HU201955B - Process for producing new ribofuranuronic acid derivatives and pharmaceutical compositions comprising such compounds - Google Patents

Abstract

In position 2 substituted 1'-desoxy-1'-(6-amino-9-puri-nyl)-.beta.-D-ribofuranuronic acid amides and thioamides of formula <IMG> are effective against raised blood pressure.

Description

The present invention relates to a process for the preparation of novel 2-substituted 1'-deoxy-1 '- (6-amino-9-purinyl) -? - ribofuranuronic acid amides and thioamides and to pharmaceutical compositions containing such compounds. These compounds are useful in the treatment of hypertension

If desired, these compounds may be substituted, for example on free amino groups.

U.S. Pat. No. 4,167,565 discloses an agent for controlling rodents, coyotes and birds, the active ingredient of which is a compound of formula (A).

US Patent Publication No. 26 10 985 discloses the preparation of compounds of general formula (B) and their use as active ingredients in pharmaceuticals.

More particularly, the present invention relates to a process for the preparation of 1'-deoxy-1 '- (6-amino-9-purynyl) -p-D-ribufuranuronic acid amides and thioamides of the general formula (I) which is substituted at the 2-position. In formula (I)

R 1 is C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, or phenyl optionally mono- or disubstituted by C 9 -C 5 halogen, C 1 -C 4 alkoxy, -SO 2 - (C 1 -C 4) alkyl, trifluoromethyl;

R ₃ is C 1 -C 4 alkyl;

R 1 is halogen; C 1 -C 4 alkyl, or -OR 4, -SR 4 or -NR 4 R 5 in which R 4 and R 5 are hydrogen or C 1 -C 4 alkyl, and

X is O or S, with the proviso that when X is O and Rt is C1-C6 alkyl then R6 is bromo, C1-C4 alkyl or OR4, -SR4- or

R4

-N (C1-C4 alkyl) wherein R4 is as defined above.

Compounds of formula (I) are hereinafter (sometimes) referred to as compounds of the invention.

The compounds of formula (I) wherein R ^represents C 1-6 bargaining or C3-7 cycloalkyl; optionally substituted with 9 to 35 halogens, C1 -C4 alkoxy, -SO2- (C1 -C4 alkyl), mono- or disubstituted phenyl;

R ₃ ^represents C 1-4 alkyl;

R6a is ^a halogen number from 9 to 35 atoms; C 1 -C 4 alkyl; or -OR4, -SR4 or NR4R5, wherein R4 and R5 are as defined above; and

X is O or S, with the proviso that when X is 0 and R 1 is C 1 -C 6 alkyl, then R 6 ^a is bromo, C 1 -C 4 alkyl, or -OR 4, -SR 4, or

R4

-N (C1-C4 alkyl) wherein R4 is as defined above.

Particularly preferred compounds of formula (I) are those of formula (Ib) wherein

R ^1b is C 1-6 alkyl or C 3-7 cycloalkyl; or phenyl optionally mono- or disubstituted with 935-halogen, C 1 -C 4 alkoxy, -SO 2 - (C 1 -C 4 alkyl), trifluoromethyl;

R ₃ ^b is C 1-4 alkyl;

R ^b is chlorine or bromine; C 1-4 alkyl; methoxy, methylthio, methylamino or dimethylamino; and

X is O or S, with the proviso that when X is O and R ^1b is C 1-6 alkyl then R ⁶ is bromo, C 1-4 alkyl, or -OR 4,

R4

-SR4-N (C1-C4 alkyl) wherein R4 is as defined above.

