GB2203149A - 1-(6-amino-9-purinyl)- beta -D-ribofuranuronic acid amides and thioamides - Google Patents

Description

1 -1 2203149 100-7069 NEW RIBOPURANURONIC ACID DERIVATIVES The invention

relates to new in position 2 substituted ll-desoxy-l,-(6amino-9-purinyl)-0--D-ribofuranuronic acid amides and thioamides, process for their production and their use in the treatment of e.g. raised blood pressure, The new, in position 2 substituted V-desoxy-11-(6-amino9-purinyl)-O-D- ribofuranuronic acid amides and thioamides produced according to the invention are referred to hereinafter as compounds according to the invention.

The compounds may be substituted where desired e.g. in free amino groups.

The invention especially provides in position 2 substituted ll-desoxy-l,(6-amino-9-purinyl)-0--D-ribofuranuronic acid amides and thioamides of formula I 4 2 - R 1 H N R ' "N N5 R 2\ 6 0 3 HO OH wherein 100-7069 1 R, signifies hydrogen, (Cl-6)alkyl which may be optionally monosubstituted by a hydroxyl, a -SH- or a -N R4 R5 group, wherein R4 and R5 signify independently from each other hydrogen or (Cl-4)alkyl; (C3-7)-alkenyl, (C3-7)alkinyl, (C3-7)cycloalkyl which.may be optionally mono- or 1-1 R4 di-substituted by a hydroxyl, a -SH- or a -N group, 11.1 RS wherein R4 and R5 are defined as above; (C3-7)cycloalkyl(C1-3)alkyl which may be optionally monoor di-substituted in the cycloalkyl ring by a hydroxyl, a -SH- or a -N __ R 5 group, wherein R4 and R5 are de fined as above; phenyl which may be optionally mono- or di-substituted by halogen with an atomic number of 9-35, (Cl-4)alkyl, (Cl-4)alkoxy, a hydroxyl, a -SH- a -S-(C1-4)alkyl, a -S02-(C1-4)alkyl, a trifluoromethyl- or a 1 j 1 R4 : 100-7069 Rs above; phenyl-(C1-6)alkyl which is optionally mono- or di substituted in the phenyl ring by halogen with an atomic number of 9-35, (Cl-4)alkyl, (Cl-4)alkoxy, a hydroxyl, a -SH-, a -S-(C1-4)alkyl-, a -S02(C1-4)alkyl- or a R4 -S02-N - group, wherein R4 and RS are defined as 1..

R5 above, and the (Cl-6)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 with an atomic number of 9-35, (C1Jalkyl, (C14)alkoxy, a hydroxyl, a -SH-, a -S(Cl-Jalkyl-, a -S02-(Cl-Jalkyl- or a -S02-N group, wherein R4 and R5 are defined as 4 -S02'-N,. group, wherein R4 and R5 are defined as RS above; a 5 or 6 membered, monocyclic heteroaryl which contains one or two nitrogen atoms or one oxygen atom or one sulphur atom and respectively one nitrogen atom; or a 5 or 6 membered, monocyclic heteroaryl-(C1-5)alkyl containing in the beteroaryl moiety one or two nitrogen atoms or one oxygen atom or one sulphur atom and respectively one nitrogen atom, whereby the alkylene moiety is straight-chain or branched and may be optionally substituted by a hydroxyl group, and R2 signifies hydrogen, (Cl-4)alkyl which may be optionally mono-substituted by a hydroxyl, a -SH- or a -N 1 R4 I R5 100-7069 group, wherein R4 and R5 are defined as above, or it signifies (C3- 8)cycloalkyl, and R3 is hydrogen or (Cl-4)alkyl which may be optionally mono-substituted by a hydroxyl, a -SH- or a -N 1.1 R4 RS group, wherein R4 and R5 are defined as above, and R6 is halogen, (Cl-4)alkyl, (C3-5)cycloalkyl, cyano, or it / R4 denotes groups of formulae -OR41 -SR41 -N wherein R4 and R5 are defined as above and X signifies = 0 or = S.

