FI87463C - Process for the preparation of novel ribofuranuronic acid derivatives - Google Patents

Description

1 87463

METHOD FOR THE PREPARATION OF NEW RIBOFURANURONIC ACID DERIVATIVES

The invention relates to novel 1'-deoxy-1 '- (6-amino-9-purinyl) -β-D-ribofuranuronic acid amides and thioamides substituted in position 2, to processes for their preparation and to their use, e.g. in the treatment of hypertension.

The novel 1'-deoxy-1 '- (6-amino-9-purinyl) -β-D-ribofuranuronic acid amides and thioamides substituted in 10 positions according to the invention are hereinafter referred to as the compounds according to the invention.

With regard to the prior art publications, it should be noted that German application DE 2 610 985 discloses β-D-1- (6-amino-9H-purin-9-yl) -1-deoxyribofuranuronic acid derivatives which have an antihypertensive effect. Finnish patent publication FI 77666 discloses N6-substituted adenosines having e.g. antihypertensive effect. U.S. Patent No. 4,167,565 discloses adenosine-5'-carboxamides for killing unwanted animals. Further, Olsson, R.A., et al. have studied the binding of certain ade-25 nosin analogs to adenosine receptors (Journal of Medicinal Chemistry, Vol. 29 (1986) No. 9, Olsson RA, et al., N6-Substituted N-alkyladenosine-5'-uronamides: Bifunctional ligands having recognition groups for Al and A2 adenosine receptors, pp. 1683-89). The present invention discloses at position 2

substituted 1'-deoxy-1 '- (6-amino-9-purinyl) -β-D-ribofuranuronic acid amides and thioamides of formula I

35 2 87463. . -όο

-3 HO OH

Wherein (C 16) alkyl may be optionally monosubstituted with hydroxyl, / R <15 -SH or -N, wherein R 4 and R 5 represent

R 5 independently of one another is hydrogen or (C 1-4) alkyl; (C3-7) alkenyl, (C37) alkynyl, (C37) cycloalkyl, which may be optionally mono- or di-substituted with a / * 25 hydroxyl, -SH or -N- group in which R4, R5 and R5 are as defined above ; (C37) cycloalkyl (C 1-4 alkyl which may be optionally mono-30 or disubstituted in the cycloalkyl ring with a hydroxyl, -SH or -N group in which R 4 and R 5 are as defined above; phenyl which may be be optionally mono- or di-substituted with halogen of atomic number 9-35, (C 1-4 alkyl, (C 1-4) alkoxy, hydroxyl, -SH-, -S- (C 1-4) alkyl, -SO 2 - (C 14) -40 R n /

alkyl, trifluoromethyl or -SO -N

'R5 3 87463 with the group wherein R4 and R5 are as defined above; phenyl- (C16) alkyl which may be optionally mono- or di-substituted on the phenyl ring by halogen having a atomic number from 9 to 35, (C: 4) alkyl, (C 1-4 alkoxy-5, hydroxyl, -SH-, -S- (C14) alkyl , -SO 2 - / R <(C 1-4) alkyl or -SO 2 -N, wherein R 10 and R 5 are as defined above, and the (C 1-4 alkylene chain is straight-chain or branched and may be optionally substituted by a hydroxyl group; -li- (C37) alkenyl, which may be optionally substituted on the phenyl ring by halogen of atomic number 9-35, (C14) alkyl, (C4-4) alkoxy, hydroxyl, -SH-, -S- (C14) alkyl, -SO2 - (C24) alkyl or -SO ..- N, in which R4 and R5 r5 have the same meaning as above, a 5- or 6-membered, monocyclic heteroaryl ring containing 1 or 25 nitrogen atoms or one oxygen atom or one sulfur atom and one nitrogen atom, respectively, or a 5- or 6-membered, monocyclic heteroaryl- (C15) alkyl containing 1 or 2 nitrogen atoms or one oxygen atom or one sulfur atom in the heteroaryl unit and one nitrogen atom, respectively, wherein the alkylene unit is straight-chain or branched and may be optionally substituted by a hydroxyl group; and R 2 represents hydrogen, (C 1-4) alkyl, which may be optionally mono-substituted with hydroxyl, -SH or R 4 / -N, wherein R and R are as defined above; or it represents (C3) cycloalkyl; and R 3 is hydrogen or (C 3-4) alkyl, which may optionally be 5 / "· -SH- or -N-, wherein R 4 and R 5 r 5 are as defined above; and R 6 is halogen, (C) alkyl, (C3) cycloalkyl, cyano or Λ -OR., -SR., -N-, R1 wherein R4 and R5 are as defined above: and X is O or S, wherein when X is O and R3 is '(C 1-4 alkyl, (C 37) cycloalkyl or phenyl-C 1-6 (C 36) alkyl, then R 6 represents (C 3-4) alkyl, (C 35) cycloalkyl, cyano or -OR 4, -SR 4 or a / R * N group in which R represents hydrogen or (C) R 15 alkyl and R 5 represents (C 1 -C 4 alkyl).

