EP0758239A1 - Use of xanthine derivatives for reducing the pathological hyper-reactivity of eosinophilic granulocytes, novel xanthine compounds and process for producing them - 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

description

Use of xanthine derivatives to reduce the pathological hyperreactivity of eosinophilic granulocytes, new xanthine compounds and processes for their preparation.

The present invention relates to the use of tertiary 1- (hydroxyalkyl) -3-alkylxanthines for the production of medicaments for the treatment of diseases which are associated with a pathologically increased reactivity of eosinophilic granulocytes, new xanthine compounds with the aforementioned substitution pattern and processes for their preparation.

The hyper-reactive eosinophilic granulocyte is at the center of the pathogenesis of certain pulmonary, cardiac and cutaneous diseases, which are primarily to be assigned to the atopic form.

The atopic form includes diseases with allergic diathesis, which are caused by exogenous, non-infectious substances (environmental allergens) on the basis of a specifically changed immunity situation. In principle, allergic diseases can affect all essential organ systems of the human body and manifest themselves in a variety of different clinical pictures such as arthalgia, asthma, erythema exudative multiforme, enteritis, nephritis, rhinitis or vasculitis (Wien Klin Wochenschr (1993) 105/23: 661 - 668) .

In clinical practice, the immunoglobulin E (IgE) -mediated immune reactions (type I allergies) dominate in the form of anaphylaxis, allergic bronchial asthma, allergic rhinitis and conjunctivitis, allergic urticaria, allergic Gastroenteritis and atopic dermatitis. There seems to be a genetic predisposition to react to substances from the natural environment (e.g. grass pollen, spores, house dust and mites, animal hair or food) with an immediate-type hypersensitivity mediated by atopic antibodies (reagents). The incidence rate is currently around 10% of the population (Pschyrembel, Klinisches Wörterbuch, Walter de Gruyter-Verlag, 255th edition, 1986, page 148) with a continuously increasing prevalence, particularly in the industrialized countries.

The finding that the worldwide increase in morbidity is linked to an increase in mortality in bronchial asthma, for example in spite of intensive efforts to improve the diagnosis and treatment options, is worrying (Deutsche Apotheker Zeitung (1993) 133/18: 1635 - 1636). This makes asthma - characterized by inflammatory processes with progressive, irreversible damage to the respiratory tract - the only chronic disease in industrialized countries in which the number of deaths increases as a result of inadequate therapy (Therapy Week (1993) 43/7: 340 - 341).

According to the current state of knowledge, chronic inflammation is the focus of the pathogenetic process, in which a large number of immune-competent cells are involved in the release of pro-inflammatory mediators. It is assumed that mainly basophilic granulocytes and mast cells are involved in the acute phase of the inflammation, the so-called early phase or immediate reaction, while for the chronic symptoms with progressive tissue loss and loss of function in the late phase reaction, eosinophilic granulocytes and possibly also neutrophils play the main role (Münch. med. Wschr. (1993) 135/5: 52).

Basophilic granulocytes and mast cells, also known as histaminocytes, start after activation by binding IgE produced in B lymphocytes specific high-affinity receptors on the cell surface and subsequent cross-linking of the bound IgE molecules by the antigen in question not only free histamine but also numerous other inflammatory mediators. These include proteases, lipid mediators such as the platelet activating factor (PAF), prostacilandins and leukotrienes, as well as a wide range of cytokines (Immunopharmaco-Iogy (1994) 27: 1 - 1 1).

Most of these mediators have a vaso- and bronchoconstrictive effect, increase mucus secretion and intervene in the regulation of hemostasis. In addition, chemotactic properties are attributed to them, which enable them to mobilize other cells involved in the inflammatory process, including the eosinophilic granulocytes responsible for the late phase reaction, which also secrete inflammatory mediators after activation by degranulation, with which the inflammatory process perpetually maintains and whose chronification is initiated.

The eosinophilic granulocyte is a highly potent effector cell with pronounced leukocyte-specific properties such as chemotaxis, adherence, phagocytosis, release of granule proteins and the formation and release of lipid mediators and reactive oxygen species, which make their dominant role in the pathogenetic process of the allergic inflammatory reaction understandable (Dt. Ärzteblatt (1992) 89/43, A,: 3574-3585).

The event after allergen exposure is initiated by recruiting eosinophils from the bone marrow and their targeted invasion into the tissue affected by the antigen, which leads to local eosinophilia with subsequent cell activation. Various immunocompetent cells, such as T-type helper cells, macrophages, neutrophils, mast cells and eosinophils themselves, are involved in these pathophysiological processes, which produce and secrete a range of factors responsible for differentiation, proliferation, migration and activation. These include the immunomodulating cytokines, such as the eosinophil-selective interleukin-5 (IL-5) formed by the T helper cells, which controls both the differentiation and proliferation and the functional activation of the eosinophilic granulocytes, and the granulocyte / macrophage colony-stimulating factor (GM-CSF) with a pronounced cell-activating effect; as well as the chemotactic factors responsible for migration and activation, such as PAF and leukotriene B ₄ (LTB ₄ ).

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

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

The pro-inflammatory lipid mediators include in particular leukotriene C ₄ (LTC ₄ ), thromboxane A ₂ (TXA ₂ ) and again PAF, which increase vascular permeability, cause vasoconstriction and obstruction of the bronchi and stimulate mucus production (pharmacy in our time (pharmacy in our time ( 1992) 21/2: 61-70). Among the protein mediators, the eosinophilic peroxidase (EPO) impress with an enzymatic effect and above all the non-enzymatic, basic proteins that are particularly relevant for the destructive processes, such as the major basic protein (MBP), the eosinophil cationic protein (ECP) and the eosinophil Derived Neurotoxin / Eosinophil Protein X (EDN / EPX). Their diverse biological properties focus on cytotoxic effects on a broad spectrum of cells, ranging from parasites to bronchial epithelial cells, nerve cells, cardiac muscle cells and tumor cells. Together with the secreted reactive oxygen metabolites, they therefore make a decisive contribution to tissue destruction with progressive loss of function in areas of allergic inflammatory reactions.