111 9 R5 Of the compounds of formula I, preferred compounds possess the formula Ia wherein R,& .- A 1 R a HN N R a):, N N R a X 0 2 \ N R 3 a/ HO OH I a signifies hydrogen, (Cl-6)alkyl, (C3-7)cycloalkyl, which may be optionally mono- or di-substituted by a hydroxyl, a -SH- or a -N - 5 100-7069 group, wherein R4 and R5 are defined as above; phenyl-(C1-6)alkyl which may be mono- or di-substituted in the phenyl ring by halogen with an atomic number of 9-35, (C14)alkyl, (Cl- 4)alkoxy, a hydroxyl, a-SH-, a -S-(C1-4)alkyl, a -S02-(CI-Jalkyl or a A4 -S02-N group, wherein R4 and R5 are defined as above, RS whereby the (Cl-6)alkylene chain is straight-chain or branched and may be optionally substituted by a hydroxyl group; or phenyl which may be optionally mono- or di-substituted by halogen with an atomic number of 9- 35, (Cl-4)alkyl, (Cl-4)alkoxy, d hydroxyl, a -SH-, a -S-(C1-4)alkyl, a - S02-(C1-4)alkyl- a trifluoromethyl- or a -S02-N ll as above, R4 RS group, wherein R4 and R5 are defined R2& is hydrogen, (Cl-4)alkyl which may be optionally mono-substituted by a hydroxyl, a -SH- or a -N group, wherein R4 and R5 are-defined as above; or (C3-6)cycloalkyl, and R3& is hydrogen or XCl-4)alkyl which may be optionally mono-substituted by a hydroxyl, a -SHor a -N 100-7069 group, wherein R4 and R5 are defined as above, and R6& is halogen with an atomic number of 9-35, (Cl-4)alkyl or R4 it denotes groups of formulae -OR41 -SR4 or -N wherein R4 and R5 are defined as above and X denotes = 0 or = S Of the compounds of formula I, especially preferred compounds possess the formula Ib, HN...I R b N b R 6 b 'kN N 2 N 0 R 3 HO OH wherein Ib signifies hydrogen, (Cl-6)alkyl, (C3-7)cycloalkyl which may be optionally mono- or di-substituted by a hydroxyl, a -SH- or a -N group, wherein R4 and R5 are defined as above; or phenyl which may be optionally monoor di-substituted by halogen with an atomic number of 9-35, (Cl-4)alkyl, a (Cl-4)alkoxy, a hydroxyl, a -SH-, a S-(Cl-Jalkyl, a-S02-(Cl-Jalkyl- a trifluoromethyl- or a ! 100-7069 -S02-N group, wherein R4 and R5 are defined as above, R2 b is hydrogen, (Cl-4)alkyl which may be optionally mono-substituted by a hydroxyl, a -SH- or a -N group, wherein R4 and R5 are defined as above; or (C3-6)cycloalkyl and R3 b 'S (Cl-4)alkyl, and _,R4 --t,R5 R6 b 'S (Cl-4)alkyl, chlorine, bromine, methoxy, methylthio, methylamino or dimethylamino and X denotes = 0 or =S.

In formula I, halogen with an atomic number of 9-35 denotes fluorine, chlorine or bromine, preferably chlorine, a (Cl-4)alkyl group is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, tert.-butyl, and if it contains up to 6 carbon atoms, it is also n-pentyl, i-pentyl, 3-pentyl, nhexyl, i-hexyl, etc.especially methyl, ethyl, isopropyl or 3-pentyl, a (Cl-Jalkoxy group is methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, ibutoxy, tert, butoxy, and if it contains up to 6 carbon atoms, it is also n-pentoxy, i-pentoxy, n-hexoxy, i-hexoxy, etc., especially methoxy, (C37)alkenyl is methallyl, butenyl, pentenyl, etc., whereby the chain may be straight or branched and the double bond may be found in various positions, but not adjacent to nitrogen, (C3-7)alkinyl is propinyl, butinyl, pentinyl, hexinyl, wherby the chain is straight or branched and the triple bond may be - 8. - 100-7069 found in various positions, but not adjacent to nitrogen. (3-7)cycloalkyl signifies cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl especially cyclopentyl. If it is substituted, the substituents are respectively in o-, p- or m-position, but-appropriately either when disubstituted in o-, ol-position, or when monosubsituted in p-position. (C3-7)cycloalkyl(C1-3)alkyl may denote the above-mentioned cycloalkyl and alkyl radicals, whereby as shown, the substituents may be bonded. Substitution of the phenyl ring may take place in o-, m- or p-position, whereby when disubstituted this is preferably in m- and p-position, and when monosubstituted this is in m or p-position. In phenylalkyl, the alkyl radicals and the substitution of_the phenyl ring are as discussed above.

The compounds according to the invention are obtained e.g. by cleavage of an isopropylidene group from in position 2 substituted ll-desoxy-l,-(6amino-9-purinyl)-21.31-isopropylidene-O-D-ribofuranuronic acid amides and thioamides e.g. of formula II p , 1 HN N' R R 2\ N 0 R 3 II wherein R,, R2, R3, R6 and X have the definitions given above.

the above process conveniently takes place by treating compounds of formula II with an agent which cleaves the isopropylidene group. Trifluoroacetic acid has proved to be 1 A.

1 3 100-7069 especially suitable for this. A further cleavable agent is aqueous hydrochloric acid or aqueous formic acid.