In the formula (I): halogen of from 9 to 35 is fluorine, chlorine or bromine, preferably chlorine; C 1-4 alkyl is methyl, ethyl, η-propyl, isopropyl, n-butyl, isobutyl, tert-butyl; C 1 -C 6 -alkyl may be, for example, n-pentyl, isopentyl, 3-pentyl, n-hexyl or isohexyl, in particular methyl, ethyl, isopropyl or 3-pentyl; C1-C4 alkoxy is, for example, methoxy, ethoxy, n-propoxy, isopropoxy, η-butoxy, isobutoxy, tert-butoxy; in these groups the carbon chain may be straight or branched. C3-7cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, especially cyclopentyl. The substituents on the benzene ring are bonded at the 0, m or p position; when monosubstituted, the substituent is preferably attached at the m or p position.

For example, the compounds of formula (I) according to the invention may be prepared by reacting a 1'-deoxy-1 '- (6-amino-9-purinyl) 2', 3'-isopropylidene-3-D of formula (Π). -ribofuranuronic acid amide or -thioamide - wherein R 1, R 3, R 6 and X are as defined above - the isopropylidene group is cleaved.

This process is conveniently carried out by treating the compounds of formula (Π) with an isopropylidene removal agent. Trifluoroacetic acid has proved particularly suitable for this purpose; however, aqueous hydrochloric acid or aqueous formic acid may also be used.

Compounds of formula (() used as starting materials are prepared by reacting a compound of formula (ΙΠ) wherein R1 is as defined above and R1 is halo, (C1-C4) -alkyl or (C3-C5) -cycloalkyl (described herein). for example, U.S. Patent No. 1,670,175, British Patent Specification No. 1,075,008, and J. Org. Chem. 1968.2583) are introduced into an isopropylidene group such that it is an acid such as p-toluene. in the presence of sulfonic acid-2HU 201955 acet with acetone, the compound of formula IV thus obtained, wherein R 1 and R 1 'are as defined above, is known in a known manner using an oxidizing agent such as pyridinium bichromate to give wherein R 1 and R 10 'are as defined above and oxidizing the resulting compound of formula (V) with a diluent such as thioml chloride and the resulting acid chloride of formula (VI) - wherein R 1 and R 1 'are as defined above with an amine of formula R 3 NH 2 Wherein R3 is as defined above, in a manner known per se. Thus, compounds of formula (Ha), which is a narrower group of compounds of formula (Π), are obtained, wherein R 1, R 3 and R 6 are as defined above.

The Ró group, as defined below, is introduced into the compounds of formula (IIa), wherein R 'is a chlorine or bromine atom, to be reacted with a compound of the general formula H'ó ahol where R ”' is -OR4, SR4 or -NR 4 R 5 wherein R 4 and R 5 are as defined above, in a strongly alkaline medium such as sodium, or by reaction with the corresponding amines in an autoclave at temperatures above 100 ° C.

Compounds of formula (Kb) prepared according to the above steps (i.e., compounds of formula (Π) wherein X is O and R 1 includes both R 1 * and R 6 '*) wherein R 1, R 3 and R 6 are as defined above, can be converted to the compounds of formula (He) (i.e., compounds of formula (Π) wherein X is sulfur) wherein R1, R3 and R6 are as defined above, by appropriate sulfurization methods. (By sulfurization, we mean replacing the oxygen of the acid amide group with a sulfur atom; the English term "thianation" has no Hungarian equivalent).

The above sulfurization process is conveniently carried out using known sulfur delivery agents: hydrogen sulfide, phosphorus pentasulfide or Lawessonreagent (p-methoxyphenylthiophosphine sulfide dimer). The most recent reagent is preferred. The reaction is carried out in a known manner. For example, when hydrogen sulfide is used, it is convenient to add the catalytic amount of hydrochloric acid and the reaction is carried out in a polar solvent such as acetic acid or ethanol. When Lawesson's reagent is used, the reaction is conveniently carried out in a dry solvent such as dry toluene or dichloromethane.

