PT99081A - PREPARATION PROCESS OF PHENYLPYRIDINOL DERIVATIVES, ITS INTERMEDIARIES AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM - Google Patents

Description

73 118 22052 / Ρ30140 -3

DESCRIPTIVE MEMORY

The present invention relates to pyridinol derivatives, processes for their preparation, intermediates in their preparation, their use as, medicaments and the pharmaceutical compositions containing them.

The compounds of this invention are agonists of a cyclic AMP-dependent protein kinase (cA-PrK) (see J. Biol. Chem., 1989, 264, 8443-8446) and are used in combating conditions where such beneficial agonism . They are likely to have anti-proliferative, anti-aggregating, cholesterol lowering, smooth muscle relaxant, lusitropic, antiallergic or anti-inflammatory activities. They are likely to be useful in the treatment of cardiovascular diseases such as congestive heart failure, cancer, psoriasis, atherosclerosis, thrombosis, chronic reversible lung diseases such as asthma and bronchitis, allergic diseases such as allergic asthma, allergic rhinitis and urticaria or gut mobility such as irritable bowel syndrome.

Thus, the present invention provides compounds of formula (1):

Ar (1) or pharmaceutically acceptable salts thereof, wherein; R ° is OH or a biopercursor thereof, R1 is 5-tetrazolyl or a biopercursor thereof, and

Ar is phenyl substituted by one to three groups independently of one another selected from C1-6 alkyl, C2-6 alkenyl, C1-6 alkoxy- C3-6 alkenyloxy, C3-6 cycloalkyl, C3-6 cycloalkoxy, C1-6 alkylthio, phenyl, phenylthio, benzyloxy C. pol polalkylfluoroalkyl, C. pol polalkylfluoroalkoxy, halo, NR², or NHCOR wherein R H is H or C ^ al alalkyl, or -X (CH₂) n Y ligados attached to carbon atoms adjacent to the

Wherein X and Y are independently from each other CH2 or Oalkin, wherein said C1-6 alkyl, C2-6 alkenyl or C1-6 alkoxy groups may be independently of one another substituted by OH, C 1-6 alkoxy, C 3-8 cycloalkyl, NR 2, CO 2 R or CONR 2; with the proviso that Ar is not phenyl substituted by 2-C ^-C alco alkoxy.

The R ° group biopercursors are derivatives thereof which are convertible in vivo into the R group.

A suitable biopercursor of the group R 0 is OR 2 in which R 2 is arylalkyl (for example phenylC 1-4 alkyl as benzyl), C 1-4 alkanoyl (for example acetyl), C 1-4 alkanoyl (eg phenyl (for example optionally substituted phenylsulfonyl or toluenesulfonyl) or C1-4 alkylsulfonyl (for example methylsulfonyl). The suitable R ° group is hydroxy or OR2, preferably hydroxy.

A suitable biopercursor of the group R1 is an N-protected tetrazolyl group. Suitable N-protecting groups include pivaloyloxymethyl, propionyloxymethyl and pivaloyloxycarbonyloxymethyl.

By the term alkyl is meant straight chain and branched alkyl.

By the term polyfluoroalkyl is a C1-6 alkyl group having at least one fluorine-substituted hydrogen, for example CF3 or CF2CF2H.

Suitably Ar is a phenyl group mono-substituted by a group defined hereinbefore, for example at the 2, 3 or 4 positions by C1-6 alkyl, C3-8 alkenyloxy, C1-6 alkylthio, phenyl, phenylthio, benzyloxy, CF3, halo or NHCOR, or at the 3- or 4-positions with C1-6 alkoxy.

Suitably Ar is a phenyl group disubstituted by < RTI ID = 0.0 >

3,4-, 3,5-, 2,3-, 2,4- or 2,5-positions by groups independently selected from alkenyl, C1-6 alkoxy, C3-6 cycloalkoxy, halo, -X (CH2) n Y- or alkoxy C--C alco alkoxy.

Suitably Ar is a phenyl group tri-substituted by any of the groups defined above, for example at the 2,3,4-, 2,3,5-, or 3,4,5-positions by groups independently selected from one another of alkenyl C₂g, alkoxy or halo.

Examples of 1-6-alkoxy include methoxy, ethoxy, propoxy, butoxy, or pentyloxy.

Examples of C 1-6 alkyl include methyl, ethyl, propyl, butyl, isobutyl or pentyl.

Examples of halo include fluorine, chlorine, bromine or iodine, preferably chlorine or bromine.