In addition, they also stimulate the release of histamine from mast cells and thus trigger new early-phase attacks in the sense of a vicious circle. The highly toxic protein mediators are also of great diagnostic importance, since in patients with diseases of the atopic form, in particular increased ECP concentrations in the serum and in other body fluids, such as bronchoalveolar lavage, sputum and nasal secretions, but also deposits of these proteins in the affected tissues as a sign of previous eosinophil activation, whereby the ECP serum levels correlate significantly with the severity of the disease, so that this parameter appears to be suitable both for objectifying the disease activity and for assessing the success of treatment after therapeutic intervention (therapy week (1991) 41 / 45: 2946-2947).

The described pathogenetic relationships in diseases of the atopic form make it clear that the focus of the allergic inflammatory process with its early and late phase reaction is the result of a complex interaction of immune cells and their inflammatory mediators, and that therapeutic progress can only be expected from a multifunctional drug who can both block the mediators of the immediate reaction and sustainably inhibit the recruitment and, above all, the activation of eosinophils in the chronic late-phase reaction (Pharmaceutische Zeitung (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 f having a tertiary hydroxyl function in the 1-position alkyl radical meet the abovementioned requirements for a therapeutic agent which is suitable for the treatment of diseases of the atopic form.

1- (5-Hydroxy-5-methylhexyl) -3-methylxanthine is described in WO 87/00523. It is used there for the treatment of peripheral and cerebral Circulatory disorders and mitochondrial mypopathies are proposed, but without any indication of their usefulness for reducing the pathological hyperreactivity of eosinophilic granulocytes and thus for the treatment of atopic diseases.

Numerous xanthine compounds are known which, because of their phosphodiesterase inhibitory activity, have bronchospasmolytic activity and are therefore suitable for the prophylaxis and symptomatic treatment of acute bronchospasm induced by mediators in the context of the asthmatic early reaction, but do not allow curative therapy of atopic diseases since they cause the basic suffering , leave the eosinophil-mediated, chronic inflammatory process of the late phase reaction unaffected. The most prominent representative of this group of substances is theophylline.

More recently, some 8-substituted 1,3-dialkylxanthines (EP 389 286; WO 92/1 1260), 1,3-trialkylxanthines (EP 421,587) and 7-sulfonylated 1,3-dialkylxanthines and 1 , 3,7,8-tetrasubstituted xanthines (WO 92/11260) have been reported which are said to reduce the number of eosinophils in the blood in an animal model with artificially induced eosinophilia. An inhibition of the functional state of the eosinophils, which is pathologically increased in atopic diseases and ultimately determines the course of the disease, primarily in the tissues affected by the allergic inflammatory process, could not be shown, so that the therapeutic value of the compounds described is not proven.

In contrast, the compounds of the formula I at the level of the cellular mediators relevant to the course of the disease show that they inhibit the early-phase reactions and in the late-phase reaction not only inhibit the recruitment of eosinophils, but also reduce their pathological hyper-responsiveness in the target tissue and thus that in the center of the selectively switch off chronic effector functions of this highly potent inflammatory cell during the chronic disease process.

In EP 544 391 the 1,3-trialkylated xanthines pentoxifylline (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-methylxanthine) for the topical treatment of psoriasis and atopic dermatitis, but without any indication that 1.) these xanthine derivatives are also suggested non-topical application are effective or 2.) can also be used topically or non-topically against other diseases of the atopic form.

The invention thus relates to the 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

R ^{1 represents} a methyl or ethyl group,

R ² for an alkyl group with 1 to 4 carbon atoms and

X represents a hydrogen atom or a hydroxyl group and n represents 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, allergic urticaria, allergic gastroenteritis or atopic dermatitis.

Compounds of the formula I in which R ^{2 represents} a methyl or ethyl group are preferably used.

Preference is furthermore given to the use of the compounds of the formula I in which R ¹ and R ² independently of one another are methyl or ethyl, X is a hydrogen atom or

Hydroxy group and n are an integer from 3 to 5.

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

The invention further relates to new compounds of formula I, and / or a physiologically tolerable salt of the compound of formula I and / or a stereoisomeric form of the compound of formula I, wherein

R ^{1 is} methyl or ethyl,

R ² alkyl with 1 to 4 carbon atoms,

X is a 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.

Preference is given to the compounds of the formula I in which R ^{2 is} methyl or ethyl, where R ¹ and R ^{2 are} not methyl at the same time when X is hydrogen and n is 4. 9

Also preferred are the compounds of the formula I in which X represents a hydrogen atom, where R ¹ and R ² do not simultaneously denote methyl when n is 4. Finally, particular preference is given to those compounds of the formula I in which

R ^{1 is} methyl,

R ^{2 is} methyl or ethyl,

X is hydrogen and n is an integer from 1 to 5

mean, wherein R ^{2 is} not methyl when n represents the number 4.

The invention further relates to an analogous process for the preparation of the new compounds of the formula I, the embodiments of which are described in principle in WO 87/00523. Thereafter, the procedure is advantageously such that a 3,7-disubstituted xanthine derivative of the formula II

R ^{2 is} an alkyl group with 1 to 4 carbon atoms and R ^{a is} an easily eliminable one

Leaving group, for example the hydrolytically removable meth, eth, prop or butoxymethyl radical or the reductively removable benzyl or

Diphenylmethyl group with unsubstituted or substituted phenyl rings mean, advantageously 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 halogen, preferably chlorine, bromine or iodine, or a sulfonic acid ester or phosphoric acid ester group, to give a 1,3,7-trisubstituted xanthine of the formula IV

is implemented, wherein R ¹ , R ² , R ^a , X and n have the meanings defined above, or alternatively in the event that X is hydrogen,

b) with a keto compound of the formula V,

H ₃ C-CO- (CH ₂ ) _n -Z (V)

in which n and Z have the meanings given above, to a 1,3,7-trisubstituted xanthine of the formula VI then implements this with a methyl or ethyl metal compound (R ¹ -M), preferably methyl or ethyl lithium (R ¹ - i) or the corresponding Grignard compounds (R ¹ -MgHal), with reductive alkylation of the carbonyl group in one 1, 3,7-trisubstituted xanthine of formula VII

transferred in which R ¹ , R ² , R ^a and n have the abovementioned meanings,

or alternatively if X is hydrogen and R ^{1 is} methyl,

c) with a carboxylic acid ester of the formula VIII,

(C _r C ₄ ) alkyl-0-CO- (CH ₂ ) _n -Z (VIII) in which n and Z have the abovementioned meanings, to give a 1,3,7-trisubstituted xanthine of the formula IX

then implements this with two equivalents of a methyl metal compound, preferably CH ₃ -Li or CH ₃ -MgHal, with double reductive alkylation of the ester function into a 1,3,7-trisubstituted xanthine of the formula X.