Compounds of formula IIb wherein R 1 is C 1 -C 4 alkyl may also be prepared by reacting a 1'-deoxy-1 '- (2-alkyl-6-hydroxy-9-purinyl) of formula (ma) β-D-ribose, wherein R ^{iv in the} formula (IIIa) is C 1 -C 4 alkyl, is reacted with acetone in the presence of an acid such as p-toluenesulfonic acid to give a compound of the formula (TVa) wherein ^R ' ^V is as defined above as defined - is oxidized with an oxidizing agent such as potassium permanganate to give an oxl4. Compound of Formula (Va) wherein ^R ' ^V is as defined above is treated with a chlorinating agent such as phosphorus oxychloride to form a compound of Formula (VIa) wherein ^{R', V} is as defined above as defined in (VH) above. reacting a compound of formula (VIIa), wherein R3 and R6 ^{, v} are as defined above, with a R1NH2 amine of formula (X), wherein R1 is as defined above, to give compounds of general formula (Hb) compounds wherein R 1 is C 1 -C 4 alkyl. The resulting compounds of formula (Db) wherein R 1 is C 1 -C 4 alkyl can be converted to the corresponding compounds of formula (Π) by the sulfurization method described above.

Other reactions described above may be carried out by known methods, for example as described in the Examples.

When R 1 in the compounds of formula (I) is a group containing NR 4 R 5 as a substituent, these compounds may form salts with strong acids. Hydrochlorides, hydrobromides and fumarates are preferred. Unless described separately for the preparation of the desired starting materials they are known, or can be prepared by known methods, or by methods similar to those described herein, or by methods known in the art.

The following non-limiting embodiments of the present invention are described in detail in these examples. In these examples, temperatures are given in degrees Celsius and are not corrected.

Example 1 Preparation of -Doxy-r- (6-cyclopentylamino-2-methyl-9-pururin) -P-D-ribofuranuronic acid (N-ethyl) amide

1.4 g of r-deoxy-r- (6-cyclopentylamino-2-methyl-9-purinyl) -2 ', 3'-isopropylidene-pD-ribofuranuronic acid (N-ethyl) amide in 10 ml of 90% trifluoro dissolved in acetic acid, the solution was allowed to stand at 0 ° C for 2 hours and then at room temperature for 1 hour, then concentrated completely in vacuo and partitioned between ethyl acetate and dilute aqueous ammonia. After separation, the organic phase is washed with brine, dried over anhydrous sodium sulfate, and after filtration, the solution is completely evaporated to dryness. The residue is dissolved in a little methanol and diethyl ether is added. The title compound was crystallized, m.p. 195197C. Yield 60%.

The starting material 1'-deoxy-Γ - (6-cyclopentylamino-2-methyl-9-purinyl) -2 ', 3'-isopropylidene-3-D-ribofuranuronic acid (N-ethyl) amide is prepared as follows: can be produced:

a) 7.8 g of r-deoxy-1 '- (6-hydroxy-2-methyl-9-purinyl) -2', 3'-isopropylidene-p-D-ribose in 120 ml of water and

To a solution of 4.8 ml of 10 N sodium hydroxide solution was added 7.5 g of potassium permanganate and the mixture was stirred for 1 hour at 30 ° C. Then 1 g of sodium bisulfite was added and the colorless solution was treated with Hyflo3.

After stirring for 5 minutes on a filter insert -3 201955 Β. The filtrate was concentrated in vacuo to about 30 ml and the pH was adjusted to 4 by addition of concentrated hydrochloric acid at 0 ° C to give 1'-deoxy-1 '- (6-hydroxy-2-methyl-9-purinyl) as a crystalline precipitate. ) -2 ', 3'-isopropylidene-pD-ribofuranuronic acid is obtained which is washed with acetone and dried at 263 DEG C. (with decomposition). Yield 82%.

b) 2.2 g of 1 * -deaxyl-1 '- (6-hydroxy-2-methyl-9-purinyl) -2', 3'-isopropylidene-β-D-ribofuranuronic acid

