RU2159617C2 - Xanthine derivatives, their stereoisomers and physiologically tolerable salts, pharmaceutical composition diminishing pathologic hyperactivity of eosinophilic granulates - Google Patents

Abstract

FIELD: pharmaceutical chemistry. SUBSTANCE: invention provides xanthine derivatives depicted by general formula I:

Description

 The invention relates to new nitrogen-containing heterocyclic compounds having biological activity, more specifically to xanthine derivatives, their stereoisomers and physiologically tolerated salts, as well as to a pharmaceutical composition having activity reducing the pathological hyperactivity of eosinophilic granules.

 Derivatives of trialkylxanthine are known to have biological activity, for example, activity reducing the pathological hyperactivity of eosinophilic granules (see application EP N 0544391, A1, A 61 K 31/52, 02.06.1993).

 The objective of the invention is to expand the range of xanthine derivatives with biological activity, in particular reducing pathological hyperactivity of eosinophilic granulocyte activity.

где R¹ - метил или этил,
R² - алкил с 1-4 атомами углерода,
X - атом водорода или гидроксил,
n - целое число от 1 до 5,
причем при R¹ - метил, R² - метил, X - атом водорода, n означает число 1, 2, 3, 5,
их стереоизомерами и физиологически переносимыми солями.The problem is solved by the proposed xanthine derivatives of the general formula (I)

where R ¹ is methyl or ethyl,
R ² is alkyl with 1-4 carbon atoms,
X is a hydrogen atom or hydroxyl,
n is an integer from 1 to 5,
and when R ¹ is methyl, R ² is methyl, X is a hydrogen atom, n means the number 1, 2, 3, 5,
their stereoisomers and physiologically tolerated salts.

The first group of preferred xanthine derivatives of general formula (I) include compounds in which R ² is methyl or ethyl.

 The second group of preferred xanthine derivatives of the general formula (I) includes compounds in which X represents a hydrogen atom.

The third group of preferred xanthine derivatives of the general formula (I) includes compounds in which R ¹ is methyl, R ² is methyl or ethyl, X is a hydrogen atom, n is an integer from 1 to 5.

 New xanthine derivatives of the general formula (I) can be prepared by known methods.

в которой R² означает алкильную группу, содержащую oт одного до четырех атомов углерода, a R^a означает легкоудаляемую группу, например гидролитически отщепляемый метильный, этильный, пропильный или бутоксиметильный остаток или удаляемую восстановлением бензильную или дифенилметильную группу с незамещенными или замещенными фенильными кольцами, целесообразно в присутствии основного агента конденсации или его соли подвергают взаимодействию
а) с алкилирующим средством формулы (III)

в которой R¹, X и n имеют вышеназванные значения, a Z означает галоген, предпочтительно хлор, бром или иод, либо группировку эфира сульфоновой кислоты или эфира фосфорной кислоты,
до получения 1,3,7-тризамещенного ксантина формулы IV

причем R¹, R², R^a, X и n имеют вышеопределенные значения или альтернативно для случая, когда Х означает водород,
б) с кето - соединением формулы V,
H₃C - СО - (СН₂)_n - Z (V)
в которой n и Z имеют вышеназванные значения,
до получения 1,3,7 - тризамещенного ксантина формулы VI

который затем с помощью метил-/ или этилметаллосоединения (R¹ - М), предпочтительно в виде метил- или этиллития (R¹-Li) или соответствующих соединений Гриньяра (R¹-MgHal) в условиях восстановительного алкилирования карбонильной группы переводят в 1,3,7-тризамещенный ксантин формулы VII

в которой R¹, R² и n имеют вышеназванные значения, или альтернативно для случая, когда X означает водород, a R¹ означает метил,
в) со сложным эфиром карбоновой кислоты формулы VIII
(C₁-C₄)алкил-O-CO-(CH₂)_n, -Z (VIII)
в которой n и Z имеют вышеназванные значения,
до получения 1,3,7-тризамещенного ксантина формул IX

в которой R^a, R² и n имеют вышеуказанные значения,
который затем действием двух эквивалентов метилметаллосоединения, предпочтительно CH₃-Li или CH₃-MgHal при двукратном восстановительном алкилировании сложноэфирной функции превращают в 1,3,7-тризамещенный ксантин формулы X

