DE2800315A1 - Adenosine desaminase inhibitor isocoformycin - useful for potentiating antitumour and antibacterial activity of formycin and adenine arabinoside - Google Patents

Abstract

Isocoformycin (3-beta-D-ribofuran osyl-3,6,7,8-tetrahydroimidazo 4,5-d 1,3 -diazepin-7-ol), of formula (I), is a new cpd:- (I) is an adenosine desaminase inhibitor useful for potentiating the antitumour and antibacterial activity of formycin and adenine arabinoside. It has higher activity han 9-beta-D-ribofuranosyl-6-hydroxymethyl-1,6-dihydropurine. In example, (I) is prepd. from 9-(2,3,5-tri-O-acetyl-beta-D-ribofuranosyl)-6-hydroxymethyl-1,6-d- ihydropurine.

Description

Case: isocoformycin

t'Isocoformycin, process 3'- its manufacture and pharmaceuticals " The invention relates to the subject matter characterized in the claims.

Isocoformycin, i.e. 3-ß-ribofuranosyl-3,6,7,8-tetrahydroimidazo [4,5-d] [1,3] -diazapin-7-ol is an analog of coformycin, the most potent inhibitor of adenosine deaminase known to date; see M. Ohno, N. Yagisawa, S. Shibahara, S. Kondo, K. Maeda and H. Umezawa, J. Am. Chem. SOG., 96: 4326 (1974). Recently, the isolation of a strong Adenosine and ara-A-desamnase inhibitors, namely 2'-deoxycoformycin, from the Fermentation liquor from a strain of Streptomyces antibioticus reported; see P.W.K. Woo and H.W. Dion, J. Heterocyclic Chem., Vol. 11 (19-4), pp. 641.

Isocoformycin has a pronounced inhibitory effect on deaminating Enzymes that inactivate formycin and adenine arabinoside. Formycin and adenine arabinoside will as antiviral agents and antitumor agents in mammals and birds used. Isocoformycin has the advantage that it has a prolonged effect made possible by formycin and adenine arabinoside.

Isocoformycin is the first synthetic nucleoside with a 7-membered ring as a base residue. It has the following physical properties: (1) F .: 185-1900C (decomp.) (2) [α] D25: -58 ° (3.0, H2O) (3) UV spectrum: #maxMeOH 281 nm ( # 9600) (4) mass spectrum: 284 (M +), 266 (M-H20), 252, 193, 163, 149, 135, 134, 121 (5) IR spectrum (KBr): 3300, 2900, 1720, 1630 , 1485, 1440, 1390, 1280, 1200, 1040 # 1100 cm 1 (6) 1 H-NMR spectrum (D2O, 10MHz): # 3.52 (2H, m, 8-CH2), 4.27 (2H, m, 5'-CH2), 4.6 # 5.1 (3H, 2 ', 3', 4'-H), 5.84 (1H, m, 7-CH), 6.72 (1H, dd , 1'-H), 7.47 (1H, s), 8.18 (1H, d) (7) 13 C-NMR spectrum (D2O, XL-100). (chemical shift (ppm) versus external TMS using dioxane (67.4 ppm) as internal standard): C11 88.5 ppm C2 146 ppm C2 71.5 C52 134 C3 '74.1 D7 74.5 C4' 86.4 C8 36 , 6 C5 '62.6 C9 125 010 133 (8) thin layer chromatography on silica gel: Rf value = 0.12 in ethyl acetate, methanol and water (4: 1: 1) Rf value = 0.31 in n-butanol, Ethanol, chloroform and 17% ammonia (4: 5: 2: 2) isocoformycin can be produced by the following process: According to process A, a 9-ß-D-ribofuranosyl-6-hydroxymethyl-1,6-dihydropurine sulfonate, whose hydroxyl groups on the ribose residue are provided with protective groups, of the general formula I. in which the radicals R are identical or different and acyl radicals of unsubstituted or halogen-substituted fatty acids with 2 to 12 carbon atoms, benzoyl groups optionally substituted by C1 4 -alkyl or C14-alkoxy radicals or halogen atoms, isopropylidene groups or optionally by C1 4 -alkyl or C1 4 -Alkoxy groups or halogen atoms are substituted trityl groups, R 'denotes a C1 4 -alkyl group optionally substituted by a C1 4 -alkoxy group, a phenyl group optionally substituted by a C1 4-alkyl group or a halogen atom, a benzyl group or p-nitrobenzyl group, treated with a base .

