SE8801236A0 - New ribofuranuronic acid derivatives - Google Patents

Abstract

The invention relates to 2-position-substituted 1'-deoxyl-1 '- (6-amino-9-purinyl) -O-D-ribofuranuronic acid amides and thioamides, in particular sDana with the formula IR 1 I) R 6 R 2 / R 3 OH OH ddr R 1 represents hydrogen, optionally monosubstituted (C 3-7) alkenyl, (C 3-7) alkynyl, (C 3-7) cycloalkyl which may be optionally mono- or disubstituted, (C 3-7) cycloalkyl- (C 1-3_) alkyl optionally may be mono- or disubstituted in the cycloalkyl ring, optionally mono- or disubstituted phenyl, phenyl- (C 1-6 alkyl which is optionally mono- or disubstituted in the phenyl ring and the (C 1-6) alkylene chain is optionally substituted by a hydroxyl group, in the phenyl ring optionally substituted phenyl ring ) alkenyl, a 5- or 6-membered monocyclic heteroaryl, or 3- or 6-membered monocyclic heteroaryl- (C 1-4) alkyl, the alkylene moiety being optionally substituted with a hydroxyl group, R 2 represents hydrogen, optionally monosubstituted (C 14) alkyl, or (C 34) -cycloalkyl, R 3 is hydrogen or optionally monosubstitute (C 1-4) alkyl, R 6 is halogen, (C 1-4) alkyl, (C 3-4) cyldoalkyl, cyano or represents groups / R 4 of the formulas -OR 4 '-SR 4' \ -N, ddr R 4 and independently represents hydrogen or (C 1-4) alkyl, and X represents = 0 or = 5. The invention also relates to the preparation of the compounds of formula I by cleavage of the isopropylidene group I compounds of formula II

Description

The novel ribofuranuronic acid amides and thioamides are effective against hypertension, and the invention also relates to a drug composition containing such an association as an active component as well as the use of the compounds in the treatment of hypertension and for the manufacture of drugs suitable for the treatment of high blood pressure. it di. 1. The invention relates to novel 2-position substituted 1'-deoxy-11- (6-amino9-purinyl) -O-D-ribofuranuronic acid amides and thioamides, to a process for their preparation and their use in the treatment of e.g. high blood pressure.

The novel 2-position-substituted 1'-deoxy-11- (6-amino-9-purinyl) -O-D-ribofuranuronic acid amides and thioamides prepared according to the invention are hereinafter referred to as the following compounds of the invention.

The associations can be substituted where desired, e.g. in free amino groups.

The invention relates in particular to 2-substituted 1'-deoxy-1 '- (6-amino-9-purinyl-13-D-ribofuranuronic acid amides and thioamides of the formula II wherein R 1 represents vate, (C 1-6 alkyl which may optionally be monosubstituted R 4. with a hydroxyl, an -SH- or an -N, - group, where R4 and R 'R independently represent hydrogen or (C1-4) alkyl; (C3-7) alkenyl, (C3-7) alkynyl, (C3. .7) cycloalkyl which may be optionally mono- or, R h disubstituted with a hydroxyl, a -511 or a -Nc 'group, wherein R 4 R and R give the definition given above; (C 3-7) cycloalkyl (C 1-3) alkyl which may or may not be mono- or disubstituted in the cycloalkyl ring having / R 4 a hydroxyl, a -SH- or a -N 2 R group, wherein R 4 and R 5 have the above definition; phenyl which may or may not be mono- or disubstituted with halogen having an atomic number 9-35, (C1) alkyl, (C1-4) alkoxy, a hydroxyl-, a -SH-, a -S- (C1-4) alkyl-, a -SO2- (C1-4) alkyl-, a trifluoro - / m4ethyl or -SO 2 -N, - group, where R 4 and R 2 are n the above 'R 2 definition; phenyl- (C 1-4 alkyl optionally mono- or disubstituted in the phenyl ring with halogen having an atomic number 9-35, (C 1-4) alkyl, (C 1-4) alkoxy, a hydroxyl-, a -SH-, a -S- (C 1-4) alkyl , A -SO 2 - (C 1-4) alkyl-R 4 or a -SO 2 -N 4 - group, where R 4 and R have the above definition R, and (the C 1-4 alkylene chain is straight-chain or branched and may be optionally substituted by a hydroxyl group; phenyl- (C3-7) alkenyl which may be optionally substituted in the phenyl ring by halogen having an atomic number 9-35, R4 (C1-4) alkyl-, a -SO2- (C1-4) alkyl- or a -SO2-N, group, ddr R4 R and Rhar as defined above: a 5- or 6-membered, monocyclic heteroaryl containing 1 or 2 nitrogen atoms or an oxygen atom or a sulfur atom and a nitrogen atom separately, or an S- or 6-membered monocyclic heteroaryl (C1 ) alkyl which in the heteroaryl moiety contains 1 or 2 nitrogen atoms or an oxygen atom or a sulfur atom and is each a nitrogen atom, the alkylene moiety being straight-chain or branched and optionally be substituted by a hydroxyl group, R 2 represents hydrogen, which may optionally be monosubstituted R 4 by a hydroxyl, a -SH- or a -NI 4 - group, wherein R 4 and R have the definition "R" above, or denote the (C3-8) cycloalkyl, R3 is hydrogen or (C1-4) alkyl which may be monosubstituted by, / R4 a hydroxyl, a -SH- or a -1 \ 1 \ group, where R4 and R have the above-mentioned R the definition, R 6 is halogen, (C 1-4) alkyl, (C 3-4) cycloalkyl, cyano, or denotes the group of the formulas -OR 4 '-SR 4' \ -N '' where R 4 and R 5 are the definition given above R, and X represents = 0 or = S.

