NO176758B - Analogous Process for Preparing Therapeutically Useful Tetrazolyl-Biphenylyl Methyl-Pyrimidines - Google Patents

Abstract

Pyrlmldin compound with Formula. wherein one of the radicals R or amdated carboxy, cyano, SOH, POH, POH, 5-tetrazolyl, optionally substituted sulfamoyl, acylamino or -Z-R ', where Z represents a bond or O, S (0) or N (R), R' means hydrogen or an all-hydrocarbon radical, which is optionally interrupted by 0 or S (0) and which is optionally substituted by halogen, hydroxy, optionally substituted amino or optionally esterified or ambled carboxy, R is hydrogen or an all-hydrocarbon residue and m is 0, 1 or 2 , and the third residue Rj. Rog RMeans the group with Formula. wherein Z represents alkylene, O, S (0) or K (R), R represents carboxy, haloalkanesulfonylamino, SOE, POH. POH. or 5-tetrazolyl, R represents hydrogen or an all-hydrocarbon radical, m represents 0, 1 or 2 and rings A and B are independently optionally substituted by halogen, an all-hydrocarbon radical which is optionally interrupted by 0 and optionally substituted by hydroxy or halogen, optionally substituted with an all-alcoholic alcohol-etherified hydroxy, optionally esterified or ambled carboxy or 5-tetrazolyl, and optionally tautomer thereof, 1 free form or 1 salt form. is manufacturable in a manner known per se and can, for example, be used as active substances in medicinal products.

Description

The present invention relates to an analogue method for the preparation of a therapeutically usable compound of formula

where R-^, is halogen, hydroxy, lower alkoxy, hydroxy-lower alkoxy, lower alkyl-lower oxy, mercapto, lower alkyl-thio, amino, di-lower alkylamino, carboxy, lower alkyl-carbonyl, carboxy-lower oxy, lower-alkylcarbonyl-lower-alkyl, lower-alkylamino-carbonyl or di-lower-alkylamino-carbonyl,

R2 is a group of formula

where Zg is C1-C2 alkylene and R5 in position 2 or 3 is attached to ring B and is 5-tetrazolyl,

R3 is lower alkyl or or lower alkenyl,

R4 is hydrogen or lower alkyl,

ring A is unsubstituted or substituted with halogen and ring B is unsubstituted and ring B is attached to position 3 or 4 on ring A,

optionally a tautomer thereof, in free form or a pharmaceutically acceptable salt thereof.

The compounds of Formula I and possibly their tautomers can exist as particularly pharmaceutically usable salts. For example, the compounds have at least one basic center and these can form acid addition salts. These are, for example, formed with strong inorganic acids, such as mineral acids, e.g. sulfuric acid, a phosphoric acid or a halogen acid, with strong organic carboxylic acids, which optionally, e.g. with halogen, substituted C 1 -C 4 alkanecarboxylic acids, e.g. acetic acid, as optionally unsaturated dicarboxylic acids, e.g. oxalic, malonic, Bernstein, maleic, fumaric, phthalic or terephthalic acids, such as hydroxycarboxylic acids, e.g. ascorbic, glycolic, lactic, malic, tartaric or citric acid, as amino acids, e.g. aspartic or glutamic acid, or as benzoic acid, or with organic sulphonic acids, which optionally, e.g. with halogen, substituted C -C -C -alkane or aryl sulfonic acids, e.g. methane- or p-toluenesulfonic acid. Corresponding acid addition salts can also be formed with an optionally further basic center present. Furthermore, the compounds I with at least one acidic group (for example COOH or 5-tetrazolyl) can form salts with bases. Suitable salts with bases are, for example, metal salts, such as alkali or alkaline earth metal salts, e.g. sodium, potassium or magnesium salts, or salts with ammonia or an organic amine, such as morpholine, thio-morpholine, piperidine, pyrrolidine, a mono-, di- or tri-lower alkylamine, e.g. ethyl, tert-butyl, diethyl, diisopropyl, triethyl, tributyl or dimethylpropylamine, or a mono-, di- or trihydroxy lower alkylamine, e.g. mono-, di- or triethanolamine. Furthermore, corresponding internal salts can be formed. Also included are salts not suitable for pharmaceutical compounds, which are, for example, added for isolation or purification of free compounds I or pharmaceutically usable salts thereof.

The term "lower" means that corresponding groups and compounds contain in particular up to 7, preferably up to 4, carbon atoms.

Halogen is particularly halogen with an atomic number up to and including 35, i.e. fluorine, chlorine or bromine, and further includes iodine.

Lower alkyl is especially C 1 -C y alkyl, i.e. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl or a corresponding pentyl, hexyl or heptyl residue. <C>3-C4-alkyl is preferred.

Lower alkyloxy is in particular C₁-Cy₃ alkoxy, i.e. methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, sec-butyloxy, tert-butyloxy or corresponding pentyloxy, hexyloxy or heptyloxy. C₁-C₁-Alkoxy is preferred.

Dilaverealkylamino means in particular di-C1-C4-alkylamino, such as dimethyl-, diethyl-, di(n-propyl)-, methylpropyl-, methylethyl-, methylbutyl- or dibutylamino.

The present invention is therefore characterized by the fact that

one reacts a compound with formula

or a tautomer and/or a salt thereof, where R'^ has the meaning given for Ri, R'3 has the meaning given for R3 and the residue R'<2> stands for the group of formula (a) where means cyano, with an azide; or (b) cleaves off the protecting group in such a compound of formula (Ila) where X-1 is N-protected 1H-tetrazol-5-yl, and when desired transfers a free compound of formula (I) obtained according to the method or a tautomer thereof to pharmaceutical acceptable salt or a pharmaceutically acceptable salt obtained according to the method of a compound of formula (I) or a tautomer thereof to the free compound of formula (I) or a tautomer thereof or to another salt.

Extensive pharmacological investigations have indicated that the compounds I and their tautomers and/or their pharmaceutically usable salts, e.g. exhibits marked angiotensin-11-antagonistic properties.

As is known, angiotensin-II has strong vasoconstrictor properties and thus stimulates aldosterone secretion and thus causes a clear sodium/water retention. The consequences of angiotensin-II activity are manifested, among other things, in an increase in blood pressure. The importance of angiotensin-II antagonists consists in suppressing the vasoconstrictions and aldosterone secretion-stimulating effect caused by angiotensin-II through competitive inhibition of the binding of angiotensin-II on the receptors.

Angiotensin-II antagonistic properties of the compounds of Formula I and their tautomers and/or pharmaceutically usable salts can be encompassed in the angiotensin-II binding test. Here, the smooth muscle cells of rats from homogenized rat aorta are used. The precipitate is suspended in 50 mM tris buffer (pH 7.4) with the addition of peptidase inhibitors. The probes are incubated for 60 minutes at 25°C with <125>I-angiotensin-II (0.175 nM) and with a varying concentration of angiotensin-II or a test compound. Incubation is then terminated by addition of ice-cold phosphate-buffered saline and filtered through Whatman GF/F filters. The filter is counted with a Gamma counter. From the dose-response curve, the ICsQ value is determined. For the compounds of Formula I and their pharmaceutically acceptable salts, IC 50 values from about 10 nM are provided.

