IE43457B1 - Novel 1-deoxyribofuranuronic acid derivatives, a method for producing them and medicaments comprising them - Google Patents

Abstract

beta -D-1-(6-Amino-9H-purin-9-yl)-1-deoxy-2,3-di-O-nitroribofuranuronic acid ethylamide of the formula I is distinguished by a very good cardiovascular action and is therefore suitable for the treatment of cardiovascular disorders. Preparation takes place by reacting beta -D-1-(6-amino-9H-purin-9-yl)-1-deoxyribofuranuronic acid ethylamide with a reagent which transfers NO2 groups.

Description

The invention relates to therapeutically valuable nitric acid esters of substituted beta-D-l-(6-amino-9Hpurine-9-yl)-l-deoxy-ribofuranuronic acids derivatives, methods for producing them and medicaments which comprise these active substances.

It is known that beta-D-l-(6-amino-9H-purine-9-yl)-1deoxy-ribofuranurohic acid esters (German Offenlegungsschrift No. 2,244,215), beta-D-l-(6-amino-9H-purine-9-yl)-1-deoxyribofuranuronamides (German Offenlegungsschrift No. 2,034,785) and beta-D-l-(6-amino-9H-purine-9-yl)-1-deoxyribofuranose derivatives nitrated on the ribose radical (German Offenlegungsschrift 2,105,560) have an advantageous cardiac action.

The present invention provides nitric acid esters of substituted beta-D-1-(6-amino-9H-purine-9-yl)-1-deoxyribofuranuronic acid derivatives of the general formula I 43487 in which 2 R and R denote a hydroxyl group or an -O-NO^ group in the case of which at least one of the radicals R^ and 2 R is an -O-NO^ group, R denotes a hydrogen atom, a straight-chained or branchedchained alkyl radical with 1 to 7 carbon atoms, and preferably 1 to 4 carbon atoms, a straight-chained or branch-chained alkoxy radical with 1 to 7 carbon atoms, preferably 1 to 4 carbon atoms, or a phenyl radical which optionally carries one or more substituents, and preferably up to 2 substituents, 6 X denotes a -NR R group or an -0-R group, preferably a -NR4r5 group, in the case of which R and R can be the same or different and represent a hydrogen atom, a straight-chained or branch-chained alkyl, alkenyl or alkynyl radical, which optionally carries one or more substituents, preferably two substituents and more especially one substituent, with up to 7 carbon atoms, preferably up to 4 carbon atoms, or a eycloalkyl radical with 3 to 7 carbon atoms, and 4 5 preferably 5 to 6 carbon atoms, or R and R together represent an alkylene group with 2 to 5 carbon atoms, and preferably with 5 carbon atoms, in which optionally a methylene group can be replaced by -0-, -S- or by a 7 7 p, NR group, in which R denotes a straight-chained or branched-chained alkyl radical with 1 to 4 carbon atoms, as for example a pentamethylene group, a 3-oxa-, a 3-thia- or a 3-aza-pentamethylene group, preferably a 3-oxa-pentamethylene group and, more especially, a pentamethylene group, and R5 denotes a hydrogen atom, a straight-chained or branchchained alkyl radical with 1 to 7 carbon atoms, preferably with 1 to 4 carbon atoms, a cycloalkyl radical with 3 to 7 carbon atoms, preferably with 5 to 6 carbon atoms, a phenyl radical, which optionally carries one or more substituents, preferably up to two substituents, and more particularly one substituent, or an aralkyl radical, preferably a benzyl radical.

Preferably use is made of compounds of the general formula I, in which 1 2 R and R denote a hydroxyl group or an -O-NO^ group, in the case of which at least one of the radicals RP and 2 R is an -0-N0? group, R is a hydrogen atom, X denotes a -NHR5 group or an -OR5 group, in the case of which R5 denotes a straight-chained or branch-chained alkyl radical, which optionally carries one or more substituents, preferably two substituents, and more particularly one substituent, with 1 to 4 carbon atoms, or a cycloalkyl radical with 3 to 7 carbon atoms, and preferably 5 or 6 carbon atoms, and R5 represents a straight-chained or branch-chained alkyl radical with 1 to 4 carbon atoms. Ά straight-chained or branch-chained alkyl group with 1 to 7 carbon atoms is for example a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.-butyl or tert.- . - 4 <345? butyl, pentyl, isopentyl, 1- or 2-methylbutyl, tert.-pentyl, hexyl, isohexyl, 1-, 2- or 3-methyl-pentyl, 1-, 2- or 3ethyl-butyl, 1,2-, 1,3- or 2,3-dimethyl-butyl, heptyl or isoheptyl group.

