DE4411660A1 - Use of xanthine derivatives to reduce the pathological hyperreactivity of eosinophilic granulocytes, new xanthine compounds and processes for their preparation - Google Patents

Abstract

Tertiary 1-(hydroxy alkyl)-4-alkyl xanthines are suitable for the preparation of medicaments for the treatment of diseases connected with a pathologically raised reactivity of eosinophilic granulocytes. The description relates to novel xanthine derivatives and to a process for producing them.

Description

The present invention relates to the use of tertiary 1- (hydroxyalkyl) -3- alkylxanthines for the manufacture of medicines for the treatment of cranes kungen with a pathologically increased reactivity of eosinophilic granulo go hand in hand, new xanthine compounds with the aforementioned substitution Samples and processes for making them.

The hyper-reactive eosinophilic granulocyte is the focus of the pathogenesis certain pulmonary, cardiac and cutaneous diseases, primarily the are atopic.

The atopic form group summarizes diseases with allergic diathesis men who are based on a specifically changed immunity situation by exoge ne, non-infectious substances (environmental allergens) are caused. Allergic In principle, diseases can affect all essential human organ systems bodies affect and manifest themselves in a multitude of different ways Diseases such as arthalgia, asthma, erythema exudative multiforme, duck ritis, nephritis, rhinitis or vasculitis (Wien Klin Wochenschr (1993) 105/23: 661-668).

In clinical practice, the immunoglobulin-E (IgE) -mediated immune dominate reactions (type I allergies) in the form of anaphylaxis, allergic bronchial asthma chial, allergic rhinitis and conjunctivitis, allergic urticaria, allergic Gastroenteritis and atopic dermatitis. It seems for the willingness ge compared to substances from the natural environment (e.g. grass pollen, spores,  House dust and mites, animal hair or food) with one due to atopic Antibody (Reagine) mediated hypersensitivity to react immediately to have a genetic predisposition. The incidence rate is currently around 10% of the population (Pschyrembel, clinical dictionary, Walter de Gruyter- Verlag, 255th edition, 1986, page 148) with continuously increasing prevalence ins especially in the industrialized countries.

The finding that the worldwide increase in morbidity despite in intensive efforts to improve diagnostic and therapeutic options also linked to an increase in mortality, for example in bronchial asthma is (Deutsche Apotheker Zeitung (1993) 133/18: 1635-1636). This is asthma - characterized by inflammatory processes with progressive, insane versibler damage to the respiratory tract - the only chronic disease in the industrialized countries, where the number of Deaths increase (Therapy Week (1993) 43/7: 340-341).

According to the current state of knowledge, the chronic inflammation is in the middle point of the pathogenetic process in which a large number of immunocompetent ter cells is involved in the release of pro-inflammatory mediators. Here it is assumed that the acute phase of inflammation, the so-called called early phase or immediate reaction, mainly basophilic granulocytes and mast cells are involved while continuing for the chronic symptoms progressive tissue loss and loss of function in the late phase reaction eosinophilic granulocytes and possibly also neutrophilic granulocytes Play the leading role (Münch. Med. Wschr. (1993) 135/5: 52).

Basophilic granulocytes and mast cells, also known as histaminocytes, set after activation by binding of IgE produced in B lymphocytes to speci fish high affinity receptors on the cell surface and subsequent cross ver Not only does the binding of the bound IgE molecules by the antigen in question Histamine, but also numerous other inflammatory mediators free. Here to include proteases, lipid mediators, such as the platelet activating factor (PAF),  Prostaglandins and leukotrienes, as well as a wide range of cytokines (Immunopharmaco-logy (1994) 27: 1-11).

These mediators are largely vaso- and bronchoconstrictive, increasing the mucus secretion and intervene in the regulation of hemostasis. Furthermore they are assigned chemotactic properties that enable them to other cells involved in the inflammatory process, including those for the late phase reaction responsible for mobilizing eosinophilic granulocytes ren, which after activation by degranulation also inflammatory mediato secrete what the inflammatory process maintains perpetually and its Chronification is initiated.

The eosinophilic granulocyte is a highly potent effector cell with distinctive Leukocyte-specific properties, such as chemotaxis, adherence, phagocytosis, Release of granule proteins and formation and release of lipids diators and reactive oxygen species, which play their dominant role in pa make the genetic process of the allergic inflammatory reaction understandable (Dt. Ärzteblatt (1992) 89/43, A₁: 3574-3585).

The event after allergen exposure is initiated by recruiting Bone marrow eosinophils and their targeted invasion of the Antigen affected tissue leading to local eosinophilia with subsequent Cell activation leads. These pathophysiological processes are different their immune-competent cells, such as T helper cells of the Th₂ type, macrophages, Neutrophils, mast cells and eosinophils themselves, are involved in a series for diffe differentiation, proliferation, migration and activation of relevant factors produzie er and secrete.

These include the immunomodulating cytokines, such as that from the T helperzel len-formed eosinophil-selective interleukin-5 (IL-5), which both the differences ornamentation and proliferation as well as the functional activation of eosinophils Granulocyte controls, and the granulocyte / macrophage colony stimulating Factor (GM-CSF) with pronounced cell-activating effect; as well as the same time Chemotactic factors responsible for migration and activation, such as PAF and leukotriene B₄ (LTB₄).  

Irrespective of this, the complement cleavage product C5a also has strong chemo tactical and cell stimulating activity for eosinophils.

The activated eosinophilic granulocyte in turn also reacts with Mediato rene synthesis and release in the form of granular proteins, lipid mediators and cytotoxic oxygen metabolites.

The pro-inflammatory lipid mediators include, in particular, leukotriene C₄ (LTC₄), thromboxane A₂ (TXA₂) and in turn PAF, which the vascular permeability increase, vasoconstriction and obstruction of the bronchi and the Mu stimulate kus production (pharmacy in our time (1992) 21/2: 61-70).

Among the protein mediators, eosinophils peroxidase (EPO) are also impressive enzymatic effect and especially those for the destructive processes relevant non-enzymatic, basic proteins, such as the major basic protein (MBP), the Eosinophil Cationic Protein (ECP) and the Eosinophil-Derived Neuro toxin / eosinophil protein X (EDN / EPX). In the foreground of their diverse biologi cytotoxic effects on a broad spectrum of Cells ranging from parasites to bronchial epithelial cells, nerve cells, heart muscle cells to tumor cells. Together with the secreted reactive Oxygen metabolites therefore play a key role in tissue destruction progressive loss of function in areas of allergic inflammatory reactions at.

They also stimulate histamine release from mast cells and thus trigger new early phase attacks in the sense of a vicious circle.

The highly toxic protein mediators also have great diagnostic benefits interpretation, since there are patients with diseases of the atopic form especially increased ECP concentrations in the serum and in other body rivers such as bronchoalveolar lavage, sputum and nasal secretions, but also deposits of these proteins in the affected tissues as a sign of have previous eosinophil activation detected, the ECP Serum levels correlate significantly with the severity of the disease, so that this parameter to objectify disease activity as well as to  Appropriate assessment of treatment success after therapeutic intervention appears (Therapy Week (1991) 41/45: 2946-2947).

