CS203068B2 - Process for preparing new derivatives of anhydrofuranose - Google Patents

Description

The present invention relates to a process for the preparation of novel anhydrofuranose derivatives of the general formula I

CH-A-O-CH

LIQUID LIQUID _from (I) where

R2 is hydrogen, alkyl, aminoalkyl, alkenyl of up to 4 carbon atoms, phenylalkyl of 1 or 2 carbon atoms in the alkyl moiety or alkanoyl of 1 to 4 carbon atoms, optionally hydroxy or alkanoyloxy of 1 to 4 carbon atoms, or halogen-substituted benzoyl or naphthoyl, alkylsulfonyl of 1 to 4 carbon atoms, toluenesulfonyl, pyridylcarbonyl, alkylcarbamoyl of 1 to 4 carbon atoms in the alkyl moiety or phenylcarbamoyl,

R3 is hydrogen, alkyl or alkenyl of up to 4 carbon atoms, optionally halogen-substituted phenylalkyl of 1 or 2 carbon atoms in the alkyl moiety, alkanoyl of 1 to 4 carbon atoms, or optionally hydroxyl or lower alkanoyloxy of 1 to 4 atoms a carbon or halogen-substituted benzoyl group and the group —A — O— represents a radical of the formula —CHOR 5 —CH 2 —O— or —CH 2 CHaOR 6 —O "in which:

R 5 and R 6, respectively, have one of the meanings given for R 3, or wherein -CH 2 OR 6 is hydrogen, or wherein two of R a, R 3 and R 5 or R 6 together represent an alkylidene or phenylalkylidene radical having from 1 to 4 carbon atoms; one of R 2, R 3 and R 5 or R 5 is other than hydrogen when the other two are hydrogen, with one of the radicals R 2 in the groups -CHOR 5 -CH 2 -O- in the meaning of the group -A-O- , R 3 and R 5 are other than methyl when the other two of these are methyl, and wherein in the compounds with -CHOR 5 -CH 2 -O- in the meaning of -A-O-, one of R 2, R 5 and R 5 is other than acetylo203068 if the other two of these radicals are an acetyl group, and wherein in the compounds with —CH (CH2 OR6) —O— in the sense of the group —A — O— one of the radicals R2, R5 and R6 is j other than benzyl when the other two of these are benzyl, and salts thereof.

Suitable lower radicals are, in particular, radicals having up to 4 carbon atoms.

Unless otherwise indicated below, each group has the number of carbon atoms in the chain equal to the number of atoms shown in Formula I.

The novel anhydrofuranose derivatives of the formula I are 1,5-anhydro-L- or -D-hexofuranose derivatives or 1,6-anhydro-L- or -D-hexofuranose derivatives, in particular 1,6-anhydro-1,2-D derivatives. -glucofuranose, 1,6-anhydro- [beta] -D-allofuranose, 1,6-anhydro-β-D-mannofuranose and 1,6-anhydro-.alpha.-idofuranose,

1,6-anhydro-α-L-gulose or the corresponding derivatives of 1,5-anhydroxylofuranose.

In particular, the alkyl radical R @ 2, R @ 3 and / or R @ 5 or R @ 8 is, for example, ethyl, isopropyl, straight or branched and in any position bonded butyl, and especially methyl or n-propyl.

Aminoalkyl group R2 is preferably a group in which the amino group can be a free amino group, a lower alkylamino group or a lower dialkylamino group such as 2-methylaminoethyl, 2-dimethylaminoethyl, 2-ethylaminoethyl and especially 2-diethylaminoethyl.

The alkenyl group R 2, R 3 and / or R 5 or R 6 is in particular alkenyl, for example isopropenyl, 2-methallyl, 3-butenyl and especially allyl.

Halogen is, for example, bromine and especially chlorine.

The alkoxy group is especially one in which the lower alkyl moiety has the meanings given for R2, R3 and / or R5 or 6R, as is the case for the ethoxy, n-propoxy, isopropoxy or, in particular, methoxy groups.

The acyl radical R @ 2, R @ 3 and / or R @ 8 and R @ 8, in particular, is an acyl radical of an organic acid and in particular an organic carboxylic acid radical. The acyl radical may in particular be an alkanoyl group, in particular an alkanoyl group such as acetyl or propionyl, or also an aroyl radical such as 1-naphthoyl or 2-naphthoyl, in particular benzoyl optionally substituted by halogen, lower alkyl, lower alkoxy, trifluoromethyl, hydroxyl or lower alkanoyloxy, such as salicyloyl or acetylsalicyloyl, as well as pyrldylcarboxylic, such as nicotinoyl, or it may also be an acyl radical of an organic sulfonic acid, such as an alkanesulfonic acid, especially a lower alkanesulfonic acid , such as methanesulfonic or ethanesulfonic acid, or arylsulfonic acid residue, especially phenylsulfonic acid, optionally substituted with a lower alkyl group such as benzenesulfonic acid or p-toluenesulfono acid as well as a carbamoyl radical, either unsubstituted or lower alkylcarbamoyl or arylcarbamoyl radicals, such as methylcarbamoyl or phenylcarbamoyl.

Ylidene radical of two radicals Rz, Rs and Rs or R6 is especially an ylidene group such as an alkylidene group, for example a methylidene, ethylidene or especially isopropylidene group, or a lower arylalkylidene residue such as a lower phenylalkylidene residue where the phenyl moiety is optionally substituted by lower alkyl, lower alkoxy, halogen and / or trifluoromethyl, and especially benzylidene.