converts, where R> 2, _D Ra ^a and n have the meanings given above,

and finally, by eliminating the leaving group R ^a from the intermediate compound of the formula IV, VII or X, the xanthine of the formula I according to the invention is obtained. 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 be easily prepared by methods known from the literature (see, for example, WO 87/00523). For example, the tertiary alcohols of the formula III can be obtained by organometallic synthesis by the sterically unhindered halogen ketones of the formula Hal- (CH ₂ ) _n -CO-CH ₂ X in a so-called build-up reaction with reductive alkylation of the carbonyl group with alkyl metal compounds R ¹ -M, in which M means metal, primarily magnesium, zinc or lithium, for example in the form of the alkylmagnesiumhalogen.de R ¹ -MgHal (Grignard compounds) or the alkyl lithium compounds R -Li under customary conditions. A similar reaction of the halogen ketones according to the formula Hal- (CH ₂ ) _n -CO-R ¹ with methyl magnesium halonides or methyl lithium likewise leads to compounds of the formula III in which X is hydrogen. The reaction of alkyl haloalkanoic acid (Hal- (CH ₂ ) _n -COO-alkyl) with two equivalents of a methyl-metal compound also offers convenient access to compounds of the formula III in which R ^{1 is} methyl and X is hydrogen. wherein the ester reacts via the ketone to the tertiary alcohol with the introduction of two methyl residues. In the same way, w-hydroxycarboxylic acid esters can be used 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 compounds in diols convert, 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 reaction of the disubstituted xanthine derivatives of the formula II with the alkylating agents in question of the formula III, V or VIII usually takes place in a distribution or solvent which is inert to the reactants. Dipolar, aprotic solvents, for example formamide, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, tetramethylurea, hexamethylphosphoric triamide, dimethyl sulfoxide, acetone or butanone in question; but it can also alcohols, such as methanol, ethylene glycol and its mono- or di (C ₁ -C ₄ ) alkyl ether, ethanol, propanol, isopropanol and the various butanols; Hydrocarbons such as benzene, toluene or xylenes; halogenated hydrocarbons such as dichloromethane or chloroform; Pyridine and mixtures of the solvents mentioned or their mixtures with water are used.

The alkylation reactions are advantageously carried out in the presence of a basic condensing agent. For this purpose, for example, alkali or alkaline earth metal hydroxides, carbonates, hydrides, alcoholates and organic bases, such as trialkylamines, for. B. triethyl or tributylamine, quaternary ammonium or phosphonium hydroxides and crosslinked resins with fixed, optionally substituted ammonium or phosphonium groups. However, the xanthine derivatives can also be used directly in the form of their separately prepared salts, for example the alkali metal, alkaline earth metal or optionally substituted ammonium or phosphonium salts. Furthermore, the disubstituted xanthine compounds can be used both in the presence of the aforementioned inorganic condensing agents and in the form of their alkali metal or alkaline earth metal salts with the aid of so-called phase transfer catalysts, for example tertiary amines, quaternary ammonium or phosphonium salts or also crown ethers, preferably in a two-phase system under the conditions of one Phase transfer catalysis, alkylate conveniently. Suitable, mostly commercially available phase transfer catalysts include tetra (C ₁ -C ₄ ) alkyl and methyltrioctylammonium and phosphonium, methyl, myristyl, phenyl and benzyltri (C ₁ -C ₄ ) alkyl and cetyltrimethylammonium - and (C _j -C ^ alkyl and benzyl triphenylphosphonium salts, where as a rule those compounds which have the larger and more symmetrically constructed cation, prove to be more effective. In the procedures described above, generally at a reaction temperature between 0 ° C and the boiling point of the reaction medium used in each case, preferably between 20 ° and 130 ° C, optionally at elevated or reduced pressure, but usually at atmospheric pressure, the reaction time being from less than one hour to several hours.

The organometallic reactions of the xanthines VI or IX functionalized in the 1-residue radical are in principle carried out in the same manner as described for the preparation of the tertiary alcohols used as alkylating agents according to formula III. For example, the reductive alkylation of the ketones VI or the esters IX can be carried out, for example, with alkyl potassium, sodium, lithium, magnesium, zinc, cadmium, aluminum and tin compounds. 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 compounds of sodium and potassium tend to undergo side reactions due to their high reactivity and those of zinc and cadmium are relatively inert, the alkyl lithium and magnesium (Grignard) compounds are usually preferred.

The strongly nucleophilic organometallic compounds are very sensitive to hydrolysis and oxidation. Safe handling therefore requires working in an anhydrous medium, possibly under a protective gas atmosphere. Usual solvents or distributing agents are primarily those which are also suitable for the production of the alkyl metal compounds. Such as come especially ethers with one or more ether oxygen atoms, for example diethyl, dipropyl, dibutyl or diisoamyl ether, 1, 2-dimethoxyethane, tetrahydrofuran, dioxane, tetrahydropyran, furan and anisole, and aliphatic or aromatic hydrocarbons, such as petroleum ether, cyclohexane , Benzene. Toluene, xylenes, diethylbenzenes and tetrahydronaphthalene in question; however, tertiary amines, such as triethylamine, or dipolar, aprotic solvents, for example hexamethylphosphoric acid triamide, and mixtures of the solvents mentioned can also be used successfully. When the carbonyl compounds VI and IX are reacted with the Grignard compounds of the formula R ¹ -MgHal, this can also be advantageous be carried out by introducing the organometallic compound in an ether and adding the ketone or the ester dropwise as a solution in dichloromethane or 1,2-dichloroethane. It is often advisable to add magnesium bromide, which is able to increase the nucleophilicity of the organometallic compound due to its participation in the complex cyclic transition state.

