CS272798B2 - Method of tertiaryhydroxyalkylanthine 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

(57) A process for the preparation of compounds of formula (I) wherein at least one of R ¹ and R 6 is a tertiary hydroxyalkyl group of formula (I) - (CH 2) n C (R 4) (OH) -CH 4, wherein R R 2 is C 1-6 alkyl and n is from 2 to 5, and if only one of R 6 or R 6 is a group of formula Ia, the other is H or an aliphatic hydrocarbon group of up to 6 carbon atoms whose carbon chain optionally interrupted by up to 2 oxygen atoms or optionally substituted by one oxo or up to two hydroxy groups, said oxo and hydroxyl groups being separated from the ring nitrogen atom by at least two carbon atoms and R ² is C 1-6 -alkyl, characterized in that reacting 3-alkylxanthines of formula II, wherein a is hydrogen, R, or oxoalkyl group - (CH ^ n - ^0-0 ° ¾ (IIIa) or - (CHjJn-CO-R (IIIb), and B is hydrogen,

R ⁵ , benzyl, diphenylmethyl, or _{in a} group of formula IIIa or IIIb, and at least one of groups A and B is _{in a} group of formula IIIa or IIIb, with at least one or two moles of the corresponding C 1 -C 3 alkyl metal compounds; reductive alkylation of carbonyl groups followed by reductive cleavage of group B if it is benzyl or diphenylmethyl, or optionally hydrolytic elimination of an alkoxymethyl or alkoxyalkoxymethyl residue from the group B position and alkylation of the 1 or 7 position when A or B is hydrogen by alkylating agents of general of formula X - Q (IV), wherein X represents a halogen or a sulfonic or phosphoric acid ester residue and Q represents a group of formula Ia or R ⁵ . The compounds produced can be used as medicaments in particular for the treatment of peripheral and eerebral blood flow disorders.

43?

The present invention ββ relates to a process for the production of novel xanthine derivatives having at least one tertiary hydroxyalkyl group at the 1 or 7-position. 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, ie 3,7-dimethyl-1- (5-oxohexyl) xanthine, has gained remarkable therapeutic significance for the medical treatment of disorders of both peripheral and cerebral blood supply. * As a new generation vasoactive drug (cf. Schweiz. Wschr. 111 (1981), pp. 637-640) has, for example, in many countries nowadays been well established among drugs used to treat peripheral arterial occlusion, while in other countries it has been 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 and the first, as well as the pharmacologically active metabolite, i.e. 1- (5-hydroxyhexyl) -3,7-dimethylxanthine, are subject in the animal body. and human rapid and complete biotransformation, which proceeds almost exclusively through the enzymatic oxidation of the OX- 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 is metabolised by drug-degrading enzymes in the first part of the liver after absorption from the stomach and intestinal tract and transport through the gastrointestinal tract to the liver, the most important organ for foreign substances. only a portion of the drug in the unchanged form achieves systemic, high blood circulation. The first-pass effects, also referred to as presystemic elimination, thus reduce the systemic utility of the unchanged drug. The inherent disadvantage of the pronounced effect of the solid passage is not so much that the oral dose is reduced by way of systemic circulation, but that the process generally exhibits considerable intra- and inter-in vivo visual 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 an intensive pharmaceutical research effort to find new xanthine derivatives which, with a similarly good or possibly even stronger pharmacologic effect and equally excellent tolerability, have significantly higher metabolic stability and thus considerably lower or a totally 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 are 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 hydroxyalkyl group and the 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 has a tertiary alcohol structure it is stable to polyfunctional microsomal liver oxidases and at the same time fulfills the other therapeutic requirements set forth above.

It is an object of the present invention to provide a process for the preparation of the tertiary hydroxyalkylxanthines of general formula 28f

R ² wherein at least one of the radicals R ¹ and R represents a group of the tertiary hydroxyalkyl formula Ia

R ⁴

- (CH ₂ ) _n -C'-CH ₃ (Ia)

OH

R ⁴ represents an alkyl group having up to 3 carbon atoms and n is an integer from 2 to 5, and if only one of R ^ or R ^ represents such a tertiary hydroxyalkyl group of formula Ia, the other of these is c

hydrogen or an aliphatic hydrocarbon group Ir having up 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 by at least 2 atoms carbon, and

R is C1-C4alkyl by reacting the 3-alkylxanthines of formula II

t in which

E ² is as defined above,

A represents a hydrogen atom, an R R group as defined above, or an oxoalkyl group of formula IIIa or IIIb

- (CH ₂ ) _n - CO - CH ₃ (lila)

- (Cff ₂ > _n - CO - R ⁴ (IIIb) a)

B represents a hydrogen atom, a R ^ group, a benzyl group, a diphenylmethyl group or an oxoalkyl group of the general formula IIIa or IIIb, wherein:

R ⁴ , R ⁶ and n are as defined above and at least one of groups A and B is an oxoalkyl group of formula IIIa or IIIb, in anhydrous solvents such as ethers, aliphatic or aromatic hydrocarbons, tertiary amines, aprotic solvents and mixtures thereof at temperatures between -20 ° C and +100 ° C with at least one or two moles of the corresponding C 1 to C 3 alkyl alkyl compounds, such as alkyl lithium or alkyl magnesium derivatives, under reductive alkylation of the carbonyl groups and subsequent reductive cleavage of Group B, if means a benzyl group or diphenylmethyl group, by chemical reduction or catalytic hydrogenolysis at atmospheric pressure or at a pressure of up to 1.0 KPa at a temperature of from 20 to 100 ° C, or, optionally, hydrolytic elimination of an alkoxymethyl or alkoxyalkoxymethyl residue from Group B under acidic conditions at heat tách pod. 100 ° C and alkylation of position 1 or position 7, if A or B is hydrogen, with alkylating agents of formula IV

X - Q (17), in which

X represents a halogen atom, a sulfonic acid ester residue or a phosphoric acid ester residue and

Q represents a tertiary hydroxyalkyl group of the formula Ia or a group R 1, in aprotic organic solvents, alcohols, aromatic or halogenated hydrocarbons, pyridine, optionally also in admixture with water, at a reaction temperature between 0 ° C and the boiling point of the reaction medium, preferably between 20 and 130 ° C.