For the determination of angiotensin-II-induced vasoconstriction, studies can be performed on isolated rabbit aortic rings. Here, aortic rings are prepared from each breast and fixed between 2 parallel clamps at an initial tension of 2 g. The rings are then immersed at 37° C in a 20 ml tissue bath and gassed with a mixture consisting of 95% O2 and 5% CO2. The isometric reactions are then measured. At 20 minute intervals the rings are alternately stimulated with 10 nM angiotensin-II (hypertensin-CIBA) and 5 nM norepinephrine chloride. Finally, the rings are incubated with selected concentrations of the test compound for treatment with the agonists. The data is analyzed with a Buxco digital computer. The concentrations causing a 50% inhibition of the initial control values are indicated as ICsg values. For the compounds of Formula I and their tautomers and/or pharmaceutically usable salts, ICgQ values from about 5 nM are determined.

That the compounds of Formula I and their tautomers and/or pharmaceutically usable salts can be reduced through angiotensin-II-induced hypertension can be verified in test models of normotensive, anesthetized rats. After calibration of the preparations with 0.9% NaCl (1 ml/kg i.v.), norepinephrine (1 jjg/kg i.v.) or angiotensin-II (0.3 pg/kg i.v.) increasing doses (3-6) of the test compound are injected intravenously through bolus injection, where after each dose in 5-minute intervals angiotensin-II is applied or norepinephrine. The blood pressure is measured directly in the carotid artery and recorded with an on-line data capture system (Buxco). The specificity of angiotensin-II antagonism is provided through selective inhibition of angiotensin-II, and not simply through norepinephrine-induced pressor effects. In this test model, the compounds of Formula I and their tautomers and/or pharmaceutically acceptable salts exhibit an inhibitory effect from a dose of about 0.3 mg/kg i.v.

Also in the test model of renal hypertensive rats, the antihypertensive activity of the compounds of Formula I and their tautomers and/or pharmaceutically usable salts can be manifested. In male rats, high blood pressure is produced by narrowing a renal artery according to the Goldblatt method. The rats are administered doses of the test compound by means of a gastric tube. Control animals receive an equivalent volume of solvent. Blood pressure and heartbeat are measured indirectly in adult animals according to the tail pinch method of Gerold et al. [" Heiv. Physiol. Acta 24 (1966), 58] before administration of the test compound or the solvent as well as during the course of the experiment measured at intervals. The pronounced antihypertensive effect can be obtained from a dose of about 30 mg/kg p.o.

Thus, the compounds of Formula I and their tautomers and/or pharmaceutically usable salts can e.g. are used as active ingredients in antihypertensive agents, such as can be added to treat high blood pressure and heart failure.

Variant a):

In 5-tetrazolyl R5 transferable residues are, for example, cyano and N-protected 5-tetrazolyl.

For the preparation of compounds with Formula I, where R5 means 5-tetrazolyl, one starts, for example, from starting material with Formula IIa, where X^ means cyano, and reacts this with an azide, e.g. with HN 3 or in particular a salt, such as an alkali metal salt, thereof or with an organozinn azide, such as a trilower alkyl or triaryl tin azide. Preferred azides are, for example, sodium and potassium azide as well as tr i -C^-C^alkyl-, e.g. triethyl- or tributyl-zinnazide and triphenylzinnazide.

Protective groups for N-protected 5-tetrazolyl include the protective groups usually used in tetrazole chemistry, especially triphenylmethyl, possibly e.g. with nitro, substituted benzyl, such as 4-nitrobenzyl, lower-alkoxymethyl, such as methoxy- or ethoxymethyl, lower alkylthio-methyl, such as methylthiomethyl, as well as 2-cyanoethyl, further lower-alkyllower-alkoxymethyl, such as 2-methoxyethoxymethyl, benzyloxymethyl and phenacyl. Cleavage of the protective groups takes place as in known methods. Thus, e.g. triphenylmethyl usually cleaved off through hydrolysis, especially in the presence of an acid, or hydrogenolysis in the presence of a hydrogenation catalyst, 4-nitrobenzyl e.g. through hydrogenolysis in the presence of a hydrogenation catalyst, methoxy- or ethoxymethyl, e.g. through treatment with a trilower alkyl, such as triethyl or tributyl tin bromide, methylthiomethyl e.g. through treatment with trifluoroacetic acid, 2-cyanoethyl e.g. through hydrolysis, for example with caustic soda, 2-methoxyethoxymethyl, e.g. through hydrolysis, e.g. with hydrochloric acid, and benzyloxymethyl and phenacyl e.g. through hydrogenolysis in the presence of a hydrogenation catalyst.

Preferably, the variants a) are suitable for the preparation of such compounds with Formula I, where the variables have meanings that are different from the unsaturated residues.

The starting materials for Formula IIa are, for example, available, starting from a connection with Formula

as the preparation thereof takes place in a manner known per se, and reacts this with a compound with Formula Illb.

It is possible, in the thus obtained starting compounds IIa, before conversion of X^ in R5 to carry out further conversions, e.g. conversions of a halogen atom, especially a chlorine atom R^, according to the technique indicated below.

The turnover preferably takes place in the presence of a base.

As bases come, for example, alkali metal hydroxides,

- hydrides, - amides, - alkanolates, - carbocations, - triphenyl methylides, - dilower alkyl amides, - amino alkyl amides or - lower alkyl silyl amides, naphthalene amides, lower alkyl amines, basic heterocycles, ammonium hydroxides, as well as carbocyclic amines in question. Examples include sodium hydroxide, -hydride, -amide, potassium tert-butylate, -carbonate, lithium triphenylmethylide, -diisopropylamide, potassium 3-(aminopropyl)-amide, -bis-(trimethylsilyl)-amide, dimethylaminonaphthalene , di-or triethylamine, or ethyl-diisopropylamine, N-methyl-piperidine, pyridine, benzyltrimethyl-ammonium hydroxide, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN) as well as 1,8-diaza-bicyclo- [5.4.0]undec-7-en (DBU).

Pharmaceutically acceptable salts of compounds of Formula I can be prepared in a manner known per se. In this way, for example, acid addition salts of compounds with Formula I are obtained through treatment with a suitable acid or a suitable ion exchange reagent. Pharmaceutically acceptable salts of compound I can be transferred in a manner known per se to free compounds I, acid addition salts e.g. through treatment with a suitable basic agent or a suitable ion exchange reagent.

Salts of compound I can be converted into other salts of compound I in a manner known per se.

Depending on the procedure or reaction conditions, the compounds I can be obtained with salt-forming, especially basic properties, in free form or in the form of salts.

Due to the close relationship between compound I in free form and in the form of its salt, above and below the free compound I and the salt thereof to understand possibly also the corresponding salts or the free compound I.

Compound I including pharmaceutically acceptable salts of salt-forming compounds can also be obtained in the form of hydrates thereof and/or including, e.g. for crystallization ion-used, solvent.

In the analogue method according to the present invention, such starting materials and intermediate products are preferably used which lead to the particularly valuable described compound

IN.

The compounds of Formula I and pharmaceutically usable salts thereof can, preferably in the form of pharmaceutically usable preparations, be used in a method for prophylactic and/or therapeutic treatment of animal or human bodies, especially as antihypertensive agents.

The pharmaceutical preparations are for enteral, as oral, further rectal or parenteral administration to warm-blooded organisms, where the pharmacological active ingredient is alone or together with usual pharmaceutical excipients. The pharmaceutical preparations contain e.g. from about 0.1$ to 100$, preferably from about 1% to about 60$, of the active ingredient. Pharmaceutical preparations for enteral or parenteral administration is e.g. such in dosage unit forms, such as dragées, tablets, capsules or suppositories, further ampoules. These are produced in a manner known per se, e.g. using conventional mixing, granulating, coating, dissolving or lyophilizing methods. In this way, pharmaceutical preparations for oral use can be obtained, combining the active ingredient with solid carriers, possibly granulating a resulting mixture and processing the mixture or the granulate, if desired or necessary after adding suitable excipients for tablets or dragee cores.