Particular compounds of this invention include: 6- (3-methoxyphenyl) -3- (5-tetrazolyl) pyridin-2 (1H) -one, 6- (3-propoxyphenyl) -3- (5-tetrazolyl) pyridin- 6- (3-benzyloxyphenyl) -3- (5-tetrazolyl) pyridin-2 (1H) -one, 6- (3-butoxyphenyl) -3- (5-tetrazolyl) pyridin- 6- (3-trifluoromethyl) -3- (5-tetrazolyl) pyridin-2 (1 H) -one, 6- (3-bromophenyl) -3- (5-tetrazolyl) pyridin- , 6- (4-butoxyphenyl) -3- (5-tetrazolyl) pyridin-2 (1H) -one, 6- (3-ethylphenyl) -3- (5-tetrazolyl) pyridin-2 (1H) - (4-isobutylphenyl) pyridin-2 (1H) -one, 6- (4-biphenyl) -3- (5-tetrazolyl) pyridin-2 (1H) -one, 6- (4-propoxyphenyl) -3- ( (4-methoxy-3-propoxyphenyl) -3- (5-tetrazolyl) pyridin-2 (1H) -one, 6- (3,4-methylenedioxyphenyl) (3,4-dichlorophenyl) -3- (5-tetrazolyl) pyridin-2 (1H) -one, 6- (3,5-dimethyl- diphenylphenoxy) -3- (5-tetrazolyl) pyridin-2 (1H) -one, 6- (3,5-diethoxyphenyl) -3- (5-tetrazolyl) 5-dibromophenyl) -3- (5-tetrazolyl) pyridin-2 (1H) -one, 6- (2,4- (5-tetrazolyl) pyridin-2 (1H) -one, 6- (2,5-dipropoxyphenyl) -3- (5-tetrazolyl) pyridin-2 (1H) , 3,4-trichlorophenyl) -3- (5-tetrazolyl) pyridin-2 (1H) -one, 6- [6- (1,2,3,4-tetrahydronaphthyl)] - 3- (5-tetrazolyl ) pyridine-2 (1H) -one, 6- (3-chlorophenyl) -3- (5-tetrazolyl) pyridin-2 (1H) -one, 6- (3-phenylthiophenyl) -3- (5-tetrazolyl) pyridine-2 (1H) -one, 6- (3-methylthiophenyl) -3- (5-tetrazolyl) pyridin-2 (1H) -one, 3,4-dimethoxyphenyl-3- (5-tetrazolyl) 1H) -one, 6- (3-butylthiophenyl) -3- (5-tetrazolyl) pyridin-2 (1H) -one,

6- (3,4-di-n-propoxyphenyl) -3- (5-tetrazolyl) pyridin-2 (1H) -one, 6- (2,3-di-n-propoxyphenyl) -3- (5-tetrazolyl) pyridine-2 (1H) -one, 6- (3-ethoxyphenyl) -3- (5-methoxyphenyl) -3- (5-tetrazolyl) (3,5-dimethoxyphenyl) -3- (5-tetrazolyl) pyridin-2 (1H) -one, 6- (2-butylthiophenyl) -3- (5- 6- (4-methoxy-2-pentyloxyphenyl) -3-methoxy-2- (1H) -one, 6- (3-allyloxyphenyl) -3- (5-tetrazolyl) pyridin- (5-tetrazolyl) pyridin-2 (1H) -one, 6- (3-iso-butoxy-4-methoxyphenyl) -3- (5-tetrazolyl) -3,5-diethoxyphenyl) -3- (5-tetrazolyl) pyridin-2 (1H) -one, 6- (5-bromo-4-methoxy-2-pentyloxyphenyl) -3- (5-tetrazolyl) pyridin- 2 (1H) -one,

6- (2-allyl-4-methoxy-3-propoxyphenyl) -3- (5-tetrazolyl) pyridin-2 (1H) -one, 6- [3- (El-propenyl) -4-methoxyphenyl] -3- - (5-tetrazolyl) pyridin-2 (1H) -one, 6- (4-methoxy-3-propoxyphenyl) -3- [5- (1-pivaloyloxymethyl) -tetrazoyl) (1H) -one, 6- [3-ethoxy-5- (2-pyridyl) -6- (4-methoxy-3-propoxyphenyl) -3- [5- (2-pivaloyloxymethyl) methoxyphenyl] -3- (5-tetrazolyl) pyridin-2 (1H) -one, 6- [3- (2,2-dimethylpropyloxy) 2- (1H) -one, 6- (3-propionamidophenyl) -3- (5-tetrazolyl) -3- (3-methoxyphenyl) -3- (5-tetrazolyl) pyridin-2 (1H) -one, 6- (4-methoxy-3-propylphenyl) -3- (5-tetrazolyl) pyridin-2 (1H) -one,

7- (3-bromo-4-methoxyphenyl) -3- (5-tetrazolyl) pyridine 6- (3-phenyl-4-methoxyphenyl) -3- (5-tetrazolyl) pyridin-2 (1 H) -one, 6- [4-methoxy-3,5-di (El-propenyl) phenyl] -3- (5-tetrazolyl) pyridin-2 (1H) -one, 6- [3- propenyl) -3-tetrazolyl) pyridin-2 (1H) -one, 6- (3-bromo-4-methoxy-5-propylphenyl) -3- (5-tetrazolyl) 1H) -one 6- (2-butylthio-3,5-diethoxyphenyl) -3- (5-tetrazolyl) pyridin-2 (1H) -one 6- (3-bromo-4-N, N-dimethylaminophenyl) - 6- (3-acetamido-4-methoxy-5-propylphenyl) -3- (5-tetrazolyl) pyridin-2 (1H) -one; 6- [3- (5-tetrazolyl) methoxy-5- (E-propenyl) phenyl] -3- (5-tetrazol-1-yl) pyridin-2 (1H) -one, 6- [3- (E-2-carbamoylethenyl) -4-methoxy -5- (1-propenyl) phenyl] -3- (5-tetrazolyl) pyridin-2 (1H) -one, and 6- (3-cyclopropylmethyloxy-4-methoxyphenyl) pyridin-2 (1H) -one and pharmaceutically acceptable salts.