The compounds of formula I are preferably prepared according to the process of the invention, in which R is methyl or ethyl, and only one of R @ ¹ or R @ 1 is a tertiary hydroxyalkyl group of the formula Ia.

Preferably, compounds of formula (I) are prepared in which R 1 or R 1 represents a ((R) -1) -hydroxy- (1 R) -methyl) pentyl, -hexyl or -heptylovone group.

Also preferred compounds of formula (I) which are prepared by the process of the invention are those compounds of formula (I) wherein R 1 is a tertiary hydroxyalkyl group, preferably R ¹ is ((R ¹ -hydroxy-1 H) -1-methyl) pentyl R 1 is methyl, or hexyl, or heptyl, R is methyl or o

ethyl and R1 are C1-C4alkyl, C1-C4hydroxyalkyl or C1-C4alkoxyalkyl in the alkoxy and alkyl moieties.

Preferred compounds of formula I also belong those in which R ¹ represents 2 3 5-hydroxy-5-methylhexyl group, R is a methyl group and R is ethoxymethyl.

13

The groups selected for R at the R or R position are. for example methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl and hexyl hydroxy and oxo derivatives thereof, the hydroxy or oxo groups being separated from these nitrogen atoms by at least two carbon atoms, such as for example hydroxyethyl, 2- and 3-hydroxypropyl, 2,3-dihydroxypropyl, 2-,

3- and 4-hydroxybutyl, 2-hydroxy-2-methylpropyl, 3,4-dihydroxybutyl, 4,5- and 3,4-dihydroxypentyl, 5,6- and 4,5-dihydroxyhexyl, 4- hydroxypentyl, 5-hydroxyhexyl, 2-oxopropyl, 3-oxobutyl, 4-oxopentyl and 5-oxohexyl, as well as alkoxyalkyl and alkoxyalkoxyalkyl groups such as methoxymethyl, methoxyethyl and methoxypropyl, ethoxymethyl , ethoxyethyl and ethoxypropyl, propoxymethyl and propoxyethyl, methoxyethoxymethyl and methoxyethoxyethyl, as well as ethoxyethoxymethyl and ethoxyethoxyethyl. According to a preferred embodiment of the process of the invention, the tertiary hydroxyalkylxanthines of formula I are prepared by substituting substituted xanthines of formula II in which R is as defined above and A and B are two identical or different traces of formula IIIa or IIIb or one group of the general formula.

IIIa or IIIb, in which case the second substituent is a hydrogen atom or a group R 6 f 5 or a stop R, where R has the same meaning as R or is a benzyl or diphenylmethyl group reacted with an alkyl metal compound containing 1 to 3 the carbon atoms in the alkyl moiety, optionally in the case of the traces of formula IIIb with methylmetallic compounds under reductive alkylation of the carbonyl groups and the formation of xanthines of the formulas Ib, Ic, Id, Ie and 1f

O.

CS 272793 B2 (Va), whereupon optionally the tertiary hydroxyalkylxanthines of the formulas Ib and 1f, which contain a hydrogen atom at the 1-position or the 7-position, are optionally reacted in the presence of basic agents or in the form of their salts with alkylating agents of the formula

X-Q (IV) wherein

X is as defined above; and g

Q is a group of formula Ia, R, or R to form trisubstituted compounds of formulas Ic, Id or Ie.

wherein in the above formulas the symbols have 2.56

R, R, R, R and n are as defined above.

O

3-alkylated mono- or dioxoalkylxanthines of the formula II in which R is as defined above and A and B represent two identical or different groups of the formulas IIIa or IIIb or also only one group of the formulas IIIa 'or IIIb and in which in the case of the second substituent, a hydrogen atom or a group R ^y or a group R 6, wherein R 6 is the same

R has the same meaning as R or is benzyl or diphenylmethyl, which are used as starting materials, are either known or can be prepared, for example, from the 3-alkylxanthines of the general formula II in which A and B 'are hydrogen atoms and sulfonyloxy- or haloketones of formula Va

Hal - (CH ₂ ) _n - CO - CH ₃ in which

Hal and n are as defined above, and Vb

Hal - (CH ₂ ) _n - CO - R ⁴ in which

Hal, R ⁴ and n are as defined above.

O

Reductive alkylation of a ketone of formula (II) wherein R is as defined above and A and B are two identical or different groups of formula (IIIa) or (IIIb) or also only one group of formula (IIIa) or (IIIb), in which case the other substituent is hydrogen or R? or a group R ^E , wherein R 6 has the same meaning as R or is a benzyl group or a diphenylmethyl group, can be carried out, for example, by treatment with alkyl potassium compounds, alkyl sodium compounds, alkyl lithium compounds, alkyl magnesium compounds, alkyl zinc compounds, alkyl cadmium compounds, alkyl aluminum compounds and alkyl tin compounds. Newly recommended alkyl titanium compounds and alkyl zirconium compounds (cf. D. Seebach et al., Angew, Chem.

