CA2044806A1

CA2044806A1 - Purine derivatives

Info

Publication number: CA2044806A1
Application number: CA002044806A
Authority: CA
Inventors: Roland Jaunin
Original assignee: F Hoffmann La Roche AG
Current assignee: F Hoffmann La Roche AG
Priority date: 1990-07-18
Filing date: 1991-06-17
Publication date: 1992-01-19
Also published as: HU209591B; NO912804L; AU8038491A; PT98348A; JPH04234391A; FI913407A7; ZA915418B; FI913407A0; IL98812A0; EP0467207A2; HUT58736A; IE912500A1; NO912804D0; MC2278A1; KR920002600A; HU912347D0; EP0467207A3

Abstract

Abstract Compounds of the formula

Description

2 ~

The present invention is concerned wi~h novel purine derivatives of the general formula 1~0~ 1 I ~, Rs wherein R 1 signifies hydrogen OT lower-alkyl;
R2 signifies amino, mono- or di-(lowcr-alkyl)amino, -SRl or -ORl;
R3 signifies hydrogen, amino, mono- or di-(lower-alkyl)amino, -SRl or-ORl;
R4, R5 and R6 signify a residue of the formula _CH2~) (a) ~
R7 signifies the group -COOR8 or a tetrazolyl residue of the formula N--N
¦¦ ~R9 ~N~ (b R 8 signifies hydrogen, an alkali, alkaline earth or ammonium cation, lower-alkyl or a residue which is cleavable under physiological conditions; and Kbr/22 .5 .91 2 2 ~

R9 signifies hydrogen or an alkali, alkaline earth or ammonium cation; provided that only one of the substituents R4, R5 and R6 is present and R2 signifies amino or mono- or di-(lower-alkyl)amino when R6 is present.
s The term "lower-alkyl" used herein denotes straight-chain or branched alkyl groups with 1-7 C atoms such as methyl, e~hyl, propyl, isopropyl, butyl and its isomers. Na+, K+, Ca2+ and Mg2 are examples of alkali and alkaline earth cations; NH4+ and o trimethylammonium are examples of ammonium ions. A residue which is cleavable under physiological conditions is e.g. pivaloy-loxymethyl .

Formula I accordingly embraces compounds of the general 15 formulae 1~0>-- I a lJNX I b R3 Rs and ~ I C
R3 ~ N N
Rfi and tautomers thereof.

Preferred compounds of formula I are those in which E~7 signifies a te~razo~yl residue (b).

Furthermore, those compounds of formula I in which Rl s signifies lower-alkyl, especially n-propyl or n-butyl, are preferred .

Representative examples of compounds of formula I
are:
4'-[(2-Amino-1,6-dihydro-6-oxo-9H-purin-9 yl)methyl]-2-biphenylcarboxylic acid, 4'- [(2-amino- 1 ,6-dihydro-6-oxo-7H-purin-7 -yl)me~hyl] -2-biphenylcarboxylic acid, 4'-[(8-butyl-1 ,6-dihydro-6-oxo-9H-purin-9-yl~methyl]-2-biphenylcarboxylic acid, 4'-~(1 ,6-dihydro-6-oxo-8-propyl-9H-purin-9-yl)methyl]-2-biphenylcarboxylic acid, 4'-[(8-butyl-6-methoxy-7H-purin-7 -yl)methyl] -2-biphenyl-carboxylic acid, 4'-[(6-amino-8-butyl-3H-purin-3-yl)me~hyl]-2-biphenyl-carboxylic acid, 4' - [( 1,6 -dihydro-6-oxo-7H-purin-7 -yl)methyl] -2-biphenyl-carboxylic acid, methyl 4'-[(6-amino-8-butyl-9H-purin-9-yl)methyl]-2-bi--phenylcarboxy1a~e, methyl 4'-~(6-amino-8-butyl-3H-purin-3-yl)methyl]-2-bi-phenylcarboxylate, me~hyl 4'- [(6-methoxy-8-propyl-9H-purin-9-yl)methyl3 -2-biphenylcarboxylate, methyl 4'- [(6-methoxy-8-propyl-7H-purin-7-yl)methyl] -2-biphenylcarboxylate, methyl 4'-[(1,6-dihydro-6-oxo-7H-purirl-7-yl)methyl]-2-biphenylcarboxylate, methyl 4'- [(2- acetamido-6 - [(diphenylc arbamoyl)oxy] -9H-purin-9-yl)methyl]-2-biphenylcarboxylate and methyl 4'-[(2-acetamido-6-[(diphenylcarbamoyl)oxy]-7H-purin-7 -yl)methyl] -2-biphenylcarboxylate.