The ketone or ester and organometallic compound are usually combined at temperatures between -20 ° and 100 ° C, preferably between 0 ° and 60 ° or at room temperature without external cooling, the alkyl metal compound usually being used in a slight excess. The reaction is then usually ended by briefly heating under reflux, for which periods of time from a few minutes to a few hours are usually sufficient. The alkanolate formed is preferably decomposed using aqueous ammonium chloride solution or dilute acetic acid.

The removal of the leaving group R ^a from the compounds of the formulas IV, VII and X to form the xanthines of the formula I according to the invention is carried out under standard conditions, which were developed primarily in the context of the protective group technique in alkaloid and peptide syntheses and are therefore assumed to be largely known can be. Thereafter, the benzyl or diphenylmethyl group optionally substituted in the phenyl ring is preferably reductively split off. In addition to the chemical reduction, in particular of the benzyl compounds with sodium in liquid ammonia, this is preferred. Elimination of the two aforementioned aralkyl groups by catalytic hydrogenolysis with the aid of a noble metal catalyst into consideration, the replacement of molecular hydrogen by ammonium formate often proving to be a hydrogen donor. A lower alcohol is usually used as the reaction medium, optionally with the addition of formic acid or ammonia; an aprotic solvent such as dimethylformamide or especially glacial acetic acid; but also theirs Mixtures with water can be used. Suitable hydrogenation catalysts are primarily palladium black and palladium on activated carbon or barium sulfate, while other noble metals such as platinum, rhodium and ruthenium often give rise to side reactions due to competing core hydrogenation and can therefore only be used to a limited extent. The hydrogenolysis is expediently carried out at temperatures between 20.degree. And 100.degree. C. and under atmospheric pressure or preferably slightly elevated pressure up to about 10 bar, reaction times of a few minutes to several hours being generally required.

The 1, 3,7-trisubstituted xanthines of the formulas IV, VII and X, which carry an alkoxymethyl group in the position of R ^a , are O, N-acetals and can therefore be easily unmasked under the usual conditions of acid hydrolysis. Preferred radicals are, for example, the methoxy, ethoxy, propoxy and butoxymethyl group. The reaction is advantageously carried out with heating in dilute mineral acids, such as hydrochloric or sulfuric acid, optionally with the addition of glacial acetic acid, dioxane, tetrahydrofuran or a lower alcohol as a solubilizer. Perchloric acid or organic acids, such as trifluoroacetic, formic and acetic acid, may also be used in conjunction with catalytic amounts of mineral acids. In principle, the ether group can also be cleaved with the aid of Lewis acids, such as zinc bromide and titanium tetrachloride, in an anhydrous medium, preferably in dichloromethane or chloroform. When cleaving in mineral acid solution, the reaction temperature should be chosen so that there is no noticeable dehydration of the 1-position tertiary hydroxyalkyl group; it should therefore generally not exceed 60 ° C.

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

The tertiary 1- (hydroxyalkyl) -3-alkylxanthine3 of the formula I have an asymmetric carbon atom if X is hydroxy or X is hydrogen and R ^{1 is} ethyl. These compounds can thus exist in stereoisomeric forms. The invention therefore relates to both the pure stereoisomeric compounds and their mixtures.

Because of their valuable pharmacological properties, the novel xanthine compounds of the formula I according to the invention are outstandingly suitable for use as active ingredients in medicaments, in particular those which provide effective prophylactic and curative treatment of diseases caused by pathological eosinophil hyperreactivity, such as those of the atopic type , enable and thus represent a significant enrichment of the pharmaceutical treasure. They can be administered either on their own, for example in the form of microcapsules, in mixtures with one another or in combination with suitable carriers.

The invention consequently also relates to medicaments which contain at least one compound of the formula I as active ingredient, with the exception of 1- (5-hydroxy-5-methylhexyl) -3-methylxanthine.

Another aspect of the present invention, which relates to all compounds falling under formula I, is the production of pharmaceutical preparations for oral, rectal, topical, parenteral or inhalative administration in the case of diseases with pathologically increased reactivity of the eosinophilic granulocytes. Suitable solid or liquid pharmaceutical preparation forms are, for example, granules, powders, tablets, dragées (micro) capsules, suppositories, syrups, emulsions, suspensions, lotions, creams, Ointments, gels, aerosols, drops or injectable solutions in ampoule form as well as preparations with a protracted active ingredient release, in the production of which usually auxiliaries, such as carriers, explosives, binders, coatings, swelling agents, lubricants or flavorings, sweeteners or Solubilizers, find use. As commonly used auxiliaries such. B. magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, milk protein, gelatin, starch, vitamins, cellulose and their derivatives, animal and vegetable oils, polyethylene glycols and solvents such as sterile water, alcohols, glycerol and polyhydric alcohols.

The pharmaceutical preparations are preferably produced and administered in dosage units, each unit containing as active ingredient a certain dose of a compound of the formula I. In the case of solid dosage units such as tablets, capsules and suppositories, this dose can be up to 1000 mg, but preferably 100 to 600 mg, and in the case of 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 of the formula I in humans - daily doses of 100 to 2000 mg of active ingredient, preferably 300 to 900 mg, with oral administration and from 10 to 500 mg, preferably 20 to 200 mg, for intravenous application indicated. Under certain circumstances, however, higher or lower daily doses may also be appropriate. The daily dose can be administered either by single administration in the form of a single dosage unit or else several smaller dosage units, or by multiple administration of divided doses at certain intervals.

Finally, the xanthine derivatives of the formula I, in the preparation of the abovementioned pharmaceutical preparation forms - if he ^f orderlich - together with other suitable active compounds, for example, ^Ant; histamines, Anticholinergics, ß ₂ mimetics, phosphodiesterase, phospholipase A ₂ and lipoxygenase inhibitors, PAF and leukotriene antagonists, corticosteroids, cromoglicic acid, nedocromil and cyclosporin A can be formulated.

The structure of all compounds described below and summarized in Table 1 was confirmed by elemental analysis and IR and ¹ H-NMR spectra.