в которой R², R^a и n имеют вышеназванные значения,
и наконец путем удаления группы R из промежуточного соединения формулы IV, VII или X получают ксантин формулы I согласно изобретению.Advantageously, the 3,7-disubstituted xanthine derivative of the formula (II)

in which R ² means an alkyl group containing from one to four carbon atoms, and R ^a means an easily removable group, for example a hydrolytically cleavable methyl, ethyl, propyl or butoxymethyl residue or a benzyl or diphenylmethyl group removed by reduction with unsubstituted or substituted phenyl rings, preferably the presence of a basic condensation agent or its salt is reacted
a) with an alkylating agent of the formula (III)

in which R ¹ , X and n have the above meanings, a Z means halogen, preferably chlorine, bromine or iodine, or a group of sulfonic acid ester or phosphoric acid ester,
to obtain 1,3,7-trisubstituted xanthine of the formula IV

wherein R ¹ , R ² , R ^a , X, and n are as defined above or alternatively when X is hydrogen,
b) with keto - a compound of formula V,
H ₃ C - CO - (CH ₂ ) _n - Z (V)
in which n and Z have the above values,
to obtain 1,3,7 - trisubstituted xanthine of formula VI

which then via methyl- / or etilmetallosoedineniya (R ¹ - M), preferably in the form of methyl or ethyllithium (R ¹ -Li) or the corresponding Grignard compounds (R ¹ -MgHal) under reductive alkylation of the carbonyl group is converted into 1,3 , 7-trisubstituted xanthine of formula VII

in which R ¹ , R ² and n have the above meanings, or alternatively for the case when X is hydrogen, and R ¹ is methyl,
c) with a carboxylic acid ester of formula VIII
(C ₁ -C ₄ ) alkyl-O-CO- (CH ₂ ) _n , -Z (VIII)
in which n and Z have the above values,
to obtain 1,3,7-trisubstituted xanthine of formulas IX

in which R ^a , R ² and n have the above meanings,
which then, by the action of two equivalents of a methyl metal compound, preferably CH ₃ -Li or CH ₃ -MgHal, is converted into a 1,3,7-trisubstituted xanthine of formula X by double reductive alkylation of the ester function

in which R ² , R ^a and n have the above values,
and finally, by removing the R group from the intermediate of formula IV, VII or X, a xanthine of formula I according to the invention is obtained.

The 3,7 - disubstituted xanthines of the formula II and alkylating agents of the formula III, V and VIII used here as starting compounds are for the most part known or can be easily obtained by methods known in the literature. So, the tertiary alcohols of the formula III can be obtained, for example, by organometallic synthesis, by means of which sterically unobstructed halo ketones of the formula Hal- (CH ₂ ) _n -CO-CH ² X are converted by the so-called building reaction using reductive alkylation of the carbonyl group with alkyl metal compounds R ¹ -M, in which M is a metal, mainly magnesium, zinc or lithium, sometimes in the form of alkyl magnesium halides R ¹ -MgHal (Grignard compounds) or alkyl lithium compounds R ¹ -Li under ordinary conditions. A similar conversion of halo-ketones of formula Hal- (CH ₂ ) _n -CO-R ^{1 with} methyl magnesium halides or methyl lithium also leads to compounds of formula III in which X is hydrogen. A convenient approach to compounds of formula III in which R ¹ is methyl and X is a hydrogen atom also gives the reaction of ω-haloalkanoic acid alkyl esters (Hal- (CH ₂ ) _n -COO-alkyl) with two equivalents of a methyl metal compound, with ether reacts via ketone followed by the formation of tertiary alcohol by the introduction of two methyl residues. Similarly, ω-hydroxycarboxylic acid esters with an unprotected or protected hydroxyl group, for example, in the form of tetrahydropyran-2-yl or methoxymethyl esters or, if necessary, in the form of a lactone as a cyclic ester, can be converted into diols by the action of methyl metal compounds, By selectively esterifying the primary hydroxyl function with sulfonic acid or phosphoric acid halides or anhydrides, active alkylating agents of formula III can be prepared.

 The disubstituted xanthine derivative of formula II reacts with said alkylating agents of formulas III, V or VIII and is usually carried out in a solvent inert to the reagents or dispersing agent. As such, first of all, dipolar, aprotic solvents are suitable, for example, formamide, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, tetramethylurea, hexamethylphosphotriamide, dimethyl sulfoxide, acetone or butanone; alcohols such as methanol, ethylene glycol and its mono- or dialkyl ethers containing from one to four carbon atoms in the alkyl group, ethanol, propanol, isopropanol and various butanols can also be used; hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as dichloromethane or chloroform; pyridine, as well as mixtures of these solvents with water.

The alkylation reaction is expediently carried out in the presence of an alkaline condensation agent. Suitable for this are, for example, hydroxides, carbonates, hydrides, alkoxides of alkali or alkaline earth metals and organic bases such as trialkylamine, triethyl or tributylamine, quaternary ammonium or phosphonium hydroxides and crosslinked resins with optionally substituted substituted ammonium or phosphonium groups. However, xanthine derivatives can be used directly in the form of their separately prepared salts, for example, alkali metal, alkaline earth metal salts or optionally substituted ammonium or phosphonium salts. In addition, disubstituted xanthine compounds can be conveniently alkylated both in the presence of the aforementioned inorganic condensing agents and in the form of their salts with alkali or alkaline earth metals using so-called phase transfer catalysts, for example tertiary amines, quaternary ammonium or phosphonium salts or also crown ethers preferably in a biphasic system under phase transfer catalysis. Most commonly suitable commercial phase transfer catalysts are, in particular, tetraalkyl- salts (containing from one to four carbon atoms in the alkyl group) and methyltrioctylammonium and phosphonium, methyl-, myristyl-, phenyl- and benzyl-trialkyl- (containing from one to four carbon atoms in the alkyl group) and cetyltrimethylammonium, as well as alkyl (containing from one to twelve carbon atoms) and benzyltriphenylphosphonium salts, and, as a rule, those compounds that have a more voluminous and more symmetrically built cat n, are more effective. In general, in the above methods, the process is carried out at a reaction temperature between 0 ^° C. and the boiling point of the reaction medium used in each case, preferably between 20 ^° C. and 130 ^° C., if necessary, at elevated or reduced pressure, but usually at atmospheric pressure, the time being reactions may range from less than one hour to several hours.