Of the compounds of formula I, preferred compounds have the formula Ia (C 1-4) alkoxy, a hydroxyl-, a -SH-, a -S- 1a HO OH where R is denoted by hydrogen, (C 3-7) cycloalkyl, which may optionally be / R 4 is mono- or disubstituted with a hydroxyl, a -SH- or a -N 2 -R group, wherein R 4 and R have the above definition; phenyl- (C) alkyl which may be mono- or disubstituted in the phenyl ring with halogen having an atomic number 9-35, (C 1-4) alkyl, (C 1-4 alkoxy, a hydroxyl-, a -SH-, a -5- (C 1-4) alkyl- , a -SO 2 -cooling or a -SO 2 -N '- (C 1-4) a1R group, wherein R4 and R have the above definition, wherein the (c1) -alkylene chain is straight-chain or branched and may be optionally substituted with a hydroxyl group, or phenyl which may be mono- or disubstituted by halogen having an atomic number 9-35, (C 1-4) alkyl, (C 1-4) alkoxy, a hydroxyl-, a -5H-, an -S- (C 1-4 alkyl- , a - Rh alkyl-, a trifluoromethyl or a -SO 2 -N ('group, where R 4 and R have the above definition, R 2 is hydrogen, (C 1-4) alkyl which may be optionally monosubstituted by an R 4 hydroxyl, a -SH- or an -N, - group, wherein R4 and R have the definition given above; or (C3-6) cycloalkyl, R3aat vate or (C1-4) alkyl which may be optionally monosubstituted by, R a hydroxyl-, a -SH1 \ 1 .; - or a -'- group, where R4 and R have the above The definition given is that halogen having an atomic number 9-35, (C1-4) alkyl or so denotes it. Groups of the formulas -OR4 '-SR4 or -1 \ 1 \ R 4' where R4 and Rhar den, 0 a " 6 4 above definition, and X denotes.-_- 0 or S.

Of the compounds of formula I, especially preferred compounds have the formula lb, Rb HN, .. ,, 1 RI b R6N '\ N0 R3b / lb HO OH dal.

R b represents hydrogen, (C 1-6) alkyl, (C 3-7) cycloalkyl which may be optionally 1 R 4 mono- or disubstituted with a hydroxyl, a -SH- or a -1'1 './' - `R group, where R 4 and R has the above definition; or phenyl which may be mono- or disubstituted by halogen having an atomic number 9-35, (C 1-4) alkyl, a (C 1-4) alkoxy-, a hydroxyl-, a -SH-, a -5- (C 1-4 alkyl- , a -2- (C 1-4) alkyl, a trifluoromethyl or a -2- / R 4 - N 2 - group, wherein R 4 and R have the above definition, R 2 is hydrogen, (C 1-4 alkyl which may optionally be mono substituted with an / R 4 hydroxyl, an -SH- or an -N 2 - group, where 114 and R have the definition given above; or (C 34) cycloalkyl, R 3b Sr (C 14) alkyl, R 6b is (C 4) alkyl, chlorine, bromine, methoxy, methylthio, methylamino or dimethylamino, and X represents = 0 or = S. 1 Formula I represents halogen with an atomic number 9-35 fluorine, chlorine or bromine, preferably chlorine, a (C1-4) alkyl group is methyl, ethyl, n-propyl, i-propyl, n-butyl, 1-butyl, tert-butyl, and if it contains up to 6 carbon atoms, From it also n-pentyl, i-pentyl, 3 -pentyl, n-hexyl, 1-hexyl, etc., especially methyl, ethyl, isopropyl or 3-pentyl, a (C 1-4) alkoxy group Sr methoxy, ethoxy, n-propo xi, I-propoxy, n-butoxy, i-butoxy, tert-butoxy, and if it contains up to 6 b carbon atoms, it is also n-pentoxy, i-pentoxy, n-hexoxy, 1-hexoxy, etc. , especially methoxy, (C3-7) alkenyl is metallallyl, butenyl, pentenyl, etc., the chain may be straight or branched and the double bond may be in different positions, but not adjacent to nitrogen, (C3-7) alkynyl is propynyl, butynyl, pentynyl , hexynyl, whereby the chain is straight or branched and the triple bond may be in different positions, but not adjacent to nitrogen. (C 3-7) cycloalkyl represents cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, especially cyclopentyl. If it is substituted, the substituents sit separately in the 0-, p.- or mstailning, but usually either in the case of disubstitution in the o-, 0-position, or in the case of monosubstitution1on in the p-position. (C 34) cycloalkyl- (C 1-3) alkyl may represent the aforementioned cycloalkyl and alkyl groups, wherein as shown substituents may be attached. Substitution of the phenyl ring can take place in the o-, m- or p-position, whereby in the case of disubstitution this is preferably in the m- and in the case of monosubstitution this is in the m- or p-position. In phenylalkyl, the alkyl groups and the substitution of the phenyl ring are as discussed above.