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, a solution of 46.3 g (0.5 mol ) Add 1-chloro-2-propanone dropwise in 50 ml of anhydrous diethyl ether. The mixture was then stirred for one hour at room temperature and then for a further hour under reflux, the tertiary alkanolate formed was decomposed by adding 50% strength aqueous ammonium chloride solution, the ether phase was separated off and the aqueous phase was shaken out with ether. The combined ethereal extracts were washed successively with aqueous sodium bisulfite and sodium bicarbonate solution and a little water, dried over sodium sulfate, filtered, concentrated under reduced pressure and the liquid residue was subjected to fractional distillation. Yield: 31.1 g (57.3% of theory)

Boiling point: 125-127 ° C

C ₄ H ₉ CIO (MG = 108.6)

The compound could also be prepared in an analogous manner from methyl or ethyl chloroacetate with twice the molar amount of methyl magnesium chloride in yields of around 60% of theory.

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

The mixture of 25.6 g (0.1 mol) of 7-benzyl-3-methylxanthine, 15.2 g (0.11 mol) of potassium carbonate and 11.9 g (0.1 1 mol) of the tertiary alcohol from stage a ) in 500 ml of dimethylformamide was heated to 110 ° to 120 ° C. with stirring for 8 hours, then filtered hot and evaporated under reduced pressure. The residue was taken up in chloroform, washed first with 1N sodium hydroxide solution, then with water until neutral, dried, the solvent was distilled off in vacuo and the solid residue was recrystallized from ethyl acetate with the addition of petroleum ether. Yield: 26.6 g (81.0% of theory)

Melting point: 115-117 ° C

C ₁₇ H ₂₀ N ₄ O ₃ (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 first treating 7-benzyl-3-methylxanthine with 1-chloro-2-propanone or methyl or ethyl chloroacetate under the reaction conditions described above to give 7-benzyl-3-methyl-1- (2- oxopropyl) xanthine or 7-benzyl-1-meth (or eth) oxycarbonylmethyl-3-methylxanthine and then reductively methylated the oxopropyl or alkoxycarbonylmethyl side chain with methyl magnesium chloride in anhydrous diethyl ether analogous to step a).

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

13.1 g (0.04 mol) of the 7-benzylxanthine from stage b) were hydrogenated in 200 ml of glacial acetic acid over 1.5 g of palladium (10%) on activated carbon at 60 ° C. and 3.5 bar within 100 hours with shaking. After cooling, the mixture was blanketed with nitrogen, the catalyst was filtered off, concentrated under reduced pressure and the solid residue was recrystallized from ethyl acetate. Yield: 7.8 g (81.8% of theory)

Melting point: 215-217 ° C

C ₁₀ H ₁₄ N ₄ O ₃ (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 was added 20 g (0.5 mol) of sodium hydroxide dissolved in 200 ml of water and stirred for one hour at 70 ° C., then added dropwise at the same temperature with 69.6 g (0.55 mol) of benzyl chloride and kept the reaction mixture between 70 ° and 80 ° C. for 3 hours. The mixture was then cooled, filtered with suction, the product was washed on a suction filter with water, dissolved hot in 1000 ml of 1N sodium hydroxide solution, filtered and slowly brought to pH 9.5 with 4N hydrochloric acid with stirring. The crystals were filtered off from the still warm solution, washed free of chloride with water and dried in vacuo. Yield: 131 g (96.9% of theory)

Melting point: 217-218 ° C

C ₁₄ H ₁₄ N ₄ O ₂ (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 give 7-benzyl-3-ethyl-1- (2-hydroxy-2-methylpropyD- xanthine (C ₁₈ H ₂₂ N ₄ O ₃ (MW = 342.4); yield: 46.1% of theory) analogous to Example 1 b) and subsequent hydrogenolytic debenzylation (yield: 97.9% of theory) according to Example 1c) crude end product was obtained, which could be purified by recrystallization from ethanol. 24

Melting point: 217-219 ° C

^C 11 ^H 16 ^N 4 ° 3 < ^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 prepared from methylmagnesium iodide and 1-chloro-3-butanone (obtainable by addition of hydrogen chloride to methyl vinyl ketone in diethyl ether) or from methylmagnesium chloride and ethyl 3-chloropropionate in dichloromethane as the reaction medium analogously to Example 1a). Yield: 60 - 70% of theory

Boiling point (18 mbar): 66 - 68 ° C

CsH ^ CIO (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 alcohol from stage a). Yield: 70% of theory)

Melting point: 92 - 94 ° C

C ₁₈ H ₂₂ N ₄ O ₃ (MG = 342.4) Analysis: Calculated: C 63.14% H 6.48% N 16.36%

Found: C 63.10% H 6.43% N 16.28% O 1- (3-hydroxy-3-methylbutyl) -3-methylxanthine

prepared by hydrogenolytic debenzylation of the product from stage b) analogously to Example 1c).

Yield: 87.2% of theory

Melting point: 203-205 ° C

CH ₁₆ N ₄ O ₃ (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 1 b 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

C ₁₉ H ₂₄ N ₄ O ₃ (MG = 356.4)

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

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

Yield: 88.2% of theory

Melting point: 241 - 243 ° C

C ₁₂ H ₁₈ N ₄ O ₃ (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) of potassium carbonate and 26.7 g (0.162 mol) of 1-chloro-4-pentanone ethylene ketal in 600 ml of dimethylformamide were analogous Example 1 b) converted to 7-benzyl-1- (4,4-ethylenedioxypentyl) -3-methylxanthine, which was subjected to ketal cleavage by further refluxing in 600 ml of 1N hydrochloric acid for 2 hours without further purification. The formed ketoildete was taken up after neutralization of the mixture with concentrated sodium hydroxide solution in chloroform and the chloroform extract was washed with water, dried over sodium sulfate and evaporated to dryness under reduced pressure. Yield: 50.4 g (98.7% of theory)