Of the compounds of formula I, preferred compounds have formula Ia 30

R and HN

35 U

HO OH 40 5 3 ^ 463 wherein R 1 represents (C 1-7) alkyl, (C 3-7) cycloalkyl which may be optionally mono- or di- / R * 5 substituted by hydroxyl, -SH- or -N- R5, wherein R4 and R5 are as defined above; phenyl- (C 1 -C 4) alkyl which may be mono- or di-10 substituted on the phenyl ring by halogen having an atomic number from 9 to 35, (C 14) alkyl, (C: 4) alkoxy, hydroxyl, -SH-, -S- (Cl 4) alkyl, '/ R' 15 -SO 2 - (C 1-4 alkyl or -SO 2 -N-, R 5 wherein R 4 and R 5 are as defined above, wherein the (C 3-6) alkylene chain is straight or branched and may be an optionally substituted hydroxyl group or phenyl which may be optionally mono- or di-substituted with halogen of atomic numbers 9 to 35, (C 1-4) alkyl, (C 1-4) alkoxy, hydroxyl, -SH-, -S- (C 1-4) alkyl, -SO 2 - (C 1-4) alkyl, trifluoromethyl or / -SO 2 -N, wherein R 4 and R 5 are as defined above, R 2a is hydrogen, (C 1-4) alkyl which may be optionally mono-substituted by hydroxyl, R4 is 35 -SH, or -N, wherein R4 and R5 are as defined above, or (C3) cycloalkyl, and R3a is hydrogen or (C1-4alkyl); i, which may be optionally mono-substituted with hydroxyl, 6-7463 / R '-SH, or -N, wherein R4 and R5 are as defined above; and

R 8a is halogen having an atomic number of 9 to 35, (C 1-4) alkyl, or represents 10 -OR 4, -SR 4 or -N groups in which R 4 and R 5

RS

mean the same as above; and X represents O or S; wherein when X represents O and Rxa represents (Cx6) alkyl, (C37) cycloalkyl or phenyl (C) alkyl, then Rga represents (C3) alkyl or the group -OR4, -SR4 or R420 / N, wherein R represents hydrogen or C 1-5 (C 3-4) alkyl and R 5 represents (C 1-4) alkyl.

Of the compounds of formula I, particularly preferred are compounds of formula Ib, b I * 35 H0 * wherein Rxb represents (Cx6) alkyne, (C37) cycloalkyl, which may be optionally mono- or di-substituted with hydroxyl, - SH-, or N - wherein R4 and R5 are as defined above; or phenyl which may be optionally mono- or di-substituted with halogen of atomic number 9-35, (Cx4) alkyl, (Cx4) alkoxy, hydroxyl, 5 -SH-, S- (C14) alkyl, -SO2- (C14) with alkyl, tri- / R *

fluoromethyl or SO, -N, wherein R

\ 10 r5 and R5 have the same meaning as above; R 2b is hydrogen, (C 1-4) alkyl which may be optionally mono-substituted with R 4 / hydroxyl, -SH, or -N, wherein R 5 and R 5 are as defined above; or (C 3-6) cycloalkyl; and R 3b is (C 14) alkyl; and R 6b is (C 14) alkyl, chloro, bromo, methoxy, methylthio, methylamino or dimethylamino; and X represents O or S; wherein when X is O and R 12 is (C 3-6) alkyl or (C 3-7) cycloalkyl, then R 8b is (C 1-6 alkyl, methoxy, methylthio or dimethylamino).

In formula I, halogen having 9 to 35 atomic numbers means fluorine, chlorine or bromine, preferably chlorine; The (C14) alkyl group is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, tert-butyl, and if it always contains 6 carbon atoms, it is also n-pentyl, i-pentyl, 3 -pentyl, n-hexyl, i-hexyl, etc., especially methyl, ethyl, iso-propyl or 3-pentyl; The (C 1-4) alkoxy group is methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, tert-butoxy, and if it always contains 6 carbon atoms, it is also n-pentoxy, i-pentoxy, n -hexoxy, i-hexoxy, etc., especially methoxy; (C37) alkenyl is 8 87463 methallyl, butenyl, pentenyl, etc., where the chain may be straight or branched and the double bond may be at a different position but not adjacent to nitrogen; (C3-) alkynyl is propynyl, butynyl, pentinyl, hexynyl-5'L, where the chain is straight or branched and the triple bond may be at different locations but not adjacent to nitrogen.

(37) -Cycloalkyl means cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, in particular cyclopentyl. If it is substituted, the substituents are in the o-, p-, or m-position, respectively, but suitably in either the o-, o'-position when disubstituted, or in the p-position when monosubstituted. (C3-7) cycloalkyl ((C1-3) alkyl may mean the abovementioned cycloalkyl and alkyl radicals which, as indicated, may have substituents. The phenyl ring may be substituted in the o-, m- or p-position, whereby when disubstituted, they are preferably in the m- and p-position, and monosubstituted in the m- or p-position In phenylalkyl, the alkyl radicals and the phenyl ring substitution are as described above.