The described pathogenetic relationships in diseases of the atopic form make it clear that the center of all ergic inflammatory process with its early and late phase reaction result nes complex interaction of immune cells and their inflammatory Mediators, and that therapeutic advances are only multifunctional len drug is expected to act as both the mediators of the immediate response blocked as well as the recruitment and especially the activation of the eosinophils is able to sustainably inhibit the chronic late-phase reaction (Pharmaceutical Newspaper (1992) 137/5: 249-258; Agents and Actions (1991) 32/1 + 2: 24-33).

Surprisingly, it has now been found that 1,3-dialkylxanthines of the formula I with ter tiarary hydroxyl function in the 1-position alkyl radical the above mentioned An demands on for the treatment of diseases of atopic forms a suitable therapeutic agent.

1- (5-Hydroxy-5-methylhexyl) -3-methylxanthine is described in WO 87/00523 described. It is used there for the treatment of peripheral and cerebral Circulatory disorders as well as mitochondrial mypopathies are suggested without that however any indications of their usability for the reduction of the pa Theological hyperreactivity of eosinophilic granulocytes and thus for treatment lung atopic diseases.

Numerous xanthine compounds are known which, owing to their phos possess phodiesterase inhibitory activity and bronchospasmolytic activity therefore for the prophylaxis and symptomatic treatment of asth Early maternal response induced by mediators of acute bronchospasm are suitable, but do not allow curative therapy of atopic diseases, because the basic suffering, the eosinophil-mediated, chronic Ent  Ignition process of the late phase reaction unaffected. Most prominent ver Theophylline is a member of this group of substances.

More recently, some 8-substituted 1,3-dialkylxanthines (EP 389 286; WO 92/11260), 1,3,7-trialkylxanthines (EP 421 587) and 7-sulfonylated 1,3- Dialkylxanthines and 1,3,7,8-tetrasubstituted xanthines (WO 92/11260) have been reported been used in an animal model with artificially induced eosinophilia Reduce eosinophils in the blood. An inhibition of the atopic crane kung pathologically increased and ultimately determine the course of the disease the functional state of the eosinophils, primarily in the allergic ent Ignition affected tissues, however, could not be shown that the therapeutic value of the compounds described is not proven is.

In contrast, the compounds of formula I on the level of for Disease events relevant cellular mediators that they are the early phases actions inhibit and not only the recruit in the late phase reaction inhibition of eosinophils, but also their pathological hyperreagibility Reduce activity in the target tissue and thus in the center of the chronic patient effector functions of this highly potent inflammation selectively turn off the cell.

In EP 544 391 the 1,3,7-trialkylated xanthines are pentoxifyl lin (3,7-dimethyl-1- (5-oxohexyl) xanthine), propentofylline (3-methyl-1- (5-oxohexyl-7- propylxanthine) and torbafylline (7-ethoxymethyl-1- (5-hydroxy-5-methylhexyl) -3-me thylxanthin) for topical treatment of psoriasis and atopic dermatitis proposed, but without any indication that 1.) these xanthine derivatives are also effective when used non-topically or 2.) also against others Diseases of the atopic form topically or non-topically can be set.  

The invention thus relates to the use of at least one compound of Formula I.

and / or a physiologically acceptable salt of the compound of formula I and / or a stereoisomeric form of the compound of formula I, wherein
R¹ represents a methyl or ethyl group,
R² for an alkyl group with 1 to 4 carbon atoms and
X represents a hydrogen atom or a hydroxy group and
n is an integer from 1 to 5,
for the manufacture of medicaments for reducing the pathological hyperreactivity of eosinophilic granulocytes. The compound of formula I is particularly suitable for the prophylaxis and treatment of atopic diseases such as anaphylaxis, allergic bronchial asthma, allergic rhinitis and conjunctivitis, all allergic urticaria, allergic gastroenteritis or atopic dermatitis.

Compounds of the formula I are preferably used in which R² represents a methyl or ethyl group.

Preference is furthermore given to the use of the compounds of the formula I in which R 1 and R² is independently methyl or ethyl, X is hydrogen or Hy droxygruppe and n are an integer from 3 to 5.

The use of 1- (5-hydroxy-5-methylhexyl) -3-methylxanthine is completely particularly preferred.  

The invention further relates to new compounds of the formula I
and / or a physiologically acceptable salt of the compound of formula I and / or a stereoisomeric form of the compound of formula I, wherein
R¹ is methyl or ethyl,
R² alkyl with 1 to 4 carbon atoms,
X is hydrogen atom or hydroxy group and
n is an integer from 1 to 5
mean, with the exception of 1- (5-hydroxy-5-methylhexyl) -3-methylxanthine.

Preferred are the compounds of formula I in which R² is methyl or Ethyl is, where R¹ and R² are not methyl when X is water Substance atom and n represent the number 4.

Also preferred are the compounds of formula I in which X is Is hydrogen atom, wherein R¹ and R² are not simultaneously methyl if n represents the number 4.

Finally, particular preference is given to those compounds of the formula I in which
R1 methyl,
R² is methyl or ethyl,
X is hydrogen atom and
n is an integer from 1 to 5
mean, where R² is not methyl when n is 4.

The invention further relates to an analogy process for the production of the new Compounds of formula I, the embodiments of which are described in WO 87/00523 are partially described. Thereafter, the procedure is advantageously such that a 3.7- disubstituted xanthine derivative of the formula II,  

in the R² an alkyl group with 1 to 4 carbon atoms and Ra an easily eliminable Leaving group, for example the hydrolytically removable meth, eth, prop or butoxymethyl or the reductively removable benzyl or diphenylmethyl group with unsubstituted or substituted phenyl rings, appropriately in the presence of a basic condensing agent or in the form of its salts

• a) with an alkylating agent of the formula III, in which R 1, X and n have the meanings mentioned above and Z is halogen, preferably chlorine, bromine or iodine, or a sulfonic acid ester or phosphoric acid ester group,
  to a 1,3,7-trisubstituted xanthine of the formula IV implemented, where R¹, R², Ra, X and n have the meanings defined above,
  or alternatively if X is hydrogen,
• b) with a keto compound of the formula V, H₃C-CO- (CH₂) _n -Z (V) in which n and Z have the meanings given above, to give a 1,3,7-trisubstituted xanthine of the formula VI reacted this with a methyl or ethyl metal compound (R¹-M), preferably methyl or ethyl lithium (R¹-Li) or the corresponding Grignard compounds (R¹-MgHal), with reductive alkylation of the carbonyl group in a 1, 3,7-trisubstituted xanthine of formula VII transferred in which R¹, R², Ra and n have the abovementioned meanings,
  or alternatively if X is hydrogen and R¹ is methyl,
• c) with a carboxylic acid ester of the formula VIII, (C₁-C₄) alkyl-O-CO- (CH₂) _n -Z (VIII) in which n and Z have the abovementioned meanings, to give a 1,3,7-trisubstituted xanthine Formula IX implements this then with two equivalents of a methyl-metal compound, preferably CH₃-Li or CH₃-MgHal, with double re-reactive alkylation of the ester function in a 1,3,7-trisubstituted xanthine of the formula X. converts, where R², Ra and n have the meanings given above,

and finally by eliminating the leaving group Ra from the intermediate Compound of formula IV, VII or X the xanthine of formula I according to the invention wins.

