CS272799B2 - Method of teriary hydroxylxanthine production - Google Patents

Abstract

The preparation method of compounds of the general formula I, where at least one from the residues R<1> and R<3> stands for tertiary hydroxyalkyl group of the general formula Ia-(CH2)n-C(R<4>)-(OH)-CH3 where R<4> stands for C1-3-alkyl and n stands for the number from 2 to 5 and if only one of the remains R<1> and R<3> represents the group Ia, then the other stands for H or aliphatic hydrocarbon group R<5> with up to 6 carbon atoms, whose carbon chain can be interrupted by 2 oxygen atoms or can be substituted for one oxo group or up to 2 oxygen atoms, while this oxo group and hydroxylic groups are separated in the ring from nitrogen atom by at least 2 carbon atoms, and R<2> stands for C1-4-alkyl, lies in the fact that they react with 3-alkylxanthine of the general formula II, where A stands for hydrogen, group R<5> or oxoalkyl group -(CH2)n-CO-CH3 (IIIa) or -(CH2)n-CO-R<4> (IIIb) and B stands for hydrogen, R<5>, benzyl, diphenylmethyl or a group of the formula IIIa or IIIb and at least one of the groups A and B represents the group of the formula IIIb or IIIb, with at least one or possibly two moles corresponding to alkyl metal compounds with 1 to 3 carbon atoms in alkyl, during reductive alkylation of carbonyl groups and subsequent reductive removal of the group B, if it means benzyl or diphenylmethyl, or possible hydrolytic elimination of alkoxy methyl or alkoxyalkoxy methyl residue from the position of the group B and alkylation of the position 1 or position 7, when A or B stands for hydrogen, by treatment of alkylation agents of the general formula X-Q (IV), where X stands for halogen or residue of ester of sulphonic or phosphoric acid and Q stands for the group of the formula Ia or group R<5>. The produced compounds can be used as pharmaceutics especially for treatment of problems with peripheral and cerebral blood circulation.<IMAGE>

Description

The present invention relates to a process for the production of novel xanthine derivatives with at least one tertiary hydrvixyl group in position 1 or position 7. The compounds produced can be used as active ingredients of medicaments which are particularly suitable for the treatment of peripheral and cerebral blood flow disorders.

1-oxoalkyl-3,7-dialkyl- and 7-oxoalkyl-1,3-dialkylxanthines or 1-hydroxyalkyl-3,7-dialkyl- and 7-hydroxyalkyl-1,3-dialkylxanthines having a secondary alcohol function are already known, which are effective in promoting blood flow. Within this class of substances, the vasotherapeutic Pentoxifylline, i.e. 3,7-dimethyl-1- (5-oxohexyl) xanthine, has gained remarkable therapeutic importance for the medical treatment of disorders of both peripheral and cerebral blood flow. As a new generation vasoactive medicament (cf. Schweiz. Med. Yfschr. 111 (1981), pp. 637-640), it has taken a firm place in many countries today, for example, amongst the drugs used to treat peripheral arterial occlusion, while in others this substance is used with great success also in insufficient cerebral blood flow.

In contrast to the clinically well-established effect of this preparation, however, there is the disadvantage that both the active substance itself and the first, as well as the pharmacologically active metabolite, i.e. 1- (5-hydroxyhexyl) -3,7-dimethylxanthine, are subject to animal body and the human rapid and complete biotransformation, which occurs almost exclusively through the enzymatic oxidation of the OXO- or hydroxyhexyl side chain and is associated with a pronounced first-pass effect. This means that, especially when administered orally, a significant portion of the administered dose after absorption from the stomach and intestinal tract and transported through the gastrointestinal tract to the liver, the most important foreign body filtering agent, metabolises the drug-degrading enzymes in the first part of the liver. only a certain portion of the drug in its unchanged form reaches the systemic, high blood circulation. The effect of the first pass, also referred to as presystemic elimination, therefore leads to a decrease in the systemic utility of the unchanged active agent. The inherent disadvantage of the pronounced first-pass effect is not so much that the oral dose is reduced by way of systemic circulation, but that this process generally exhibits considerable intra- and inter-individual variability (cf. Schweiz. Med. Wschr. 110 ( 1980), pp. 354-362, which makes it difficult to establish a binding dose schedule and thus may adversely affect treatment success.

As a result of this unsatisfactory condition, there is an understandable desire of clinicians as well as intensive pharmaceutical research efforts to find new xanthine derivatives which, with a similarly good or possibly even stronger pharmacological effect and equally excellent tolerability, have significantly higher metabolic stability and thus substantially lower or a completely negligible first-pass effect and which would consequently significantly improve the certainty of treatment with respect to the dosage problems described above. Preparations of this type would represent real progress in the medical treatment of peripheral and cerebral blood flow disorders, which have to be counted among the most common causes of disease and death in industrialized countries.

Surprisingly, it has now been found that the unexplored branching of the alkyl portion of the secondary hydroxyaliyl group on a hydroxyl-bearing carbon atom independently of its position on the xanthine skeleton at position 1 and / or 7 leads to compounds whose hydroxyalkyl side chain now with tertiary alcohol structure is stable to polyfunctional microsomal liver oxidases, which also satisfy the other therapeutic requirements set forth above.

The present invention relates to a process for the preparation of tertiary hydroxyalkylxanthines of the formula I

CS 272 799 B2 2

OR ³

in which at least one of the radicals R and ^RJ represents a tertiary hydroxyalkyl group of the formula Ia

CH,

I ³

- (CH ₂ ) _n -C-CH ₃ (Ia),

AND

OH where n is an integer from 2 to 5, and if only one of the radicals R @ 1 or R @ ³ represents such a tertiary hydroxyalkyl group of the formula (Ia), the other one represents a hydrogen atom or an aliphatic hydrocarbon group R @ 6 wherein the carbon chain is optionally interrupted by up to 2 oxygen atoms or is optionally substituted by one oxo group or up to two hydroxyl groups, said oxo group and hydroxyl groups being separated from the ring nitrogen atom by at least 2 carbon atoms, and

R represents a C 1 -C 4 alkyl group consisting of: 3-alkylxanthines of formula II

in which o

R is as defined above,

A represents a hydrogen atom, an R1 group or an alkoxycarbonylalkyl group of the formula III

II

- _{(CH2) ^n-C-OR} (III) wherein

R ^a represents a C 1 -C 4 alkyl group, and

B represents a hydrogen atom, an R group, a benzyl group, a diphenylmethyl group or an alkoxycarbonylalkyl group of the formula III, wherein n is as defined above

CS 272 799 B2 and at least one of residues A and B represents an alkoxycarbonylalkyl group of formula III, reacts with two equivalents of a methyl metal compound, such as methyllithium or methylmagnesium halide, for one alkoxycarbonyl function, followed by reductive cleavage of residue B, represents a benzyl or diphenylmethyl group, by chemical reduction or catalytic hydrogenolysis at atmospheric pressure or at a pressure of up to 1.0 MPa, or optionally by hydrolytic elimination of an alkoxymethyl or alkoxyalkoxymethyl residue from the position of residue B under acidic conditions at temperatures below 100 ° C and alkylation of position I; position 7 when A or B is hydrogen, in aprotic solvents, alcohols, aromatic or halogenated hydrocarbons, pyridine, optionally also in admixture with water, by the action of alkylating agents of formula IV

X-Q (IV) wherein

X is a halogen atom or a sulfonic acid ester or a phosphoric acid ester group and a

Q represents a tertiary hydroxyalkyl group of formula Ia or R ⁴ , in anhydrous solvents such as ethers, aliphatic or aromatic hydrocarbons, chlorinated aliphatic hydrocarbons, tertiary amines, aprotic solvents and mixtures thereof, at a temperature between -20 ° C and 100 ° C.