Melting point: 104-105 ° C

^C 18 ^H 20 ^N 4 ° 3 < ^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 commercially available 20% solution in tetrahydrofuran and 300 ml of dichloromethane was cooled to -25 ° C. and then added dropwise with a solution of 34 g (0.1 mol) of Product from stage a) added, the temperature rising to 20 ° C. The mixture was stirred for a further hour at room temperature, mixed with saturated ammonium chloride solution, the organic phase was separated off, the aqueous phase was shaken out several times with dichloromethane, the combined dichloromethane extract was washed with water, dried and evaporated and the solid residue was recrystallized from ethyl acetate. Yield: 28.3 g (79.4% of theory) Melting point: 132-133 ° C ₁₉ H ₂₄ N ₄ O ₃ (MW = 356.4)

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

was prepared according to Example 1c) by hydrogenolytic debenzylation of the product from stage b). Yield: 65.9% of theory

Melting point: 188-189 ° C

^C 12 ^H 18 ^N 4 ° 3 ^<MW = 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 preparation was carried out analogously to Example 5a) using 7-benzyl-3-ethyl-xanthine from Example 2a) as the starting material. Yield: 82.4% of theory

Melting point: 139 - 141 ° C

C ₁₉ H ₂₂ N ₄ O ₃ (MG = 354.4)

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

The product from stage a) was reacted with methyl magnesium chloride as in Example 5b). Yield: 81.9% of theory

Melting point: 155 - 157 ° CC ₂₀ H ₂₆ N ₄ O ₃ (MW = 370.5)

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

3-ethyl-1- (4-hydroxy-4-methylpentyl) xanthine

The compound was obtained by hydrogenolytic debenzylation of the product from step b) analogously to Example 1c). Yield: 71.3% of theory)

Melting point: 214-216 ° C

C ₁₃ H ₂₀ N ₄ O ₃ (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 described in detail in PCT application WO 87/00523.

Example 8: 1- (5,6-Dihydroxy-5-methylhexyl) -3-methylxanthine

a) 1-Chloro-5,6-isopropylidenedioxy-5-methylhexane

A mixture of 264 g (1.2 mol) of methyl sulfoxonium iodide and 28.8 g (1.2 mol) of sodium hydride was added to a mixture with nitrogen Stir at 40 ° C, dropwise added 1000 ml of anhydrous dimethyl sulfoxide within 10 minutes. After the evolution of gas had ended (about 2 hours), a solution of 134.6 g (1 mol) of 1-chloro-5-hexanone in 30 ml of dimethyl sulfoxide was added dropwise over the course of about 20 minutes. The mixture was stirred at room temperature for 2 hours, slowly added 500 ml of ice water while cooling with ice and the 1-chloro-5,6-epoxy-5-methylhexane formed was extracted with diethyl ether (yield: 130.5 g (87.8% of theory) ; C ₇ H ₁₃ CIO (MW = 148.6)). For hydrolytic cleavage of the epoxy ring, the product was stirred in a mixture of 60 ml of water, 600 ml of tetrahydrofuran and 1 ml of 70% perchloric acid for 5 days at room temperature. Then it was neutralized with sodium carbonate solution, the tetrahydrofuran was largely distilled off and the resulting 1-chloro-5,6-dihydroxy-5-methylhexane was extracted with chloroform. (Yield: 124.8 g (85.3% of theory); C ₇ H ₁₅ CIO ₂ (MW = 166.6)).

The diol was then converted into the dioxolane in a conventional manner using 2,2-dimethoxypropane in acetone with acid catalysis. Yield: 67.2% of theory

Boiling point (0.5 mbar): 84 - 86 ° C

C ₁₀ H ₁₉ CIO ₂ (MG = 206.7)

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

The diol from stage a) could be quantified with 7-ethoxymethyl-3-methylxanthine analogously to Example 1b) to 7-ethoxymethyl-1- (5,6-isopropylidenedioxy-5-methylhexyl) -3-methylxanthine (C ₁₉ H ₃₀ N ₄ O ₅ MW = 394.5), from which the end product was obtained by acid hydrolysis with simultaneous opening of the dioxolane ring and elimination of the 7-hour ethoxymethyl radical. For this purpose, 19.7 g (0.05 mol) of the xanthine compound in a mixture of 300 ml of 1 N hydrochloric acid and 30 ml of glacial acetic acid were heated to 70 ° C. for 15 hours with stirring, made alkaline after cooling with sodium carbonate and washed with chloroform, then neutralized with 1N hydrochloric acid and with chloroform extracted. The evaporation residue was recrystallized from ethyl acetate after filtration through a silica gel column in the eluent chloroform / methanol (10: 1).

Yield: 1 1.5 g (77.6% of theory)

Melting point: 181-182 ° C

C ₁₃ H ₂₀ N ₄ O ₄ (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, prepared from 7-benzyl-3-methylxanthine and 1-chloro-5-hexanone analogously to Example 1 b), was treated with ethyl magnesium chloride according to Example 5b) reductively ethylated on the keto group and the resulting 7-benzyl-1- (5-hydroxy-5-methylheptyl) -3-methylxanthine was then debenzylated hydrogenolytically under the conditions of Example 1c). Yield: 70.2% of theory

Melting point: 169-170 ° C

C ₁₄ H ₂₂ N ₄ O ₃ (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, prepared from 7-benzyl-3-ethylxanthine (Example 2a) and 1-chloro-5-hydroxy-5-methylhexane (WO 87 / 00523) according to Example 1 b) with a yield of 65% of theory (C ₂₁ H ₂₈ N ₄ O _3. MG 384.5); Melting point: 112-114 ° C), was using Ammonium formate as hydrogen source debenzylated hydrogenolytically. For this purpose, 3.84 g (0.01 mol) of the benzyl compound and 1.0 g (0.016 mol) of ammonium formate in 30 ml of ethanol over 2 g of palladium (10%) on activated carbon were stirred at 35 ° C. for several days, the Successive addition of further ammonium formate up to a total amount of 4.4 g (0.07 mol) has proven itself. It was filtered, the filtrate was concentrated, the residue was taken up in sodium carbonate solution, washed with chloroform, the aqueous phase was brought to pH 4 with hydrochloric acid, the product was extracted with chloroform and recrystallized from ethyl acetate after drying and evaporation. Yield: 2.0 g (67.9% of theory)

Melting point: 180 - 182 ° C

^C 14 ^H 22 ^N 4 ° 3 < ^MW = 294.4) Analysis: Calculated: C 57.12% H 7.53% N 19.04% Found: C 56.77% H 7.66% N 18.93 %