This invention covers all tautomeric, geometric and optical isomeric forms of the compounds of formula (1). In the particular case where R ° is hydroxy the compound may exist in its tautomeric keto form:

The compounds of formula (1) may form pharmaceutically acceptable base addition salts with metal ions, such as alkali metals, for example sodium or potassium, or with an ammonium ion.

In order to use a compound of formula (1) or a pharmaceutically acceptable salt thereof in the treatment of humans and other mammals, it is normally formulated according to

Common pharmaceutical practice as a pharmaceutical composition.

The compounds of formula (I) and their pharmaceutically acceptable salts may be administered in a common manner for the treatment of the indicated diseases, for example oral, sublingual, parenteral, transdermal or rectally, via inhalation or via oral administration.

The compounds of formula (1) and their pharmaceutically acceptable salts which are active when administered orally or buccally may be suitably formulated in dosage forms such as liquids, syrups, tablets, capsules and lozenges. An oral liquid formulation will generally consist of a suspension or solution of the compound or salt in a liquid carrier, for example, ethanol, glycerin or water with a flavoring or coloring agent. When the composition is in the form of a tablet, any pharmaceutical carrier commonly used in the preparation of solid formulations may be used. Examples of such carriers include starch, celluloses, lactose, sucrose and magnesium stearate. When the composition is in the form of a capsule, any customary capsulation is suitable, for example using the above carriers in a hard gelatin capsule shell. When the composition is in the form of a soft gelatin shell capsule, it may be considered any pharmaceutical carrier commonly used in the preparation of dispersions or suspensions, for example aqueous gums, celluloses, silicates or oils and are incorporated in a soft gelatin capsule shell .

Typical parenteral compositions are a solution or suspension of the compound or salt in a sterile aqueous or non-aqueous carrier optionally containing a parenterally acceptable oil or a solubilizing agent, polyethylene glycol, polyvinylpyrrolidone, lecithin, 2-pyrrolidone, cyclodextrin, peanut oil , or sesame oil.

A typical suppository formulation comprises a compound of formula (1) or a pharmaceutically acceptable salt thereof which is

active agent when administered in this manner, with a binding and / or lubricating agent, for example polymeric glycols, gelatins, cocoa butter or other low melting vegetable waxes or fats or the synthetic analogues thereof.

Typical transdermal formulations comprise a conventional aqueous or non-aqueous carrier, for example, a cream, ointment, lotion or paste or are in the form of a medicated patch, patch or membrane.

Typical inhalation compositions are in the form of a solution, suspension, or emulsion which may be administered in the form of an aerosol using a conventional propellant such as dichlorodifluoromethane or trichlorofluoromethane, or are in the form of a powder for insufflation.

Preferably the composition is in unit dosage forms, for example a metered tablet, capsule or aerosol dose, whereby the patient can self-administer a single dose.

Each dosage unit for oral administration conveniently contains from 0.001 mg / kg to 30 mg / kg, and preferably from 0.005 mg / kg to 15 mg / kg, and each dosage unit for parenteral administration conveniently contains from 0.001 mg / kg to 10 mg / kg of a compound of formula (1) or a pharmaceutically acceptable salt thereof calculated as the free acid. The daily dosage regimen for oral administration is suitably about 0.001 mg / kg to 120 mg / kg of a compound of formula (1) or a pharmaceutically acceptable salt thereof, calculated as the free acid. The daily dosage regimen for parenteral administration is suitably from 0.001 mg / kg to 40 mg / kg, for example about 0.005 mg / kg to 10 mg / kg, of a compound of. formula (1) or a pharmaceutically acceptable salt thereof calculated as the free acid. The active ingredient may be administered as required, for example, 1-8 times per day or by infusion. The compositions of the invention are agonists 73 118 22052 / Ρ30140 -10-

of a cA-PrK and are used to combat conditions where this agonism is believed to be beneficial. Such conditions may be treated by oral, sublingual, rectal, parenteral and inhalation administration. For inhalation administrations the dosages are controlled through a valve, are administered as necessary and for an adult are conveniently in the range 0.1-5.0 mg of a compound of formula (1) or a pharmaceutically acceptable salt thereof .