Preferably, all of the foregoing and subsequent compounds of the anhydrofuranos derivative type are 1,6-anhydro- [beta] -D-glucofuranose derivatives.

The novel compounds have valuable pharmacological properties.

The anhydrofuranos derivatives according to the invention are particularly characterized by fibrinolytic and thrombolytic effects, as can be demonstrated in animal experiments, for example by oral administration of about 10 to 200 mg / kg, in particular about 10 to 100 mg / kg to rats. The fibrinolytic and thrombolytic effect is manifested in an experiment corresponding to the publication of M. Ruegg, L. Riesteter and R. Jacques in Pharmacology 4, 242-254 (1970) by reducing the dissolution time of the euglobulin clot.

In view of the fibrinolytic and thrombolytic effects, compounds of formula I are particularly suitable in general, wherein the group -A-O- is a radical of the formula -CHORs-CH2-O-, and R2, R3 and Rs are independently of each other a lower alkyl radical; 2 to 7 carbon atoms, lower alkenyl, lower arylalkyl, lower alkanoyl of 3 to 7 carbon atoms, benzoyl, halobenzoyl, lower alkylbenzoyl, lower alkoxybenzoyl, trifluoromethylbenzoyl, hydroxybenzoyl, lower alkanoyloxybenzoyl, α-naphthoyl, β-naphthoxybonyl or two of R 2, R 3 and R 5 are hydrogen and the third of R 2, R 3 and R 5 is lower alkyl, lower alkenyl, lower arylalkyl, lower alkanoyl or aroyl, or two of R a, R 5 and R 5 are lower alkylidene or lower an arylalkylidene group and the third of R 2, R 3 and R 5 is hydrogen, lower alkyl, lower alkenyl, lower aralkyl, lower alkanoyl or aroyl, wherein one of the radicals R 2,

R 3 and R 5 are other than hydrogen when the other two of these are hydrogen, and wherein one of R 2, R 3 and R 5 is other than methyl when the other two are methyl, and one of R 2 R 5 and R 8 have a meaning other than acetyl when the other two of these are acetyl.

Particularly suitable of the compounds of formula (I) are those wherein the group —A — O — represents a radical of the formula —CHOR 5 —CH 2 —O-, and R 2, R 5 and R 5 independently of one another are hydrogen, lower alkyl, lower alkenyl, benzyl, lower alkylbenzyl lower alkoxybenzyl, halobenzyl, trifluoromethylbenzyl, lower alkanoyl, benzoyl, halobenzoyl, lower alkylbenzyl, lower alkoxybenzoyl, trifluoromethylbenzoyl, hydroxybenzyl, lower alkanoyloxybenzoyl or pyridylcarbonyl, or two of which R @ 1, R @ 3, R @ 3, R @ 3, R 2, R 3 and R 5 are different from hydrogen when the other two are hydrogen, and one of R 2, R 5 and R 5 is not methyl, when the other two are methyl, and one of R 2, R 3 and R 5 are not acetyl n, when the other two of these residues are acetyl.

Particular mention should be made of the compounds of formula (I) wherein the group —A — O — represents a radical of the formula —CHOR 5 —CH 2 —O—,

R2 represents hydrogen, a lower alkyl group having 1 to 3 carbon atoms, a dialkylaminoalkyl group having all lower alkyl groups together with up to 7 carbon atoms, benzyl, chlorobenzyl, lower alkanoyl group having 2 to 4 carbon atoms, benzoyl, o-hydroxybenzoyl, lower o-alkanoyloxybenzoyl of 2 to 4 carbon atoms in the lower o-alkanoyloxy moiety, naphthoyl, lower alkylcarbamoyl of up to 4 carbon atoms, phenylcarbamoyl, lower alkylsulfonyl of 1 to 3 carbon atoms, phenylsulfonyl, toluylsulfonyl or pyridylcarbonyl, and R 3 i R 5 is independently hydrogen, C 1 -C 3 lower alkyl, benzyl, chlorobenzyl or benzoyl, one of R 2, R 3 and R 5 being other than hydrogen when the other two are hydrogen, and one of R 2, R 1 and R 5 does not represent a methyl group if the other two and of these radicals are a methyl group, and wherein one of the radicals R 2, R 3 and R 5 is not an acetyl group if the other two of these radicals are an acetyl group.

Particularly suitable are compounds of formula I wherein the group —A — O — is a radical of the formula —CHOR 5 —CHa —O--, R 2 is a lower C 2 -C 4 alkanoyl, benzoyl, o -hydroxybenzoyl, lower o-alkanoyloxybenzoyl group C 2 -C 4 lower o-alkanoyloxy, naphthoyl or pyridylcarbonyl; and R 3 and R 5 are each independently hydrogen, C 2 -C 3 lower alkyl, benzyl, chlorobenzyl, benzoyl or o-hydroxybenzoyl.

Particularly suitable are compounds of formula I wherein -A-O- is a radical of formula -CHOR 5 -CH 2 -O-, R 2 is hydrogen, and R 3 and R 5 are each independently C 1 -C 3 alkyl, allyl, methallyl, benzyl or chlorobenzyl.

In particular, the compounds of formula (I) wherein the group —A — O— is a radical of the formula —CHOR 5 —CH 2 —O—,

R 2 is hydrogen, C 2 -C 4 lower alkanoyl, benzoyl, o -hydroxybenzoyl, o -acetoxybenzoyl, naphthoyl or pyridylcarbonyl, and R 5 and R 5 are each independently C 1 -C 3 lower alkyl, benzyl, chlorobenzyl, benzoyl, o-hydroxybenzoyl, o-acetoxybenzoyl or naphthoyl group.