The compounds of the invention are obtained, for example, from 2'-deoxy-1 '- (6-amino-9-purinyl) -2'.3'-isopropylidene-β-D-ribofuranuronic acid pyramides and thioamides substituted in position 2, having e.g. formula II, m, A) ..

r3 m 35 wherein R, R, ,, Rj, R & and X are as defined above, by cleavage of the isopropylidene group.

The above process is preferably carried out by treating the compounds of formula II with a substance which cleaves the isopropylidene group. Tri-fluoroacetic acid has proven to be particularly suitable for this purpose. Other cleavage agents are aqueous solutions of hydrochloric acid or formic acid.

The compounds of formula II used as starting materials are obtained by introducing an isopropylidene protecting group into the compounds of formula III, 10 R, hn "'-V \ ^ 7 ln 15 ^

OH OH

Wherein Rx is as defined above and R6 'is halogen, (C1) alkyl or (C35) cycloalkyl, (described e.g. in DE-OS 1 670 175; British Patent 1,075,008 and JOC (1968) 2583), carrying out the reaction with acetone in the presence of an acid, e.g.

25 p-toluenesulfonic acid to give compounds of formula IV, (R, HN ")

Rs y 10 87 463 where R: and R. ' have the same meaning as above, followed by oxidation of the compounds in a known manner to give compounds of formula V,

3 HN

A

° / ° \ H00C \ y \

V

wherein R 1 and R 8 are as defined above, using an oxidant, e.g. pyridine dichromate, and in the next step converting them in a known manner using a chlorinating agent such as thionyl chloride to an acid chloride of formula VI, R.

20 Ηίί ^.; AQC.>

: .. “'(J

0 0 X.

wherein R 1 and R 8 'have the same meaning as above, and thereby reacting it in a known manner with a compound of formula VII,

S

35 NH VII

/ R3 n 87463 wherein R2 and R3 are as defined above to form compounds of formula IIa

Y

5 HN

, .ιΊχ) R 6 S / ° \ | Ha> v / r3 (partial structure of the compounds of formula II), wherein Rx, R2, R3 and R6 'have the same meaning as above.

The radical Rg '' ', as defined below, is introduced into compounds of formula IIa in which Rg' is chlorine or bromine by reacting them with compounds of formula HR6 '' 'in which Rg' '' represents a cyano group or - OR, -SR4 or / R · -N, wherein R4 and R5 are as defined above, in a strongly basic medium, e.g. in the presence of sodium, or by reacting them with the corresponding amines in an autoclave at a temperature of about 100 ° C. Compounds of formula Hb, h / '

M

Hb ’rH?

Y

12 87463 compounds of the formula II in which X represents = O and R6 has the meanings of Rg 'and R6' '') in which R3, R2, R3 and Rg have the same meanings as defined above, which compounds have been obtained according to the above steps, by suitable thianation to the compounds of formula Ile, H, / ',, ώΟ

“IIC

«3 Π 15 ^ (compounds of formula II in which X represents = S) in which R 1, R 2, R 1 and R c have the same meaning as above.

The thianation process is conveniently carried out using known thianating agents, e.g. hydrogen sulphide, phosphorus pentasulphide or LAWESSON's reagent (p-methoxyphenylthiophosphine sulphide dimer). The latter reagent is preferred. The reaction itself is carried out in a known manner. If e.g. hydrogen sulfide is used, preferably an acid, e.g. hydrochloric acid, is added in catalytic portions and the reaction is carried out in a polar solvent such as acetic acid or ethanol. When using LAWESSON's reagent, the reaction is suitably carried out in a dry solvent. such as toluene-30 or methylene chloride.

Another process for the preparation of compounds of formula Hb wherein R 1 is (C) alkyl is such that 1'-deoxy-1 '(2-alkyl-6-hydroxy-9-purinyl) -β-D- ribose, 35 13 87463

OH

Y)

5 rw ^ nXV

o lila

OH OH

Wherein R 61V is (C 1-4) alkyl is reacted with acetone in the presence of an acid, e.g. p-toluenesulfonic acid, to form compounds of formula IVa,

OH

15

R6iV ^ N

IVi 20 Π

V

wherein Rgiv is as defined above, these are then oxidized using an oxidant, e.g. potassium permeate 25, in a basic medium to prepare compounds of formula Va,

OH

jcV) 30 Rgiv ^ N ^ \ N / ηο ^ Λ | oo 14 B 7 463 wherein Rglv is as defined above, then these are treated with a chlorinating agent, e.g. phosphorus oxychloride, thus converting them to compounds of formula Via, 5 Cl. A)

Vv 0 „N

“0 Via

V

o o x 15 where Rgiv is as defined above, then these are reacted with the above-mentioned compounds of formula VII to prepare compounds of formula VIIIa, ic> J 0 0

X

wherein R 2, R 3 and R 9m are as defined above and are modified by reaction with compounds of formula X,

R1-NH2 X

Wherein Rx is as defined above, to compounds of formula Hb wherein Rg is (C1-4alkyl). The compounds of formula Hb thus obtained, wherein Rg is (C3 is 874634) alkyl, can be converted by the thianination described above to correspond to compounds of formula II.