The compounds of this invention may be co-administered with other pharmaceutically active compounds, for example in combination, concurrently or sequentially. Conveniently, the compounds of this invention and other active compound (s) are formulated into an individual pharmaceutical composition. Examples of compounds which may be included in pharmaceutical compositions with the compounds of formula (1) are bronchodilators such as sympathomimetic amines, for example isoprenaline, isoetharine, sulbutamol, phenylephrine and derivatives of ephedrine or xanthine, for example theophylline and aminophylline, antihistamines, such as those inhibiting the synthesis or inactivation of DNA, for example methotrexate, fluorouracil, cisplatin, actinomycin D, anti-atherosclerotic agents, for example cholesterol-lowering drugs, such as HMGCoA reductase inhibitors, bile acid sequestrants, drugs for the treatment of psoriasis, for example retinoids and anthralin, anti-inflammatories, for example corticosteroids, non-steroidal anti-inflammatory drugs such as aspirin , anti-thrombotic agents, for example dipyridamole or fibrinolytic agents.

In another aspect, the present invention provides a process for the preparation of the compounds of formula (1) or pharmaceutically acceptable salts thereof, which process comprises reacting a compound of formula (2):

NC

OH

Air

In which Ar is as defined above, with an azide salt, and optionally thereafter: formation of a biopercursor of R ° and / or R1 formation of a pharmaceutically acceptable salt.

A compound of formula (2) is suitably reacted with an azide salt such as ammonium, sodium, potassium or aluminum azide in an organic solvent such as dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone or tetrahydrofuran at an elevated temperature, e.g. 40-200øC, preferably at the reflux temperature of the reaction mixture.

A compound of formula (1) wherein R 0 is OH may be converted to the corresponding compound, where R 6 and OR 2 by reaction with R 2 L wherein R 2 is as defined above and L is a leaving group such as halo, for example , bromine, chlorine, iodine.

A compound of formula (1) may be converted to an N-protected tetrazolyl derivative by reaction with a suitable N-protecting agent in a customary manner, for example with a pivaloyloxymethyl halide.

A compound of formula (2) may suitably be prepared by reacting a compound of formula (3):

ArCOCH = CHL1 (3) wherein Ar is as defined above and L1 is a displaceable group, with a compound of formula (4): â € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒH2 CNC0 CH2 CN (4)

In a compound of formula (3), L1 is suitably hydroxy or a derivative thereof, for example L1 is protected hydroxy such as silyloxy, an acid residue (e.g. C1-4 alkanoyloxy) or an ether residue (for example, methoxy or ethoxy). Alternatively, L 1 may be a secondary amino group, for example 73 118 22052 / Ρ 30140 -12-

di-C 1-6 alkylamino such as dimethylamino or a cyclic amino group such as piperidino, pyrrolidino or morpholino. Preferably L · 1 is hydroxy or dimethylamino.

An alkali metal (e.g., sodium) salt of a compound of formula (3) in which L ^ is hydroxy is suitably treated with a compound of formula (4) under mildly alkaline aqueous conditions, for example in water in the presence piperidine and glacial acetic acid at an elevated temperature, for example 30-200øC, preferably at the reflux temperature of the reaction mixture.

Alternatively, a compound of formula (3) wherein L 1 is a secondary amino group, for example dimethylamino, is treated with a compound of formula (4) in a suitable solvent such as dimethylformamide, a C 1-4 -alkyl or pyridine a a high temperature, for example 30-200 DEG C., preferably at the reflux temperature of the reaction mixture, optionally in the presence of a base, such as pyridine or an alkali metal alkoxide, for example sodium methoxide.

Compounds of formula (3) in which L 1 is hydroxy may be suitably prepared by reaction under basic conditions of a compound of formula (5): (5)

ArC0 CH3 in which Ar is as defined above, with a compound of formula HCOL2 wherein L2 is a leaving group. L 2 is suitably ethoxy or methoxy. Conveniently, a solution of a compound of formula (5) and a compound of formula HCOL2 in a suitable organic solvent, such as diethyl ether, is treated with a suitable base such as an alkali metal alkoxide, e.g. room temperature. The resulting reaction mixture is preferably extracted with water and the aqueous extract containing the alkali metal salt of a compound of formula (3) in which L 1 is hydroxy is then treated

With a compound of formula (4) as described above. The compounds of formula (5) are known and may be prepared by methods known in the art.

Compounds of formula (3) in which L 1 is a secondary amino group (e.g., dimethylamino) may be suitably prepared by the reaction of a compound of formula (5) with a compound of the formula (OR 3) 2 L 1 in which R 3 is (OR 3) 2 L 1 is dimethyl diethyl acetal of Ν, Ν-dimethylformamide or), or with a compound of formula HCL 13 where L 1 is a secondary amino group (for example HCL 13 is tridimethylaminomethane).

Alternatively, a compound of formula (2) may be prepared by demethylation of a compound of formula (6):

Ar (6) wherein Ar is as defined above.