Suitable carriers are especially fillers, such as sugar, e.g. lactose, sucrose, mannitol or sorbitol, cellulose preparations and/or calcium phosphate, e.g. tricalcium phosphate or calcium hydrogen phosphate, further binder, such as starch glue, using e.g. maize, wheat, rice or potato starch, gelatin, tragacanth gum, methyl cellulose and/or polyvinylpyrrolidone and, when desired, explosives, such as the above-mentioned starches, further carboxymethyl starch, cross-linked polyvinylpyrrolidone, agar or alginic acid or a salt thereof, which sodium alginate. Aids are primarily flow control and lubricants, e.g. silicic acid, talc, stearic acid or a salt thereof, such as magnesium or calcium stearate, and/or polyethylene glycol. Dragon cores are coated with suitable, possibly gastric juice-resistant coatings, where concentrated sugar solutions are used, which may contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, lacquer solutions in suitable organic solvents or solvent mixtures or, for the production of gastric juice- resistant coatings, solutions of suitable cellulose preparations, such as acetyl cellulose phthalate or hydroxypropyl methylcellulose phthalate. The tablets or dragee coatings can have dyes or pigments added, e.g. for identification or for clarification of different active ingredient doses.

Additional orally usable pharmaceutical preparations are gelatin capsules as well as weak, closed capsules of gelatin and an emollient, such as glycerin or sorbitol. The injectable capsules can contain the active substance in the form of a granule, e.g. in a mixture with fillers, such as lactose, binders such as starch and/or lubricants, such as talc or magnesium stearate, and possibly stabilizers. In soft capsules, the active ingredient is preferably in a suitable liquid degree, such as fatty oils, paraffin oil or liquid polyethylene glycols, dissolved or suspended, where stabilizers can also be added.

As rectally applicable pharmaceutical preparations, e.g. suppositories in consideration, which consist of a combination of the active ingredient together with a suppository base. As a suppository base material, e.g. natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols and higher alkanols. Furthermore, gelatin rectal capsules can also be used which contain a combination of the active substance with a base substance. As base material comes e.g. liquid triglycerides, polyethylene glycols and paraffin hydrocarbons into consideration.

For parenteral administration, aqueous solutions of an active substance in water-soluble form are suitable in the first instance, e.g. a water-soluble salt, further suspensions of the active ingredient, such as corresponding oily injection suspensions, where a suitable lipophilic solvent or carrier is used, such as fatty oil, e.g. sesame oil, or synthetic fatty acid ester, e.g. ethyl oleate or triglycerides, or aqueous injection suspensions, containing viscosity-increasing substances, e.g. sodium carboxymethylcellulose, sorbitol and/or dextran, and optionally also stabilizers.

The dosage of the active substance may depend on various factors, such as method of application, warm-blooded species, age and/or individual condition. Normally, for a patient of about 75 kg, by oral application, an approximate daily dose is about 10 mg to about 250 mg.

The examples below illustrate the above-mentioned invention. Temperatures are given in degrees Celsius. "THF" means "tetrahydrofuran".

Example 1

6-(n-butyl )-5-(2'-cyanobiphenyl-4-ylmethyl)-4-hydroxy-2-methyl-pyrimidine (910 mg, 2.54 mmol) and tributyltin azide (1.68 g, 5.08 mmol) in o-xylene (30 ml) is stirred for 24 hours under reflux. The reaction mixture is evaporated in vacuo and the residue is reacted with CH 2 Cl 2 /CH 3 OH/NH 3 (5:3:1, 50 ml) and the mixture is stirred for 30 minutes. After renewed evaporation in vacuo, the residue is separated by means of flame chromatography (silica gel 60, 40-63 pm, CH2CI2/CE3OH/NE3 = 160:10:1). 6-(n-butyl)-4-hydroxy-2-methyl-5-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-pyrimidine is obtained as amorphous solid particles which crystallize from acetic ester.

Melting point: 236°C (decomposition).

The starting material can e.g. be produced as follows:

a) To a solution of 3-oxoheptanoic acid ethyl ester (9.5 g, 55.1 mmol) in absolute THF (100 ml) at room temperature

portionwise added NaH (80% in white oil, 2.4 g, 55.1 mmol). After the addition is complete, this is stirred for 30 minutes and finally a solution of 4-bromomethyl-2'-cyano-biphenyl (15.0 g, 55.1 mmol) in absolute THF (150 ml) is added dropwise. The reaction mixture is stirred for 12 hours at room temperature and finally evaporated in vacuo. The residue is partitioned between ethyl acetate and H2O and the organic phase is washed with H2O and saturated NaCl solution, dried (Na2SO4) and evaporated in vacuo. Flame chromatography (silica gel 60, 40-63 pm, hexane/acetic ester = 9:1) provides 2-(2'-cyanobiphenyl-4-ylmethyl)-3-oxoheptanoic acid ethyl ester as an oil, which is directly further worked up.

b) To a solution of sodium methanolate (3.22 g, 57.8 mmol) in absolute methanol (45 mL) acetamidine hydrochloride is

(3.64 g, 38.5 mmol) added at room temperature. After 10

minutes, a solution of 2-(2'-cyanobiphenyl-4-ylmethyl)-3-oxo-heptanoic acid ethyl ester (7.0 g, 19.26 mmol) in absolute methanol (30 ml) is added dropwise. The yellow suspension is stirred for 24 hours at 50° C. and finally evaporated in vacuo. The residue is suspended in H2O and the suspension is acidified with IN hydrochloric acid to pH 5 and then extracted with acetic acid. The organic phase is washed with saturated NaCl solution, dried (Na 2 SO 4 ) and evaporated. Flame chromatography (silica gel 60, 40-63 pm, CH2CI2/CH3OH = 98:2) affords 6-(n-butyl)-5-(2'-cyanobiphenyl1-4-ylmethyl)-4-hydroxy-2-methylpyrimidine, which becomes crystallized from diethyl ether and directly further worked up.

Example 2

Starting from 5-(2'-cyanobiphenyl-4-ylmethyl)-4-hydroxy-2-methyl-6-(n-propyl)-pyrimidine and tributyltin azide, 4-hydroxy-2- methyl 6-(n-propyl)-5-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-pyrimidine. White crystals from vinegar.

Mp.: 206°C (decomposition).

The starting material can, for example, be prepared as follows: a) Through alkylation of 3-oxohexanoic acid ethyl ester with 4-bromomethyl-2'-cyanobiphenyl as described in Example la) one obtains 2-(2'-cyanobiphenyl-4-ylmethyl)-3-oxo- hexanoic acid ethyl ester, which is purified through flame chromatography (silica gel 60, 40-63 pm, hexane/acetic ester = 4:1) is purified, as an oil. This is directly further processed. b) By reacting 2-(2'-cyanobiphenyl-4-ylmethyl)-3-oxohexanoic acid ethyl ester with acetamidine hydrochloride and sodium methanolate in methanol in the manner described in Example lb) 5-(2'-cyanobiphenyl-4-ylmethyl) is obtained )-4-hydroxy-2-methyl-6-(n-propyl)-pyrimidine. This is directly further processed.

Example 3

Starting from 6-(n-butyl)-5-(2'-cyanobiphenyl-4-ylmethyl)-4-hydroxy-2-(n-propyl)-pyrimidine and tributyltin azide, one obtains as described in Example 1 6-(n -butyl)-4-hydroxy-2-(n-propyl)-5-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-pyrimidine. White crystals from isopropanol/diethyl ether.