E~specially preferred compounds of formula I are:
4'-[(8-P.utyl-1 ,6-dihydro-6-oxo-7H-purin-7-yl)methyl] -2-biphenylearboxylic acid, 4'-~(1 ,6-dihydro-6-oxo-8-propyl-7H-purin-7-yl)methyl]-2-s biphenylcarboxylic acid, 4' - [( 8-butyl-6-methoxy-9H-purin-9-yl)methyl] -2-biphenyl-carboxylic acid, 4' - ~(6-amino-8-butyl-9H-purin-9-yl)methyl] -2-biphenyl-carboxylic acid, 0 8-butyl-1,9-dihydro-9-[[2'-(lH-tetrazol-5-yl)-4-biphenyl-yl]methyl]-6H-purin-6-one and 8 -butyl- 1,7 -dihydro-7 - [ [2' -(1 H-tetrazol-S -yl) -4 -biphenyl-yl]methyl]-6H-purin-6-one.

s The compounds of formula I can be manufac~ured in accordance with the invention by reacting a compound of the general formula R2~

~0~ 11 R3a N
Rl wherein R2a signifies a residue R:2 defined above, whereby the amino, mercapto or hydroxy group can be present in protected form; R3a signifies a residue R3 as defined above, whereby the amino, mercapto or hydroxy group can be present in protected form; R10 signifies hydrogen or ~ N,N-or N,O-ke~al or aminal; and Rl has the significance given above;
with a compound of the general formula ZX III

wherein X represents a leaving group and Z represents a residue of the formula --CH2~ (a') R7a represents the group C OoR8a or a te~azolyl residue of the formula s N N
R1 1 (b') ~N '~

R8a signifies lower-alkyl or a residue which is cleavable under physiological conditions and Rll signifies a protecting group, cleaving off from the reaction product any protecting groups which may be present and, if desired, saponifying an ester group R8a and cleaving an ether or thioether group R2 and/or, if desired, converting the reaction product into a salt. 5 The reaction of a compound of formula II with a compound of formula III is conveniently carried out in an inert organic solvent in the presence of a base. Lower aliphatic alcohols such as methanol or ethanol are examples of suitable inert organic 0 solvents.

Alkali metal alcoholates such as sodium me$hylate or sodium ethylate are examples of bases which can be used in the reaction. The reac~ion temperature is not critical, the reaction is 2s preferably carried out at room temperature. Halogen, especially bromine, tosyloxy and mesyloxy are examples of leaving groups X
in the compound of formula III. Trityl or benzyloxymethyl are examples of protecting groups Rl l .

The reaction of the compounds of formula II with compounds of formula III yields compounds of formula I in which any amino, mercapto or hydroxy groups present can be in protected form and in which a tetrazolyl residue which may be present is in protected form. These protecting groups can be cleaved off in a manner known per se. The cleavage of a trityl group Rll can be effected e.g. by treatment with bases such as aqueous-alcoholic sodium hydroxide solution, whereby a lower 5 alkyl ether or thioelher group R2 and R3 which may be present is simultaneously cleaved off.

An ester group R8 and an ether or thioether group R2 or R3 can be saponi~ied in a manner known per se, e.g. by treatment 0 with bases such as aqueous-alcoholic sodium hydroxide solution.

Acyl residues such as acetyl are examples of protecting groups for amino groups; alkyl or acyl groups such as methyl or acetyl are examples of hydroxy protecting grollps. A N,O-aminal 15 is, for example, a sugar residue such as l-ribosyl.

The compounds of formula I are inhibitors of angiotensin II
receptors and can be used for the treatment of high blood pressure. Furthermore, the compounds of formula I inhibit ~he 20 migration and proliferation of cells of the vascular smooth musculature and prevent proliferative aTteriosclerotic lesions.
The compounds of formula I can accordingly be used for the prophylaxis of arteriosclerosis, especially after bypass operations or angioplasty, and for the treatment of patients having 25 progressive a~teriosclerosis.