After stirring with phosphorus oxychloride (16.8 ml) in an oil bath at 85 ° C for 15 minutes, 1.6 ml of N, N-diethylaniline was added and the mixture was stirred at the same temperature for a further 2 hours. The residue was dissolved in 60 ml of tetrahydrofuran. The solution was cooled to 40 ° C and ethylamine was added with stirring until the mixture became basic after 10 minutes. The solution was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, After drying over sulfate, the solution is completely evaporated and the residue is purified on silica gel, eluting with ethyl acetate. The resultant purified 1'-deoxy-r- (6-chloro-2-methyl-9-purinyl) -2 'is obtained. 3'-Isopropylidene-β-D-ribofuranuronic acid (N-ethyl) amide is a white foam with an Rf of 0.5 when developed with ethyl acetate. Yield: 57%.

c) 1.2 g of l'-deoxy-1 '- (6-chloro-2-methyl-9-purinyl) 2', 3'-isopropylidene-p-D-ribofuranuronic acid (Netyl) amide and Cyclopentylamine (30 ml) in dioxane (30 ml) was heated in a 105 ° C oil bath for 1 hour. After cooling, the filtrate was evaporated and the residue was purified on a silica gel column using ethyl acetate as eluent. '-Deoxy-1' - (6-cyclopentylamino-2-methyl-9-purinyl) -2 ', 3'-isopropylidene-β-ribofuranuron15 acid (N-ethyl) -amide white foam with an Rf value 0.45, developed with ethyl acetate. Yield: 90%.

In a similar manner to that described in Example 1, compounds of the general formula (I) listed in the following table were prepared, wherein R 1, R 3 and R 10 are as defined in the table and X is oxygen.

The serial number of the example rl R3 rO Op.'C Second p-methoxyphenyl et Me 221-224 Third cyclopentyl et Me 196-198 4th cyclopentyl et isopropylthiopyrazole amorphous 6th cyclopentyl et Br 188-190 7th cyclopentyl et Sample check 226-229 8 * cyclopentyl et MeS amorphous 9th ** cyclopentyl et Me2N amorphous 10th cyclopentyl et MEHNE 193-194 12th p-ethoxyphenyl et Me 120-125 13th 3,4-dimethoxyphenyl et Me 236-239 14th 3-pentyl et Me 181-183 15th m-fluorophenyl et Me 137-142 16th p-fluorophenyl et Me 257-259 17th p-chlorophenyl et Me 255-258 18th isopropyl et Me 187-194 19th p- (trifluoromethyl) phenyl et Me 248-260

* Rf: 0.4 (methylene chloride / ethanol 9: 1) ** Rf: 0.5 (ethyl acetate / methanol 9: 1)

1'-Deoxy-1 '- (6-cyclopentylamino-2-methyl-9-purinyl) -2', 3'-isopropylidene-pD-ribofuranuron-50-acid (N-ethyl) amide which can be used as starting material for the preparation of compounds of the formula (,) in which R jelentése is R ', for example, by the following process:

(a) Trimethyl ester of ortho-formic acid (8.8 ml) was added dropwise at room temperature to 7.4 g of 1'-deoxy-1 '- (6-chloro-2-methyl-9-purinyl) -? - D-ribose and 4.2 g of p -toluenesulfonic acid in 120 ml acetone. After 3 hours, the precipitate was filtered and washed first with acetone and then with diethyl ether. The dried precipitate was added in 60 portions with stirring to a mixture of 3.6 g of sodium bicarbonate, 150 ml of water and 75 ml of ethyl acetate. The organic layer was separated, washed with brine, dried (Na 2 SO 4) and evaporated. - (6-Cyclopentylamino-2-chloro-9-purmyl) -2 ', 3'-isopropylide η-β-D-ribose is obtained with an Rf of 0.5.

b) 8.7 g of 1'-riboxy-1 '- (6-cyclopentylamino-2-chloro-9-purinyl) -2', 3'-isopropylidene-3-D-ribose,

After stirring at room temperature for 18 hours, 30.5 g of pyridinium bichromate and 130 ml of dimethylformamide are added, the aqueous phase is extracted three times with ethyl acetate. The organic phase is extracted with a saturated aqueous solution of sodium bicarbonate and the basic extract is obtained. The organic phase was washed with saturated brine, dried over sodium sulfate, the organic phase was concentrated and the residue was diluted with diethyl ether to give a crystalline solid.