The compounds of the invention are obtained from Lex. by cleavage of an isopropylidene group from A 2-position substituted 11-deoxy-1 '- (6-amino-9-purinyl) -2', 3-Isopropylidene-8-D-ribofuranuronic acid amides and thioamides, e.g. with the formula II N ■ R1 ddr R1 'R2' R3 'R6 and X have the meanings given above.

The above-mentioned leaching process suitably takes place by treating compounds of formula II with an agent which cleaves the isopropylidene group. Trifluoroacetic acid has been found to be particularly useful for this purpose. An additional cleavage agent is aqueous hydrochloric acid or aqueous formic acid.

The compounds of formula II used as starting compounds are obtained by introducing into an isopropylidene protecting group 1 compounds of formula III, OH OH where R 1 has the above definition and R 6 'represents halogen, (C 1-4) alkyl or (C 3-8) cycloalkyl, (e.g. described in DE-OS 1 670 175; British Pat. 1 075 008 and (OC (1968) 2583), by reacting it with acetone in the presence of an acid, e.g. p-toluenesulfonic acid, wherein compounds of formula IV HN1 where R1 and R6 'have the above definition are obtained, then oxidize them at the edge set to form compounds of formula V, R6' HO> el 6 III Iv V where R1 and R6 'has the above definition, using an oxidizing agent, e.g. pyridinium dichromate, and then these convert edge salt using a chlorinating agent, such as thionyl chloride, to an acid chloride of formula VI, 7 Cl OC VI oa> c where R 1 and R 6 'have the above definition, and then react it with a Training of formula VII, VII where R2 and R3 have the above definition, set aside to form compounds of the formula ha NN, .., .., RI / R3 ha (substructure of compounds of formula II), where RI , R 2, R 3 and R 6 'have the above definition.

The group R6m, which has the definition given below, is introduced into figs of the formula Ha, where R6 'is chlorine or bromine, by reacting them with compounds of the formula 1-1126m, where R61 "represents a cyano group or / R4. groups of the formulas -OR4, -SR4 or -Ns, where R4 and R have the definition given above, in a strongly alkaline medium, eg in the presence of sodium, or by reacting them with the corresponding amines in an autoclave at temperatures above I00 ° C. The compounds of formula IIb HIKR1 8 R / II 60 112 \ NC R3 IIb (compounds of formula 11, where X denotes = 0 and R6 includes the meanings of both R6 'and R6 ") where R1 'R2' R3 and R6 have the above definition, obtained according to the preceding steps, are converted by appropriate tianation to compounds of formula IIc Ile (compounds of formula II, where X represents 2: 5) where R1, R2, R3 and R6 has the above definition.

The thawing process is suitably carried out using candiing agents, e.g. hydrogen sulfide, phosphorus pentasulfide or Lawesson's reagent (p-methoxyphenylthiophosphine sulfide dimer). The latter reagent is the lecture. The reaction itself takes place on the edge. If e.g. hydrogen sulfide is used, an acid, such as hydrochloric acid, is suitably added in catalytic doses, and the reaction is carried out in a polar solvent, such as acetic acid or ethanol. When using Lawesson's reagent, the reaction is conveniently carried out in a dry solvent, such as toluene or methylene chloride.

A further method for the preparation of compounds of formula lib, wherein R 6 is (C 1-4) alkyl, is that P-deoxy-P- (2-alkyl-6-hydroxy-9-purinyl) -13-D-ribose of formula Ma , OH OH OH NN 14 R61v.N 0 HO 9 IIIa where R6iv is (C1-4) alkyl, reacted with acetone in the presence of an acid, e.g. ptoluenesulfonic acid, to form compounds of formula IVa, OH IVa where R6iv has the above definition, after which these are oxidized using an oxidizing agent, e.g. potassium permanganate, 1 an alkaline medium, for the preparation of compounds of the formula Va, OH Where R6iv has the above definition, these are then reacted with a chlorinating agent, eg phosphorus oxychloride, whereby they are converted into compounds of the formula VIa, OxO C1 N 0 0 00 ddr R6iv has the above definition, these are then reacted with the above-mentioned compounds of formula VII for the preparation of compounds of formula Villa, Cl 00 Villa where R21 R3 and R6iv have the above definition, and these are converted by reaction with compounds of formula X, R 1 -NH 2 X where R 1 has the above definition, to form compounds of formula IIb, wherein R 6 is (C 1-4) alkyl. The compounds of formula IIb thus obtained, wherein R6 is (C1-4) alkyl, can be converted by thianation as described above into the corresponding compounds of formula IL. The other reactions described above take place using known methods, e.g. also using of the procedures described in the examples.