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

7-Benzyl-3-ethylxanthine (Example 2a) and 1-chloro-5-hexanone were converted to 7-Benzyl-3-ethyl-1- (5-oxohexyl) xanthine analogously to Example 1b) (C ₂₀ H ₂₄ N ₄ O _3rd MW = 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 (C ₂₂ H ₃₀ N ₄ O ₃ MW = 398.5; yield: 86.9% of theory; melting point: 93-94 ° C.), which was debenzylated by hydrogenolysis as in Example 10. The end product could be recrystallized from ethanol. Yield: 66.5% of theory

Melting point: 165-166 ° C

^C 15 ^H 24 ^N 4 ° 3 < ^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 (C ₂₁ H ₂₈ N ₄ O ₃ MW = 384.5; melting point: 83 - 85 ° C), produced in 77.5% yield from 7-benzyl-3-methylxanthine and 1-bromo-6-hydroxy-6-methylheptane (WO 87/00523) analogously to Example 1 b), was debenzylated according to Example 1 c) by hydrogenolysis. Yield: 82.2% of theory

Melting point: 166-167 ° C

C ₁₄ H ₂₂ N ₄ O ₃ (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 was carried out with 7-benzyl-3-ethylxanthine from Example 2a), the hydrogenolytic debenzylation using ammonium formate being carried out analogously to Example 10. Yield: 72.4% of theory

Melting point: 163 - 165 ° C

C ₁₅ H ₂₄ N ₄ O ₃ (MW = 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

Bei- XR ¹ R ² melting point spipl

1 1 H CH ₃ CH ₃ 215 -217

2 1 H CH3 C ₂ H ₅ 217 -219

3 2 H CH ₃ CH ₃ 203-205

4 2 H CH ₃ C ₂ H ₅ 241-243

5 3 H CH ₃ CH ₃ 188-189

6 3 H CH ₃ CH ₅ 214-216

7 4 H CH ₃ CH ₃ 192-193

8 4 OH CH ₃ CH ₃ 181-182

9 4 HC ₂ H ₅ CH ₃ 169-170

10 4 H CH ₃ C ₂ H ₅ 180-182 At n XR ¹ R melting point spipl

1 1 4 HC ₂ H ₅ C ₂ H ₅ 165 - 166

12 5 H CH ₃ CH ₃ 166-167

13 5 H CH ₃ C ₂ H ₅ 163-165

Pharmacological testing and results

1. Inhibitory effect against the pro-inflammatory mediators of the early phase reaction

The inhibitory effect of the compounds according to formula I on the pro-inflammatory early-phase mediators histamine, PAF and leukotriene D (LTD ₄ ) was investigated on isolated segments of the respiratory tract organs of albino guinea pigs, the inhibition of the contractions which can be triggered with these mediators serving as measurement parameters.

Freshly prepared organs from male animals were used to carry out the experiment.

The trachea was broken down into its rings, of which 5 were tracheal rings

Silk threads linked into a chain, in an organ bath at 37 ° C warmer and

Carbogen-bubbled Tyrode solution suspended under a tensile load of 0.5 g and by adding histamine dihydrochloride (bath concentration: 3 x 10 ^"7 g / ml)

Absence (control experiment) or in the presence of the test substances

Contraction were brought.

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 LTD ₄ 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 preparation effect was assessed on the basis of the IC ₅₀ values, which represent the concentration in g / ml at which the organ contraction produced in the control experiment was reduced by half. The results are summarized in Table 2.

Table 2: Inhibitory effects on the pro-inflammatory early phase mediators

Anti-constrictive compound (IC ₅₀ in g / ml)

Example Histamine PAT LTD ₄ Trachea Lung Lung

4 10 1 -3

5 30 3 10

6 30 3 1 -3

7 10-30 10-30 10-30

8 10-30 6 10

9 10-30 10 10-30

12 3- 10 3-6 6- 10 Anti-constrictive compound (IC ₅₀ in // g / ml)

Example Histamine PAT LTD ₄ Trachea Lung Lung

13 10 - 30 1

Pentoxifylline 30-60 3 30-60

Torbafylline 60 3 - 6 10 - 30

Inhibition of the antigen-induced early phase reaction in presensitized guinea pigs

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

The experiment was carried out 20 days later using the method of Konzett and Rössler (Arch. Exp. Path. And Pharmak. (1940) 195: 75). For this purpose, the animals were anesthetized with pentobarbital, artificially ventilated, treated with alcuronium chloride to switch off spontaneous breathing and divided into groups of 6 animals each. Intravenous administration of ovalbumin as an antigen at a dose of 1 mg / kg triggered a long-lasting asthma attack as a result of an acute bronchospasm induced by mediators during the early asthmatic reaction, the intensity of which was quantified by the contraction level in the thoracogram.

The test preparations were also administered intravenously 15 minutes before the antigen challenge. The animals in the control group received pure 0.9% saline instead. The number of Animals of the respective group were determined in which the asthma reaction of the control animals was reduced by at least 40%. The results are shown in Table 3.

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 human eosinophilic granulocytes by the late-phase mediators IL-5, GM-CSF, C5a and PAF was investigated with the help of the lucigenin-dependent chemiluminescence (CL) reaction.

