CS203067B2 - Process for preparing new derivatives of anhydrofuranose - Google Patents

Description

(54) Process for the production of new anhydrofuranose derivatives

The present invention provides a process for the preparation of the novel anhydrofuranose derivatives of formula (I)

CH ~ A -o ^ ch \ /

CHOR? -CHOR? (I) wherein

R 2 is hydrogen, C 1 -C 4 alkyl, C 1 -C 4 aminoalkyl, C 1 -C 4 alkenyl, phenylalkyl having 1 or 2 carbon atoms or C 1 -C 4 alkanoyl or optionally C 1 -C 4 alkanoyloxy or halogen substituted beinzoyl or naphthoyl, C 1 -C 4 alkylsulfonyl, toluenesulfonyl, pyridylcarbamyl, alkylcarbamoyl, C 1-4 alkylcarbamoyl, or phenyl;

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 up to 4 carbon atoms, or optionally hydroxyl or alkanoyloxy of 1 to 4 carbon atoms or halogen: a substituted benzoyl group, and -A-O- is a radical of the formula -CHOR5-CH2-O- or _CH (CH2OR6) -O- in which:

R 5 and R 6 have one of the meanings given for R 3, or wherein -CH 2 OR 6 is hydrogen, or wherein two of R 2, R 3 and R 5 or R 6 together represent an alkylidene or phenylalkylidene radical wherein the alkyl moiety contains 1 to 4 carbon atoms; wherein one of R2, R3 and R6 and R6, respectively, is other than hydrogen when the other two are hydrogen, and wherein in the compounds with the group —CHORs — CH2 —O — in the meaning of the grouping —A — O— one of R2 is , R 5 and R 5 have a meaning other than methyl when the other two of these are methyl, and wherein in the —CHORs — CH2 —O— in the meaning of —A — O— one of R 2, R 8 and R 8 is different importance than an acetyl group when the other two of these radicals are aicetylovou ^one group, and in compounds with O- -CHjCHzORsj in terms --A O- one of the radicals R2, R3 and R6 is yin importance than benzyl if the other two of these radicals are benzyl and their salts.

Suitable lower radicals are, in particular, radicals having up to 4 carbon atoms. An aliphatic residue is a residue whose free bond results from an atom that is not a member of the aromatic system.

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

The novel anhydrofuranose derivatives of the formula I are 1,5-anhydro-L- or -D-hexofiurarose derivatives, in particular 1,6-anhydro-β-D-glucofuranose, 1,6-anhydro-β-D-allofuranosyl derivatives. , 6-anhydro- [beta] -D-allofuranose, 1,6-anhydro- [beta] -D-mannofuranose and 1,6-anhydro-.alpha.-D-furanose, 1,6-anhydro-.alpha.-L-gulose or the like derivatives 1,5-anhydroxylofuranose.

In particular, the alkyl group 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.

The 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 a 2-methyliminoethyl, 2-dimethylaminoethyl, 2-ethylaminomethyl group.

In particular, the alkenyl group R @ 2, R @ 3 and / or R @ 6 or R @ 6 is, 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 Re, such as in the case of ethoxy, n-propoxy, isopropoxy or, in particular, methoxy.

The aryl radical R @ 2, R @ 3 and / or R @ 5 and R @ 8, in particular, is, in particular, an acyl radical of an organic acid and in particular an organic carboxylic acid radical. The acylating radical may in particular be an alkanoyl group, in particular a lower alkanoyl group such as an acetyl or propionyl group, or also an aroyl group such as a group. 1-naphthoyl or 2-naphthoyl, in particular benzoyl, which is optionally substituted by halogen-, lower-alkyl, lower-alkoxy, trifluoromethyl, hydroxyl or lower-alkanoyloxy, such as salicyloyl or acetylsalicyloyl, as well as pyridylcarboxylic, such as- is, for example, a group. 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 acid or ethanesulfonic acid, or an arylsulfonic acid residue, especially a lower alkanesulfonic acid, such as substituted with a lower alkyl group such as benzenesulfonic acid or p-toluenesulfonic acid, as well as a carbamoyl moiety, either unsubstituted or lower alkylcarbamoyl or arylcarbamoyl, such as methylcarbamoyl or phenylcarbamoyl.

The Ylidene radical of the two radicals R2, R3 and R5 and R6, respectively, is particularly lower ylidene, such as lower alkylidene, for example methylidene, ethylidene or especially isopropylidenoic, or lower arallkylidene, such as lower phenylalkylidene, where the phenyl moiety is phenyl optionally substituted by lower alkyl, lower alkoxy, halogen and / or trifluoromethyl, and in particular is benzylidene.