In particular, the compounds as described in the examples, and particularly 1,6-anhydro-3,5-di-O-benzoyl-2-O-nicotinoyl- (3-D-glucofuranose, 1,6-anhydro- 2-O-benzoyl-3,5-di-O-benzyl-.0-D-glucofuranose, 1, 4-anhydro-5S-di-O-benzyl-5S-D-allofuranose, 1,6-anhydro-2- O-benzoyl-3,5-di-O-benzyl-β-D-allofuranose and 1,6-anhydro-3,5-di-O-benzyl- β-D-glucofuranose.

The novel anhydrofuranose derivatives can be prepared by methods known per se by reacting them in a compound of formula VII.

(VID where

And it has the above meaning,

Y3 represents an oxo group,

Y 2 represents hydrogen and OR 2 as defined above, or Y 3 represents hydrogen and OR 3 as defined above, and

Y 2 represents an oxo group, reduces the oxo group to a hydroxyl group and, if desired, introduces, varies or cleaves the obtained compounds into the obtained compounds and / or separates the obtained racemate mixtures into pure racemates and / or 203068 or resolves the obtained racemates into optical antipodes and / or the obtained salts are converted into the free compounds or other salts, or the obtained free compounds are converted into their salts.

The reduction can be carried out in a customary manner, in particular a reducing agent from the group of hydrides, such as a metal hydride, in particular a complex metal hydride, for example sodium hydride.

In the compounds obtained, the substituents can be converted, introduced or cleaved in the customary manner in the customary manner, or the compounds obtained can be converted in conventional manner into other end products.

Thus, in compounds containing at least one free hydroxyl group, this group can be converted to form a substance containing a radical R 2, R 3, R 5, or R 6 other than hydrogen, especially as described above.

Furthermore, in compounds containing at least one alkenyl radical R 2, R 3, R 5 or R 6, it can be hydrogenated, for example with hydrogen in the presence of a catalyst, such as hydrogen in the presence of a palladium or platinum catalyst. In this case, groups which are hydrogenolytically cleavable can be cleaved off simultaneously.

Further, compounds containing at least one cleavable moiety can be cleaved off. Thus, especially in compounds containing a residue cleavable by solvolysis, such a residue can be cleaved solvolytically, for example, hydrolytically or alcoholytically. The hydrolytically or alcoholytically cleavable radical is, for example, an ylidene radical which is formed from two radicals R @ 2, R @ 3 and R @ 5 and R @ 6 respectively and which is cleaved under gentle conditions in a conventional manner by water or an alcohol such as a lower alkanol such as methanol or ethanol. acids such as inorganic acids such as any of the hydrohalic acids such as hydrochloric acid or by treatment with an organic acid such as one of the carboxylic acids or dicarboxylic acids such as acetic acid or sulfonic acids such as p-toluenesulfonic acid. Said cleavage is preferably carried out in the presence of a diluent, wherein one reactant, for example an alkaline reagent or an organic acid such as acetic acid, can simultaneously serve as a diluent. Mixtures of solvents and diluents may also be used. If an alcohol is used, it is preferably carried out in the presence of a hydrohalic acid, in particular hydrochloric acid, and if water is used, it is preferably in the presence of an organic carboxylic acid, in particular formic or oxalic acid, and in particular acetic acid. the reaction is carried out, if necessary, with cooling, but preferably at room or elevated temperature (e.g. at about 25 to 150 ° C, optionally in a closed vessel under pressure and / or in an inert gas environment such as atmosphere When the alcohol used in the presence of anhydrous acid, especially hydrogen chloride, is used as the reagent in the abovementioned reactions, one of the two hydroxyl groups, together etherified by the formation of the ylidene moiety, can be etherified simultaneously as it is released. used to introduce et a hydroxyl group into a compound obtainable according to the invention.

In a compound having a hydrogenolytically cleavable group, first of all in the case of a hydroxyl group etherified with an optionally substituted benzyl radical, or in the case of a benzylidenedioxyl group, such a group can be converted to a hydroxyl group according to known methods, for example by treatment with hydrogen at birth or catalytically activated. by treatment with hydrogen in the presence of a noble metal catalyst such as a palladium catalyst.

In the compound obtained with the acyl radical R 2, R 3 and / or R 5 or R 6, the acyloxy group can be converted to a hydroxyl group, for example by hydrolysis or alcoholysis, preferably in the presence of a slightly basic agent such as some acid alkali metal carbonates. In this case, the hydroxyl group can also be liberated during the cleavage of the ylidene residue, for example by reaction of the corresponding compound with an alcohol in the presence of an acid. When water in the presence of an acid is used to cleave the ylidene residue, both hydroxyl groups etherified with such a group are obtained in free form. The esterified hydroxyl group can be converted to another esterified hydroxyl group.

In the compound obtained with the acyl radical R 2, R 3 and / or R 5 or R 6, this radical can be converted into an alkyl, alkenyl or arylalkyl radical in a conventional manner. This conversion to the correspondingly etherified hydroxyl group is preferably carried out by reacting the starting material with a correspondingly reactively esterified alcohol derivative, for example as mentioned hereinbefore. The reaction of the acyloxy groups of the starting material is preferably carried out in the presence of an acid, in particular a mineral acid, such as a hydrohalic acid, for example hydrochloric acid, or particularly in a reaction with a reactive esterified alcohol in the presence of a suitable acid binding agent such as silver, lead or mercury. or in the presence of the corresponding oxide or tertiary base, and alcohol and metal derivatives such as corresponding alkali metal compounds, for example sodium or potassium, or caustic earth metals such as magnesium or silver compounds may also be used. Instead of an acid, an ion-exchange resin may also be used. This reaction is preferably carried out in the presence of a solvent, and alcoholic reagents may also be used as such.