The compounds of formula II used as starting compounds are obtained by introducing an isopropyliden protecting group into compounds of formula III, HN --Rl 1 N N R,, N N 6 0 H OH OH M wherein R, is defined as above and R6, denotes halogen, (Cl-4)alkyl or (C3-5)cycloalkyl, (described for example in DE-05 1 670 173; BRIT. PAT 1 075 008 and JOC (1968) 2583), by reacting it with acetone in the presence of an acid, for example p-toluenesulphonic acid, whereby componds of formula IV HN N _1 N R6,, N N 0 HO P Y 1V wherein R, and R6, are defined as above, are obtained, then oxidising them in known manner to form compounds of formula V, /11 HN N R 0 0 HOOC 100-7069 v wherein R, and R61 are defined as above, using an oxidation agent, for example pyridinium dichromate, and subsequently converting this in known manner, using a chlorination agent such as thionyl chloride, into the acid chloride of formula VI, R HN' N R 6 0 C10C j 1 i 0 6 XI V 1 wherein R, and R6, are defined as above, and then reacting this with a compound of formula VII, R2 R3 11-1 11.1 NH VII wherein R2 and R3 have the definitions given above, in known manner, to form compounds of formula IIa 4 ,., R 1 HN N N - R It"N i,) R 6 0 0 2\ N Y R 3 : 100-7069 IIa (partial structure of compounds of formula II), wherein R,, R2, R3 and R61 are defined as above.

The radical R6", which is defined as below, is introduced into compounds of formula lIa, wherein R6' is chlorine or bromine, by reacting them with compounds of formula HR6" wherein R6'11 denotes a cyano group or groups of formulae -OR41 -SR4 or -N - R4 wherein R4 and R5 are defined as above, in --" R 5 a strongly alkaline medium, for example in the presence of sodium, or by reacting them with the corresponding amines in an autoclave at temperatures of above 1001C. The compounds of formula IIb 1 R N R N) 6 0 R tt 0 2 N C R 3 -IIb 100-7069 (compounds of formula II, wherein X denotes = 0 and R6 comprises the significancies of both R61 and R6") wherein R,, R21 R3 and R6 are defined as above which are obtained according to the preceding steps are converted by appropriate thianation into compounds of formula IIc 11 R IIC R R 3 (compounds of formula II, wherein X denotes = S) wherein R,, R2, R3 and R6 are defined as above.

The thianation process is suitably effected using known thianation agents, for example hydrogen sulphide, phosphorus pentasulphide or LAWESSONIS REAGENT (p-methoxyphenylthiophosphine sulphide dimer). The latter reagent is preferred. The reaction itself takes place in known manner. If for example hydrogen sulphide is used, an acid such as hydrochloric acid is conveniently added in catalytic doses, and the reaction is carried out in a polar solvent such as acetic acid or ethanol. When using LAWESSONIS REAGENT, the reaction is conveniently carried out in a dry solvent such as toluene or methylene chloride.

A further method for the production of compounds of formula IIb, wherein R6 'S (Cl-4)alkyl, is that V-desoxy-11(2-alkyl6-hydroxy-9-purinyl)-O-Dribose of formula IIIa, 4 OH N R 6 iv." N 0 HO 1.1 0 OH OH 100-7069 Ma wherein R6'V is (Cl-4)alkyl, is reacted with acetone in the presence of an acid, for example p-toluenesulphonic acid, to form compounds of formula IVa, R 6 1 v OH N 0' 1Va wherein R61V is defined as above, then these are oxidised using an oxidation agent, for example potassium permanganate, in an alkaline medium, to produce compounds of formula Va, OH N R 1 v,;N N 6 0 N 0 HT,- C 'I.1 0 0 4 Va 100-7069 wherein R6iV is defined as above, then these are treated with a chlorination agent, for example phosphorus oxichloride, thus being converted into compounds of formula V1a, cl INI:1 N R 6!v 0 N 0 cl 0 0 X VIa wherein R6iV is defined as above, then these are reacted with the above- mentioned compounds of formula VII to produce compounds of formula VIIIa, cl R2 R 3 N '.-- N N 1 R 6 i v 0 0, N f: N 0 N...,C..0 0 0 X vina wherein R2, R3 and R6iv are defined as above, and these are converted by reacting with compounds of formula X, R,-NH2 X wherein R, is defined as given above, to form compounds of formula Ub, wherein R6 is (Cl-4)alkyl. The compounds of formula Nb thus obtained, wherein R6 is (Cl-4)alkyl, may be converted by 1 - is - 100-7069 thianation as described above into the corresponding compounds of formula II.

The other above-described reactions take place using known methods, for example also using the processes described in the examples.

If in the compounds of formula I, R, denotes groups which are substituted by a -N R4 --- RS group, these compounds can form salts with strong acids. Preferred salts are the hydrochlorides, hydrobromides or fumarates.

Insofar as the production of the required starting materials is not described, these are known or may be produced by known processes, or analogously to the processes described here, or analogously to known processes.

In the following examples, all temperatures are given in degrees celsius and are uncorrected.

Example 1: ll-desoxy-l'-(2-methyl-6-cyclopentylamino-9purinyl)-O-Dribofuranuronic acid N-ethylamide ! 100-7069 1.4 g of ll-desoxy-l'-(2-methyl-6-cyclopentylamino-9purinyl)-21,31isopropylidene-O-D-ribofuranuronic acid-N-ethylamide are left to stand for 2 hours at 0 and for 1 hour at room temperature in-10 ml of 90% trifluoroacetic acid. The mixture is then totally concentrated under reduced pressure and the residue is partitioned between ethyl acetate and diluted, aqueous ammonia. After washing with saturated, aqueous sodium chloride solution, the product is dried over sodium sulphate and totally concentrated. The residue is dissolved in a little methanol and the final product is crystallised by adding ethylether. M.p. 195-1970.