Preferably, all of the foregoing and subsequent compounds of the anhydrofuranose derivative type are 1,6-ainhydro- (3-D-glucofuranose) derivatives.

The novel compounds have valuable pharmacological properties.

The anhydrofuranos derivatives according to the invention are particularly characterized by fibrionolytic and throtalbolytic 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 fibrionolytic and thrombolytic effect is demonstrated in an experiment conducted by M. Ruegg, L. Riesteter and R. Jacqueis in Pharmacology 4, 242-254 (1970) by reducing the dissolution time of the euglobulin precipitate.

Particularly suitable for the fibrionolyitic and thrombolytic effects are compounds within the scope of the compounds of formula (I) wherein the group —A — O — represents a radical of the formula —OHORs — CH2 —O—, and R2, R3 and R5 are each independently alkyl , alkenyl, aryl, alkyl or alkanoyl, benzoyl, halobenzoyl, alkylbenzoyl, alkoxybenzoyl, trifluoromethylbenzoyl, hydroxybenzoyl, alkanooyloxybenzoyl203067, .alpha.-naphthoyl, .beta.-naphthoyl, R.sub.3 and R @ 3; R 2, R 3 and R 5 are alkyl, alikenyloxy, arylalkyl, alkanoyl or aroyl, or two of R 2, R 3 and R 5 are alkylidene or arylalkylidene; and the third of R 2, R 3 and R 5 is hydrogen, alkyl, alkenyl, arylalkyl , alkanoyl or aroyl, wherein one of R 2, R 3 and R 5 is j other than hydrogen when the other two of these radicals are hydrogen, and wherein one of the radicals R 2, R 3 and R 5 has a meaning other than methyl when the other two radicals are a methyl group, and wherein one of the radicals R 2, R 3 and R 5 is other than acetyl when the other two of these are acetyl.

Among the compounds of formula (I), those particularly preferred are those wherein the group -A-O- is a radical of the formula -CHOR 5 -CH 2 -O-, and R 2, R 5 and R 5 are each independently hydrogen, lower alkyl, lower alkenyl, benzyl, lower alkylbenzyl, lower alkoxybenzyl, halobenzyl, trifluoromethylbenzyl, lower alkanoyl, benzoyl, halobenzoyl, lower alkylbenzoyl, lower alkoxybenzoyl, trifluoromethylbenzoyl, hydroxybenzoyl, lower alkanoyloxybenzoyl or R @ 1 radicals, or R @ 1 or R @ 2 or R @ 2; wherein one of the radicals R 2, R 3 and R 5 is different from hydrogen when the other two of these radicals are hydrogen, wherein one of the radicals R 2, R 3 and R 5 is not a methyl group when the other two of these radicals are a methyl group; one of the radicals R @ 2, R @ 3 and R 5 is not an acetyl group if the other two of these residues are an acetyl group.

In particular, compounds of formula (I) wherein -A-O- are -CHOR 5 -CH 2 -O-, R 2 is hydrogen, lower alkyl having 1 to 3 carbon atoms, dialkylaminoalkyl having all alkyl groups lower and together with up to 7 carbon atoms, benzyl, chlorobenzyl, 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, lower alkylcarbamoyl having up to 4 carbon atoms, phenylcarbamoyl, lower alkylsulfonyl having 1 to 3 carbon atoms, phenylsulfonyl, toluylsulfonyl or pyridylcarbonyl, and R3 and R5 independently of one another denote hydrogen, lower alkyl having 1 to 3 carbon atoms, benzyl, chlorobenzyl or benzoyl, wherein one of the radicals R 2, R 5 and R 5 m other than hydrogen when the other two of these radicals are hydrogen, and wherein one of the radicals R 2, R 3 and R 5 is not methyl, where the other two of these radicals are methyl, and wherein one of the radicals R 2, R 3 and R 5 is not acetyl when the other two of these radicals are acetyl.

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

Particularly suitable are compounds within the scope of the compounds of formula (I) wherein -A-O- is a radical of the formula -CHORs-CH 2 -O-, R 2 is hydrogen, and R 11 is independently of one another a lower alkyl group having 1 to 3 atoms carbon, allyl, methallyl, benzyl or chlorobenzyl.