 When xanthines VI and IX, which have functional groups in position 1, react with an organometallic compound, the process proceeds in the same way as in the preparation of tertiary alcohols used as alkylating agents according to formula III. Thus, reductive alkylation of ketones VI or esters IX can be carried out, for example, by potassium alkyl, sodium alkyl, alkyl lithium, magnesium magnesium, zinc zinc, alkyl cadmium, alkyl aluminum and alkyl tin compounds. Recently recommended recent titanium and alkyl zirconium compounds are also applicable. Since, however, the alkyl metal compounds of sodium and potassium are prone to side reactions due to their high reactivity, and similar zinc and cadmium compounds are relatively inert, alkyl lithium and alkyl magnesium compounds (Grignard compounds) are usually preferred.

Strongly nucleophilic organometallic compounds are very sensitive to hydrolysis and oxidation. Their use requires work in an anhydrous environment, and, if necessary, in a protective gas atmosphere. Typical solvents or dispersants are, first of all, those which are also suitable for the preparation of alkyl metal compounds. As such, we are primarily talking about ethers with one or more ether oxygen atoms, for example diethyl, dipropyl, dibutyl or diisoamyl ethers, 1,2-dimethoxyethane, tetrahydrofuran, dioxane, tetrahydropyran, furan and anisole and such aliphatic or aromatic hydrocarbons as petroleum ether, cyclohexane, benzene, toluene, xylene, diethylbenzene and tetrahydronaphthalene; tertiary amines such as triethylamine, or dipolar aprotic solvents such as hexamethylphosphotriamide, as well as mixtures of these solvents, can also be used successfully. In the reaction of carbonyl compounds VI or IX with Grignard compounds of the formula R ₁ -MgHal, it is also possible to successfully carry out the process such that the organometallic compound is placed in ether and a ketone or ester is added dropwise to it in the form of a solution in dichloromethane or 1,2- dichloroethane. It is often advisable to add magnesium bromide, which, due to its participation in the complex cyclic transition state, could increase the nucleophilicity of the organometallic compound.

The addition of a ketone or ester to an organometallic compound occurs, as a rule, at temperatures between -20 ^° C and 100 ^° C, preferably between 0 ^° C and 60 ^° C or at room temperature without external cooling, and the alkyl metal compound is usually used in a slight excess. Then the substitution usually ends with short-term heating under reflux, for which, as a rule, a period of time from a few minutes to several hours is sufficient. The decomposition of the resulting alcoholate is preferably carried out with an aqueous solution of ammonium chloride or diluted acetic acid.

The removal of the leaving group R ¹ from the compounds of formulas IV, VII and X during the formation of xanthines of formula I according to the invention is carried out under standard conditions, which were primarily developed within the framework of the technology of protective groups in the synthesis of alkaloids and peptides and, therefore, can be largely known in advance.

Then, if necessary, preferably reductively, the benzyl or diphenylmethyl group replacing in the phenyl ring is cleaved. Along with the chemical method of reducing, in particular, the benzyl compound with sodium in liquid ammonia, the aforementioned aralkyl groups are mainly eliminated by catalytic hydrogenolysis using a noble metal catalyst, and often ammonium formate as a hydrogen donor is a substitute for molecular hydrogen. In this case, the reaction medium is usually lower alcohol, if necessary with the addition of formic acid or even ammonia; an aprotic solvent such as dimethylformamide or especially glacial acetic acid; but mixtures thereof with water may also 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 due to the competing ring hydrogenation reaction often predispose to side reactions and therefore are only used as a last resort. In practice, hydrogenolysis is carried out at temperatures between 20 ^° C. and 100 ^° C. at atmospheric pressure, or preferably at slightly elevated pressure, to about 10 bar, moreover, as a rule, the reaction takes from a few minutes to several hours.