The ll-desoxy-l'-(2-methyl-6-cyclopentylamino-9-purinyl)21,31isopropylidene-o--D-ribofuranuronic acid-N-ethylamide used as the starting material may be produced e.g. as follows:

a) -1 7.5 g of potassium permanganate are added to a solution of 7.8 g of ll- desoxy-l,-(2-methyl-6-hydroxy-9-purinyl)-21,3isopropylidene-e-D-ribose in 120 C of water and 4.8 ml of 1ON sodium hydroxide, and the mixture is stirred for 1 hour at 300. Then, 1 g of sodium hydrogen sulphite is added and the colourless solution is filtered over Hyflo after stirring for 5 minutes. The filtrate is then concentrated to ca. 30 ml under reduced pressure, and set at pH 4 with concentrated hydrochloric acid at 0. Vdesoxy-l,-(2-methyl6-hydroxy-9-purinyl)-21,31-isopropylideneO-Dribofuranuronic acid is precipitated in crystalline form. M.p. after washing with-acetone and drying: 263 (decomp.).

100-7069 b) 3.3 g of ll-desoxy-l'-(2-methyl-6-hydroxy-9-purinyl)21,31-isopropylidene-O--D-ribofuranuronic acid are stirred into 16.8 ml of phosphorus oxychloride for 15 minutes in an oil bath of 850, then mixed with 1.6 C of N,N-diethylaniline and stirred for a further 2 hours at the same temperature. The mixture is subsequently totally concentrated under reduced pressure and the residue is dissolved in 60 C of tetrahydrofuran. This solution is cooled to -40' and is mixed with ethylamine until a basic reaction takes place. After 10 minutes, the solution is poured onto ice water and shaken with ethyl acetate. After washing with saturated sodium chloride solution and drying over sodium sulphate, the solution is totally concentrated and the residue is eluted on silica gel with ethyl acetate. The purified l,-desoxy-l,-(2-methyl-6chloro9-purinyl)-21,31-isopropylidene-O-D-ribofuranuronic acidNethylamide is a white foam and in ethyl acetate has a Rf value of 0.5.

c) 1.2 g of ll-desoxy-l,-(2-methyl-6-chloro-9-purinyl)21,31-isopropylidene-o-D-ribofuranuronic acid-N-ethylamide and 1.2 ml of cyclopentylamine are stirred into 30 C of dioxane for 1 hour in an oil bath of 1050. After cooling, filtration is effected, the filtrate is concentrated and the residue is eluted on 60 g of silica gel with ethyl acetate. The pure lldesoxy-l,-(2-methyl-6-eyclopentylamino-9-purinyl)-21,31-isopro"pylidene-0D-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 defined as follows and wherein X is always = 0 are obtained analogously to example 1:

Example R,

100-7069 R2 R3 R6 M. P.

2 p-Methoxyphenyl H Et Me 221-2240 3 Cyclopentyl H Et Me 196-1980 4 Cyclopentyl H Et Isopropyl amorphous Cyclopentyl H Et Cl 133-1350 6 Cyclopentyl H Et Br 188-1900 7 Cyclopentyl H Et MeO 226-2290 8 Cyclopentyl H Et MeS amorphous 9 Cyclopentyl H Et Me2N amorphous Cyclopentyl H Et MeHN 193-1940 11 H H Et Br 240-2410 12 p-Ethoxyphenyl H Et Me 120-1250 13 3,4-Dimethoxyphenyl H Et Me 236-2390 14 3-Pentyl H Et Me 181-1830 m-Fluorophenyl H Et Me 137-1420 16 p-Fluorophenyl H Et Me 257-2590 17 p-Chlorophenyl H Et Me 255-2580 18 Isopropyl H Et Me 187-1940 19 p-Trifluoromethylphenyl H Et Me 248-2500 The ll-desoxy-l'-(2-chloro-6-cyclopentylamino-9-purinyl)-21,31isopropylidene-0-D-ribofuranuronic acid-N-ethylamide also useful as the starting material for the preparation of compounds of formula II wherein R6 has the significance of R6" may be produced e.g. as follows:

a) 8.8 ml of ortho-formic acid trimethylester is added in drops at room temperature to 7.4 g of V-desoxy-11-G-chloro-6cyclopentylamino-9-purinyl)O-D-ribose and 4.2 g of p-toluene-sulphonic acid in 120 ml of acetone. After 3 hours, the 11 100-7069 deposit is filtered off and washed with acetone and diethylether. Then, the dried deposit is added in portions whilst stirring to a solution of 3. 6 g of sodium hydrogen carbonate in 150 C of water and 75 ml of ethyl acetate. The organic -phase is separated, washed with saturated 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 mixture of methylene chloride/ethanol 9:1. The pure ll-desoxy-l'-(2chloro-6-cyclopentylamino-9-purinyl)-21,31-isopropylidene-0-D-ribose has a Rf value of 0.5.

