WO1995015946A1 - Piperazine-substituted pyrroloanthracene as immuno-moderators - Google Patents

Abstract

Piperazine-substituted pyrroloanthracenes of general formula (I) in which E and L together form a heterocyclic radical of formula (A) are produced if either furanoanthracene is reacted with piperazine alkyl amines or unsbustituted pyrolloanthracene is first reacted with dihalogen alkyl compounds and then with corespondingly substituted piperazines or if furane derivatives are first reacted with piperazine alkyl amines and then condensed with anthracenes. The novel compounds can be used as active agents in medicaments, especially in immuno-modulators.

Description

 PIPERAZINE-SUBTITUATED PYRROLOANTHRACENES AS IMMUNO MODULATORS

The present invention relates to piperazine-substituted pyrroloanthracenes, processes for their preparation and their use in medicaments.

Publication US 48 04-751 A discloses polycyclic dicarboximides with an antipsychotic and anxiolytic effect.

In most autoimmune theories, T-lymphocytes are cited as initiators of many cellular processes that lead to tissue destruction and symptoms associated with specific autoimmune diseases [Paul, E.W. 1984, Fundamental Immunology, Ravens Press, New York). Rheumatoid arthritis is an example of such diseases and adjuvant-induced arthritis in the rat is considered a representative animal model for it [Lombardino, J.G. 1985, Nonsteroidal Antiinflammatory Drugs, John Wiley & Sons, New York]. For the rat adjuvant arthritis model, a large number of studies have shown that T cells are involved in the progression of the disease. In addition, T cells from adjuvant disease rats transmit this disease to healthy animals in the absence of any source of antigen or other inflammatory factors.

Accordingly, inhibition of T cell function or activation should positively affect both the adjuvant arthritis in the rat and the course of disease in various human autoimmune diseases.

Recently, a serotonin-type receptor has been identified on Jurkart cells [Aune, T., M. Kelley, UA Ranges, GE Bombera, MP 1990, J. Immunol. 145, 1826] by which is believed to regulate T cell function. Therefore, selective antagonists of this receptor are believed to inhibit T cell proliferation.

The present invention relates to piperazine-substituted pyrroloanthracenes of the general formula (I)

in which

A and D are identical or different and represent hydrogen, hydroxyl, halogen, cyano, carboxy, nitro, trifluoromethyl, trifluoromethoxy, or represent straight-chain or branched alkyl or alkoxy each having up to 8 carbon atoms,

R ¹ and R ^{2 are the} same or different and represent hydrogen, halogen, cyano, formyl, phenyl or hydroxy, or

 stand for straight-chain or branched alkoxy with up to 8 carbon atoms, or

stand for straight-chain or branched alkyl or alkenyl each having up to 8 carbon atoms, which may optionally be up to 2 times identical or different by hydroxy, nitro, phenyl, halogen, by straight-chain or branched alkoxy having up to 6 carbon atoms or by a group of the formula -NR ³ R ^{4 are} substituted, wherein

R ³ and R ^{4 are the} same or different and are hydrogen, straight-chain or branched alkyl having up to 6 carbon atoms or phenyl,

E and L together form a heterocyclic radical of the formula

wherein

R ⁵ and R ^{6 are} identical or different and are hydrogen, halogen, phenyl or straight-chain or branched alkyl having up to 8 carbon atoms, which is optionally substituted by carboxy or by straight-chain or branched alkoxycarbonyl having up to 6 carbon atoms,

R ⁷ , R ⁸ , R ⁹ and R ^{10 are the} same or different and are hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms, or each R ⁷ and R ⁸ and / or R ⁹ and R ¹⁰ together represent the rest of the formula O form a represents a number 2, 3, 4, 5, 6, 7 or 8,

R ¹¹ denotes aryl having 6 to 10 carbon atoms, which is optionally substituted up to 3 times identically or differently by halogen, hydroxy, nitro, cyano, trifluoromethyl, trifluoromethoxy or by straight-chain or branched alkyl or alkoxy each having up to 8 carbon atoms, or

R ^{11 is} hydrogen, cycloalkyl having 3 to 8 carbon atoms, pyridyl or pyrimidyl, or

 straight-chain or branched alkyl having up to 10 carbon atoms, which is optionally substituted up to 2 times the same or different by phenyl, which in turn is up to 3 times the same or different by halogen, hydroxy, nitro, cyano, trifluoromethyl, trifluoromethoxy or by straight-chain or branched alkyl or alkoxy, each having up to 8 carbon atoms, and their salts.

Physiologically acceptable salts are preferred in the context of the present invention. Physiologically acceptable salts of piperazine-substituted pyrroloanthracenes can be salts of the substances according to the invention with mineral acids, carboxylic acids or sulfonic acids. Particularly preferred are, for example, salts with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid, maleic acid or benzoic acid. Salts in the context of the present invention are also salts of monovalent metals such as alkali metals and the ammonium salts. Sodium, potassium and ammonium salts are preferred.

The compounds according to the invention exist in stereoisomeric forms which either behave like images and mirror images (enantiomers) or do not behave like images and mirror images (diastereomers). The invention relates to both the antipodes and the racemic forms as well as the diastereomer mixtures. Like the diastereomers, the racemic forms can be separated into the stereoisomerically uniform constituents in a known manner.