(1933), pp. 12-26 are also applicable. However, since the sodium and potassium alkyl metal compounds tend to cause side reactions due to their high reactivity, and the zinc and cadmium alkyl metal compounds, on the other hand, are less reactive, alkyl lithium compounds and alkyl magnesium compounds (Grgignard compounds) are usually preferred.

Strongly nucleophilic organometallic compounds are highly sensitive to hydrolysis and oxidation. Safer handling of these substances therefore requires working in an anhydrous environment, optionally under a protective gas atmosphere. Common solvents or diluents are, in particular, those which are also suitable for the production of alkyl metal compounds. Suitable ethers are, in particular, ethers having one or more etheric oxygen atoms (Vb), for example diethyl ether, dipropyl ether, dibutyl ether or diisoamyl ether, 1,2-dimethoxyethane, tetrahydrofuran, diohexane, tetrahydropyran, furan and anisole, as well as aliphatic or aromatic hydrocarbons, such as petroleum ether, cyclohexane _} benzene, toluene, xylenes, diethylbenzenes and tetrahydronaphthalene; however, it is also possible to use tertiary amines such as triethylamine or dipolar aprotic solvents such as hexamethyltriophosphoric acid, as well as mixtures of the solvents mentioned. In the reaction of carbonyl compounds with Grignard compounds of formula R ⁴ -MgHal, The process of claim 1 wherein the organometallic compound is introduced in ether and the ketone is added dropwise as a solution in dichloromethane or 1,2-dichloroethane. The addition of magnesium bromide, which has the ability to increase the nucleophilia of the organometallic compound by virtue of its participation in the complex cyclic transition melt, is often recommended.

The reaction of the ketone and the organometallic compound is generally carried out at temperatures between -20 ° C and 100 ° C, preferably at temperatures between 0 ° C and 60 ° C 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 decomposition of the formed alkoxide is preferably carried out in aqueous ammonium chloride solution or by treatment with dilute acetic acid.

Reductive cleavage of the benzyl group or diphenylmethyl group from the compounds of formula Ie to give xanthine derivatives of formula If containing a hydrogen atom at the 7-position is carried out under standard conditions which have been developed primarily under the protecting group technique in the synthesis of alkaloids and peptides. it can be assumed that they are well known. In addition to chemical reduction, in particular in the case of benzyl derivatives with sodium in liquid ammonia (cf. Houben-Weyl, Vol. XI / 1 (1957), p.

974-975), preferably elimination of both of the above aralkyl groups by catalytic hydrogenolysis in the presence of noble metal catalysts (cf. Houben-Weyl, Vol. XI / 1 (1957), pp. 968-971 and Vol. IV / 1) c, part 1 (1980), pp. 400-404). 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 charcoal or barium sulphate, while other noble metals such as platinum, rhodium and ruthenium are often prone to 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 a slightly elevated pressure of up to about 1.0 MPa, reaction times of from several minutes to several hours being generally required.

The 1,3,7-trisubstituted xanthines of the formula Ie which contain an alkoxymethyl group or an alkoxyalkyloxymethyl group in the position of the substituent R® are Ο, Η-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), also forming the 7H derivatives of the formula If 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 solvent. Also suitable are perchloric acid or organic acids such as trifluoroacetic acid, formic acid and acetic acid, together with catalytic amounts of mineral acids. In particular, alkoxyalkoxymethyl derivatives can also be cleaved with Lewis acids, such as zinc bromide and titanium tetrachloride, in an anhydrous medium, preferably dichloromethane or chloroform, whereby the intermediate 7-bromomethyl or 7-bromosine derivatives are self-hydrolyzed in connection with the aquatic environment. When cleaving in a solution containing a mineral acid, the reaction temperature should be chosen so as to avoid noticeable 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 alkylations with reagents of formula (IV) is generally carried out in a diluent or solvent inert to the reactants. Particularly suitable as such are dipolar, aprotic solvents, for example formamide, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, 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 containing from 1 to 4 carbon atoms, but both together have 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. ^Xanthine derivatives ® ° bou however also be used directly in the form of their salts, in particular produced, for example as alkali metal salts, alkaline earth salts or optionally substituted ammonium or phosphonium salts mentioned for the alkylation reaction. Further, the mono- and disubstituted 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 salts or in the form of alkaline earth metal salts, using so-called phase transfer catalysts, e.g. tertiary 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 moieties, 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) benzyltrialkylammonium salts, (cetyltrimethylammonium) salts, (C 1 -C 12) alkyltriphenylphosphonium salts, and benzyltriphenylphosphonium salts, the compounds having a larger and symmetric cation are generally found to be more effective.

When introducing the groups of formula Ia and the groups R ⁵ and R ⁶ in the above processes is carried out generally at a reaction temperature between 0 ° C and the boiling point of the used reaction medium, preferably at temperatures between 20 ° C and 130 ° C, optionally at 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 in which one of the substituents R1 and R2 is a dihydroxyalkyl group, the dihydroxyalkyl group can be built up or introduced by conventional methods, as described, for example, in EP-OS 75 850.

The tertiary hydroxyalkylxanthines of formula (I) may contain one or two asymmetric carbon atoms depending on the chain length of the alkyl R 1 (at least 2 carbon atoms) and / or the substituent structure R 1 (eg 2-hydroxypropyl) and are therefore present in stereoisomeric forms. The invention therefore relates to both pure stereoisomeric compounds and mixtures thereof.