Preferably, the process of the present invention provides compounds of formula I wherein R is methyl or ethyl and only one of R ¹ or R 6 is a tertiary hydroxyalkyl group of formula Ia.

3

Preferably, the prepared compound of formula I wherein R or R ^J is [(AO-1) -hydroxy- (a? -L) -methyl] pentyl group, hexyl group or -heptyl.

Also preferred are compounds of formula I wherein R ¹ is a tertiary hydroxyalkyl group, preferably R ¹ is [(ω -1) -hydroxy- (w-1) - methyl] -pentyl, -hexyl or -heptyl, R is methyl or ethyl and is C1-C4 alkyl, C1-C4 hydroxyalkyl or C1-C4 alkoxyalkyl; alkoxy and alkyl moieties.

Preferred compounds of formula I also include those wherein R R is znamená 3

5-hydroxy-5-methylhexyl, R is methyl and R is ethoxymethyl.

The groups selected for R ⁴ at the R ⁴ or R ⁴ position are, for example, methyl, ethyl, propyl, isopropyl, hutyl, isobutyl, pentyl and hexyl, their hydroxy and oxo derivatives, the hydroxy group optionally the oxo group in these groups is separated from the nitrogen atom by at least two carbon atoms, such as hydroxyethyl, 2- and 3-hydroxypropyl, 2,3-dihydroxypropyl, 2-, 3- and 4-hydroxybutyl, 2-hydroxy -2-methylpropyl, 3,4-dihydroxybutyl, 4,5- or 3,4-dihydroxypentyl, 5,6- and 4,5-dihydroxyhexyl, 4-hydroxypentyl, 5-hydroxyhexyl, 2-oxopropyl a group, 3-oxobutyl, 4-oxopentyl and 5-oxohexyl, as well as alkoxyalkyl and alkoxyalkoxyalkyl groups such as methoxymethyl groups pina, methoxyethyl and methoxypropyl, ethoxymethyl, ethoxyethyl and ethoxypropyl, propoxymethyl and propoxyethyl, methoxyethoxymethyl and methoxyethoxyethyl, as well as ethoxyethoxymethyl and ethoxyethoxyethyl.

CS 272 799 B2

According to a preferred embodiment of the process of the invention, the tertiary hydroxyalkylxanthines of the formula I can be prepared by substituting substituted xanthines of the formula II in which R is as defined above and A and B represent two identical or different groups III or only one group of formula m _and in this case the second substituent is hydrogen, R ^ or R ⁵ , where R ⁵ has the same meaning as R ^ or is benzyl or diphenylmethyl, reacting with methyl metal compounds by reductive alkylation of alkoxycarbonyl groups to form xanthines of formulas Ib to If;

(Ib), (Io), (0B _{2) n}

C - CH ₃ OH (Id)

(le) a

and optionally thereafter the obtained tertiary hydroxyalkylxanthines of the formulas Ib and Xf, which contain a hydrogen atom at the 1-position or the 7-position, are optionally alkylated in the presence of basic agents or in the form of their salts by the alkylating agents of formula IV

X-Q (CIV) in which

X is as defined above and

Q is a group of formula Ia, R, or R to form trisubstituted compounds of formula Ic, Id or Ie, wherein in the above compounds R ² , R 6, R 6 and n are as defined above,

3-alkylated mono- or di- (ω-alkoxycarbalalalkyl) xanthines of the general formula II, in which R ² is as defined above and A and B represent two identical or different groups of the general formula III or only one group of the general formula III and in which case the second substituent is a hydrogen atom or a group R ^ or a group R ^, wherein R ^ has the same meaning as R ^ or is the benzyl or diphenylmethyl group which are used as starting materials for the process according to the invention, are known compounds or they can be readily prepared, for example, from the 3-alkylxanthines of the formula II in which A and B are hydrogen atoms and the alkyl esters of the -sulfonyloxy or ω-halocarboxylic acids of the formula V ii

Hal - CCB ₂ ) _n - C - R ^and (V), in which

R ^a is C 1 -C 4 alkyl and Hal and n are as defined above.

The reductive alkylation of esters of formula (II) in which R is as defined above and A and B are two identical or different groups of formula (III) or only one group of formula (III), in which case the second substituent is hydrogen or R R or R ^, wherein R ^ has the same meaning as R ^ or is benzyl or diphenylmethyl, can be carried out, for example, by treatment with methyl, potassium, methyl, lithium, magnesium, methylzinc, methylcadmium, methyl aluminum and methyl tin compounds. it also recommends the use of methyl lithium and methyl zirconium compounds (cf. D. Seebach et al., Angew. Chem. 95 (1983), pp. 12-26). Since the methylmetal compounds derived from sodium and potassium tend to co-react with them due to their high reactivity and the methylmetal compounds derived from zinc and cadmium are relatively low reactive, preferably methyllithium and methylmagnesium derivatives (Grignard compounds) are preferably used.

Strongly nucleophilic organometallic compounds are very sensitive to hydrolysis and oxidation.

Therefore, safe handling of these compounds requires work in an anhydrous environment, optionally under a protective gas atmosphere. Common solvents and diluents are, in particular,

CS 272 799 B2 which are also suitable for the production of alkyl metal compounds. Suitable ethers are, in particular, ethers having one or more etheric oxygen atoms, for example diethyl ether, dipropyl ether, dibutyl ether 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. Tertiary amines such as triethylamine or dipolar aprotic solvents, for example hexamethylphosphoric triamide, as well as mixtures of the solvents mentioned, can also be used successfully.

The reaction of the carboxylic acid esters with the Grignard compounds of the formula CH 2 -MgHal can advantageously also be carried out by introducing the organometallic compound in ether and dropping the ester in the form of a solution in dichloromethane or 1,2-dichloroethane. It is often recommended to add magnesium bromide which, by virtue of its involvement in the formation of a complex cyclic transition state, has the ability to increase the nucleophilia of an organometallic compound.

The reaction of the ester and the organometallic compound is generally carried out at temperatures between -20 ° C and 100 ° C, preferably at temperatures between 0 ° C and 60 ° 0 or at room temperature without external cooling, the alkyl metal compound usually being used in a slight excess. Thereafter, the reaction is terminated, usually by briefly heating to reflux, a time span of from a few minutes to a few hours being usually sufficient. The resulting alkoxide is preferably decomposed in aqueous ammonium chloride solution or by treatment with dilute acetic acid.

Reductive cleavage of the benzyl group and the diphenylmethyl group of the compounds of formula Ie to give the xanthine derivatives of formula 1f of the invention which contain a hydrogen atom at the 7-position is carried out under standard conditions elaborated primarily in the protecting group technique of alkaloid and peptide synthesis. , so they can be assumed to be widely known. In addition to chemical reduction, especially in the case of benzyl derivatives with sodium in liquid ammonia (cf. Houben-Weyl, Vol. XI / 1 (1957), pages 974 to 975), the elimination of both of the above aralkyl groups by catalytic hydrogenolysis in the presence of catalysts noble metals (cf. Houben-Weyl, Vol. XI / 1 (1957), pp. 968-971 and Vol. IV / 1c, Part 1 (1980), pp. 400 to 404). The reaction medium is usually a lower alcohol (optionally with the addition of formic acid or ammonia), an aprotic solvent such as dimethylformamide or, in particular, glacial acetic acid; However, mixtures with water may also be used. Particularly suitable hydrogenation catalysts are palladium black and palladium on activated carbon or barium sulphate, while other noble metals such as platinum, rhodium and ruthenium often tend to undergo side reactions due to competitive core hydrogenation and are therefore only applicable under certain conditions. The hydrogenolysis is conveniently carried out at temperatures between 20 ° C and 100 ° C and at atmospheric pressure, or preferably at slightly increased pressures up to about 10 bar, reaction times of from several minutes to several hours being generally required.