The 1,3,7-trisubstituted xanthines of formulas IV, VII and X containing an alkoxymethyl group as R ^a represent 0, N-acetals and, as a result, are readily cleaved under normal conditions of acid hydrolysis. Preferred residues are, for example, a methoxy group, an ethoxy group, a propoxy group and a butoxymethyl group. The reaction is preferably carried out by 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 dissolving agent. Perchloric acid or organic acids, such as trichloroacetic, formic and acetic acids, are sometimes used in combination with catalytic amounts of mineral acids. The cleavage of the ester group can in principle also be carried out using Lewis acids, such as zinc bromide and titanium tetrachloride, in an anhydrous medium, preferably in dichloromethane or chloroform. When splitting in a solution of mineral acid, the reaction temperature should be chosen so that there is no noticeable dehydration of the tertiary hydroxyalkyl group located in position 1; therefore, it should not, as a rule, exceed 60 ^o C.

 The compounds of formula I are deprotonated at position 7 and therefore form salts and solvates with basic substances. By these are meant pharmaceutically acceptable salts of alkali and alkaline earth metals and salts and solvates with organic bases, for example ethylenediamine, or basic amino acids: lysine, ornithine and arginine. Thus, the invention also relates to pharmacologically tolerated salts and / or solvates of 1,3-dialkylxanthines according to formula (I).

Tertiary 1- (hydroxyalkyl) -3-alkylxanthines of formula (I) contain one asymmetric carbon atom, when X is hydroxyl or X is hydrogen, and R ¹ is ethyl. Thus, these compounds can exist in stereoisomeric forms.

 As already mentioned above, the proposed xanthine derivatives of the general formula (I) have an activity that reduces the pathological hyperactivity of eosinophilic granulocytes and therefore they can be an active substance of a pharmaceutical composition of the corresponding purpose.

 Thus, the second object of the invention is a pharmaceutical composition having an activity that reduces the pathological hyperactivity of eosinophilic granulocytes, which in addition to at least one target additive contains at least one xanthine derivative of the above general formula (I) and / or its stereoisomer and / or its physiologically tolerated salt in an effective amount.

 The proposed pharmaceutical composition may be in the form of standard liquid or solid dosage forms for oral, rectal, local, parenteral or inhalation use in diseases with pathologically increased activity of eosinophilic granulocytes.

 Suitable solid or liquid dosage forms are, for example, granules, powders, tablets, dragees, (micro) capsules, suppositories, syrups, emulsions, suspensions, lotions, creams, ointments, gels, aerosols, drops or injection solutions in ampoule form, and sustained release preparations of a biologically active substance, in the manufacture of which auxiliary agents are usually used, such as carriers, disintegrants, coating binders, for swelling, for lubrication, flavoring agents, sweeteners or things CTBA, dissolving. Commonly used adjuvants include magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, slippers, milk protein, gelatin, starch, vitamins, cellulose and its derivatives, animal and vegetable oils, polyethylene glycol and solvents, such as distilled water, alcohols, glycerin and polyols.

 Preparations are preferably made and prescribed in dosage units, each unit containing as a active ingredient a specific dose of a compound of formula (I). In solid dosage forms, such as tablets, capsules and suppositories, these dosages can be up to 1000 mg, but preferably from 100 to 600 mg, and in injection solutions in ampouled form, up to 300 mg, but preferably from 20 to 200 mg

 For the treatment of adult patients, daily doses of from 100 to 2000 mg of biologically active substance, preferably from 300 to 900 mg for oral administration and from 10 to 500 mg, preferably from 20 to 200 mg, are determined by the effectiveness of the effects of the compounds of formula (I) on humans with intravenous administration.

 However, in some circumstances, higher or lower daily doses may be established. Obtaining a daily dose can be achieved both by a single dose in the form of a single dosage unit, or by several, but smaller doses, as well as by multiple doses of divided doses at certain intervals.

Finally, in the production of the aforementioned galenic formulations, xanthine derivatives of formula I, if necessary, can be used together with other suitable biologically active substances, for example, antihistamines, anticholinergics and β ₂ mimetics, phosphodiesterase inhibitors, phospholipase A ₂ and lipoxygenases, FAT antagonists and leukotriene, corticosteroids, chromoglycine, nedocromil, as well as cyclosporin A.

 The preparation of xanthine derivatives of the general formula (I) is illustrated by the following examples.

Example 1
1- (2-hydroxy-2-methylpropyl) -3-methylxanthine
a) 1-chloro-2-hydroxy-3-methylpropane
To 44.9 g (0.6 mol) of methylmagnesium chloride in the form of a 20% solution in tetrahydrofuran and 200 ml of dry diethyl ether was added dropwise with stirring at a temperature from 0 to 5 ^o C a solution of 46.3 g (0.5 mol) of 1-chloro-2-propanone in 50 ml of anhydrous diethyl ether. Then it was first stirred for 1 hour at room temperature and then another 1 hour at the boil under reflux, the resulting tertiary alcoholate was decomposed by adding a 50% aqueous solution of ammonium chloride, the ether layer was separated, and the aqueous layer was extracted with ether.