Compounds of the general formula (I) in which

A and D are the same or different and are hydrogen, hydroxy, fluorine, chlorine, bromine, carboxy, nitro, trifluoromethyl, trifluoromethoxy or

 stand for straight-chain or branched alkyl or alkoxy each having up to 6 carbon atoms,

R ¹ and R ^{2 are the} same or different and represent hydrogen, fluorine, chlorine, bromine, cyano, formyl, phenyl or hydroxy, or

 stand for straight-chain or branched alkoxy with up to 6 carbon atoms, or

stand for straight-chain or branched alkyl or alkenyl each having up to 6 carbon atoms, which may optionally be up to 2 times identical or different by hydroxy, nitro, phenyl, fluorine, chlorine, bromine, by straight-chain or branched alkoxy having up to 4 carbon atoms or by a group of the formula -NR ³ R ^{4 are} substituted, wherein

R ³ and R ^{4 are the} same or different and and hydrogen, straight chain or branched alkyl having up to 4 carbon atoms or phenyl,

E and L together form a heterocyclic radical of the formula

wherein

R ⁵ and R ^{6 are the} same or different and are hydrogen, fluorine, chlorine, bromine, phenyl or straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally substituted by carboxy or by straight-chain or branched alkoxycarbonyl having up to 4 carbon atoms,

R ⁷ , R ⁸ , R ⁹ and R ^{10 are the} same or different and are hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms, or each R ⁷ and R ⁸ and / or R ⁹ and R ¹⁰ together represent the rest of the formula Form O, a denotes a number 2, 3, 4, 5, 6 or 7,

R ^{11 is} phenyl which may be up to 3 times the same or different by fluorine, chlorine, bromine, hydroxy, nitro, cyano, Trifluoromethyl, trifluoromethoxy or substituted by straight-chain or branched alkyl or alkoxy each having up to 6 carbon atoms, or

R ^{11 is} hydrogen, cyclopentyl, cyclohexyl, cycloheptyl, pyridyl or pyrimidyl, or

 straight-chain or branched alkyl having up to 8 carbon atoms, which is optionally up to 2 times the same or different substituted by phenyl, which in turn is up to 3 times the same or different by fluorine, chlorine, bromine, hydroxy, nitro, cyano, trifluoromethyl , Trifluoromethoxy or substituted by straight-chain or branched alkyl or alkoxy each having up to 6 carbon atoms, and their salts.

Compounds of the general formula (I) in which

A and D are identical or different and represent hydrogen, hydroxyl, fluorine, chlorine, bromine or straight-chain or branched alkyl having up to 4 carbon atoms,

R ¹ and R ^{2 are the} same or different and represent hydrogen, fluorine, chlorine, bromine, cyano, formyl, phenyl or hydroxy, or

 stand for straight-chain or branched alkoxy with up to 4 carbon atoms, or

stand for straight-chain or branched alkyl or alkenyl, each having up to 4 carbon atoms, optionally up to 2 times the same or different by hydroxy, nitro, phenyl, fluorine, chlorine, bromine straight-chain or branched alkoxy having up to 3 carbon atoms or substituted by amino or aminomethyl,

E and L together form a heterocyclic radical of the formula

form,

wherein

R ⁵ and R ^{6 are} identical or different and are hydrogen, fluorine, chlorine, bromine, phenyl or straight-chain or branched alkyl having up to 4 carbon atoms, which is optionally substituted by carboxy or by straight-chain or branched alkoxycarbonyl having up to 3 carbon atoms,

R ⁷ , R ⁸ , R ⁹ and R ^{10 are the} same or different and represent hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms, or in each case R ⁷ and R ⁸ and / or R ⁹ and R ¹⁰ together represent the rest of the formula = Form O, a denotes a number 2, 3, 4, 5 or 6,

R ^{11 is} phenyl, optionally up to 3 times the same or different by fluorine, chlorine, bromine. Hydroxy, nitro, cyano, Trifluoromethyl, trifluoromethoxy or substituted by straight-chain or branched alkyl or alkoxy each having up to 4 carbon atoms, or

R ^{11 is} hydrogen, cyclopentyl, cyclohexyl, cycloheptyl, pyridyl or pyrimidyl, or

 straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally up to 2 times the same or different substituted by phenyl, which in turn is up to 3 times the same or different by fluorine, chlorine, bromine, hydroxy, nitro, cyano, trifluoromethyl , Trifluoromethoxy or substituted by straight-chain or branched alkyl or alkoxy each having up to 4 carbon atoms, and their salts.

In addition, processes for the preparation of the compounds of the general formula (I) according to the invention were found, characterized in that

[A] compounds of the general formula (II)

in welcher

in which

A, D, R ¹ , R ² , R ⁵ and R ^{6 have} the meaning given above, with compounds of the general formula (III)

in welcher a und R¹¹ die oben angegebene Bedeutung haben, in inerten Lösemitteln, in Anwesenheit einer Base und/oder Hilfsmittels, gegebenenfalls unter Schutzgasatmosphäre umsetzt, oder

in which a and R ^{11 have} the meaning given above, in inert solvents, in the presence of a base and / or auxiliary, if appropriate under an inert gas atmosphere, or

[B] Compounds of the general formula (IV)

in which

A, D, R ¹ , R ² , R ⁵ and R ^{6 have} the meaning given above, first by reaction with compounds of the general formula (V)