Suitable demethylating agents include sodium iodide and chlorotrimethylsilane in an organic solvent such as acetonitrile, or a halohydrocarbon, for example dichloromethane or chloroform, at elevated temperature (for example 30-80 ° C) or ambient, or thiomethoxide of sodium in an organic solvent such as dimethylformamide at an elevated temperature, for example 40-120 ° C. The Ar group in the compounds of formula (2), (5) or (6), preferably (5) or (6) can be appropriately functionalized by aromatic substitution processes known in the art. For example, a bromo group may be introduced into a suitably substituted phenyl ring (for example, 2- and 4-substituted disubstituted by electron donor groups, such as C1-6 alkoxy) by reaction with a brominating agent such as N-bromosuccinimide or bromine in a solvent such as

73 118 22052 / Ρ30140 -14-dimethylformamide. Alternatively, a nitro group may be introduced into a phenyl ring by reaction with a suitable nitrating agent, such as nitronium tetrafluoroborate. Such a group may be rapidly hydrogenated to an amino group which if desired can be converted to an NHCOR group by reaction with LCOR in which L is a leaving group and R is defined as above. Suitable examples of the LCOR reagent include acid halides (L is halo, for example chlorine or bromine) or acid anhydrides (L is OCOR).

Other suitable functionalisations include the introduction of an allyl group ortho to a hydroxy substituent on a phenyl ring by reaction with an allyl halide, for example bromine, to form an allyloxy derivative by heating undergoing a Claisen rearrangement to form an ortho- allyl-hydroxy. the hydroxy group may in turn be functionalized, for example by reaction with a C1-6 alkyl halide to form a C1-6 alkoxy group. If desired, an allyl group may be converted to an E-1-propenyl group by reaction with a strong base, such as sodium methoxide. This may occur during the conversion of a compound of formula (5) into a compound of formula (2) as described above if such a base is used. An El-propenyl group may be cleaved to formyl group by reaction with an oxidizing agent such as N-methylmorpholine-N-oxide in the presence of a catalyst such as osmium tetroxide to form a 1,2-dihydroxypyl group which in reaction with an oxidizing agent such as sodium periodate forms the formyl group. Alternatively the E-1-propenyl group may be directly converted to a formyl group by reaction with a mixture of osmium tetroxide and sodium periodate or by reaction with ozone. A formyl group may in turn be additionally functionalized, for example it may be converted to a hydroxymethyl group by reaction with a suitable reducing agent such as sodium borohydride, subsequently reacting the hydroxymethyl group, for example with an alkyl halide to form an alkoxymethyl group 1-6. Alternatively, a formyl group may be reacted with a suitable Wittig or Wittig reagent such as (R40) 2 P (O) CH2 COO2 or Ph3 P = CHCO2 R4 in

Which R 4 is C 1-4 alkyl to form a CH = CHCO 2 R 4 'group is optionally hydrolyzed to form a -CH = CHCO 2 H group. A -CH = CHCO2 R4 group may be converted to a -CH = CHCONR2 group by reaction with an amine HNR2 or a chemical equivalent thereof, wherein R is defined as above. Alternatively, a -CH = CHCOOH group may be converted to an acid halide, for example the acid chloride, by reaction with oxalyl chloride, which may then be reacted with an amine HNR2 or a chemical equivalent thereof. An example of a chemical equivalent is ammonium hydroxide which will form a CH = CHCONH 2 group.

A compound of formula (6) is suitably prepared by the reaction of a compound of formula (2) wherein Ar is as defined above with an O-methylation agent such as dimethylformamide dimethyl acetal in dimethylformamide or trimethylphosphite at an elevated temperature 40-120 ° C).

The pharmaceutically acceptable base addition salts of the compounds of formula (1) may be prepared by standard procedures, for example by reacting a solution of the compound of formula (1) with a base solution.

The following biological test methods, data and Examples serve to illustrate this invention.

Cyclic-AMP orotein kinase (cA-PrK) aether activity The cA-PrK Type II was prepared from the heart muscle of a cow. The supernatant from a muscle homogenate (3 ml of 10 mM potassium phosphate, 1 mM EDTA per g tissue) was applied to a DEAE-cellulose column equilibrated with the homogenization buffer and the type-A c-PrK was eluted with homogenization buffer containing 350 mM sodium chloride (Rannels et al., 1983, Methods Enzymol., 99, 55-62).

In type IIa cA-PrK was assayed for phosphotransferase activity by incubating the enzyme at 30 ° C for 5 minutes with [γ-32 P] -adenosine triphosphate and a peptide substrate such

(Malencik et al., 1983, Anal Biochem., 132, 34-40). The reaction was quenched by the addition of hydrochloric acid and [32 P] -phosphopeptide was quantified by spotting the reaction mixture on phosphocellulose papers. The concentration of the compound required to give 10% phosphotransferase activation is given as EC10 (μΜ). The compounds of Examples 1 to 26 had EC10 values in the range of 10-130 μΜ.

Inhibition of platelet aggregation Platelet-rich human plasma was separated from freshly collected blood (acid / citrate / dextrose) and treated with 100 μ ace acetylsalicylic acid for 15 minutes at 37 ° C. A washed platelet suspension was then prepared in a Hepes-isotonic saline buffer after a single centrifugation step and adjusted to a concentration of 1.5 × 10 8 cells / ml. Aliquots of this suspension were preincubated with compounds for 5 minutes at 37 ° C, and then challenged with 1.0 μM U46619. The extent of aggregation after 2 minutes was expressed as a percentage of the control and the results obtained are expressed as IC 50 (concentration to cause 50% inhibition of platelet aggregation, μΜ). The compounds of Examples 2, 4, 5, 11-13, 15, 19-23 and 25-26 had IC 50 values in the range of 0.8-300 μΜ.