According to method B, the protective groups R in the compound of general formula I are formed to form a compound of general formula II in which R 'has the preceding meaning has been removed. The compound of the general formula II is then treated with a base.

In general, alkyl or aryl sulfonates can be derived from alcohols readily hydrolyze to the original alcohols when treated with an aqueous base. Accordingly, experiments on the anhydrous solvolysis of the sulfonates also led general formula I does not produce the desired result.

After numerous investigations it was surprisingly found that when treating a sulfonate of the general formula I in 1,2-dimethoxyethane with sodium hydroxide solution, a new compound that can be detected by thin layer chromatography arises, which is gradually converted into another new compound with A max at 280 nm will. The first compound is the one deprotected Sulphonate of the general formula II and, in the case of the last-mentioned compound, isocoformycin.

The base treatment in method A is either in a heterogeneous System or in a homogeneous system at temperatures from 0 to 500C.

When working in the heterogeneous system, the sulfonate becomes the general one Formula I in a water-immiscible organic solvent, such as methylene chloride, 1,2-dichloroethane, epichlorohydrin, 1 1, 2,2-tetrachloroethane, chloroform, benzene or toluene, dissolved and with an organic or inorganic base, preferably in the presence of a phase transfer agent such as a tetra-n-alkylammonium halide or a tetra-n-alkylphosphonium halide having 3 to 12 carbon atoms in the Alkyl radicals.

Particularly preferred reaction conditions are given below: The sulfonate of the general formula I is dissolved in methylene chloride. The solution is mixed with more than 10 equivalents of a 0.5 N sodium hydroxide solution. Afterward the reaction mixture is mixed with about 0.05 equivalents of the phase transfer agent offset. The heterogeneous reaction mixture is stirred vigorously at room temperature, until there is no sulfonate used as a starting product by thin-layer chromatography of the general formula I can be demonstrated more.

The bases used are inorganic bases, such as alkali metal or alkaline earth metal hydroxides, such as sodium, potassium, calcium, barium and magnesium hydroxide, or alkali metal alcoholates, such as sodium and potassium methylate or ethylate, or aluminum hydroxide, organic Bases such as 1,8-diazabicylo [5,4,0] undecene-7, morpholine, cyclohexylamine, piperidine, Thiomorpholine or a basic ion exchange resin is used.

In the case of the homogeneous phase process, the treatment with the base is used without using the phase transfer agent in a water-miscible organic Solvents such as acetone, dioxane, 1,2-dimethoxyethane, tetrahydrofuran, acetonitrile, Dimethyl sulfoxide or dimethylformamide.

The bases mentioned above are used.

In process B, the protective groups are removed, by treating the sulfonate of general formula I at room temperature with a solution of ammonia in a cabbage, such as methanol or ethanol, or with an anion exchange resin, when R in the sulfonate of the general formula 1 is acyl, benzoyl or substituted Benzoyl radical means, or with a weakly acidic reagent, such as acetic acid, trifluoroacetic acid, or an acidic ion exchange resin when R is in the sulfonate of the general formula I means an isopropylidene group, trityl or substituted trityl group.

The compound of general formula II is isolated and in one aqueous medium treated with one of the aforementioned bases. The base treatment is carried out at temperatures from 0 to 50 ° C., preferably at room temperature.

The sulfonate of the general formula I in which R 'is the methyl group means is known; see M. Ohno et al., J. Amer.

Chem. Soc. 96: 4326 (1974).

The sulfonates of the general formula I are obtained by reacting 9-ß-D-roibofuranosyl-6-dihxdroxymethyl-1,6-dihydropurine, the hydroxyl groups of which on the ribose radical are provided with protective groups, of the general formula IV in which R has the same meaning as in general formula I, with a reagent of the general formula VR '- S02X (V) in which R' has the same meaning as in general formula I and X denotes a halogen atom or an imidazole group, manufactured. Examples of compounds of the general formula V are hesyl chloride, phenylsulphonyl halides, p-methyl or p-halophenylsulphonyl halides, benzylsulphonyl halides, p-nitrobenzylsulphonyl halides, alkylsilfonylimidazoles, alkoxyalkylsulphonylimidazoles, alkoxyalkylsulphonylimidazoles, alkoxyalkylsulphonylimidazoles, alkoxyalkylsulphonylimidazoles, p-benzylimidazol-orsulphonyl-halo-phenylsulphonylsulphonylsulphonylsulfonylsulfonylsulphonylsulfonylsulfonylsulfonylsulfonylsulfonylsulfonylsulfonylsulfonylsulfonylsulfonylsulfonylsulfonylsulfonylsulfonylsulfonylsulfonylsulfonylsulfonylsulfonylsulfonylsulfonylsulfonylsulfonyl halides,

The reaction is carried out at room temperature in an inert organic Solvents such as acetone, 1,2-dimethoxyethane or dioxane, preferably in the presence a weak base such as sodium or potassium carbonate or pyridine in an inert gas atmosphere carried out.