b) 8.7 g of ll-desoxy-l,-(2-chloro-6-cyclopentylamino-9-purinyl)21,31-isopropylidene-19.-D-ribose and 30.5 g of pyri dinium dichromate are stirred for 18 hours at room tem perature in 130 ml of dimethylformamide. The mixture is then poured onto water and the aqueous phase is shaken out three times with ethyl acetate. This phase is then extracted with a saturated, aqueous solution of sodium hydrogen carbonate, the basic extract is adjus ' ted to pH 1 with 5N hydrochloric acid and shaken out with ethyl acetate. After washing with saturated sodium chloride solution and drying over sodium sulphate, the organic phase is concentrated, diluted with diethylether, whereby the V-desoxy-11-(2-chloro-6-cyclo pentylamino-9-purinyl)-0-D-ribofuranuronic acid crystallises out. M.p. 246-2531.

c) 4 g of the above acid are heated in 40 ml of thionyl chloride for 20 minutes in an oil bath of 450. When the evolution of gas has ended, the mixture is concentrated under reduced pressure and the acid chloride formed is dissolved in 40 C of methylene chloride. It is then cooled 100-7069 in an ice bath and gaseous ethylamine is introduced whilst stirring until the reaction becomes basic. The methylene chloride phase is then washed with water, dried over sodium sulphate and concentrated. The V-desoxy-11Qchloro-6cyclopentylamino-9-purinyl)-21,31-isopropylidene-O--D-r ibofuranuronic acid-N-ethylamide remains behind as a white foam. Rf in methylene chloride/ethanol 9:1 = 0.7.

The preparation of compounds of formula II, R6 having the significance of R6" and X being = 0 is performed starting from the above compound of formula IIa wherein R6' is chlorine in a manner known per se e.g._by reaction with an alcohol, amine etc.

Example 20: ll-desoxy-l,-(21-methyl-6-cyclopentylamino-9purinyl)0--Dribofuranuronic acid-N-ethylthioamide a) ll-desoxy-l'-(2-methyl-6-cyclopentylamino-9-purinyl)-21,31isopropyliden-a-D-ribofuranuronic acid-N-ethylthioamide.

1.7 g of ll-desoxy-l'-(2-methyl-6-cyclopentylamino-9-purinyl)-21,31isopropylidene-0-D-ribofuranuronic acid-N-ethylamide (starting compound of example 1) are stirred with 0.77 g of LAWESSONIS REAGENT in 38 C of toluene for 2 hours in an oil bath of 100. The mixture is subsequently totally concentrated under reduced pressure, the residue is dissolved in60 ml of ethyl acetate and stirred for 112 hour with 25 g of neutral aluminium oxide. After filtration, the filtrate is concentrated and is used in the next stage without further purification. Rf in ethyl acetate: 0.7.

b) ll-desoxy-l,-(2-methyl-6-cyclopentylamino-9-purinyl)-0--Dribofuranuronic acid-N-ethylthioamide.

1 100-7069 1.5 g of ll-desoxy-l,-(2-methyl-6-cyclopentylamino-9purinyl)-21,31isopropylidene-O-D-ribofuranuronic acidN-ethylthioamide are dissolved at room temperature in 7.5 ml of 90% trifluoroacetic acid and left to stand for 2 hours. The solution is subsequently totally concentrated under reduced pressure. The residue is dissolved in ethyl acetate, mixed with aqueous ammonia and totally concentrated under reduced pressure. The crystalline residue of the compound named in the title, is then purified by eluting on 30 g silica gel with a mixture of methylene chloride/ethanol 9:1. Finally, the pure fractions are crystallised from ethyletherlpentane. M.p. 168-170.

The following compounds of formula I in which R,, R2, R3 and R6 are defined as follows and wherein X is always S are obtained analogously to example 20.

Example R, R2 R3 R6 m 21 3-Pentyl H Et Me amorphous 22 p-Ethoxyphenyl H Et Me 202-2050 23 p-Methoxyphenyl H Et Me 222-2250 24 3,4-Dimethoxyphenyl H Et Me 221-2240 4-Methylsulfonylphenyl H Et Me 164-1670 The compounds according to the invention are notable for their interesting pharmacological properties. They can therefore be used as medicaments.- In particular, the compounds according of the invention have antihypertensive activity, as can be deduced from the results of the following trials:

! 100-7069 Measurement of the binding to adenosine Al and A2 receptors in membranes from the rat's cortex or from the cerebral cortex or striatum of the pig, using the method of R.F. BRUNS, G.H. LU and T.A..PUGUEY, which is desribed in MOLEC. PHARMACOL. 29, 331-346 (1986).