Anti-proliferative activity

The compounds to be tested were dissolved in dimethylsulfoxide and diluted 1:10 000 with DMEM (Dulbecco's Modified Eagle's Medium) containing 10% fetal bovine serum to obtain concentrations of 12.5, 25, 50 and 100 μΜ used in the assay: Indicator cells consisting of human colorrectal (SW-620, NRK-52 and HT-29) cell lines were plated at a density of 1000 cells in 0.1 ml MEM medium in 96-well plates. Cells were incubated for 4 days at 37 ° C and 10% CO 2 atmosphere. On the fifth day, tetrazolium reagent (50 μg MTT / 250 μl total volume of medium) was added for 16-20 hours. Insoluble formazan was dissolved in 150 μΐ dimethylsulfoxide and the absorbance was measured using a 560 nm microculture plate reader interconnected with an IBM computer. Growth of the cell line and inhibition

Were expressed in terms of mean triple absorbance unit of samples followed by subtraction of mean background absorbance. The IC50 values (concentration exhibiting 50% inhibition growth) were determined from the dose-response curves. (Cancer Res., 48 / 589-601, 1988). In the SW-620 cell line the compound of Example 23 had an IC 50 value in the range of 56-90 μΜ. In the NRK-52 cell line the compound of Example 23 had a JC50 value in the range of 46-48 μΜ. In the HT-29 cell line the compound of Example 23 had an IC50 value in the range of 55-66 μΜ.

Inhibition of spontaneous contraction in the guinea pig colon The guinea pig colon segments (2 cm) were suspended under 2 g of tension in standard organ baths containing Krebs solution. The tissues were connected at the free end to isometric transducers that allow to register and display the voltage developed in chart registers. In-line computer capture and analysis was used to quantify the effects of test compounds on spontaneous contractions. Inhibitory responses were calculated as% of maximum inhibition of spontaneous contraction distance in 3 consecutive readings before and after the 2 minute dose. The concentration of compound which caused 50% inhibition on spontaneous contraction is given as ECjjo (μΜ). The compounds of Examples 5, 15-17 and 23 had EC50 values in the range of 2-25 μ.

Bronchodilatation - In vitro (Traaual Spiral)

Swabs of guinea pig trachea were suspended in standard organ baths containing Krebs solution. The tissues were connected at the free end to isometric transducers that allow to register and display the voltage developed in chart registers. The stress was developed spontaneously and the concentrations of the test compounds were cumulatively added. The concentration of compound which caused 50% inhibition of spontaneously developed stress is given as IC q ((μΜ).

The compounds of Examples 5 and 23 had IC 50 values of 11 and 6.5 μΜ respectively. 73 118 22052 / Ρ30140 -18-

Measurement of cardiac muscle relaxation time in rabbit ventricle

Papillary muscles of right ventricle of albino female rabbits from New Zealand were placed in standard organ baths containing oxygenated Krebs solution. One end of the muscle was attached to an isometric transducer that allows recording the contractile force and its first derivative in chart recorders. Test compounds were added to the bath in a cumulative manner. The relaxation time was calculated as the time taken from the peak tension until the end of the contraction. At concentrations of 30-100 μ, the compounds of Examples 12 and 23 caused a 10-20% decrease in relaxation time indicating a lusitropic effect of the use in the treatment of cardiovascular diseases such as congestive heart failure.

Example 1 6- (3-Methoxyphenyl) -3- (5-tetrazolyl) pyridin-2 (1H) -one a) 3'-Methoxyacetophenone (15 g) and dimethylformamide dimethylacetal (16 ml) were heated together at 120 In dimethylformamide (80 ml) for 6 hours. The dark red solution was diluted with ethyl acetate (400 ml), washed with water (5 x 100 ml), dried (MgSO4) and the solvent was removed under reduced pressure, the obtained oil was dissolved in dimethylformamide (80 ml), and cyanoacetamide (10.08 g) and sodium methoxide (10.8 g) was added and the mixture was heated at 130 ° C for 35 minutes. The dark red solution was poured into 5% aqueous acetic acid (400 ml), the precipitated product collected by filtration and washed with water, ethanol and diethyl ether. Recrystallization from n-butanol gave 3-cyano-6- (3-methoxyphenyl) pyridin-2 (1H) -one (15.14 g), melting point 251 ° C, as a colorless solid. b) 3-Cyano-6- (3-methoxyphenyl) pyridine-2 (1H) -one (1 g), sodium azide (0.39 g) and ammonium chloride (0.32 g) in N-methylpyrrolidin-2-one (10 ml) at 140 ° C for 2 hours. The reaction mixture was poured into 10% aqueous acetic acid (150 ml), and the precipitated solid was collected by filtration, washed with water and recrystallized from n-butanol to give the compound

(DMSO-d 6) 3.87 (s, 3H), 6.92 (d, 1H), 7.98 (d, 1H), 7.98 , 13 (m, 1H), 7.41-7.50 (m, 3H) and 8.48 (d, 1H).