The sulfonates of the general formula I can also be treated by treatment a compound of the general formula IV with Sodium hydride in anhydrous tetrahydrofuran or 1,2-dimethoxyethane with subsequent addition of reagent V.

The compounds of the general formula IV can be prepared from 9- (2t, 3 ', 5'-tri-0-acetyl-B-D-ribofuranosyl) -purine according to the method of Linschitz and Connolly (cf. H. Linschitz and J.S. Connolly, J. Am. Chem. Soc., 90: 2980 (1968); M. Ohno, N. Yagisawa, S. Shibahara, S. Kondo,, Maeda and H. Umezawa, J. Am. Chem. Soc., 96: 4326 (1974)).

The deacetylated compound of general formula IV is used as an inhibitor known for adenosine deaminase; see.

B. Evans and R. Walfenden, J. Am. Chem. Soc. 92: 4751 (1970).

The following reaction scheme gives the entire process for making isocoformycin: CH 050 HO HN ~ 2 02R HO 4 aT ~ HS 9> [experienced-A RO # {F Df o Ha)) OR OR procedure-B oe OH (I) CII, OSO, R'I isocoformycin Re -SO HO 0 (v) CHzOFi OH (I1) IT RO y {) (IV) (k bR R, R 'and X have the meanings given above.

Isocoformycin can be isolated as follows, for example perform: After the reaction of the compound of the general formula I or II with a base, the aqueous alkaline solution freed from the organic solvent becomes Solution neutralized with acetic acid and with water to about 5 times the volume diluted. The solution is then applied to a cation exchange resin (Dowex 50W or Amberlite IR120) packed column attached. The eluent is aqueous Ammonia solution used.

After evaporation of the eluate with A max at 280 nm, crude is obtained Isocoformycin in the form of a yellow powder. By further column chromatography Purification on silica gel or cellulose gives pure isocoformycin. Isocoformycin is made from water or from a mixture of water and a corresponding organic Solvent, such as methanol, ethanol or acetone, recrystallized.

As mentioned earlier, isocoformycin is a valuable ingredient that the deamination of formycin, adenine arabinoside, cordycepin and pharmacologically compatible derivatives of these compounds under the action of those in mammals and adenosine deaminase present in birds. The inhibitory effect of Isocoformycin versus adenosine deaminase can be broken down using formycin and determine adenosine as substrate. 3 ml of a solution of adenosine or formycin in 0.05 M phosphate buffer (12 mg / ml, pH 7.5 or 6.5) are in a 1 cm long Quartz cell and 0.1 ml of a solution containing a known amount of isocoformycin contains in distilled water. The reaction is by adding 0.1 ml enzyme solution (adenosine deaminase from calf intestine in an amount of 1 mg / ml 0.025 m ammonium acetate or takadiastase-Y in an amount of 4 mg / ml distilled water) started.

The decrease in optical density is in the case of adenosine at 265 nm and in the case of formycin at 295 nm with a Beckmann spectrophotometer that equipped with a Gilford recorder, recorded for 2 minutes. The inhibitor concentration for 50 percent inhibition (1D50), the difference in optical densities becomes calculated. The results are shown in Table I.

Table I ID50 (mol / liter) s Xnz me i Calf intestines at 250C at 450C \ bu - calf intestine at 25 ° C at 45 ° C <ra- adenosine | Formycin Adenosine Fornycin I. rrbibitaren \ rOcOfornycin 8.6 x 10-8 7.5 z 10-8'1, 1 x 10-t 10 E 9-ß-D-ribo- furanosyl-6- hydroxymethyl 1,6-dihydro- purine 5.8 x 10 6 2.6 x 10 6 2.8 x 10 4 2.0 x 10 As can be seen from Table I, the inhibitory effect of isocoformycin against the deamination of formycin or adenosine is stronger than the corresponding effect of 9-β-D-ribofuranosyl-6-hydroxymethyl-1,6-dihydropurine, which acts as an inhibitor for adenosine deaminase is known.