 The combined ether extracts were washed successively with aqueous solutions of sodium bisulfite and sodium bicarbonate, as well as a small amount of 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.)
T. bale. 125 - 127 ^o C
C ₄ H ₉ ClO (M.v. 108.6) -
The compound can also be obtained in a similar manner from methyl or ethyl esters of chloroacetic acid and a double molar amount of methyl magnesium chloride in yields of about 60% of theory.

b) 7-benzyl-1- (2-hydroxy-2-methylpropyl) -3-methylxanthine
A mixture of 25.6 g (0.1 mol) of potassium carbonate and 11.9 g (0.11 mol) of tertiary alcohol from step a) in 500 ml of dimethylformamide was heated for 8 hours with stirring at a temperature of 110 to 120 ^° C, then filtered while hot and evaporated under reduced pressure. The residue was removed with 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.)
Mp 115-117 ^o C
C ₁₇ H ₂₀ N ₄ O ₃ (M.W. 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 was also obtained by the method in which 7-benzyl-3-methylxanthine was first converted by reaction of 1-chloro-2-propanone or chloroacetic acid methyl or ethyl ester into 7-benzyl-3-methyl-1- (2- oxopropyl) xanthine or 7-benzyl-1-meth (or et) hydroxycarbonylmethyl-3-methylxanthine and then the oxopropyl or alkoxycarbonylmethyl side chain was reductively methylated with methyl magnesium chloride in anhydrous diethyl ether as described in step a).

c) 1- (2-hydroxy-2-methylpropyl) -3-methylxanthine
13.1 g (0.04 mol) of 7-Benzylxanthine from step b) in 200 ml of glacial acetic acid was hydrogenated with shaking over 1.5 g of palladium (10%) on activated carbon at 60 ^° C. and 3.5 bar for 100 hours. After cooling, it was purged 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.)
Mp 215-217 ^o C
C ₁₀ H ₁₄ M ₄ O ₃ (M.W. 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-methylpropyl) -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 caustic soda dissolved in 200 ml of water and stirred for 1 hour at 70 ^° C, 69 were added dropwise at the same temperature , 6 g (0.55 mol) of benzyl chloride and kept the reaction mixture for 3 hours at a temperature between 70 and 80 ^o C. Then it was cooled, filtered cold on the suction filter, washed on the suction filter with water, dissolved in 1000 ml of hot 1n caustic soda, filtered and using 4 N. hydrochloric acid was slowly adjusted to pH 9.5 with stirring. The crystallization product was filtered off from the still warm solution, washed with chloride-free water and dried in vacuum.

Yield: 131 g (96.9% of theory).
Mp 217-218 ^o C
C ₁₄ H ₁₄ N ₄ O ₂ (M.W. 270.3)
b) 3-ethyl-1- (2-hydroxy-2-methylpropyl) -xanthine
The reaction of 7-benzyl-3-ethylxanthine from step a) with 1-chloro-2-hydroxy-2-methylpropane from Example 1a) to produce 7-beneyl-3-ethyl-1- (2-hydroxy-2-methylpropyl) xanthine C ₁₈ H ₂₂ N ₄ O ₃ (M.w. 342.4); yield: 46.1% of theory. ) and its subsequent hydrogenolytic debenzylation (yield: 97.9% of theory) in accordance with Example 1c), a crude final product was obtained, purified by recrystallization from ethanol.

Mp 217-219 ^o C
C ₁₁ H ₁₆ N ₄ O ₃ (M.W. 252.3)
Analysis: Calculated 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-methylbutane.

 The compound was obtained from methylmagnesium iodide and 1-chloro-3-butanone (which can be obtained by addition of hydrogen chloride to methyl vinyl ketone in diethyl ether) or from methylmagnesium chloride and ethyl 3-chloropropionic acid in dichloromethane as a reaction medium, as in Example 1 a).

 Yield: 60 - 70% of theory.

T.kip (18 mbar) 66 - 68 ^o C
C ₅ H ₁₁ ClO (M.W. 122.6).

b) 7-benzyl-1- (3-hydroxy-3-methylbutyl) -3-methylxanthine
obtained analogously to example 1b) from 7-benzyl-3-methylxanthine and tertiary alcohol from stage a).

 Yield: 70% of theory.

Mp 92-94 ^o C
C ₁₈ H ₂₂ N ₄ O ₃ (M.W. 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
Obtained by hydrogenolytic debenzylation of the product from stage b), analogously to example 1 c).

 Yield: 87.27% of theory.

Mp 203 - 205 ^o C
C ₁₁ H ₁₆ N ₄ O ₃ (M.W. 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
Obtained analogously to example 1b) from 7-benzyl-3-ethylxanthine (example 2a) and 1-chloro-hydroxy-3-methylbutane (example 3a).

Yield: 71.8% of theory
Mp 133-135 ^o C
C ₁₉ H ₂₄ N ₄ O ₃ (M.W. 356.4)
b) 3-ethyl-1 - (3-hydroxy-3-methylbutyl) -xanthine
Obtained in accordance with example 1B) by hydrogenolytic debenzylation of the product from stage a).