The 1,3,7-trisubstituted xanthines of formula Ie which contain an alkoxymethyl group or an alkoxyalkyloxymethyl group at the R ⁹ substituent are O, N-acetals. Accordingly, their substituents at the 7-position can be cleaved under normal conditions by acid hydrolysis (cf. Houben-Weyl, Vol. VI / 1b (1984), pp. 741-745), and the 7H-derivatives of formula 1f are also formed. Preferred hydrolytically eliminable groups are, for example, methoxy, ethoxy and propoxymethyl, as well as methoxyethoxymethyl and ethoxyethoxymethyl. The reaction is preferably carried out with heating in dilute mineral acids such as hydrochloric acid or sulfuric acid, optionally with the addition of glacial acetic acid, dioxane, tetrahydrofuran or a lower alcohol as co-solvents. Also suitable are perchloric acid or organic acids such as trifluoroacetic acid, formic acid and acetic acid, together with a catalytic amount of mineral acids. In particular, alkoxyalkoxymethyl derivatives can also be cleaved by Lewis acids, such as zinc bromide and titanium tetrachloride, in anhydrous medium, preferably dichloromethane or chloroform, whereby the intermediate 7-bromomethyl or 7-bromosine derivatives are hydrolyzed spontaneously

CS 272 799 B2 in relation to aqueous processing. When cleaving in a solution containing a mineral acid, the reaction temperature must be chosen so that there is no appreciable dehydration of the tertiary hydroxyalkyl group at the 1-position. The reaction temperature should therefore generally be below 100 ° C.

The reaction of the disubstituted xanthine derivatives of formula (II) with the corresponding alkylation agents of formula (I) is usually carried out in a diluent or solvent inert to the reactants. Suitable in particular are dipolar, aprotic solvents, for example formamide, dimethylformamide, dimethylacetamide, H-methyl-pyrrolidone, tetramethylurea, hexamethylphosphoric triamide, dimethylsulfoxide, acetone or hutane; however, alcohols such as methanol, ethylene glycol and its mono- or dialkyl ethers may also be used, the alkyl group having 1 to 4 carbon atoms and both together having at most 5 carbon atoms, ethanol, propanol, isopropyl alcohol and various butyl alcohols; hydrocarbons such as benzene, toluene or xylenes; halogenated hydrocarbons such as dichloromethane or chloroform; pyridine as well as mixtures of said solvents or mixtures with water.

The alkylation reactions are conveniently carried out in the presence of a basic condensing agent. Suitable for this purpose are, for example, alkali and alkaline earth metal hydroxides, carbonates, hydrides and alkoxides as well as organic bases such as trialkylamines, for example triethylamine or tributylamine, quaternary ammonium hydroxides or phosphonium hydroxides and crosslinked resins with fixed, optionally substituted ammonium or phosphonium groups. However, the xanthine derivatives may also be used immediately in the form of their specially prepared salts, for example in the form of alkali metal salts, alkaline earth metal salts or in the form of optionally substituted ammonium or phosphonium salts, for the said alkylation reaction. Further, the mono- and di-substituted xanthine derivatives can be conveniently alkylated in the presence of the above inorganic condensation agents as well as in the form of their alkali metal or alkaline earth metal salts, using so-called phase transfer catalysts, e.g. amines, quaternary ammonium or phosphonium salts or else crown ethers, preferably in a two-phase system under phase transfer catalysis conditions. Suitable, mostly commercially available phase transfer catalysts include, but are not limited to, tetraalkylammonium and tetraalkylphosphonium salts of 1 to 4 carbon atoms in the alkyl radicals, methyltrioctylammonium salts, methyltrioctylphosphonium salts, methyl-trialkylammonium salts of 1 to 4 carbon atoms in alkyls, myristyl-trialkylammonium salts C 1 -C 4 alkyl, C 1 -C 4 phenyltrialkylammonium salts and C 1 -C 4 alkyl benzyltrialkylammonium salts, Cetyltrimethylammonium salts as well as C 1 -C 12 alkyltriphenylphosphonium salts and benzyltriphenylphosphonium salts wherein the compounds having a larger and symmetric cation are generally more effective.

The introduction of the groups of formula (Ia) as well as of the groups R ⁴ and R ⁴ according to the above-mentioned processes is generally carried out at a reaction temperature between 0 ° C and the boiling point of the reaction medium in use, preferably at temperatures between 20 ° C and 130 ° C; elevated or reduced pressure, but usually at atmospheric pressure, the reaction time may be less than one hour or up to several hours.

In compounds where one of R ¹ and R represents a dihydroxyalkyl group, a dihydroxyalkyl group can be built, optionally introduced by conventional methods, as described for example in EP-75850.

The tertiary hydroxyalkylxanthines of formula (I) may contain one asymmetric carbon atom depending on the structure of the substituent R ⁴ (e.g. 2-hydroxypropyl) and are therefore present in stereoisomeric forms. The invention therefore relates both to pure stereoisomeric compounds and to mixtures thereof.

The xanthine derivatives of formula (I) produced by the process of the present invention are suitable for use on account of their valuable faimacological properties and favorable metabolic properties, for example against polyfunctional micromomal liver oxidases.

As an active ingredient of medicaments, in particular those which enable a more effective prophylactic and curative treatment of diseases caused by disorders of peripheral and cerebral blood flow, such as peripheral arterial occlusion and thus represent enrichment in the field of medicaments. These compounds may be administered alone, for example in the form of microcapsules, in admixture with each other or in combination with suitable carriers.

Accordingly, the present invention also relates to medicaments which contain at least one compound of the formula I as active substance.

the medicaments of the invention are generally administered orally or parenterally, although in principle rectal administration is also possible.

Suitable solid or liquid galenic preparations are, for example, granules, powders, tablets, dragee (micro) capsules, suppositories, syrups, emulsions, suspensions, aerosols, drops or injectable solutions in the form of ampoules, as well as preparations with delayed delivery of the active substance. In general, auxiliaries such as carriers, disintegrants, binders, coatings, shoes, lubricants and lubricants, flavorants, sweeteners or co-solvents are used in the manufacture.

Frequently used excipients are, for example, magnesium carbonate, titanium dioxide, milk sugar, mannitol and other sugars, talc, milk proteins, gelatin, starch, vitamins, cellulose and its derivatives, animal and vegetable oils, polyethylene glycols and solvents such as sterile water, alcohols, glycerin and polyhydric alcohols.

Preferably, the pharmaceutical compositions are prepared and administered in unit dosage form, each unit containing as an active ingredient a particular dose of a compound of formula I. For solid dosage units such as tablets, capsules and suppositories, the dosage may be up to 1000 mg, preferably up to 600 mg, and for injection solutions in the form of ampoules, up to 300 mg, but preferably from 20 to 200 mg.

For the treatment of adult patients, depending on the efficacy of the compounds of formula I, daily doses of from 100 to 2000 mg of active compound, preferably 300 to 900 mg, for oral administration and 10 to 500 mg, preferably 20 to 200 mg, for intravenous administration are indicated to humans. . However, higher lower doses per day may also be administered as appropriate. The daily dose can be administered either as a single administration in the form of a single dosage unit or also in the form of several smaller dosage units, as well as multiple administration of a divided dose at certain intervals.

Finally, the xanthine derivatives of the formula I can also be combined with other suitable active ingredients, such as, for example, antithrombotics, antihyperlipidemics, analgesics, sedatives, antidepressants, antianginal agents, cardiotonics, antiarrhythmics, diuretics, antihypertensives including blockers. receptors and calcium channel blockers, plasma replacement, as well as other vasotherapeutics.

The structure of all the compounds listed below was confirmed by elemental analysis as well as 1 H-spectrum and 1 H-NMR spectra. The compounds of formula I, which were prepared according to the examples below, as well as the compounds produced in an analogous manner, are summarized in Table 1.

