CS272800B2 - Method of tertiary hydroxyalkylxantine 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) * Compounds of formula I wherein at least one of R 1 and R ³ is a target. hydroxyalkyl group of formula Ia "( ^c H2) n" G (R 4) (OH) -CH 3, wherein R ⁴ represents C 1-3 -alkyl and n is a number from 2 to 5, and when only one of R 1 or R ³ represents a group of formula Ia then the other is H or an aliphatic hydrocarbon group R5 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 or up to two hydroxy groups, said oxo and hydroxyl groups being from the nitrogen atom in The ring is separated by at least 2 carbon atoms and R ³ is C 1-4 -alkyl, prepared by hydrating the 3-alkylxanthines of formula II, wherein A is a hydrogen group R ⁵ or an alkenyl group of formula III - (CH 2) _n -l -CH = C (R ⁴⁾ -CH 3, 'B represents hydrogen; R ^5' benzyl, diphenylmethyl, or a group of the formula III, wherein at least one of a and B represents an alkenyl group of formula III, which may contain a double bond -C = C- also in positional i somatic arrangements on a branched carbon atom, under acid catalysis and subsequent reductive cleavage of residue B; when it is benzyl or diphenylmethyl; or optionally 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 1 or 7) when A or B is H ^; by treatment with alkylating agents XQ, wherein X is a halogen or a sulfonic or phosphoric acid ester residue and Q is a target.

hydroxyalkyl group or a group of formula Ia ^with R / in aqueous solution or suspension in the presence of strong acids' at a reaction temperature between O ° C and 60 ° C according to the Markovnikov's rule. The compounds produced can be used as medicaments, in particular for the treatment of peripheral and cerebral blood flow disorders.

CS 272 800 B2

The present invention 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 perfusion disorders. 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 which They are effective in promoting blood circulation. Within this class of substances, the vasotherapeutic Pentoxifylline, ie, 3,7-dimethyl-1- (5-oxohexyl) xanthine, was not of 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, IVschr. 111 (1981); pp. 637-640). today, for example, it has taken a firm place in many countries among drugs used to treat peripheral arterial occlusion; whereas in other countries 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 its first as well as the pharmacologically active metabolite, i.e. 1- (5-hydroxyhexyl) -3,7-dimethylxanthine, are subject in the body animal and human rapid and complete biotransformation, which occurs almost exclusively through the enzymatic oxidation of αχό- or hydroxyhexyl side chain and is associated with a pronounced first-pass effect (the so-called first-paas effect). I.e; that, first of all, 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, i.e. the most important organ for foreign substances systemic, large bloodstream only a certain portion of the drug in unchanged form. The effect of the first pass, also referred to as presystemic elimination, thus leads to a decrease in the systemic utility of the unchanged active ingredient. The inherent disadvantage of the pronounced effect of the first passage is not that the oral dose is reduced by way of systemic circulation, but that this passage generally exhibits considerable intra- and inter-individual variability (cf. Schweiz. Med. IVschr. 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 completely negligible first-pass effect ”and which would consequently significantly improve the certainty of treatment; regarding the dosing 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 established; that the unexplored branching of the alkyl moiety of the secondary hydroxyalkyl group on the hydroxyl-bearing carbon atom independently of its position on the xanthine skeleton at position 1 and / or 7 results in compounds whose hydroxyalkyl side chain now with tertiary alcohol structure is stable to polyfunctional microsomal liver oxidases ; and which also meet the other therapeutic requirements set forth above.

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

-ί '<

CS 272 800 82

^{ν θ} ** 13 wherein at least one of R and R represents a tertiary hydroxyalkyl group of formula Ia

R ⁴

AND

- (CH ₂ ) _n -C-CH ₃ (Ia)

OH where

R ⁴ represents an alkyl group of up to 3 carbon atoms and n represents an integer from 2 to 5

3 and if only one of the radicals R or R represents such a tertiary hydroxyalkyl group of the formula (Ia), the other radical is a hydrogen atom 5 or an aliphatic hydrocarbon group R having up to 6 carbon atoms, the carbon chain of which is optionally interrupted by up to 2 atoms oxygen or optionally substituted by one oxo group or up to two hydroxyl groups, the oxo group and the 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 by hydrating the 3-alkylxanthines of formula II

(II) in which 2

R is as defined above,

A represents a hydrogen atom, a group or an alkenyl group of the formula III ( ^CH 2) n - ^CH = C - ^CH 3 (III)

3?

CS 272 800 B2 where

R ⁴ and n are as defined above, and

B is hydrogen, R ⁵ / benzyl group, diphenylmethyl group or an alkenyl group of formula XII / wherein R and n are as defined above, and at least one of A and B represents an alkenyl group of formula III 'which may contain a double bond -C = Also in positional x-isomeric arrangements on a branched carbon atom, under acid catalysis and subsequent reductive cleavage of residue B, when this residue is benzyl or diphenylmethyl / chemical reduction or catalytic hydrogenolysis at atmospheric pressure or at pressure up to 1.0 MPa at a temperature of from 20 to 100 ° C, or optionally hydrolytic elimination of the alkoxymethyl or alkoxyalkoxymethyl residue from the position of residue B under acidic conditions at temperatures below 100 ° C and alkylation of position 1 or position 7 when A or B is hydrogen, 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 at temperatures between 20 and 130 ° C, by the action of alkylating agents of formula IV

X-Q (IV) wherein

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

O represents a tertiary hydroxyalkyl group of the formula Ia or R in aqueous solution or suspension in the presence of strong acids such as sulfuric acid, nitric acid, phosphoric acid or also hydrohalic and sulfonic acids, acid ion exchange resins, boron trifluoride complexes or oxalic acid, at a reaction temperature between 0 ° C and SO ° C according to Markovnik's rule.

Preferably, the process of the present invention produces compounds of formula I wherein R is methyl or ethyl and only one of the two R 3 or R 3 is a tertiary hydroxyalkyl group of formula Ia.

3

Preferably, compounds of formula (I) are prepared in which R or R represents a ((n-1) hydroxy - (- (1 -)) pentyl) pentyl, n -hexyl or -heptyl 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 ⁴ is ((w-1) hydroxy (n-1) methyl) R ² is methyl or ethyl, and R is C 1 -C 4 alkyl, C 1 -C 4 hydroxyalkyl, or C 1 -C 4 alkoxyalkyl; alkoxy and alkyl moieties.