A straight-chained or branch-chained alkenyl group with 2 to 7 carbon atoms is for example a vinyl, allyl, isopropenyl, 1-pentenyl or 1,3-butadienyl group.

A straight-chained or branch-chained alkynyl group with 2 to 7 carbon atoms is for example an ethynyl, propargyl, 2-butynyl, 1-pentynyl or 2-hexynyl group.

A cyeloalkyl group with 3 to 7 carbon atoms is for example a cyclopropyl, cyclopentyl, 2- or 3-methyl-cyclopentyl, a cyclohexyl group, a methylcyclohexyl or cycloheptyl group.

A straight-chained or branch-chained alkoxy radical with 1 to 7 carbon atoms is for example a methoxy, ethoxy, n-propoxy, isopropoxy, allyloxy, n-butoxy or n-heptyloxy group.

Suitable substituents for the phenyl radical are the following: straight-chained or branch-chained alkyl radicals with 1 to 4 carbon atoms, as for example methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl or tert.-butyl groups, straight-chained or branch-chained alkoxy radicals with 1 to 4 carbon atoms, as for example a methoxy, ethoxy, propoxy, isopropoxy or butoxy group, nitro groups and halogen atoms.

As substituents for any alkyl, alkenyl and alkynyl groups it is possible to use straight-chained and branchchained alkoxy groups with 1 to 4 carbon atoms, nitro groups and halogen atoms.

The term “halogen atoms is to be understood to mean chlorine, fluorine and bromine atoms.

The subject matter of the present invention further comprises a method for the production of compounds of the general formula 1 3 in which R , R , R and X have the above-mentioned meanings, characterised in that a nucleoside of the general formula II OH OH xn which R and X have the above-mentioned meanings is reacted with a reagent transferring groups.

This reaction with the reagent transferring -KOj groups is carried out in a conventional manner. For example one can use nitric acid and preferably a mixture of nitric acid and acetic anhydride.

Conveniently the production of the compounds in accordance with the invention using a mixture of nitric acid and acetic anhydride can be carried out at low temperatures and preferably between -70°C and room temperature. Generally the purine nucleoside is simply stirred into the cooled fuming nitric acid and the mixture is left at a low temperature until the reaction is terminated. Under these relatively mild conditions the glycoside bond, which is sensitive to acidic hydrolysis is substantially protected against attack. In order to protect the amino group of the adenosine radical it is to be recommended to add, even before the addition of the nucleoside, a nitrite catcher, as for example urea, to the nitric acid in order to protect the adenosine radical against disamination by nitrous acid. The reaction which rapidly progresses to the formation of 2'- and, respectively, 3'-mononitrate esters and 2',31-dinitrate esters, is terminated within a few hours in the case of the temperature range indicated.

For further processing the reaction mixture is poured onto ice and neutralised with solid sodium hydrogen carbonate.

The mixture of the nitrate esters is removed from the aqueous phase by extraction as for example by means of ethyl acetate and then fractional crystallisation and/or column chromatography is used for separation.

The beta-D-l-(6-amino-9H-purine-9-yl)-1-deoxy-ribo7 furanuronamides used as starting compounds can be produced, for example, by reaction of beta-D-l-(6-amino-9H-purine-9yl)-1-deoxy-ribofuranuronic esters (see German Offenlegungsschrift 2,317,770) or of beta-D-l~(6-amino-9H-purine-9~ yl)-l-deoxy-ribofuranuronic acid halides (see German Offenlegungsschrift 2,213,180) with the corresponding amines, beta-D-l-(6-amino-9H-purine-9-yl)-1-deoxy-ribofuranuronic acid esters from beta-D-l-(6-amino-9H-purine9-yl)-1-deoxy-ribofuranuronic acids by conversion into the corresponding silver salt and reaction of the silver salt with the corresponding alkyl halide (see German Offenlegung sschrift 2,136,741).

The compounds in accordance with the invention of the general formula I are characterised by a very satisfactory action on the heart and blood circulation, and more especially they have a surprisingly pronounced coronarydilating action. The unusually long persistence of their action is particularly surprising. It is of special significance that this action can also be achieved in the case of oral administration.