If in the compounds of formula I R1 represent groups which are substituted by a -NZ4 group, these compounds may form salts with strong \ R acids. Preferred salts are the hydrochlorides, hydrobromides or fumarates.

In the case of which the preparation of the required starting materials is not described, these are kanda or can be prepared by Wanda processes, or analogously to those described in the process or analogously to kanda processes. via 11 1 the following examples Sr all temperatures given in degrees Celsius and uncorrected.

Example 1: 1'-Desoxy-11- (2-methyl-6-cyclopentylamino-9-purinyl) -13-Dribofuranuronic acid-N-ethylamide 1.4 g 11-deoxy-1 '- (2-methyl-6-cyclopentylamino -9-Purinyl) -2 ', 3'-isopropylidene-O-D-ribofuranuronic acid-N-ethylamide is allowed to stand for 2 hours at 00 and 11 hours at room temperature in 10 ml of 90% trifluoroacetic acid. The mixture is then completely concentrated under reduced pressure, and the residue is partitioned between ethyl acetate and dilute ammonia aqueous solution. After washing with matt aqueous sodium chloride solution, the product is dried over sodium sulphate and concentrated completely. The residue is dissolved in a small amount of methanol, and the final product is crystallized by the addition of ethyl ether. M.p. 195-197 °.

The starting material using 11-deoxy-β- (2-methyl-6-cyclopentylamino-9-purinyl) -2 ', 3s-isopropylidene-O-D-ribofuranuronic acid-N-ethylamide can be prepared e.g. In the following manner: a) 7.5 g of potassium permanganate were added to a charge of 7.8 g of 1'-deoxy-1- (2-methyl-6-hydroxy-9-purinyl) -2 ', 3'-isopropylidene O-D-ribose in 120 ml of water and 4.8 ml of 1N sodium hydroxide, and the mixture is stirred for 1 hour at 0 °. Then 1 g of sodium sulfate is added, and the colorless solution is filtered over Hyflo after stirring for 5 minutes. The filtrate is then concentrated to about 30 ml under reduced pressure and adjusted to pH 4 with concentrated hydrochloric acid at 0. 11-Desoxy-1 '- (2-methyl-6-hydroxy-9-purinyl) -2', 3'-isopropylidene BD-ribofuranuronic acid precipitates in crystalline form. M.p. after washing with acetone and drying: 263 ° (s8nd,). b) 3.3 g of β-deoxy-β- (2-methyl-6-hydroxy-9-purinyl) -2 ', 3,1-isopropylidene-BD-ribofuranuronic acid are stirred in 16.8 ml of phosphorus oxychloride for 1 minute in an oil bath of 8 °, then mixed with 1.6 ml of N, N-diethylaniline and stirred for a further 2 hours at the same temperature. The mixture is then concentrated completely under reduced pressure, and the residue is dissolved in 60 ml of tetrahydrofuran. This solution is cooled to -0 ° and mixed with ethylamine until a basic reaction takes place. After 10 minutes, pour the solution into ice water and shake with ethyl acetate. After washing with matt sodium chloride solution and drying over sodium sulphate, the pouch is concentrated completely and the residue is eluted on silica gel with ethyl acetate. The purified deoxy-11- (2-methyl- 6-chloro-9-purinyl) -2 ', 3'-isopropylidene-BD-ribofuranuronic acid N-ethylamide is a white foam and has an ethyl acetate of Rf value of 0, 5. 1.2 g of 1t-deoxy-11- (2-methyl-6-chloro-9-purinyl) -2 ', 3'-isopropylidene-8-D-ribofuranuronic acid N-ethylamide and 1.2 ml of cyclopentylamine are stirred. ml dioxane 11 12 hours in an oil bath of 10 °. After cooling, filtration is carried out, the filtrate is concentrated and the residue is eluted on 60 g of silica gel with ethyl acetate. The pure 1'-deoxy-V- (2-methyl-6-cyclopentylamino-9-purinyl) -2 ', 3'-isopropylidene-β-D-ribofuranuronic acid N-ethylamide is obtained as a white foam. Rf value in ethyl acetate: 0.45.