The xanthine derivatives of formula (I) produced by the process of the invention are suitable for use as an active ingredient of medicaments, in particular those which permit more effective prophylactic and curative treatment of diseases due to their valuable pharmacological properties and favorable metabolic properties, for example against polyfunctional microsomal liver oxidases. disorders of peripheral and cerebral blood flow, such as peripheral arterial occlusion, and thus represent enrichment of the drug region. 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 according to 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, dragees, (micro) capsules, suppositories, syrups, emulsions, suspensions, aerosols, drops or injectable solutions in the form of ampoules, as well as sustained-release formulations. they are generally used in the manufacture of adjuvants such as carriers, disintegrants, binders, coatings, shoe shells, lubricant lubricants, flavor enhancers, sweeteners or co-solvents. 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 dose of a compound of formula I. D solid dosage units, such as tablets, capsules and suppositories, may be up to 1000 mg, preferably 100 mg. up to 600 mg, and for injection solutions in the form of ampoules, is up to 300 mg, but is preferably 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 or 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 antithrombotics, antihyperlipidemics, analgesics, sedatives, antidepressants, antianginal agents, cardiotonic drugs, 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 IR and ¹ H-NMR spectrum values. Compounds of formula (I) which were prepared according to the examples below, as well as compounds of formula (I) prepared in an analogous manner

I are summarized in Table 1.

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

Example 1 1- (5-hydroxy-5-methylhexyl) -3-methyl-7-propylxanthine (Compound 9)

To a suspension of 61.3 g (0.2 mol) of 3-methyl-1- (5-oxohexyl) -7-propylxanthine in 2 liters of anhydrous ether was added dropwise at room temperature with vigorous stirring at room temperature. mol) of methylmagnesium chloride as a 20% solution in tetrahydrofuran, the internal temperature rising to about 30 ° C. The reaction mixture is then heated under stirring for 2 hours at reflux, saturated aqueous ammonium chloride solution is added to quench the resulting alkoxide, the organic phase is separated and washed twice with 500 ml of water each time. The combined aqueous phases are again thoroughly extracted with ether. The dichloromethane extract was combined with the ether phase, dried over sodium sulfate, and evaporated under reduced pressure to give 59.0 g of crude product (91.5% of theory) which was purified by recrystallization from diisopropyl ether.

Yield: 49.8 g (77.2% of theory)

Mp 81-82 ° C

Analysis calc'd for C ^ 16 ^ ^ 26 26 26 ^ ^ 4 ^ (C ° l l ^e hmotnost hmotnost hmotnost 322 322, 322 322,4): C, 59.61; H, 8.13; N, 17.38.

Found: C 59.72, H 8.09, N 17.44.

The reaction is more favorable when a Grignard reagent solution is introduced, diluted with 200 ml of anhydrous ether, and 3-methyl-1- (5-oxohexyl) -7-propylxanthine, dissolved in 300 ml of absolute dichloromethane, is added dropwise with stirring. The reaction mixture is stirred at room temperature for 1 hour, at which point the ketone is completely reacted. An aqueous ammonium chloride solution was added to the reaction mixture, the organic solvent was distilled off under reduced pressure, and the tertiary alcohol was extracted with chloroform. The yield of pure product is 92.1% of theory.

Example 2 1- (5-hydroxy-5-methylheptyl) -3,7-dimethylxanthine (Compound 10)

20.0 g (0.15 mol) of ethylmagnesium bromide as a 40% solution in ether are introduced and 27.8 g (0.1 mol) of 3,7-dimethyl-1- (5-oxohexyl) xanthine in 1 liter are added. of absolute ether dropwise with stirring at room temperature to form a volumetric precipitate. The reaction mixture is heated and then further stirred at reflux for 1 hour. The reaction mixture is then worked up as described in the above example

1. 25 g of an oily crude product (81.1% of theory) were obtained, which was slowly crystallized and the crystallizate was purified by recrystallization from diisopropyl ether with the addition of a small amount of ethyl acetate at boiling point.

Yield; 22.9 N (74.3% of theory).

Melting point 83-84 ° C

Anal. Calcd for ^C 15 ^H 24 ^N 4 ^O 3 (Lolcellone Weight = 308.4) C 58.42%, H 7.84%, K 18.17%;

found: 58.33% C, 8.02% H, 18.21% 17.

Example 3 1- (5-hydroxy-5-methylhexyl) -7- (2-hydroxy-2-methylpropyl) -3-methylxanthine (compound 11) a) 3-methyl-1- (5-oxohexyl) -7- ( 2-oxopropyl) xanthine

22.2 g (0.1 mol) of 3-methyl-7- (2-oxopropyl) -xanthine are mixed together with 14.8 g (0.11 mol) of 1-chloro-5-hexanone and 15.2 g (0.11 mol) of potassium carbonate in 500 ml of dimethylformamide for 1.5 hours at 110 ° C. The reaction mixture is allowed to cool slowly with further stirring, filtered, the filter salt is washed thoroughly with dimethylformamide, the solution is concentrated under reduced pressure, the residue is taken up in 200 ml of methanol, 50 ml of water and 2 ml of concentrated sulfuric acid are added. the mixture was refluxed for 1 hour. After removing the methanol under reduced pressure, the residue was basified by the addition of 33% sodium hydroxide solution and carefully extracted with chloroform. The combined chloroform extracts were washed with a small amount of water until neutral, dried over sodium sulfate and the solvent was distilled off in vacuo to give 25.8 g (80.5% of theory) of a solid crude product which was recrystallized from ethanol with the addition of petroleum ether. boiling point.