7 1 100-7069 Further testing of the activity of the compounds according to the invention on the isolated, perfused rat's kindneys for the following parameters:

-renin secretion renal haemodynamics (vasodilation) inhibition of the release of noradrenaline from the nerve ends following electro-stimulation of the renal nerves according to the method of H.J. SCHUREK, J.P. BRECHT, H. LOHFERT and K. RIERHOLZER, described in COMMUNICATION a la REUNION de 11ASSOCIATION DES PHARMACOLOGISTES LOUVAIN UCL 4th June 1977, as well P.H. VANHOUTTE, D. BROWNING, E. COEN, T.J. VERBEUREN, L. ZONNEKEYEN and M.G. COLLINS described in HPYERTENSION 4, 251-256 (1982).

measurement of blood pressure, heart rate, urine production and renin activity in the plasma of wake, NaCl-depleted, and -replated normotensive or spontaneously hypertensive rats which have catheters implanted in the abdominal aorta and the Vena cava, following i.v. administration or administration of the compounds according to the invention as an infusion or a bolus, according to the method of J.F.M. SMITS and J.M. BRODY described in Am. J. Phyiol. 247, Rl 003-Rl 008 (1984).

From the results of the trials, it can be-deduced that both an inhibition of renin secretion and of the release of noradrenaline from the nerve ends, and direct vasodilation, take part in the anti-hypertensive activity of the compounds according to the invention.

100-7069 From this, it is evident that the compounds according to the invention can not only be used as anti-hypertensive agents, but can also effect coronary vasodilation. They protect further the vascular endothelium by inhibiting platelet aggregation and by activating leucocytes. They reduce also the blood lipid level.

For the above indications of the compounds according to the invention, the compound of example 2 is preferred.

An indicated daily dose is from about 10 to 500 ing if desired administered in unit dosage form up to 4 times a day containing about 5 to 250 mg together with solid or liquid carrier substances.

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

The invention therefore relates 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 the production of these medicaments in known manner. They can be produced by using conventional pharmaceutical adjuvants and carriers.

_k

Claims (15)

WHAT WE CLAIM IS:

1.

wherein 100-7069 In position

2 substituted V-desoxy-11-(6-amino-9-purinyl)-O-D- ribofuranuronic acid amides and thioamides.

In position 2 substituted V-desoxy-11-(6-amino-9-purinyl)-0--Dribofuranuronic acid amides and thoamides of formula I H R 1 N R N NY R 2\ 6 X 0 3 HO OH 1 R, signifies hydrogen, (Cl-,)alkyl which may be optionally R4 monosubstituted by a hydroxyl, a -SH- or a -N R5 group, wherein R4 and R5 signify independently from each other hydrogen or (Cl-Jalkyl; (C3-7)-alkenyl, (C3-7)alkinyl, (C3-7)cycloalkyl which may be optionally mono- or R4 111 di-substituted by a hydroxyl, a -SH- or a -N group, R5 wherein R4 and R5 are defined as above; (C3-7)cycloalkyl(C1-3)alkyl which may be optionally monoor di-substituted in the cycloalkyl ring by a hydroxyl, a -SH- or a -N 100-7069 group, wherein R. and R5 are de- RS fined as above; phenyl which may be optionally mono- or di-substituted by halogen with an atomic number of 9-35, (Cl-4)alkyl, (Cl-Jalkoxy,.a hydroxyl, a SH- a -S-(C1-4)alkyl, a -S02-(C1-4)alkyl, a trifluoromethylor R4 a -S02-N group, wherein R4 and R5 are defined as RS above; phenyl-(C1-6)alkyl which is optionally mono- or disubstituted in the phenyl ring by halogen with an atomic number of 9-35, (Cl-4)alkyl, (C14)alkoxy, a hydroxyl, a -SH-, a -S-(C1-4)alkyl-, a -S02(C1-4)alkyl- or a / R4 -SO2-N R5 above, and the (Cl-6)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 with an atomic number of 9-35, (Cl-4)alkyl, (Cl-4)alkoxy, a hydroxyl, a -SH-, a - S-(C1-4)alkyl-, a -S02-(Cl-Jalkyl- or a R4 -S02-N group, wherein R4 and R5 are defined as - group, wherein R4 and R5 are defined as RS above; a 5 or 6 membered, monocyclic heteroaryl which contains one or two nitrogen atoms or one oxygen atom or one sulphur atom and respectively one nitrogen atom; or a 5 or 6 membered, monocyclic heteroaryl-(C1- 5)alkyl containing in the heteroaryl moiety one or two nitrogen atoms or one oxygen atom or one sulphur atom and i Y 0 100-7069 respectively one nitrogen atom, whereby the alkylene moiety is straightchain or branched and may be optionally substituted by a hydroxyl group, and R2 - signifies hydrogen, (Cl-4)alkyl which may be optionally mono-substituted by a hydroxyl, a -SH- or a -N R5 group, wherein R4 and R5 are defined as above, or it signifies (C3- 8)cycloalkyl, and R3 is hydrogen or (Cl-4)alkyl which may be optionally mono-substituted by a hydroxyl, a -SH- or a -N 1.1 R4 RS group, wherein R4 and RS are defined as above, and R6 is halogen, (Cl-4)alkyl, (C3-5)cycloalkyl, cyano, or it denotes groups of formulae - OR4, -SR41 -N wherein R4 and RS are defined as above and.