In particular, compounds of formula (I) wherein -A-O- is a radical of 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 independently of one another are lower alkyl having 1 to 3 carbon atoms, benzyl, chlorobenzyl, benzoyl, o-hydroxybenzoyl, o-acetoxybenzoyl or naphthoyl.

Particular mention should be made of the compounds as described in the examples, and in particular 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- [beta] -D-glucofuranose, 1,6-anhydro-3,5-di-O-benzyl- [beta] -D-allofuranose, 1,6- anhydro-2-O-benzoyl-3,5-di-O-benzyl-β-D-allofuranose, and 6-anhydro-3,5-di-O-benzyl-β-D-glucofuranose.

The novel compounds can be prepared using known methods by reacting a compound of formula VI

ch - a - o - _ch \ hor - chor ° _z (where n

A is -CHOR 5 ° -CH 2 -O- or -CH 2 CHaOR 6 ( ^O ) -O- and at least one residue

R 2, R 3, R ⁵ , and R 6 are hydrogen and others have the meaning of R 2, R 3, R 5, or R e, or a reactive ester thereof, reacted with an alcohol or acid corresponding to the radical R 2, R 3 and / or R 5, or a reactive derivative thereof, and if desired, the substituted compounds are introduced, altered and / or cleaved into the obtained compounds, and / or the racemate mixtures obtained are separated 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.

Thus, a compound of formula VI can be reacted with a reactive ester of an alkanol, an alkenol or an arylalkanol. In particular, the reactive ester of an alkanol, alkenol or arylalkanol is an ester of a strong inorganic or organic acid, such as especially hydrohalic acids, for example hydrochloric, hydrobromic or hydroiodic acids, or sulfuric acid, or an ester of an organic sulfoacid such as aromatic or aliphatic sulfonic acids, for example benzenesulfonic acid. bromobenzenesulfonic, 4-toluenesulfonic, lower alkanesulfonic, for example methanesulfonic or ethanesulfonic acids. Thus, alkyl chloride is preferably used for reactions with a compound of formula VI; alkyl bromide, alkyl iodide, benzenesulfonyloxyalkane, 4-bromobenzenesulfonyloxyalkane, 4-toluenesulfonyloxyalkane, methanesulfonyloxyalkane, or ethanesulfonyloxyalkane, optionally the corresponding alkenol or arylalkanol derivative. It is preferably carried out in the presence of a basic agent such as potassium hydroxide or an alkali metal carbonate such as sodium carbonate or potassium carbonate, an alkali metal acid carbonate such as sodium bicarbonate or potassium carbonate, or in the presence of silver oxide.

Further, a compound of formula VI can be treated wherein at least one hydroxyl group is converted to a reactive esterified hydroxyl group, in particular a halogen such as bromine or iodine, an alkanol, an alkenol or an arylalkanol, or a corresponding metal salt such as a sodium salt.

Further, an acyl radical R 2, R 5 and / or R 6, optionally R 6, can be introduced into a compound of formula VI wherein at least one hydroxyl group is converted to a reactive esterified hydroxyl group, in particular to a halogen atom such as bromine or iodine. An acyl radical R 2, R 3 and / or R 5 and / or R 8 can be introduced into the compound of the formula VI with free hydroxyl groups according to known acylation procedures by treating the compound of the formula VI with an acid with the corresponding acyl radical, preferably corresponding reactive a derivative of such an acid.

A preferred acid derivative, in particular a carboxylic acid, is, for example, a halide such as chloride or anhydride, optionally also a mixed anhydride such as an anhydride with a lower alkyl ester of carbonic acid (obtainable, for example, by reaction of a suitable salt such as ammonium, lower alkyl ester of haloformate, for example with ethyl chloroformate] or as a mixed anhydride with a suitable, optionally substituted lower alkanecarboxylic acid, such as pivalic, an activated ester of such an acid, for example an N-hydroxyamino or N-hydroxyimino ester, such as Nhydroxyimide amber or such as lower alkanol with electron withdrawing groups such as nitro, acyl groups such as lower alkanoyl groups such as acetyl groups or with aroyl groups such as benzoyl groups or optionally functionally modified carboxyl groups such as lower alkoxycarbonyl groups, for example methoxycarbonyl or ethoxycarbonyl groups or carbamoyl groups, for example Ν, Ν-dimethylcarbamoyl or cyano groups. The alkanol which may be substituted is methanol or phenol, such as cyanomethanol or 4-nitrophenol.

if necessary, the reaction is carried out in the presence of a suitable condensing agent and / or catalyst. The acid can be used, for example, in the presence of a dehydrating condensing agent such as a carbodiimide, for example dicyclohexylcarbodiimide, optionally together with a catalyst such as a copper salt, for example copper (I) chloride or cuprous chloride, or with a N-alkynylamino or lower alkoxyacetylene compound. The acid halide may be used, for example, in the presence of an acid-binding base coupling agent such as pyridine or a lower trialkylamine, for example triethylamine, or an anhydride, for example in the presence of a suitable carbodiimide and optionally in the presence of a catalyst such as zinc chloride.