The other reactions described above are carried out using known methods, e.g. also using the methods described in Examples 5.

If in the compounds of the formula I R 1 tar- / R * are groups substituted by a -N group-, then these compounds can form salts with strong acids. Preferred salts are hydrochlorides, hydrobromides or fumarates.

If the preparation of the required starting materials has not been described, these are known or can be prepared by known methods, or analogously to the methods described herein, or analogously to known methods.

20 In the following examples, all temperatures are given in ° C and are uncorrected.

Example 1: 1 * -Deoxy-1 '- (2-methyl-6-cyclopentylamino-9-purinyl) -1β-D-ribofuranuronic acid-N-ethylamide 1.4 g of 1'-deoxy-1' - ( 2-Methyl-6-cyclopentylamino-9-purinyl) -2 ', 3'-isopropylidene-β-D-ribofuranuronic acid N-ethylamide is allowed to stand for 2 h at 0 ° C and for 1 h at room temperature in 10 ml. 90% in trifluoroacetic acid. The mixture is then concentrated completely under reduced pressure and the residue is partitioned between ethyl acetate and dilute aqueous ammonia. After washing with saturated aqueous sodium chloride solution, the product is dried over sodium sulfate and concentrated completely. The residue is dissolved in a small amount of methanol and the final product is crystallized by adding ethyl ether. Sp. 195-197 °.

The starting 1'-deoxy-1 '- (2-methyl-6-cyclopentylamino-9-purinyl) -2', 3'-isopropyl-87'3-diene-β-D-ribofuranuronic acid N-ethylamide can be prepared e.g. as follows: a) 7.5 g of potassium permanganate are added 7.8 g of 1'-deoxy-1 '- (2-methyl-6-hydroxy-9-purinyl) -2-, 3'-isopropylidene-β-D- ribose in 120 ml of aqueous solution and 4.8 ml of 10N sodium hydroxide solution, and the mixture is stirred for 1 h at 30 °. 1 g of sodium hydrogen sulphite is then added and the colorless solution is filtered through Hyflo after stirring for 5 min. The filtrate is then concentrated to a volume of about 30 ml under reduced pressure and the pH is adjusted to 4 with concentrated hydrochloric acid at 0 °. 1'-Deoxy-1 '- (2-methyl-6-hydroxy-9-purinyl) -2', 3'-isopropylidene-β-D-ribofuranuronic acid precipitates in crystalline form. Sp. with acetone after washing and drying: 15 263 ° (decomposes).

b) 3.3 g of 1'-deoxy-1 '- (2-methyl-6-hydroxy-9-purinyl) -2', 3'-isopropylidene-8-D-ribofuranuronic acid are mixed with 16.8 ml of phosphorus oxychloride for 15 minutes at 85 ° In an oil bath, 1.6 ml of NN-diethylaniline are then stirred in and stirred for a further 2 h 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 -40 ° and stirred with ethylamine until a basic reaction occurs. After 10 min, the solution is poured into ice water and shaken with ethyl acetate. After washing with saturated sodium chloride solution and drying over sodium sulfate, the solution is concentrated completely and the residue is eluted on silica gel with ethyl acetate. Purified 1'-deoxy-1 '- (2-methyl-6-chloro-9-purinyl) -2', 3'-isopropylidene-β-D-ribofuranuronic acid N-ethylamide is a white foam with an Rf value of 0.5 in ethyl acetate.

c) 1.2 g of 1'-deoxy-1 '- (2-methyl-6-chloro-9-purinyl-3H) -2', 3'-isopropylidene-β-D-ribofuranuronic acid N-ethylamide and 1.2 ml of cyclopentylamine mix with 30 ml of dioxane for 1 h in an 105 ° oil bath. After cooling, filtration is carried out, the filtrate is concentrated and the residue is eluted on 60 g of silica gel with ethyl acetate. Pure 1'-deoxy-1 '- (2-methyl-6-cyclopentylamino-9-purinyl) -2', 3'-isopropylidene-β-5D-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, R2, R3 and R6 are as defined below and in which X is always = O, are obtained analogously to Example 1:

Eg R: R2 R3 Rg Sp 2 p-methoxyphenyl H Et Me 221-224 ° 3 cyclopentyl H Et Me 196-198 ° 4 cyclopentyl H Et isopropyl amorphous 15 cyclopentyl H Et MeO 226-229 ° 6 cyclopentyl H Et MeS amorphous 7 cyclopentyl H Et Me2N amorphous 8 cyclopentyl H Et MeHN 193-194 ° 9 p-ethoxyphenyl H Et Me 120-125 ° 20 10 3,4-dimethoxyphenyl H Et Me 236-239 ° 11 3-pentyl H Et Me 181 -183 ° 12 m-fluorophenyl H Et Me 137-142 ° 13 P-fluorophenyl H Et Me 257-259 ° 25 14 p-chlorophenyl H Et Me 255-258 ° 15 isopropyl H Et Me 187-194 ° 16 P-trifluoromethyl - phenylphenyl H Et Me 248-250 ° 30 1'-deoxy-1 '- (2-chloro-6-cyclopentylamino-9-purinyl) -2', 3'-isopropylidene-β-D-ribofuranuronic acid-N- ethylamide, which is also useful as a starting material for the preparation of compounds of formula II in which R & has the same meaning as R6 ,,, / 35 can be prepared e.g. as follows: a) 8.8 ml of trimethyl ester of ortho-formic acid are added dropwise at room temperature 7.4 g 1 '-Desoksi-1' - (2-

ie B 7 4 6 S

chloro-6-cyclopentylamino-9-purinyl) -β-D-ribose and 4.2 g of p-toluenesulfonic acid in 120 ml of acetone. After 3 h, the precipitate is filtered and washed with acetone and diethyl ether. The dried precipitate 5 is then added in small portions with stirring to a solution of 3.6 g of sodium hydrogen carbonate in 150 ml of aqueous solution and 75 ml of ethyl acetate. The organic phase is separated, washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated.

The oily residue is then purified by eluting on 140 g of silica gel with a 9: 1 mixture of methylene chloride and ethanol. The Rf value of pure 1'-deoxy-1 '- (2-chloro-6-cyclopentylamino-9-purinyl) -2', 3'-isopropylidene-β-D-ribose is 0.5.

B) 8.7 g of 1'-deoxy-1 '- (2-chloro-6-cyclopentylamino-9-purinyl) -2', 3'-isopropylidene-β-D-ribose and 30.5 g of pyridine dichromate are stirred for 18 h at room temperature 130 ml in dimethylformamide. The mixture is then poured into water and the aqueous phase is shaken 3 times with ethyl acetate. This phase is then extracted with saturated aqueous sodium carbonate solution, the pH of the basic extract is adjusted to 1 with 5N hydrochloric acid and the extract is shaken with ethyl acetate. After washing with saturated sodium chloride solution and drying over sodium sulfate, the organic phase is concentrated, diluted with diethyl ether to give 1'-deoxy-1 '- (2-chloro-6-cyclopentylamino-9-purinyl) -β-D-ribofuranuronic acid crystalline acid. Sp. 246-253 °.

c) 4 g of the above acid are heated with 40 ml of thionyl chloride for 20 min in a 45 ° oil bath. 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 passed with stirring until the reaction becomes basic. The methylene chloride phase is then washed with water, dried over sodium sulfate and concentrated. 1'-Deoxy-1 '- (2-chloro-19 87463 6-cyclopentylamino-9-purinyl) -2', 3'-isopropylidene-β-D-ribofuranuronic acid N-ethylamide remains as a white foam. Rf in methylene chloride / ethanol 9: 1 = 0.7.

The preparation of compounds of formula II in which Rg is the same as R '' 1 and X is = O is carried out starting from the above compound of formula Ha in which R6 'is chlorine, in a manner known per se, e.g. by reaction with alcohol, amine, etc. with.

Example 17: 1 * -Deoxy-1 '- (21-methyl-6-cyclopentylamino-9-purinyl) -β-D-ribofuranuronic acid-N-ethyl-thioamide a) 1'-Deoxy-1' - (2 -methyl-6-cyclopentylamino-9-15 purinyl) -2 ', 3'-isopropylidene-β-D-ribofuranuronic acid N-ethylthioamide 1.7 g of 1'-deoxy-1' - (2-methyl-6-cyclopentyl) -aminoamino-9-purinyl) -2 ', 3'-isopropylidene-β-D-ribofuranuronic acid N-ethylamide (starting material of Example 1) 20 is mixed with 0.77 g of LAWESSON reagent in 38 ml of toluene for 2 h in a 100 ° oil bath . The mixture is then concentrated completely under reduced pressure, the residue is dissolved in 60 ml of ethyl acetate and stirred for 1/2 h 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.

b) 1'-Deoxy-1 '- (2-methyl-6-cyclopentylamino-9-purinyl) -β-D-ribofuranuronic acid N-ethylthioamide 30 1.5 g of 1'-deoxy-1' - (2-methyl-6 -cyclopentylamino-9-purinyl) -2 ', 3'-isopropylidene-BD-ribofuranuronic acid-N-ethylthioamide is dissolved in 7.5 ml of 90% trifluoroacetic acid at room temperature and left to stand for 2 h. The solution 35 is then completely concentrated under reduced pressure. The residue is dissolved in ethyl acetate, mixed with aqueous ammonia and concentrated completely under reduced pressure. The crystalline residue of the title compound is then purified by eluting with 30 g of silica gel with a 9: 1 mixture of methylene chloride and ethanol. Finally, the pure fractions are crystallized from ethyl ether / pentane. 5 Sp. 168-170 °.