X signifies = 0 or = S.

3. Compounds of formula Ia a HN N R 6a AZZ-, N a 1 R, \ ",k 0 R 4 a/ N 3 HO OH 1.1 R4 11,1 RS t - 100-7069 wherein Rja signifies hydrogen, (Cl-6)alkyl, (C3-7)cycloalkyl, which may be optionally mono- or di-substituted by a hydroxyl, -SH- or a -N' group, wherein R4 and R5 are defined as above; phenyl-(C16)alkyl which may be mono- or di-substituted in the phenyl ring by halogen with an atomic number of 9-35, (Cl-4)alkyl, (Cl- 4)alkoxy, a hydroxyl, a-SH-, a -S-(C1-4)alkyl, a -S02-(C1-4)alkyl or 111R4 -S02-N group, wherein R4 and R5 are defined as above, RS whereby the (Cl-6)alkylene chain is straight-chain or branched and may be optionally substituted by a hydroxyl group; or phenyl which may be optionally monoor di-substituted by halogen with an atomic number of 9- 35, (Cl-4)alkyl, (Cl-4)alkoxy, a hydroxyl, a -SH-, a -S-(Cl-Jalkyl, a - S02-G1-4)alkyl- a trifluoromethyl- or a -S02-N as above, ..I R4 ll R group, wherein R4 and R5 are defined R2a is hydrogen, (Cl-4)alkyl which may be optionally mono-substituted by a hydroxyl, a -SH- or a -N group, wherein R4 and R5 are defined as above; or (C3-6)cycloalkyl, and j 1k R4 S R3 a is hydrogen or (Cl-4)alkyl which may be optionally ! 100-7069 mono-substituted by a hydroxyl, a -SH- or a -N R4 group, wherein R4 and R5 are defined as above, and R5 R6 a is halogen with an atomic number of 9-35, (Cl-Jalkyl or 1.1 R4 N it denotes groups of formulae -OR41 -SR4 or - 9 wherein R4 and R5 are defibed as above and X denotes = 0 or = S.

4. Compounds of formula Ib R 1 b N R b R 6 X N 0 2 N HO OH R3 wherein R5 Ib R1b signifies hydrogen, (C16)alkyl, (C3-7)cycloalkyl which may be optionally mono- or di-substituted by a hydroxyl, a -SH- or a -N' group, wherein R4 and RS are defined as above; or phenyl which may be optionally mono- or 100-7069 di-substituted by halogen with an atomic number of 9-35, (Cl-4)alkyl, a (Cl-4)alkoxy, a hydroxyl, a -SH-, a S(C1-4)alkyl, a-SO2-(CI-Jalkyl- a trifluoromethyl- or a R4 -S02-N group, wherein R4 and RS are defined as RS above, R2 b is hydrogen, (Cl-4)alkyl which may be optionally mono-substituted by a hydroxyl, a -SH- or a -N-,--" group, wherein R4 and R5 are defined as above; or (C3-6)cycloalkyl and R3 b S (Cl-Jalkyl, and R4 RS R6 b is (Cl-4)alkyl, chlorine, bromine, methoxy, methylthio, methylamino or dimethylamino and X denotes = 0 or =S.

5. Compounds according to claims 1 to 4 selected from:

ll-Desoxy-l'-(2-methyl-6-cyclopentylamino-9-purinyl)-0--D-ribofuranuronic acid-N-ethylthioamide.

ll-Desoxy-l'-(2-chloro-6-cyclopentylamino-9-purinyl)-O-D-ribofuranuronic acid-N-ethylamide.

ll-Desoxy-l,-(2-bromo-6-cyclopentylamino-9-purinyl)-O-D-ribofuranuronic acid-N-ethylamide.

i R J n 100-7069 ll-Desoxy-l'-(2-methyl-6-cyclopentylamino-9-purinyl)-f3--Dribofuranuronic acid-N-ethylamide.

ll-Desoxy-l,-(2-ethyl-6-cyclopentylamino-9-purinyl)-O-D-ribofuranuronic acid-N-ethylamide.

ll-Desoxy-l'-(2-isopropyl-6-cyclopentylamino-9-purinyl)-ODribofuranuronic acid-N-ethylamide.

ll-Desoxy-l'-(2-methyl-6-p-methoxyphenylamino-9-purinyl)-Dribofuranuronic acid-N-ethylamide.

ll-Desoxy-l'-(2-methylamino-6-cyclopentylamino-9-purinyl)-fsDribofuranuronic acid-N-ethylamide.

ll-Desoxy-l'-(2-methylthio-6-cyclopentylamino-9-purinyl)-0-Dribofuranuronic acid-N-ethylamide.

ll-Desoxy-l'-(2-dimethylamino-6-cyclopentylamino-9-purinyl)O-Dribofuranuronic acid-N-ethylamide.

ll-Desoxy-l'-(2-methoxy-6-cyclopentylamino-9-purinyl)-O-Dribofuranuronic acid-N-ethylamide.

ll-Desoxy-l,-(2-bromo-6-amino-9-purinyl)-O-D-ribofuranuronic acid-Nethylamide.