Preferred compounds of formula I also include those in which R R is a known 5-hydroxy-5-methylhexyl group. R is a methyl group and R is an ethoxymethyl group.

13

The groups selected for R in the R or R position are, for example, methyl / ethyl, propyl, xsopropyl, butyl, isobutyl, pentyl and hexyl, their hydroxy and oxo derivatives, the hydroxy or oxo group being separated from these nitrogen atoms by at least two carbon atoms, such as a hydroxyethyl group,

2- and 3-hydroxypropyl / 2/3-dxhydroxypropyl, 2-, 3- and 4-hydroxybutyl, 2-hydroxy-2-methylpropyl / 3/4-dihydroxybutyl; 4,5CS 272 000 B2 optionally 3,4-dihydroxypentyl, 5,6- or 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, methoxyothyl and methoxypropyl, othoxymethyl, othoxyethyl and ethoxypropyl, propoxymethyl and propoxyethyl, methoxyethoxymethyl and methoxyethoxyethyl, and ethoxyethyl and an ethoxyethoxyethyl group.

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 of the formula III or only one group of formula III and in this case the second substituent represents a hydrogen atom, or a group R ³ or a group R 6, where the group R has the same meaning as the group R 0 or a benzyl group or a diphenylmethyl group in an acid-catalysed structural element of formula III which conforms to the Markovnikov rule, to form xanthines of formulas Ib to 1f:

and? - N

CS 272 800 B2

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

X - Q. (IV) '

X is as defined above; and

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

3-alkylated mono- or dialkenylxanthines of the general formula II, in which R 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, in which case the second hydrogen, n or R or R, wherein R has the same meaning as c

R or is benzyl or diphenylmethyl; which are required as starting materials, are either known compounds 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 haloalkenes of formula V

Χ- (0 ^Η 2) π_ ₁ - ^0Η = C - CHg (V) in which

X, R and n are as defined above (cf., for example, DE-OS 27 14 953).

Addition of water to the double bond OC- alkenylxanthinů of formula II wherein R has the above meanings, ^- and A and B represent two identical or different groups of the formula III, or only one of A and B represents a group of formula III, and in this case, the second substituent is hydrogen or R ⁵ or R ⁵ , where R ⁵ has the same meaning as R ⁵ or is benzyl or diphenylmethyl, ⁵ corresponds to the Markovnikov rule according to which the hydroxyCS 272 800 B2 group enters the carbon atom s fewer hydrogen atoms to form tertiary alcohols; it can be carried out, for example, in an aqueous solution or suspension in the presence of strong acids, such as sulfuric acid, nitric acid or phosphoric acid. Hydrogen halides and sulfonic acids such as trifluoromethylsulfonic acid, ion exchange resins in the H ⁺ -cycle, boron trifluoride complexes or oxalic acid are also used as catalysts. Preferably, however, the reaction is carried out in sulfuric acid, with sulfuric acid concentrations of from 50 to 85% and temperatures of from 0 ° C to 10 ° C being generally sufficient. Depending on the circumstances, it is also possible to work at lower or higher acid concentrations and / or at lower or higher reaction temperatures. In any case, however, the reaction temperature should be kept as low as possible, observe disturbing back dehydration to olefin.

The addition of an acid-inert solvent such as 1,4-dioxane, benzene or toluene also has advantages. Since acid-catalyzed hydration, especially when using higher acid concentrations, may give rise to esters, it is recommended to add large amounts of water to the reaction mixture after acid treatment to hydrolyze the ester under brief heating or to treat the reaction mixture under alkaline conditions.

Reductive cleavage of the beznyl group and the diphenylmethyl group from the compounds of formula (Ie) to produce xanthine derivatives of formula (1f) which contain a hydrogen atom at the 7-position; is carried out under standard conditions; which have been developed primarily in the context of the technique of protecting groups in the synthesis of alkaloids and peptides, so that 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), pp. 974-975), the elimination of both of the above aralkyl groups by catalytic hydrogenolysis in the presence of noble metal base (cf. Houben-Weyl, 3V. XI / 1 (1957); pp. 988-971 and vol. IV / 1c, part 1 (1980), pp. 400-404). The oak reaction medium is usually a lower alcohol (optionally with 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. Suitable hydrogenation catalysts are, in particular, palladium black and palladium on activated charcoal or barium sulfate, while other precious metals such as platinum ^1, rhodium and ruthenium frequently have a tendency toward side reactions because of the competitive hydrogenation of the nucleus, 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 elevated pressure up to about 10 bar, 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 alkoxyalkylaxymethyl group in the R-position are představ, Ν-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); wherein 7H-derivatives of the general 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. Particularly alkoxyalkoxymethyl derivatives can also be cleaved with Lewis acids; such as zinc bromide and titanium tetrachloride, in an anhydrous medium, preferably in dichloromethane or chloroform, wherein the intermediate 7-bromomethyl or 7-bromosine derivatives formed are hydrolyzed spontaneously in connection with the

CS 272 300 B2. When cleaving in a mineral acid-containing solution, 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 xynthin derivatives of formula (IX) with the corresponding alkylating agents of formula (IV) is generally carried out in a diluent or solvent; which is inert to the reactants. Oako such are in particular dipolar, aprotic solvents / for example formamide; dimethylformamide; dimethylacetamide, N-methylpyrrolidone, tetramethylurea, hexamethylphosphoric triamide, dimethylsulfoxide, acetone or butanone, however, alcohols such as methanol, ethylene glycol and its mono- or dialkyl ethers thereof may also be used, the alkyl group having 1 to 4 carbon atoms; and both together have, however, no more than 5 carbon / ethanol atoms, 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, hydroxides; alkali and alkaline earth metal 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 an alkali metal salt, an alkaline earth metal salt, or in the form of optionally substituted ammonium or phosphonium salts; for said 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 or alkaline earth metal salt, while 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, methyltrioctylphosphonium salts, methyltrioctylphosphonium salts, methyl-trialkylammonium salts of 1 to 4 carbon atoms in alkyls, myristyl (C 1 -C 4) alkyl (C 1 -C 4) alkyltralkylammonium salts and (C 1 -C 4) banzyltrialkylammonium (C 1 -C 4) alkyl; furthermore, cetyltrimethylammonium salts as well as alkyltriphenylphosphonium salts of 1 to 12 carbon atoms in the alkyl moiety and benzyltriphenylphosphonium salts, with those compounds having a larger and symmetric cation generally proving to be more effective.