The following compounds of formula I, in which R 1, R 2, R 3 and R 6 Kr defined as Will and where X is always = 0, are obtained analogously to Example 1: Example R 1 R 2 R 3 R 6 M.p. 2 p-Methoxyphenyl H Et Me 221-224 ° 3 Cyclopentyl H Et Me 196-198 ° 4 Cyclopentyl H Et Isopropyl amorphous Cyclopentyl H Et Cl 133-1 ° 6 Cyclopentyl H Et Br 188-190 ° 7 Cyclopentyl H Et Met) 226 -229 ° 8 Cyclopentyl H Et MeS amorphous 9 Cyclopentyl H Et Me2N amorphous Cyclopentyl H Et MeHN 193-194 ° 11 p-Ethoxyphenyl H Et Me 120-1 ° 12 3,4-Dimethoxyphenyl H Et Me 236-239 ° 13 3- Pentyl H Et Me 181-183 ° 14 m-Fluorophenyl H Et Me 137-142 ° p-Fluorophenyl H Et 'Me 257-259 ° 16 p-Chlorophenyl H Et Me 255-258 ° 17 Isopropyl H Et Me 187-194 ° 18β-Trifluoromethylphenyl H Et Me 248-2 ° P-Desoxy-1142-chloro-6-cyclopentylamino-9-purinyl-2 ', 31-isopropylidene-β-Dribofuranuronic acid-N-ethylamide, which is also useful as a starting material for preparation of compounds of formula II, wherein R6 has the meaning of R6 "', can be prepared, for example, as follows: a) 8.8 ml of orthoformic acid trimethyl ester was added dropwise at room temperature to 7.4 g of β-deoxy-11- (2- chloro-6-cyclopentylamino-9-purinyl) -O-D-ribose and 4.2 g of ptoluenesulfonic acid in 120 ml of acetone. hours, the precipitate is filtered off and washed with acetone and diethyl ether. Then the dried precipitate was added in portions and with stirring to a solution of 3.6 g of sodium bicarbonate in 1 ml of water and 75 ml of ethyl acetate. The organic phase is separated, washed with. •. ••• • .8.4. • •• •• •• •••• • • • ■; 04:::::: "4": •• • • • 6 I ••• • • • • • ••• • • • • • • • • • •• •• i • • •• •• • • 13 matt sodium chloride solution, dried over sodium sulphate and concentrated. The oily residue is then purified by eluting on 140 g of silica gel with a 9: 1 mixture of methylene chloride / ethanol. The pure 1'-deoxy-1142-chloro-6-cyclopentylamino-9-purinyl) -2 ', 3'-isopropylidene-8-D-ribose had an Rf value of 0.5. b) 8.7 g of 1'-despx1-1'42-chloro-6-cyclopentylamino-9-purinyl-2, 3'-isopropylidene-13-D-ribose and 30.5 g of pyridinium dichromate are stirred for 118 hours at room temperature 1 130 ml dimethylformamide. The mixture is then poured onto water, and the aqueous phase is shaken out 3 times with ethyl acetate. This phase is then extracted with a matt aqueous solution of sodium bicarbonate, the basic extract is adjusted to pH 1 with 5N acetic acid and shaken out with ethyl acetate. After washing with concentrated sodium chloride solution and drying over sodium sulfate, the organic phase is concentrated and diluted with diethyl ether, whereby 11-deoxy-11- (2-chloro-6-cyclopentylamino-9-purinyl) -8-D-ribofuranuronic acid crystallizes out. M.p. 246-253 °. c) 4 g of the above acid are heated in 40 ml of thionyl chloride for 20 minutes in an oil bath of °. When gas evolution ceases, the mixture is concentrated under reduced pressure, and the acid chloride formed is dissolved in 40 ml of methylene chloride. It is then cooled in an ice bath, and gaseous ethylamine is introduced with stirring until the reaction mixture becomes basic. The methylene chloride phase is then washed with water, dried over sodium sulfate and concentrated. 11-Desoxy-1- (2-chloro-6-cyclopentylamino-9-purinyl) -2 ', 31-isopropylidene-β-D-ribofuranuronic acid-N-ethylamide remains as a white foam. RI in methylene chloride / ethanol 9: 1 = 0.7.

The preparation of compounds of formula II, where .R6 had the meaning for and X is = 0, is carried out starting from the above-mentioned compound of the formula ha, where R6 'is chlorine, in and of itself Want sat, e.g. by reaction with an alcohol, amine, etc.

Example 19: 11-Desoxy-1T- (2-methyl-6-cyclopentylamino-9-purinyl-13-Dribofuranuronic acid-N-ethylthioamide a) 1'-Desoxy-1,42-methyl-6-cyclopentylmino-9-purinyl ) -2 ', 3'-Isopropylidene- (3-D-ribofuranuronic acid N-ethylthioamide 1.7 g 1'-deoxy-β- (2-methyl-6-cyclopentylamino-9-purinyp-21,3'- isopropylidene-BD-ribofuranuronic acid N-ethylamide (starting compound in Example 1) is stirred with 0.77 g of Lawesson's reagent in 38 ml of toluene for 2 hours in an oil bath of 100 °, the mixture is then concentrated completely under reduced pressure, the residue is dissolved in 60 ml ethyl acetate and stirred for 1 1/2 hours with 25 g of neutral alumina.

After filtration, the filtrate is concentrated and used in the next step without further purification. Rf in ethyl acetate: 0.7. 14 1 '-Desoxy-β- (2-methyl-6-cyclopentylamino-9-purinyl) -O-D-ribofuranuronic acid-N-ethylthioamide. 1.5 g of 11-deoxy-β- (2-methyl- 6-cyclopentylamino-9-purinyl) -2 ', 3'-isopropylidene-OD-ribofuranuronic acid N-ethylthioamide are dissolved at room temperature in 7.5 ml 90% - in trifluoroacetic acid and leave for 2 hours. The solution is then completely concentrated under reduced pressure. The residue is dissolved in ethyl acetate, mixed with ammonia water solution and concentrated completely under reduced pressure. The crystalline residue of the title compound is then purified by elution on 30 g of zincage with a 9: 1 mixture of methylene chloride / ethanol. Finally, the pure fractions are crystallized from ethyl ether terpentane. M.p. 168-1700.