The inhibitory activity on angiotensin II receptors can be determined in vitro by means of a radioreceptor binding test using adrenal membranes of dogs.
Adrenal membranes of dogs are prepared freshly for each test. The adrenals are homogenized in 250 mM saccharose solution and centrifuged for 10 minutes at 4000 rev. The super-natant is delipidated and recentrifuged for 30 nninu~es at 4000 3s rev. The resulting sediment is rehomogenized in a volume of tes~
buffer (50 mM Tris/HCl, pH 7.4, 25 MnC12, lmM EDTA, 05~o w/v BSA, 0.01% w/v NaN3) so that the membrane protein concen-tration is about 1 mg/ml.

For the binding test 100 ~1 of adrenal membrane suspension are incubated with 50000 cpm of (3(125 I) Tyr) angiotensin II in the presence of 5 ~Ll of dimethyl sulphoxide for 5 20 minutes at 2~C while shaking. The test substances are dissolved in dimethyl sulphoxide and tested in concentrations of 10-9M to 10-4M in this system. The unspecific binding of (3(125 I)Tyr) angiotension II is determined in the presence of 1 ~lM of non-iodinated angiotensin II. Filtration of an aliquot of 180 ~11 l o over a Whatman membrane terminates the incubation. The membrane is washed twice with 180 ~11 of test buffer each time.
Membrane-bound radioactivity is measured in a Packald gamma counter.

The results are given as IC 5û values, which denote those concentrations of the inhibitors in the test system which inhibit the specific binding of (3(125 I)Tyr) angiotension II to its receptor by 50%. IC 50 values are determined from the inhibition curves (percentage binding against the decadic logarithm of the inhibitor concentration). All single values are averages from triple determinations. The IC 50 values given are averages from at least three independent tests. In the calculation of the specific binding of (3(125 I)Tyr) angiotension II the unspecific binding is subtracted each tirne.
2s The results obtained using compounds of formula I in this test are compiled in the following Table:

2 ~

Tab_e I

Compound IC 50_ ~,uM) 4'-[(1,6-Dihydro-6-oxo-8-propyl-7H-purin-7 -yl)methyl] -2-biphenylcarboxylic acid 0 . 3 65 4'-[(8-Butyl-6-methoxy-9H-purin-9-yl)-methyl]-2-biphenylcarboxylic acid 0.458 4'-[(8-Butyl-1 ,6-dihydro-6-oxo-7H-purin-7-yl)methyl]-2-biphenylcarboxylic acid 0.167 4'-[(6-Amino-8-butyl-9H-purin-9-yl)methyl] --2-biphenylcarboxylic acid 0 . 5 3 4 8 -Butyl- 1,9 -dihydrs-9- [ [2' -(1 H-tetrazol-5 -yl) --4-biphenylyl]methyl3-6H-purin-6-one 0.0955 8-Butyl-1,7-dihydro-7-[[2'-(lH-tetrazol-5-yl)--4- biphenyly 1] methy 1 ] -6H-purin- 6 - one 0 . 0 6 5 8 The compounds can be administered enterally, parenterally or ~opieally in the folm o~ usual galenical prepalations. Pre-25 parations in ~he form of tablets, capsules, syrups, suspensions,solutions and suppositolies are suitable e.g. for enteral administration. Preparations in the form of infusion or injection solutions are suitable for parenteral administra~ion.

The dosages in which ~he preparations are administered can vzry depending on the rnode of use and route of administration as well as according to the requirements of the patients.

Dosages of about 0.5-500 mg/kg, preferably 1-100 mg/kg, body weight per day generally come into consideration in the case of adults.

9 2 ~

The preparations can contain inert as well as pharmaco-dynamically active additives. Table~s or granulates e.g. can contain a series of binders, fillers, carrier ma~erials or diluen~s.
Liquid preparations can be present, for example, in the form of a s sterile water-miscible solution. Capsules can contain a filler or thickener in addition ~o the active ingredient. Furthermore, flavour-irnproving additives as well as the substances usually used as preserving~ stabilizing, moisturizing and emulsifying agents as well as salts for varying the osmotic pressure, buffers O and other additives can also be present.

The previously mentioned carrier materials and diluents can be organic or inorganic substances, e.g. water, gelatine, lactose, starch, magnesium stearate, talc, gum arabic, polyalkylene glycols 5 and the like. It is a prerequisite that all adjuvants used in the manufacture of the preparations are non-toxic.