The compounds with basic groups may be obtained in the form of acid addition salts, particularly pharmaceutically usable, forming non-toxic salts, for example with inorganic acids such as hydrochloric, hydrobromic, sulfuric or phosphoric acid, or with organic acids such as aliphatic, cycloaliphatic, cycloaliphatic -aliphatic, aromatic, araliphatic, heterocyclic or heterocyclic-aliphatic carboxylic or sulfonic acids such as acetic, propionic, succinic, glycolic, lactic, malic, tartaric, citric, ascorbic, maleic, phenylacetic, benzoic, 4-aminobenzoic, anthranilic 4-hydroxybenzoic, salicylic, aminosalicylic, embonic or nicotinic, as well as methanesulfonic, ethanesulfonic, 2-hydroxyethanesulfonic, ethylenesulfonic, benzenesulfonic, p-toluenesulfonic, sulfanil, or cyclohexylsulfamic. Salts of this type can be obtained, for example, from free compounds containing basic groups, by reaction with acids or with suitable anion exchange resins.

In view of the close relationships between the novel compounds in free form and in the form of the corresponding salts, in the foregoing and in the following description, the terms free compounds or salts and possibly corresponding salts or free compounds are meant wherever this would make sense and wherever expedient.

The novel compounds can be obtained as mixtures of isomers, such as racemates or diastereoisomeric mixtures, or in the form of pure isomers, such as optically active ingredients. Separation of the resulting mixture of isomers into pure isomers is carried out according to known methods. Racemates can be separated into optical antipodes by virtue of physicochemical differences, such as solubility differences, differences in diastereoisomeric salt properties, or fractional crystallization from an optically active solvent, or by chromatography, in particular on thin layers, on an optically active carrier on which division into optical antipodes. In this case, the pharmacologically more active or less toxic pure isomer, in particular the more active or less toxic, is isolated from both active antipodes.

The above processes can be carried out using known methods, without solvents or preferably in the presence of diluents or solvents, if necessary, with cooling or heating, under elevated pressure and / or in an inert gas environment such as nitrogen atmosphere.

With respect to all substituents in the molecule, if desired, especially in the presence of readily hydrolyzable O-acyl residues, particularly gentle reaction conditions such as short reaction times, use of mildly acidic or basic agents at low concentrations, stoichiometric relative proportions, suitable catalysts, solvents, temperature and / or pressure conditions.

The invention also relates to such process embodiments starting from a compound obtainable at any stage of the process as an intermediate, and the remaining steps of the process being carried out with such a compound or interrupted at any stage, or the starting compound is formed under reaction conditions. or is used in the form of a reactive derivative or salt. In this connection, it is preferable to use starting compounds from which the compounds of the invention which are particularly valuable are obtained in the process according to the invention.

The starting materials are known or can be prepared using known methods.

The invention further relates to pharmaceutical compositions comprising an anhydrofuranose derivative of the formula I, wherein R 2 and R 3 independently of one another are hydrogen, alkyl, alkenyl, arylalkyl or acyl, and the group "A-O" represents a radical of the formula -CHOR 5 -CH 2 -O- or —CH (CH2OR6j-O-), wherein R5 and R5, respectively, have the meanings given for R2, or wherein two of R2, R5 and R5 or R6 together represent an ylidene radical.

Preferred pharmaceutical compositions are those containing an anhydrofuranose derivative within the range of the aforementioned compounds, or the individual compound as such.

The pharmaceutical compositions of the invention preferably contain an effective amount of the active ingredient together or in admixture with inorganic or organic, solid or liquid, pharmaceutically acceptable carriers suitable for enteral, parenteral or topical administration. Suitable compounds are those which do not react with anhydrofuranos derivatives, such as water, gelatin, lactose, starches, stearyl alcohol, magnesium stearate, talc, vegetable oils, benzyl alcohols, gums, propylene glycols, petrolatum or other known drug carriers. The pharmaceutical preparations may be, for example, tablets, dragees, capsules, suppositories, creams, ointments or liquid solutions (for example, elixirs or syrups), suspensions or emulsions. The pharmaceutical preparations may be sterilized and / or contain adjuvants such as preservatives, stabilizers, wetting agents and / or emulsifiers, solubility enhancers, salts for adjusting the osmotic pressure and / or buffers. Said pharmaceutical preparations may contain, if desired, other pharmaceutically valuable substances, prepared by conventional methods, for example using conventional methods of mixing, granulating or dragee-forming. They contain about 0.1 to 75%, in particular about 1 to 50%, of the active ingredient.

The invention further relates to treating warm-blooded individuals to achieve fibrinolytic, thrombolytic and / or anti-inflammatory effects by administering a pharmaceutical composition of the invention. The daily dose preferably contains about 50 to 500 mg, preferably about 100 to 300 mg of active ingredient in about 70 kg of a warm-blooded individual.

Further examples describe the process of the invention in more detail. Temperatures are given in degrees Celsius.

Example 1

To a solution of 11.4 g, 6-anhydro-3,5-di-O-benzyl-2-oxo- (3-D-glucofuranose in 140 ml of methanol) was added 1 g of sodium borohydride under ice-cooling. The reaction mixture is evaporated in vacuo, the residue is taken up in ether and the ether phase is washed with water until neutral, after drying and evaporation of the ether phase, crystals are obtained which are recrystallized from ethyl acetate / petroleum ether to give 10-anhydro-SS. 117 DEG-119 DEG, [ _{.alpha.] D} @ ²⁰ = -38.6 DEG (chloroform). Further fractions of this material can be isolated from the mother liquors.