In the examples below, ether is understood to mean diethyl ether and vacuum or lower pressure is to be understood by vacuum or lower pressure, which is achieved by using a water pump.

Example 1

7- (5-hydroxy-5-methylhexyl) -3-methylxanthine (Compound No. 1)

CS 272 799 B2

CHI ³

C-CHI

OH

To 22.4 g (0.3 mol) of methylmagnesium chloride in the form of a commercially available 20% solution in tetrahydrofuran and slowly adding 29.4 g (0.1 mol) of 7- (4- ethoxycarbonylbutyl) -3-methylxanthine in 300 mL of anhydrous dichloromethane. Upon completion of the addition, the reaction mixture is heated and maintained at reflux for 2 hours. reflux condenser. Dilute acetic acid is added to decompose the resulting alkoxide, then the mixture is evaporated under reduced pressure, the residue is taken up in 200 ml of hot 11 sodného sodium hydroxide solution, filtered while cooling, and after cooling to room temperature, 6ΙΓ hydrochloric acid solution to pH 9. The precipitate is filtered off, washed until neutral and dried under reduced pressure.

Yield: 24.3 B (86.7% of theory).

Melting point: 228-230 ° C.

For Cj -HH HH ((molecular weight = 280.3) calculated 55.70% C, 7.19% H, 19.99% K; Found: C, 55.60; H, 7.31; H, 19.92.

Example 2

1,7-bis (5-hydroxy-5-methylhexyl) -3-methylxanthine (Compound No. 2)

(a) 1-chloro-5-hydroxy-5-methylhexane

OH ³ '- 1 - (oh ₂ ) ₄ - O - ch ₃ OH

89.8 g (1.2 mol) of methylmagnesium chloride as a 20% solution in tetrahydrofuran are introduced together with 500 ml of anhydrous ether and a solution of 82.3 g (0.5 mol) of ethyl ester is added dropwise with stirring at 0-5 ° C. Of 5-chloropentanoic acid in 100 mL of absolute ether. Then the reaction mixture was further stirred at room temperature for 30 minutes and refluxed for 2 hours. The reaction mixture was poured onto ice, and 50% aqueous ammonium chloride solution was added until the precipitate was completely redissolved. The resulting solution was extracted several times with ether, the ether extract was washed successively with aqueous sodium bisulfite solution and sodium bicarbonate solution as well as water, dried over sodium sulfate, filtered and the solvent was removed by evaporation under reduced pressure. The evaporation residue is subjected to fractional distillation.

Yield; 65.3 6 (86.7% of theory).

Boiling point 95-97 ° C / 2000 Pa.

Refractive index: - 1.4489.

Summary formula: C 1 H 4 C 10 (molecular weight = 150.65).

b) 1,7-bis (5-hydroxy-5-methylhexyl) -3-methylxanthine

-r?

CS 272 799 B2 10

A mixture of 14 g (0.05 mol) of 7- (5-hydroxy-5-methylhexyl) -3-methylxanthine (Example 1), 8.2 g (0.054 mol) of 1-chloro-5-hydroxy-5-ethylhexane (Example 2a) and 7.5 g (0.054 mol) of potassium carbonate in 300 ml of dimethylformamide are stirred for 18 hours at 110 ° C, then the reaction mixture is filtered while hot and the filtrate is concentrated under reduced pressure. The residue is taken up in chloroform, washed first with dilute sodium hydroxide solution and then with water until neutral, dried over sodium sulfate and the solvent is distilled off under reduced pressure.

Preferably, the crude product can be converted to an analytically pure material by filtration through a silica gel column using a 10: 1 mixture of chloroform and methanol followed by stirring in diisopropyl ether.

Yield: 14.9 g (75.5% of theory).

Melting point: 93-95 ° C.

Analysis: for (MW = 394.5) calculated 60.89% C, 8.69% H, 14.20% N;

Found: C, 60.89; H, 8.98; N, 14.17.

The same compound is also obtained by reacting 1,7-bis (4-ethoxycarbonylbutyl) -3-methylxanthine with at least 4 equivalents of methylmagnesium chloride in an analogous manner to that described in Example 4c) or Example 5.

Example 3

7- (5-hydroxy-5-methylhexyl) -3-methyl-1-propylxanthine (Compound No. 3)

g (0.14 mol) of 7- (5-hydroxy-5-methylhexyl) -3-methylxanthine (Example 1) was heated together with 18.5 g (0.15 mol) of 1-bromopropane and 20.7 g ( 0.15 mol) of potassium carbonate in 300 ml of dimethylformamide is stirred at 130 DEG C. for 8 hours. After cooling and concentration under reduced pressure, dilute sodium hydroxide solution is added and then the mixture is carefully extracted with chloroform. The organic phase yields a neutral reaction after washing with water, drying 11

The crude product was most easily purified by filtration through a silica gel column eluting with chloroform: methanol (25: 1) and stirred in diisopropyl ether.

Yield: 36.5 g (80.9% of theory).

Melting point: 59-60 ° C.

For C ^ gSSSNN ^O ^ (MW = 322.4) calculated: 59.61% C, 8.13% H, 17.38% N;

found: C 59.43, H 8.01, H 17.29%

Example 4

7-Ethoxymethyl-1- (5-hydroxy-5-ethylhexyl) -3-methylxanthine (Compound No. 5)

(a) 7-ethoxymethyl-3-methylxanthine

and ( ₁ ) with ethoxymethyl chloride:

g (0.5 mol) of 3-methylxanthine is dissolved in a hot solution of 20 g (0.5 mol) of sodium hydroxide in 400 ml of water. After filtration, the reaction mixture is concentrated in vacuo, distilled several times with methanol and the sodium salt is dried under high vacuum.

The dried salt was suspended in 1.3 L of dimethylformamide, 47.3 S (0.5 mol) of ethoxymethyl chloride was added with stirring, and the mixture was stirred at 110 ° C for 18 hours. Thereafter, the reaction mixture is filtered while hot, evaporated under reduced pressure, the residue is dissolved in 500 ml of a 2ΪΓ solution of sodium hydroxide and extracted with chloroform to remove 1,7-dialkylated 3-methylxanthine as a by-product. The alkaline aqueous solution was adjusted to pH 9 by adding 2ΪΓ hydrochloric acid with stirring, the resulting crystallizate was filtered off, washed first with water to remove chloride ions and then with methanol, and then dried under reduced pressure.

Yield: 77.6 g (69.2% of theory).

Melting point: 263-264 ° 0.

Summary formula: (molecular weight = 224.2).

ag) with ethoxymethyl 4-toluenesulfonate:

(starting from 4-toluenesulfonic acid chloride and sodium acetate)

104.9 g (0.55 mol) of 4-toluene-sulfochloride are dissolved in 100 ml of dimethylformamide and 45.1 ε (0.55 mol) of anhydrous sodium acetate are added under stirring and with ice-cooling. After stirring an additional 1 hour at room temperature, 78.1 g (0.75 mol) of formaldehyde diethylaetal are added dropwise to the reaction mixture. The reaction mixture was stirred again at room temperature for 1 hour, and then 83 g (0.5 mol) of 3-methylxanthine was added. Then, the reaction mixture is heated at 90 DEG C. for 2 hours without addition of a basic condensing agent, cooled, the precipitated product is filtered off cold, additionally washed with cold dimethylformamide and water to remove chloride ions, rinsed with methanol and recrystallized from dimethylformamide. .

OS 272,799 B2

Yield: 98.1 g (87.5% of theory).