-4HU 201955Β'-deoxy-1 '- (6-cyclopentylamino-2-chloro-9-purinyl) -? - D-ribofuranuronic acid, m.p. 246253'C.

c) 4 g of thionyl chloride in 40 ml of thionyl chloride were heated in a 45 ° C oil bath for 20 minutes. After gas evolution was complete, the mixture was concentrated in vacuo and the acid chloride was dissolved in 40 ml of dichloromethane and cooled in an ice bath. until the gaseous ethylamine is introduced with stirring until the reaction is generally basic. The dichloromethane layer was washed with water, dried over sodium sulfate and evaporated. This gives l'-deoxy-1 '- (6-cyclopentylamino-2-chloro-9-purinyl) -2', 3'-isopropylidene-pD-ribofuranuronic acid (N-ethyl) amide as a white foamy residue, 15 having an Rf of 9: 1 in dichloromethane: ethanol = 0.7.

Compounds of formula (Π) wherein R R is R * 'and X is oxygen are prepared by reacting a compound of general formula (Ra) wherein R' 'is chlorine in a manner known per se with, for example, an alcohol or an amine.

Example 20 Preparation of 25 '-Deoxy-1' - (6-cyclopentylamino-2-methyl-9-pururin) -3-D-ribofuranuronic acid (N-ethyl) thioamide

a) Preparation of 1 '-Deoxy-1' - (6-cyclopentylamino-2-methyl-9-pururin) -2 ', 3'-isopropylidene-3-D-ribofuranuronic acid (N-ethyl) thioamide

1.7 g of r-deoxy-1 '- (6-cyclopentylamino-2-methyl8)

9-purinyl) -2 ', 3'-isopropylidene-pD-ribofuranuronic acid (N-ethyl) amide (starting material from Example 1) was stirred with 0.77 g of LaLessesson reagent in 38 ml of toluene in an oil bath maintained at 100 ° C for 2 hours. The mixture was completely evaporated in vacuo and the residue was dissolved in ethyl acetate (60 mL) and stirred with neutral alumina (25 g) for 30 min. After filtration, the filtrate was evaporated and used without further purification for the next step. Rf of the title product, developed with ethyl acetate, is 0.7.

b) Preparation of 1'-Deoxy-1 '- (6-cyclopentyl-2-methyl-9-puryl) -3-D-ribofuranuronic acid (N-ethyl) thioamide

1/5 g of r-deoxy-1 '- (6-cyclopentylamino-2-methyl-9-purinyl) -2', 3'-isopropylidene-3-D-ribofuranuronic acid (N-ethyl) thioamide 7.5 ml After standing for 2 hours in 90% trifluoroacetic acid, the mixture was completely evaporated in vacuo. The residue was dissolved in ethyl acetate, stirred with aqueous ammonia solution and concentrated in vacuo to a residue. recrystallized from a mixture of diethyl ether and pentane, m.p. 168-170 ° C

In a similar manner to that described in Example 20, the compounds of formula (I) listed below were prepared wherein R 1, R 3 and R 6 are as defined in the table and X is sulfur.