Yield: 23.1 g (72.1% of theory)

Melting point 111-113 ° C

Analysis for C 15 H 20 N 4 O 4 (Molecular Weight = 320.3) calculated C 56.24%, H 6.29%, N 17.49%;

Found: C, 56.31; H, 6.35; N, 17.21.

b) 1- (5-hydroxy-5-methylhexyl) -7- (2-hydroxy-2-methylpropyl) -3-methylxanthine

To 22.4 g (0.3 mol) of methylmagnesium chloride as a commercial 20% solution in tetrahydrofuran, 32.0 g (0.1 mol) of double oxoalkylated xanthine from step a) in 100 ml are slowly added under excretion of moisture and vigorous stirring. of anhydrous dichloromethane. After the addition was complete, the reaction mixture was heated at reflux for 2 hours, then the reaction mixture was worked up as described in Example 1 and the crude product was recrystallized from ethyl acetate.

Yield 25.8 g (73.2% of theory)

121-123 ° C

Analysis for C 17 H 28 N 4 O 4 (Molecular Weight = 352.4) calculated C 57.93, H 8.01, N 15.90.

Found: C, 57.70; H, 7.93; N, 15.83.

Example 4

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

The title compound was prepared in an analogous manner to that described in Example 1 by Grignard synthesis of 7-ethoxymethyl-3-methyl-1- (5-oxohexyl) xanthines by treatment with methylmagnesium chloride in anhydrous ether.

^- temperature: mp 102-103 ° C.

Analysis calculated for C 16 ^H 26 ^{N 4} O 4 (Molecular Weight = 338.4) C 56.79, H 7.74, R 16.56;

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

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

7-Benzyl-3-methylxanthine

ch ₂

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

° 13 ^Ε 12 ^Ε 4θ2 (molecular weight = 256,2)

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

7-Benzyl-3-methylxenthin is reacted first with 1-chloro-5-hexanone to give 7-benzyl-3-methyl-1- (5-oxohexyl) xanthine (yield 90.4% of theory; m.p. 84 ° C), then the oxohexyl side chain is reductively methylated with methylmagnesium chloride in anhydrous ether analogously to Example 1 (yield: 60.2% of theory, mp 108-110 ° C).

Analysis calculated for C 20 H 26 N 4 ^O 3 ( ^Molecular Weight = 370.5) 64.84% C, 7.0? % H, 15.12% N;

Found: C 65.00, H 7.21, N 15.24.

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

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

Yield: 9.6 g (85.6% of theory)

Mp 192-193 ° C

Analysis for ^C 13 ^H 20 ^N 4 ^O 3 (MW 280.3) calculated 55.70% C, 7.19% H, 19.99% H;

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

The title compound can also be prepared by hydrolytic dealkoxymethylation from 7-ethoxymethyl-1- (5-hydroxy-5-methylhexyl) -3-methylxanthine.

13.5 e (0.04 mol) of 7-methoxymethyl-1- (5-hydroxy-5-methylhexyl) -3-methylxanthine (Compound No. 5, arer. Example 4-) in a mixture of 300 ml of 1N hydrochloric acid solution and 30 ml of glacial acetic acid is heated for 2.5 hours while stirring at 70 ° C, after cooling, the reaction mixture is neutralized with 4N sodium hydroxide solution and then the product is extracted with chloroform. The chloroform solution was dried, evaporated to dryness under reduced pressure, and the evaporation residue was filtered through a silica gel column eluting with 10: 1 chloroform: methanol as the eluent.

Yield: 7.7 g (68.7% of theory).

Melting point: 191-192 ° C

By hydrolytic cleavage of the propoxymethyl group from 1- (5-hydroxy-5-methylhexyl) -3-methyl-7-propoxymethylxanthine (cf. compound 34) of the same type, the corresponding 7H-derivative is obtained in 75% yield, i.e. of the title compound.

Table 1

Compounds of formula I:

compound number

R ^e melting point (° C)

-CH,

CH- I

(CH-b-C-CE)

AND

OH

228-230, _3-CC-ÍCHg) ^ - CH ₃

AND

OH

Γ ³

- (ch ₂ ) ₄ -c-ch ₃

OE

93-95

CH,

-CH ₃ - (CH ₂ ) ₄ -C-CH ₃

59-60

OH compound number

R ² melting point (° C)

-CH ₃ -CH 2 - (CH ₂ ) ₄ -C-CH ₃

AND

OH

CH.

AND

H ₃ CC- (CH ₂ ) ₄ -CK ₃ -CH ₂ -OC ₂ H ₅

OH

CH ₃

HC-C- (CH _O) -CH-,

OH

106-107

102-103

192-193

CH.

H.C-C- (CH) 1

OH

-CH0

-ch ₂ -c-ch ₃

78-80

GS 272798 B2 compound number melting point (° C)

CH.

OH ··

H ₃ CC- (CH ₂ ) ₄ -CH-i

-CH ₂ -CH-CH ₃

119-120

OH

CH-CHE..CC- (CH _o hOH

- = 3¾

- 82

CH10 H ₃ C-CH ₂ -C- (CH _{2) 4} -CH83 - 84

OH

CH_

-CHCHh ₃ CO- (CH _{2) 4} - CH ₃

OH

-ch ₂ -c-ch ₃

OH

121 - 123 Compound No. ^R

GS 272798 B2 melting point (° C)

CH 12 H ₃ CC- (CH ₂ ) ₃ -CH.

^-C 3 ^H 7

- 98

OH ch ₃

I h ₃ cc- (ch ₂ ) ₅ - -c ₂ h ₅

OH

-CH ₃

- 87

CH.