Q- [CH ₂ ] _a -S (V), in which a has the meaning given above

Q for halogen or for a typical leaving group, but preferably for

Bromine stands, and

S has the meaning of Q given above or represents carboxy or an activated carbonyl radical, in inert solvents, optionally in the presence of a base, into the compounds of the general formula (VI)

in which

A, D, a, R ¹ , R ² , R ⁵ and R ^{6 have} the meaning given above, and

T comprises the scope of Q and S given above, transferred, and in a second step, likewise in the presence of a base and a solvent, with compounds of the general formula (VII)

in welcher

in which

R ^{11 has} the meaning given above, implements, or

[C] initially compounds of the general formula (III) by reaction with compounds of the general formula (VIII)

in welcher

in which

R ⁵ and R ^{6 have} the meaning given above, in the compounds of the general formula (IX)

in welcher

in which

in welcher R ⁵ , R ⁶ , R ¹¹ and a have the meaning given above, and then with anthracenes of the general formula (X)

in which

A, D, R ¹ and R ^{2 have} the meaning given above, in inert solvents, and in the event that R ⁷ and R ⁸ and / or R ⁹ and R ¹⁰ do not together form the rest of the formula = O, after usual methods reduced, and optionally the above-mentioned substituents varied by known methods.

The processes according to the invention can be illustrated by the following formula schemes:

Customary organic solvents which do not change under the reaction conditions are suitable as solvents for the processes. These preferably include ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether, 1,2-dimethoxyethane or hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions, or halogenated hydrocarbons such as dichloromethane, trichloromethane, tetrachloromethane, or dichloro-ethylene-benzene, trichloro-methylene chloride , Triethylamine, pyridine, dimethyl sulfoxide, dimethylformamide, hexamethylphosphoric triamide, acetonitrile, acetone or nitromethane. It is also possible to use mixtures of the solvents mentioned. Xylene is preferred.

In general, inorganic or organic bases can be used as bases for the processes according to the invention. These preferably include alkali hydroxides or such as sodium hydroxide, potassium hydroxide or lithium hydroxide, barium hydroxide, alkali or alkaline earth carbonates such as sodium carbonate, potassium carbonate, calcium carbonate or cesium carbonate, or alkali or alkaline earth alcoholates such as sodium or potassium methoxide or potassium tert. butylate, or lithium diisopropylamide (LDA), or organic amines (trialkyl (C ₁ -C ₆ ) amines) such as triethylamine, or heterocycles such as 1,4-diazabicyclo [2.2.2] octane (DABCO), 1,8-diazabicyclo [ 5.4.0] undec-7-ene (DBU), pyridine, diaminopyridine, methylpiperidine or morpholine. It is also possible to use alkali metals such as sodium or their hydrides such as sodium hydride as bases. Potassium carbonate, sodium hydride, potassium tert-butoxide and cesium carbonate are preferred.

In general, the base is used in an amount of 0.05 mol to 10 mol, preferably 1 mol to 2 mol, in each case based on 1 mol of the compounds of the general formulas (III), (V) and (VII).

Lewis acids such as zinc chloride, titanium tetrachloride, boron tribromide, aluminum chloride or lithium perchlorate or thionyl chloride, phosphorus trichloride, phosphorus pentachloride, phosphorus tribromide or oxalyl chloride are suitable as auxiliaries for activating the carboxylic acid function in the compounds of the general formula (V) and for the Diels-Alder reaction. Also suitable are carbonyl compounds such as carbonyldiimidazole or 1,2-oxazolium compounds such as 2-ethyl-5-phenyl-1,2-oxazolium-3-sulfonate or propane phosphoric anhydride or isobutyl chloroformate or benzotriazolyloxy-tris (dimethylamino) phosphonium hexyl fluorophosphate or phosphonic acid chloride or methanesulfonate or phosphonic acid chloride. optionally in the presence of bases such as triethylamine or N-ethylmorpholine or N-methylpiperidine or dicyclohexylcarbodiimide and N-hydroxysuccinimide.

The processes according to the invention are generally carried out in a temperature range from 0 ° C. to + 180 ° C., preferably from + 20 ° C. to + 150 ° C.

The process according to the invention is generally carried out at normal pressure. However, it is also possible to carry out the process under overpressure or under underpressure (for example in a range from 0.5 to 5 bar). The reduction of carbonyl functions is generally carried out using complex hydrides such as lithium aluminum hydride or sodium borohydride, preferably using lithium aluminum hydride in inert solvents such as ethers or hydrocarbons or mixtures thereof, preferably in ethers such as diethyl ether, tetrahydrofuran or dioxane, in a temperature range from 0 ° C. to + 150 ° C, preferably from + 20 ° C to + 100 ° C, at normal pressure.

The derivatizations of the substituents R ¹ , R ² , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ listed above are generally carried out according to methods known from the literature, examples being the reduction of aldehydes or alkoxycarbonyl compounds to alcohols ( a), the reduction of double bonds (b) and the alkylation (c) are to be explained with the following: a) The reduction of carbonyl compounds to the corresponding alcohols is generally carried out using hydrides, such as lithium aluminum hydride or sodium borohydride, preferably in the case of the alkoxycarbonyl compounds using lithium aluminum hydride and in the case of the aldehydes preferably with sodium borohydride in inert solvents such as ethers, hydrocarbons or alcohols or mixtures thereof, preferably in ethers such as diethyl ether, tetrahydrofuran or dioxane, or alcohols such as ethanol, in the case of the aldehydes preferably with sodium borohydride in ethanol, in a temperature range from 0 ° C to + 150 ° C, preferably from +20 ° C to + 100 ° C, at normal pressure.