For topical application the active subs~ances are conven-iently used in the form of transdermal application systerns.
The invention is illus~rated in more detail by the following Examples:
~a~
2s 5.24 g of 2-acetamido-6-[(diphenylcaIbamoyl)oxy1 9H-purine [Can. J. Chem. 65~ 1436 (1987)] were suspended in 90 ml of abs. methanol. A solution of 13.5 mmol of sodium methylate in 9 ml of abs. methanol was added at room temperature. The 30 solution was stirred at room temperature for 1 hour, ~he methanol was evaporated at 35-4ûC with the exclusion of air and moisture, the residue was taken up in 18 ml of dimethylformamide~ treated with a solution of S.0 g (16.5 mmol) of methyl 4'-bromomethyl-biphenyl-2-carboxylate [EP 253'310] in 10 ml of abs. dimethyl-3s formamide and stirred at 40C for 4 hours. The solvent wasevaporated in a vacuum and the residue was chromatographed (SiO2/ethyl acetate:methanol 9:1 v/v). After recrystallization from ethyl acetate there were obtained methyl 4'-[(2-acetamido-lo 2~8~

6-[(diphenylcarbamoyl)oxy]-9H-purill-9-yl)- methyl]-2-biphenyl-carboxyla~e (white crystals, m.p. 186-188C~ and methyl 4'-[(2-acetamido-6- [(diphenylcarbamoyl)oxy] -7H-purin -7 -yl)methyl] -2-biphenylcarboxylate (white crystals, m.p. 175-177C).

xample 2 a) 0.8 g of methyl 4'-[~2-ace~amido-6-[(diphenylcarbamoyl)-oxy]-9H-purin-9-yl)methyl3-2-biphenylcarboxylate was dis-0 solved in 30ml of ethanol and 15 ml of 2N NaOH/H20. Thesolution was refluxed for 18 hours, cooled and adjusted to pH 2.0 with conc. HCl at 0-5~C. The precipitate was filtered off lmder suction, and washed with water and ether. The filtrate was concentrated in a vacuum at 40C. The precipitate was washed as 5 above and the entire product was recrys~allized from lN HCl.
There was obtained 4'-[(2-amino-1,6-dihydro-6-oxo-9H-purin-9-yl)methyl]-2-biphenylcarboxylic acid hydrochloride as white crystals of melting point >250C.

20 b ) In an analogous manner, from methyl 4'-[(2-acetamido-6-[(diphenylcarbamoyl)oxy]-7H-purin-7-yl)methyl~ -2-biphenylcarboxylate there was obtained 4'-[(2-amino-1,6-dihydro-6-oxo-7H-purin-7-yl)methyl]-2-biphenylcarboxylic acid hydrochloride as white crygtals of melting point >250C.
Example 3 In analogy to Example 1, frvm ~.4 g of inosine and 7.6 g of methyl 4'-bromomethylbiphenyl-2-earboxylate (EP 253'310) 30 there was ob~ained methyl 4'-[(1,6-dihydro-6-oxo-7H-purin-7-yl)methyl]-2-biphenylcarboxylate in the form of white crys~als of melting point 209-211C.

E~
a) 1.0 g (2.77 mmol) of methyl 4'-[(1,6-dihydro-6-oxo-7H-purin-7-yl)methyl]-2-biphenylcarboxylate was dissolved in 20 ml of methanol and 5 ml of conc. ammonia solution. 10 ml of lN NaOH solution were added and the mixture was refluxed for 1 hour. After distilling of~ the solvent the residue was dissolved in 10 ml of H20 and neutralized with 10 rnl of lN HCl solutioIl.
Thç precipitate was filtered off under suction, washed with water, 5 dried in a vacuum, then dissolved in about 20 ml of 2N ammonia solution and filtered. The filtrate was lyophilized in a vacuum.
There was obtained 4'-[(1,6-dihydro-6-oxo-7H-purin-7-yl)methyl]-2-biphenylcarboxylic acid ammonium salt as a white powder, m.p. 100C (decomposition with NH3 evolution).
Example 5 Analogouc,ly to Example 1, from 3.10 g of 8-butyl-6-methoxy-9H-purine and 5.34 g of 4'-bromomethylbiphenyl-2-5 carboxylate (EP 253'310) there were obtained methyl 4'- [~8-butyl-6-methoxy-9H-purin-9-yl)methyl] -2-biphenylcarboxylate and methyl 4'-[(8-butyl-6-methoxy-7 H-purin-7-yl)methyl3-2-bi-phenylcarboxylate as light yellow oils.