Most of the 3,7-disubstituted xanthines of the formula II and alkylating agents of the formulas III, V and VIII used as starting materials are known or can easily be prepared by methods known from the literature (see, for example, WO 87/00523). Thus, the tertiary alcohols of the formula III can be obtained, for example, by organometallic synthesis by the sterically non-hindered halogen ketones of the formula Hal- (CH₂) _n -CO-CH₂X in a so-called build-up reaction with reductive alkylation of the carbonyl group with alkyl metal compounds R¹ -M, where M is metal, primarily magnesium, zinc or lithium, for example in the form of the alkylmagnesium halides R¹-MgHal (Grignard compounds) or the alkyl lithium compounds R¹-Li under customary conditions. A similar reaction of the haloketones according to the formula Hal- (CH₂) _n -CO-R¹ with methyl magnesium halides or methyl lithium also leads to compounds of the formula III in which X is hydrogen.

The reaction of ω-haloalkanoic acid realkylestern (Hal- (CH₂) _n -COO-alkyl) with two equivalents of a methyl-metal compound, with a convenient access to compounds of formula III, in which R¹ is methyl and X represents hydrogen atom Ester reacted via the ketone to the tertiary alcohol with the introduction of two methyl radicals. In the same way, ω-hydroxy-carbonic acid esters with or without protection of the hydroxy group, for example in the form of tetrahydropyranyl (2) or methoxymethyl ether or, if appropriate, also lac-tones as cyclic esters, with methyl metal Convert compounds into diols from which active alkylating agents of the formula III are obtained by selective esterification of the primary hydroxyl function with sulfonic acid or phosphoric acid halides or anhydrides.

The implementation of the disubstituted xanthine derivatives of formula II with those concerned The alkylating agents of the formula III, V or VIII are usually carried out in one distribution or solvent inert to the reactants. When such come mainly dipolar, aprotic solvents, such as forma mid, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, tetramethyl urine substance, hexamethylphosphoric triamide, dimethyl sulfoxide, acetone or butanone in Question; alcohols such as methanol, ethylene glycol and the like can also be used Mono- or di (C₁-C₄) alkyl ether, ethanol, propanol, isopropanol and the various those of butanols; Hydrocarbons such as benzene, toluene or xylenes; halogenated Hydrocarbons such as dichloromethane or chloroform; Pyridine and mischun  gene of the solvents mentioned or their mixtures with water use Find.

The alkylation reactions are conveniently carried out in the presence of a basic one Condensing agent carried out. Alkali or Alkaline earth metal hydroxides, carbonates, hydrides, alcoholates and organic bases, such as Trialkylamines, e.g. B. triethyl or tributylamine, quaternary ammonium or Phos phonium hydroxides and crosslinked resins with fixed, optionally substituted Ammonium or phosphonium groups. The xanthine derivatives can also directly in the form of their separately prepared salts, such as the alkali, alkaline earth or optionally substituted ammonium or phosphonium salts be set. The disubstituted xanthine compounds can also be so probably in the presence of the aforementioned inorganic condensing agents as well in the form of their alkali or alkaline earth salts with the help of so-called phases transfer catalysts, for example tertiary amines, quaternary ammonium or Phosphonium salts or crown ethers, preferably in a two-phase Alkylate the system comfortably under the conditions of a phase transfer catalysis. Suitable, mostly commercially available phase transfer catalysts are under other tetra (C₁-C₄) alkyl and methyltrioctylammonium and phosphonium, Methyl, myristyl, phenyl and benzyl tri (C₁-C₄) alkyl and cetyltrimethylammoni um- and (C₁-C₁₂) alkyl and benzyl triphenylphosphonium salts, wherein in usually those compounds that are the larger and more symmetrically constructed cation possess, prove to be more effective.

The procedures described above generally refer to a reaction temperature between 0 ° C and the boiling point of the ver used reaction medium, preferably between 20 ° and 130 ° C, optionally at elevated or reduced pressure, but usually at atmospheric pressure, with the response time ranging from less than an hour to can be several hours.

In the case of the organometallic reactions, the 1-residue residue is functionalized In principle, the xanthines VI and IX are carried out in the same way as for the preparation of the tertiary alcohols used as alkylating agents in accordance  Formula III described. The reductive alkylation of ketones VI and Ester IX, for example with alkyl potassium, sodium, lithium, magnesium, zinc, Cadmium, aluminum and tin compounds are made. The recently recommended alkyl-titanium and zirconium compounds (D. Seebach et al., Angew. Chem. 95 (1983), pp. 12-26) can also be used. However, since the alkyl metal verbin sodium and potassium due to their high reactivity to secondary actions tend and those of zinc and cadmium are relatively inert are usually the alkyl lithium and magnesium (Grignard) compounds gene preferred.

The strongly nucleophilic organometallic compounds are very hydrolysis and sensitive to oxidation. Their safe handling therefore requires working in anhydrous medium, possibly under a protective gas atmosphere. Usual Lö The means of distribution or distribution are primarily those that are also suitable for the manufacturers alkyl metal compounds are suitable. As such, especially ethers come along one or more ether oxygen atoms, for example diethyl, dipropyl, Dibutyl or diisoamyl ether, 1,2-dimethoxyethane, tetrahydrofuran, dioxane, Te trahydropyran, furan and anisole, and aliphatic or aromatic kohlwas substances such as petroleum ether, cyclohexane, benzene. Toluene, xylenes, diethylbenzenes and Tetrahydronaphthalene in question; but it can also be tertiary amines, such as Triethylamine, or dipolar, aprotic solvents, such as hexamethylphosphoric acid retriamide, and mixtures of the solvents mentioned used with success become. When the carbonyl compounds VI or IX are reacted with the Grignard Compounds of the formula R¹-MgHal can also advantageously be used in this way that, that the organometallic compound is placed in an ether and that Add ketone or the ester as a solution in dichloromethane or 1,2-dichloroethane drips. An addition of magnesium bromide is often recommended because of its Participation in the complex cyclic transition state called nucleophilicity of the organometallic compound is able to increase.

The ketone or ester and organometallic compound are combined in usually at temperatures between -20 ° and 100 ° C, preferably between 0 ° and 60 ° or at room temperature without external cooling, taking the alkyl metal compound usually used in a slight excess. On  in conclusion, the reaction is usually carried out by briefly heating Reflux ended, which usually takes from a few minutes to we enough hours. The alkanolate formed is decomposed before preferably with aqueous ammonium chloride solution or dilute acetic acid.

The elimination of the leaving group Ra from the compounds of the formulas IV, VII and X to form the xanthines of the formula I according to the invention takes place under Standard conditions, especially in the context of protecting group technology Alkaloid and peptide syntheses have been developed and thus largely be knows can be assumed.