M.p.: 208°C-210°C.

The starting material can, for example, be prepared as follows, a) By reacting 2-(2'-cyanobiphenyl-4-ylmethyl)-3-oxoheptanoic acid ethyl ester with butyramidine hydrochloride and sodium methanolate in methanol by the method described in Example 1b) one obtains 6-( n-butyl)-5-(2'-cyanobiphenyl-4-ylmethyl)-4-hydroxy-2-(n-propyl)-pyrimidine, which is purified by flame chromatography (silica gel 60, 40-63 pm, CH2C12/CH3OH = 98:2). This is directly further processed.

Example 4

Starting from 5-(2'-cyanobiphenyl-4-ylmethyl)-2,6-di-(n-butyl)-4-hydroxypyrimidine and tributyltin azide, 2,6-di-(n -butyl)-4-hydroxy-5-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-pyrimidine. White crystals from vinegar.

M.p.: 212-213°C.

The starting material can, for example, be prepared as follows, a) By reacting 2-(2'-cyanobiphenyl-4-ylmethyl)-3-oxoheptanoic acid ethyl ester with valeramidine hydrochloride and sodium methanolate in methanol, one obtains in the same way as described in Example lb) 5- (2'-cyanobiphenyl-4-ylmethyl)-2,6-di-(n-butyl)-4-hydroxy-pyrimidine, which is purified by flame chromatography (silica gel 60, 40-63 pm, CH2C12/CH3OH = 98:2 ). This is directly further processed.

Example 5

Starting from 6-(n-butyl)-4-chloro-5-(2'-cyanobiphenyl-4-ylmethyl)-2-methyl-pyrimidine and tributylzinnazide, 6-(n-butyl )-4-chloro-2-methyl-5-[2'-(1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-pyrimidine as amorphous solids.

Temp. 120°C-122°C.

The starting material can, for example, be prepared as follows, a) N,N-dimethylaniline (1.67 ml, 13.15 mmol) is first added to 11 ml of POCl3 at 0°C with stirring and finally 6-(n-butyl1)- 4-Hydroxy-2-methyl-5-(2'-cyanobiphenyl-4-ylmethyl)-pyrimidine (4.7 g, 13.15 mmol). The reaction mixture is slowly heated and stirred for 1.5 hours under reflux. The reaction mixture is thus poured into water at a temperature of 20-25° C. This is allowed to stand for 30 minutes and then extracted with diethyl ether. The organic phase is dried (Na 2 SO 4 ) and evaporated and the residue purified by flame chromatography (silica gel 60, 40-63 pm, CH 2 Cl 2 ). 6-(n-butyl)-4-chloro-5-(2'-cyanobiphenyl-4-ylmethyl)-2-methylpyrimidine is thus obtained, which is then directly further processed.

Example 6

Starting from 6-(n-butyl)-5-(2'-cyanobiphenyl-4-ylmethyl)-4-methoxy-2-methylpyrimidine and tributyltin azide, 6-(n-butyl)-4 is obtained in the manner described in Example 1 -methoxy-2-methyl-5-[2'-(1H-tetrazol-5-yl)biphenyl 1-4-ylmethyl]-pyrimidine. White crystals from acetic ester/diethyl ether.

M.p.: 113-115'C.

The starting material can, for example, be prepared as follows,

a) To a solution of sodium methanolate (355 mg, 6.38 mmol) in absolute methanol (5 ml) 6-(n-butyl)-4-chloro-5-(2'-cyanobiphenyl-4-ylmethyl )-2 -methylpyrimidine (1.0 g, 2.66 mmol) in absolute methanol (10 mL) was added dropwise. The reaction mixture is stirred for 24 hours at room temperature and finally evaporated in vacuo. The residue is partitioned between ethyl acetate and H 2 O and the organic phase washed with H 2 O and saturated NaCl solution, dried (Na 2 SO 4 ) and evaporated in vacuo. The crude product is purified by means of flame chromatography (silica gel 60, 40-63 pm, CH2Cl2/CH3OH = 98:2). Thus, 6-(n-butyl)-5-(2'-cyanobiphenyl-4-ylmethyl)-4-methoxy-2-methylpyrimidine is obtained, which is directly further processed.

Example 7

Starting from 6-(n-butyl)-5-(2'-cyanobiphenyl-4-ylmethyl)-4-(2-methoxyethoxy)-2-methylpyrimidine and tributyltin azide, one obtains in the manner described in Example 1 6-(n- butyl)-4-(2-methoxyethoxy)-2-methyl-5-[2'-(1H-tetrazol-5-yl)biphenyl-4-yl-methyl]-pyrimidine. White crystals from acetic acid/hexane.

M.p.: 133-135°C.

The starting material can, for example, be prepared as follows: a) Sodium (122 mg, 5.32 mmol) is dissolved in 10 ml of 2-methoxyethanol at room temperature. Finally, a solution of 6-(n-butyl)-4-chloro-5-(2'-cyanophenyl)-2-methyl-pyrimidine (1.0 g, 2.66 mmol) in 2-Methoxyethanol (5 ml) added dropwise. The reaction mixture is stirred for 24 hours at room temperature and finally evaporated in vacuo. The residue is partitioned between ethyl acetate and H 2 O and the organic phase washed with H 2 O and saturated NaCl solution, dried (Na 2 SO 4 ) and evaporated in vacuo. The crude product is purified by means of flame chromatography (silica gel 60, 40-63 pm, CH2CI2/CH3OH = 98:2). 6-(n-butyl)-5-(2'-cyanobiphenyl-4-ylmethyl)-4-(2-methoxyethoxy)-2-methylpyrimidine is thus obtained, which is directly further processed.

Example 8

Starting from 6-(n-butyl)-5-(2'-cyanobiphenyl-4-ylmethyl)-4-dimethylamino-2-methylpyrimidine and tributyltin azide, 6-(n-butyl)-4 is obtained in the manner described in Example 1 -dimethyl-amino-2-methyl-5-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-pyrimidine. White crystals from acetone.

M.p.: 195°C-197°C.

The starting material can, for example, be produced as follows:

a) To a solution of 6-(n-butyl)-4-chloro-5-(2'-cyano-biphenyl-4-ylmethyl)-2-methylpyrimidine (1.0 g, 2.66 mmol) in

ethanol (10 ml), dimethylamine (33% in ethanol, 1.9 ml) is added. The reaction mixture is stirred for 24 hours under reflux and finally evaporated in vacuo. The residue is partitioned between ethyl acetate and HgO and the organic phase washed with Et2O and saturated NaCl solution, dried (NagSO4) and evaporated in vacuo. The crude product is purified by means of flame chromatography ((silica gel 60, 40-63 pm, CH2CI2/CH3OH = 98:2). 6-(n-butyl)-5-(2'-cyanobiphenyl1-4-ylmethyl)- 4-dimethylamino-2-methylpyrimidine, which is directly further processed.

Example 9

Starting from 6-(n-butyl)-5-(2'-cyanobiphenyl-4-ylmethyl)-4-hydroxy-2-isopropyl-pyrimidine and tributyltin azide, 6-(n-butyl) is obtained in the manner described in Example 1 -4-hydroxy-2-isopropyl-5-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-pyrimidine.

M.p.: 234-236°C (from isopropanol/diethyl ether; decomposition).