The following compounds of formula I, in which R 1, R 2, R 3 and R 6 Sr are defined as follows and where X is always = 5, are obtained analogously to Example 20.

Example R1 R2 R3 R6 M.p. 21 3-Pentyl H Et Me amorphous 22 p-Ethoxyphenyl H Et Me 202-20 ° 23 p-Methoxyphenyl H Et Me 222-2 ° 24 3,4-Dimethoxyphenyl H Et Me 221-224 ° 4-Methylsulfonylphenyl H Et Me 164 -167 ° The compounds of the invention are notable for their interesting pharmacological properties. They can clarfOr be used as l'Aemedel.

Specifically, the compounds of the invention have antihypertensive activity, which can be inferred from the results of the following experiments: Feeding of the binding to adenosine A1 and A2 receptors in membranes from the rat cortex or from the cerebral cortex or striatum has pig using the method of R.F. Bruns, G.H. Lu and T.A. Pugsley, as described in Molec.

Pharmacol. 29, 331-346 (1986).

Further testing of the activity of the compounds of the invention on isolated, perfused renal kidneys with respect to the following parameters: renin secretion renal hemodynamics (vasodilation) inhibition of the release of norepinephrine from nerve endings after electro-stimulation of the renal nerves according to the method of Schurek, 3.P.

Brecht, H. Lohfert, and K. Hierholzer, described in Communicaton a la Reunion de l'Association des Pharmacologists Louvain UCL June 4, 1977, as well as P.M. Vanhoutte, D. Browning, E. Coen, T.). Verbeuren, L.

Zonnekeyen and M.G. Collins described in Hypertension 4, 251-256 (1982). feeding of blood pressure, heart rate, urine output and plasma renin activity in awake, NaCl-depleted and substituted normotensive or spontaneously hypertensive rats having catheters implanted in the abdominal aorta and vena cava, after i.v. administration or administration of the compounds of the invention as an infusion or bolus according to the method described by J.F.M. Smits and 3.M. Brody I Am. 3. Physiol. 247, RI 003-121 008 (1984).

From the results of the experiments one can conclude that both an inhibition of the renin secretion and of the release of noradrenaline from the nerve vessels, and direct vasodilation, Ina- in the antihypertensive activity of the compounds according to the invention.

From delta it is clear that the compounds according to the invention can not only be used as antihypertensive agents but also can effect coronary vasodilation. They further protect the male endothelium by inhibiting platelet aggregation and by activating leukocytes. They also reduce blood lipid levels.

For the above indications for compounds of the invention, the compound of Example 2 is preferred.

For the above-mentioned application as antihypertensive agents, the dose to be used varies according to the substance used, the type of administration and the desired treatment. Generally, however, satisfactory results are obtained with a daily dose of about 0.01 to 10 mg per kg of body weight. If required, administration may be in 2 to 4 portions or also in the form of sustained release. For larger mammals, the daily dose in the range is approximately 500 mg; suitable dosage forms for e.g. oral or non-oral administration usually contains about 5 to 250 mg together with solid or liquid bar substances.

The compounds of the invention may be administered separately or in suitable dosage form. The medical forms, e.g. a Risning or a tablet, can be prepared analogously to Wanda methods.

The invention relates to fragrances and also to medicaments which contain the compounds according to the invention in free form or in the form of their physiologically acceptable salts, as well as to the preparation of these medicaments by the edge. They can be prepared using conventional pharmaceutical adjuvants and carriers.

Claims (10)