When a compound of formula (VI) is used in which at least one hydroxyl group is present in the form of a reactive esterified hydroxyl group, the acyl radical R 2, R 3 and / or R 5 or R 8 may optionally be introduced by reaction with an acid salt with the corresponding acyl radical. Suitable salts include, for example, alkali metal salts, such as sodium or potassium salts, or silver salts.

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

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

Further, in compounds containing at least one alkylene 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 can be removed by hydrogenolytic cleavage can be simultaneously removed.

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 alcohololytically. Hydrolytically or alcohololytically cleavable radical is, for example, an ylidene radical which is made up of two radicals R @ 2, R @ 5 and R @ 6 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. in the presence of an acid, for example inorganic, such as one of the hydrohalic acids, for example 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 particularly in the presence of 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 If the alcohol used in the above reactions is an alcohol in the presence of anhydrous acid, especially hydrogen chloride, one of the two hydroxy groups together etherified by the formation of the ylidene moiety can be etherified simultaneously as the R is released. use at the same time to introduce e of a therapeutically modified hydroxyl group into a compound obtainable according to the invention.

In a compound having a hydrogenolytically cleavable group, in particular in the case of a hydroxyl group, an etherified, 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. as a hydrogen treatment in the presence of a noble metal catalyst such as a palladium catalyst.

In the compound obtained with an acyl radical R 2, R 5 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 one of the alkali metal acid 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 in particular with a reactive esterified alcohol in the presence of a suitable acid binding agent such as silver, lead or mercury. in the presence of the corresponding oxide or tertiary base, and alcohol and metal derivatives such as the corresponding compounds of alkali metals such as 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 can be obtained in the form of acid addition salts, particularly pharmaceutically usable, forming non-toxic salts, for example with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid 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, naphlalenesulfonic, sulfanil or cyclohexylsulfamic. Salts of this type can be obtained, for example, from free compounds containing basic groups, reactions and acids or with suitable anion exchange resins.

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

The novel compounds can be obtained as mixtures of isomers such as racemates or diastereoisomer 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, for example, by 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, if necessary, with cooling or heating, under elevated pressure and / or in an inert gas environment such as a 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, the 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 those embodiments of the process starting from a compound obtainable at any stage of the process as an intermediate, and the remaining steps of the process carried out with such a compound, or the process is interrupted at any stage, or the starting compound is formed after 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 general formula I, wherein Ra and R3 independently of one another are hydrogen, alkyl, alkenyl, arylalkyl or acyl, and the group —A — O— represents a radical of the formula —CHOR5 — CH2 —O— or

CH (CH 2 OR 6 -O-) wherein R 5 and R 6 have the meanings given for R 2, or wherein two of R a, R 3 and R 5 or R 6 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 which are 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 in liquid form may be solutions (e.g. elixirs or syrups), suspensions or emulsions. The pharmaceutical preparations can 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 means, for example using conventional methods of mixing, granulating or dragee-forming. They contain about 0.1 to 75%, in particular about 1 and 50% of 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 50-500 mg, preferably about 100-300 mg of active ingredient in a warm-blooded individual weighing 70 kg.

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

Example 1

A solution of 3.72 g of nicotinic acid chloride in 10 ml of pyridine is added dropwise at about 25 DEG to a solution of 6 .gamma., 6-anhydro-3,5-di-O-benzyl- [beta] -D-glucofuranose in 15 ml of pyridine. After standing at 25 ° for 1 hour, the reaction mixture was partitioned between water and ether, the ether phase was washed with sodium bicarbonate solution to water to pH 7, then dried over sodium sulfate and evaporated in vacuo followed by crystallization from chloroform / petroleum ether. 98 DEG-100 DEG and [ _.alpha. ] _{D @} ²⁰ = + 13.6 DEG (chloroform). An additional fraction of 1,6-anhydro-3,5-di-O-benzyl-2-O-nicotinoyl-4-D-glucofuranose is obtained from the inert liquors.