Example 2 6- (3-Propoxyphenyl) -3- (5-tetrazolyl) pyridin-2 (1H) -one a) 3 '-hydroxyacetophenone (13.6 g), iodopropane (10.7 ml) and potassium carbonate (13.8 g) in dimethylformamide (80 ml) at 90 ° C for 20 hours. The reaction mixture was diluted with ethyl acetate (400 ml), washed with 2N sodium hydroxide (2 x 100 ml) and water (4 x 100 ml), dried (MgSO4), filtered and the solvent removed under reduced pressure reduced to give 3'-propoxyacetophenone (16.46) as an oil. NMR (DMSO-d6) 0.99 (t, 3H), 1.66-1.83 (m, 2H), 2.58 (s, 3H), 3.98 (t, 3H) , 7.19 (dd, 1H) and 7.39-7.57 (m, 3H). The following compounds were prepared in a similar manner from phenol and the appropriate alkyl iodide. 3'-Butoxyacetophenone: oil, yield 90%, 1 H NMR δ (DMSO-d6) 0.94 (t, 3H), 1.37-1.52 (m, 2H), 1.66-1, 77 (m, 2H), 2.57 (s, 3H), 4.02 (t, 2H), 7.19 (dd, 1H) and 7.39-7.55 (m, 3H). Benzyloxyacetophenone: oil, 89% yield, 1 H NMR δ (CDCl3) 2.57 (s, 3H), 5.09 (S, 2H), 7.17 (dd, 1H), and 7.29 -7.56 (m, 8H). 4-methoxy-3'-propoxyacetophenone starting from 3'-hydroxy-4'-methoxyacetophenones (A. Brossi et al., J. Org. Chem., 1967, 32, 1269): - oil, 71% yield, 1 H NMR δ (CDCl 3) 1.05 (t, 3H), 1.87 (m, 2H), 2.56 (S, 3H), 3.93 (S, 1H), 4.04 (t, 2H) , 6.88 (d, 1H), 7.52 (d, 1H), and 7.57 (dd, 1H). NMR (DMSO-d6) 0.98 (t, 6H) 1.66-1.80 (m, 4H), 2.55 (s, 3H) , 3.96 (t, 4H), 6.73 (t, 1H) and 7.04 (d, 2H). 3 ', 5'-Diethoxyacetophenone: - oil, yield 64%, 1 H NMR δ (DMSO- d 6) 1.42 (t, 6H), 2.56 (s, 3H), 4.05 (q, 4H) , 6.64 (t, 1H) and 7.07-202.552 / Ρ30140 (d, 2θ). (DMSO-d 6) 0.96 (t, 3H), 1.04 (t, 3H), 1.62-1.84 (m, 4H), 2.55 (s, 3H), 3.88 (t, 2H), 3.99 (t, 2H) and 7.03-7.11 (m, 3H). 37.47-Dipropoxyacetophenone: - 95% yield, 1 H-NMR δ (CDCl3) 1.00-1.19 (m, 6H), 1.78-2.02 (m, 4H), 2.55 (S , 3H), 3.98-4.17 (m, 4H), 6.87 (d, 1H), 7.52 (s, 1H) and 7.54 (d, 1H). 3-allyloxyacetophenone: oil, 71% yield, 1 H NMR δ (CDCl3) 2.58 (s, 3H), 4.57 (d, 2H), 5.27-5.47 (m, 2H ), 5.96-6.15 (m, 1H), 7.12 (dd, 1H), 7.31 (t, 1H) and 7.49-7.55 (m, 2H). 47-Methoxy-27-pentyloxyacetophone: - starting from 47-methoxy-27-hydroxyacetophenone and iodopentane, yield 92%, 1 H NMR δ (DMSO- d 6) 0.86 (t, 3H), 1.20-1, (M, 4H), 1.74-1.85 (m, 2H), 2.49 (s, 3H), 3.82 (s, 3H), 4.09 (t, 2H), 6.56 -6.62 (m, 2H) and 7.66 (d, 1H). 3-iso-butoxy-4-methoxyacetophenone: - starting from 47-methoxy-37-hydroxyacetophenone and isobutyl bromide using acetone as solvent, yield 68%, 1 H NMR δ (DMSO-d 6) δ (S, 3H), 3.76 (s, 3H), 3.78 (d, 1H), 3.86 (s, 3H) 06 (d, 1H), 7.42 (d, 1H) and 7.62 (dd, 1H). 37-Allyloxy-47-methoxyacetophenone: starting from 47-methoxy-37-hydroxyacetophenone and allyl bromide, 67% yield, δ NMR (CDCl3) 2.55 (s, 3H), 3.95 (s, 3H ), 4.63-4.68 (m, 2H), 5.29-5.47 (m, 1H), 6.02-6.18 (m, 1H), 6.90 (d, 1H), 7.53 (d, 1H) and 7.60 (dd, 1H). (2,2-dimethylpropyloxy) -4-methoxyacetophenone: - starting from 47-methoxy-3β-hydroxyacetophenone and 1-bromo-2,2-dimethylpropane, yield 76%, 1 H NMR (CDCl3), Î' , 7 (S, 9H), 2.56 (S, 3H), 3.69 (S, 2H), 6.88 (d, 1H) and 7.50-7.58 (m, 2H). 3-ethoxy-4,7-methoxyacetophenone: - starting from 3, -hydroxy-4, -methoxyacetophenone and iodoethane using acetone as solvent, 83% yield, 1 H NMR δ (CDCl 3): δ , 3H), 4.17 (q, 2H), 6.89 (d, 1H),