The starting compound can be prepared as follows:

After portions and with stirring at about 25 °, 30 g of 10-anhydro-5'-di-O-benzyl-5-D-glucofuranose are introduced into a solution of 12 g of P 4 O 10 in 200 ml of absolute dimethylsulfoxide. After standing at about 25 DEG C. for 20 hours, the reaction solution is added dropwise to a solution of 25 g of sodium bicarbonate in 500 ml of water, the reaction mixture is diluted with a liter of water and shaken with ether. The ether phase was washed three times with water and once with brine and dried over magnesium sulfate. A yellow oil is obtained, i.e. 1,6-anhydro-3,5-di-O-benzyl-2-oxo-β-D-glucofranose, which is further processed directly.

Example 2

To a solution of 7-gl, 6-anhydro-3,5-di-O-benzyl-5-D-glucofuranose and 1.42 g of powdered potassium hydroxide in 30 ml of absolute dimethylsulfoxide was added dropwise 2.61 g (2.05 ml) of dimethylsulfate. . After 2 and 4 hours at 25 °, an additional portion of 1.42 g of potassium hydroxide and 2.05 ml of dimethyl sulfate was added, followed by heating at 60 ° for 2 hours. The reaction mixture is then evaporated in vacuo, the residue is taken up in water and ether and the ether phase is washed with water until neutral, dried and evaporated. The oil obtained is filtered through 100 g of silica gel in chloroform. To give a colorless oil L G-anhydro-3,5-di-O-benzyl-2-O-methyl-.beta.-D-glukof URANOS of [ «] _D ²⁰ = - 3 ° (chloroform).

Example 3

A solution of 7 g of le-anhydro-N-di-O-benzyl-β-D-glucofuranose, 9.65 g (10 ml) of methyl isocyanate and 0.5 ml of triethylamine in 110 ml of benzene is allowed to stand for 15 hours at about 25 °. The mixture is evaporated to dryness and the syrup obtained is dried at 1 Pa. A viscous, colorless syrup of 1,6-anhydro-3,5-di-O-benzyl-2- (N-methylcarbamoyl) -β-D-glucofuranosine is obtained, [α] D ²⁰ - 16.9 ° (chloroform).

Example 4

A solution of 7-gl, 6-anhydro-3,5-di-O-benzyl-β-D-glucofuranose, 8.15 g (7.45 ml) of phenyl isocyanate and 10 drops of triethylamine in 100 ml of benzene was heated at reflux for 4 hours. backflow. After evaporation to dryness, the syrupy residue is chromatographed on 350 g of silica gel in chloroform / acetone (50: 1) to give a viscous syrup of 1,6-anhydro-3,5-di-O-benzyl-2-O- (N). -phenylcarbamoyl-β-D-glucofuranose [α] _D ²⁰ = -27.1 ° (chloroform).

Example 5

To a solution of 5-gl, 6-anhydro-3,5-di-O-benzyl- (3-D-glucofuranose in 30 ml of pyridine) was added a solution of 2.3 g (1.91 ml) of benzoyl chloride in 10 ml of chloroform and the reaction mixture. After 15 hours at 25 DEG C. After the addition of water, the reaction mixture is concentrated in vacuo to a syrup which is dissolved in ether and the ether phase is shaken with 1N hydrochloric acid solution, 5% sodium bicarbonate solution and water and then dried. and evaporated to give 1,6-anhydro-2-O-benzoyl-3,5-di-O-benzyl- [beta] -D-glucofuranose crystals, which were recrystallized from a mixture of ether and petroleum ether, m.p. [ _.alpha. ] _{D @} ²⁰ = + 7.3 DEG (chloroform).

Example 1 a d 6

To a cooled solution of 5 g of 1,6-anhydro-3,5-di-O-benzyl- [beta] -D-glucofuranose in 50 ml of pyridine was added a solution of 6.2 g of p-tosyl chloride in 20 ml of chloroform. After 5 hours at 60 'and 15 hours at 25 ° the reaction mixture is diluted with water and evaporated in vacuo to a syrup which was taken up in ether and the solution is shaken with 1 N hydrochloric acid, 5 ^lo / o sodium bicarbonate sodium carbonate and water. After drying and evaporation of the ether phase, crystals of 1,6-anhydro-3,5-di-O-benzoyl-2-O- (p-toluenesulfonyl) -S-D-glucofuranose are obtained, which are 92 DEG-92.5 DEG and [ _.alpha. ] _D @ ²⁰ = -40.6 DEG (chloroform).

Example 7

To a cooled solution of 5 g of 1,6-anhydro-3,5-di-O-benzyl-5-D-glucofuranose in 50 ml of pyridine was added a solution of 3.68 g (2.44 ml) of mesyl chloride in 20 ml of chloroform. The reaction mixture was allowed to stand for 15 hours at 25 °. Workup as in Example 6 gave 1,6-anhydro-3,5-di-O-benzyl-2-O-methylsulfonyl-1-D-glucofuranose crystals having a melting point of 142-144 ° after recrystallization from methanol; [α] _D ²⁰ = -22.4 ° (chloroform).