Additionally the compounds in accordance with the invention of the general formula I are characterised by a glucagon-like activity: for example, an increase in arterial glucose level (hexokinase method, described in H.U. Bergmeyer, Methoden der enzymatischen Analyse, Verlag Chemie, Weinheim, 1974) and a long-lasting decrease in plasma free fatty acid levels (titrimetry according to V.P. Dole, J. Clinic. Invest. 35, 150 (1956) are observed.

The compounds in accordance with the invention of - 8 43457 the general formula I, optionally in combination with other pharmagologically active substances, are therefore suitable to be administered parenterally and orally, for example for treatment of angina pectoris, post infarct conditions, for prophylactic treatment of patients threatened by infarction, for treatment of cardiac insufficiency, idiopathic hypoglycemia and hyperinsulinism.

Preceding investigations revealed that from the prior art adenosine derivatives possessing high effectiveness with respect to their action on the heart, compound A (see Table 1) exert an exceptionally strong and longlasting coronary-dilating action. Therefore the compounds in accordance with the invention were compared with this compound A with respect to their coronary-dilating action.

The results shown in Table 1 were obtained by using the well-known method of Langendorff in a modified version from isolated hearts Of guinea-pigs. The range of concentration was from 0,001 to 5.0 p.g active compound per ml of the nutritive solution (Krebs-Henseleit). The average effective concentration (CE.„) from which the results of 60 Table 1 were obtained ranged from 0.005 to 1.0 [ig/ml.

As one measure for the long lasting action the relative area below the graph of the coronary flow versus time was determined. This integration was carried out starting at the time where the nutritive solution containing the active substance was substituted by a neutral nutritive solution, which was effected, when the coronary flow reached a maximum value, up to the time the coronary flow fell back to the original level. These results are reproduced in column 2 of Table 1.

As a further parameter indicating the long lasting action the time of fading away of the effectiveness was determined, that is to say the time from the point, where the coronary flow reached its maximum value to the point the coronary flow was reduced again to the original level.

These results are reproduced in column 3 of Table 1.

From Table 1 it can easily be seen that the new compounds B to E in accordance with the invention show a very strong action with regard to the coronary flow, which persists for a longer period of time than the action of the prior art compound A. - 10 <34 57 ΤΑΒΙΕ 1 Action on coronary flow */ relative area below the graph of the coronary flow versus time **/ time from maximum value of coronary flow to point, where original value is reached again 43487 It is possible to produce medicaments which comprise one or more of the compounds in accordance with the invention as an active substance, possibly also mixed with other pharmacologically active substances, as for example cardiac glycosides, beta-receptor blockers, sedatives, tranquilizers and substances which reduce the cholesterine and the lipid level. The medicaments can be produced in a conventional maimer for example for enteral, percutaneous or parenteral administration by combining the active substance with a suitable pharmaceutical vehicle, as for example a filler, a diluent, a corrective material and/or other components which are conventional for medicaments. The medicaments can be produced for example in a solid form as tablets or capsules or in a liquid form as solutions or suspensions. If required, they can be stabilised or they can comprise adjuvants such as preserving, stabilising, moistening or emulsifying materials, salts for changing the osmotic pressure or buffers. Preparations suitable for oral administration can comprise, if necessary, flavouring and sweetening materials. The pharmaceutical vehicles can also comprise conventional diluting or tabletising additives, such as cellulose powder, maize starch, lactose, and talcum, as are conventional for such purposes.

The production of the pharmaceutical preparations is carried out in a conventional manner, as for example by means of conventional mixing, granulating or dragee making methods. The pharmaceutical preparations can comprise 0.1% to 50%, and preferably 1% to 10% of the active substance in accordance with the invention. The administration can be enteral, for example oral or parenteral, the individual doses lying between 0.05 and 50 mg, and preferably between 0,1 and 5 mg of active substance. The doses indicated can be administered 1 to times daily, for example at mealtimes and/or in the evening.

The individual dose, the frequency of administration and the duration of the treatment are to be in accordance with the nature and severity of the disease.

The invention therefore also includes medicaments, which are characterised by a content of one or more of the compounds in accordance with the invention, possibly also mixed with other pharmacologically active materials, and their production.