Melting point: 265 ° C.

and ^) with ethoxymethyl 4-toluenesulfonate (using 4-toluenesulfonic acid and acetic anhydride as starting materials)

With stirring and cooling, 226 g (1.2 mol) of 4-toluenesulfonic acid monohydrate are dissolved in 450 g (4.4 mol) of acetic anhydride and then the solution obtained is heated at 70 DEG C. for 30 minutes. The resulting acetic acid and excess acetic anhydride are distilled off under reduced pressure, the residue is diluted with 100 ml of toluene and the solution is stirred under cooling into 450 ml of dimethylformamide such that the internal temperature does not exceed 20 ° C. After dropwise addition of 230 g (2.2 mol) of formaldehyde diethyl acetal and stirring for 1 hour at 20 ° C, 166.1 g (1 mol) of 3-methylxanthine are added. The reaction mixture is heated and stirred at 100 DEG C. for 1 hour, then cooled, the precipitated product is filtered off, washed successively with 250 ml of dimethylformamide, water and methanol and recrystallized from dimethylformamide.

Yield: 201 g (89.7% of theory).

Melting point: 264-265 ° C.

b) 1- (4-ethoxycarbonylbutyl) -7-ethoxymethyl-3-methylxanthine

22.4 g (0.1 mol) of 7-ethoxymethyl-3-methylxanthine from step a), 23.0 g (0.11 mol) of ethyl 5-bromopentanoate and 15.2 g (0.11 mol) of potassium carbonate The reaction mixture is reacted in 500 ml of dimethylformamide at 110 DEG C. in an analogous manner to Example 3, and then the reaction mixture is worked up. A solid crude product is obtained which is recrystallized from diisopropyl ether with the addition of a small amount of ethyl acetate at boiling point.

Yield: 27.6 g (78.3% of theory).

Melting point: 74-76 ° C.

Analysis: for (molecular weight - 352.4) calculated 54.53% 0, 6.86% Ξ, 15.90% N;

found 54.87% 0, 7.13% H, 16.04% N.

c) 7-ethoxymethyl-1- (5-hydroxy-5-methylhexyl) -3-methylxanthine ch ₂ -O-ch ₂ -ch ₃

0 '

CS 272 799 B2

Ε 35.2 g (0.1 mol) of the ester from step b) in 1 liter of anhydrous ether is added dropwise with vigorous stirring at room temperature 22.4 g (0.3 mol) of methylmagnesium chloride as a 20% solution in tetrahydrofuran (dropwise) ), the internal temperature rising to about 30 ° C. The reaction mixture was then heated to reflux for 2 hours with stirring.

A saturated aqueous ammonium chloride solution was added to quench the resulting alkoxide, the organic phase was separated and washed twice with 300 ml of water each time. The combined aqueous phases are again thoroughly extracted with dichloromethane. The dichloromethane extract was then combined with the ether phase, dried over sodium sulfate, filtered, evaporated under reduced pressure and the residue recrystallized from diisopropyl ether with the addition of ethyl acetate and petroleum ether.

Yield: 27.6 s (81.6%, theory).

102-103 ° C.

For C ^ HH ,NN ^O ^ (MW = 338.4) calculated 56.79% O, 7.74% H, 16.56% N;

Found: C, 56.76; H, 7.82; N, 16.59.

The reaction is even more favorable if a Grignard reagent solution is introduced, diluted with 150 ml of anhydrous ether, and a solution of the ester of step b) in 200 ml of absolute dichloromethane is added dropwise while stirring at 10-15 ° C. The reaction mixture was then further stirred at room temperature for 2 hours while the ester was fully reacted. An aqueous ammonium chloride solution was then added to the mixture, the organic solvent was distilled off under reduced pressure, and the tertiary alcohol was extracted with chloroform. The yield of pure product is 90.8% of theory.

Example 5 1- (5-hydroxy-5-methylhexyl) -3-methylxanthine (Compound No. 6)

(a) catalytic hydrogenolysis of 7-benzyl-1- (5-hydroxy-5-methylhexyl) -3-methylxanthine: 7-benzyl-3-methylxanthine

To a suspension of 83 g (0.5 mol) of 3-methylxanthine in 500 ml of methanol was added 20 g (0.5 mol) of sodium hydroxide dissolved in 200 ml of water and the mixture was stirred at 70 ° C for 1 hour and then at the same temperature. 85.5 g (0.5 mol) of benzyl bromide are added dropwise and the reaction mixture is maintained at a temperature between 70 and 80 ° C for 5 hours. Then the reaction mixture is cooled, filtered cold, the product washed with water on the filter, dissolved in 1000 ml of 1N sodium hydroxide solution (hot), filtered and slowly adjusted to pH 9 by addition of 4N hydrochloric acid, 5. The crystallizate is filtered off from the still hot solution, washed with water until the chloride ions are removed and dried in vacuo.

Yield: 81.7 g (63.8% of theory).

Melting point: 262-264 ° C.

Summary formula: (molecular weight = 256.2).

7-Beazyl-1- (4-ethoxycarbonylbutyl-3-methylxanthine)

CS 272 799 B2

A mixture of 25.6 g (OJ ¹⁸⁰¹ ) of 7-beazyl-3-methylxanthine, 15.2 g (0.11 mol) of potassium carbonate and 23.0 g (0.11 mol) of 5-bromopentanoic acid ethyl ester in 500 ml of dimethylformamide is added. The mixture is heated at 110-120 [deg.] C. with stirring for 8 hours, then the reaction mixture is filtered hot and evaporated under reduced pressure. The residue is taken up in chloroform and the chloroform solution is washed first with 1N sodium hydroxide solution and then with water until neutral, dried, the solvent is distilled off under reduced pressure and the solid residue is recrystallized from diisopropyl ether with addition of ethyl acetate and petroleum ether.

Yield: 31.2 g (81.2% of theory).

Melting point: 72-73 ° C.

Anal. Calc'd for C 20 H 24 F 4 O 4 (Molecular Weight 384.4) C 62.49%, 6.29% 8, 14.57% N, Found C 62.41, H 6.45%, 14.53% 8.

7-Benzyl-1- (5-hydroxy-5-methylhexyl) -3-methylxanthine

22.4 g (0.3 mol) of methylmagnesium chloride are presented in the form of a commercially available 20% solution in tetrahydrofuran and, with the exclusion of moisture and with vigorous stirring, 38.4 g (0.1 mol) of the ester described above are slowly added at room temperature. in 200 ml of anhydrous dichloromethane. Upon completion of the addition, the reaction mixture was heated and heated to reflux for 2 hours. It was then worked up as described in Example 4c) and the crude product was recrystallized from ethyl acetate with the addition of petroleum ether.

Yield: 28.8 g (77.7% of theory).

Melting point: 109-111 ° C.

Analysis: ^ ¾ ^ 0¾ ^(nolekulov and weight = 370.5) calculated 64.84% C, 7.07% H, 15.12% N;

Found: C 65.00, H 7.21, N 15.24.

1- (5-hydroxy-5-methylhexyl) -3-methylxanthine

CS 272 799 B2

14.8 S (0.04 mol) of the above 7-benzylxanthine are hydrogenated in 200 ml of glacial acetic acid in the presence of 1.5 g of palladium (5%) on activated carbon at 60 DEG C. and at a pressure of 50 psi. 24 hours for shaking. After cooling, the catalyst is filtered off under a nitrogen atmosphere, the filtrate is concentrated under reduced pressure and the solid residue is recrystallized from ethyl acetate.

Yield: 9.6 g (85.6% of theory).

Melting point: 192-193 ° C.

Analysis: Calculated: C, 55.70; H, 7.19; N, 19.99.