The introduction of the groups of the formula Ia as well as the groups R and R 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; 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.

3

In compounds in which one of the substituents R and R is a dihydroxyalkyl group, the dihydroxyalkyl group can be built 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 ⁴ (at least 2 carbon atoms) and / or the structure of the substituent R ⁵ (e.g. 2-hydroxypropyl) and are therefore present. stereoisomeric forms. The invention therefore relates to both pure stereoisomeric compounds and mixtures thereof.

The xanthine derivatives of the formula (I) according to the invention are suitable on account of their valuable pharmacological properties and favorable metabolic properties,

CS 272 800 B2, for example, against polyfunctional microsomal liver oxidases, ^{1 in} an excellent manner for use as an active ingredient of medicaments, in particular those which allow for more effective prophylactic and curative treatment of peripheral and cerebral perfusion disorders such as peripheral arterial occlusion. 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, dragees, (micro) capsules, suppositories, syrups, 'emulsions,' suspensions, 'aerosols, drops or injectable solutions in the form of ampoules, as well as sustained-release formulations. "whose manufacture usually involves excipients; as carriers, disintegrants, binders, coating agents; botnadsl; lubricants and lubricants, flavorants, sweeteners or cosolvents. 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 vicocarboxylic alcohols.

Preferably, the pharmaceutical compositions are prepared and administered in unit dosage form, each unit containing as an active ingredient a dose of the compound of Formula I. For solid dosage units such as tablets, capsules and suppositories, this dosage may be up to 1000 mg, but preferably 100 to 600 mg, and for injection solutions in ampoule form, up to 300 mg; however, it 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 ingredient, preferably 300 to 900 mg, for oral administration of 10 to 500 mg, preferably 20 to 200 mg, for intravenous administration are indicated to humans. However, depending on circumstance 3e, they may also administer higher or lower doses daily. The daily dose can be administered either as a single administration in the form of a single dosage unit or 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, antihyperlipidomics, analgesics, sedatives, antidepressants, antianginal agents, cardiotonics, antiarrhythmics, diuretics, including antihypertensives. calcium channel, 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 spectra. The compounds prepared according to the following examples, as well as the compounds produced in an analogous manner, are summarized in Table I.

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 by using a water pump.

Example 11 1- (5-hydroxy-5-methylhexyl) -3,7-dimathylxanthine (Compound No. 14)

(a) 3,7-dimethyl-1- (5-methyl-4-hexenyl) xanthine

CS 272 800 82

3.0 g (0.05 mol) of 3/7-dimethylxanthine, 8.0 g (0.06 mol) of 1-chloro-5-methyl-4-hexene and 8.3 g (0.05 mol) of carbonate The reaction mixture was stirred at 110 ° C for 22 hours in 200 ml of DMF.

After removal of the solvent under reduced pressure, 100 ml of 1N sodium hydroxide solution were added to the residue, and the reaction mixture was extracted thoroughly with dichloromethane. The extract is extracted again with dilute sodium hydroxide solution, washed with water until neutral, dried, evaporated under reduced pressure and the residue recrystallized from diisopropyl ether.

Yield: 10.1 g (73.1% of theory);

Analysis for:

14 ^ 20 ^ ^Η 4θ2 (MW = 276.3) calculated 50.85% C, 7.30% H / Nj 20.27% Found 60.50% C, 7.24% H, 20.32% N .

b) 1- (5-hydroxy-5-methylhexyl) -3,7-dimethylxanthine

H ₃ c-c OH

CH,

A solution of 3.5 g (0.034 mol) of the xanthines from step a) in 50 ml of dioxane and 50 ml of 50% sulfuric acid was stirred at 10 ° C for 24 hours. The reaction mixture was then made alkaline under ice-cooling with 2N sodium hydroxide solution and the product was carefully extracted with dichloromethane. The hexafluoromethane extract was washed successively with 1N sodium hydroxide solution and water, dried and evaporated under reduced pressure. The residue can be purified by recrystallization from a mixture of diisopropyl ether and isopropyl alcohol.

Yield: 7.8 g (77.9% of theory).

Melting point: 120 to 121 ^Q C

For ^C 14 ^H 22 ^N 4 ° 3 (molecular weight - 294/4) calculated C 57.13%, H 7.53%, N 19.03%;

Found: C, 57.21; H, 7.74; N, 18.78.

Alternatively, the title compound can be prepared from xanthines # 6 (cf. Example 9) and a methylating agent in an analogous manner to that described in step a).

CS 272 300 B2

Example 2

3-ethyl-1- (6-hydroxy-6-methylhoptyl) -7-methylxanthine (Compound No. 13)

30.4 g (0.1 mol) of 3-ethyl-7-methyl-1- (6-methyl-5-heptenyl) xanthine (prepared analogously to Example 1a) are allowed to react in 150 ml of dioxane and 50% acid each time. The reaction mixture is worked up to obtain an oily product which, after a long standing, crystallizes and recrystallizes from diisopropyl ether.

Yield: 25.7 g (79% theoretical)

Melting point: 8S to 87 ° C

Analysis for ^C] _G ^H 26 ^N 4 O3 ^(m ° l ^s to l ^u ° and the mass 322.4) calculated 59.81% C '8.13% H, 17.38% N;

found 59.68% c; 8. 16% H / 17.54% N.

Example 3 1- (4-hydroxy-4-methylpentyl) -3-methyl-7-propylxanthine (Compound No. 12)

After the reaction of 29.0 g (0.1 mol) of 3-methyl-1- (4-methyl-3-pentenyl) -7-propylxanthine in 150 ml of dioxane and 50% sulfuric acid each and after working up the reaction mixture in an analogous manner to as described in Example 1b, 26.3 g of crude product (85.3% of theory) are obtained, which can be purified by recrystallization from diisopropyl ether with the addition of a small amount of ethyl acetate at boiling point.

Yield: 23.4 g (75.9% of theory)

Melting point: 96-98 ° C

Analysis for ^C 24 ^H i5 ^N4 O3 (molecular weight 308.4) calculated 58 [42% C, 7.84% H; 18.17% N;

found 58, 49% c, 7.82% H, 18.99%.

