Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
  • A61K31/52—Purines, e.g. adenine
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D473/00—Heterocyclic compounds containing purine ring systems
  • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
  • C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
  • A61K31/52—Purines, e.g. adenine
  • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
  • A61P11/06—Antiasthmatics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/08—Antiallergic agents

Definitions

• 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.
• 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 va
• IgE immunoglobulin E
• type I allergies dominate in the form of anaphylaxis, allergic bronchial asthma, allergic rhinitis and conjunctivitis, allergic urticaria, allergic Gastroenteritis and atopic dermatitis.
• substances from the natural environment e.g. grass pollen, spores, house dust and mites, animal hair or food
• 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.
• 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).
• PAF platelet activating factor
• prostacilandins and leukotrienes
• 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. ⁇ chtblatt (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.
• 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 ).
• IL-5 interleukin-5
• GM-CSF granulocyte / macrophage colony-stimulating factor
• chemotactic factors responsible for migration and activation such as PAF and leukotriene B 4 (LTB 4 ).
• 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).
• 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).
• MBP major basic protein
• ECP eosinophil cationic protein
• EDN / EPX eosinophil Derived Neurotoxin / Eosinophil Protein X
• 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.
• 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).
• 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.
• xanthine compounds 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.
• 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.
• 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.
• R 1 represents a methyl or ethyl group
• R 2 for an alkyl group with 1 to 4 carbon atoms
• 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.
• n are an integer from 3 to 5.
• 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
• R 1 is methyl
• R 2 is methyl or ethyl
• X is hydrogen and n is an integer from 1 to 5
• 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,
• 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
• R 1 , R 2 , R a , X and n have the meanings defined above, or alternatively in the event that X is hydrogen,
• n and Z have the meanings given above
• a 1,3,7-trisubstituted xanthine of the formula VI 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
• 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.
• 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.
• a basic condensing agent for example, alkali or alkaline earth metal hydroxides, carbonates, hydrides, alcoholates and organic bases, such as trialkylamines, for.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• alkyl titanium and zirconium compounds D. Seebach et al., Angew. Chem. 95 (1983), pp. 12-26
• 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.
• 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.
• 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.
• 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.
• 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.
• Lewis acids such as zinc bromide and titanium tetrachloride
• the compounds of formula I can be deprotonated in position 7 and therefore form salts and solvates with basic agents.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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 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.
• 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).
• 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
• Example 2a 7-benzyl-3-ethylxanthine (Example 2a) and 1-chloro-3-hydroxy-3-methylbutane (Example 3a). Yield: 71.8% of theory
• 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.
• 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)
• 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.
• Example 1 3-Ethyl-1- (5-hydroxy-5-methylheptyl) xanthine
• 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
• 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.
• the trachea was broken down into its rings, of which 5 were tracheal rings
• the lung was cut longitudinally into 2 to 3 strips, which were followed as described above.
• 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.
• Anti-constrictive compound (IC 50 in g / ml)
• the experiment was carried out 20 days later using the method of Konzett and Rössler (Arch. Exp. Path. And Pharmak. (1940) 195: 75).
• 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.
• 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.
• 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.
• 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 ⁇ M 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:
• 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 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% ).
• 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.

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  • 1995-03-21 AU AU19510/95A patent/AU695488B2/en not_active Ceased
  • 1995-03-21 WO PCT/EP1995/001060 patent/WO1995026727A1/de not_active Application Discontinuation
  • 1995-03-21 RU RU96121791/14A patent/RU2159617C2/ru active
  • 1995-03-21 KR KR1019960705541A patent/KR100373948B1/ko not_active IP Right Cessation

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