Found: C, 55.63; H, 7.30; N, 20.00.

b) hydrolytic dealkoxymethylation from 7-ethoxymethyl-1- (5-hydroxy-5-methylhexyl) -3-methylxanthine (from Example 4c)

13.5 of 5 (0.04 mol) of the xanthine derivative of Example 4c) in a mixture of 300 ml of 1N hydrochloric acid solution and 30 ml of glacial acetic acid are heated at 70 ° C for 2.5 hours with stirring, after cooling the reaction mixture is neutralized 4N sodium hydroxide solution and then the product is extracted with chloroform. The chloroform solution is dried, evaporated to dryness under reduced pressure, and the evaporation residue is filtered through a silica gel column using a 10: 1 mixture of chloroform and methanol as the coupling agent and recrystallized from ethyl acetate.

Yield: 7.7 g (68.7% of theory).

Melting point: 191-192 ° C.

Hydrolytic cleavage of the propoxymethyl group from 1- (5-hydroxy-5-methylhexyl) -3-methyl-7-propoxymethylxanthine (Compound No. 34) of the same type gives the 7H-derivative in 75% yield.

Example 6

7- (2,3-dihydroxypropyl) -1- (5-hydroxy-5-methylhexyl) -3-methylxanthine (Compound # 56)

A mixture of 28 g (0.1 mol) of the xanthine derivative of Example 5 (Compound No. 6), 12.2 g (0.11 mol) of 1-chloro-2,3-propanediol and 15.2 g (0.11 mol) of potassium carbonate in 500 ml of dimethyl16

CS 272 799 B2 formamide 3β is stirred at 110 ° C for 18 hours, then filtered while hot and concentrated under reduced pressure. The oily crude product which slowly crystallizes can be purified preferably by filtration through a silica gel column in a solvent mixture consisting of a 10: 1 mixture of chloroform and methanol, followed by recrystallization from ethyl acetate with the addition of petroleum ether at boiling point.

Yield: 26.1 g (73.6% of theory).

Melting point: 105-107 ° C.

For C ^ HHggll ^O ^ (molecular weight = 354.4) calculated 54.22% C, 7.39% H, 15.81% N;

Found:% C, 53.87;% H, 7.47;% N, 15.71.

The compounds prepared according to the preceding examples as well as the compounds prepared in an analogous manner are summarized in the following Table I.

Table I

Compounds of formula I:

compound _,,, temperature RRR _{number is (} by ₀₎

-CH 2 CH ₃ (CH ₃ ) ₄ -O-CH ₃ OH

228 - 23Ο

Γ ³

H ₃ CC- (CH ₂ ) ₄ OH

-CH,

-C3H7

-CH,

-CH,

-OH,

CH,

AND

- (ch ₂ ) ₄ -c-oh ₃

OH

CH,

I ³

- (ch ₂ ) ₄ -c-ch ₃

OH

CH,

AND

- (CH ₂ ) ₄ -CH ₃ OH

- 95

- 60

106-107

CH ₃ h ₃ cc- (ch ₂ ) ₄ OH oh ₃ h ₃ cc- (ch ₂ ) ₄ OH ch ₃ h ₃ cc- (ch ₂ ) ₄ OH

CH,

-CH,

-CH,

-OH ₂ -OC ₂ H ₅

102-103

-H

192-193

O

II

-CH ₂ -C-CH ₃

- 80

CS 272 799 B2 Compound # 1

K ^J melting point (° C)

Cfi ^ OH 1 8 H ₃ CO- (CH ₂ ) _r OH CH ₂ ³ -ch ₃ 1 —OH2 —CH — CH3 9 Hj 0 — C— 4 “ OH -ch ₃ - ^σ 3 ^ CH [ ³ CH, F 11 H-CC- (CH3) ₄ -OH OH; ³ —CH ^ -CH ₂ -C-CH ³ I OH 12 H ₃ CC- (CH ₂ ) ₃ - OH CH, ( -OH ₃ 13 5, σ-Ο- (ΟΗ „) _ς - I ⁵ OH CH, t ³ -c ₂ H ₅ -CH ₃ 14 KJC-C- _{(CH2) 4} - OH CH, f -ch ₃ -ch ₃ 15 Dec H, CC- (CH3) —— ³ 1 ⁵ OH CH- Ϊ ³ -ch ₃ -CH ₃ 16 I-C-C-CCH. OH CH, 1 -CH ₃ - <¥ 7 17 HJC CCHg-C) ^ - OH CH ³ 1 -c ₂ h ₅ -ch ₃ 18. h ₃ cc- (ch ₂ ) ₄ - -c ₂ h ₅ ~ ^G 3 * 7

119-120

- 82

121 - 123

- 98

- 87

120-121

112-113

- 94

- 71

OH

CS 272 799 B2 melting point (° C)

CH, h ₃ c- (CH ₂ ) ₃ OH

CH,

AND

H ₃ CC- (CH ₂ ) ₃ oh

CH,

AND

H, CC- (CH ₉ ), ³ I ³

OH

CH,

I ³

H ₃ CC- (CH ₂ ) ₂ OH

CH,

I ³ h ₃ c- (CH ₂ ) ₂ OH

CH,

AND

H, CC- (OH), ³ I

OH

- ° 4 ^H 9 f ^N 3 h ₃ cc- (ch ₂ ) ₅ OH

CH, h ₃ c- (ch ₂ ) ₄ 0Ξ ch ₃ h ₃ co- (ch ₂ ) ₄ OH

-CH,

-CH,

117-118 • ^C 2 ^H 5

- ° 2 ^H 6

-CH,

-o ₂ h ₅

-CH, ^C 4 ^H 9

-CH,

-CH,

-CH,

-CH,

-CH,

-C ₃ H 7 CH ₃

- (ch,) _9- c-ch

AND

OH

-ch ₂ -o-ch ₃

-CH ₂ O-CH ₃

- 95

- 93

146-147

122

135-137

- 70

- 54

- 94

-c ₂ h ₅

-CH ₂ -O-CH ₃

- 63

CH,

¹³ C-c- (CH ₂ ) ₃ OH

CH,

AND

H ₃ CC- (CH ₂ ) ₃ - OH

CH,

CS 272 799 B2

ÍC

-CH,

-c ₂ h ₅

KjC-C-CCHg 1 '- CH ₃

OH '

CE-,

H 2 O-O- (O 2) 4 OH

CH,

1 h ₃ c- (CH ₂ ) ₄ OH

-σ ₂ Η ₅

-CH,

H ₃ C-O- (CH ₂ ) ₂ --CH ₃

CH,

AND

H (C-C-CCH 3) 4

OH

CH,

I ³ h ₃ c- (CH ₂ ) ₄ OH

-ch ₂ -o-ch ₃

-CH ₂ -O-CH ₃

-CH ₂ -OC ₂ H _5-CH₂-O-

CH,

J.

OH

-CH ₃ - (CH ₂ ) ₂ -O-CH ₃

-o ₂ h ₅

- (CH ₂ ) ₂ -O-CH ₃

H ₅ C ₂ -O- (CH ₂ ) ₂ - -CH ₃

CH,

I ³

- (ch ₂ ) ₄ -c-ch ₃

OH melting point (° C)

- 101

- 96

105-107

68-70

- 85

- 65

- 99

- 79

I ³ h ₃ c- (CH ₂ ) ₄ OH

-ch ₃ - (ch ₂ ) ₂ -oc ₂ h ₅

CS 272 799 B2 compound number melting point (° C)

CH,

I h ₃ cc- (ch ₂ ) ₄ OH h ₃ co- (ch ₂ ) ₃ 42 ch ₃ h ₃ cc- (ch ₂ ) ₄ OH

OH,

I ³ h ₃ cc- (ch ₂ ) ₄ OH ch ₃ h ₃ cc- (ch ₂ ) ₄ Ah oh ₃ h ₃ cc- (ch ₂ ) ₄ oh ch ₃

H ₃ CC- (CH ₂ ) ₂ OH

CH,

I ³ h ₃ cc- (ch ₂ ) ₄ ΟΞ

CH,!