Example 4 N- (5-hydroxy-5-methylhexyl) -3-methylxanthine (Compound No. 1)

CS 272 800 B2

A mixture of 26.2 g (0.1 mol) of 3-methyl-7- (5-methyl-4-hexenyl) xanthine in 300 ml of dioxane and 300 ml of 5U / l sulfuric acid is stirred at 30 ° C for 24 hours. The mixture was neutralized with ice-cold 2N aqueous sodium hydroxide solution, evaporated under reduced pressure and the residue was taken up in 1 l of hot 1M aqueous sodium hydroxide solution. The hot solution is filtered and, after cooling to room temperature, a 6N hydrochloric acid solution is added dropwise with stirring to pH 9. The precipitate is filtered off, washed neutral and dried under reduced pressure.

Yield: 19.6 g (69.9% of theory)

Melting point: 228-230 DEG C. Analysis of the ^A (MW 280/3) calculated 55.70% C, 7.19% H, 19.99% N S Found 55.50% C, 7.31% H, 19 , 92% N.

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

A mixture of 14 g (0.05 mol) of 7- (5-hydroxy-5-methylhexyl) -3-methylxanthine (Example 4) / 6.2 g (0.054 mol) of 1-chloro-5-hydroxy-5-methylhexane and 7 0.5 g (0/054 mol) of potassium carbonate in 300 ml of dimethylformamide was stirred at 110 DEG C. for 18 hours. The reaction mixture was filtered while hot and the filtrate was 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

For C ₂₀ ^H 34 ^W 4 ° 4 (MW 394/5) calculated 60.89% C, 8/59% H; 14/20% N;

CS 272 000 B2 found 60/89% C, ‘8/98% H / 14.17% N,

The title compound can also be prepared from 1- (7-bis- (5-methyl-4-haxenyl) -3-methylxanthine) by double addition of water in an analogous manner to Example 1b).

Example 6

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

g (0.14 mol) of 7- (5-hydroxy-5-methylhexyl) -3-methylxanthine (Example 4) was heated 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 under stirring for 8 hours at 130 ° C. After cooling and concentration under reduced pressure, dilute sodium hydroxide solution was added and then the mixture was carefully extracted with chloroform. The organic phase is washed with water until neutral, dried over sodium sulphate and evaporated under reduced pressure to an oily crude product which is most easily purified by filtration through a silica gel column using chloroform / methanol (25: 1) as eluent and stirring in diisopropyl ether.

Yield: 36.5 g (80.9% of theory)

Melting point: 59-60 ° C

Analysis for ^C] _G ^H 26 ^N 3 ⁰ 4 (MW »322/4) 59/61 Calculated% C, 8.13% H, 17.38% Found 59.43 Nj% C, 8.01% H, 17.29% N.

Example 7

7- (5-hydroxy-5-methylhexyl) -1,3-dimethylxanthine (Compound No. 4)

CH

CS 272 800 B2

From 27.6 g (0.1 mol) of 1,3-dimethyl-7- (5-methyl-4-hexenyl) xanthine with acid-catalyzed hydration analogous to that described in Example 1b) and recrystallization of the crude product obtained using isopropyl alcohol. and ether gives the pure title compound in a yield of 23.6 g (80.2% of theory).

Melting point; 10S to 107 ^Q C

Analysis for ^C 14 ^H 22 ^N 4 ° 3 (MW 294.36) calculated C 57.13%, 7/53% H / 19.03%. Found: C 57.39, H 7.67%. , 28% N.

Example 8

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

(a) 7-methoxymethyl-3-methylxanthine

and 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 g (0/5 mol) of ethoxymethylchloride was added with stirring) and the mixture was stirred at 110 ° C for 18 hours. Then the reaction mixture is filtered while hot, evaporated under reduced pressure, the residue is dissolved in 500 ml of 2N sodium hydroxide solution and the chloroform extraction is carried out in order to remove 1/7-dialkylated 3-methylxanthine which is formed as a by-product. The alkaline aqueous solution was adjusted to pH 9 by addition of 2N hydrochloric acid solution with stirring / the resulting crystallizate was filtered off; washed first with water to remove the chloride ions and then with methanone; and then dried under reduced pressure.

Yield: 77.6 g (69.2% of theory)

Melting point: 263-264 ° C

Empirical formula ^{C H} g] _2 ^N4 O3 (MW 224/2) and ₂₎ with ethoxymethyl 4-toluensulfonátemr (chloride using 4-toluenesulfonic acid and sodium acetate as starting materials)

104.9 g (u, 55 mol) of 4-toluenesulfochloride are dissolved in 100 ml of dimethylformamide and 45 ml (0.55 mol) of anhydrous sodium acetate are added under stirring and with ice-cooling. After stirring at room temperature for 1 h, 78.1 g (0/75 mol) of formaldehyde diethyl acetal are added dropwise to the reaction mixture. The reaction mixture was stirred again at room temperature for 1 hour, and then 33 g (0.5 mol) of 3-roethoxyixanthine was added. Thereafter, the reaction mixture is heated at 90 ° C for 2 hours without addition of the basic condensing agent / the precipitated product is filtered off cold; it is additionally washed with cold dimethylformamide and water to remove chloride ions / rinsed with methanol and recrystallized from diUS 272,000Bz of methylformamide.

Yield: 98.1 g (87) 5% of theory)

Melting point: 265 DEG C. and ₃ ) with othoxymethyl 4-toluenesulfonate (using 4-toluene-3-sulfonic acid with acetic anhydride as starting material)

Under 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 ° C for 30 min. 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 DEG C., 1SG, 1 g (1 mol) of 3-methylxanthine is 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) -7-ethoxymethyl-1- (5-methyl-4-hexenyl) -3-methylxanthine

to 11.2 g (0.05 mol) of 7-ethoxymethyl-3-methylxanthine in 300 ml of dimethylformamide were added 7.5 g (0.054 mol) of potassium carbonate and 7.2 g (0.054 mol) of 1-chloro-5-methyl -4-hexene and the mixture was heated to 110 ° C with stirring for 5 hours. The reaction mixture is filtered while hot, the filtrate is concentrated under reduced pressure, the residue is taken up in chloroform, the chloroform solution is washed first with 1N aqueous sodium hydroxide solution and then with water until neutral, dried over sodium sulphate, the solvent is distilled off under reduced pressure and recrystallized from petroleum ether.

Yield: 13.8 g (86.1% of theory)

Melting point: 53 ° C

Analysis for ⁽ -'jg ^ ¹ 24 ^N 4 ° 3 ( ^(η ° 1θΙ '^{; υ} 1 ° νέ weight 320.4)

H, 7.55; N, 17.49.

found: C 60.09, H 7.71, N 17/43.