Example 8

A solution of 18.1 gl, 5-anhydro-2-O-benzyl-3-On-propyl- (3-D-xylofuranose) in 180 ml ethanol is hydrogenated in the presence of 1.5 g of 5% palladium on carbon, such as of catalyst at normal pressure and room temperature for 12 hours. Hydrogen consumption is 1.58 liters (103%). The catalyst is filtered off, washed with ethanol, and the filtrate is evaporated to dryness in a water pump vacuum. The 1,5-anhydro-3-On-propyl-5S-D-xylofuranose obtained is distilled under high vacuum from a spherical flask. Boiling point is 105 ° to 130 ° (bath temperature) at 27 mm Hg, optical rotation [ «] ^_D20 = -17 ° ± 1 ° (c = 1.225, chloroform], and R _f = 0.1 when chromatographed on a thin layer Silica gel in ether / petroleum ether 1: 2.

Example 9

A mixture of 15 g of 1S-anhydro-5H-di-O-benzyl-4-D-glucofuranose in 60 ml of pyridine and 14 g of acetylsalicyl chloride in 40 ml of chloroform is reacted for 2 hours at 50 °. After addition of ice water, it is taken up in chloroform and the chloroform layer is shaken successively with 2 N hydrochloric acid solution, 5% sodium bicarbonate solution and water. After drying over anhydrous sodium sulfate and further conventional work-up, 1,6-anhydro-2-O-salicyloyl-5-di-O-benzyl-4-D-glucofuranose is obtained as an oil which is chromatographed on silica gel with cyclohexane and dried. ethyl acetate in a ratio of 7: 3, [α] ^D = + 7.0 ° (chloroform, c = 1).

Example 10

A solution of 5-gl, 6-anhydro-2-O-salicyloyl-3,5-di-O-benzyl- [beta] -D-glucofuranose in 30 ml of pyridine is acetylated at 50 DEG C. with 10 ml of acetic anhydride. After 15 hours, methanol is added at about 25 °, the solution is distilled off, and the residue is taken up in chloroform. The chloroform phase is shaken with 1 N hydrochloric acid solution, sodium bicarbonate solution and water. A syrupy 1,6-anhydro-2-O-acetylsalicyloyl-3,5-di-O-benzyl- 3-D-glucofuranose is obtained, which is crystallized from ether. Mp 87-88 ° and [α] _D ²⁰ = -5.2 ° (chloroform, c = 1.55).

Example 11

To a solution of 8 gl, 6-anhydro-3,5-di-A-benzyl-d-glucofuranose in 40 ml of absolute dimethylsulfoxide was added 1.23 g of sodium hydride dispersion and after completion of hydrogen evolution a solution of 4.5 g of 2- of diethylaminoethyl chloride in 25 ml of dimethylsulfoxide. After 2 hours, the reaction mixture is evaporated at 60 °, the residue is taken up in ether and the ether phase is washed with water and brine. After drying and evaporation, 1,6-anhydro-2-O- (2-diethylaminoethyl) -3,5-di-O-benzyl-1H-glucofuranose is obtained as an oil which is chromatographed on silica gel with chloroform and acetone 8: 2, [ _.alpha. ] _{D @} ²⁰ = + 2.6 DEG (chloroform, c = 3.2).

Treatment with a solution of hydrogen chloride in ethanol gives the corresponding hydrochloride, m.p. 113 DEG-114 DEG, [ _.alpha. ] _{D @} ²⁰ = 0 DEG (chloroform, c = 1.05).

Example 12

GL A solution of 5, 6-anhydro-2-O-benzoyl-3,5-di-O-benzyl-.beta.-D-glucofuranose in methanol was hydrogenated at about 25 ° to 5 ° / _o palladium on carbon. The consumption of 1 molar equivalent of hydrogen is complete in an hour, after which the hydrogenation is stopped. Crystals having a melting point of 121-122 ° gave 1,6-anhydro-2-O-benzoyl-3-O-benzyl-β-D-glucofuranose. Example 13

A solution of 26.0 g of 2,5-di-O-acetylsalicyloyl-3-O-benzyl-1,6-anhydro- [beta] -D-glucofuranose in 860 ml of a 1 N solution of hydrogen chloride in absolute ethanol is allowed to stand at room temperature for 20 hours. The solvent and hydrogen chloride were distilled off under reduced pressure. The residue was taken up in ether and the solution was washed with saturated sodium bicarbonate solution and water, then dried over sodium sulfate, filtered, and the filtrate was freed of solvent. The residue was purified by column chromatography on 1200 g of silica gel, eluting with ether: petroleum ether (1: 1).

: 1 to give 2,5-di-O-salicyloyl-3-O-benzyl-1,6-anhydro- < 1 > -D-glucofuranose as white crystals of m.p. 102-103.5 [deg.] With optical rotation [[alpha]] _D ²⁰ = -3 ° ± 1 ° (chloroform, c = 0.818).

Example 14

Analogously to Example 5, 1,6-anhydro-3,5-dl-O-benzyl- [beta] -D-allofuranose and benzoyl chloride 1,6-anhydro-2-O-benzoyl-3,5-di-benzoyl chloride were obtained. -O-benzyl-β-D-allofuranose, mp 128.5-129 °.