Then the benzyl or diphenylmethyl group, optionally substituted in the phenyl ring pe preferably reductively split off. In addition to chemical reduction special of the benzyl compounds with sodium in liquid ammonia comes here for preferably the elimination of the two aforementioned aralkyl groups by ka analytical hydrogenolysis with the help of a noble metal catalyst, wherein the replacement of molecular hydrogen by ammonium formate is often considered Proven hydrogen donor. Usually serves as the reaction medium lower alcohol, optionally with the addition of formic acid or Am moniac; an aprotic solvent, such as dimethylformamide or in particular Glacial acetic acid; but their mixtures with water can also be used. Ge Suitable hydrogenation catalysts are primarily palladium black and palla dium on activated carbon or barium sulfate, while other precious metals such as platinum, Rhodium and ruthenium are often occasions due to competing nuclear hydrogenation give side reactions and are therefore only of limited use. The hydroge nolysis is useful at temperatures between 20 ° and 100 ° C and below Atmospheric pressure or preferably slight excess pressure up to about 10 bar leads, usually reaction times from a few minutes to several Hours are needed.

The 1,3,7-trisubstituted xanthines of the formulas IV, VII and X, which are an alkoxyme bear thyl group in the position of Ra, represent O, N-acetals and can be consequently easily demas under the usual conditions of acid hydrolysis kieren. Preferred radicals are, for example, the methoxy, ethoxy, propoxy and  Butoxymethyl group. The reaction is advantageously diluted with heating Mineral acids, such as hydrochloric or sulfuric acid, optionally with the addition of Glacial acetic acid, dioxane, tetrahydrofuran or a lower alcohol as a dissolver medium, performed. Perchloric acid or organic acid can also be found ren, such as trifluoroacetic, formic and acetic acid, in connection with catalytic Amounts of mineral acids in question. The cleavage of the ether group can be done in principle piell also with the help of Lewis acids, such as zinc bromide and titanium tetrachloride, in anhydrous medium, preferably in dichloromethane or chloroform leads. When cleaved in mineral acid solution, the reaction temperature is to be chosen so that no noticeable dehydration of the 1-position tertiary Hydroxyalkyl group occurs; therefore, it should generally not exceed 60 ° C ten.

The compounds of formula I can be deprotonated in position 7 and therefore form salts and solvates with basic agents. For this come preferred the pharmaceutically acceptable alkali and alkaline earth metal salts and the salts and Solvates with organic bases, for example ethylenediamine or the basic ones Amino acids lysine, ornithine and arginine. The invention thus relates also pharmacologically acceptable salts and / or solvates of 1,3-dialkylxanthines according to formula I.

The tertiary 1- (hydroxyalkyl) -3-alkylxanthines of formula I have an asymmetric cal C atom when X is hydroxy or X is hydrogen and R¹ is ethyl These compounds can thus exist in stereoisomeric forms. The The invention therefore relates both to the pure stereoisomeric compounds and their mixtures.

The new xanthine compounds of formula I according to the invention are suitable excellent because of their valuable pharmacological properties for use as active ingredients in medicinal products, in particular those which an effective prophylactic and curative treatment of pathological Diseases related to eosinophils hyperreactivity, such as those of atopic  Form circle, enable and thus a significant enrichment of the doctor depicting mid-range. You can either do it alone, for example in Form of microcapsules, in mixtures with each other or in combination with suitable carriers are administered.

The invention therefore also relates to medicaments which have at least one Contain compound of formula I as an active ingredient, wherein 1- (5-hydroxy-5-methyl hexyl) -3-methylxanthine is excluded.

Another aspect of the present invention that relates to all of Formula I related compounds is the manufacture of pharmaceutical accessories horsemanships for oral, rectal, topical, parenteral or inhalative administration for diseases with pathologically increased responsiveness of the eosinophi len granulocytes. Suitable solid or liquid pharmaceutical preparation forms are, for example, granules, powders, tablets, coated tablets (micro) capsules, suppositories Chen, syrups, emulsions, suspensions, lotions, creams, ointments, gels, aerosols oils, drops or injectable solutions in ampoule form as well as preparations with protra here active ingredient release, in the production of which usually auxiliary materials, such as Carriers, explosives, binders, coatings, swelling agents, lubricants or lubricants, Flavors, sweeteners or solubilizers find use. When commonly used auxiliaries are e.g. B. magnesium carbonate, titanium dioxide, Lak tose, mannitol and other sugars, talc, milk protein, gelatin, starch, vitamins, Cellulose and its derivatives, animal and vegetable oils, polyethylene glycols and Solvents such as sterile water, alcohols, glycerin and polyvalent Al called kohole.

The pharmaceutical preparations are preferably in dosage units prepared and administered, each unit being an active ingredient contains a correct dose of a compound of the formula I. With fixed dosage units, such as tablets, capsules and suppositories, this dose can be up to 1000 mg, but preferably 100 to 600 mg, and for injection solutions in ampoule form up to 300 mg, but preferably 20 to 200 mg.  

For the treatment of an adult patient - depending on the effectiveness of the Compounds according to formula I in humans - daily doses of 100 to 2000 mg Active ingredient, preferably 300 to 900 mg, when administered orally and from 10 to 500 mg, preferably 20 to 200 mg, indicated for intravenous administration. Under certain circumstances, however, higher or lower daily doses can also be given be brought. The administration of the daily dose can be done both by single administration in Form of a single dosage unit or several smaller doses units as well as multiple doses in certain In intervals.

Finally, the xanthine derivatives of formula I in the preparation of the pre mentioned galenical forms of preparation - if necessary - together with other suitable active ingredients, for example antihistamines, anticholinergics, β₂ mimetics, phosphodiesterase, phospholipase A₂ and lipoxygenase hem men, PAF and leukotriene antagonists, corticosteroids, cromoglicic acid, Ne docromil and cyclosporin A can be formulated.

The structure of all described below and summarized in Table 1 Compounds were determined by elemental analysis and IR and 1 H-NMR spectra secured.  

Manufacturing examples Example 1: 1- (2-Hydroxy-2-methylpropyl) -3-methylxanthine a) 1-Chloro-2-hydroxy-2-methylpropane

To 44.9 g (0.6 mol) of methyl magnesium chloride in the form of a 20% solution in Tetrahydrofuran and 200 ml of dry diethyl ether were added with stirring at 0 ° to 5 ° C a solution of 46.3 g (0.5 mol) of 1-chloro-2-propanone in 50 ml of water dropwise free diethyl ether. Then there was an hour at room temperature and then reflux for an additional hour stirred, the tertiary alkanolate formed by adding 50% aqueous Ammonium chloride solution decomposed, the ether phase separated and the aqueous Phase shaken with ether. The combined ethereal extracts were washed successively with aqueous sodium hydrogen sulfite and sodium hydrogen carbonate Solution and a little water, dried over sodium sulfate, filtered, concentrated reduced pressure and subjected the liquid residue to a fractionated Distillation.

Yield:
31.1 g (57.3% of theory)
Boiling point: 125-127 ° C
C₄H₉ClO (MW = 108.6)

The compound could also be prepared in an analogous manner from methyl chloroacetate. or ethyl ester with twice the molar amount of methyl magnesium chloride in Aus loot to produce 60% of theory.

b) 7-Benzyl-1- (2-hydroxy-2-methylpropyl) -3-methylxanthine

The mixture of 25.6 g (0.1 mol) 7-benzyl-3-methylxanthine, 15.2 g (0.11 mol) Ka lium carbonate and 11.9 g (0.11 mol) of the tertiary alcohol from stage a) in 500 ml Dimethylformamide was heated to 110 ° to 120 ° C. with stirring for 8 hours then filtered hot and evaporated under reduced pressure. You took  the residue with chloroform, washed first with 1N sodium hydroxide solution, then with Water neutral, dried, the solvent distilled off in vacuo and kri installed the solid residue from ethyl acetate with the addition of Pe trolether around.