 Yield: 88.2% of theory.

Mp 241-243 ^o C
C ₁₉ H ₁₈ N ₄ O ₃ (M.W. 266.3)
Analysis: Calculated: C 54.12%; H 68.1%; N, 21.04%.

 Found: C 53.89%; H 6.86%; N, 21.03%.

Example 5
1- (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 ethylene ketal 1-chloro-4-pentanone in 600 ml of dimethylformamide as described in Example 1b), they were converted to 7-benzyl-1- (4,4-ethylenedioxypentyl) -3-methylxanthine, which was subjected to ketal digestion without further purification by heating it for two hours under reflux in 600 ml of 1N. of hydrochloric acid. After neutralizing the mixture with a concentrated sodium hydroxide solution, the ketone formed was extracted with 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.)
Mp 104 - 105 ^o C
C ₁₈ H ₂₀ N ₄ O ₃ (M.v. 340.4)
b) 7-benzyl-1- (4 hydroxy-4-methylpentyl) -3-methylxanthine
A mixture of 9 g (0.12 mol) of methylmagnesium chloride as a standard 20% solution in tetrahydrofuran and 300 ml of dichloromethane was cooled to -25 ^° C and then 34 g (0.1 mol) of the product from step a) was added dropwise to the solution , while the temperature increased to 20 ^o C. Stirring was continued for another hour at room temperature, then a saturated solution of ammonium chloride was added, the organic layer was separated, the aqueous layer was extracted several times with dichloromethane, the combined dichloromethane extracts were washed with water, dried and evaporated, but firm The th residue was recrystallized from ethyl acetate.

Yield: 28.3 g (79.4% of theory)
Mp 132-133 ^o C
C ₁₉ H ₂₄ N ₄ O ₃ (M.W. 356.4)
c) 1- (4-hydroxy-4-methylpentyl) -3-methylxanthine
Obtained in accordance with example 1C) by hydrogenolytic debenzylation of the product from stage b).

 Yield: 65.9% of theory.

Mp 188 - 189 ^o C
C ₁₂ H ₁₈ N ₄ O ₃ (M.W. 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 is carried out similarly to that described in example 5a) using 7-benzyl-3-ethyl-xanthine from example 2a) as the starting material
Yield: 82.4% of theory.

Mp 139-141 ^o C
C ₁₉ H ₂₂ N ₄ O ₃ (M.W. 354.4)
b) 7-benzyl-3-ethyl-1- (4-hydroxy-4-methylpentyl) xanthine.

 The reaction product of step a) was reacted with methylmagnesium chloride as described in Example 5b).

 Yield: 81.1% of theory.

Mp 155-157 ^o C
C ₂₀ H ₂₆ N ₄ O ₃ (M.W. 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 is obtained by hydrogenolytic debenzylation of the reaction product of stage b), analogously to example 1c).

 Yield: 71.3% of theory.

Mp 214-216 ^o C
C ₁₃ H ₂₀ N ₄ O ₃ (M.W. 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- (5,6-dihydroxy-5-methylhexyl) -3-methylxanthine
a) 1-chloro-5, b-isopropylidenoxy-5-methylhexane
To a nitrogen-purged mixture of 264 g (1.2 mol) of trimethylsulfonium iodide and 28.8 g (1.2 mol) of sodium hydride were added dropwise over 10 minutes with stirring at 40 ^° C. 1000 ml of anhydrous dimethyl sulfoxide. At the end of the gas evolution (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. It was stirred for two hours at room temperature, while cooling with ice, it was slowly mixed with 500 ml of ice water and the resulting 1-chloro-5,6-epoxy-5-methylhexane was extracted with diethyl ether (yield: 130.5 g (87.8% of theory. ); C ₇ H ₁₃ ClO (M.v. 148.6)). For hydrolytic cleavage of epoxyhydrin, it 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 a soda solution, tetrahydrofuran was 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 ₁₇ H ₁₅ ClO ₂ (M. c. 166.6)). Then, in the usual manner, by the action of 2,2-dimethoxypropane in acetone under the conditions of acid catalysis, the diol was converted to dioxolane.

 Yield: 67.2% of theory.

T.kip. (0.5 bar) 84 - 86 ^o C
C ₁₀ H ₁₉ ClO ₂ (M.W. 206.7)
b) 1- (5,6-dihydroxy-5-methylhexyl) -3-methylxanthine
The diol from step a) was reacted with 7-ethoxymethyl-3-methyl-xanthine as described in Example 1b) with the quantitative formation of 7-ethoxymethyl-1- (5,6-isopropylidenedioxy-5-methylhexyl) -3-methylxanthine (C ₁₉ H ₃₀ N ₄ O ₅ , M.V. 394.5), from which the final product was obtained by acid hydrolysis with simultaneous opening of the dioxolane ring and cleavage of the 7-ethoxymethyl group. For this, 19.7 g (0.05 mol) of xanthine compound in a mixture of 300 ml of 1N. hydrochloric acid and 30 ml of glacial acetic acid were heated for 15 hours with stirring to 70 ^° C, after cooling, they were made alkaline with sodium carbonate and washed with chloroform, then neutralized with 1N. hydrochloric acid and was extracted with chloroform. The evaporation residue after filtration through a silica gel column using a chloroform / methanol mixture (10: 1) as the mobile phase was recrystallized from ethyl acetate.