I ^J

H ₃ CC - (CE ₂ ) ₄ I

OH

CH.

-CH.

-CH120-121

H ₃ CC- (CH ₂ ) ₅ -CH.

-CH112-113

OH compound 1 number ^R melting point (° C)

CH I 3

H ₃ CC- (CH ₂ ) ₅ OH

-CH92-94

CH 17 H ₃ CC- (CH ₂ ) ₄ -C ₂ H ₅

OH

-CE98

CH.

H ₃ CC- (CH ₂ ) ₄ -C ₂ H ₅

-C ^

- 71

OH

CH.

I ³

H ₃ C-CH ₂ -C- (CH ₂ ) ₄ - -CH ₃ OH

_C3 H7

86-87

15 'compound number

CHh ₃ cc- (CH ₂ ) ₃ -CH ₃

OH

CH ₂₁ H ₃ CC- (CH ₂ ) ₃ -C ₂ H ₅

OH

CHR '

-CH-CH22 h ₃ cc- (CH ₂ ) ₃ - -c ₂ h ₅ ^C 3 ^H 7

OH

CHH ₃ CC- (CH ₂ ) ₂ - -CH ₃ OH

- Melting point (° C)

117-118

- 95

- 93

146-147 compound number melting point (° C)

CH,

AND

H ₃ CC- (CH ₂ ) ₂ -C ₂ H ₅

OH

-CH

122

CH,

AND

H ₃ CC- (CH ₂ ) ₂ OH

-CE.

-C ^

135-137

-c ₄ Hs ch ₃ . - (ch ₂ ) ₂ -c-ch ₃

OH

- 70

CH.

H ₃ CC- (CH ₂ ) ₅ -ch ₃ -ch ₂ -o-ch ₃

- 54

OH

GS 272798 32 Compound No. ^R Melting point (° C)

H ₃ CC- (CH ₂ ) ₄ - -CH ₃ -GH ₂ O-CH ₃ 92-94

OH

CH, r

H ₃ CC- (CH ₂ ) ₄ -C ₂ H ₅ -CH ₂ -O-CH ₃ 61-63

OH

CH,

AND

H ₃ CC- (CH ₂ ) ₃ - -GH ₃ -CH ₂ -O-CH ₃ 99-101

OH

CH ,.

I ^J

H ₃ CC- (CH ₂ ) ₃ -C ₂ H ₅ -CK ₂ -O-CH ₃ 94-96

OH compound number

R ²

5 Melting point (° C)

32 CH. 1 H ₃ CC- (CH ₂ ) ₂ - OH -ch ₃ -CH ₂ -O-CH ₃ 105-107 CH ₃ j 33 H ₃ CC- ( _C H ₂ ) ₄ - -c ₂ h ₅ -CH ₂ -OC ₂ H ₅ 68 - 70 1 OH CH. I ³ 34 h ₃ cc- (ch ₂ ) ₄ - -ch ₃ -CH 2 O-C 6 83 - 85 Oh Γ ³ 35 H ₃ CO- (CH ₂ ) ₂ - -CH ₃ - (CH ₂ ) ₄ -C-CH ₃ 63 - 65

OH

CS 272798 £ 2 compound number melting point (° C)

36 h ₃ cc- (CH ₂ ) ₄ -OH -CH ₃ - (CH ₂ ) ₂ -O-CH ₃ 98-99 ch ₃ i ^J • 37 1 h ₃ cc- (ch ₂ ) ₄ - -C ₂ H ₅ - (CH ₂ ) ₂ -O-CH ₃ 71

Okay

CH.

38 h ₅ c ₂ -o- (ch ₂ ) ₂ - -ch ₃ - (CH ₂ ) ₄ -C-CH ₃ 1 OH 77 - 79 ³⁹ ch ₃ ! H ₃ CC - (CH ₂ ) ₄ - I -ch ₃ - (CH ₂ ) ₂ -OC ₂ H ₅ 75 40 1 OH ch ₃ 1 h ₃ cc- (ch ₂ ) ₄ - -c ₂ h ₅ - (CH ₂ ) ₂ -oc ₂ h ₅ 52-54 1 OH

CS 272798 ⁵² compound number melting point (° C) ch ₃

H ₃ CO- (CH ₂ ) ₃ - -CH ₃ - (CH ₂ ) ₄ -C-CH ₃ 45-47

OH

CH42 H ₃ CC- (CH ₂ ) ₄ - -CH ₃ - (CH ₂ ) ₃ -O-CH ₃ 83-84

OH ch ₃ l

H ₃ CC - (CH ₂ ). _4- -C ₂ H ₅ - (CH ₂ ) ₃ -O-CH ₃ 72-73

OH

CH,

AND

H, CO- _(CH?) I

OH

-CH ₃ -CH ₂ -O- (CH ₂ ) ₂ -O-CH ₃ 88-89 Compound No. ^K

CS 272298 B2 melting point (° C)

CH. 1 45 H ₃ CC- (CH ₂ ) ₄ -C ₂ H ₅ -CH ₂ -O- (CH ₂ ) ₂ -O-CH ₃ oil 1 OH ch ₃ 46 H ₃ CC- (CH ₂ ) ₂ - -C 4 -CH ₂ -O- (CH ₂ ) ₂ -O-CH ₃ 97-98 OH CH I ³ 47 H ₃ CC- (CH ₂ ) ₄ - -CH ₃ - (CH ₂ ) ₂ -O- (CH ₂ ) ₂ -OC H ₅ oil OH Γ ³ 48 H ₃ CC- (CH ₂ ) ₄ - " ^C 2 ^H 5 - (CH ₂ ) ₂ -O- (CH ₂ ) ₂ -OC ₂ H ₅ oil