The starting material can, for example, be prepared as follows: a) By reacting 2-(2'-cyanobiphenyl-4-ylmethyl)-3-oxoheptanoic acid ethyl ester with isobutyramide hydrochloride and sodium methanolate in methanol as described in Example lb) one obtains 6-(n- butyl)-5-(2'-cyanobiphenyl-4-ylmethyl)-4-hydroxy-2-isopropyl-pyrimidine, which is purified through flame chromatography (silica gel 60, 40-63 pm, CH2CI2/CH3OH = 98:2) and directly further processed.

Example 10

To a suspension of 2,6-di-(n-butyl)-4-hydroxy-5-[2'-(1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-pyrimidine (1.2 g, 2.7 mmol) in 60 ml of ethanol, 2.7 ml of an IN solution of KOH in ethanol is added. The resulting solution is evaporated in a vacuum. After addition of isopropanol, crystallization occurs. The crystals are filtered off and dried at 100°C in vacuum. 2,6-di-(n-butyl)-4-hydroxy-5-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-pyrimidine potassium salt is thus obtained. Temp. 276-278°C (decomposition).

Example 11

Starting from 2,6-di-(n-butyl)-4-hydroxy-5-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-pyrimidine and 1N NaOH in ethanol, one obtains on the The method described in Example 10 2,6-di-(n-butyl)-4-hydroxy-5-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-pyrimidine- sodium salt, which is crystallized from acetonitrile.

Temp. 333-335°C (decomposition).

Example 12

Starting from 6-(but-1-en-4-yl)-2-(n-butyl)-5-(2'-cyanobi-phenyl-4-ylmethyl)-4-hydroxy-pyrimidine and tributyltin azide, one obtains on the The method described in Example 1 6-(but-1-en-4-yl)-2-(n-butyl)-4-hydroxy-5-[2'-(1H-tetrazol-5-yl)-biphenyl-4 -ylmethyl]-pyrimidine.

M.p.: 203-205°C (from acetic acid/HgO; decomposition).

The starting material can, for example, be prepared as follows: a) Through alkylation of 3-oxohept-6-enoic acid ethyl ester with 4-bromomethyl-2'-cyanobiphenyl as described in Example la) one obtains 2-(2'-cyanobiphenyl-4-ylmethyl)- 3-oxohept-6-enoic acid ethyl ester, which can be purified by flame chromatography (silica gel 60, 40-63 pm, hexane/acetic ester = 9:1) and directly further processed.

b) Through reaction of 2-(2'-cyanobiphenyl-4-ylmethyl)-3-oxohept-6-enoic acid ethyl ester with valeramidine hydrochloride and

sodium methanolate in methanol as described in Example lb) yields 6-(but-1-en-4-yl)-2-(n-butyl)-5-(2'-cyanobiphenyl-4-ylmethyl)-4-hydroxy- pyrimidine, which is purified through flame chromatography (silica gel 60, 40-63 pm, acetate/hexane = 1:1) and is directly further processed.

Example 13

Starting from 4-amino-6-(n-butyl)-5-(2'-cyanobiphenyl-4-ylmethyl)-2-methyl-pyrimidine and tributyltin azide, 4-amino-6-( n-butyl)-2-methyl-5-[2*-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-pyrimidine.

M.p.: 177-179°C (from methanol; decomposition).

The starting material can, for example, be produced as follows:

a) 6-(n-butyl)-4-chloro-5-(2'-cyanobiphenyl-4-ylmethyl)-2-methyl-pyrimidine (0.2 g, 0.53 mmol) and 2 ml NH3 in 10 ml ethanol becomes

kept for 4 days in a bomb tube at 120°C. After evaporation in vacuo, the residue is purified by means of flame chromatography (silica gel 60, 40-63 pm, CH2CI2/CH3OE = 95:5). 4-amino-6-(n-butyl)-5-(2'-cyanobiphenyl-4-ylmethyl)-2-methyl-pyrimidine is thus obtained, which is directly further processed.

Example 14

Starting from 6-(n-butyl)-5-(2'-cyanobiphenyl-4-ylmethyl)-2-methyl-4-methylthio-pyrimidine and tributyltin azide, 6-(n-butyl) is obtained in the manner described in Example 1 -2-methyl-4-methylthio-5-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-pyrimidine.

M.p.: 176-178°C (from acetic acid; decomposition).

The starting material can, for example, be prepared as follows: a) 6-(n-butyl)-4-chloro-5-(2'-cyanobiphenyl-4-ylmethyl)-2-methyl-pyrimidine (1.0 g, 2.66 mmol ) and sodium methanethiolate (0.21 g,

2.92 mmol) is stirred in 10 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone for 6 hours at room temperature. The reaction mixture is poured into H2O and extracted with acetic acid. The organic phase is washed thoroughly with H 2 O, dried (Na 2 SO 4 ) and evaporated in vacuo. Flame chromatography (silica gel 60, 40-63 pm, hexane/acetic ester = 4:1) affords 6-(n-butyl )-5-(2'-cyanobiphenyl-4-ylmethyl)-2-methyl-4-methylthio-pyrimidine, which is directly further processed.

Example 15

Starting from 6-(n-butyl)-5-(2'-cyanobiphenyl-4-ylmethyl)-2-ethyl-4-hydroxy-pyrimidine and tributyltin azide, 6-(n-butyl) is obtained in the manner described in Example 1 -2-ethyl-4-hydroxy-5-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-pyrimidine.

M.p.: 235-237°C (from isopropanol; decomposition).

The starting material can, for example, be prepared as follows: a) By reacting 2-(2'-cyanobiphenyl-4-ylmethyl)-3-oxoheptanoic acid ethyl ester with propionamidine hydrochloride and sodium methanolate in methanol, one obtains in the manner described in Example 1b) 6-( n-butyl)-5-(2'-cyanobiphenyl-4-ylmethyl)-2-ethyl-4-hydroxy-pyrimidine, which is purified by flame chromatography in (silica gel 60, 40-63 pm, CH2Cl2/CH3OH = 98 :2) and directly further processed.

Example 16

Starting from 6-(n-butyl)-5-(2'-cyanobiphenyl-4-ylmethyl)-4-(2-hydroxyethoxy)-2-methylpyrimidine and tributyltin azide, one obtains in the manner described in Example 1 6-( n-butyl)-4-(2-hydroxyethoxy)-2-methyl-5-[2'-(1H-tetrazol-5-yl)-biphenyl 1-4-ylmethyl]-pyrimidine.

M.p.: 168-170°C (from acetic acid; decomposition).

The starting material can, for example, be prepared as follows: a) To a solution of sodium (0.12 g, 5.3 mmol) in 20 ml of ethylene glycol, 6-(n-butyl)-4-chloro-5-(2'-cyanobiphenyl) -4-ylmethyl)-2-methyl-pyrimidine (1.0 g, 2.6 mmol) added. The reaction mixture is stirred for 3 hours at 100° C. After evaporation in vacuo, the residue is partitioned between ethyl acetate and H 2 O and the organic phase is dried over Na 2 SO 4 and evaporated in vacuo. Flame chromatography (silica gel 60, 40-63 pm, CH2Cl2/CH3OH = 95:5) affords 6-(n-butyl)-5-(2'-cyanobiphenyl-4-ylmethyl)-4-(2-hydroxyethoxy )-2- methyl - pyrimidine, which is directly further processed.

Example 17

Starting from 6-(n-butyl)-5-(2'-cyanobiphenyl-4-ylmethyl)-4-ethoxycarbonylmethoxy-2-methyl-pyrimidine and tributyltin azide, 6-(n-butyl)-4 is obtained as described in Example 1 -ethoxy-carbonylmethoxy-2-methyl-5-[2'-(1H-tetrazol-5-yl)biphenyl 1-4-ylmethyl]-pyrimidine as amorphous solids.