Isocoformycin is also a valuable, powerful synergist for formycin and adenine arabinoside for their anti-tumor activity.

Isocoformycin shows together with formycin a strongly synergistic one Effect in inhibiting cell proliferation in cell cultures. The inhibiting effect of Formycin with or without isocoformycin on the multiplication of murine leukemia L-1210 cells is measured according to the Lowry method; see O.H.

Lowry, N.J. Rosenbrough, A.L. Farr and R.J. Randall, J. Biol.

Chem., Vol. 193 (1951), p. 265. The results are compiled in Table II.

Table II Inhibition of the proliferation of murine leukemia L-1210 cells with formycin and isocoformycin No. Formycin isocoformycin inhibition (%) 1 0.0 µg / ml 0.0 ng / ml O 2 0.20 0.0 8 3 0.0 0.20 0 4 0.0 0.50 -4 5 0.20 0.20 42 6 0.20 0.50 55 In addition, there is a marked increase in the survival time of mice, who have been implanted with murine leukemia L-1210 cells1 after intraperitoneal Administration of formycin combined with isocoformycin. The corresponding values are summarized in Table III.

The respective doses are given two hours after the implantation 105 L-1210 cells administered intraperitoneally once daily for 10 days.

Table III Extension of survival of mice with b-1210 by treatment with formycin with or without isocoformycin Formycin (50 µg / ml) No. Isocoformycin without with Survival survival duration, days T '/ C% duration, days T / C% 1 50 µg / ml 8.0 93 15.0 174 1 - 25 1 10.0 93 15.0 174 3 12.5 8.5 116 14.0 163 4 6.2 9.0 99 12.0 140 5 3.1 9.0 105 14.0 163 6 1.5 8.0 93 12.5 145 7 | 0 8.6 100 10.5 122 Isocofrmycin is also able to maintain the activity of formycin against gram-negative bacteria. For example, on a nutrient agar with a content of 50 μg / ml formycin, the diameter of the zone of inhibition against Eschericia coli NIHJ is determined by the disk method. (8 mm) measured at the following concentrations of isocoformycin: Isocoformycin (µg / ml) Hemmohofdurcxhmesser (mm) 200 36.0 40 32.0 10 25.0 2.5 22.0 Isocoformycin itself has no inhibitory effect against Escherichia coli NIHJ at a concentration of 2 mg / ml without formycin.

The examples illustrate the invention.

Example 1 6-mesyloxymethyl-9- (2 ', 3', 5'-tri-0-acety-β-D-ribofuranosyl) -1,6-dihydropurine (I) The one from 9- (2 ', 3', 5'-tri-O-acetyl-β-D-ribofuranosyl) -purine according to the procedure von Linschitz and Connolly (cf. J. Am.

Chem. Soc., Vol. 90 (1968), p. 2979) is produced in 60 ml of anhydrous acetone dissolved. 4.5 g of anhydrous K2CG3 are added to the solution. Then 0.57 ml (840 mg) are added all at once under argon at room temperature Hesyl chloride added. The mixture is stirred vigorously until about 2 hours No more starting product can be detected by thin layer chromatography.

The inorganic components are filtered off and with fresh Acetone washed. The filtrate and wash liquids are combined and reduced under reduced pressure Evaporated pressure.

The mesylate is obtained in the form of a yellow foam (I, R = acetyl, R '= methyl) in a yield of 1.65 g (95 percent of theory) with the following properties: UV spectrum: # max MeOH 297 nm (r 3900), 290 nm (E 4300 at pH 1); [α] D24 -17 ° (c 1.5, MeOH); Mass spectrum: 393 (M + -OMs), 349 (393-Ac), 333 (393-OAc), 259 (triacetyl ribose); IR spectrum (KBr): 3400, 1745, 1610, 1580, 1360, 1230, 1175, 1050 cml 1 H NMR Spectrum (CDCl3): & 2.11 (9H, s, Ac), 3.01 (3H, s, SCH3), 4.30-4.50 (5H, m, 5'-CH2, -CH2OMs, H4), 5.34 (1H, t, 6-CH), 5.50-6.00 (3H, m, H1, H2,, H3,), 7.10 (1H, s), 7.50 (1H, s).

