ltd. Imidazo[4,5-b]-pyridiniummethyl-containing cephem compounds having broad antibacterial spectrum activity
WO2000032606A1 (fr) * 1998-11-27 2000-06-08 Shionogi & Co., Ltd. COMPOSÉS DE CÉPHÈME À BASE D'IMIDAZO[4,5-b]PYRIDINIUMMÉTHYLE À LARGE SPECTRE ANTIBACTÉRIEN
US6518263B1 (en) 1998-11-27 2003-02-11 Shionogi & Co., Ltd. Imidazo[4,5-b]pyridiniummethyl-containing cephem compounds having broad antibacterial spectrum
EP1224932A1 (fr) * 1999-08-20 2002-07-24 Sagami Chemical Research Center Medicaments inhibant la mort cellulaire
EP1224932A4 (fr) * 1999-08-20 2002-10-16 Sagami Chem Res Medicaments inhibant la mort cellulaire
WO2001074771A1 (fr) * 2000-04-04 2001-10-11 Smithkline Beecham P.L.C. Derives de pyrrole-2, 5-dione destines au traitement du diabete
US7220774B2 (en) 2000-11-07 2007-05-22 Novartis Ag Indolylmaleimide derivatives
US7825124B2 (en) 2000-11-07 2010-11-02 Rainer Albert Indolylmaleimide derivatives
US6645970B2 (en) 2000-11-07 2003-11-11 Novartis Ag Indolylmaleimide derivatives
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
US8377927B2 (en) 2005-02-09 2013-02-19 Arqule, Inc. Compositions and methods for treatment of cancer
US7713969B2 (en) 2005-02-09 2010-05-11 Arqule, Inc. Compositions and methods for treatment of cancer
US9447088B2 (en) 2005-02-09 2016-09-20 Arqule, Inc. Compositions and methods for treatment of cancer
US8754078B2 (en) 2005-02-09 2014-06-17 Arqule, Inc. Compositions and methods for treatment of cancer
US8232285B2 (en) 2007-06-22 2012-07-31 Arqule, Inc. Quinazolinone compounds and methods of use thereof
US8513292B2 (en) 2007-06-22 2013-08-20 Arqule, Inc. Compositions and methods for the treatment of cancer
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
CN101348482B (zh) * 2008-08-04 2012-05-09 东华大学 3-酰胺基-4-吲哚马来酰亚胺化合物及其制备方法和应用
US8703782B2 (en) 2011-05-17 2014-04-22 Novartis Ag Substituted indole derivatives
US9029396B2 (en) 2011-05-17 2015-05-12 Novartis Ag Substituted indole derivatives

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