Examples of a batch for the production of 100,000 tablets each containing 1 mg of active substance 0.100 kg p-D-l-(6-amino-9H-purine-9-yl)-18.200 kg 7.200 kg 0.300 kg 0,400 kg 0.500 kg 0.100 kg 0.500 kg 0.200 kg 17.500 kg deoxy-3-O-nitroribofuranuronethylamide (1) maize starch (2) lactose (3) amorphous silicic acid (4) sodium lauryl sulphate (5) gelatine (6) glycerine (7) talcum (8) magnesium stearate (9) The active substance (1) is mixed with 1 kg of (3) and the mixture is finely powdered. To this mixture 7.20 kg of (2), the rest of (3), (4) and (5) is added. After mixing and sieving this powder mixture is moistened with a solution of (6) and (7) in 7 1 water and granulated through a sieve with a mesh width of 1.25 mm. This granulate is dried and thoroughly mixed with the rest of (2), (8) and (9) and then pressed on a rotating machine to form tablets with a weight of 175 mg.

Examples of a batch for the production of 100,000 capsules each containing 1 mg of active substance 0.100 kg p-D-l-(6-amino-9H-purine-9-yl)-1-deoxy2, 3 -di-0-nitroribofuranuronethylaiid.de (1) 6.200 kg lactose (2) 2.250 kg carboxymethylcellulose (3) 0.450 kg polyvinylpyrrolidone (4) 9.000 kg (1), (2) and (3) are mixed and finely powdered. (4) is dissolved in 3 1 of water. The powder mixture is moistened with this solution and granulated through a sieve with a mesh width of 1.25 mm. The granulate is dried and capsules of size 4 are filled with 90 mg of the granulate.

Following is a description by way of Example of methods of carrying the invention into effect.

Example 1. 1.67 g of urea are added carefully while stirring to 28 ml of ice-cooled 100% nitric acid. Then at 6°C 43487 .0 g (17 mmoles) of beta-D~l-(6-amino-9H-purine-9-yl)-1deoxy-ribofuranuronic acid methyl ester are added within a period of 20 minutes in small portions and the solution is allowed to stand for 20 hours at -10°C.

The preparation is poured onto 250 ml of ice/water, covered with ethyl acetate and neutralised with solid NaHCOg. The ethyl acetate phase is separated off and the aqueous phase is extracted four more times with respective portions of 80 ml of ethyl acetate. The bulked ethyl acetate phases are dried over Na^SO^ and evaporated down to a syrup-like consistency, which consists of a mixture of mono- and dinitrated product. Traces of unreacted starting product remain in the aqueous phase.

The syrup is taken up in approximately 20 ml of ethyl acetate and placed on a silica gel column packed in ethyl acetate (3 x 80 cm). Then eluation is firstly carried out with 500 ml of ethyl acetate and eluation is then carried out with stepwise gradients of respective 100 ml portions of ethyl acetate comprising 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, and, respectively, 3.5% of methanol (that is to say seven times 100 ml), and finally eluation is carried out with 750 ml of ethyl acetate comprising 4% methanol. Fractions of approximately 20 ml are obtained, which are examined chromatographically on silica gel foils in chloroform/methanol (4 to 1). The corresponding fractions (Rf value of the dinitrated product: approximately 0.7 and Rf value of the mononitrated product: approximately 0.6) are jointly condensed and yield 1.70 g (26%) of beta-D-1(6-amino-9H-purine-9-yl)-1-deoxy-2,3-di-0-nitroribofuran- 15 13457 uronic acid methyl ester as a yellowish foam and, respectively, 3.70 g (64%) of beta-D-l-(6-amino-9H-purine-9-yl)-1deoxy-3-O-nitroribofuranuronic acid methyl ester as a colourless foam. Both substances are chromatographically and analytically pure. Beta-D-l-(6-amino-9H-purine-9-yl)1-deoxy-2,3-di-0-nitro-ribofuranuronic acid methyl ester can be recrystallised from acetic acid; fusing point: 167°C.

Beta-D-1-(6-amino-9H-purine-9-yl)-1-deoxy-3-0-nitroribofuranuronic acid methyl ester precipitates in an amorphous condition from methanol with a fusing point of 100 to 112°C.

In a similar manner by reaction with beta-D-1-(6amino-9H-purine-9-yl)-l-deoxy-ribofuranuronic acid ethyl ester it is possible to obtain beta-D-1-(6-amino-9Hpurine-9-yl)-1-deoxy-2,3-di-0-nitro-ribofuranuronic acid ethyl ester and beta-D-l-(6-amino-9H-purine-9-yl)-1-deoxy3-0-nitro-ribofuranuronic acid ethyl ester.