The reduction of a double bond is generally carried out by hydrogenation with hydrogen in the presence of a catalyst such as platinum or platinum oxides, rhodium, ruthenium, chlorotris (triphenylphosphine) rhodium, or palladium on charcoal, preferably with palladium on charcoal in a temperature range from 0 ° C. to + 150 ° C, preferably from + 25 ° C to + 100 ° C. b) Protic solvents such as methanol, ethanol and / or aprotic solvents such as tetrahydrofuran, toluene, dimethylformamide, methylene chloride, dioxane or ethyl acetate are suitable as solvents for the hydrogenation.

The hydrogenation is carried out at a pressure of 1 to 300 atm, preferably at 1 to 20 atm. c) The alkylation is generally carried out in one of the solvents listed above with alkylating agents such as (C ₁ -C ₈ ) alkyl halides, sulfonic acid esters or substituted or unsubstituted (C ₁ -C ₈ ) dialkyl or (C ₁ -C ₈ ) Diaryl sulfates, preferably methyl iodide, p-toluenesulfonic acid ester or dimethyl sulfate.

Some of the compounds of the general formula (II) are known or new and can then be prepared, for example, by anthracene or its substituted derivatives, with maleic anhydride or its substituted derivatives, such as citraconic anhydride, in one of the solvents listed above, preferably toluene or xylene , in a temperature range from 100 to 150 ° C, preferably at 140 ° C, or in an aprotic solvent, such as methylene chloride, in the presence of one of the Lewis acids listed above, for example aluminum chloride, in a temperature range from 0 ° C to 80 ° C, preferably at room temperature to + 40 ° C.

The compounds of the general formulas (III), (V), (VII), (VIII) and (X) are known per se or can be prepared by customary methods.

Some of the compounds of the general formula (IX) are known or new and can then be prepared as described above.

Some of the compounds of the general formula (IV) are also known or new and can then, for example, as described above for the compounds of the general formula (II), by reacting anthracene or its Substituted derivatives with substituted or unsubstituted succinimides can be prepared.

The compounds of the general formula (VI) are new and can be prepared, for example, as described above.

The compounds of the general formula (I) according to the invention surprisingly show an immunomodulating effect.

They are therefore suitable for the treatment of rheumatoid arthritis, multiple sclerosis, muscle weakness, lupus erythematosus disseminatus, Graves' disease, psoriasis, graft rejection, Hashimoto's, thyroiditis, inflammatory bowel diseases, inflammation of the gastrointestinal tract, primary liver cirrhosis and autoimmune anemia.

Adjuvant arthritis model in the rat

Freund's adjuvant (FA) is made by adding 10 mg / ml of heat-killed Mycobacterium butyricum in extra-heavy mineral oil. Lewis rats receive a 0.1 ml injection of FA (1 mg / animal) subcutaneously into the right hind paw. There is an acute inflammation, which is characterized by redness, edema and a predominant neutrophil cell infiltration (primary reaction). Swelling areas in the treated paw on day 5 are followed by an increase in swelling (chronic inflammatory response) between days 10 and 12 and the appearance of swelling in the opposite untreated paw (secondary immune response).

The cell infiltration of chronic inflammation and the second immune response are predominantly mononuclear, indicating the presence of cell-directed immunization. The animals are observed daily and the swelling is measured in millimeters on days 12 and 16 with a manually adjustable micrometer. The swelling peaks on the 16th day, when the animals are killed and tissue samples are taken for histological evaluation. The extent of the swelling is determined by calculating the greatest difference between the 16th and the 0th day of the ankle diameter.

The animals receive the compounds according to the invention in a suspension of 5% polyethylene glycol and 0.5% Tween 80 in phosphate buffer solution p.o. or i.p. on days 0, 1, 2, 5, 7, 9, 12 and 14 [cf. see L. Sokoloff, 1984, Int. Rev. Exp. Pathol. 26, 107; M.E.J. Bittingham et al., 1989, J. Exp. Med. 171, 339; K.M. Connolly et al., 1989, Agents and Actions 27, 328].

Table A:

 E.g. no. Inhibition of swelling (%) after administration of 10 mg / kg i.p.

2 4

 11 32

 29 24

 30 47

 33 33

 39 20

 40 29

 58 40

 59 53

 60 40

 61 50

 62 90

 63 26

 64 76

 71 82

 72 87

 74 76

 82 35

 87 22

 88 73

 89 42

 90 45

 91 18

 108 55

109 34 The in vitro activity of the compounds according to the invention results from their ability to inhibit T cell proliferation, which is previously stimulated by serotonin.

Inhibition of 5-HT dependent T cell proliferation

Peripheral mononuclear blood cells (PBMC) are obtained from the blood of healthy volunteers from the butty coat. After isolation using isolymph gradients (Pharmacia), the PBMC are washed twice and used directly. Purified T cells are formed by E-Rossette formation with sheep erythrocytes [cf. Blue, M.-L., J..F. Daley, H. Levine, KA Craig and SF Schlossman, 1986, Biosynthesis and surface expression of T8 by peripheral blood T4 + cells in vitro, J. Immunol. 137, 1202]. Monocytes are partially removed by adhesion to tissue platelet cultures. PBMC, T cells or purified T cells (depleted of monocytes) with 5 × 10 ⁵ / ml, 100 μl / well are in RPMI-1640 medium with 10% fetal calf serum (GIBCO) and L-glutamine in 96-well Microculture plates (Becton-Dickinson) cultured under a 5% CO ₂ atmosphere at 37 ° C for 7 days. The cultures are mixed with 1 μCi ³ H-thymidine for 6 h on the 7th day, collected on filter paper, and the incorporated radioactivity is determined by means of liquid scintillation counting.