Yield: 11.5 g (77.6% of theory.)
Mp 181-182 ^o C
C ₁₃ H ₂₀ N ₄ O ₄ (M.W. 296.3)
Analysis: Calculated: C, 52.69%; H 6.80%; N, 18.91%;
Found: C 52.46%; H 6.90%; N, 18.66%.

Example 8
1- (5-hydroxy-5-methylheptyl) -3-methylxanthine
7-benzyl-3-methyl-1- (5-oxohexyl) -xanthine obtained from 7-benzyl-3-methyl-xanthine and 1-chloro-5-hexanone as in Example 1b) was reductively ethylated at the keto group with ethyl magnesium chloride in accordance with Example 5b) and the resulting 7-benzyl-1- (5-hydroxy-5-methylheptyl) -3-methylxanthine was debenzylated under the conditions of Example 1c).

 Yield: 70.2% of theory.

Mp 169 - 170 ^o C
C ₁₄ H ₂₂ N ₄ O ₃ (M.W. 294.4)
Analysis: Calculated: C 57.13%; H 7.53%; N 19.03%,
Found: C 56.90%; H 7.55%; N 18.96%
Example 9
3-ethyl-1- (5-hydroxy-5-methylhexyl) -xanthine
7-benzyl-3-ethyl-1- (5-hydroxy-5-methylhexyl) -xanthine obtained from 7-benzyl-3-ethylxanthine (example 2a) and 1-chloro-5-hydroxy-5-methylhexane according to example 1b ) with a yield of 65% of theory. (C ₂₁ H ₂₈ N ₄ O ₃ ; M.W. 384.5; mp 112 - 114 ^° C), were hydrogenolitically debenzylated using ammonium formate as a source of hydrogen. For this, 3.84 g (0.01 mol) of the benzyl derivative and 1.0 g (0.016 mol) of ammonium formate in 30 ml of ethanol were stirred for several days over 2 g of palladium (10%) on activated carbon at 35 ^o C, while The gradual introduction of an additional amount of ammonium formate to a total amount of 4.4 g (0.07 mol) gave a good result. The reaction mixture was filtered, the filtrate was evaporated, the residue was taken up in sodium carbonate solution, washed with chloroform, the aqueous layer was adjusted with hydrochloric acid to pH 4, the product was shaken with chloroform, and after drying and evaporation it was pericrystallized from ethyl acetate.

 Yield: 67.9% of theory.

Mp 180-182 ^o C
C ₁₄ H ₂₂ N ₄ O ₃ (M.W. 294.4)
Analysis: Calculated: C 57.12%; H 7.53%; N, 19.04%.

Found: C 56.77%; H 7.66%; N18.93%
Example 10
3-ethyl-1- (5-hydroxy-5-methylheptyl) -xanthine
7-benzyl-3-ethylxanthine (Example 2a) and 1-chloro-5-hexanone analogously to Example 16) were converted to 7-benzyl-3-ethyl-1- (5-oxohexyl) -xanthine (C ₂₀ H ₂₄ N ₄ O ₃ ; M. v. 368.4; yield: 81.7% of theory; mp 123-125 ^° C). The reductive ethylation of the keto group with ethyl magnesium chloride according to Example 5b) led to 7-benzyl-3-ethyl-1- (5-hydroxy-5-methylheptyl) -xanthine (C ₂₂ H ₃₀ N ₄ O ₃ , M.w. 398.5; yield : 86.9% of theory; mp 93-94 ^° C), which were hydrogenolitically debenzylated in the same manner as in Example 9. The final product was recrystallized from ethanol.

 Yield: 66.5% of theory.

Mp 165 - 166 ^o C
C ₁₅ H ₂₄ N ₄ O ₃ (M.W. 308.4)
Analysis: Calculated: C, 58.42%; H 7.84%; N, 18.17%
Found: C 58.30%; H 8.05%; N, 18.33%.

Example 11
1- (6-hydroxy-6-methylheptyl) -3-methylxanthine
7-benzyl-1- (6-hydroxy-6-methylheptyl) -3-methylxanthine (C ₂₁ H ₂₈ N ₄ O ₃ , M.W. 384.5; mp: 83-85 ^o C, obtained from in a yield of 77.5% from 7-benzyl-3-methylxanthine and 1-bromo-6-hydroxy-6-methylheptane analogously to example 1b), they were hydrogenolytically debenzylated according to example 1c).