PATENT REQUIREMENTS 1 2-Stable substituted 1'-deoxy-1 '- (6-amino-9-purinyl-6-D-ribofuranuronic acid amides and thioamides. 11-Desoxy-1,46-amino-9-purinyl) -BD-ribofuranuronic acid amides and thioamides according to claim 1, characterized in that the formula Ht (./I, tr.-kNyN '* 44 - ""' ■ N ) R 6 .XO R 2 \ R 3 where R 1 represents vate, (C 1-6) alkyl which may be optionally monosubstituted by a hydroxyl, an -SH- or an -N 5 -, R 4 - group, wherein R 4 and R 6 R independently represent (C3-7) alkenyl, (C3-7) alkynyl, (C3-7) cycloalkyl which may be optionally mono- or, Rh disubstituted with a hydroxyl, a -51-1 or a -1S -r group wherein R 4 R and R have the above definition: (C 34) cycloalkyl (C 1-3) alkyl which may be optionally mono- or disubstituted in the cycloalkyl ring having, R 1 a hydroxyl, a -5H- or an -N ('group, where R4 and R have the definition given above; phenyl which may be mono- or disubstituted by halogen having an atomic number 9-35, (C1-4) alkyl, (C1-4) alkoxy, a hydroxyl-, a -SH- , a -S- (C 1-4) alkyl-, a -SO 2 - (C 1-4) alkyl-, a trifluoroR 4 methyl- or a -2- N (-group, where R 4 and R 2 have the above-defined \ R definition; phenyl- (C 1-6) alkyl optionally mono- or disubstituted in the phenyl ring with halogen having an atomic number 9-35, (C 1-4) alkyl, (C 1-4) alkoxy, a hydroxyl-, a -SH-, a -S- (C 1-4 alkyl, a -932- (C1-4) alkyl-HO OH 17 or a -2-N4-4 group, wherein R4 and R had the above definition R4, R4, and (C1-6alkylene chain is straight or branched and branched and optionally substituted with a hydroxyl group, phenyl- (C 34) alkenyl which may be optionally substituted, 1 phenyl ring with halogen having an atomic number 9-35, (C 1-4) alkyl, (C 1-4) alkoxy, a hydroxyl , A -5H-, a / R4 (C1-4) alkyl-, a -SO2- (C1-4) alkyl- or a -SO2 --- N group, where R4 \ R and Rbar have the above definition a 5- or 6-membered, monocyclic heteroaryl containing 1 or 2 nitrogen atoms or an oxygen atom or a sulfur atom and each having a nitrogen atom; or a 5- or 6-membered monocyclic heteroaryl (C 1-4) alkyl containing in the heteroaryl moiety or 2 nitrogen atoms or an oxygen atom or a sulfur atom and each one nitrogen atom, wherein the alkylene moiety is straight chain or branched and may be optionally substituted by a hydroxyl group, R 2 represents vale, (C 1-4) alkyl which may be optionally monosubstituted, Rh having a hydroxyl, a -SH- or a -1 \ <7 group, wherein R 4 and R 2 bear the R definition set forth above, or denotes (C 3-4) cycloalkyl, R 3 is hydrogen or (C 14) alkyl which may be optionally monosubstituted by a hydroxyl, a -SH- or a -N / 4- group, wherein R 4 and R had the definition given above, R 6 is halogen, (C 1-4) alkyl, (C 3-4) cycloalkyl, cyano, or it represents the group RH of the formulas -OR 4, -5R 4, where R 4 and R 6 are as defined above. "R specified definition, and X denotes = 0 or = S. Compounds according to claim 2, characterized in that they have the formula HNI R1a a1La R6 a R2 \ R 3 HO OH 18 wherein R is hydrogen, (C3-7) cycloalkyl, which may be optionally mono- or disubstituted by a hydroxyl-, a -SH- or a --N / 4- \ R group, where R4 and R had the above definition; phenyl- (C 1-6) alkyl which may be mono- or disubstituted in the phenyl ring with halogen having an atomic number 9-35, R 4 -SH-, a -S- (C 1-4) alkyl-, a -SO 2 - (C 1-4) alkyl or a -SO 1 -N 2 -, R "group, wherein R 4 and R had the above definition, wherein the alkylene chain Sr is straight-chain or branched and may be optionally substituted with a hydroxyl group; or phenyl which may be optionally mono- or disubstituted with halogen having an atomic number 9-35, (C1-4) alkyl, (C1-4) -alkoxy, a hydroxyl-, a -SH-, a -S- (C1-4) alkyl-, a -SO2- (C1-4alkyl) / / Rh is a trifluoromethyl or a -SO 2 -NN "r group, wherein R 4 and R had the definition given above, R 2 is hydrogen, (C 1-4) alkyl which may be optionally monosubstituted by a, R 4 hydroxyl-, a -SH- or a 'group, wherein R 4 and R were as defined above; or (C 3-6) cycloalkyl, R 3a is hydrogen or (C 1-4) alkyl which may be optionally monosubstituted by a hydroxyl, a -SH- or a -N group, where R4 and R bore the definition given above, R6a is r halogen with an atomic number 9-35, (c1-4) alkyl or so denotes the 4.. groups of the formulas -OR4, -SR4 or -N \ where R4 and R had the definition 'R' above, and X represents = 0 or = S. Compounds according to claim 2, characterized in that they have the formula 1b (C 1-4) alkyl, (C 1-4) alkoxy, a hydroxyl-, a 19 lb HO OH wherein R 1b