The test substances are dissolved in 10 mM HCl in order to reach a final concentration of 1 mM each. The compounds are mixed 3 × with series in order to obtain a final concentration between 33 μM - 0.1 μM. PWM (1: 200, poke weed mitogen) and 5-HT (100 μM, serotonin) containing the test substances are added to monocyte-free human T cells. The positive control (maximum proliferation) is obtained from cultures with T cells, PWM and 5-HT. The negative control (minimal proliferation) is obtained from cultures with T cells and PWM without 5-HT. The inhibitory activity of the test substances is expressed as IC ₅₀ in μM.

The new active ingredients can be converted in a known manner into the customary formulations, such as tablets, dragées, pills, granules, aerosols, syrups, emulsions, suspensions and solutions, using inert, non- toxic, pharmaceutically suitable carriers or solvents. The therapeutically active compound should in each case be present in a concentration of about 0.5 to 90% by weight of the total mixture, ie in amounts which are sufficient to achieve the dosage range indicated.

The formulations are prepared, for example, by stretching the active ingredients with solvents and / or carriers, optionally using emulsifiers and / or dispersants, e.g. if water is used as the diluent, organic solvents can optionally be used as auxiliary solvents.

The application is carried out in the usual way, preferably orally or parenterally, in particular perlingually or intravenously.

In the case of parenteral use, solutions of the active ingredient can be used using suitable liquid carrier materials.

In general, it has proven to be advantageous to administer amounts of approximately 0.001 to 1 mg / kg, preferably approximately 0.01 to 0.5 mg / kg of body weight in the case of intravenous administration in order to achieve effective results, and the dosage is approximately in the case of oral administration 0.01 to 20 mg / kg, preferably 0.1 to 10 mg / kg body weight.

Nevertheless, it may be necessary to deviate from the amounts mentioned, depending on the body weight or the type of application route, on the individual behavior towards the medication, the type of its formulation and the time or interval at which the administration takes place . In some cases it may be sufficient to make do with less than the above-mentioned minimum quantity, while in other cases the above-mentioned upper limit must be exceeded. In the case of application of larger quantities, it may be advisable to distribute them in several individual doses over the day. Output connections

Example I

9,10-dihydro-9,10 [3 ', 4'] furanoanthracene-12,14 (11H, 15H) -dione

180 g (1.01 mol) of anthracene are suspended together with 100 g (1.02 mol) of maleic anhydride in 1000 ml of xylene. The suspension dissolves when heated to 140 ° C. and precipitates again after refluxing for 10 minutes. After cooling to room temperature, the precipitated cream-colored crystals are washed with xylene and ether and dried.

Mp: 261-263 ° C

Yield: 259.9 g (92.8%)

Example II

4- [4- (4-fluorophenyl) piperazin-1-yl] propionitrile

100 g (0.55 mol) of 1- (4-fluorophenyl) piperazine are dissolved in 300 ml of toluene and 0.9 ml of diazabicycloundecene (DBU) are added. With stirring and ice cooling, 63.2 ml (0.96 mol) of acrylonitrile are added dropwise within 20 min so that the Temperature is kept below 30 ° C. After 24 h, the mixture is cooled to 10 ° C .; the colorless crystals which have precipitated are washed with ether / petroleum ether 1: 1 and dried (97.4 g). After concentrating the mother liquor, another 30.5 g are obtained. Mp 84-86 ° C

Yield: 127.9 g (98.8%)

Example III

3- [4- (4-fluorophenyl) piperazin-1-yl] propylamine

127.5 g (0.547 mol) of the compound from Example II are in a steel autoclave in 250 ml of methanol and 100 ml of liquid ammonia with 30 g of Raney nickel / iron = 85:15 at 100-120 bar and 90 ° C. for about 5 hours hydrated. After the catalyst has been suctioned off, it is washed with methanol and the mother liquor is concentrated on a rotary evaporator. The oily residue is triturated with ether / petroleum ether and the colorless crystals are filtered off with suction.

Melting point: 56-58 ° C

Yield: 96.1 g (74%)

Example IV

9,10-Dihydro-9,10 [3 ', 4'] - 1 1-methyl-furanoanthracen-12,14- (11H, 15H) -dione

1 g (0.0056 mol) anthracene and 0.63 g (0.0056 mol) citraconic anhydride in 30 ml methylene chloride p.A. stirred and mixed in portions with 0.75 g (0.0056 mol) of aluminum chloride. After 4 hours of stirring at room temperature, the black solution is poured onto ice water. After extracting twice with methylene chloride, the mixture is washed twice with water, dried with sodium sulfate and concentrated on a rotary evaporator in a water jet vacuum. The remaining oil is triturated with ether / petroleum ether = 1: 1 and the crystalline precipitate is filtered off with suction.