The starting material can, for example, be prepared as follows: a) To a solution of 6-(n-butyl)-5-(2'-cyanobiphenyl-4-ylmethyl)-4-hydroxy-2-methyl-pyrimidine (2.0 g, 5.6 mmol) in 50 ml of N,N-dimethylformamide is added NaH (0.17 g, 5.6 mmol, 80% in white oil). The reaction mixture is stirred for 30 minutes at room temperature. Finally, bromoacetic acid ethyl ester (0.81 ml, 7.3 mmol) is added. After 3 hours, this is evaporated in vacuo and the residue distributed between ethyl acetate and HgO. The organic phase is dried with NaCl and evaporated in vacuo. Flame chromatography (silica gel 60, 40-63 pm, hexane/acetic ester 4:1) affords 6-(n-butyl)-5-(2'-cyanobiphenyl-4-ylmethyl)-4-ethoxycarbonylmethoxy-2-methyl-pyrimidine, which is directly further processed.

Example 18

Starting from 5-[3-bromo-2'-cyanobiphenyl-4-ylmethyl]-2,6-di-(n-butyl)-4-hydroxy-pyrimidine and tributyltin azide, one obtains as described in Example 1 5-[3- bromo-2'-(1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-2,6-di-(n-butyl)-4-hydroxy-pyrimidine.

M.p.: 222-224°C (from isopropanol/diethyl ether, decomposition).

The starting material can, for example, be prepared as follows: a) 4-methyl-2'-cyanobiphenyl is added to a solution of AICI3 (21.0 g, 0.157 mol) in tetrachloroethane. Under stirring

this is heated at 60°C. To the resulting solution, a solution of bromine (20.7 g, 0.13 mol) in 100 ml of tetrachloroethane is added dropwise at 60°C and the reaction mixture is stirred for 24 hours. After adding a further 6.2 g of AICI3 and heating at 70° C, it is not possible to determine an educt using thin-layer chromatography (toluene). Reac-

The reaction mixture is thus reacted with 200 ml of concentrated hydrochloric acid under ice cooling and the organic phase is separated and evaporated in a vacuum. The residue is dissolved in ethyl acetate and the solution washed with HgO and sodium carbonate solution, dried (MgSC^) and evaporated in vacuo. Flame chromatography (silica gel 60, 40-63 pm, hexane/acetic ester = 4:1) affords 3-bromo-2'-cyano-4-methylbiphenyl, which is recrystallized from cyclohexane.

Temp. 104-106°C. b) After adding benzoyl peroxide (0.1 g) under UV irradiation at 100 -HCC a solution of bromine (5.6 g, 0.035 mol) in 20 ml of tetrachloroethane added dropwise. After 30 minutes, the reaction mixture is cooled and evaporated in vacuo. Recrystallization of the residue from acetic ester affords 3-bromo-4-bromomethyl-2'-cyano-biphenyl.

Melting point: 152-153° C.

c) Through alkylation of 3-oxoheptanoic acid ethyl ester with 3-bromo-4-bromomethyl-2'-cyano-biphenyl as described in Example

la) 2-(3-bromo-2'-cyano-biphenyl-4-ylmethyl)-3-oxoheptanoic acid ethyl ester is obtained which is purified by means of flame chromatograph in (silica gel 60, 40-63 pm, hexane/acetic ester = 9 :1) and directly further processed.

d) Through reaction of 2-(3-bromo-2'-cyano-biphenyl-4-yl-methyl)-3-oxo-heptanoic acid ethyl ester with valeramidine hydrochloride

and sodium methanolate in methanol as described in Example 1b) 5-[3-bromo-2'-cyano-biphenyl-4-ylmethyl]-2,6-di-(n-butyl)-4-hydroxy-pyrimidine is obtained, which is purified by means of flame chromatography (silica gel 60, 40-63 pm, CH2Cl2/CH3OH = 98:2) and directly further processed.

Example 19

Starting from 5-(3'-cyanobiphenyl-4-ylmethyl)-2, 6-di-(n-butyl)-4-hydroxy-pyrimidine and tributyltin azide, one obtains as described in Example 1 2,6-di-(n- butyl)-4-hydroxy-5-[3'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-pyrimidine as amorphous solids.

The starting material can, for example, be prepared as follows: a) 4-methylphenyltrimethyltin (5.9 g, 20 mmol), 3-iodobenzonitrile (5.0 g, 22 mmol) and tetrakis(triphenylphosphane)palladium

(1.16 g, 1 mmol) in 60 ml of o-xylene is stirred for 12 hours under reflux. After cooling at room temperature, the black suspension is filtered and the filtrate evaporated in vacuo. The residue is dissolved in ethyl acetate and the solution washed with a solution of potassium fluoride in HgO (10%), dried with NaCl and evaporated in vacuo. Flame chromatography (silica gel 60, 40-63 pm, hexane/acetic ester = 9:1) provides 3'-cyano-4-methyl-biphenyl, which is directly further processed.

b) 3'-cyano-4-methyl-biphenyl (1.8 g, 9.3 mmol), N-bromosuccinimide (1.66 g, 9.3 mmol) and α,α'-azoisobutyronitrile

(20 mg) in 30 ml of tetrachloromethane is stirred for 6 hours under reflux. After evaporation of the reaction mixture in vacuo, the residue is dissolved in ethyl acetate and the solution washed with HgO, dried (NagSO^) and evaporated in vacuo. Crystallization from ethyl acetate/hexane affords 4-bromomethyl-3'-cyanobiphenyl.

M.p.: 106-108°C.

c) Through alkylation of 3-oxoheptanoic acid ethyl ester with 4-bromomethyl-3'-cyano-bisphenyl on the described in Example la)

in this way, 2-(3'-cyanobiphenyl-4-ylmethyl)-3-oxoheptanoic acid ethyl ester is obtained, which is purified using flame chromatograph (silica gel 60, 40-63 pm, hexane/acetic ester = 9:1) and further processed direct. d) By reacting 2-(3'-cyanobiphenyl-4-ylmethyl)-3-oxoheptanoic acid ethyl ester with valeramidine hydrochloride and sodium methanolate in methanol in the manner described in Example lb) 5-(3'-cyanobiphenyl-4-ylmethyl) is obtained )-2,6-di-(n-butyl)-4-hydroxy-pyrimidine, which is purified by means of flame chromatograph in (silica gel 60, 40-63 pm, CH2C12/CH3OH = 98:2) and directly further processed.

Example 20

Starting from 5-(2'-cyanobiphenyl-3-ylmethyl)-2,6-di-(n-butyl)-4-hydroxy-pyrimidine and tributyltin azide, one obtains in the manner described in Example 1 2,6-di-( n-butyl)-4-hydroxy-5-[2'-(1H-tetrazol-5-yl)biphenyl-3-ylmethyl]-pyrimidine.

M.p.: 185-187°C (from isopropanol/diethyl ether, decomposition).