The purine used as the starting material can be prepared as follows:

In an analogous manner to J.C.S. Perkin I, 1855 (1973), from 36.0 g of 4,5-diamino-6-hydroxy-pyrimidine hemisulphate 2s (Aldrich) there was obtained 5,6-bis(valerylamino~pyrimidin-4-(3H)-one, melting point 220-230C, therefrom 6-amino-5-valerylaminopyrimidin-4(3H)-one, melting point >250C, and firlally 8-butyl-2-chloTo-9H-purine, melting point 75-77C.

l.Z2 g of sodium were dissolved in 37 ml of abs. methanol.
37 ml of dimethylformamide were added and the methanol was removed in a vacuum with the exclusion of moisture. The residue was cooled to 0C, 5.0 g of 8-butyl-2-chloro-9H-purine were added and the mixture was stirred at 90C for 38 hours. The solution was cooled to 0C and the pH was adjusted to 7.0 by the addition of 2N HCl solution. The precipita~e was filtered off, washed with water and dried in a vacuum. The product was purified by chromatography (sio27 MeOH:ethyl acetate 1:4 v/v).

1 2 % ~

~-Butyl-6-methoxy-9H-purine was obtained as white crystals of melting point 156-158C .

xample 6 In analogy to Example 1, from 2.90 g of 6-methoxy-8-propyl-9H-purine and 5.34 g of 4'-bromomethylbiphenyl-2-car-boxylate [F,P 253'310] there were ob~ained methyl 4'-[(6-meth-oxy-8-propyl-9H-purin-9-yl)methyl]-2-biphenylcarboxylate (m.p.
0 82-84C) an~ methyl 4'-[(6-methoxy-8-propyl-7H-purin-7-yl)-methyl]-2-biphenylcarboxylate (m.p. 147-150C) as white crystals.

The purine used as the starting material was prepared as s described in Example S starting from 4~5 -diamino-6-hydroxy-pyrimidine hemisulphate via 5,6-bis(butyrylamino)pyrimidin-4(3H)-one, 6-amino-5-butyrylaminopyrimidin-4(3H)-one, melting point >2~0C~ and 2-chloro-8-propyl-9H-purine, meltirlg point 115-117C. 6-Methoxy-8-propyl-9H-purine of melting point 1~4-20 156C was obtained.

Example 7 3.70 g of methyl 4'-[(8-butyl-6-methoxy-9H-purin-9-yl~-2s rnethyl]-2-biphenylcarboxylate were dissolved in 35 ml of MeOH~
treated with 30 ml of 1.0N NaOH and refluxed fol 15 hours. The mi~ture was treated with 30 ml of l.ûN HCl at 5-10C. The pre-cipitate was dissolved in ethyl acetate and the organic phase was washed wi~h water. After evaporating the solven~ the residue 30 was purified by chromatography (SiO2~ ethyl acetate: methanol 4:1 v/v). 4'-[~8-Butyl-6-methoxy-9H-purin-9-yl)methyl]-2-biphenylcarboxylic acid, m.p. >2S0C, was obtained.

In an analogous manner, from methyl 4'-[(8-butyl-6-meth-35 oxy-7H-purin-7-yl)methyl]-2-biphenylcarboxylate there was obtained 4'[(8-butyl-6-methoxy-7H-purin-7-yl)me~hyl]-2-biphenylcarboxylic acid as white crystals, m.p. >240C.

1 3 2 ~

Example 8 a) 0.6 g of 4'-[(8-butyl-6-methoxy-9H-purin-9-yl]-2-bi-phenylcarboxylic acid was dissolved in 20 ml of abs. methanol, s ~eated with 20 ml of lN NaOH solution and refluxed for 15 hours.
The mixture was ~iltered while hot, cooled to 0~C and treated with 13 ml of methylene ehloride. The turbid solution was adjusted slowly to pH 8.5 with 2N HCl solution at 0-5C. Af~er distilling off the methanol and methylene chloride in a vacuum and eooling the 10 product was fil~ered off under suction, dissolved in H2O and the solution was filtered and adjusted to pH 5.2 with 0.5 N HCl solution. The crystals were filtered off under suction, washed with water and dried in a vacuum. 4'-[(8-Butyl-1,6-dihydro-6-oxo-9H-purin-9-yl)methyl~-2-biphenylcarboxylic acid was 5 obtained. White crystals, m.p. >250C.