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

CS 272 800 B2

The 15.0 g (0.05 mol) alkenylxanthine of step b) was reacted in 100 ml dioxane and 10 ml 50% sulfuric acid in the same manner as described in Example 1b) and then worked up. The solid residue obtained is recrystallized from diisopropyl ether with the addition of ethyl acetate and petroleum ether.

Yield: 13.5 g (79.8% of theory)

Melting point: 102-103 ° C

Analysis ^ΐ5 Η 26 ° ^{Κ θ} 4 4 (MW 338/4) calculated 55.79% C, 7.74% H /% N, 16.56;

Found: 55.75% C; 7.82% H / 16.59% N.

Example 9 1- (5-hydroxy-5-methylhexyl) -3-methylxanthine (Compound No. 5)

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

35.2 g (0.1 mol) of 7-oenzyl-3-methyl-1- (5-methyl-4-hexenyl) xanthine (made from 7-benzyl-3-methylxanthine and 1-chloro-5-methyl- The 4-hexene is analogously to Example 1a) or 8b) is stirred in a mixture of 200 ml dioxane and 200 ml 50% sulfuric acid for 24 hours at 10 ° C. The reaction mixture is then rendered alkaline with 2N aqueous sodium hydroxide solution with good ice-cooling and the product is carefully extracted with chloroform, the chloroform extract is washed first with 1N aqueous sodium hydroxide solution, then with water until neutral, dried / solvent distilled off under reduced pressure. The solid residue was recrystallized from ethyl acetate with the addition of petroleum ether.

Yield: 30.2 g (81/5% of theory)

Melting point: 109-111 ° C

For C 20 H 26 N 4 O 403 (MW 370.5) calculated 64.84% C / 7.0 /% H / 15.12% N;

found 65.00% C / 7.21% H / 15.24% N.

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

CS 272 SOO 02

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

Yield: 9, t> g (85.6% of theory)

Melting point: 102-193 ° C

Analysis for ^C] .3 ^H 20 ^N 4®3 ^(my - ⁰ to ^Lj l ^s and weight 280.3) calculated 55, '70% C, 7.19% H, 19.99% N;

found 55.63% C, 7, 30% H, 20.00% N.

b) hydrolytic dealkoxymethylation from 7-athoxymethyl-1- (5-hydroxy-5-methylhexyl) -3-methylxanthines of Example 8c) (Compound No. 5)

13.5 g (0.04 mol) of the xanthine derivative of Example 8c) in a mixture of 8 ml of 1N hydrochloric acid solution and 30 ml of glacial acetic acid are heated to 70 DEG C. for 2 hours with stirring, after cooling the reaction mixture is neutralized. sodium hydroxide solution and then the product was extracted with chloroform. The chloroform solution was dried, evaporated to dryness under reduced pressure, and the evaporation residue was filtered through a pad of silica gel, eluting with chloroform: methanol (10: 1) as the eluent.

Yield: 0.7 g (6u, 7% of theory)

Melting point: 191-192 ° C

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

Example 10

7- (3,4-dioxhydroxybutyl) -1- (5-hydroxy-5-methylhexyl) -3-methylxanthine (Compound No. 55)

a) 7- (3-Butonyl) -1- (5-hydroxy-5-methylhexyl) -3-methylxanthine

28/0 g (0.1 mol) of compound No. 6 (Example 9) was reacted with 15.3 g (0.11 mol)

97% of 1-bromo-3-butene and 15.2 g (0.11 mol) of potassium carbonate in 500 ml of dimethylformamide under the conditions described in Example 5. After completion of the reaction, the reaction mixture was worked up. The reaction product, without previous column chromatography, is obtained in pure form by a single recrystallization from ethyl acetate with the addition of petroleum ether at boiling point.

Yield: 26.9 g (80.4% of theory)

CS 272 600 B2

Melting point: 105-107 ° C

Summary pattern: C (molecular weight 334/4)

b) 7- (3/4-epoxybutyl) -1- (5-hydroxy-5-methylhexyl) -3-methylxanthine

15.8 g (0.078 mol) of 85% 3-chloroperbenzoic acid are added to a solution of 22 g (0.056 mol) of xanthine from step a) in 250 ml of chloroform under nitrogen atmosphere and stirring at room temperature over about 15 minutes. After stirring at room temperature for 43 hours, 10% sodium dithionite solution / 10% sodium hydrogen carbonate solution and water are added sequentially to wash, then the mixture is dried under vacuum and evaporated to give an epoxide in an oily product farm in almost quantitative yield. ( ^c 17 ^H 26 ^W 4 ° 4 'molecular weight - 350.4), which can be used immediately in the following. reaction step c).

c) 7- (3,4-dihydroxybutyl) -1- (5-hydroxy-5-methylhexyl) -3-methylxanthine (Compound No. 55)

A solution of 23 g (0.065 mol) of the compound of step b) and a mixture of 120 ml of tetrahydrofuran and 80 ml of water was stirred and stirred at room temperature with the addition of 0.4 ml (70%) of perchloric acid. After stirring at room temperature for 5 days, the mixture was neutralized with saturated sodium bicarbonate solution, the reaction mixture was evaporated in vacuo, the residue taken up in chloroform and the chloroform solution purified by silica gel column chromatography using 10: 1 chloroform / methanol as eluent. reagents.

Yield: 19.4 g (81% of theory)

Melting point: 116-118 ° C

Analysis for C 55 ^HggNN ^Og (MW 358/4) calculated 55.42% C / 7/66% H? 15/21% _of N Found 55.13% C,% H, 7/84; 14/98% N.

18.

CS 272 SOO 32

Example 11

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

A mixture of 23 g (0.1 mol) of the xanthine derivative of Example 9 (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 dimethylformamide is stirred at 11 ° C for 1 hour, the reaction mixture is filtered hot and the filtrate is evaporated under reduced pressure. The oily crude product which slowly crystallizes is purified preferably by filtration through a silica gel column using a 10: 1 mixture of chloroform and methanol, followed by recrystallization from ethyl acetate with the addition of petroleum ether at boiling point.