The starting material can, for example, be prepared as follows: a) By reacting 3-methylphenyl-trimethyltin with 2-iodobenzonitrile as described in Example 19a) 2'-cyano-3-methylbiphenyl is obtained, which is purified using a flame chromatograph in (silica gel 60, 40-63 pm, hexane/acetic ester = 9:1) and directly further processed. b) By reacting 2'-cyano-3-methyl-biphenyl with N-bromosuccinimide as described in Example 19b), 3-bromomethyl-2'-cyano-biphenyl is obtained, which is purified using column chromatography (silica gel 60, 40 -63 pm, hexane/acetic ester = 8:1) and directly further processed. c) Through alkylation of 3-oxoheptanoic acid ethyl ester with 3-bromomethyl-2'-cyano-biphenyl in the manner described in Example la) 2-(2'-cyanobiphenyl-3-ylmethyl)-3-oxoheptanoic acid ethyl ester is obtained, which is purified by using a flame chromatograph (silica gel 60, 40-63 pm, hexane/acetic ester = 9:1) and further processed directly. d) Through reaction of 2-(2'-cyanobiphenyl-3-ylmethyl)-3-oxoheptanoic acid ethyl ester with valeramidine hydrochloride and sodium methanolate in methanol as described in Example lb) 5-(2'-cyanobiphenyl 1-3-ylme) is obtained tyl )-2 , 6-di-(n-butyl )-4-hydroxy-pyrimidine, which is purified by means of column chromatography (silica gel 60, 40-63 pm, CH 2 Cl 2 /CH 3 OH = 98:2) and which is passed on directly processed.

Example 21

Starting from 5-[2-(2'-cyanobiphenyl-4-yl)ethyl]-2,6-di-(n-butyl)-4-hydroxy-pyrimidine and tributyltin azide, one obtains in the same way as in Example 1 2, 6-di-(n-butyl)-4-hydroxy-5-[2-(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)ethyl]-pyrimidine.

M.p.: 217-218°C (from isopropanol/acetic ester, decomposition).

The starting material can, for example, be prepared as follows: a) To a solution of methoxymethyl-triphenyl-phosphonium chloride (2.57 g, 7.5 mmol) in 25 ml of anhydrous tetrahydrofuran is

room temperature a solution of lithium bis(trimethylsilyl)-amide in tetrahydrofuran (1 M, 7.5 ml, 7.5 mmol) was added dropwise. After 30 minutes, under ice-cooling, a solution of 2'-cyano-4-formylbiphenyl (1.04 g, 5 mmol) in 30 ml of tetrahydrofuran is added dropwise and the reaction mixture is then stirred for 30 minutes at room temperature. The reaction mixture is poured into 150 ml of ice-cold saturated ammonium chloride solution and extracted with diethyl ether. The organic phase is washed with H 2 O, dried (Na 2 SO 4 ) and evaporated in vacuo. The residue is purified by means of flame chromatography (silica gel 60, 40-63 pm, hexane/acetic ester = 4:1). 2'-cyano-4-(2-methoxyethenyl)-biphenyl is thus obtained, which is directly processed further.

b) 2'-cyano-4-(2-methoxyethenyl)-biphenyl (8.2 g, 34.9 mmol) is suspended in 120 ml of formic acid (95%) and the suspension stirred

for 30 minutes at room temperature. The resulting solution is diluted with 1.5 1 H 2 O and the mixture extracted with diethyl ether. The organic phase is washed with saturated NaHCO 3 solution, dried (MgSO 4 ) and evaporated in vacuo. The residue is purified using flame chromatography (silica gel

60, 40-63 pm, hexane/acetic ester = 2:1). 2'-cyano-4-(2-oxoethyl)-biphenyl is thus obtained, which is directly further processed.

c) To a solution of 2'-cyano-4-(2-oxoethyl)-biphenyl (2.5 g, 11.3 mmol) in 50 ml of methanol, portionwise

added with stirring NaBH4 (0.86 g, 22.62 mmol) under ice-cooling. After stirring for 30 minutes at 0°C, the reaction mixture is evaporated in vacuo and the residue distributed between diethyl ether and HgO. The organic phase is washed with HgO, dried (NagSO4) and evaporated in vacuo. After flame chromatography in (silica gel 60, 40-63 pm, hexane/acetic ester = 1:1) 2'-cyano-4-(2-hydroxyethyl)-biphenyl is obtained, which is directly further processed.

d) To a solution of 2'-cyano-4-(2-hydroxyethyl)-biphenyl (2.23 g, 10 mmol) and triphenylphosphane (2.9 g, 11 mmol) in 50 ml

CHgClg N-bromosuccinimide (1.96 g, 11 mmol) is added with stirring at 0°C. The reaction mixture is stirred for 12 hours at room temperature and finally evaporated in vacuo. After flame chromatography in (silica gel 60, 40-63 pm, hexane/acetic ester = 4:1) 4-(2-bromomethyl)-2'-cyano-biphenyl is obtained, which is directly further processed.

e) Through alkylation of 3-oxoheptanoic acid ethyl ester with 4-(2-bromomethyl)-2'-cyano-biphenyl according to the method described in Example

la) 2-[2-(2'-cyanobiphenyl-4-yl)ethyl]-3-oxoheptanoic acid ethyl ester is obtained, which is purified by means of flame chromatograph in (silica gel 60, 40-63 pm, hexane/acetic ester = 6 :1) and directly further processed.

f) By reacting 2-[2-(2'-cyanobiphenyl-4-yl)ethyl]-3-oxo-heptanoic acid ethyl ester with valeramidine hydrochloride and

sodium methanolate in methanol in the same way as described in Example lb) 5-[2-(2'-cyanobiphenyl-4-yl)ethyl]-2,6-di-(n-butyl)-4-hydroxy-pyrimidine is obtained, which is cleaned using

by flame chromatography (silica gel 60, 40-63 pm, CH2Cl2/CH3OH = 95:5).

M.p.: 166-167'C.

Example 22

Starting from 6-(n-butyl)-5-(2'-cyanobiphenyl-4-ylmethyl)-4-hydroxy-pyrimidine and tributyltin azide, one obtains in the same way as described in Example 1 6-(n-butyl)-4- hydroxy-5-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-pyrimidine.

M.p.: 215-219°C (from ethanol, decomposition).

The starting material can, for example, be prepared as follows: By reacting 2-(2'-cyanobiphenyl-4-ylmethyl)-3-oxoheptanoic acid ethyl ester with formamidine hydrochloride and sodium methanolate in methanol according to the method described in Example 1b) 6-(n-butyl) is obtained )-5-(2'-cyanobiphenyl-4-ylmethyl)-4-hydroxypyrimidine.

Temp. 169-171°C (from vinegar).

Example 23

6-(n-Butyl)-5-(2'-cyanobiphenyl-4-ylmethyl)-4-methoxycarbonyl-2-methylpyrimidine (3.0 g, 7.5 mmol) and tributyltin azide (12.46 g, 37.5 mmol) in o-xylene (75 ml) is stirred for 48 hours at 120°C. After evaporation of the reaction mixture in vacuo, the residue is dissolved in diethyl ether and chlorine-hydrogen is added to the solution. The resulting precipitate is filtered off and thus dissolved in IN kalilut. The solution is extracted with diethyl ether, acidified with 2N hydrochloric acid and finally extracted with acetic acid. The organic phase is washed with saturated NaCl solution, dried (NagSO4) and evaporated in vacuo.

Flame chromatography (silica gel 60, 40-63 pm, CH2CI2/CH3OH/NH3 = 40:10:1) affords 6-(n-butyl)-4-carboxy-2-methyl-5-[2'-(1H-tetrazole- 5-yl)biphenyl-4-ylmethyl]-pyrimidine.

[M.P.: 120-122°C (from isopropanol/water)].