h ₃ cc- (CH ₂ ) ₄ OH

CH,

-c ₂ h ₅ - (ch ₂ ) ₂ -oo ₂ h ₅

CH,

I ³

-ch _3- (ch ₂ ) ₄ -c-ch ₃

OH

-CH ₃ - (CH ₂ ) ₃ -O-CH ₃

-C ₂ H ₅ - (CH ₂ ) ₃ -O-CH ₃

-CH ₃ -CH ₂ -O- (CH ₂ ) ₂ -O-CH ₃

- 54

- 47

- 84

- 73

- 89

OH

-C ₂ H ₅ -GH ₂ -O- (CH ₂ ) ₂ -O-CH ₃

-C ₄ H _g -CH ₂ -O- (CH ₂ ) ₂ -O-CH ₃

-CH ₃ - (CH ₂ ) ₂ -O- (CH ₂ ) ₂ -OC ₂ H ₅

-o ₂ h ₅ - (ch ₂ ) ₂ -o (ch ₂ ) ₂ -oo ₂ h ₅ oh ₃

-CH ₃ - (CH ₂ ) ₄ -C-CH ₃

OH oil

- 98 oil oil h ₃ cc-ch ₂

- 67

CS 272 799 B2 compound number melting point (° C)

CH,

I ³ h ₃ c- (CH ₂ ) ₄ OH

CH,

1 ³

H-C-CCH 2 OH

CH,

AND

H ₃ CC- (CH ₂ ) ₄ OH

O

II

K ^C-C-CCHCH ^OH m

i-c-ch- (ch ₂ ) ₄ -CH ₃ -CH ₂ -CH ₂ -CH ₂ -OH 78-80 ft

-CH ₃ -CCH ₂ ) ₄ -C-CH ₃ oil

-CH-CH.

-CH.

CH,

I h ₃ cc- (ch ₂ ) ₄ 0Η

CH,

1 h ₃ c- (CH ₂ ) ₄ OH

-OHa

-CH.

OH

I. (ch ₂ ) ₄ -ch-ch ₃

CH,

I ³

- (ch ₂ ) ₄ -c-ch ₃

OH

CH,

I ³

- (ch ₂ ) ₄ -c-oh ₃

OH (CH ₀ ) - CH-CH 2 -

Ί i

OH OH

-CH-OH-CH,

II

OH OH

- 71 oil oil

116-118

105-107

Testing of pharmacological properties and results of pharmacological tests

1. Effect on peripheral arterial blood flow disorders

In the last decade, the notion of pathophysiology and hence the medical treatment of chronic peripheral arterial occlusions has seen a remarkable turn in that the scientific and therapeutic interest has shifted increasingly from macrocirculation to microcirculation, and in particular to the capillary bed through which the adjacent tissue is nourished. by substrate exchange, which is mediated by diffusion. Microcirculation disorders result in deficiencies in cellular supply and consequent tissue ischemia, so treatment should be directed to suppress the pathological inhomogeneity of the capillary nutritional blood flow and thereby normalize the local partial oxygen pressure (p0 ₂ ) in the ischemic tissue.

Therefore, testing the compounds produced by the process of the present invention for their improved tissue delivery effect was performed by measuring the partial oxygen pressure in the ischemic skeletal muscle in the experiment described by D. V. 1UBBERS (Prog.

Resp. Res. 3 (Karger, Basel-1969), pp. 136-146), KESSIER (Prog. Resp. Res. 3 (Karger, Basel 1969), pp. 147-152 and Anesthesiology 45 (1976), p. 184), while it was at

CS 272 799 B2 experiments used as a comparative standard preparation of Pentoxifylline.

Male Beagle dogs in natriumpentobarbital narcosis (35 mg / kg ip) were used as test animals in which Arteria femoralis and a certain area of the lower leg were released on the right hind limb and Vena femoralis was released on the left hind limb for infusion and Arteria femoralis for blood flow measurement and appropriate cannulae inserted. The animals were administered Alcuronium chloride (0.1 mgAg i · v. And then 0.05 mg / kg ip every 30 minutes for relaxation) and artificial respiration was introduced to prevent spontaneous contraction of the negative muscle and to measure the oxygen partial pressure and on the other hand to ensure a uniform supply of oxygen for breathing.

Another catheter connected to the Vena femoralis of the right hind limb was used to control the lactate concentration in the venous blood. A multiconductor surface electrode wire is now connected to the exposed muscle area to continuously register the partial pressure of oxygen. Once the oxygen partial pressure curve has stabilized, the Arteria femoralis is closed by means of a clamp, whereupon the oxygen partial pressure in the muscle supplied by this vessel drops rapidly. and then due to spontaneous opening of the collateral blood vessels again slightly increases and finally stabilizes at a value that is considerably lower compared to healthy muscle. At this point in time, the test substance is administered in an aqueous solution either by intravenous infusion (i. V.) (0.6 mg / kg / min) or 25 mgAg intraduodenally (i. D.) And the increase in partial pressure of oxygen in ischemic muscle is measured. Each time before and after the capsules as well as the administration of the substance, venous blood is collected to determine the washed lactate and to check the physiological state of the animals. In addition, the gas concentration (oxygen partial pressure and carbon dioxide partial pressure) and the pH value in the arterial blood of the ischemic limb are examined at the beginning and at the end of each experiment.

The maximum increase in oxygen partial pressure in% after administration of the substance during vascular occlusion (n = 2-11) is used as a measurement parameter for the efficacy of the formulation in a single experiment.

From these measured values, a dimensionless activity index W is calculated for each compound by expressing the value of the percentage of positive experiments and the mean increase in oxygen partial pressure in% given by each positive value, taking into account both interindividual differences in muscle vascularization topology and individual differences in response application of the compound, thereby allowing a more reliable comparison of the efficacy of the individual compounds.

2. Effect on regional blood circulation in the brain

The effect of the compounds produced by the process of the invention on regional blood circulation in the brain is investigated by the FA GIBBS heat conduction technique (Proc. Soc. Exp. Biol. (Ν. Y.) 3J. (1933), p. 141 et seq.), H. HENSEL ( Naturwissenschaften 43 (1956), p. 477 et seq.) And E. BETZe (Acta Neurol. Scand. Suppl. 14 (1965), p. 29-37) on both sexes in natriumpentobarbital narcosis (35 mgAg ip), again, it uses the standard Pentoxifylline therapeutics for comparison purposes. In this method, a heat conduction probe located on the surface of the brain in the area of Gyrus marginalis frontalis determines the heat conduction from the heating point to the adjacent temperature measuring point in the probe, which directly corresponds to the amount of blood flow to the brain. Thus, the percentage increase in the heat conduction value λ after administration of the formulation represents a measure of the improvement in blood flow.

The compounds are administered intravenously in aqueous solution. The dose is 3 mg of test substance per kg body weight. For each test preparation, 3 to 5 individual experiments are performed and the mean percent increase in brain blood flow is determined from the measured values obtained.

3. Acute toxicity:

Determination of the LD ^ _Q by standard methods in mortality observed during 7 days in mice (NMRI) after a single intravenous (iv) or intraperitoneal (ip) administration.