Example 15

Analogously to Example 4, 1,6-anhydro-3,5-di-O-benzyl-2, 6-anhydro-3,5-di-O-benzyl- (2-D-allofuranose and phenyl isocyanate) were obtained. -O- (N-phenylcarbamoyl) - (3-D-allofuranose, mp 125-128 ° C) Example 16

To a solution of 3 g, 6-anhydro-3-O-benzyl- [beta] -D-glucofuranose in 20 ml of pyridine was added 3 ml of benzoyl chloride and the reaction mixture was allowed to stand at 50 [deg.] For 2 days. Then a small amount of water was added, the highest proportion of pyridine was evaporated in vacuo and the residue was stirred with ice. Crystals of 1,6-anhydro-2,5-di-O-benzoyl-3-O-benzyl- (SD-glucofuranose) are thus obtained in the form of crystals, m.p. 136 DEG-137 DEG. _D ²⁰ = -9.1 ° (chloroform, c = 1.04) Example 17

To a solution of 12.6 g of 3-O-benzyl-1,6-anhydro- [beta] -D-glucofuranose in 100 ml of methylene chloride and 15 ml of pyridine was added dropwise a solution of 21.8 g of acetylsalicylic chloride with stirring at 40 DEG over 15 hours in 100 ml methylene chloride. After addition of 20 ml of water, both methylene chloride and pyridine are distilled off under reduced pressure. The residue was taken up in diethyl ether and the solution was washed with ice-cold 2 N hydrochloric acid solution, saturated sodium bicarbonate solution and water. After drying, filtration and evaporation, the residue obtained is chromatographed on a column of 1200 g of silica gel, eluting with a 1: 1 mixture of ether and petroleum ether. This gives 2,5-di-O-acetylsalicyloyl-3-O-benzyl-1,6- anhydro / 3-D-glycofuranose is obtained, which is deacetylated as described in Example 13. the product is an oil, R _f = 0.65 (methylene chloride, ethyl acetate = 85: 15, finished plate silica gel [Merck]).

Example 18

The following compounds are obtained in a similar manner:

1.

2-O-acetyl-1,6-anhydro-3,5-di-O-benzyl-.beta.-D-glucofuranose, [ _.alpha. ] _D @ ²⁰ = -20.6 DEG (chloroform),

2.

1,6-anhydro-3,5-di-O-benzyl- (S-D-glucofuranose), m.p. 112-113 °;

3.

1,6-anhydro-3-O-benzyl-, α-D-glucofuranose, m.p. 102-103 °,

4.

1,6-anhydro-3,5-O-benzyl-2-O-nicotinoyl- _1,3 -D-glucofuranose, m.p. 98-100 °;

5.

1,6-anhydro-2,3,5-tri-O-benzyl- [beta] -D-glucofuranose, m.p.

6.

2-O-acetyl-6-Anhydro-5-O-benzyl-3-O-methyl- / 3-D-glycofuranose is obtained, _Rf = 0.23 (thin layer chromatography on silica) cyclohexane and ethyl acetate (2: 1),

7.

1,6-anhydro-5-O-benzyl-3-O-benzy 1-3-O-methyl-β-D-glucofuranose, [α] _D ²⁰ = 8 ° ± ± 1 ° (chloroform),

8.

2-O-acetyl-6-Anhydro-5-O-benzyl-3-O-propyl- / 3-D-glucofuranose, _Rf = 0.30 (thin layer chromatography on silica gel) cyclohexane and ethyl acetate (2 : 1),

9.

1,6-anhydro-5-O-benzyl-3-on-propyl- N -D-glucofuranose, [α] _D ²⁰ = -4 ° ± 1 ° (chloroform),

10.

2-O-acetyl-1,6-anhydro-5-O-p-chlorobenzyl-3-O-n-propyl- [beta] -D-glucofuranose, yellowish oil,

11.

1,6-anhydro-5-O-p-chlorobenzyl-3-O-n-propyl-β-D-glucofurancza, clear yellowish oil,

12.

1,6-anhydro-2-O-methyl-3,5-di-O-n-propyl-β-D-glucofuranose, [α] _D ²⁰ = + 15 ° ± 1 ° (chloroform),

13.

1,6-anhydro-3,5-di-O-methyl- β-D-glucofuranose, boiling point: 140 to 150 ° (external temperature), 7 Pa,

14.

1,6-anhydro-2-O-methyl-3,5-di-O-n-propyl-β-D-glucofuranose, colorless oil, boiling point: 90 to 100 ° (external temperature), 5 Pa,

15 Dec

1,5-anhydro-2-O-methyl-3-O-n-propyl- (3-D-xylofuranose), boiling point: 45 °, 3 Pa,

16.

1,5-anhydro-2-O-benzyl-3-O-n-propyl- (3-D-xylofuranose), boiling point: 110 °, 1 Pa,

17.

1,6-anhydro-3,5-di-O-benzyl- [3-D-allofuranose, boiling point: 60 to 62 °,

18.

1,6-anhydro-2,3,5-tri-O-benzoyl-5-Dallofuranose,

19 Dec

1,6-anhydro-2,3,5-tri-O-benzoyl- (3-D-glucofuranose),

20 May

1,6-anhydro-3,5-di-O-benzyl-2-O- (α-naphthoyl) - β-D-allophuranose,

21.

1,6-anhydro-3,5-di-O-benzyl-2-O- (ε-naphthoyl) -β-D-glucofuranose,

22nd

1,1-anhydro-3,5-di-O-benzyl-2-O - ((3-naphthoyl) -β-D-glucofuranase),

23.

2-O-acetyl-1,6-anhydro-3,5-di-O-benzyl-d-D-allofuranose.

Example 19

Capsules containing 0,1 g of the active substance may be prepared as follows (for 10 000 capsules):

Composition 1,6-anhydro-3,5-di-O-benzyl- [beta] -D-glucofuranose 1000 g absolute ethanol 100 gL, 6-anhydro-3,5-di-O-benzyl-β-D-glucofuranose mixed with ethanol and the mixture is filled using a suitable capsule device soft gelatin capsule.