The beta-D-1-(6-amino-9H-purine-9-yl)-1-deoxyribofuranuronic acid ethyl ester used as a starting product can be produced in accordance with the method described in the German Offenlegungsschrift 2,244,215.

Example 2.

Firstly 700 mg of urea are added while stirring to 11.0 ml of ice-cooled 100% HNO^ and then 2.0 g (6.5 mmoles) of beta-D-1-(6-amino-9H-purine-9-yl)-1-deoxy-ribofuranuronethylamide are added in small portions within a period of minutes. The solution is stirred for 3 hours on an ice bath and then poured onto 50 ml of ice/water and neutralised with solid NaHC03. Following this the preparation is extracted with five 20 ml portions of ethyl acetate. The organic phases are dried over Na„S0. and £. 4 condensed in vacuo. 2.3 g of yellow syrup are produced.

In a thin layer chromatogram (silica gel, CHCl^/CH^CN/MeOH (5 to 4 to 1) two closely adjacent spots are found.

Beta-D-l-(6-amino-9H-purine-9-yl)-1-deoxy-2,3-di-0nitro-ribofuranuronethylamide has an Rf value of 0.7 and beta-D-l-(6-amino-9H-purine-9-yl)-1-deoxy-3-0-nitroribofuranuronethylamide has an Rf value of 0.5.

The 2.3 g of syrup are taken up in 20 ml of CHC13/ CH3CN (6 to 4). The undissolved residue is filtered off and after reerystallisation from 50 ml of methanol yields 250 mg (11%) of beta-D-l-(6-amino-9H-purine-9-yl)-1-deoxy3-0-nitro-ribofuranuronethylamide in the form of colourless needles.

The filtrate is taken up on a silica gel column (3.2 cm in diameter x 70 cm). Eluation is firstly carried out with 500 ml of CHC13/CH3CN (6 to 4) and then with respective 100 ml portions of CHC13/CH3CN (6 to 4), to which increasing quantities of MeOH (2, 4, 6, 8%) are added and finally eluation is carried out with 1 litre of CHCl3/CH3CN/MeOH (5 to 4 to 1). Fractions of approximately 20 ml are taken and their composition is checked chromatographically on silica gel foils in CHCl3/CH3CN/MeOH (5 to 4 to 1). The corresponding fractions are condensed so as to lead to the production of 400 mg (15.5%) of beta-D-l-(6amino-9H-purine-9-yl)-1-deoxy-2,3-di-0-nitro-ribo-furanuronethylamide and 700 mg (31%) of beta-D-l-(6-amino-9H-purine17 43457 9-yl)-l-deoxy-3-0-nitro-ribofuranuronethylamide, both as a colourless foam.

Beta-D-1-(6-amino-9H-purine-9-yl)-l-deoxy-2,3-di-0nitro-ribofuranuronethylamide is recrystallised from CH^CN and leads to colourless needles with a fusing point of 163 to 165°C with decomposition.

Beta-D-1 - (6 -anjino -9H-purine-9 -yl) -1 -deoxy-3 -0 -nitroribofuranuronethylamide is produced as colourless needles on recrystallisation from methanol with a fusing point of 200°C with decomposition.

The beta-D-1-(6-amino-9H-purine-9-yl)-1-deoxyribofuranuronethylamide used as a starting material can be produced in accordance with the method described in the German Offenlegungsschrift 2,034,785.

Example 3. g of urea and then 11.7 g (40 mmoles) p-D-l-(6amino-9H-purine-9-yl)-1-deoxyribofuranuronmethylamide are added slowly to 80 ml of 100% nitric acid at -5°C. The reaction mixture is allowed to stand for 6 hours at 0°C and is then poured onto 400 g of ice. This mixture is covered with 200 ml of ethyl acetate and neutralised with solid NaHC03. After several extractions of the aqueous phase with ethyl acetate the combined extracts are dried with sodium sulfate. Then the solvent is distilled off under reduced pressure. The residual mixture of products is separated by column chromatography (silica gel neutral (Merck) 450 g, solvent chloroform/ethanol 40 to 1). From the first fractions 2.4 g (16%) of p-D-l-(6-amino-9Hpurine-9-yl)-l-deoxy-2,3-di-0-nitroribofuranuronmethylamide 43487 are obtained, after recrystallisation and drying (6 hours at 40°C in vacuo), the product decomposes at 146 to 148°C.