Yield:
26.6 g (81.0% of theory)
Melting point: 115-117 ° C
C₁₇H₂₀N₄O₃ (MG = 328.4)

Analysis:
Calculated: C 62.18%; H 6.14%; N 17.06%
Found: C 62.60%; H 6.18%; N 17.00%

The compound could also be prepared by using 7-benzyl-3-methylxanthine first with 1-chloro-2-propanone or methyl or ethyl chloroacetate under the reaction conditions described above to 7-benzyl-3- methyl 1- (2-oxopropyl) xanthine or 7-benzyl-1-meth (or eth) oxycarbonylmethyl- Implemented 3-methylxanthine and then the oxopropyl or alkoxycarbonyl methyl side chain with methyl magnesium chloride in anhydrous diethyl ether ana log stage a) reductively methylated.

c) 1- (2-Hydroxy-2-methylpropyl) -3-methylxanthine

13.1 g (0.04 mol) of the 7-benzylxanthine from stage b) were in 200 ml of glacial acetic acid over 1.5 g palladium (10%) on activated carbon at 60 ° C and 3.5 bar within 100 Hydrogenated with shaking for hours. After cooling, it was blanketed with nitrogen, filtered off the catalyst, concentrated under reduced pressure and crystallized the solid residue from ethyl acetate.

Yield:
7.8 g (81.8% of theory)
Melting point: 215-217 ° C
C₁₀H₁₄N₄O₃ (MG = 238.3)

Analysis:
Calculated: C 50.41%; H 5.92%; N 23.52%
Found: C 50.10%; H 5.90%; N 23.40%

Example 2: 3-ethyl-1- (2-hydroxy-2-methylproyl) xanthine a) 7-Benzyl-3-ethylxanthine

To a suspension of 90 g (0.5 mol) of 3-ethylxanthine in 500 ml of methanol 20 g (0.5 mol) of sodium hydroxide dissolved in 200 ml of water and one was stirred Hour at 70 ° C, then added dropwise 69.6 at the same temperature g (0.55 mol) of benzyl chloride and held the reaction mixture between for 3 hours 70 ° and 80 ° C. The product was then cooled, suction filtered with cold suction the suction filter washed with water, dissolved hot in 1000 ml of 1 N sodium hydroxide solution, fil trated and slowly brought to pH 9.5 with 4 N hydrochloric acid with stirring. You fil the crystals separated from the still warm solution, washed chloride with water free and dried in vacuo.

Yield:
131 g (96.9% of theory)
Melting point: 217-218 ° C
C₁₄H₁₄N₄O₂ (MG = 270.3)

b) 3-ethyl-1- (2-hydroxy-2-methylpropyl) xanthine

By reacting 7-benzyl-3-ethylxanthine from stage a) with 1-chloro-2-hydroxy- 2-methylpropane from Example 1a) to 7-benzyl-3-ethyl-1- (2-hydroxy-2-methylpro pyl) -xanthine (C₁₈H₂₂N₄O₃ (MW = 342.4); yield: 46.1% of theory) analogously Example 1b) and subsequent hydrogenolytic debenzylation (yield: 97.9% of theory) according to Example 1c) gave crude end product which could be purified by recrystallization from ethanol.

Melting point: 217-219 ° C
C₁₁H₁₆N₄O₃ (MG = 252.3)

Analysis:
Calculated: C 52.37%; H 6.39%; N 22.21%
Found: C 52.19%; H 6.29%; N 21.75%

Example 3: 1- (3-Hydroxy-3-methylbutyl) -3-methylxanthine a) 1-Chloro-3-hydroxy-3-methylbutane

The compound was made from methyl magnesium iodide and 1-chloro-3-butanone (obtainable by addition of hydrogen chloride to methyl vinyl ketone in diethyl ether) or from methylmagnesium chloride and 3-chloropropionate in dichloromethane prepared as a reaction medium analogous to Example 1a).

Yield:
60-70% of theory
Boiling point (18 mbar): 66-68 ° C
C₅H₁₁ClO (MG = 122.6)

b) 7-Benzyl-1- (3-hydroxy-3-methylbutyl) -3-methylxanthine

prepared analogously to Example 1b) from 7-benzyl-3-methylxanthine and the tertiary Al alcohol from stage a).

Yield:
70% of theory)
Melting point 92-94 ° C
C₁₈H₂₂N₄O₃ (MG = 342.4)

Analysis:
Calculated: C 63.14%; H 6.48%; N 16.36%
Found: C 63.10%; H 6.43%; N 16.28%

c) 1- (3-Hydroxy-3-methylbutyl) -3-methylxanthine

produced by hydrogenolytic debenzylation of the product from stage b) analogous to Example 1c).

Yield:
87.2% of theory
Melting point 203-205 ° C
C₁₁H₁₆N₄O₃ (MG = 252.3)

Analysis:
Calculated: C 52.37%; H 6.39%; N 22.21%
Found: C 52.13%; H 6.52%; N 22.08%

Example 4: 3-Ethyl-1- (3-hydroxy-3-methylbutyl) xanthine a) 7-Benzyl-3-ethyl-1- (3-hydroxy-3-methylbutyl) xanthine

prepared analogously to Example 1b from 7-benzyl-3-ethylxanthine (Example 2a) and 1- Chloro-3-hydroxy-3-methylbutane (Example 3a).

Yield:
71.8% of theory
Melting point: 133-135 ° C
C₁₉H₂₄N₄O₃ (MG = 356.4)

b) 3-ethyl-1- (3-hydroxy-3-methylbutyl) xanthine

obtained according to Example 1c) by hydrogenolytic debenzylation of the product tes from stage a).

Yield:
88.2% of theory
Melting point: 241-243 ° C
C₁₂H₁₈N₄O₃ (MG = 266.3)

Analysis:
Calculated: C 54.12%; H 6.81%; N 21.04%
Found: C 53.89%; H 6.86%; N 21.03%

Example 5 1- (4-Hydroxy-4-methylpentyl) -3-methylxanthine a) 7-Benzyl-3-methyl-1- (4-oxopentyl) xanthine

First, 38.4 g (0.15 mol) of 7-benzyl-3-methylxanthine, 22.4 g (0.162 mol) Potassium carbonate and 26.7 g (0.162 mol) of 1-chloro-4-pentanone ethylene ketal in 600 ml Dimethylformamide analogous to Example 1b) for 7-benzyl-1- (4,4-ethylenedioxypentyl) -3- implemented methylxanthine, which one without further purification of a ketal cleavage by refluxing in 600 ml of 1N hydrochloric acid for 2 hours. The born Detached ketone was neutralized with concentrated sodium hydroxide solution taken up in chloroform and the chloroform extract washed with water,  Dried over sodium sulfate and dried to dryness under reduced pressure steams.