b ) In an analogous manner, from 4'-[(8-butyl-6-methoxy-7H-purin-7-yl~methyl]-2-biphenylcarboxylie acid there was obtained 4'-[(8-butyl-1 ,6-dihydro-6-oxo-7H-purin-7-yl)methyl]-2-bi-20 phenylearboxylic acid. White erystals, m.p. >250C.
Example 2 In analogy to Example 8, from methyl 4'-[(6-methoxy-8-25 propyl-9H-purin-9-yl~methyl]-2-biphenylearboxylate there was obtained 4'-~1,6-dihydro-6-oxo-~propyl-9H-purin-9-yl)me~h-yl]-2-bipheylearboxylie aeid, m.p. 190-192C (dee.), and from methyl 4'-[~6-methoxy-8-propyl-7H-purin-7-yl~methyl]-2-biphenylearboxylate there was obtained 4'-[(1,6-dihydro-6-oxo-30 8-propyl-7H-purin-7-yl)methyl]-2-biphenylcarboxylic acid, m.p.
>250C.
Example 1 0 3s In analogy to Exarnple 1, from 2.88 g of 8-butyl-adenine (J. Am. Chern. Soe. 105, 2050 (1983)] and 5.4 g of 4'-bromomethylbiphenyl-2-earboxylate there were obtained methyl 4'-[(6-amino-8-butyl-9H-purin-9-yl)methyl] -2-biphenylcarboxylate, melting point 204-206C, and methyl 4'-~(6-amino-8-butyl-3H-purin-3 -yl)methyl] -2-biphenylcarboxyla~e, melting point 174-176C .

S ~LL

0.6 g ~14.4 mmol) of methyl 4'-[(6-amino-8-butyl-9H-purin-9-yl)methyl]-2-biphenylcarboxylate was dissolved in 10 ml of methanol, treated with 5.0 ml of lN NaOH and refluxed for 1.5 10 hours. The solution was filtered, cooled to 0-5 C, treated dropwise with 5.0 ml of lN HCl solution and left to stand overnight. The product was filtered off under suctivn, washed with water and ether and dried in a vacuum. 4'-~6-Amino-8-butyl-9H-purin-9-yl)methyl]-2-biphenylcarboxylic acid was 15 obtained. White crystals, m.p. 250-253C.

Example 1 2 In an analogous manner to Example 11, from methyl 4'-[(6-20 amino-8-butyl-3H-purin-3-yl)methyl]-2-biphenylcarboxylate there was obtained 4'-[(6-amino-8-butyl-3H-purin-3-yl)methyl]-2-biphenylcarboxylic aeid, melting point >260C.

In analogy to Example 1, from 3.1 g of 8-butyl-6-methoxy-9H-purine and 9.8 g of 5-~4'-bromomethylbiphenyl-2-yl3-2-triphenylmethyltetrazole there were obtained 8-butyl-6-methoxy-9- [ [2'-(tripheylmethyltetrazol-5 -yl)-4-biphenylyl] -30 methyl]purine as an oil and 8-butyl-6-methoxy-7-[[2'-~triphenyl-methyltetrazol-5-yl)-4-biphenylyl]methyl]purine as white crys~als, m.p. 161 -163C .

1.0 g ( 1.50 mmol) of 8-butyl-6-methoxy-9-[ L2'-(triphenyl-35 me~hyltetrazol-5-yl)-4-biphenylyl]methyl]purine was dissolved in 20 ml of methanol, treated with 20.0 ml of NaOH (l.ON/H~O) and refluxed for 20 hours. The methanol was evaporated in a vaeuum.
The pH was adjusted to 4.9 with 1.0 N HCI solution at 0-5C. The crystallized-ollt product was filtered, washed with water and dried in a vacuum. There was obtained 8-butyl-1,9-dihydro-9-[[2'-(lH-tetra7O1-5-yl)-4-biphenylyl]methyl]-6H-purin-6-one, melting point 203-205C, as white crys~als.
s Analogollsly, from 8-butyl-6-methoxy-7-[[2'-(triphenyl-methyltetrazol-5-yl)-4-biphenylyl]methyl]purine there was obtained 8 -butyl- 1,7 -dihydro-7 - [ [2' -(1 H-tetrazol-5 -yl) -4-biphenylyl]methyl]-6H-purin-6-one, melting point 220-224C
o (dec.).