Claims (5)

I will invent the object A process for the preparation of novel anhydrofuranose derivatives of the general formula I 0 ' CH-AO-CH 2 hor-chor _of (I) wherein R2 is hydrogen, alkyl, aminoalkyl, alkenyl of up to 4 carbon atoms, phenylalkyl of 1 or 2 carbon atoms in the alkyl moiety or alkanoyl of 1 to 4 carbon atoms, optionally hydroxy or alkanoyloxy of 1 to 4 carbon atoms, or halogen-substituted benzoyl or naphthoyl, alkylsulfonyl of 1 to 4 carbon atoms, toluenesulfonyl, pyridylcarbonyl, alkylcarbamoyl of 1 to 4 carbon atoms in the alkyl moiety or phenylcarbamoyl, R 5 represents hydrogen, alkyl or alkenyl of up to 4 carbon atoms, optionally halogen-substituted phenylalkyl of 1 or 2 carbon atoms in the alkyl moiety, alkanoyl of 1 to 4 carbon atoms or optionally hydroxyl or lower alkanoyloxy of 1 to 4 carbon atoms or a halogen-substituted benzoyl group and the group "A-O" represents a radical of the formula -CHOR 5 -CH 2 -O- or -CH (CH 2 OR 6) -O- in which: R 5 and R 6, respectively, have one of the meanings given for R 5, or wherein -CH 2 OR 6 represents hydrogen, or wherein two of the radicals R 2, R 5 and R 5 or R 6 together represent an alkylidene or phenylalkylidene radical having from 1 to 4 carbon atoms; one of R 2, R 5 and R 5 or R 6 is other than hydrogen when the other two are hydrogen, wherein in the compounds with the group -CHOR 5 -CH 2 -O- in the meaning of the group "A-O" one of the radicals R 2, R 5 and R 5 are other than methyl when the other two of these are methyl, and wherein in the compounds and —CHORs — CH2 —O— in the meaning of —A — O— one of R2, R5, and R5 has another a radical than an acetyl group, when the other two of these radicals are an acetyl group, and wherein in the compounds with —CH (CH2OR6) —O— in the sense of the grouping —A — O— one of the radicals Rz, Rs and Re has a different if the other two of these radicals are benzyl and their salts, characterized in that in the compound of formula VII (VID wherein: And it has the above meaning, Y 2 is oxo, Y 2 is hydrogen and OR 2 is as defined above, or Y 3 represents hydrogen and OR 5 as defined above, and Y 2 represents oxo, reduces the oxo group to a hydroxyl group and, if desired, introduces, varies or cleaves the substituents into the obtained compounds and / or separates the obtained racemate mixtures into pure racemates and / or the racemates obtained are resolved into optical antipodes and / or the obtained salts are converted into the free compounds or other salts, or the obtained free compounds are converted into their salts. 2. A process according to claim 1, wherein the compound of formula (VII) is reduced by treatment with a hydride reducing agent. 3. A process according to any one of claims 1 and 2, wherein the starting compound of formula (VII) is used, wherein the group -A-O- is a radical of -CHOR5-CH2-O-, R2 represents hydrogen, lower alkyl of 1 to 3 carbon atoms, lower dialkylamino (lower alkyl) together of up to 7 carbon atoms, benzyl, lower alkanoyl of 2 to 4 carbon atoms, benzyl, o-hydroxybenzoyl, lower o-alkanoyloxybenzoyl a C 2 -C 4 lower o-alkanoyloxy group, a naphthoyl, lower alkylcarbamoyl group of up to 4 carbon atoms, a phenylcarbamoyl, a lower C 1 -C 3 alkylsulfonyl group, a toluylsulfonyl or pyridylcarbonyl group, and R 3 and R 5 are each independently hydrogen lower alkyl having 1-3 carbon atoms, benzyl, chlorobenzyl or benzoyl group, wherein one of the radicals R 2 ^1, R 3 and Rg is other than hydrogen if the other two of said radicals are hydrogen, and wherein one of the radicals R 2, R 3 and R 8 are other than methyl when the other two radicals are methyl and wherein one of R 2, R 5 and R 5 is other than acetyl when the other two are acetyl and one of Y 2 and Y 5 is oxo and the other OR 2 or OR 3. 4. A process according to any one of Claims 1 and 2, wherein the starting compound of formula (VII) is used, wherein the group —A — O — represents the radical —CHOR5 — CH2 —O—. R2 represents lower alkanoyl of 2 to 4 carbon atoms, benzoyl, o-hydroxybenzoyl, lower o-alkanoyloxybenzoyl of 2 to 4 carbon atoms in the lower o-alkanoyloxy group, naphthoyl or pyridylcarbonyl, R3 and R5 independently of one another represent hydrogen, lower alkyl having 2 or 3 carbon atoms, benzyl, chlorobenzyl, benzoyl or o-hydroxybenzoyl, and one of Y 2 and Y 3 is oxo and the other OR 2 or OR 8. 5. Process according to one of Claims 1 and 2, characterized in that the starting compounds of the general formula (VII) are used, wherein the group —A — O — represents the radical —CHOR5 —CH2 —O—, R 2 is hydrogen, C 2 -C 4 lower alkenoyl, benzoyl, o-hydroxybenzoyl, o -acetoxybenzoyl, naphthoyl or pyridylcarbonyl, and R 5 and R 5 are independently C 1 -C 3 lower alkyl, benzyl, chlorobenzyl, benzoyl , o-hydroxybenzoyl, o-acetoxybenzoyl or naphthoyl, and one of Y 2 and Y 3 is oxo and the other OR 2 or OR 3.