Yield:
50.4 g (98.7% of theory)
Melting point: 104-105 ° C
C₁₈H₂₀N₄O₃ (MG = 340.4)

b) 7-Benzyl-1- (4-hydroxy-4-methylpentyl) -3-methylxanthine

A mixture of 9 g (0.12 mol) of methyl magnesium chloride in the form of the commercial usual 20% solution in tetrahydrofuran and 300 ml dichloromethane cooled to -25 ° C and then dropwise with a solution of 34 g (0.1 mol) of the product from stage a) were added, the temperature rising to 20 ° C. The mixture was stirred for a further hour at room temperature, with saturated Am monium chloride solution added, the organic phase separated, the aqueous Phase shaken several times with dichloromethane, the combined dichloromethane Extract washed with water, dried and evaporated and the solid back was recrystallized from ethyl acetate.

Yield:
28.3 g (79.4% of theory)
Melting point: 132-133 ° C
C₁₉H₂₄N₄O₃ (MG = 356.4)

c) 1- (4-Hydroxy-4-methylpentyl) -3-methylxanthine

was carried out according to Example 1c) by hydrogenolytic debenzylation of the product prepared from stage b).

Yield:
65.9% of theory
Melting point: 188-189 ° C
C₁₂H₁₈N₄O₃ (MG = 266.3)
Analysis:
Calculated: C 54.12%; H 6.81%; N 21.04%
Found: C 53.86%; H 6.88%; N 20.93%

Example 6: 3-Ethyl-1- (4-hydroxy-4-methylpentyl) xanthine a) 7-Benzyl-3-ethyl-1- (4-oxopentyl) xanthine

The illustration was carried out analogously to Example 5a) using 7-benzyl-3-ethyl xanthine from Example 2a) as starting material

Yield:
82.4% of theory
Melting point: 139-141 ° C
C₁₉H₂₂N₄O₃ (MG = 354.4)

b) 7-Benzyl-3-ethyl-1- (4-hydroxy-4-methylpentyl) xanthine

The product from stage a) was analogous to Example 5b) with methyl magnesium chloride implemented.

Yield:
81.9% of theory
Melting point: 155-157 ° C
C₂₀H₂₆N₄O₃ (MG = 370.5)

Analysis:
Calculated: C 64.84%; H 7.07%; N 15.12%
Found: C 64.95%; H 7.18%; N 15.10%

c) 3-Ethyl-1- (4-hydroxy-4-methylpentyl) xanthine

The compound was obtained by hydrogenolytic debenzylation of the product obtained from stage b) analogously to Example 1c).

Yield:
71.3% of theory)
Melting point: 214-216 ° C
C₁₃H₂₀N₄O₃ (MG = 280.3)

Analysis:
Calculated: C 55.70%; H 7.19%; N 19.99%
Found: C 55.50%; H 7.20%; N 20.23%

Example 7: 1- (5-Hydroxy-5-methylhexyl) -3-methylxanthine

The preparation methods for this compound are in PCT application WO 87/00523 described in detail.

Example 8: 1- (5,6-Dihydroxy-5-methylhexyl) -3-methylxanthine a) 1-Chloro-5,6-isopropylidenedioxy-5-methylhexane

To a nitrogen-blanketed mixture of 264 g (1.2 mol) trimethylsul foxonium iodide and 28.8 g (1.2 mol) sodium hydride were stirred at 40 ° C 1000 ml of anhydrous dimethyl sulfoxide were added dropwise in the course of 10 minutes. After the gas evolution ceased (about 2 hours), it was carried out dropwise Add a solution of 134.6 g (1 mol) of 1-chloro-5-hexanone in 30 ml of dimethyl sulfoxide within about 20 minutes. It was 2 hours at room temperature stirred, slowly mixed with ice cooling with 500 ml of ice water and the 1-chloro-5,6-epoxy-5-methylhexane formed is extracted with diethyl ether (yield: 130.5 g (87.8% of theory); C₇H₁₃ClO (MG = 148.6)).

For the hydrolytic cleavage of the epoxy ring, the product was in a Ge mix from 60 ml water, 600 ml tetrahydrofuran and 1 ml 70% perchlor acid stirred for 5 days at room temperature. Then with soda solution neutralized, the tetrahydrofuran largely distilled off and the resulting 1-chloro-5,6-dihydroxy-5-methylhexane extracted with chloroform. (Yield: 124.8 g (85.3% of theory); C₇H₁₅ClO₂ (MW = 166.6)).

The diol was then processed in a conventional manner with 2,2-dimethoxypropane converted into the dioxolane in acetone under acidic catalysis.

Yield:
67.2% of theory
Boiling point (0.5 mbar): 84-86 ° C
C₁₀H₁₉ClO₂ (MG = 206.7)

b) 1- (5,6-Dihydroxy-5-methylhexyl) -3-methylxanthine

The diol from stage a) was analogous to Example 7 with 7-ethoxymethyl-3-methylxanthine 1b) Quantitatively to 7-ethoxymethyl-1- (5,6-isopropylidendioxy-5-methylhexyl) -3-me implement thylxanthine (C₁₉H₃₀N₄O₅, MG = 394.5), from which acidic Hy drolysis with simultaneous opening of the dioxolane ring and splitting off the 7stän The remaining ethoxymethyl residue was obtained. In addition, 19.7 g (0.05 mol) of the xanthine compound in a mixture of 300 ml of 1N hydrochloric acid and 30 ml of glacial acetic acid heated to 70 ° C. for 15 hours after cooling len made alkaline with sodium carbonate and washed with chloroform finally neutralized with 1N hydrochloric acid and extracted with chloroform. The Ab Vapor residue was after filtration through a silica gel column in the eluent Chloroform / methanol (10: 1) recrystallized from ethyl acetate.

Yield:
11.5 g (77.6% of theory)
Melting point 181-182 ° C
C₁₃H₂₀N₄O₄ (MG = 296.3)

Analysis:
Calculated: C 52.69%; H 6.80%; N 18.91%
Found: C 52.46%; H 6.90%; N 18.66%

Example 9: 1- (5-Hydroxy-5-methylheptyl) -3-methylxanthine

7-benzyl-3-methyl-1- (5-oxohexyl) xanthine made from 7-benzyl-3-methylxane thin and 1-chloro-5-hexanone analogously to Example 1b), was with ethyl magnesium chloride according to Example 5b) reductively ethylated on the keto group and the resultant 7-Benzyl-1- (5-hydroxy-5-methylheptyl) -3-methylxanthine then among the Conditions of Example 1c) hydrogenolytically debenzylated.