Example 2

To a solution of 7-gl, 6-anhydro-3,5-di-O-benzyl-β-D-glucofuranose in 30 ml of absolute dimethylsulfoxide was added 2.7 g of powdered potassium hydroxide, followed by dropwise addition of 5.2 g (4.7 g). ml) benzyl chloride. After the reaction has subsided, the reaction mixture is allowed to stand

1.5 hours at about 25 ° C. The reaction solution is evaporated in vacuo, taken up in ether and water, the ether phase is separated and washed with water until neutral. Drying and concentration gave an oil which was chromatographed on 200 g of silica gel. Drying under 1 Pa vacuum gave a colorless oil which slowly crystallized. It has a melting point of 50-55 ^C. [a] _D ²⁰ = + 8.3 ° (chloroform) goes ol, 6-anhydro-2,3,5-tri-O-benzyl - /? - D-glucofuranose.

Example 3

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 the reaction mixture at 60 ° for 2 hours. Then the reaction mixture is 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. There was thus obtained a colorless oil of 1,6-anhydro-3,5-dl-O-benzyl-2-O-methyl-β-D-glucofuranose [α] D ²⁰ = -3 ° (chloroform).

He attaches

A solution of 7-gl, 6-anhydro-3,5-di-O-benzyl- [beta] -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 room temperature. 25 °, then evaporated to dryness and the obtained syrup is dried at 1 Pa. A viscous, colorless syrup is obtained with [α] _D ²⁰ = -16.9 ° (chloroform) 1,6-anhydro-3,5-di-O-benzyl-2- (N-methylcarbamoyl) -, 6-D-glucof uranosy.

Example 1 a d 5

A solution of 7-gl, 6-anhydro-3,5-di-O-benzyl-5-D-glucofuranose, 8.15 g (7.45 ml) of phenyl isocyanate and 10 drops of triethylamine in 100 ml of benzene was heated for 4 hours. boil-back. flow. After evaporation to dryness, the syrup 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) -3-D-glucofuranose [α] _D ²⁰ = -27.1 ° (chloroform).

Example 1 a d 6

To a solution of 5-gl, 6-anhydro-3,5-di-O-benzyl-β-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 was stirred at room temperature. left at 25 ° for 15 hours. After addition of water, the reaction mixture is evaporated in vacuo to a syrup which is dissolved in ether and the ether phase. The mixture was shaken with 1 N hydrochloric acid, sodium bicarbonate solution and water, dried and evaporated. Crystals of 1,6-anhydro-2-O-benzoyl-3,5-dl-O-benzyl- (2-D-glucofuranose) are recrystallized from a mixture of ether and petroleum ether, m.p. [ _.alpha. ] _{D @} ²⁰ = + 7.3 DEG (chloroform).

Example 7

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

Example

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 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 7 gave 1,6-anhydro-3,5-di-O-benzyl-2-O-methylsulphonyl- N -D-glucofuranose crystals having a melting point of 142-144 ° C after recrystallization from methanol. [ _.alpha. ] _{D @} ²⁰ = -22.4 DEG (chloroform).

Example 9

A mixture of 15 g, 6-anhydro-3,5-di-O-benzyl-O-D-glucofuranose in 60 ml of pyridine and 14 g of acetylsalicylic acid in 40 ml of chloroform is allowed to react for 2 hours at 50 °. After addition of ice water, remove with chloroform and shake the chloroform layer 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-SS-di-O-benzyl-4-D-glucofuranose is obtained as an oil which is chromatographed on silica gel using cyclohexane / ethyl ester. of acetic acid in a ratio of 7: 3. [α] _D ²⁰ equals + 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 evaporated 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-1H-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-O-benzyl- (3-D-glucofuranose) in 40 ml of absolute dimethylsulfoxide was added 1.23 g of sodium hydride dispersion and after completion of hydrogen evolution a 4.5 g solution was added. After 2 hours, the reaction mixture is evaporated at 60 DEG C., the residue is taken up in ether and the ether phase is washed with water and brine, and dried and evaporated to give 1,6-anhydride of 2-diethylaminoethyl chloride. 2-O- (2-diethylaminoethyl] -3,5-di-O-benzyl- | SD glycofuranose is obtained as an oil which was chromatographed on silica gel using chloroform and acetone in a ratio of 8: 2 [ «] _D ²⁰ = + 2.6 ° (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

A solution of 5 g of 1,6-anhydro-2-O-benzoyl-3,5-di-O-benzyl- [beta] -D-glucofuranose in methanol is hydrogenated at about 25 [deg.] To 5 [deg.] Palladium on carbon. The consumption of 1 molecular equivalents of hydrogen is complete per hour, after which the hydrogenation is discontinued. Crystals having a melting point of 121 DEG -122 DEG gave 1,6-anhydro-2-O-benzoyl-3-O-benzyl- [beta] -D-glucofuranose.