The example is R1 to R3 impose Op.'C number 21. 3-Pentyl Et Me amorphous 22. p-Ethoxyphenyl Et Me 202-205 23. p-Methoxyphenyl Et Me 222-225 24. 3,4-Dimethoxyphenyl Et Me 221-224 25. 4- (Methylsulfonyl) phenyl Et Me 164-167 The compounds of the present invention deserve attention. have pharmacological properties, and so Compound Adenosine is A1 and A2 They can be used as a medicine. Ul. receptors compounds which lower blood pressure (an- Example No. Boundary boundaries they are hypertensive, and this is their characteristic 50 (Nanomolar) from the results of the following tests. lower upper In the rat cortex or guinea pig brain, First 0.2 20 in the cortex and in the striatum of the guinea pig Second 3 300 Al and A2 adenosine on the cell membrane 55 Third 4 400 receptor binding R.F. Bruns and work- 4th 10 1000 et al., Molec. Pharmacol. 29th 5th 0.2 20 331 (1986) /. 6th 0.2 20 7th 1 100 The chemical compounds of the present invention 60 8 1 100 and 2-phenylaminoadenosine (CV 1808). 10th 3 300 results in the following table. 11th 3 300 We summarized: 12th 10 1000 13th 2 200 65 14th 1 100

-5HU 201955Β

Compound respectively. Example No. Limits for AzadenosineA1 and A2 Receptor Binding (Nanomolar) lower upper 15th 2 200 16th 1 100 17th 0.1 10 18th 0.5 50 19th 0.7 70 20th 1 100 21st 10 1000 24th 8 800 25th 2 200 CV1808 5.61 6.57

The effects of the compounds of the invention on isolated, perfused rat kidney were investigated for the following parameters:

-reninelválasztás;

- haemodynamic changes in the kidney (vasodilation);

- the inhibition of the release of noradrenaline from the renal nerves by electrical stimulation, by H.J. Schurek et al., Communication on La Réunion de l'Association des Pharmacologists Louvain, 4 June 177; and Ρ. Vanhoutte et al., Hypertension 4.251 (1982).

Blood pressure, heart rate, urinary output, and renin activity were measured in alert, desalted, and salt-restored normal or hypertensive rats implanted with a catheter in the abdominal aorta and cerebrovascular vein, followed by intravenous or infusion of the compounds of the invention. By the method of Brody / Am. J. Physiol.247, Rl 003 (1984) /.

Subsequent amounts of the compounds of the present invention and CV 1808 reduce blood pressure by 30 mmHg in rats or larger mammals.

Vegyületill. Example No. Rat μ-g ^ g arc. Rat oral activity% of i.v. to Larger mammals pg / kgi.v. First 10 50 700 Second 75 85 5250 5th 15 35 1050 11th 15 10 1050 12th 103 30 7210 13th 276 10 19320 14th 27 60 1890 15th 71 45 4970 20th 45 65 3150 21st 207 80 14070 24th 1000 10 70000 CV1808 190 20 13300

From the results of the above studies, it can be concluded that the inhibition of reninel secretion and the release of noradrenaline from nerve endings, as well as the direct vasodilatory effect of the compounds of the present invention, They may also be used as coronary vasodilators. These compounds also protect the vascular endothelium by both inhibiting platelet aggregation and activating leukocytes; they also lower blood lipids. 55

Among the compounds of the invention, the compound described in Example 2 is preferred for use in the above indications.

When the compounds of the present invention are used as antihypertensive agents, the dosage will depend upon the particular agent, the mode of administration and the treatment desired. Generally, however, satisfactory results can be obtained if the compound of the invention is approximately 65 daily

0.01 mg / kg body weight to about 10 mg / kg body weight If required, the dosage may be administered in 2 to 4 divided doses per day or in sustained release form. In larger mammals, e.g. mg; for example, dosage units suitable for oral or parenteral administration will generally contain about 5250 mg of the active ingredient of the invention together with solid or liquid carriers.

The compounds of the present invention may be used alone or in a suitable dosage form. Suitable pharmaceutical forms, such as tablets or solutions, may be prepared in a known manner or by methods known in the art.

The invention also relates to the preparation of pharmaceutical compositions containing a compound of the invention in free form or in the form of a physiologically acceptable salt thereof. These compositions may be formulated with conventional pharmaceutically acceptable excipients and carriers in known manner.