Yield: 25.1 g (73.6% of theory)

Melting point: 105 to 107 ° 0

Analysis for ^C ^ IQ ^H 5 ^N 4 ° 5 (molecular weight 254.4) calculated 54.22% C, 7.39% H, 15, '81% N;

found 53) C 37%, 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 number R ¹ R ² R ³ melting point ( 1 H -ch ₃ CH- 1 220 - Z - (CH ₂ ) 4 -C-CH ₃ and OH CH1 ³ f ^H 3 2 H ₃ C. -C- (CH _{2) 4} - OH -ch ₃ - (ch ₂ ) ₄ -c-ch ₃ 93-95 OH CH, 1 3 - ^C 3 ^H 7 -ch ₃ - (ch ₂ ) ₄ -c-ch ₃ 59 - 60

OH

CS 272 800 82 compound number melting point (° C)

-CH,

-CH,

CH,

AND

-Cch ₂ ) ₄ -c-ch ₃

OH

10S-107

CH, i ·

H ₃ CC- (CH ₂ ) ₄ OH

-CH ₂ • ch ₂ -oc ₂ h ₅

102-103

CH,

AND

H ₃ CC- (CH ₂ ) ₄ OH

-CH,

-H

192-193

CH,

I ³

H ₃ CC- (CH ₂ ) 4 OH

-CH,

II

CH ₂ -C-CH ₃

- 80

CH,

I ³ h ₃ cc- (ch ₂ ) ₄ 0Η

-CH,

OH

CH ₂ -CH-CH ₃

119-120 ^{10 H} 3 '

CH, h ₃ c- (CH ₂ ) ₄ OH

CH,

¹³ c-ch ₂ -c- (ch ₂ ) ₄ oh

CH,

I ”

H ₃ CC- (CH ₂ ) 4 OH

CH, ³

HgCl FCH-C ^ Goh CH ₃ H ₃ CO- (CH _2);

OH

CHg

H ₃ C ₃ - (CH ₂ ) ₄ OH

-gh ₃

-CH,

-CH,

-CH, ^C 2 ^H 5

-CH,

- ^C 3 ^H 7

- 82

-ch ₃

- 84

CH,

I ³

-CH 2 -C-CH 3 or I

121 - 123

- ^C 3 ^H 7

- 98

-CH,

-ch ₃

- 37

120-121

CS 272 300 B2 compound number melting point (° C)

CH ₃ C - (CH ₂ ) ₅ OH

-ch ₃

-CH,

112-113

CH, h ₃ cL (ch ₂ ) ₅₀ °

-CH,

- ^C 3 ^H 7

92-94

CH, ³

H ₃ ^C -C- ( ^CH 2) ₄ OH θ 2 → 5

-CH,

9ti ^CH 3

H ₃ CC- (CH ₂ ) 4 OH " ^C 2 ^H 5" ^C 3 ^H 7

- 71

CH, h ₃ c-ch ₂ -c- (ch ₂ ) ₄ OH

-CH,

-c ₃ h ₇

- 87

CH,

I ^J h ₃ cc- (ch ₂ ).

OH

-CH,

-CH,

117-118

CH,

1 h ₃ c- (CH ₂ ) ₃ OH

- ^C 2 ^H 5

-CH,

- 95

CH,

I ^J

H ₃ CC - (CH ₂ ) ₃ OH 1

-CgHy

- 93

CH,

AND

H ₃ CC- (CH ₂ ) ₂

OH

-CH,

-CH,

146-147

CH,

I h ₃ cc- (ch ₂ ) ₂ 0 ° ^C 2 ^H 5

-CH,

122

CH,

I ³

H ₃ ce- (CH ₂ ) 20Η

-CH,

-c ₃ h ₇

135-137

CS 272 800 B2 compound _R 1 _R ² _R ³ melting number (_ ° C)

2S ' ^C 4 ^H 9

- ^C 4 ^H 9

CH, i

- (CH ₂ ) ₂ - c - CH ₃ OH

- 70

CH,.

I ^J h ₃ cc- (ch ₂ ) ₅ 0Η

-CH,

-ch ₂ -o-ch ₃

- 54

CH _{3 C -} (CH ₂ ) ₄ OH

CH,

I • ΟΙ

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

CH,

1 h ₃ cc- (ch ₂ ) ₃ OH ch ₃ h ₃ cc- (ch ₂ ) ₂ oh

CH ₃ h ₃ c- (CH ₂ ) ₄ I

OH

CH,

I ³ h ₃ c- (CH ₂ ) ₄ OH

H ₃ CO- (CH ₂ ) ₂ -

CH,

I ^J H ₃ CO- (CH _{2) 4} OH

-CH 2 ^C 2 ^H 5

-CH, ^C 2 ^H 5

-CH, θ2 ^ 5

-CH,

-OH,

-CHgO-CHg

-CH ₂ -O-CH ₃

-ch ₂ -o-ch ₃

-ch ₂ -o-ch ₃

-ch ₂ -o ~ ch ₃ .ο ₂ -ο-ο ₂ η ₅

-ch ₂ -oc ₃ h ₇

CH (oh ₂ ) ₄ -c- ₃

OH

-CH ₃ -ch ₂ ) ₂ -o-ch ₃

92-94

- 63

- 101

- 96

105-107

68-70

- 85

- 65

- 99

CS 272 800 B2 Compound _R 1 _R 2 Melting point number (° C)

CH, h ₃ c- (CH ₂ ) ₄ ' ^C 2 ^H 5

- (ch ₂ ) ₂ -o-ch ₃

OH h ₅ c ₂ -o- (ch ₂ ) ₂ -ch ₃

CH,

I ^J

- (ch ₂ ) ₄ -c-ch ₃

OH

- 79

CH,

I ^J H ₃ CO- (CH _{2) 4} OH

-CH ₃ - (CH ₂ ) ₂ -oc ₂ h ₅

CH,

I ^J h ₃ cc- (ch ₂ ) ₄ OH ^C 2 ^H 5

- (ch ₂ ) ₂ -oc ₂ h ₅

- 54 h ₃ co- (ch ₂ ) ₃ -ch ₃

CH,

I ^J ~ _{(CH2) 4-CH 3} -c

OH

- 47

CH,

1 h ₃ c- (CH ₂ ) ₄ OH

-ch _3- (ch ₂ ) ₃ -o-ch ₃

- 84

CH, h ₃ cc- (ch ₂ ) ₄ 0Η

-c ₂ h ₅ - (ch ₂ ) ₃ -O-ch ₃

- 73

CH,

1 h ₃ c- (CH ₂ ) ₄ OH

-CH ₃ -CH ₂ -O- (CH ₂ ) ₂ -O-CH ₃

- 89

CH,

I ³ h ₃ cc- (ch ₂ ) ₄ OH

-c ₂ h ₅ -ch ₂ -o- (ch ₂ ) ₂ -o-ch ₃ oil

4S

CH, h ₃ c- (CH ₂ ) ₂ OH

-c ₄ H _g -ch ₂ -o- (ch ₂ ) ₂ -o-ch ₃

- 98

CH,

1 h ₃ c- (CH ₂ ) ₄ OH

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

CS 272 800 B2 compound _R 1 ^ 2 number melting point (° C)