Example 13

A solution of 26.0 g of 2,5-di-O-acetylsalicyloyl-3-O-benzyl-1,6-anhydro-O-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 are then 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 using 1: 1 ether: petroleum ether to give 2,5-di-O-salicyloyl-3-O-benzyl-1,6-anhydro- [3]. -D-glucofuranoses as white crystals, m.p. 102-103.5 ° and optical rotation [α] _D ²⁰ = -3 ° ± 1 ° (chloroform, c = 0.818).

Example 14

21.5 g of 2-O-acetyl-1,6-anhydro-3,5-di-O-benzyl-4-D-allofuranose are stirred for 15 hours with a solution of 0.8 g of potassium carbonate in 500 ml of methanol at a temperature of ca. 20 °. The reaction mixture was evaporated, the residue was taken up in ether and the ether solution was washed with water. After drying, filtering and evaporating the ethereal phase of the solution, a syrup is obtained which is purified by chromatography on a silica gel column, eluting with a 3: 1 mixture of methylene chloride and ethyl acetate. The 1,6-anhydro-3,5-di-O- thus obtained is thus obtained. benzyl / 3-D-allofuranosa precipitated as white crystals, mp 60-62 °, _Rf = 0.42 (thin layer chromatography on silica gel] in the system methylene chloride: ethyl acetate 3: 1 [a] ^0.20 = + 17 ° ± 1 ° (chloroform, c = 0.979).

Example 15

Analogously to Example 6, 1, 6-anhydro-3,5-di-O-benzyl-β-D-allofuranose and benzoyl chloride 1,6-anhydro-2-O-benzoyl-3,5-di were obtained. -O-benzoyl-4-D-allofuranose, m.p. 128.5-129 °.

Example 16

Analogously to Example 5, 1,6-anhydro-3,5-di-O-benzyl-2-O-1,6-anhydro-3,5-di-O-benzyl-N-allofuranose and phenyl isocyanate were obtained. - (N-phenylcarbamoyl-η 3 -D-allofuranose, melting point: 126-128 °).

Example 17

To a solution of 3g, 6-anhydro-3-O-benzyl-1H-D-glucofuranose in 20 ml of pyridine was added 3 ml of benzoyl chloride and the reaction mixture was allowed to stand at 50 ° 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. As crystals thereby obtained _{1,6-anhydro-2,5-di-O-benzoyl-3-O-benzyl-3-one} D-glucofurano se. 136 DEG-137 DEG. [.Alpha.] _D @ ²⁰ = -9.1 DEG (chloroform, c = 1.04).

Example 18

As in Example 8, 1,6-anhydro-3,5-di-O-benzyl- is obtained from 1,6-anhydro-5'-di-O-benzyl-1-D-allofuranose and α-naphthoic acid chloride. 2-O- (α-naphthoyl) -4-D-allofuranose, m.p. 113-114 °.

Example 19

In analogy to Example 6, 1,6-anhydro-3,5-di-O-benzyl-2 is obtained from 1,6-anhydro-5S-di-O-benzyl-1-D-glucofuranose and α-naphthoic acid chloride. -O- (α-naphthoyl) - β-D-glucofuranose, oil, [α] _D ²⁰ = -14.4 ± 0.3 ° (cyclohexanone-ethyl acetate 7: 3, silica gel plates).

Example 20

Analogous to Example 6, 1,6-anhydro-3,5-di-O-benzyl-2 is obtained from 1,6-anhydro-5α-di-O-benzal-4-D-glucofuranose and α-naphthoic acid chloride. -O- (3'-naphthoyl) - N -dlucofuranose.

Example 21

To a solution of 12.6 g of 3-O-benzyl-1,6-anhydro-1H-glucofuranose in 100 ml of methylene chloride and 15 ml of pyridine was added dropwise a solution of 21.8 g of acetylsalicylic acid chloride in 100 ml. ml of 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. There was thus obtained 2,5-di-O-acetylsalicyloyl-3-O-benzyl-1H-anhydro-1H-D-glucofuranose which was desacetylized as described in Example 13. The product was obtained as an oil with Rf = 0. 65 (methylene chloride-ethyl acetate 85: 15, silica gel plates [Merck]).