By continuation of the eluation 1.2 g (9%) of β-D-l(6-amino-9H-purine-9-yl)-1-deoxy-2-O-nitroribofuranuronmethylamide are obtained. After recrystallisation from methanol this compound decomposes at 190°C.

By further continuation of the eluation 3.7 g (26%) of p-D-l-(6-amino-9H-purine-9-yl)-l-deoxy-3-0-nitro-ribofuranuronmethylamide are obtained. After recrystallisation from methanol this compound decomposes above 200°C.

The β-D-l-(6-amino-9H-purine-9-yl)-1-deoxyribofuranuronmethylamide used as a starting material can be produced in accordance with the method described in the German Offenlegungsschrift 2,034,785.

Example 4.

According to Example 3 by nitration of 6.6 g (20 mmoles) p-D-l-(6-amino-9H-purine-9-yl)-1-deoxyribofuranuronethylamide and separation of the products by column chromatography 1.2 g (17%) of p-5-l-(6-amino-9H-purine-9yl)-1-deoxy-2-O-nitroribofuranuronethylamide are obtained as the second fraction of the chromatography. After recrystallisation the compound decomposes at about 175°C.

Example 5. 100 ml of 100% nitric acid (density 1.52) are cooled to -5°C. While stirring 6 g urea and then 9.5 g (28 mmoles) of $-D-l-(6-amino-9H-purine-9-yl)-l-deoxyribofuranuronisopropylamide are slowly added. After stirring for five hours at 0°C the reaction mixture is poured onto 400 g of ice and covered with 200 ml of ethyl acetate and neutralised with 200 g of solid NaHCO^. After complete extraction of the aqueous phase with ethyl acetate the extracts are combined, dried with sodium sulfate and then the solvent is distilled off in vacuo. By extracting the residual mixture of products (about 10 g) with a boiling ethyl acetate a fractional part of p-D-l-(6-amino-9Hpurine-9-yl)-l-deoxy-2,3-di-0-nitroribofuranuronisopropylamide is obtained as an insoluble residue. The isolation of the rest is carried out by column chromatography with 450 g of neutral silica gel (Merck). For eluation a mixture of chloroform/ethanol (40 to 1 in the beginning and 10 to 1 later on) is used. 3.1 g (27%) of p-D-l-(6amino-9H-purine-9-yl)-l-deoxy-2,3-di-0-nitroribofuranuronisopropylamide are obtained. This compound melts at 170 to 172°C.

By continuation of the eluation 1.8 g.(17.5%) of β-Dl-(6-amino-9H-purine-9-yl)-l-deoxy-2-0-nitroribofuranuronisopropylamide are obtained. After recrystallisation from methanol the compound decomposes at 193°C.

By further continuation of the eluation 2.5 g (23%) of f3-D-l-(6-amino-9H-purine-9-yl)-l-deoxy-3-0-nitroribofuranuronisopropylamide are obtained. This compound crystallises with 1 mole of crystal water and melts at 143°C under decomposition.

The β-D-l-(6-amino-9H-purine-9-yl)-1-deoxyribofuranuronisopropylamide used as a starting material can be produced in accordance with the method described in German Offenlegungsschrift 2,034,785. - 20 43457 Example 6.

In the same manner as described in Example 5 bynitration of 10 g (30 mmoles) of f-D-l-(6-amino-9H-purine9-yl)-1-deoxy-ribofuranuron-n-butylamide and subsequent separation of the products by column chromatography 0.4 g (3.1%) of P-D-l-(6-amino-9H-purine-9-yl)-l-deoxy-2,3-di-0nitroribofuranuron-n-butylamide are obtained as first fraction of the chromatography. The compound can be recrystallised from ethyl acetate and decomposes at 156°C.

By continuation of the eluation of the chromatography column 1 g (8.7%) of fi-D-l-(6-amino-9H-purine-9-yl)-ldeoxy-2-0-nitroribofuranuron-n-butylamide is obtained which decomposes above 105°C.

By further eluation 3 g (26%) of p-D-l-(6-amino-9H15 purine-9-yl)-l-deoxy-3-0-nitroribofuranuron-n-butylamide are obtained. After recrystallisation from methanol this compound decomposes at 187°C.

The p-D-l-(6-amino-9H-purine-9-yl)-1-deoxyribofuranuron-n-butylanide used as a starting material can be produced in accordance with the method described in the German Offenlegungsschrift 2,034,785.