II-Desoxy-l'-(2-methyl-6-p-ethoxyphenylamino-9-purinyl)-0,Dribofuranuronic acid-N-ethylamide.

ll-Desoxy-l'-(2-methyl-6-(3,4-dimethoxyphenyl)amino-9-purinyl)-O-Dribofuranuronic acid-N-ethylamide.

i 100-7069 ll-Desoxy-lt-(2-methyl-6-(3-pentyl)-amino-9-purinyl)-0--D-ribofuranuronic acid-N-ethylamide.

ll-Desoxy-l,-(2-methyl-6-m-fluorophenylamino-9-purinyl)-ODribofuranuronic acid-N-ethylamide.

ll-Desoxy-l'-(2-methyl-6-p-fluorophenylamino9-purinyl)-O-Dribofuranuronic acid-N-ethylamide.

ll-Desoxy-l'-(2-methyl-6-p-chlorophenylamino-9-purinyl)-fDribofuranuronic acid-N-ethylamide.

ll-Desoxy-l'-(2-methyl-6-isopropylamino-9-purinyl)-O-D-ribofuranuronic acid-N-ethylamide.

ll-Desoxy-l,-(2-methyl-6-p-trifluoromethylphenylamino-9-purinyl)-0--Dribofuranuronic acid-N-ethylamide.

ll-Desoxy-l,-(2-methyl-6-(3-pentyl)-amino-9-purinyl)-O-D-purinyl)-O-Dribofuranuronic acid-N-ethylthioamide.

ll-Desoxy-l,-(2-methyl-6-p-ethoxyphenylamino-9-purinyl)-ODribofuranuronic acid-N-ethylthioamide.

ll-Desoxy-l'-(2-methyl-6-p-methoxyphenylamino-9-purinyl)-0Dribofuranuronic acid-N-ethylthioamide.

ll-Desoxy-l'-(2-methyl-6-(3,4-dimethoxyphenyl)-amino-9-purinyl)-O-Dribofuranuronic acid-N-ethylthioamide.

ll-Desoxy-l'-(2-methyl-6-(4-methylsulfonylphenyl)-amino-9purinyl)-0--Dribofuranuronic acid-N-ethylthioamide.

h R 1 1

6. Process for the production of in position 2 substituted ll-desoxy-l'- (6-amino-9-purinyl)-O-D-ribofuranuronic acid amides and thioamides characterised in that the isopropylidene protecting group is cleaved from in position 2 substituted ll-desoxy-l'-(6-amino-9-purinyl)-21,31- isopropylidene-O-D-ribofuranuronic acid amides and thioamides.

7.. Process for the production of in position 2 substituted ll-desoxy-l'(6-amino-9-purinyl)-JS-D-ribofuranuronic acid amides and thioamides of formula I according to claim 2, characterised in that the isopropylidene group is cleaved from in position 2 substituted.11-desoxy-l,-(6-amino-9purinyl)-21,31-isopropylidene-15-D-ribofuranuronic acid amides and thioamides of formula II, ,, R 1 HN N R X ' N) R 2\ N 0 R 3 wherein R,, R21 R3, R6 and X have the definitions given in claim 2.

8. A process for the production of in position 2 substituted ll-desoxy-l'(6-amino-9-purinyl)-O-D-ribofuranuronic acid amides and thioamides substantially as hereinbefore described with reference to any one of the examples.

k

9.

In position 2 substituted ll-desoxy-l'-(6-amino-9-purinyl)O-Dribofuranuronic acid amides and thioamides whenever produced by the process of claim 7.

10. -Pharmaceutical composition containing as an active agent in position 2 substituted ll-desoxy-l'-(6-amino-9-purinyl)P-D-ribofuranuronic acid amides and thioamides, in association with a pharmacologically acceptable adjuvant and/or diluent.

11. Pharmaceutical composition containing as an active agent a compound of any one of the claims 1 to 5 in association with a pharmacologically acceptable a.djuvant and/or diluent.

12. Use of in position 2 substituted V-desoxy-11-(6-amino-9purinyl)-0--Dribofuranuronic acid amides and thioamides in the treatment of raised blood pressure.

13. Use of in position 2 substituted V-desoxy-11-(6-amino-9purinyl)-O-D-ribofuranuronic acid amides. and thioamides of formula I according to any one of claim 2 to 5 in the treatment of raised blood pressure.

14. Use of in position 2 substituted V-desoxy-11-(6-amino-9purinyl)-O-Dribofuranuronic acid amides and thioamides for the preparation of medicaments suitable for treating raised blood pressure.

15. Use of in position 2 substituted V-desoxy-11-(6-amino-9purinyl)-O-Dribofuranuronic acid amides and thioamides of formula I according to any one of claim 2 to 5 for the preparation of medicaments suitable for treating raised blood pressure.

Publihhed 1988 at The Patent C)ffice, State House, 6W1 Holborn, London WC1R 4TP. Further copies may be obtained from The Patent Office, T