The ~etrazole used as the starting ma~erial can be prepared as follows:

55.0 g of 5-[4'-methylbiphenyl-2-yl]tetrazole [EP 291'969]
are added eo 700 ml of abs. methylene chloride. 30.g g (40.5 ml~
of N-ethyldiisopropylamine were added. 64.8 g of triphenyl-methyl chloride were added at room temperature and the mixture was stirred at room temperature for 28 hours. The solvents were 20 evaporated in a vacuum, the residue was purified by chromato-graphy (SiO2/CH2C12) and the 5-[4'-methylbiphenyl-2-yl]-2-triphenylmethyltetrazole was recrystallized from diethyl ether.

91.5 g of 5-[4'-methylbiphenyl~2-yl]-2-triphenylmethyl-25 tetrazole, 36.2 g of N-bIomosuccinimide and 1.92 g of dibenzoyl peroxide in 4B0 ml of carbon tetrachloride were heated under reflux for 48 hours and then cooled. The succinimide precipitate was filtered o~f and washed with carbon tetrachloride. The filtrate was concentrated, the residue was chromatographed using 30 CH2Cl2 and the 5-[4'-bromomethylbiphenyl-2-yl]-2-tri-phenylme~hyltetrazole was recrystallized from hexane. M.p. 128-~32C.

1 6 `~

E~xam~lç A

Tablets can be manufactured from $he following ingredients in a conventional manner:

.I~redients Per tablet Compound of formula I S mg Lactose 125 mg Maize starch 65 mg Talc 4 mg Magnesium stearate 1 mg Tablet weighg 200 mg Example B

A filling for gelatine capsules can be manufactured from the following ingredients:
In~edients Per capsule Compound of formula I 10 mg Lactose 165 mg Maize starch 20 mg Talc 5 mg Capsule fill weight 200 mg

Claims

1. Purine derivatives of the general formula wherein R1 signifies hydrogen or lower-alkyl;
R2 signifies amino, mono- or di-(lower-alkyl)amino, -SR1 or -OR1;
R3 signifies hydrogen, amino, mono- or di-(lower-alkyl)amino, -SR1 or-OR1;
R4, R5 and R6 signify a residue of the formula (a) R7 signifies the group -COOR8 or a tetrazolyl residue of the formula (b) R8 signifies hydrogen, an alkali, alkaline earth or ammonium cation, lower-alkyl or a residue which is cleavable under physiological conditions; and R9 signifies hydrogen or an alkali, alkaline earth or ammonium cation; provided that only one of the substituents R4, R5 and R6 is present and R2 signifies amino or mono- or di-(lower-alkyl)amino when R6 is present.

2. Compounds in accordance with claim 1 of the general formula Ia wherein R1, R2, R3 and R4 have the significance given in claim 1.

3. Compounds in accordance with claim 1 of the general formula Ib wherein R1, R2, R3 and R5 have the significance given in claim 1.

4. Compounds in accordance with claim 1 of the general formula Ic wherein R1, R2, R3 and R6 have the significance given in claim 1.