Claims (6)

PATENT CLAIMS A process for the preparation of 1'-deoxy-1 '- (6-9-purinyl) -8-D-ribofuranuronic acid amide and thioamide derivatives of the general formula (I) wherein: wherein R 1 is C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, or phenyl optionally mono- or disubstituted by C 9 -C 5 halogen, C 1 -C 4 alkoxy, -SO 2 - (C 1 -C 4) alkyl, trifluoromethyl; R3 is C1-C4 alkyl; R 1 is halogen; C 1 -C 4 alkyl, or -OR 4, -SR 4 or -NR 4 R 5 in which R 4 and R 5 are hydrogen or C 1 -C 4 alkyl, and X is O or S, with the proviso that when X is O and R 1 is C 1 -C 6 alkyl, then R 1 is bromo, C 1 -C 4 alkyl or OR 4, -SR 4 - or -N-R 4 Wherein R 4 is C 1 -C 4 alkyl and R 8 is C 1 -C 4 alkyl, characterized in that a 1'-deoxy-1 '- (6-amino- 9-Purinyl) -2 ', 3'-isopropylidene-p-D-ribofuranuronic acid amide or thioamide, wherein R1, R3, R6 and X in the general formula (Π) are as defined above, cleaved. The process according to claim 1, wherein the 2-substituted 1'-deoxy-r- (6-amino-2-methyl-9-purinyl) -? - D-ribofuranuronic acid amide of formula (Ia) and - thioamide derivatives - wherever in formula (Ia) R 1 * is C 1-6 alkyl or C 3-7 cycloalkyl; halogen, optionally substituted with 9 to 35 carbon atoms, C1 -C4 alkoxy, -502C1 -C4 alkyl, mono- or disubstituted phenyl; ^R3 is C1 -C4 alkyl; R0 is a halogen atom of 9 to 35 atoms; C 14 alkyl; or -OR4, -SR4 or NR4R5, wherein R4 and R5 are as defined above; and X is O or S, with the proviso that when X is O and R 1 is C 1 -C 6 alkyl, then R * is bromo, C 1 -C 4 alkyl, or -OR 4, -SR 4, or -N-R 4 R5 wherein R4 is hydrogen or (C1-C4) alkyl and R5 is (C1-C4) -alkyl, wherein the appropriate starting material of formula (Π) is used. The process according to claim 1 for the preparation of the 2-position substituted 1'-deoxy-1 '- (6-9-purinyl) -pD-ribofuranuronic acid amide and thioamide of formula Ib, wherein Ib R ^1b is C 1-6 alkyl or C 3-7 cycloalkyl; or phenyl optionally mono- or disubstituted by 935-halogen, C 1-4 -alkoxy, -SO 2 - (C 1-4 -alkyl), trifluoromethyl; R 3 ^b is C 1-4 alkyl; R ^b is chlorine or bromine; C 1-4 alkyl; methoxy, methylthio, methylamino or dimethylamino; and X is O or S, with the proviso that when X is O and R ^1b is C 1 -C 6 alkyl, then R ^b is bromo, C 1 -C 4 alkyl, or -OR 4, -SR 4, or -N-R 4 Wherein R 4 is hydrogen or (C 1 -C 4) alkyl and R 8 is (C 1 -C 4) alkyl, wherein the appropriate starting material of formula (Π) is used. A process for the preparation of a medicament for lowering blood pressure, coronary vasodilator and lowering lipid level in the blood, characterized in that a compound of formula (I) produced by the process of claim 1, wherein Rt, R3, R0 and X are as defined in claim 1. , mixed with conventional carriers and / or other excipients in the pharmaceutical formulation to form a medicament. 5. A4. A process according to claim 1, wherein the active ingredient is a compound of formula (Ia) prepared by the process of claim 3, wherein R 1, R 5, R 6 and X are as defined in claim 3. A process according to claim 4 wherein the active ingredient is a compound of formula (Ib) produced by the process of claim 4 wherein R ^1b , R 3, R 10 'and X are as defined in claim 3.