OK compound number ³ temperature. melting point (° C)

CHCH 49 H, C-C-CH, I

OH

-CH ₃ - (CH ₂ ) ₄ -C-CH ₃

1h

- 67

CH,

AND

H ₃ CC- (CH ₂ ) ₄ - -ch ₃ -ch ₂ -ch ₂ -ch ₂ -oh • OH

- 80

CH 51 H ₃ CC- (CH ₂ ) ₄ - -CH ₃ - (CH ₂ ) ₄ -C-CH ₃ oil

OH

CH52 E ₃ CO- (CH _{2) 4} I,

OH

OH '. AND

-CH ₃ - (CH ₂ ) ₄ -CH-CH ₃ ¢ 9-71 compound

Melting point number (° C)

CH.

H ₃ CC- (CH ₂ ) ₄ - -CH ₃ (CH ₂ ) ₄ -C-CH ₃ oil

OH

OH

CH54 C H-CH- _{(CH2) 4} - ₃ -GH

- (CH ₂ ) ₄ -C-CH ₃ oil

OH

H ₃ CC- (CH ₂ ) ₄ -CH ₃ - (CH ₂ ) ₂ -CH-OH ₂ ^{116-118 0H} OH OH

CH.

H ₃ CC- (CH ₂ ) ₄ ch ₃ -ch ₂ -ch-ch ₂

105-107

OH

OH OH

Pharmacological testing, 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 here in particular to the capillary bed through which the neighboring tissue exchange by a substrate that 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 (pOg) 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 an experiment described by DV LBBERS (Prog. Resp. J (Karger, Basel 1969)). 136-146) and III. KESSLER (Prog. Resp. Res. 2. (Karger, Basel 1969), pp. 147-152 and Anesthesiology 45 (1976), p. 184), using Pentoxifylline as a comparative standard preparation.

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 of the preparation and Arteria femoralis for measuring blood flow and appropriate cannulas are inserted. The animals were given Alcuronium chloride (0.1 mg / kg iv, and then 0.05 mg / kg ip every 30 minutes) for relaxation, and artificial respiration was introduced to prevent spontaneous muscle contraction with a negative effect on the measurement of 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 attached to the exposed muscle area to continuously register the partial oxygen pressure. Once the oxygen partial pressure curve has stabilized, the Arteria femoralis is closed with a clamp, whereupon the oxygen partial pressure in the muscle supplied by the vessel decreases rapidly and then slightly increases again due to spontaneous opening of the collateral vessels and finally settles at a value substantially lower. compared to healthy muscle. At this point in time, the test substance is administered in aqueous solution either by intravenous infusion (i.v.) (0.6 mg / kg / min) or at a dose of 25 mg / kg intraduodenally (i.d.) and the increase in partial pressure of oxygen in the ischemic muscle is measured. Each time before and after the closure as well as after 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. (N, Y.) 31 (1933), p. 141 et seq.), By 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 mg / kg ip) again using 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 percent increase in heat conduction value after administration of the formulation represents a measure of improved 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 were performed and the mean percent increase in brain blood flow was determined from the measured values obtained.

3. Acute toxicity:

Determination of LD 50 values is performed by standard methods using mortality observed over 7 days in mice (NMRI) following a single intravenous (ivv) or intraperitoneal (i.p.) administration.

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 Mouse Mice Compound Closure Toxicity ^Model

number route of administration: i.v .: 0.6 mg / kg / min i.d .: 25 mg / kg efficiency index W (cf. page 58) LD ₅₀ (wash in mg / kg 3 i. V. 1650 i.v .: 100-20 i.d. 1250 4 i. V. 1300 i.v .: 100-200 5 i.v. (0.3 mg / kg / min) 2080 i.v .: 1504300 i.d. 2909 i.p .: 300-600 6 i.d. 700 i.v .: γ 200 8 i.v. 1400 i.v .:> 200 10 i.d. 1965 i.v .:> 200 12 i.v. 866 i.d. 2337 i.v .:> 200

merge- closure model toxicity nina. number route of administration: i.v .: 0.6 mg / kg / min i.d .: 25 mg / kg efficiency index (cf. page 58) W LD ₅₀ (mouse) in mg / kg 14 i.v. 960 i.v. :> 200 16 i.V. 999 % i.p. : 150-300 17 ' i.v. 1525 i., v. :> 200 18 i.v. 1578 i.v. : 100-200 28 i.d. 2100 i.v. :> 200 32 i.v. 2650 :> 200 i.v. X.d. 566 37 i. V. 1400 i.d .. 950 i.v. > 200 39 i.v. 1567 i.d. '1996 · i.v .: > 200 44 i.v. 1199 i.v .: > 200 50 i.v. 2631 · i.d. 733 i.v .: > 200 Pentoxy- fyllin i.v. 891 i.v .: 187-209 i.d. 643 i.p .: 219-259

and

Table 3 Effect on regional blood supply to the brain of narcotized cats after intravenous administration 3 mg / kg and acute mouse toxicity toxicity LD ^ _Q in mg / kg compound number median brain blood increment ΔΆ in% ek projako 3 15.5 - Example: 100 - 200 9 9.4 i.v .: 100-200 16 25.8 - i.p .: 150-300 17 9.4. i .:> 200 18 9.4 i.V. 100 - 200 22nd 12.0 i.v .:> 200 27 Mar: 10.3 i.v .:> 200 43 19.8 i .:> 200 48 14.6 i .:> 200 pentoxi- fyllin 8.6 i.v .: 187-209 i.p .: 219-259

(mouse)

Λ.