Example 22

In a similar manner, these compounds are obtained!

1.

2-O-acetyl-1,6-anhydro-3,5-di-O-benzyl-4-D-glucofuranose, [α] _D ²⁰ = -20.6 ° (chloroform),

2.

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

3.

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

4.

1,6-anhydro-3,5-di-O-benzyl- (3-D-mannofuranose), m.p. 117-119 °;

5.

2-0-acetyl-6-anhydro-5-0-benzyl-3-0-methyl -? - D-glycofuranose is obtained, _Rf = 0.23 (thin layer chromatography on silica gel, cyclohexane and ethyl acetate (2: 1 )

6.

1 H -anhydro-SO-benzyl-SO-methyl-β-D-glucofuranose, [α] _D ²⁰ = -8 ° ± 1 ° (chloroform),

7.

2-O-acetyl-6-Anhydro-5-O-benzyl-3-one-propyl -? - D-glycofuranose is obtained, _Rf = 0.30 (thin layer chromatography on a silica lu) cyclohexane and ethyl acetate (2: 1),

8.

1,6-anhydro-5-O-benzyl-3-On-propyl- [beta] -D-glucofuranose, [ _.alpha. ] _D @ ²⁰ = -4 DEG. + -. 1 DEG (chloroform);

9.

2-O-acetyl-1,6-anhydro-5-O-chlorobenzyl-3-O-n-propyl- (3-D-glucofuranose, yellowish oil),

10.

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

11.

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

12.

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

13.

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

1,6-anhydro-2-O-methyl-3-O-n-propyl- (3-D-xylofuranose), boiling point: 45 °, 3 Pa,

16.

-1,5-anhydro-2-O-benzyl-3-On-propyl- / 3 ^I -Dxylofuranosa Boiling point: 110 °, 1 Pa,

17.

1,5-anhydro-3-O-n-propyl-, 3-D-xylofuranose, boiling point: 105-130 ° (bath temperature),

Bye,

18.

1,8-anhydro-2-O-benzoyl-3-O-benzyl-β-D-glucofuranose, m.p. 121-122 °,

19 Dec

2,5-di-O-salicyloyl-3-O-benzyl-1,6-anhydro-1H-D-glucofuranose, melting point: 102-103.5 °,

20 May

1,6-anhydro-3,5-di-O-benzyl- (3-D-allofuranose), m.p. 60-62 °;

21.

1,6-anhydro-2,3,5-tri-O-benzoyl-, d-D-allofuranose, m.p. 163-165 °; and

22nd

1,6-anhydro-2,3,5-tri-O-benzoyl-5-D-glucofuranose, m.p. 138-140 °.

Example 23

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

Ingredients:

1,6-anhydro-3,5-di-O-benzyl-β-D-glucofuranose 1000 g absolute ethanol 100 gl, 6-anhydro-3,5-di-O-benzoyl- / 3-D-glucofuranose is stirred with the ethanol and the mixture is filled using a suitable capsule device soft gelatin capsules.

Claims (8)