CH. I '

48 h ₃ cc- (CH ₂ ) ₄ -OH - ^C 2 ^H 5 - (ch ₂ ) ₂ -o- (ch ₂ ) ₂ - oc ₂ h ₅ oil ch ₃ I CH i ^J 49 1 H, C-C-CH AND OH -ch ₃ - (ch ₂ ) ₄ -c-ch ₃ 65 - 67 Oh ch ₃ 50 h ₃ ^c- c-Cch ₂ ) ₄ - -ch ₃ -CH ₂ -CH ₂ -CH ₂ -OH 78 - 80 OH CH, 0 51 η ₃ ο-ο- (οη ₂ ) ₄ -ch ₃ - (ch ₂ ) ₄ -CH ₃ oil OH CH i J OH 52 h ₃ cc- (ch ₂ ) ₄ -OH 0 -ch ₃ - (CH ₂ ) ₄ -ch-ch ₃ 69-71 CH i J 0 53 H ₃ C-N- _{(CH2) 4} - -ch ₃ ~ (CH £) ₄ -C-CH ₃ oil Oh OH I h ₃ c-ch- (ch ₂ ) ₄ - OH, 1 54 -ch ₃ - (ch ₂ ) ₄ -c-ch ₃ oil Oh 55 CH, I ³ h ₃ c- (CH ₂ ) ₄ -OH -ch ₃ - (CH 2) - CH-CH, <i <£ (i Z OH OH 116-118 53 ch ₃ h ₃ cc- (ch ₂ ) ₄ -oh -ch ₃ -CH, -CH-CH2.2 ₍ 2 OH OH 105-107 - Testing of pharmacological properties and results of pharmacological tests 1. Effect for peripheral arterial blood flow disorders The last decade has occurred in images of pathophysiology and tim even modicamentos treating chronic peripheral arterial occlusions to a remarkable turnaround in that the scientist- and therapeutic interest shifted in growing degree from macrocirculation to microcirculation and here especially to capillary bed through which nutrition occurs adjacent tissue

CS 272 800 82 by diffusion-mediated substrate replacement. As a consequence, microcirculation disorders exhibit deficiencies in the cellular supply and resulting 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 pressure of oxygen in ischemic skeletal muscle in the experiment described by D. W., LUBBERS (Prog. Resp. Res. 3 (Karger, Basel 1959, pp. 136-146) and M. KESSLER (Prog. Resp. Res. (Karger, Basel 1959), pp. 147-152 and Anesthesiology 45 (197S), p. 184). as a comparative standard preparation of Pentoxifylline.

Male Beagle dogs in natriumper.tobarbital anesthesia (35 mg / kg ip) were used as test animals in which Arteria femoralis and some leg area were released on the right hind limb and Vena femoralis was released on the left hind limb for infusion. specimen and Arteria femoralis for blood flow measurement 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 thereafter for relaxation) and artificial respiration was introduced to prevent spontaneous muscle contraction with a negative effect on the measurement of partial pressure of oxygen and aoy On the other hand, an even oxygen supply for breathing was ensured

Another carter attached to the femoral vein of the right hind limb served to control lactate concentration in the venous blood. The surface electrode is now connected to the exposed area of the muscle for continuous registration of the partial electrode ^. oxygen pressure. Oakmi le stabilizes the oxygen partial pressure curve, closes the Arteria femoralis with a clamp, whereupon the oxygen partial pressure in the muscle supplied by this vessel drops rapidly and then increases slightly again due to spontaneous opening of the collateral vessels and finally settles at a value that is considerably lower compared to healthy muscle. At this point, the test substance is administered in an aqueous solution either by intravenous infusion (iv) (0.6 mg / kg / min) or at a dose of 25 mg / kg intraduodenally (id) 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 Oako measurement parameter for the efficacy of the formulation serves in a single experiment to maximize the increase in oxygen partial pressure in% after drug administration during the vascular occlusion (n = 2-11).

of 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 response to the applied compounds and thus allows a more reliable comparison of the activity 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 flow to the brain is examined by the heat conduction technique of F.A. GIBBS (Proc. Soc. Exp. Biol. (N.Y.) 31 (1933)) 141 et seq .; H. HENSEL (Naturwissenschaften 43 (1956); p. 477 et seq.) And E. BETZe (Acta Neurol. Scand. Suppl. 14 (1965), p. 29-37) in cats of both sexes in natriumpentobarbital narcosis (35 mg / kg ip), ”again using the standard Pentoxifylline therapeutics for comparison purposes. In this method, it is determined by means of a heat conduction probe located on the surface of the brain in the area of Gyrus marginalis frontali3 the conduction of heat from the heating point to the adjacent temperature measuring point in the probe, which directly

CS 272 800 B2 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 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 are performed and the mean percent increase in brain blood flow is determined from the measured values obtained.

fi

3. Acute toxicity:

Values are determined by standard methods using mortality observed over 7 days in mice (NMRI) following a single intravenous (i.v.) or intraperitoneal (i.p.) application.

The results of these tests; which unequivocally demonstrate the predominance of the compounds of formula (1) produced by the process of the invention over the standard formulation of Pentoxifylline; The following tables 2 and 3:

Table 2

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

merge- nina number closure model Toxicity ^LD 5o ^(n, y in ^§ 'mg / kg route of administration: i.v .: 0.6 mg / kg / min i.d .: 25 mg / kg efficiency index W (cf. page 62) 3 i.v. 1650 i.v .: 100-200 i.d. 1250 4 i.v. 1300 i.v .: 100-200 5 i.v. (0.3 mg / kg / min) 2080 i.v .: 150-300 i.d. 2909 i.p .: 300-600 6 i.d. 700 i.v .:> 200 8 i.v. 1400 i.V .:> 200 10 i.d. 1965 i.v .:> 200 12 i.v. 866 i.d. 2337 EI: 200 14 i.v. 950 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 i.d. 566 i.v .: y 200 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. 2531 i.d. 733 i.v .:> 200

CS 272 800 B2 - nina cap model

i.v .: 0.8 mg / kg / min

i.d .: 25 mg / kg efficiency index W (cf. page 62) toxicity

LD ₅₀ (mouse) in mg / kg

Pentoxyfyllin i.v

891

i.v .: 187-209

i.d.