The starting material can, for example, be produced as follows:

a) 6-(n-butyl)-4-chloro-5-(2'-cyanobiphenyl-4-ylmethyl)-2-methyl-pyrimidine (16.0 g, 42.6 mmol), tributyl-vinyl-tin ( 14.9 ml,

51.1 mmol) and bis(triphenylphosphane)-palladium(II) dichloride (0.57 g, 0.82 mmol) in dimethylformamide (160 ml) are stirred for 2 hours at 90°C. After cooling at room temperature, the reaction mixture is diluted with HgO and extracted with diethyl ether. The organic phase is washed three times with potassium fluoride solution (10%), dried (NagSO4) and evaporated in vacuo. The residue is purified by means of flame chromatography (silica gel 60, 40-63 pm, hexane/acetic ester = 3:1) and the product finally recrystallized from diisopropyl ether/hexane. 6-(n-butyl)-5-(2'-cyanobiphenyl-4-ylmethyl)-2-methyl-4-vinylpyrimidine is obtained in this way. (M.P.: 115-117°).

b) In a solution of 6-(n-butyl)-5-(2'-cyanobiphenyl-4-ylmethyl)-2-methyl-4-vinylpyrimidine (14.6 g, 39.7 mmol) in

CH2C12 (275 ml) and methanol (275 ml) are introduced at -70°C ozone until a blue color remains. The reaction mixture is then stirred for a further 30 minutes at -70°C and argon is then passed through until the mixture becomes colourless. Then dimethylsulfide (29 mL, 0.4 mol) and NaHCO 3 (0.5 g) are added. The cooling bath is removed and the reaction mixture is stirred for 12 hours at room temperature. After evaporation of the reaction mixture in vacuo and flame chromatography of the residue (silica gel 60, 40-63 pm, hexane/acetic ester = 4:1) 6-(n-butyl)-5-(2'-cyanobiphenyl-4-ylmethyl)- 4-formyl-2-methylpyrimidine. [Mp.: 114-115° (from diisopropyl ether )] .

c) To a solution of 6-(n-butyl)-5-(2'-cyanobiphenyl-4-ylmethyl)-4-formyl-2-methylpyrimidine (8.8 g, 0.024 mol) in

methanol (135 ml), sodium cyanide (5.81 g, 0.12 mol), activated manganese dioxide (0.474 mol) and acetic acid (2.4 ml) are added and the resulting suspension is then stirred for 12 hours at room temperature. After filtering the reaction mixture, the filtrate is evaporated in vacuo and the residue distributed between acetic acid and saturated NaHCC 3 solution. The organic

the phase is washed with saturated NaCl solution, dried (NagSC^) and evaporated in vacuo. Flame chromatography (silica gel 60, 40-63 pm, hexane/acetic ester = 2:1) affords 6-(n-butyl)-5-(2'-cyanobiphenyl-4-ylmethyl)-4-methoxycarbonyl-2-methylpyrimidine, which is directly further processed.

Example 24

Tablets, each containing 50 mg of active ingredient, e.g. 2,6-di-(n-butyl)-4-hydroxy-5-[2'-(1H-tetrazol-5-yl)biphenyl 1-4-ylmethyl]pyrimidine can be prepared as follows:

Composition (for 10,000 tablets):

The active substance is mixed with lactose and 292 g of potato starch, the mixture moistened with an alcoholic solution of gelatin and granulated through a sieve. After drying, the rest of the potato starch, talc, magnesium stearate and highly dispersed silicon dioxide are mixed with it and the mixture is pressed into tablets each weighing 145.0 mg and 50.0 mg of active substance content, which, if desired, have dividing lines for finer adjustment of the dosage.

Example 25

Lacquer tablets, each containing 100 mg of active ingredient, e.g. 2,6-di-(n-butyl)-4-hydroxy-5-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-pyrimidine, may be prepared as follows: Composition (for 1,000 pills):

The active substance, lactose and 40 g of corn starch are mixed and moistened with a paste, prepared from 15 g of corn starch and water (while heating) and granulated. The granulate is dried, the rest of corn starch, talc and calcium stearate are added and mixed with the granulate. The mixture is pressed into tablets (weight: 280 mg) and these are varnished with a solution of hydroxypropylmethylcellulose and shellac in dichloromethane (final weight of the varnish tablet: 283 mg).

Example 26

In an analogous manner as in Examples 25 and 26, tablets and varnish tablets, containing another compound of Formula I or a tautomer and/or a pharmaceutically usable salt of a compound of Formula I, e.g. according to Examples 1 to 23, be prepared.

Claims (7)

1. Analogous process for the preparation of a therapeutically useful compound of formula where R^> is halogen, hydroxy, lower alkoxy, hydroxy-lower alkoxy, lower alkyl-lower oxy, mercapto, lower alkyl-thio, amino, di-lower alkylamino, carboxy, lower alkyl-carbonyl, carboxy-lower oxy, lower-alkylcarbonyl-lower-alkyl, lower-alkylamino-carbonyl or di-lower-alkylamino-carbonyl, R2 is a group of formula where Z2 is C1-C2 alkylene and R5 in position 2 or 3 is attached to ring B and is 5-tetrazolyl, R3 is lower alkyl or or lower alkenyl, R4 is hydrogen or lower alkyl, ring A is unsubstituted or substituted with halogen and ring B is unsubstituted and ring B is attached to position 3 or 4 on ring A, optionally a tautomer thereof, in free form or a pharmaceutically acceptable salt thereof, characterized by reacting a compound of formula or a tautomer and/or a salt thereof, where R'i has the meaning given for Ri, R'3 has the meaning given for R3 and the residue R'<2> stands for the group of formula (a) where means cyano, with an azide; or (b) cleaves off the protecting group in such a compound of formula (Ila) where X^ is N-protected 1H-tetrazol-5-yl, and when desired transfers a free compound of formula (I) obtained according to the method or a tautomer thereof to pharmaceutically acceptable salt or a pharmaceutically acceptable salt obtained according to the method of a compound of formula (I) or a tautomer thereof to the free compound of formula (I) or a tautomer thereof or to another salt. 2. Analogous process according to claim 1 for the preparation of 6-(n-butyl)-4-hydroxy-2-methyl-5-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-pyrimidine or a tautomer and /or a pharmaceutically acceptable salt thereof, characterized in that corresponding starting materials are used. 3. Analogous process according to claim 1 for the production of 6-(n-butyl)-4-hydroxy-2-(n-propyl)-5-[2'-(1H-tetrazol-5-yl)bi-phenyl-4 -ylmethyl]-pyrimidine or a tautomer and/or pharmaceutically acceptable salt thereof, characterized in that corresponding starting materials are used. 4. Analogous process according to claim 1 for the preparation of 2,6-di-(n-butyl)-4-hydroxy-5-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]pyrimidine or a tautomer and/or a pharmaceutically acceptable salt thereof, characterized in that corresponding starting materials are used. 5 . Analogous method according to claim 1 for the preparation of 6-(n-butyl)-4-hydroxy-2-isopropyl-5-[2'-(1H-tetrazol-5-yl)bi-phenyl-4-ylmethyl]-pyrimidine or a tautomers and/or pharmaceutically acceptable salts thereof, characterized by the use of corresponding starting materials. 6. Analogous method according to claim 1 for the production of 6-(n-butyl)-2-ethyl-4-hydroxy-5-[2'-(1H-tetrazol-5-yl)biphenyl 1-4-ylmethyl]pyrimidine or a tautomer and/or pharmaceutically acceptable salt thereof, characterized in that corresponding starting materials are used. 7. Analogous process according to claim 1 for the preparation of 6-(n-butyl)-4-hydroxy-5-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-pyrimidine or a tautomer and/or pharmaceutically acceptable salt thereof, characterized by using corresponding starting materials.