The following compounds of formula I, wherein R 1 # R 2, R 3 and R 6 are as defined below and wherein X is always = S, are obtained analogously to Example 17.

10 Eg R3 R2 R3 R6 Sp.

18 3-pentyl H Et Me amorphous 19 p-ethoxyphenyl H Et Me 202-205 ° 20 p-methoxyphenyl H Et Me 222-225 ° 21 3,4-dimethoxyphenyl H Et Me 221-224 ° 15 22 4-methylsulfonylphenyl H Et Me 164-167 °

The compounds of the invention are significant for their interesting pharmacological properties. They can therefore be used as medicines.

In particular, the compounds of the invention have antihypertensive (antihypertensive) activity, which can be demonstrated by the results of the following experiments: Measurement of adenosine A1 and A2 receptor binding in membranes obtained from rat cortex (cortex) or cerebral cortex (cerebral cortex) ) is performed using RF BRUNS, G, H, LU, and T.A. PUGSLEY according to MOLEC. Pharmacol. 29, 331-346 (1986).

Further testing of the activity of the substances according to the invention was performed on isolated, perfused rat kidneys to obtain the following parameters: 35 - renin secretion - renal hemodynamics (vasodilation, vasodilation) 2i 87463 - inhibition of noradrenaline release following nerve nerve electrical stimulation H.J. SCHUREK, J.P. BRECHT, H. LOHFERT and K. HIERHOLZER according to the method described in COMMUNICATION a 5 la REUNION de 1’ASSOCIATION DES PHARMACOLOGISTES LOUVAIN UCL on June 4, 1977, as well as P.M. VANHOUTTE, D. BROWNING, E. COEN, T.J. VERBEUREN, L. ZONNEKEYEN and M. G. COLLINS according to the method described in HYPERTENSION 4, 251-256 (1982).

10 - Measurement of blood pressure, heart rate, urinary output and renin activity in plasma from awake, NaCl-depleted, and replicated, normal-blooded or spontaneously hypertensive rats with catheters inserted into the abdominal aorta and V which measurement is performed iv administration or after infusion or bolus administration of the compounds of the invention by J.F.M. SMITS and J.M. BRODY according to the method described in Am. J. Physiol. 20 247, R1100-R1008 (1984).

From the results of the experiments, it can be concluded that both the inhibition of renin secretion and the release of noradrenaline from the nerve endings and the direct vasodilation are involved in the antihypertensive activity of the compounds according to the invention.

From this, it is apparent that in addition to the use of the compounds of the invention as antihypertensive agents, the compounds may also affect coronary vasodilation. They also protect vascular endothelium by inhibiting platelet aggregation and activating leukocytes. They also lower blood fat levels.

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

The dosage to be used as antihypertensive agents for the above application will vary depending on the agent used, the mode of administration and the desired therapeutic effect. In general, however, satisfactory results are obtained with daily doses of about 0.01 to 10 mg / kg body weight; if necessary, the administration can be carried out in 2-4 batches or even in 5 immediate-release forms. For larger mammals, the daily dose is between about 10 and 500 mg; Suitable dosage forms, e.g., for oral or non-oral administration, will usually contain from about 5 to about 250 mg of a compound of the invention in association with solid or liquid carriers.

The compounds of the invention may be administered alone or in a suitable dosage form. Dosage forms, e.g. solution or tablet, can be prepared analogously to known methods.

Therefore, the invention also relates to medicaments containing the compounds according to the invention in free form or in the form of their physiologically tolerable salts, as well as to the preparation of these medicaments in a known manner. They can be prepared using conventional pharmaceutical adjuvants and carriers.

Claims (18)