Claims (18)

1. CLAIMS:1. Compounds of the general formula I in which 1 2 R and R denote a hydroxyl group or an O-NO., group in the case of which at least one of the radicals R^ and 2 . R is an -O--NO2 group, R denotes a hydrogen atom, a straight-chained or branch chained alkyl radical with 1 to 7 carbon atoms, a straight-chained or branch-chained alkoxy radical with 1 to 7 carbon atoms, or a phenyl radical which optionally carries one or more substituents, 4 5 6 X denotes a -NR R group or an -0-R group, in the case of which 4 5 R and R can be the same or different and represent a hydrogen atom, a straight-chained or branch-chained alkyl, alkenyl or alkynyl radical, which optionally carries one or more substituents, with up to 7 carbon atoms, or a cycloalkyl radical with 3 to 7 carbon 4 5 atoms, or R and R together represent an alkylene group with 2 to 5 carbon atoms, in which optionally a methylene group can be replaced by -0-, -S- or by a _ 7 7 NR group, in which R denotes a straight-chained or branch-chained alkyl radical with 1 to 4 carbon atoms, and θ R denotes a hydrogen atom, a straight-chained or branchchained alkyl radical with 1 to 7 carbon atoms, a cycloalkyl radical with 3 to 7 carbon atoms, a phenyl radical, which optionally carries one or more substituents, or an aralkyl radical.

2. Compounds of the general formula I in which 1 2 R and R have the meanings given in claim 1, R is a hydrogen atom, 5 6 X denotes a -NHR group or an -OR group, in the case of which R denotes a straight-chained or branch-chained alkyl radical, which optionally carries one or more substituents, with 1 to 4 carbon atoms, or a cycloalkyl radical with 3 to 7 carbon atoms, and R 5 represents a straight-chained or branch-chained alkyl radical with 1 to 4 carbon atoms.

3. Compounds of the general formula I in which 1 2 R and R have the meanings given in claim 1, R 5 is a hydrogen atom, X denotes a -NHR 5 group, in the case of which 5 R denotes a straight-chained or branch-chained alkyl radical with 1 to 4 carbon atoms or a cycloalkyl radical with 5 or 6 carbon atoms.

4. p-D-l-(6-amino-9H-purine-9-yl!-l-deoxy-2-ΰnitroribofuranuronethylamiae.

5. Beta-D-l-(6-amino-9H-purine-9-yl)-l-deoxy-3-0nitroribofuranuronethylamide.

6. Beta-D-l-(6-amino-9H-purine-9-yl)-1-deoxy-2,3di-O-nitro-ribofuranuronethylamide.

7. β-D-l-(6-amino-9H-purine-9-yl)-1-deoxy-2-O-nitroribofuranuronisopropylamide.

8. p-D-l-(6-amino-9H-purine-9-yl)-l-deoxy-S-O-nitroribofuranuroni sopropylamide.

9. . p-D-l-(6-ajnino-9H-purine-9-yl) -1-deoxy-2,3-diO-nitroribofuranuroni sopropylamide.

10. A method for the production of compounds of the general formula I as claimed in claim 1 characterised in that a nucleoside of the general formula II m 2 OH OH in which R and X are as defined in claim 1 is reacted in a conventional manner with a reagent transferring -N0 2 groups.

11. A method in accordance with claim 10, characterised in that as a reagent transferring -N0 2 groupsuse is made of nitric acid.

12. A method in accordance with claim 10, characterised in that as a reagent transferring -N0 2 groups use is made of a mixture of nitric acid and acetic anhydride in the presence of a nitrite catcher.

13. A medicament comprising one or more compounds as claimed in claim 1.

14. A medicament in accordance with claim 13 comprising in addition other pharmacologically active substances.

15. A method for the production of medicaments in accordance with claims 13 and 14, characterised in that one or more compounds of the general formula I, if desired also mixed with other pharmacologically active materials, is mixed with a non-toxic inert solid or liquid vehicle, conventional in such preparations, which is suitable for therapeutic administration.

16. A pharmaceutical preparation comprising 0.1% to 50% by weight of a compound according to any one of claims 1 to 9 in admixture with one or more solid or liquid non-toxic pharmaceutically acceptable inert carriers.

17. A method for the preparation of compounds of the general formula I according to claim 10 substantially as described with reference to any one of the specific examples hereinbefore set forth.

18. A compound of the general formula I according to claim 1 when prepared by the method claimed in any one of claims 10 to 12.