Table 3: Inhibition of the antigen-induced early phase response in guinea pigs

Association of protected animals after i.v. Administration of 10 mg / kg 25 mg / kg

Example Number% share Number% share

2 2/6 33 4/6 67

4 1/6 17 3/6 50

7 2/6 33 4/5 80

8 3/6 50 3/6 50

9 4/6 67 5/6 83

12 3/6 50 4/6 67

Pentoxifylline 1/6 17 2/6 33

Torbafylline 0/6 0 0/6 0 For this purpose, purified eosinophils were obtained from venous human blood by known 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 for 10 minutes at 37 ° C and then with IL-5 (10 ² U / ml), GM-CSF (10 ³ U / ml), C5a (10 ^"7 M) or PAF (10 ^{* 6} M) activated or water was added to determine 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 Percent of that of the positive control calculated according to the following formula:

CL _X - CL _B x 100

CL _Δ - C

CL _X the activity after stimulation of those pretreated with the xanthines

Cells, CL _{A describe} the activity after stimulation of the cells pretreated with water and CL _B 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

Compound residual activity in% of positive control A off after stimulation with

Example IL-5 GM-CSF C5a PAF

7 42 63 19 17

Pentoxifylline 57 70 56 45

Torbafylline 58 125 51 58

Inhibition of the antigen-induced late phase response

In a chronic long-term test on guinea pigs provoked with human serum antigen, the inhibitory effect of the compounds of the formula I on the pathologically increased chemotactic infiltration of eosinophilic granulocytes into the peritoneal space (in vivo) and their functional state (ex vivo) was investigated. The animals of the preparation group (n = 6) were treated with the test substance in a daily oral dose of 80 mg / kg for 15 weeks, while the animals of the control group (n = 6) received the vehicle (carboxymethyl cellulose). After the third week of treatment, all 12 animals were provoked by weekly intraperitoneal administration of 1 ml of human serum antigen and each 48 hours later subjected to peritoneal lavage with 50 ml of 5% glucose solution, in which the number of infiltrated eosinophils and after their isolation via discontinuous Percoll -Density gradients (purity>95%; V ability> 98%) reactivity to PAF and C5a using the Actin polymerization determined by flow cytometry and by means of the Boyden chamber technique in comparison between the two animal groups.

Here, for example, the compound from preparation example 7 caused a significant reduction (p <0.01) in the number of eosinophils (34.9 4.8%; x SD) that had migrated into the peritoneal space compared to the control animals (42.2 5.8% ). In addition, the eosinophils of the treated animals showed a significant reduction (p <0.05) of the chemotactic migration triggered by PAF or C5a compared to that of the control animals; the initial phase (<10s) of actin polymerization induced with PAF (10 nM) was also significantly reduced.

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

Claims

Claims:

Use of at least one compound of formula I.

and / or a physiologically acceptable salt of the compound of the formula and / or a stereoisomeric form of the compound of the formula I, where

R ^{1 represents} a methyl or ethyl group, R ^{2 represents} an alkyl group with 1 to 4 carbon atoms and X represents a hydrogen atom or a hydroxy group and 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 at least one compound of formula I or its salt is used, in which R ^{2 is} methyl 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 R ¹ and R ² independently of one another are methyl or ethyl, X is a hydrogen atom or hydroxyl group and n is an integer from 3 to 5.

4. Use according to one or more of claims 1 to 3, characterized in that 1- (5-hydroxy-5-methylhexyl) -3-methylxanthine or its salt is used.

5. Use according to one or more of claims 1 to 4 for the treatment and / or prophylaxis of diseases of the atopic group.

6. Use according to one or more of claims 1 to 5 for the treatment and / or prophylaxis of anaphylaxis, allergic bronchial asthma, 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 additionally an effective amount of at least one compound from the group of antihistamines, anticholinergics, ß ₂ mimetics, phosphodiesterase, phospholipase A ₂ - and lipoxygenase inhibitors, PAF and leukotriene antagonists, Corticosteroids, Cromoglicinsäure, Nedocromil and Cyclosporin A uses.

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 R ^{1 is} methyl or ethyl,

R ² alkyl with 1 to 4 carbon atoms,

X is a hydrogen atom or hydroxy group and n is an integer from 1 to 5

mean, the compound of the formula I in which R ¹ and R ^{2 are} simultaneously methyl, X is a hydrogen atom and n is the number 4, is excluded.

10. A compound according to claim 9, characterized in that in formula IR ^{2 is} 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.

R ^{1 is} methyl,

R ^{2 is} methyl or ethyl,

X is hydrogen and n is an integer from 1 to 5

mean.

13. A process for the preparation of the compounds of the formula I according to claims 9 to 12, characterized in that a 3,7-disubstituted xanthine derivative of the formula II,

R ^{2 is} an alkyl group with 1 to 4 carbon atoms and R ^{a is} an easily eliminable one

Leaving group in the form of hydrolytically removable meth, eth, prop or

Butoxymethylrestes or the reductively removable benzyl or

Diphenylmethyl group with unsubstituted or substituted phenyl rings, advantageously 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 is a 1,3,7-trisubstituted xanthine of the formula IV

implemented, where R, R ² , R ^a , X and n have the meanings defined above,

or alternatively in the event that X denotes hydrogen atom,

with a keto compound of the formula V,

H ₃ C-CO- (CH ₂ ) _n -Z (V)

in which n and Z have the meanings given above, to a 1,3,7-trisubstituted xanthine of the formula VI

(VI)

reacting this subsequently with a methyl or ethyl-metal compound (R ¹ -M) in the form of methyl or ethyl lithium ^(R1 -Li), or the corresponding Grignard reagents (R ¹ -MgHal) by reductive alkylation of the carbonyl group in a 1,3,7-trisubstituted xanthine of formula VII

transferred, in which R \ R> 2 _D Ra ^a and n have the abovementioned meanings,

or alternatively if X is hydrogen and R ^{1 is} methyl,

with a carboxylic acid ester of the formula VIII,

(C _r C ₄ ) alkyl-0-CO- (CH ₂ ) _n -Z (VIII)

in which n and Z have the abovementioned meanings,

to a 1, 3,7-trisubstituted xanthine of the formula IX reacting this then reacted with two equivalents of a methyl-metal compound in the form of CH ₃ or CH ₃ -Li -MgHal under double reductive alkylation of the Esterfunktion in a 1, 3,7- trisubstituted xanthine of formula X

converts, where R, R ^a and n have the meanings given above,

and finally splitting off the leaving group R ^a from the intermediate compound of the formula IV, VII or X to form the xanthine of the formula I and, if desired, converting it into a pharmaceutically acceptable salt.

14. Medicament, characterized by the content of a therapeutically effective amount of at least one compound of the formula I according to one or more of claims 9 to 12 or prepared according to claim 13.

15. A method for producing a medicament according to claim 14, characterized in that at least one compound of formula I according to one or more of claims 9 to 12 with pharmaceutically suitable and physiologically tolerable carriers and additives, diluents and / or other active ingredients or Brings excipients in a suitable dosage form.