CS 272798-2

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

Today, it is well known that a drug that exclusively acts to augment blood vessels or compositions with a very potent vasodilator component of action is unsuitable for the treatment of microcirculation disorders, since, on the one hand, the physiological vasodilatory reserve is usually completely depleted, while on the other thus, the danger of Steale's phenomenon, which means a harmful redistribution of the nutritional blood flow 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 _r up to a concentration of 100 [mu] g / ml, while Pentoxifylline extends over a concentration range of 10 to 100 [mu] g / ml, depending on the dose of 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. Quench If in fact the animals for 5 weeks by compound number 5, wherein the daily administered intraperitoneally to each of 3 mg / kg / ip, it was possible using the histochemical staining method demonstrated that: ^- both the examined muscles of the ischemic leg (tibialis anterior and extensor digitorum longus), the proportion of oxidized fibers increased substantially. In contrast, Pentoxyfillin did not show any direct effect on muscle metabolism in a comparable experiment conducted in the same manner.

The predominance of the xanthines of Formula 1 has also been shown in another bhronic assay to investigate the effect of the contractility of the ischemic skeletal muscle of rats with ligated true Arteria femoralis. 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 ischemic muscle fatigue in electrical irritation is then determined with about 80 contractions / min contraction intensity decrease after 1, 15 and 40 minutes of stimulation compared to untreated control animals. In doing so, for example, Compound No. 5 apparently results in a significant improvement in muscle performance in the ischemic limb as a result of optimized metabolism, even achieving normal contractility values as in the left healthy (non-ischemic) muscle of untreated animals. This improvement coincides with increased control of mitochondrial respiration (RCR = Respirators Control Rate). 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 muscular energy metabolism disorders of various origins, in particular mitochondrial myopathies.

SUBJECT OF THE INVENTION

Claims (5)

A process for the preparation of a tertiary hydroxyalkylxanthine of the general formula I in which at least one of the radicals R 1 and R 2 represents a tertiary hydroxyalkyl group of the general formula Ia R ⁴ - (CH ₂ ) _n -C-CH ₃ (1a) OH where R ⁴ represents an alkyl group having up to 3 carbon atoms and n is an integer from 2 to 5, and if only one of R ^ or fP represents such a tertiary hydroxyalkyl group of formula Ia, the other of these is hydrogen or an aliphatic hydrocarbon group R s of up 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 by at least 2 carbon atoms from the ring nitrogen atom, and R is C 1 -C 4 alkyl, characterized in that the 3-alkylxanthines of formula II are reacted in which o R is as defined above, A represents a hydrogen atom, an R R group as defined above, or an oxoalkyl group of formula IIIa or IIIb - (CH ₂ ) n - CO - CH ₃ - (CH ₂ ) _n - CO - R ⁴ (IIIa) (IIIb) and B is hydrogen, R, benzyl, diphenylmethyl or oxoalkyl of formula IIIa or IIIb, wherein: R ⁴ , R ⁶ and n are as defined above and at least one of A and B is an oxoalkyl group of formula IIIa or IIIb, in anhydrous form. solvents such as ethers, aliphatic or aromatic hydrocarbons, tertiary amines, aprotic solvents, and mixtures thereof at temperatures between -20 ° C and +100 ° C with one to two moles of the corresponding C 1 -C 3 alkyls, such as alkyl lithium - or alkylmagnesium derivatives, by reductive alkylation of carbonyl groups followed by reductive cleavage of group B, where this group represents a benzyl group or a diphenylmethyl group, by chemical reduction or catalytic hydrogenolysis at atmospheric pressure or at a pressure of up to 1.0 MPa at 20 to 100 ° C, or hydrolytic elimination of the alkoxymethyl or alkoxyalkoxymethyl radical from the group B position under acidic conditions at temperatures below 100 ° C and alkylation of position 1 or position 7 when A or B is hydrogen by treatment with alkylating agents of formula IV ), in which X represents a halogen atom, a sulfonic acid ester residue or a phosphoric acid ester residue and Q represents a tertiary hydroxyalkyl group of the formula I and or a group R ^ in aprotic organic solvents, alcohols, aromatic or halogenated hydrocarbons, pyridine, optionally also in a mixture with water, at a reaction temperature between 0 ° C and the boiling point of the reaction medium. 2. A process according to claim 1, wherein the corresponding compounds of formula (II) and (IV) are used as starting materials to produce compounds of formula (I): Wherein R is methyl or ethyl, and R and R are as defined in point 1, wherein only one of the two substituents R 1 or R 2 is a tertiary hydroxyalkyl group of formula (Ia) as defined in point 1. 3 .. A method according to claim 1 or 2, characterized in that starting from a corresponding compound of formula II and IV to give compounds of formula I wherein R \ R ² and R are as defined in paragraph 1 or 2, wherein R 6 or R 6 represents a C (R) -hydroxy- (R) -1-methylpentyl, -hexyl or -heptyl group. 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 produce compounds of the formula I in which R ¹ represents a tertiary hydroxyalkyl group of formula Ia, wherein: preferably R1 is / ((R) -1) -hydroxy- (C1-l) -methyl) pentyl, i -hexyl or -heptyl, R is methyl or ethyl and R is alkyl of 1 to 4 carbon atoms, hydroxyalkyl of 1 to 4 carbon atoms or alkoxyalkyl of 1 to 4 carbon atoms 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: Wherein R is a 5-hydroxy-5-methylhexyl group, R is a methyl group, and R 1 is an ethoxymethyl group.