CS 272 799 B2

The results of these tests, which clearly demonstrate the superiority of the compounds of formula I produced by the process of the invention over the standard formulation of Pentoxifylline, are summarized in Tables 2 and 3 below:

Table 2

Effect on peripheral arterial blood flow disorders in the dog closure model and acute toxicity in mice

compound number closure model route of application: i. v .: 0.6 mg / kg / min efficiency index W (cf. page 57) toxicity M ₅₀ (mouse) in mg / kg i. d. r 2i 5 mg / kg 3 i. v. 1650 i .: 100-200 i. d. 1250 4 i. v. 1300 i .: 100-200 5 i- v. (0.3 mg / kg / min) 2080 i .: 150-300 i. d. 2909 i. p. 300-600 6 i. d. 700 i .:> 200 8 i. v. 1400 i. v. ^ 200 12 i. v. 866 i. d. 2337 i .:> 200 14 i. v. 960 i. knows:> 200 16 i. v. 999 i .: p. 150-300 17 i. v. 1525 i .:> 200 18 i. v. 1578 i .: T00-200 28 i, d. 2100 i .:> 200 32 i. v. 2650 i. d. 566 i .:> 200 37 i. v. 1400 i. d. 950 i .:> 200 39 i. v. 1567 i. d. 1996 i .:> 200 44 i. v. 1199 i. v.> 200 50 i. v. 2631 i. d. 733 i .:> 200 Pentoxifyllin i. v. 89 T i .: 187-209 i. d. Table 3 643 i .: 219-259

Effect on regional cerebral blood flow of narcotized cats after intravenous administration of 3 mg / kg and acute toxicity in mice

CS 272 799 16 25.8 and. p .: 150-300 17 9.4 and. in.: > 200 18 9.4 and. in.: 100-200 22nd 12.0 and. in.: > 200 27 Mar: 10.3 and. in.: > 200 43 19.8 and. in.: > 200 48 14.6 and. in.: > 200 Pentoxifyllin 8.6 and. in.: 187-209 and. P .: 219-259

The unambiguous predominance of the compounds produced by the process of the invention, in particular with respect to Pentoxifylline, a xanthine derivative most commonly used to treat peripheral and cerebral blood flow disorders, can also be proven by other special experiments.

Today, it is well known that pharmaceuticals that exclusively act to augment blood vessels or compositions with a very potent vasodilating component of action are unsuitable for the treatment of microcirculatory disorders, since, on the one hand, the physiological vasodilatory reserve is usually completely depleted, danger of Steale's phenomenon, which means a harmful redistribution of the nutritional flow of blood in microcirculation, leading to the burden of already under-supplied diseased tissue. For this reason, the inhibitory effect on vascular contraction induced on the isolated washed ear of the rabbit by norfenephrine was investigated. For example, compound 5 shows no inhibitory effect on norfenephrine up to a concentration of 100 µg / ml, while Pentoxifylline extends over a concentration range of 10 to 100 µg / ml depending on the dose of the vessel which has been narrowed by norfenephrine.

In a chronic experiment in rats with one-sided closure of Arteria-iliaca, it can be shown that the compounds of formula I can favorably influence metabolism in ischemic skeletal muscle. For example, if animals are treated for 5 weeks with, for example, compound 5, with 3 mg / kg i.p. administered daily intraperitoneally, the histochemical staining method shows that the ischemic limbs (Tibialis anterior and Extensor digitorum longus) significantly increased the proportion of oxidized fibers. In contrast, Pentoxifylline showed no direct effect on muscle metabolism in a comparable experiment conducted in the same manner.

The predominance of the xanthines of Formula I has also been shown in another chronic test in which the effect of contractility of the isohemic skeletal muscle of rats with ligated true Arteria femoralis is examined. Animals are dosed for 20 days with the respective test preparation at a daily oral dose of 25 mg / kg via an esophagus probe. The degree of isohemic muscle fatigue in electrical irritation is then determined with about 80 contractions / min decrease in contraction intensity after 1, 15 and 40 minutes of stimulation compared to untreated control animals. For example, compound 5, apparently due to the optimization of metabolism, significantly improves muscle performance in the ischemic limb, even achieving normal contractility values as in the left healthy (non-ischemic) muscle of untreated animals. This improvement coincides with increased mitochondrial respiratory control (RGR). Pentoxifylline proved to be ineffective in these experiments.

The compounds produced by the process of the invention are therefore also suitable for the treatment of muscle energy metabolism disorders of various origins, in particular mitochondrial myopathies.

Claims (5)

BACKGROUND OF THE INVENTION Τ. Process for preparing tertiary hydroxyalkyixanthinů general formula I wherein at least one of the radicals B ¹ and E ^ represents the tertiary hydroxyalkyl group of the formula Ia CH, I ³ OH C a), wherein n is an integer from 2 to 5, and if only one of the radicals E ¹ or E 2 represents such a tertiary hydroxyalkyl group of the formula Ia, the other radical is a hydrogen atom or an aliphatic hydrocarbon group R ⁴ to 6 carbon atoms, the carbon chain of which is optionally interrupted by up to 2 oxygen atoms or optionally substituted by one oxo group or up to two hydroxyl groups, said oxo group and hydroxyl groups being separated from the ring nitrogen atom by at least 2 carbon atoms, and E ² represents a C 1 -C 4 alkyl group, characterized in that the 3-alkylxanthines of formula II O B CH) in which E is as defined above, A represents a hydrogen atom, an E ⁴ group or an alkoxycarbonylalkyl group of the general formula III 0 lt - (CH _{2) n} -C 0E ^and CHI), CS 272 799 B2 where R ^a represents a C 1 -C 4 alkyl group, and B is hydrogen, R 1, benzyl, diphenylmethyl, or alkoxycarbonylalkyl of formula III, wherein R 3 and n are as defined above, and at least one of A and B is alkoxycarbonylalkyl of formula III, react with two equivalents of a methylmetal compound , such as methyl lithium or methyl magnesium halide, to a single alkoxycarbonyl function followed by reductive cleavage of residue B when the residue is a benzyl or diphenylmethyl group, by chemical reduction or catalytic hydrogenolysis at atmospheric pressure or pressure up to 1.0 KPa, or by hydrolytic elimination of alkoxymethyl or an alkoxyalkoxymethyl radical from the position ώ, γ & υ B of the acidic conditions p? I. temperatures below 100 ° C and alkylation of position 1 or position 7 when A or B represents a hydrogen atom in aprotic organic solvents, alcohols, aromatic or halogenated hydrocarbons, pyridine, optionally also in admixture with water, by alkylating the reagents of formula IV X - Q (IV) in which X is a halogen atom or a sulfonic acid ester or a phosphoric acid ester group and a Q represents a tertiary hydroxyalkyl group of formula (Ia) or a group r 'in anhydrous solvents such as ethers, aliphatic or aromatic hydrocarbons, chlorinated aliphatic hydrocarbons, tertiary amines, aprotic solvents' and mixtures thereof at temperatures between -20 ° C and 100 ° C ° 0. 2. A process according to claim 1, wherein the corresponding compounds of the formulas II and IV are used as starting materials to form a compound of the formula I in which: 2 I 3 R is methyl or ethyl and R and R ^J are as defined in paragraph 1, wherein only one of R ^ or R ^ is t. a hydroxyalkyl group of formula (Ia) as defined in point 1. 3. The method according to claim 1 or 2, characterized in that the starting materials used are corresponding compounds of formula II and IV to give compounds of formula I wherein R ¹ or R is [(a-1) -hydroxy- (ω-1) -methyl] pentyl, hexyl or 1 -hepty2 nominal 7 group, the remaining R and R or R @ ^J are as defined in paragraph 1 or 2 respectively. Process according to one or more of Claims 1 to 3, characterized in that the corresponding compounds of the formulas II and IV are used as starting materials to give compounds of the formula I in which R ¹ represents a tertiary hydroxyalkyl group of the formula Ia, preferably R ¹ is [(ω-1) -hydroxy- (tu-1) -methyl] pentyl, hexyl or -heptyl, R ² is methyl or ethyl and R is an alkyl group having 1 to 4 carbon atoms, a (C 1 -C 4) hydroxyalkyl group or a (C 1 -C 4) alkoxyalkyl group in the alkoxy and alkyl moieties. 5. A process according to claim 4, wherein the corresponding compounds of the formulas II and IV are used as starting materials to produce the compounds of the formula I in which: 1 2 í R represents 5-hydroxy-5-methylhexyl group, R is methyl and R ^J is ethoxymethyl.