Example 2 -6-Tosyloxymethyl-9- (2 ', 3', 5'-tri-0-acetyl-β-D-ribofuranosyl) -1 6-dihydronurine (I) 215 mg of alcohol IV are dissolved in 10 ml of anhydrous 1,2-dimethoxyethane dissolved and treated all at once with 76 mg of sodium hydride at room temperature. The reaction mixture is stirred for 1 hour under argon, treated with 400 mg of tosylimidazole and then Stirred for 4 hours, after which there is no starting material by thin layer chromatography more can be proven. Then 50 ml of 0.4 M phosphate buffer have a pH value 6.5 added.

After extracting twice with 25 ml of chloroform each time, it is used with 5prozeitigen NaHCO3 and water and dried over Na2SO4. After removing the solvent one receives 211 mg (82 percent of theory) tosylate (I, R = acetyl, R '= p-methylphenyl) as yellow foam.

Example 3 Isocoforzycin 410 mg of mesylate I, which according to Example 1 has been obtained, are dissolved in 10 ml of 1,2-dimethoxyethane. The solution will be mixed with 10 ml of 1N NaOH. The homogeneous brown solution is then 16 hours at Stirred room temperature, after which no mesylate I can be found by thin-layer chromatography more can be proven.

The organic solvent is removed under reduced pressure.

The remaining aqueous solution is adjusted to pH with acetic acid 7 neutralized and diluted to 50 ml with water.

The solution is packed onto a 80 ml Dowex 50WX2 (NH4 + form) Pillar put on. The elution is carried out with 0.5 N ammonia solution. The factions with #max at 280 nm are combined and evaporated to 100 mg of a yellow powder. To Chromatography on silica gel using ethyl acetate and methanol (5: 1 parts by volume), 51 mg (21 percent of theory) of isocoformycin are finally obtained in the form of a colorless powder.

B e i s i e l 4 isocoformycin 211 mg of that obtained according to example 2 Tosylate I are dissolved in 10 ml of acetonitrile. The solution is mixed with 10 ml of 0.5N Ba (OH) 2 solution offset. The resulting homogeneous brown solution is then stirred for 4 hours, after which tosylate I can no longer be detected by thin-layer chromatography. To Treatment of the reaction mixture according to Example 2 gives 21 mg (20 percent d.Th.) Isocoformycin.

Example 5 Isocoformycin 68 mg of the mesylate obtained according to Example 1 I are dissolved in 4 ml of 1,2-dichloroethane. 1 ml of 1N NaOH is added to the solution. After adding 6 mg of tetra-n-butylammonium bromide as phase transfer reagent the heterogeneous reaction mixture was stirred vigorously for 3 hours at room temperature. the end 30 mg (44 percent of theory) of unchanged mesylate are obtained from the organic phase. According to Example 3, 14 mg (35 percent of theory or 62%) are converted from the aqueous phase Percent corrected) isocoformycin isolated.

Example 6 9-ß-D-ribofuranosyl-6-mesyloxethyl-1 16-dihydropurine (II) 1.65 g of the mesylate I prepared according to Example 1 are stored for 1 hour at room temperature with 20 ml of a 2Cprozentiqen solution of Treated ammonia in methanol After evaporation of the solvent, 1.4 g of a brown foam are obtained. Sine after chromatography on silica gel using ethyl acetate and Analysis sample obtained from methanol (5: 1 parts by volume) has the following properties: UV spectrum: #max MeOH 285 nm (3760); [α] 25 D -38 ° (c 1.0, MeOH); 1 H-NMR spectrum (D20, 100MHz): # 3.55 (3H, s, SCH3), 4.26 (2H, m, 5'-CH2), 467 (1H, m, 4'H), 4.75 (1H, m , 3'H), 4.83 (2H, m, -CH2ONs), 5.10 (1H, m, 2'H), 5.72 (1H, t, 6-CH), 6.18 (1H, d, 1'H) , 7.64 (1H, s, 2-H), 8.11 (IH, s, 8-H).

Example 7 Isocoformycin 1.4 g of the mesylate obtained according to Example 6 II are treated with 40 ml of 1N NaOH for 1 hour at room temperature.

The reaction mixture is neutralized to pH 7 with acetic acid and diluted to 200 ml with water.

The mixture is then poured into a 100 ml IR120 (NH4 +: H + = 1: 1) packed column attached. 0.5N ammonia is used as the eluent. 553 mg of a yellow powder are obtained. This powder is column chromatographed to Avicell using ethyl acetate, methanol and water (5: 1: 1 Volume parts) cleaned further. After recrystallization from ethanol 400 is obtained mg (40 percent of theory) isocoformycin in the form of a colorless powder.