23 87463 A process for the preparation of therapeutically useful 1'-deoxy-1 '- (6-amino-9-purinyl) -fl-D-ribofuranuron-5 acid amides and thioamides substituted in the 2-position of formula I, 10. AnA., / [»6 * o XX 15. OH OH wherein Rx represents (C1-6) alkyl which may be optionally monosubstituted by hydroxyl, R4-20 / -SH or -N, wherein R and R independently of one another are hydrogen or (C14) alkyl; (C37) alkenyl, (C37) alkynyl, (C37) cycloalkyl, which may be optionally mono- or di-substituted with R4 / hydroxyl, -SH or -N, where R1, X5 and R5 are the same. as above; (C3-7) cycloalkyl (C33) alkyl, which may be optionally mono- or di-substituted on the cycloalkyl ring by hydroxyl, / 4 40 with the group -SH or -N, in which R4 and R5 mean ... R5 24 87463 are as defined above; phenyl which may be optionally mono- or di-substituted with halogen of atomic numbers 9 to 35, (C 1-4) alkyl, (C 14) alkoxy, hydroxyl, -SH-, -S- (C 1-4) alkyl, -SO 2 - (C 14) - 5'-alkyl, trifluoromethyl or -SO, -N \ r5, wherein R4 and R5 are as defined above; phenyl- (C 1-6) alkyl which may be optionally mono- or di-substituted on the phenyl ring by halogen having a atomic number from 9 to 35, (C 14) alkyl, (C 14) alkoxy, hydroxyl, -SH-, -S- (C 14) alkyl, - S02 ~ R 1 / (C 14) alkyl or -SO 2 -N, wherein R 4 R 5 and R 5 are as defined above, and the (C 16) alkylene chain is straight or branched and may be optionally substituted by a hydroxyl group; phenyl- (C 3-7) alkenyl which may be optionally substituted on the phenyl ring by halogen of atomic number 9-35, (C 14) alkyl, (C 7 -C 4) alkoxy, hydroxyl, -SH-, -S-fC 4) with alkyl, -SO 2 - (C 1-4) alkyl; / 4 or -SO-N, wherein R and R "30 \ R5 are as defined above; A 5 or 6 membered monocyclic heteroaryl ring containing 1 or 2 nitrogen atoms or one oxygen atom or one sulfur atom for 35 minutes and one nitrogen atom, respectively; or 5 or 6 membered, monocyclic heteroaryl- (C15) alkyl containing 1 or 2 nitrogen atoms or one oxygen atom or one sulfur atom and one nitrogen atom, respectively, in the heteroaryl unit, the alkylene unit being straight-chain or branched and may be optionally substituted by a hydroxyl group; and 87463 R 2 represents hydrogen, (C 1-4) alkyl which may be optionally mono-substituted with hydroxyl, -SH- or / R 4 With 5 -N, wherein R and R4 are the same as R5 as defined above; or it represents (C3e) cycloalkyl; and R 3 is hydrogen or (C 1-4) alkyl, which may be optionally substituted with (R) -SH or -N, wherein R 4 and R 5 R5 has the same meaning as above; and R 9 is halogen, (C 14) alkyl, (C 3-5) cycloalkyl, cyano or a 20 / -OR 4, -SR 4, -N group, r 5 wherein R 4 and R 5 are as defined above: and X is O or S; wherein when X is O and Rx is (Cx6) alkyl, (C37) cycloalkyl or phenyl- (C16) alkyl, then Rf is (C3) alkyl, (C35) cycloalkyl, cyano or -OR4, -SR4 or R4 30 / N groups in which R 4 represents hydrogen or (C 14) R 5 alkyl and R 5 represents (C 1 -C 4 alkyl), characterized in that 1'-deoxy-1 '- (6-amino-9-purinyl) -2' The isopropylidene group is cleaved from a 3'-isopropylidene-HD-ribofuranuronic acid amide or thioamide substituted in the 2-position of formula II, wherein R, R2, R3, Rg and X have the same meaning as above. Process according to Claim 1, characterized in that compounds of the formula Ia are prepared, R a 25 HO OH. . wherein RLa represents (C3-6) alkyl, (C3-7) cycloalkyl, which may be optionally mono- or di-d / 30 / substituted with hydroxyl, -SH- or -N -groups, wherein R4 and R5 is as defined above; 35 phenyl- (C16) alkyl which may be mono- or di-substituted on the phenyl ring by halogen having an atomic number from 9 to 35, (C34) alkyl, (C1-4) alkoxy, hydroxyl, -SH-, -S- (C1-4) alkyl , 27 87 463 / R * -SO 2 - (C 4 -C 4) alkyl or -SO 2 -N, 5 r 5 wherein R 4 and R 5 are as defined above, wherein the (C 6) alkylene chain is straight-chain or branched and may be optionally substituted by a hydroxyl group ; or phenyl which may be optionally mono-10 or disubstituted with halogen of atomic numbers 9 to 35, (C 1-4) alkyl, (C 1-4) alkoxy, hydroxyl, -SH-, -S- (C 1-4) alkyl, -SO 2 - (Cx 4) alkyl, trifluoromethyl or