Melting point: 158-161 ° C

Yield: 1.3 g (80%)

Example V

9,10-dihydro-9,10 [3 ', 4'] furanoanthracene-12,14 (11H, 15H) -dione

180 g (1,01 mol) Anthrazen werden zusammen mit 100 g (1,02 mol) Maleinsäureanhydrid in 1000 ml Xylol suspendiert. Die Suspension geht beim Aufheizen auf 140°C in Lösung und fällt nach 10 min Kochen unter Rückfluß erneut aus. Nach Abkühlen auf Raumtemperatur werden die ausgefallenen cremefarbenen Kristalle mit Xylol und Ether gewaschen und getrocknet.

180 g (1.01 mol) of anthracene are suspended together with 100 g (1.02 mol) of maleic anhydride in 1000 ml of xylene. The suspension dissolves when heated to 140 ° C. and precipitates again after refluxing for 10 minutes. After cooling to room temperature, the precipitated cream-colored crystals are washed with xylene and ether and dried.

Mp: 261-263 ° C

Yield: 259.9 g (92.8%)

Example VI

3- {4- [bis- (4-fluorophenyl) methyl] piperazin-1-yl} propionitrile

 21.2 g (0.073 mol) of 1-bis (4-fluorophenyl) methylpiperazine (Janssen) are stirred with 100 ml of toluene in a flask flushed with argon; add 0.9 ml DBU and stir. 8.5 ml (0.129 mol) of acrylonitrile are added dropwise to the resulting solution in about 15 min below 30 ° C. (ice bath cooling, slightly exothermic). The solution is left to stand at room temperature for 3 days and rotated in on a rotary evaporator at about 40 ° C./20 mbar. About 30 ml of ether / petroleum ether 1: 1 is added to the remaining oil and triturated. The cream-colored crystals are filtered off, washed with ether / petroleum ether and dried.

Melting point: 71-73 ° C

Yield: 19.2 g (76.5% of theory) Example VII

3 - [4- [bis- (4-fluorophenyl) methyl] piperazin-1-yl} propylamine

The hydrogenation of 18.5 g (0.0542 mol) of the compound from Example II is carried out in a steel autoclave in 100 ml of methanol and 30 ml of liquid ammonia with the addition of 4 g of RaNi at 60-70 bar and 70 ° C. for about 6 hours . After filtering off the catalyst, it is washed with methanol, the residue is discarded and the mother layer is concentrated on a rotary evaporator at about 35 ° C. in a water jet vacuum. The colorless oil obtained is reacted further without additional purification. Yield: 18 g (97% of theory)

Manufacturing examples

example 1

13- {3- [4- (4-fluorophenyl) piperazin-1-yl] propyl} -9.10-dihydro-9.10 [3 ', 4'] -pyrroloanthracene-12.14 (1 1H, 15H ) dion

7.9 g (0.028 mol) of the compound from Example I are suspended together with 7.8 g (0.03 mol) of the compound from Example III in 100 ml of xylene and boiled under reflux for 1.5 hours on a water separator. After cooling to room temperature, the solution is left to stand for 3 hours and the colorless crystals which have precipitated are filtered off with suction, washed with ether / petroleum ether and dried (9.5 g). After concentrating the mother liquor, a further 4.4 g of the title compound are obtained.

Mp: 162-164 ° C

Yield: 13.9 g (98%)

The examples listed in Tables 1, 2 and 3 are prepared in analogy to the instructions in Example 1:

Beispiel 58

Example 58

13- {3- [4- (4-Fluorophenyl) piperazin-1-yl] propyl} -9,10,11,12,14,15-hexahydro-9,10 [3 ', 4'] pyrroloanthracene

100 ml of absolute dioxane are placed in a heated flask under argon and 2.5 g (0.065 mol) of lithium aluminum hydride are suspended with stirring.

After heating to 90 ° C., 11 g (0.022 mol) of the compound from Example 1 are added in portions over the course of 10 minutes. The suspension is then boiled under reflux for 6 h. After cooling to room temperature, 2.5 ml of water and 7.5 ml of dilute KOH are added dropwise with vigorous stirring, the mixture is boiled under reflux for 10 minutes, the voluminous precipitate is suctioned off hot and washed with dioxane.

 After concentrating the mother liquor on a rotary evaporator, the oily residue is dissolved in methylene chloride, washed twice with water and the organic phase is dried with sodium sulfate and concentrated in a rotary evaporator. The remaining oil is triturated with ether / petroleum ether and the colorless crystals are suction filtered and dried.

Mp: 94-96 ° C

Yield: 85.7%

The compounds listed in Tables 4, 5, 6, 7, 8, 9 and 10 are prepared in analogy to the procedure in Example 58:

Beispiel 145

Example 145

13- {3- [4- (bis-4-fluorophenyl) methyl) piperazin-1-yl] propyl} -9.10-dihydro-9.10 [3 ', 4'] pyrroloanthracene-12.14 (1 1H, 15H) dione

 5.2 g (0.015 mol) of the compound from Example III, dissolved in 15 ml of xylene, are added dropwise to a suspension of 4.1 g (0.015 mol) of the compound from Example I in 100 ml of xylene and added in a water separator for 1.5 h cooked. The solution is cooled to room temperature and concentrated on a rotary evaporator at 50 ° C / 20 mbar. The remaining oil is triturated with ether / petroleum ether 1: 1. The cream-colored crystals are filtered off and dried.