 Yield: 82.2% of theory.

Mp 166-167 ^o C
C ₁₄ H ₂₂ N ₄ O ₃ (M.W. 294.4)
Analysis: Calculated: C 57.12%; H 7.53% :; N, 19.04%.

 Found: C 56.82%; H 7.74%; N, 19.01%.

Example 12
3-ethyl-1- (6-hydroxy-6-methylheptyl) -xanthine
According to Example 12, a reaction sequence was carried out with 7-benzyl-3-ethyl-xanthine from Example 2a), the hydrogenolytic debenzylation of ammonium formate being carried out analogously to Example 9.

 Yield: 72.4% of theory.

Mp 163-165 ^o C
C ₁₅ H ₂₄ N ₄ O ₃ (M.W. 308.4)
Analysis: Calculated: C, 58.42%; H 7.84%; N, 18.17%.

 Found: C 57.83%; H 7.64%; N, 18.04%.

Pharmacological experiments and its results
1. Inhibitory activity against pro-inflammatory mediators of the early phase reaction
The inhibitory activity of the compounds according to formula 1 against early inflammatory pro-inflammatory mediators - histamine, FAT and leukotriene D ₄ (LTD ₄ ) was studied on isolated segments of the respiratory tract organs of albino guinea pigs, and the inhibition of contractions induced by these mediators served as a measurement parameter.

For experiments, freshly prepared organs of males were used each time. The trachea was cut into rings, of which in each case 5 cartilaginous rings of the trachea connected by a silk thread into a chain were suspended under a tensile load of 0.5 g in an organ bath with Tyrode's solution heated to 37 ^° C and by adding histamine dihydrochloride and adding histamine dihydrochloride (concentration in the bath: 3 • 10 ^-7 / ml), in the absence (control experiment) or in the presence of the test substances, they were reduced.

The lung was cut lengthwise into 2-3 strips, which were treated in the same way as described above, however, the tensile load was 1 g and the reduction was caused by FAT or LTD ₄ at a concentration in the bath of 10 ^-9 or 10 ^-8 g / ml.

 Each experiment included a parallel study of 6 organ blanks (n = 6).

Evaluation of the activity of the drug was carried out using IC ₅₀ values, i.e. the concentration, expressed in μm / ml, at which the organ contractions caused in the control experiment decreased by half. The results are summarized in table 1.

 Guinea pigs - albinos of both sexes with a body weight of 180 to 220 g were sensitized by subcutaneous injection of 1 mg of ovalbumin each time (0.1% solution in physiological solution of sodium chloride) for two consecutive days. The experiment was carried out after 20 days according to the method of Konzett and Rossler (Arch. Exp. Path. Und Pharmak. (1940) 195: 75). For this, the animals were anesthetized with pentobarbital, they were given artificial respiration; to exclude spontaneous breathing, alkuronium chloride was used and divided into groups of 6 animals each. Intravenous administration of ovalbumin as an antigen at a dose of 1 mg / kg caused a prolonged attack of asthma as a result of acute bronchospasm induced by mediators as part of an asthmatic early reaction, the intensity of which was characterized by the amplitude of contractions in the thoracogram.

 The test drugs were used intravenously each time 15 minutes before antigen challenge. Instead, animals in the control group received a pure 0.9% sodium chloride solution. To assess the effect of the drug, the number of animals of the corresponding group was determined in which the asthmatic reaction of control individuals was reduced by at least 40%.

 The results are summarized in table 2.

Claims (5)

1. Xanthine derivatives of the general formula I

where R ¹ is methyl or ethyl;
R ² is alkyl with 1 to 4 carbon atoms;
X is a hydrogen atom or hydroxyl;
n is an integer from 1 to 5;
moreover, when R ¹ is methyl, R ² is methyl, X is a hydrogen atom, n means the number 1, 2, 3, 5,
their stereoisomers and physiologically tolerated salts. 2. Xanthine derivatives of the general formula I according to claim 1, wherein R ² is methyl or ethyl.  3. Xanthine derivatives of the general formula I according to claim 1, wherein X is a hydrogen atom. 4. Xanthine derivatives of the general formula I according to claim 1, in which R ¹ is methyl, R ² is methyl or ethyl, X is a hydrogen atom, n is an integer from 1 to 5. 5. A pharmaceutical composition having an activity reducing eosinophilic granulocyte pathological hyperactivity, comprising an active substance based on xanthine derivatives and at least one target additive, characterized in that it contains at least one compound of the general formula I as an active substance

where R ¹ is methyl or ethyl; R ² is alkyl with 1 to 4 carbon atoms;
X is a hydrogen atom or hydroxyl;
n is an integer from 1 to 5,
and when R ¹ is methyl, R ² is methyl, X is a hydrogen atom, n means 1, 2, 3, 5,
and / or its stereoisomer, and / or its physiologically tolerated salt in an effective amount.

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