represents hydrogen, (C 3-7) cycloalkyl which may optionally be mono- or disubstituted by a hydroxyl, a -SH- or an -N \ R - group, where R4 and R had the above definition; or phenyl which may be mono- or disubstituted by halogen having an atomic number 9-35, (C 1-4) alkyl, a (C 1-4) alkoxy-, a hydroxyl-, a -SH-, an S (C 1-4) alkyl-, a- SO 2 - (C 1-4) alkyl-, a trifluoromethyl- or a -2-,. R 4 is -N- group, wherein R 4 and R 5 are as defined above, R 2 is bvate, (C 1-4) alkyl which may be optionally mono-substituted with a hydroxyl, a -SH- or an -N, - group, wherein R 4 and R bore the definition given above `R; or (C 3-6) cyldoalkyl, R 3b Sr (C 1-4) alkyl, R 6b Sr (C 1-4) alkyl, chlorine, bromine, methoxy, methylthio, methylamino or dimethylamino and X represents = O or = S. Compounds according to Claims 1 to 4, characterized in that they are selected from: 1'-deoxy-11- (2-methyl-6-cyclopentylamino-9-purinyl) -β-D-ribofuranuronic acid N-ethylamide, 11- deoxy-1,42-chloro-6-cyclopentylamino-9-purinyl) -1H-D-ribofuranuronic acid N-ethylamide, 11-deoxy-11- (2-bromo-6-cyclopentylamino-9-purinyl) -8-D-ribofuranuronic acid -ethylamide, 11-deoxy-1,1- (2-methyl-6-cyclopentylamino-9-purinyl) -BD-ribofuranuronic acid N-ethylamide, 1'-deoxy-11- (2-ethyl-6-cyclopentylamino-9- Purinyl) -D-ribofuranuronic acid N-ethylamide, 1'-deoxy-11- (2-isopropyl-6-cyclopentylamino-9-purinyl) -O-D-ribofuranuronic acid N-ethylamide, 1'-deoxy-1'- (2-methyl-6-p-methoxyphenylamino-9-purinyl) -BD-ribofuranuronic acid N-ethylamide, 1T-deoxy-11- (2-methylamino-6-cyclopentylamino-9-purinyl) -13-D-ribofuranuronic acid N- Ethylamide, 1'-deoxy-1- (2-methylthio-6-cyclopentylamino-9-puryl) -fi-D-ribofuranuronic acid N-ethylamide, 1'-deoxy-1 '- (2-dimethylamino-6-cyclopentylamino-9- purinyl) -13-D-ribofuranuronic acid-N-ethylamide, 11-deoxy-β- (2-methoxy-6-cyclopentyl amino-9-purinyl) -13-D-ribofuranuronic acid 15 N-ethylamide, 11-deoxy-1142-bromo-6-amino-9-purinyl) -O-D-ribofuranuronic acid-N-ethylamide, 1'-deoxy-11- (2-methyl-6-p-ethoxyphenylamino-9-purinyl) -13-D-ribofuranuronic acid N-ethylamide, 11-deoxy-β- (2-methyl-6- (3,4-dimethoxyphenyl) amino-9-purinyl) -O-D-ribofuranuronic acid N-N-ethylamide, β-deoxy-1 '- (2-methyl-6- (3-pentyl) amino-9-purinyl) -O-D-ribofuranuronic acid-Nethylamide, 11-deoxy- 1- '(2-Methyl-6-m-fluorophenylamino-9-purinyl) -13-D-ribofuranuronic acid N-ethylamide, 11-deoxy-11- (2-methyl-6-p-fluorophenylamino-9-purinyl) - -D-riboturanuronic acid N-ethylamide, 1'-deoxy-11- (2-methyl-6-p-chlorophenylamino-9-purinyl) -BD-rthofuranuronic acid N-ethylamide, 11-deoxy-1''42-methyl-6-isopropylamino- 9-Purinyl) -13-D-ribofuranuronic acid N-ethylamide, 11-deoxy-1,42-methyl-6-p-trifluoromethylphenylamino-9-purinyl) -13-D-ribofuranuronic acid N-ethylamide, 11-deoxy-11 - (2-methyl-6- (3-pentyl) amino-9-purinyl) -O-D-ribofuranuronic acid 21 N-ethylthioamide, 11-deoxy-β- (2-methyl-6-p-ethoxyphenylamino-9- puriny1) - $ - D-ribofuranuronic acidN-e thylthioamide, 11-deoxy-11- (2-methyl-6-p-methoxyphenylamino-9-purinyl-8-D-ribofuranuronic acid N-ethylthioamide, β-deoxy-11- (2-methyl- 6- (3,4 -dimethoxyphenyl) amino-9-purinyl) -8-D-ribofuranuronic acid N-ethylthioamide, and It-deoxy-11- (2-methyl-644-methylsulfonylphenynamino-9-purinyl) -13-D-ribofuranuronic acid N-ethylthioamide . Process for the preparation of 2-position substituted 1'-deoxy-β- (6-amino-9-purinyn-1-D-ribofuranuronic acid amides and thioamides of the formula I according to Claim 2, characterized in that the isopropylidene group is cleaved from In the 2-position substituted 11-deoxy-1 '- (6-amino-9-purinyl) -2 • 13'-isopropylidene-13, -D-ribofuranuronic acid amides and thioamides of formula II, MN., 1 II dar R1 'R2' R3 'R6 and X bore the definitions given in claim 2. Pharmaceutical composition, characterized in that it contains as active agent a compound according to any one of claims 1 to 5 in combination with a pharmacologically acceptable adjuvant and / or diluent. Use of 2-position substituted 1'-deoxy-1'46-amino-9-purinyl) -13-D-ribofuranuronic acid amides and thioamides in the treatment of hypertension. Use of 2-substituted 1'-deoxy-1 '- (6-amino-9-purinyl) - (3-D-ribofuranuronic acid amides and thioamides of the formula I according to any one of 22 claims 2 to 5 in treatment of elevated blood pressure. Use of 2-position substituted 11-deoxy-11- (6-amino-9-purinyl) -O-D-ribofuranuronic acid amides and thioamides for the preparation of Non-suitable agents for the treatment of hypertension.