643

i.p .: 219-259

Table 3

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

compound number median increment of cerebral blood flow as Δλν% toxicil in and LD ₅₀ (mouse) mg / kg 3 15.5 i.v .: 100 - 200 9 9/4 i.v .: 100 - 200 16 25/8 i.p .: 150-300 17 9.4 i.v .: > 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.v .: > 200 48 14/6 i.v .: > 200 pentoxifyllin 8/6 i.v .: i.p .: 187 - 209 219-259

The distinctive predominance of the compounds produced by the process of the invention, in particular against Pentoxifylline (i.e., xanthine derivative), which is most commonly used to treat peripheral and cerebral blood flow disorders, can also be conclusively confirmed by other special experiments.

It is generally known that drugs which exclusively act to augment blood vessels or compositions with a very potent vasodilator component of action are unsuitable for the treatment of microcirculation disorders; whereas, on the one hand, the physiological vasodilatory reserve is usually completely exhausted; whereas, on the other hand, there is a danger of Steale's phenomenon which entails a harmful redistribution of the nutritional flow of blood in microcirculation resulting in a burden on already under-supplied diseased tissue. For these reasons, the inhibitory effect on vascular contraction induced on the isolated washed ear of a rabbit by norfenephrine was examined. In this case, for example, the compound number 5, up to a concentration of 100 [mu] g / ml, has no inhibitory effect against the effect of norfenephrine; whereas Pentoxifylline extends over a concentration range of 10 to 100 µg / ml depending on the vessel dose; which have been narrowed by the action of norfenephrine.

In a chronic experiment in rats with a one-sided closure of Arteria-iliaca, one can show; The compounds of formula (I) may have a beneficial effect on metabolism in ischemic skeletal muscle. Indeed, if animals are treated for 5 weeks with, for example, compound number 5 (3 mg / kg i.p.) are administered daily intraperitoneally, the histochemical staining method can be used to show that ische27 in both muscles examined.

CS 272 800 B2 limbs (Tibialis anterior and Extensor digitorum longus) significantly increased in the presence 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 xanthines of formula I has also been shown in another chronic test to examine the effect of contractility of the ischemic skeletal muscle of rats with ligated true Arteria femoralis. The animals are dosed for 20 days with the respective test preparation at a daily oral dose of 25 mg / kg via a gavage tube. Then, the degree of ischemic muscle fatigue under electrical irritation is determined with about 80 contractions / min contraction intensity decrease by 1; 15 and 40 minutes of stilumation as compared to untreated control animals. In this connection, 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 occurs concomitantly with increased control of mitochondrial respiration (PCR = Respiratooy 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.

Claims (5)

SUBJECT OF THE INVENTION 1. A process for preparing tertiary hydroxyalkylxanthinů general formula I wherein at least one of R and R represents a tertiary hydroxyalkyl group of formula Ia. _{(CH2) n -C-CH3} (Ia) OH where R is alkyl of up to 3 carbon atoms and n is an integer from 2 to 5, 13 and when only one of R or R is such a tertiary hydroxyalkyl group of formula (Ia); the other of these radicals represents a hydrogen atom or an aliphatic hydrocarbon group R 0 of up to 6 carbon atoms; the carbon chain of which 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 (a) CS 272 800 B2 R is C 1 -C 4 alkyl, characterized in that the 3-alkylxanthines of formula II are hydrated in which R is as defined above, A represents a hydrogen atom, an R group or an alkenyl group of formula III R ^{4 '} - ( ^CH 2) _{n -} 1' ^{CH = C-CH} 3 ( ¹ⁿ ) 'where 4 R and n are as defined above, and B represents a hydrogen atom, an R group, a benzyl group, a diphenylmethyl group or an alkenyl group of formula III, Wherein R, R and n are as defined above, and at least one of A and ES is an alkenyl group of formula III which may contain a -C = C double bond also in positional isomeric arrangements on a branched carbon atom under acid catalysis and subsequent reductive cleavage of residue B when it is benzyl or diphenylmethyl, by chemical reduction or catalytic hydrogenolysis at atmospheric pressure or at a pressure of up to 1.0 MPa at a temperature of from 20 to 100 ° C, or by hydrolytic elimination of an alkoxymethyl or alkoxyalkoxymethyl radical from the position of residue B under acidic conditions at 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 mixed with water, at a reaction temperature between 0 ° C and the boiling point of the reaction by treating with alkylating agents of formula IV X - Q (IV) in which X represents a halogen atom or a sulfonic acid ester residue or a phosphoric acid ester residue and Q represents a tertiary hydroxyalkyl group of the formula Ia or R in aqueous solution or suspension in the presence of strong acids such as sulfuric acid, nitric acid, phosphoric acid or also hydrohalic and sulfonic acids, acidic ion exchange resins, boron trifluoride complexes or acid oxalic, at a reaction temperature between 0 ° C and 60 ° C according to Markovnikov rule. 2. The process according to claim 1, wherein the corresponding compounds of the formulas II and IV are used as starting materials to give the compounds of the formula I in which: Wherein R is methyl or ethyl and R and R have the meanings indicated; 13, wherein only one of R or R is tertiary hydroxy 29 CS 272 800 B2 an alkyl group of the formula la as defined in point 1. 3. Process according to claim 1 or 2, characterized in that the corresponding compounds of the formulas II and IV are used as starting materials to produce the compounds of the general formula: Of formula I wherein R or R is / (C 1-6) hydroxy - (C 1-1) methyl) pentyl; -hexyl or -heptyl, wherein R and the remaining R or R are as defined in 1 or 2. 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 the radical is a tertiary hydroxyalkyl group of the formula Ia. R is methyl or ethyl, and R is C1 -C4 alkyl / hydroxyalkyl; R is methyl ([beta] - (1) -hydroxy- (tu-1) -methyl) pentyl, -hexyl or -heptyl, R is methyl or ethyl; C 1 -C 4 or C 1 -C 4 alkoxyalkyl in the alkoxy and alkyl moieties. 5. The method of item 4; characterized in that the corresponding compounds of the formulas II and IV are used as starting materials to form the compounds of the formula I; ve Wherein R is 5-hydroxy-5-methylhexyl, R is methyl and R is ethoxymethyl.