Yield:
70.2% of theory
Melting point: 169-170 ° C
C₁₄H₂₂N₄O₃ (MG = 294.4)

Analysis:
Calculated: C 57.13%; H 7.53%; N 19.03%
Found: C 56.90%; H 7.55%; N 18.96%

Example 10: 3-Ethyl-1- (5-hydroxy-5-methylhexyl) xanthine

7-benzyl-3-ethyl-1- (5-hydroxy-5-methylhexyl) xanthine made from 7-benzyl-3- ethylxanthine (Example 2a) and 1-chloro-5-hydroxy-5-methylhexane (WO 87/00523) according to Example 1b) with a yield of 65% of theory (C₂₁H₂₈N₄O₃; MG = 384.5); Melting point: 112-114 ° C), was made using ammonium formate as hydrogen source debenzylated by hydrogenolysis. In addition, 3.84 g (0.01 mol) of the benzyl compound and 1.0 g (0.016 mol) of ammonium formate in 30 ml Ethanol over 2 g palladium (10%) on activated carbon at 35 ° C for several days stirs, whereby the gradual addition of further ammonium formate to egg a total of 4.4 g (0.07 mol) of proven. It was filtered, the filtrate concentrated, the residue taken up in sodium carbonate solution with chloroform washed, the aqueous phase brought to pH 4 with hydrochloric acid, the product with Chloroform shaken and after drying and evaporating from acetic acid recrystallized.

Yield:
2.0 g (67.9% of theory)
Melting point: 180-182 ° C
C₁₄H₂₂N₄O₃ (MG = 294.4)

Analysis:
Calculated: C 57.12%; H 7.53%; N 19.04%
Found: C 56.77%; H 7.66%; N 18.93%

Example 11: 3-Ethyl-1- (5-hydroxy-5-methylheptyl) xanthine

7-Benzyl-3-ethylxanthine (Example 2a) and 1-chloro-5-hexanone were reacted analogously to Example 1b) to 7-benzyl-3-ethyl-1- (5-oxohexyl) xanthine (C₂₀H₂₄N₄O₃; MG = 368 , 4; yield: 81.7% of theory; melting point: 123-125 ° C). The reductive ethylation of the keto group with ethyl magnesium chloride according to Example 5b) gave 7-benzyl-3-ethyl-1- (5-hydroxy-5-methylheptyl) xanthine (C₂₂H₃₀N₄O _3, MW = 398.5; yield: 86.9% of the Theory; melting point: 93-94 ° C), which was ana log Example 10 hydrogenolytically debenzylated. The end product could be recrystallized from ethanol.

Yield:
66.5% of theory
Melting point: 165-166 ° C
C₁₅H₂₄N₄O₃ (MG = 308.4)

Analysis:
Calculated: C 58.42%; H 7.84%; N 18.17%
Found: C 58.30%; H 8.05%; N 18.33%

Example 12: 1- (6-Hydroxy-6-methylheptyl) -3-methylxanthine

7-benzyl-1- (6-hydroxy-6-methylheptyl) -3-methylxanthine (C₂₁H₂₈N₄O₃, MW = 384.5; Melting point 83-85 ° C), produced with 77.5% yield from 7-benzyl-3-me thylxanthine and 1-bromo-6-hydroxy-6-methylheptane (WO 87/00523) as in Example 1b), was debenzylated hydrogenolytically according to Example 1c).

Yield:
82.2% of theory
Melting point: 166-167 ° C
C₁₄H₂₂N₄O₃ (MG = 294.4)

Analysis:
Calculated: C 57.12%; H 7.53%; N 19.04%
Found: C 56.82%; H 7.74%; N 19.01%

Example 13: 3-Ethyl-1- (6-hydroxy-6-methylheptyl) xanthine

According to Example 12, the reaction sequence with 7-benzyl-3-ethylxanthine from Bei game 2a) carried out, the hydrogenolytic debenzylation with ammoni transformed analogously to Example 10.

Yield:
72.4% of theory
Melting point: 163-165 ° C
C₁₅H₂₄N₄O₃ (MG = 308.4)

Analysis:
Calculated: C 58.42%; H 7.84%; N 18.17%
Found: C 57.83%; H 7.64%; N 18.04%

Table 1

Compounds according to formula I.

Pharmacological testing and results 1. Inhibitory effect against the pro-inflammatory mediators of the Early phase response

The inhibitory effect of the compounds according to formula I on the pro-inflammatori Early-stage mediators histamine, PAF and leukotriene D₄ (LTD₄) were added isolated segments of the respiratory tract of albino guinea pigs below seeks to inhibit the contractions that can be triggered with these mediators served as a measurement parameter.

To carry out the experiment, freshly prepared organs were male cher used animals.

The trachea was broken down into its rings, of which 5 tracheal rings each, linked with a silk thread to form a chain, suspended in an organ bath at 37 ° C. and car-aerated Tyrode solution under a tensile load of 0.5 g and by adding histamine dihydrochloride (Bath concentration: 3 × 10 ^-7 g / ml) were brought into contraction in the absence (control experiment) or in the presence of the test substances.

The lung was cut longitudinally into 2 to 3 strips, which were followed as described above. However, the tensile load was 1 g and the contraction was triggered with PAF or LTD₄ at a bath concentration of 10 ^-9 or 10 ^-8 g / ml.

Each experiment involved the parallel examination of 6 organ preparations (n = 6).

The assessment of the drug effect was based on the IC₅₀ values that Represent the concentration in µg / ml at which the Or gas contraction was reduced by half. The results are in Table 2 summarized.  

Table 2

Inhibitory effects on the pro-inflammatory early phase mediators

2. Inhibition of the antigen-induced early phase reaction on presensibili guinea pigs

Albino guinea pigs of both sexes with a body weight of 180 up to 220 g were administered by subcutaneous administration of 1 mg ovalbumin (0.1% dissolved in physiological saline) on two consecutive days gene sensitized.

The experiment was carried out 20 days later using the Konzett method and Rössler (Arch. exp. Path. and Pharmak. (1940) 195: 75). For this, the Animals anesthetized with pentobarbital, artificially ventilated, to switch off the Spontaneous breathing treated with alcuronium chloride and in groups of 6 tie each divided. By intravenous administration of ovalbumin as an antigen in one dose of 1 mg / kg was a long-lasting asthma attack as a result of one in the frame the asthmatic early reaction induced by mediators acute broncho spasm triggered, its intensity over the contraction height in the thoraco grams was quantified.

The investigational medicinal products were also given intravenously 15 minutes before the Antigen-Pro vocation applied. The animals in the control group received pure 0.9% instead Saline. The number of Animals of the respective collective determined, in which the asthma reaction of the Kon troll animals was reduced by at least 40%. The results are shown in Table 3 posed.

3. Inhibition of eosinophil activation by mediators of the late phase reaction

The inhibitory effect of the xanthines according to formula I on the activatability of huma eosinophilic granulocytes by the late-phase mediators IL-5, GM-CSF C5a and PAF were measured using lucigenin-dependent chemiluminescence (CL) - Reaction examined.  

Table 3

Inhibition of the antigen-induced early-phase response at the sea pig

For this purpose, purified eosinophils were obtained from venous human blood using known test methods (Arch. Dermatol. Res. (1987) 279: 470-477 and J. Invest. Dermatol. (1986) 86: 523-528), with the test substances in the concentration of 100 µM or with pure water (positive control (A)) pretreated at 37 ° C for 10 minutes and then with IL-5 (10² U / ml), GM-CSF (10³ U / ml), C5a (10 ^-7 M ) or PAF (10 ^-6 M) activated or mixed with water for the determination of the basal activity (B). The CL reaction was monitored for 30 minutes at 37 ° C.