Subject A process for the preparation of novel anhydrofuranose derivatives of the general formula I CH-A-O-CH 2 / CHOR 2 -CHOR 2 (I) wherein R @ 2 is hydrogen, C1 -C4 alkyl, C1 -C4 aminoalkyl, C1 -C4 alkenyl, phenylalkyl having 1 or 2 carbon atoms or C1 -C4 alkanoyl , optionally a hydroxyl or C1-C4 alkanoyloxy group or a halogen-substituted benzoyl or naphthoyl group, a C1-C4 alkylsulfonyl group, a toluenesulfonyl, a pyridylcarbamoyl group, a C1-C4 alkylcarbamoyl group or a phenylcarbamoyl group, 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 up to 4 carbon atoms or optionally hydroxy or alkanoyloxy of 1 to 4 carbon atoms, or a halogen-substituted benzoyl group and a group —A — O— means a radical of the formula —CHOR5 —CH2 —O— or —CH (CH 2 OR 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 2, R 3 and R 5 or R 6 together represent an alkylide of the invention or a phenylalkylidene residue wherein the alkyl moiety contains 1-4 carbon atoms; one of the radicals R @ 2, R @ 3 and R @ 5 and R @ 6, respectively, is other than hydrogen when the other two are hydrogen and wherein in the compounds with the group —CHORs —CH2 --O-- in the meaning of the grouping —A —O- R 3 and R 5 are other than methyl when the other two of these are methyl, and in the compounds with -CHOR 5 -CH 2 - in the meaning of -A-O-, one of R 2, R 3 and R 5 is other 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 R 2, R 5 and R 6 has a meaning other than benzyl if the other two of these are benzyl and their salts, characterized in that the compound of formula (VI) CH-A-O-CH-hor (chor) (VI) wherein A represents a radical -CHOR 5 ° -CH 2 -O- or CH (CH 2 OR 6 °) -O-, and at least one radical R ² °, R 3 ^O , R 5 ° and R 6 ° denotes hydrogen and others have the meaning R 2, R 3, R 5, optionally R 6, or a reactive ester thereof, is reacted with an alcohol or acid corresponding to the radical R 2, R 3 and / or R 5, or R 6, or a reactive derivative thereof, and, if desired, substituted, introduced into the compounds obtained; are cleaved, and / or the racemate mixtures obtained are separated into pure racemates, and / or the racemates obtained are resolved into optical antipodes, and / or the obtained salts are converted into free compounds or other salts, or the obtained free compounds are converted into salts thereof . 2. A process according to claim 1, wherein the compound of formula VI is reacted with a reactive ester of the corresponding alcohol having the substituents R2, R3, R5 or R6. 3. A process according to claim 1, wherein at least one hydroxyl group in a compound of formula VI is converted to a reactive esterified hydroxyl group and then treated with a corresponding alcohol containing R @ 2, R @ 3, R @ 5 or R @ 6. R2, R3, R5 or R6. 4. The process of claim 3 wherein the compound of formula VI is treated with an acid or a reactive derivative thereof. Process according to one of Claims 1 to 4, characterized in that a compound of the general formula (VI) is used as the starting material, wherein the group "A-O" represents the radical -CHOR ^{5 O} -CH 2 -O-, R 2 is hydrogen, C 1 -C 3 alkyl, C 1 -C 4 dialkylaminoalkyl, benzyl, C 2 -C 4 alkanoyl, benzoyl, o-hydroxybenzoyl, o-alkanoyloxybenzoyl of 2 to 4 carbon atoms o-alkanoyloxy moieties, naphthoyl, alkylcarbamoyl of up to 4 carbon atoms, phenylcarbamoyl, alkylsulfonyl of 1 to 3 carbon atoms, toluylsulfonyl or pyridylcarbonyl and R 3 and R 5 are each independently hydrogen, alkyl of 1 to 3 carbon atoms, benzyl, a chlorobenzyl or benzoyl group wherein one of R2, R3 and R5 is other than hydrogen when the other two of said radicals are hydrogen, and wherein one of R2, R5 and R5 is other than methyl when the other two are are methyl, and wherein one of R2, R3 and R5 is other than acetyl, p wherein the other two of said residues are acetyl. Process according to one of Claims 1 to 4, characterized in that a compound of the general formula (VI) is used as the starting material, wherein the group "A" O "represents the radical" CHOR ⁵ O "CH ² -O", R 2 is C 2 -C 4 alkanoyl, benzoyl, o -hydroxybenzoyl, C 2 -C 4 -alkanoyloxybenzoyl, o -alkanoyloxy, naphthoyl or pyridylcarbonyl, and R 3 and R 5 are each independently hydrogen, C 2 -C 4 alkyl; or 3 carbon atoms, benzyl, chlorobenzyl, benzoyl or o-hydroxybenzoyl. 7. A process according to any one of claims 1 to 4, wherein the compound of formula VI is used as the starting material, wherein the group -A-O- is the radical -CHOR ⁵ -CH 2 -O-, R 2 is hydrogen and R 5 and R 5 are independently C 1 -C 3 alkyl, allyl, methallyl, benzyl or chlorobenzyl. Process according to one of Claims 1 to 4, characterized in that a compound of the general formula (VI) is used as the starting material, wherein the group "A-O" represents the radical -CHOR ^{5 O} -CH 2 -O-, R 2 is hydrogen, C 2 -C 4 alkanoyl, benzoyl, o -hydroxybenzoyl, o -acetoxybenzoyl, naphthoyl or pyridylcarbonyl, and R 3 and R 5 are independently C 1 -C 3 alkyl, benzyl, chlorobenzyl, benzoyl, o a hydroxybenzoyl, o -acetoxybenzoyl or naphthoyl group.