Melting point: 188-190 ° C

Yield: 8.1 g (90.3% of theory)

The examples listed in Tables 1 1 and 12 are prepared in analogy to the instructions in Example 1:

Example 165

13- {3- [4 (bis-4-fluorophenyl) methyl] piperazin-1-yl] propyl} -9,10,11,12,14,15-hexahydro-9,10 [3 ', 4' ] pyrroloanthracene

Under argon, 6.9 g (0.011 mol) of the compound from Example 1 are introduced in portions over a period of 10 minutes into a 90 ° C. suspension of 1.3 g (0.034 mol) of lithium aluminum hydride in 150 ml of dioxane pA with vigorous stirring. The suspension is boiled under reflux (100 ° C.) for 6 h, cooled to room temperature and 1.3 ml of H ₂ O are carefully added dropwise with stirring. 3.9 ml of dilute chewing lye are then added dropwise and the mixture is boiled for 10 minutes and suction filtered while hot. The remaining precipitate is washed with dioxane and discarded. The mother liquor is cooled to room temperature and concentrated on a rotary evaporator at approx. 40 ° C / 20 mbar. The oily residue is mixed with methylene chloride / water, extracted twice with methylene chloride, the organic phase is washed 5 times with H ₂ O and dried over Na ₂ SO ₄ and concentrated on a rotary evaporator at 35 ° C./20 mbar. 6.59 g of oil are obtained.

The oil obtained is dissolved in 80 ml of pA ether and added with 2.65 g of maleic acid (0.0228 mol) dissolved in pA THF. The white crystalline precipitate is suctioned off with ether and washed.

 Melting point: 198-200 ° C

 Yield: 8.2 g (89%)

The compounds listed in Table 2 are prepared in analogy to the procedure of Example 13:

The compounds listed in Tables 15 and 16 are prepared analogously to the instructions in Example 58.

The compounds listed in Table 17 are prepared analogously to the instructions in Examples 145.

The compounds listed in Table 18 are prepared analogously to the instructions in Example 165.

Claims

claims 1. Piperazine-substituted pyrroloanthracenes of the general formula (I)

in which A and D are the same or different and represent hydrogen, hydroxy, halogen, cyano, carboxy, nitro, trifluoromethyl, trifluoromethoxy, or  stand for straight-chain or branched alkyl or alkoxy each with up to 8 carbon atoms, R ¹ and R ^{2 are the} same or different and represent hydrogen, halogen, cyano, formyl, phenyl or hydroxy, or  stand for straight-chain or branched alkoxy with up to 8 carbon atoms, or stand for straight-chain or branched alkyl or alkenyl each having up to 8 carbon atoms, which may optionally be up to 2 times identical or different by hydroxy, nitro, phenyl, halogen, by straight-chain or branched alkoxy having up to 6 carbon atoms or by a group of the formula -NR ³ R ^{4 are} substituted, wherein R ³ and R ^{4 are the} same or different and are hydrogen, straight-chain or branched alkyl having up to 6 carbon are atoms or phenyl, E and L together form a heterocyclic radical of the formula

wherein R ⁵ and R ^{6 are} identical or different and are hydrogen, halogen, phenyl or straight-chain or branched alkyl having up to 8 carbon atoms, which is optionally substituted by carboxy or by straight-chain or branched alkoxycarbonyl having up to 6 carbon atoms, R ⁷ , R ⁸ , R ⁹ and R ^{10 are the} same or different and are hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms, or each R ⁷ and R ⁸ and / or R ⁹ and R ¹⁰ together represent the rest of the formula Form O, a denotes a number 2, 3, 4, 5, 6, 7 or 8, R ^{11 means} aryl having 6 to 10 carbon atoms, optionally up to 3 times the same or different by halogen. Hydroxy, nitro, cyano, trifluoromethyl, trifluor methoxy or substituted by straight-chain or branched alkyl or alkoxy each having up to 8 carbon atoms, or R ^{11 is} hydrogen, cycloalkyl having 3 to 8 carbon atoms, pyridyl or pyrimidyl, or  straight-chain or branched alkyl is substituted by up to 2 times the same or different by phenyl, which in turn is up to 3 times the same or different by halogen, hydroxy, nitro, cyano, trifluoromethyl, trifluoromethoxy or by straight-chain or branched alkyl or alkoxy with each up to 8 carbon atoms can be substituted, and their salts. 2. Piperazine-substituted pyrroloanthracenes according to claim 1, in which A and D are identical or different and represent hydrogen, hydroxyl, fluorine, chlorine, bromine, carboxy, nitro, trifluoromethyl, trifluoromethoxy or straight-chain or branched alkyl or alkoxy each having up to 6 carbon atoms, R ¹ and R ^{2 are the} same or different and represent hydrogen, fluorine, chlorine, bromine, cyano, formyl, phenyl or hydroxy, or represent straight-chain or branched alkoxy having up to 6 carbon atoms, or stand for straight-chain or branched alkyl or alkenyl each having up to 6 carbon atoms, which may be up to 2 times the same or different by hydroxy, nitro, phenyl, fluorine, chlorine, Bromine, are substituted by straight-chain or branched alkoxy having up to 4 carbon atoms or by a group of the formula -NR ³ R ⁴ , in which R ³ and R ^{4 are the} same or different and are hydrogen, straight-chain or branched alkyl having up to 4 carbon atoms or phenyl, E and L together form a heterocyclic radical of the formula form,