The residual activity of the cells pretreated with the test substances was determined in Pro calculated from that of the positive control using the following formula:

in which
CL _X the activity after stimulation of the cells pretreated with the xanthines,
CL _A the activity after stimulation of the cells pretreated with water and
CL _{B describe} the basal activity of unstimulated cells pretreated with water.

The test results are shown in Table 4.

Table 4

Inhibition of eosinophil activation by late phase mediators

4. Inhibition of the antigen-induced late phase response

In a chronic long-term trial on human serum antigen ten guinea pigs was the inhibitory effect of the compounds of formula I.  the pathologically increased chemotactic infiltration of eosinophilic granulo cytocytes in the peritoneal space (in vivo) and their functional state (ex vivo) is looking for.

The animals of the preparation group (n = 6) were exposed to the test substance for 15 weeks treated in a daily oral dose of 80 mg / kg, while the animals of the Control group (n = 6) received the vehicle (carboxymethyl cellulose). After Third week of treatment, all 12 animals were weekly through intraperitoneal 1 ml of human serum antigen provoked and 48 hours each later subjected to peritoneal lavage with 50 ml of 5% glucose solution, in which the number of infiltrated eosinophils and after their isolation via discount continuous Percoll density gradients (purity <95%; viability <98%) the rea Compatibility with PAF and C5a based on actin polymerization flow cytomas tric and by means of the Boyden chamber technology in the comparison between the two animals collective certain.

In this case, for example, the connection from production example 7 brought about a significant decrease (p <0.01) in the number of people entering the peritoneal space migrated eosinophils (34.9 ± 4.8%; x ± SD) compared to the control animals (42.2 ± 5.8%). In addition, the eosinophils of the treated animals showed compared to those of the control animals, a significant reduction (p <0.05) of chemotactic migration triggered with PAF or C5a; even those with PAF (10 nM) induced initial phase (<10s) of actin polymerization was significantly ver diminishes.

This is clear evidence that the compounds of formula I anti gene-induced, pathological hyperreactivity of eosinophilic granulocytes in the ent reduce inflammatory tissue and therefore for prophylaxis and treatment diseases of the atopic form are particularly suitable.

Claims (16)

1. Use of at least one compound of the formula I. and / or a physiologically acceptable salt of the compound of formula I and / or a stereoisomeric form of the compound of formula I, wherein
R¹ represents a methyl or ethyl group,
R² for an alkyl group with 1 to 4 carbon atoms and
X represents a hydrogen atom or a hydroxy group and
n is an integer from 1 to 5,
for the manufacture of medicaments for reducing the pathological hyperreactivity of eosinophilic granulocytes. 2. Use according to claim 1, characterized in that min at least a compound of formula I or its salt is used in the R² for Me is ethyl or ethyl. 3. Use according to claim 1 or 2, characterized in that at least one compound of the formula I or its salt is used in which
R¹ and R² independently of one another methyl or ethyl,
X is hydrogen atom or hydroxy group and
n is an integer from 3 to 5. 4. Use according to one or more of claims 1 to 3, since characterized in that 1- (5-hydroxy-5-methylhexyl) -3-methylxanthine or whose salt sets in. 5. Use according to one or more of claims 1 to 4 for the Treatment and / or prophylaxis of diseases of the atopic form ses. 6. Use according to one or more of claims 1 to 5 for Treatment and / or prophylaxis of anaphylaxis, allergic bronchial asthma chial, allergic rhinitis and conjunctivitis, allergic urticaria, allergic Gastroenteritis and atopic dermatitis. 7. Use according to one or more of claims 1 to 6 for oral rectal, topical, parenteral or inhalation administration. 8. Use according to claim 7, characterized in that additional effective amount of at least one compound from the group Antihi staminics, anticholinergics, β₂-mimetics, phosphodiesterase-, phospholipase A₂- and lipoxygenase inhibitors, PAF and leukotriene antagonists, corticosteroi which uses cromoglicic acid, nedocromil and cyclosporin A. 9. A compound of formula I and / or a physiologically acceptable salt of the compound of formula I and / or a stereoisomeric form of the compound of formula I, wherein
R¹ is methyl or ethyl,
R² alkyl with 1 to 4 carbon atoms,
X is hydrogen atom or hydroxy group and
n is an integer from 1 to 5
mean, the compound of formula I, in which R¹ and R² simultaneously methyl, X is a hydrogen atom and n is 4, is excluded. 10. A compound according to claim 9, characterized in that in formula I R² represents methyl or ethyl. 11. A compound according to claim 9 or 10, characterized in that in Formula I the radical X represents hydrogen atom. 12. A compound according to claims 10 and 11, characterized in that in formula I.
R1 methyl,
R² is methyl or ethyl,
X is hydrogen atom and
n is an integer from 1 to 5
mean. 13. A process for the preparation of the compounds of formula I according to claims 9 to 12, characterized in that a 3,7-disubstituted xanthine derivative of formula II, in which R² is an alkyl group with 1 to 4 carbon atoms and Ra is an easily eliminable leaving group in the form of the hydrolytically removable meth, eth, prop or butoxymethyl radical or the reductively removable benzyl or diphenylmethyl group with unsubstituted or substituted phenyl rings in the presence of a basic condensing agent or in the form of its salts

• a) with an alkylating agent of the formula III, in which R 1, X and n have the meanings given above and Z represents chlorine, bromine, iodine or a sulfonic acid ester or phosphoric acid ester group,
  to a 1,3,7-trisubstituted xanthine of the formula IV implemented, where R¹, R², Ra, X and n have the meanings defined above,
  or alternatively in the event that X denotes hydrogen atom,
• b) with a keto compound of the formula V H₃C-CO- (CH₂) _n -Z (V) in which n and Z have the meanings given above, to give a 1,3,7-trisubstituted xanthine of the formula VI then implements this with a methyl or ethyl metal compound (R¹-M) in the form of methyl or ethyl lithium (R¹-Li) or the corresponding Grignard compounds (R¹-MgHal) with reductive alkylation of the carbonyl group 1,3,7-trisubstituted xanthine of formula VII transferred in which R¹, R², Ra and n have the abovementioned meanings,
  or alternatively if X is hydrogen and R¹ is methyl,
• c) with a carboxylic acid ester of the formula VIII, (C₁-C₄) alkyl-O-CO- (CH₂) _n -Z (VIII) in which n and Z have the abovementioned meanings,
  to a 1,3,7-trisubstituted xanthine of formula IX implements this then with two equivalents of a methyl metal compound in the form of CH₃-Li or CH₃-MgHal with two-fold reductive alkylation of the ester function in a 1,3,7-trisubstituted xanthine of the formula X. converts, where R², Ra and n have the meanings given above,

and finally the leaving group Ra from the intermediate compound of the formula IV, VII or X split off to form the xanthine of formula I and this, if desirably converted to a pharmaceutically acceptable salt. 14. Medicinal product, characterized by the content of a therapeutically effective ven amount of at least one compound of formula I according to one or several of claims 9 to 12 or produced according to claim 13. 15. A method for producing a medicament according to claim 14, characterized characterized in that at least one compound of formula I according to one or more of claims 9 to 12 with pharmaceutically suitable and physio logically compatible carriers and additives, diluents and / or brings their active ingredients or adjuvants into a suitable dosage form.