R 4 / -SO 2 -N, wherein R 4 and R 5 are as defined above; R 2a is hydrogen, (C 1-4) alkyl, which may be optionally mono-substituted with hydroxyl, / R '-SH, or -N, wherein R 4 and R 5 are as defined above; or (C36) cycloalkyl; and R 3a is hydrogen or (C 1-6 alkyl, which may be optionally mono-substituted with hydroxyl, R4 / -SH-, or -N, where R and R are -. : \ r5 35 the same as above; and Rga is halogen having an atomic number of 9 to 35, (C3) alkyl, or means 40 -OR4, SR4 or -N, wherein R4 and R5 are as defined above; and X represents O or S; wherein when X is O and R 28 284646 is (C 1-6) alkyl, (C 3-8) cycloalkyl or phenyl (C 1-8) alkyl, then R 6a is (C 1-6 alkyl or -OR 4, -SR 4 or 5 N - a group wherein R is hydrogen or R 5 (C 4) alkyl and R 5 is (C 4 -C 4) alkyl. Process according to Claim 1, characterized in that compounds of the formula Ib are prepared, R b 13 f 'Lb 5 xn lb 20 r 3 Π HO OH 25 in which R 1b represents (C 3-6) alkyl, (C 37) cycloalkyl, which may optionally be mono- or di- / * substituted by hydroxyl, -SH-, or N-R-, wherein R4 and R5 are as defined above; or phenyl which may be optionally mono- or di-substituted with halogen of atomic number 9-35, 35 (C34) alkyl, (C4-4) alkoxy, hydroxyl, -SH-, S- (C1-4) alkyl, -SO2- ( C 1-4 alkyl, trifluoromethyl or SO, -N, wherein R 40, R 27b and R 5 are as defined above; R 2b is hydrogen, (C 1-4 alkyl which may be optionally mono-substituted with 5 / hydroxyl); , -SH-, or -N, wherein R and Rc are as defined above, or (C36) cycloalkyl, and R3b is (C1-C4) alkyl, and R6b is (C3-Alkyl, chloro, bromo, methoxy, methylthio, methylamino or dimethylamino, and X is O or S, wherein when X is O and R3b is (C16) alkyl or (C37) cycloalkyl, then R6b is (C) alkyl, methoxy, methylthio or dimethylamino. Process according to Claim 1, characterized in that one of the following compounds is prepared: 1'-deoxy-1 '- (2-methyl-6-cyclopentylamino-9-purinyl) -β-D-ribofuranuronic acid-N -ethylthioamide, 1'-deoxy-1 '- (2-methyl-6-cyclopentylamino-9-purinyl) -β-D-ribofuranuronic acid-N-ethylamide,. . 1'-deoxy-1 '- (2-ethyl-6-cyclopentylamino-9-purinyl) -β-D-ribofuranuronic acid N-ethylamide,: 30'-deoxy-1' - (2-isopropyl- 6-Cyclopentylamino-9-purinyl) -β-D-ribofuranuronic acid N-ethylamide, 1'-deoxy-1 '- (2-methyl-6-p-methoxyphenylamino-9-35 purinyl) -β-D-ribofuranuronic acid N-ethylamide, 1'-deoxy-1 * - (2-methylamino-6-cyclopentylamino-9-purinyl) -β-D-ribofuranuronic acid-N-ethylamide, 30 87463 1'-deoxy-1 '- (2-methylthio -6-cyclopentylamino-9-purinyl) -β-D-ribofuranuronic acid-N-ethylamide, 1'-deoxy-11- (2-dimethylamino-6-cyclopentylamino-9-5 purinyl) -β-D-ribofuranuronic acid-N- ethylamide, 1'-deoxy-1 '- (2-methoxy-6-cyclopentylamino-9-purinyl) -β-D-ribofuranuronic acid-N-ethylamide, 1'-deoxy-1' - (2-methyl- 6-p-Ethoxyphenylamino-9-purinyl) -β-D-ribofuranuronic acid N-ethylamide, 1'-deoxy-1 '- (2-methyl-6- (3,4-dimethoxyphenyl) amino-9-purinyl ) -β-D-ribofuranuronic acid-N-ethylamide, 1'-deoxy-1 '- (2-methyl-6 - (3-pentyl) -amino-9-purinyl) -β-D-ribofuranuronic acid-N-ethylamide, 1'-deoxy-1 '- (2-methyl-6-m-fluorophenylamino-9-Puri-20 yl) -β-D-ribofuranuronic acid-N-ethylamide, 1'-deoxy-11- (2-methyl-6-p-fluorophenylamino-9-purinyl) -fl-D-ribofuranuronic acid-N-ethylamide, il · 1'-deoxy-1 '- (2-methyl-6-p-chlorophenylamino-9-purinyl) -β-D-ribofuranuronic acid N-ethylamide, 1'-deoxy-1' - (2-methyl- 6-Isopropylamino-9-purinyl) -β-D-ribofuranuronic acid N-ethylamide, 1'-deoxy-1 '- (2-methyl-6-p-trifluoromethylphenylamino-9-purinyl) -β- D-ribofuranuronic acid N-ethylamide, 1'-deoxy-1 '- (2-methyl-6- (3-pentyl) -amino-9-purinyl) -β-D-purinyl) -β- D-ribofuranuronic acid-N-ethyl-thioamide, 3i 87463 1'-deoxy-1 '- (2-methyl-6-p-ethoxyphenylamino-9-purinyl) -β-D-1-bofuranuronic acid-N-ethyl] thloamide, 1' -deoxy-1 '- (2-methyl-6-p-methoxyphenylamino-9 -5 purinyl) -β-D-ribofuranuronic acid-N-ethylthioamide, 1'-deoxy-1' - (2-methyl-6- (3 , 4 -dimethoxyphenyl) -amino-9-purinyl) -β-D-ribofuranuronic acid N-ethylthioamide-10'-deoxy-1 '- (2-methyl-6- (4-methylsulfonylphenyl) amino-9 -purinyl-)-f-D-ribofuranuronihappo-n-ethyl-litioamidi. 32 87463