wherein R ⁵ and R ^{6 are the} same or different and are hydrogen, fluorine, chlorine, bromine, phenyl or straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally substituted by carboxy or by straight-chain or branched alkoxycarbonyl having up to 4 carbon atoms, R ⁷ , R ⁸ , R ⁹ and R ^{10 are the} same or different and are hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms, or R ⁷ and R ⁸ and / or R ⁹ and R ¹⁰ together form the radical of the formula = O, a denotes a number 2, 3, 4, 5, 6 or 7, R ^{11 is} phenyl, which is optionally up to 3 times the same or different by fluorine, chlorine, bromine, hydroxy, nitro, cyano, trifluoromethyl, trifluoromethoxy or by straight-chain or branched alkyl or alkoxy each having up to 6 carbon atoms, or R ^{11 is} hydrogen, cyclopentyl, cyclohexyl, cycloheptyl, pyridyl or pyrimidyl, or  straight-chain or branched alkyl having up to 8 carbon atoms, which is optionally up to 2 times the same or different substituted by phenyl, which in turn is up to 3 times the same or different by fluorine, chlorine, bromine, hydroxy, nitro, cyano, trifluoromethyl , Trifluoromethoxy or substituted by straight-chain or branched alkoxy each having up to 6 carbon atoms, and their salts. 3. piperazine-substituted pyrroloanthracenes according to claim 1 wherein A and D are the same or different and represent up to 4 for hydrogen, hydroxyl, fluorine, chlorine, bromine or straight-chain or branched alkyl Carbon atoms stand R ¹ and R ^{2 are the} same or different and represent hydrogen, fluorine, chlorine, bromine, cyano, formyl, phenyl or hydroxy, or  stand for straight-chain or branched alkoxy with up to 4 carbon atoms, or  stand for straight-chain or branched alkyl or alkenyl each having up to 4 carbon atoms, which may optionally be up to 2 times identical or different by hydroxy, nitro, phenyl, fluorine, chlorine, bromine, by straight-chain or branched alkoxy having up to 3 carbon atoms or by Amino or aminomethyl are substituted, E and L together form a heterocyclic radical of the formula form,

wherein R ⁵ and R ^{6 are the} same or different and are hydrogen, fluorine, chlorine, bromine, phenyl or straight-chain or branched alkyl having up to 4 carbon atoms, which is optionally substituted by carboxy or by straight-chain or branched alkoxycarbonyl having up to 3 carbon atoms, R ⁷ , R ⁸ , R ⁹ and R ^{10 are the} same or different and are hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms, or each R ⁷ and R ⁸ and / or R ⁹ and R ¹⁰ together represent the rest of the formula = Form O, a is a number 0, 1, 2, 3 or 4 means R ^{11 is} phenyl, which is optionally up to 3 times the same or different by fluorine, chlorine, bromine, hydroxy, nitro, cyano, trifluoromethyl, trifluoromethoxy or by straight-chain or branched alkyl or alkoxy each having up to 4 carbon atoms, and their substitution Salts. 4. piperazine-substituted pyrroloanthracenes according to claim 1 to 3 for therapeutic use. 5. A process for the preparation of piperazine-substituted pyrroloanthracenes according to claim 1 to 3, characterized in that [A] compounds of the general formula (II)

in which A, D, R ¹ , R ² , R ⁵ and R ^{6 have} the meaning given above, with compounds of the general formula (III)

in which a and R ^{11 have} the meaning given above, in inert solvents, in the presence of a base and / or auxiliary, if appropriate under an inert gas atmosphere, or [B] Compounds of the general formula (IV)

in which A, D, R ¹ , R ² , R ⁵ and R ^{6 have} the meaning given above, first by reaction with compounds of the general formula (V) Q- [CH ₂ ] _a -S (V), in which a has the meaning given above Q represents halogen or a typical leaving group, but preferably bromine, and S has the meaning of Q given above or represents carboxy or an activated carbonyl radical, in inert solvents, optionally in the presence of a base, into the compounds of the general formula (VI)

in which A, D, a, R ¹ , R ² , R ⁵ and R ^{6 have} the meaning given above, and T comprises the scope of Q and S given above, transferred, and in a second step, likewise in the presence of a base and a solvent, with compounds of the general formula (VII)

in which R ^{11 has} the meaning given above, implements, or [C] initially compounds of the general formula (III) by reaction with compounds of the general formula (VIII)

in which R ⁵ and R ^{6 have} the meaning given above, in the compounds of the general formula (IX)

in which R ⁵ , R ⁶ , R ¹¹ and a have the meaning given above, and then with anthracenes of the general formula (X)

in which A, D, R ¹ and R ^{2 have} the meaning given above, in inert solvents, and in the event that R ⁷ and R ⁸ and / or R ⁹ and R ¹⁰ do not together form the rest of the formula = O, after usual methods reduced, and optionally the above-mentioned substituents varied by known methods. 6. Medicament containing at least one piperazine-substituted pyrroloanthracene according to claim 1 to 3. 7. Medicament according to claim 6 for immunomodulation. 8. A process for the preparation of medicaments according to claim 6 and 7, characterized in that the piperazine-substituted pyrroloanthracenes are optionally converted into auxiliaries and excipients in a suitable application form. 9. Use of the piperazine-substituted pyrroloanthracenes according to claim 1 to 3 for the manufacture of medicaments. 10. Use of piperazine-substituted pyrroloanthracenes according to Claims 1 to 3 for the production of immunomodulators.