Claims (17)

Case: Isocoformycin "Isocoformycin, process for its production and medicines "P a t e n t a n s p r ü c h e 1. Isocoformycin of the formula 2. Process for the preparation of the compound of claim 1, characterized in that a 9β-D-ribofuranosyl-6-hydroxymethyl-1,6-dihydroxypurine sulfonate of the general formula I, in which the hydroxyl groups in the ribose radical are provided with protective groups, in which the radicals R are identical or different and an acrylic radical of an unsubstituted or halogen-substituted fatty acid having 2 to 12 carbon atoms, a benzoyl group optionally substituted by a lower alkyl or alkoxy radical or a halogen atom, an isopropylidene group or an optionally substituted by a lower alkyl or alkoxy radical or a falogen atom-substituted trityl group and R 'represents a lower alkyl radical optionally substituted by a lower alkoxy radical, a phenyl group optionally substituted by a lower alkyl radical or an H-log atom, a benzyl or p-nitrobenzyl group, treated with a base. eeichnet that the treatment with the base is carried out under an inert gas atmosphere. 4. The method according to claim 2, d a d u r c h g e k e n n -z e i c h n e t that the treatment dt the base in a water immiscible organic solvents. 5. The method according to claim 4, d a d u r c h g e k e n n -z e i c n e t that the following is an organic solvent immiscible in water, methylene chloride, 1,2-dichloroethane, epichlorohydrin, 1,1,2,2-tetrachloroethane, chloroform, benzene or Toluene used. 6. The method according to claim 4, d a d u r c h g e k e n n -z e i c Note that: nan treatment with the base in the presence of a phase transfer agent performs. 7. The method according to claim 6, d a d u r c h g e k e n n -z e i c n e t that the phase transfer agent used is tetra-n-alkylammonium halide 3 to 12 carbon atoms in the alkyl radicals or / tetra-n-alkylphosphonium halide with 3 to 12 carbon atoms in the used as residues. 8. The method according to claim 2, d a d u r c h g e k e n n -z e i c n e t that treatment with the base in a water-miscible organic Solvent carries out. 9. The method according to claim 8, d a d u r c h g e k e n n -z e i c n e t that the organic solvent miscible with water is acetone, dioxane, 1,2-dimethoxyethane, tetrahydrofuran, acetonitrile, dimethyl sulfoxide or dimethylformamide used. 10. The method according to claim 2, d a d u r c h g e k e n n -z e i c n e t that the base is an alkali or alkaline earth metal hydroxide, alkali metal alcoholate, 1,8-diazabicyclo [5,4,0] undecene-7, morpholine, cyclohexylamine, Piperidine, Thiomorpholine or a basic ion exchange resin is used. 11. A process for the preparation of the compound according to claim 1, characterized in that the protective groups on the ribose radical of a 9β-D-ribofuranosayl-6-hydroxymethyl-1,6-dihydropurine, the hydroxyl groups of which are protected on the ribose radical, of the general formula I in which R and Ri have the same meaning as in claim 2, removed and the resulting compound of general formula II in which R 'has the same meaning as in claim 2, treated with a base. 12. The method according to claim 11, d a d u r c h g e k e n n -z e i c N e t that one can remove the Scautzgruppen by treating the sulfonate with a solution of ammonia in alcohol or an anion exchange resin. 13. The method according to claim 11, d a d u r c h g e k e n n -z e i c Note that one can remove the protecting groups by treating the sulfonate with a weakly acidic reagent. 14. The method according to claim 13, d a d u r c h g e k e n n -z e i c Not that acetic acid, propionic acid, trifluoroacetic acid are used as weakly acidic reagents or an acidic ion exchange resin is used. 15. The method according to claim 11, d a d u r c h g e k e n n -z e i c It does not mean that the treatment with the base is carried out under an inert gas atmosphere. 16. The method according to claim 11, d a d u r c h g e k e n n -z e i c n e t that an alkali metal or alkaline earth metal hydroxide, alkali metal alcoholate, 1,8-diazabicyclo [5,4,0] undecene-7, morpholine, cyclohexylamine, piperidine, thiomorpholine or a basic ion exchange resin is used. 17. Medicaments containing isocoformycin according to claim 1.