5. Compounds in accordance with any one of claims 1-4, wherein R7 signifies a tetrazolyl residue of formula (b).

6. Compounds in accordance with any one of claims 1-5, wherein R1 signifies lower-alkyl, especially n-propyl or n-butyl.

7. 4'-[(2-Amino-1,6-dihydro-6-oxo-9H-purin-9-yl)-methyl]-2-biphenylcarboxylic acid, 4'-[(2-amino-1,6-dihydro-6-oxo-7H-purin-7-yl)methyl]-2-biphenylcarboxylic acid, 4'-[(8-butyl-1,6-dihydro-6-oxo-9H-purin-9-yl)methyl]-2-biphenylcarboxylic acid, 4'-[(1,6-dihydro-6-oxo-8-propyl-9H-purin-9-yl)methyl]-2-biphenylcalboxylic acid, 4'-[(8-butyl-6-methoxy-7H-purin-7-yl)methyl]-2-biphenyl-carboxylic acid, 4'-[(6-amino-8-butyl-3H-purin-3 -yl)methyl]-2-biphenyl-carboxylic acid, 4'- [( 1 ,6-dihydro-6-oxo-7H-purin -7 -yl)methyl]-2-biphenyl-carboxylic acid, methyl 4'-[(6-amino-8-butyl-9H-purin-9-yl)methyl]-2-bi-phenylcarboxylate, methyl 4'-[(6-amino-8-butyl-3H-purin-3-yl)methyl]-2-bi-phenylcarboxylate, methyl 4'-[(6-methoxy-8-propyl-9H-purin-9-yl)methyl]-2-biphenylcarboxylate, methyl 4'-[(6-methoxy-8-propyl-7H-purin-7-yl)methyl]-2-biphenylcarboxylate, methyl 4'-[(1,6-dihydro-6-oxo-7H-purin-7-yl)methyl]-2 -biphenylcarboxylate, methyl 4'-[(2-acetamido-6-[(diphenylcarbamoyl)oxy]-9H-purin-9-yl)methyl]-2-biphenylcarboxylate or methyl 4'-[(2-acetamido-6-[(diphenylcarbamoyl)oxy]-7H-purin-7-yl)methyl]-2-biphenylcarboxylate.

8. 4'-[(8-Butyl-1,6-dihydro-6-oxo-7H-purin-7-yl)methyl]-2-biphenylcarboxylic acid.

9. 4'-[(1,6-Dihydro-6-oxo-8-propyl-7H-purin-7-yl)methyl]-2-biphenylcarboxylic acid.

10. 4'-[(8-Butyl-6-methoxy-9H-purin-9-yl)methyl]-2-biphenylcarboxylic acid.

11. 4'-[(6-Amino-8-butyl-9H-purin-9-yl)methyl]-2-biphenylcarboxylic acid.

12. 8-Butyl-1,9-dihydro-9-[[2'-(1H-tetrazol-S-yl)-4-biphenylyl]methyl]-6H-purin-6-one.

13. 8-Butyl-1,7-dihydro-7-[[2'-(1H-tetrazol-5-yl)-4-biphenylyl]methyl]-6H-purin-6-one.

14. Purine derivatives in accordance with any one of claims 1-13 for use as therapeutically active substances.

15. Purine derivatives in accordance with any one of claims 1-13 for use in the control or prevention of high blood pressure and arteriosclerosis.

16. A process for the manufacture of a compound in accordance with any one of claims 1-13, which process comprises reacting a compound of the general formula II
wherein R2a signifies a residue R2 as defined in claim 1, whereby the amino, mercapto or hydroxy group can be present in protected form; R3a signifies a residue R3 as defined in claim 1, whereby the amino, mercapto or hydroxy group can be present in protected form; R10 signifies hydrogen or a N,N- or N,O -ketal or aminal; and R1 has the significance given in claim 1;
with a compound of the general formula Z-X III
wherein X represents a leaving group and Z represents a residue of the formula (a') R7a represents the group -COOR8a or a tetrazolyl residue of the formula (b') R8a signifies lower-alkyl or a residue which is cleavable under physiological conditions and R11 signifies a protecting group, cleaving off from the reaction product any protecting groups which may be present and, if desired, saponifying an ester group R8a and cleaving an ether or thioether group R2 and/or, if desired, converting the reaction product into a salt.

17. A medicament, containing a purine derivative in accordance with any one of claims 1-13 and a therapeutically inert excipient.

18. A medicament for the control or prevention of high blood pressure and arteriosclerosis, containing a purine derivative in accordance with any one of claims 1-13 and a therapeutically inert excipient.

19. The use of a purine derivative in accordance with any one of claims 1-13 in the control or prevention of illnesses.

20. The use of a purine derivative in accordance with any one of claims 1-13 in the control or prevention of high blood pressure and arteriosclerosis.

21. The use of a purine derivative in accordance with any one of claims 1-13 for the manufacture of medicaments for the control or prevention of high blood pressure and/or arterio-sclerosis.

22. Purine derivatives in accordance with any one of claims 1-13, whenever prepared according to the process as claimed in claim 16 or by an obvious chemical equivalent thereof.

23. The invention as hereinbefore described.

24. A method of treating or preventing high blood pressure and/or arteriosclerosis which comprises administering to a patient requiring such treatment an effective amount of a purine derivative in accordance with any one of claims 1-13.