1.49 (t, 3H), 2.57 (s, 3H), 3.94-7.53-7.60 (m, 2H). 3-allyl-4-methoxyacetophenone: starting from 3-allyl-4 H -hydroxyacetophenone, yield 87% as an oil. 1 H NMR δ (CDCl 3) 2.55 (s, 3H), 3.40 (d, 2H), 3.89 (s, 3H), 5.02-5.10 (m, 2H), 5.90- 6.04 (m, 1H), 6.88 (d, 1H), 7.77 (d, 1H) and 7.85 (dd, 1H). (b) Starting from 3'-propoxyacetophenone (9 g), after recrystallization from ethanol, 3-cyano-6- (3-propoxyphenyl) pyridin-2 (1H) -one (3.49 g) was prepared. mp 240-241 ° C according to the procedure of Example 1 (a). (c) Starting from 3-cyano-6- (3-propoxyphenyl) pyridin-2 (1H) -one (1 g), after recrystallization from n-butanol, the title compound (0.61 g) mp 270-271 ° C according to the procedure of Example 1 (b).

Example 3 6- (3-butoxyphenyl) -3- (5-tetrazolyl) pyridin-2 (1H) -one (a) 3'-Butoxyacetophenone (17.3 g) and dimethylformamide dimethyl acetal (11.9 g) in dimethylformamide (90 ml) for 15 hours. The dark red solution was cooled to room temperature, cyanoacetamide (8.3 g) and sodium methoxide (10.3 g) were added and the mixture was boiled for an additional 3 hours. The reaction mixture was poured into 10% aqueous acetic acid (300 ml), the precipitated product was filtered off, washed with water and recrystallized from n-butanol to give 3-cyano-6- (3-butoxyphenyl) pyridine -2 (1H) -one (10.66 g) m.p. 201-202 ° C. (b) Starting from 3-cyano-6- (3-butoxyphenyl) pyridin-2 (1H) -one (2.15 g), after recrystallization from n-butanol, the title compound (0.55 g ) m.p. 259-260 ° C, according to the procedure of Example 1 (b).

73 118 22052 / Ρ30140 -22-

Example 4 6- (3-Benzyloxyphenyl) -3- (5-tetrazolyl) pyridin-2 (1H) -one (a) Starting from 3'-benzyloxyphenylacetophenone (20.2 g), after recrystallization from ethanol, the 3-cyano-6- (3-benzyloxyphenyl) pyridin-2 (1H) -one (2.6 g), m.p. 202-203 ° C, according to the procedure of Example 3 (a). (b) Starting from 3-cyano-6- (3-benzyloxyphenyl) pyridin-2 (1H) -one (1 g), after recrystallization from dimethylformamide, the title compound (0.35 g) 276 ° C (decomp.) / According to the procedure of Example 1 (b). 1 H-NMR (DMSO-d 6) 5.23 (S, 2H), 6.91 (d, 1H), 7.16-7.20 (m, 1H), 7.31-7.54 , 8H), 8.47 (d, 1H) and 12.67 (br s, 1H).

Example 5 6- (3-Bromophenyl) -3- (5-tetrazolyl) pyridin-2 (1H) -one (a) Starting from 3'-bromoacetophenone (13.2 g), after recrystallization from n- 3-cyano-6- (3-bromophenyl) pyridin-2 (1H) -one (21.8 g), melting point 309 ° C (decomp.) according to the procedure of Example 1 The). 1H NMR δ (DMSO-d6) 6.89 (br s, 1H), 7.48 (t, 1H), 7.75 (d, 1H), 7.83 (d, 1H), 8.06 (s , 1H), 8.21 (d, 1H), and 12.75 (br s, 1H). (b) Starting from 3-cyano-6- (3-bromophenyl) pyridin-2 (1H) -one (1.37 g), after recrystallization from dimethylformamide, the title compound (0.39 g) of melting point 285-286 ° C according to the procedure of Example 1 (b).

Example 6 6- (3-Trifluoromethyl) -3- (5-tetrazolyl) pyridin-2 (1H) -one (a) Starting from 3-trifluoromethylacetophenone (9.4 g), after recrystallization from ethanol, there was prepared 3-cyano-6- (3-trifluoromethylphenyl) pyridin-2 (1H) -one (11.38 g), melting point 255-256 ° C, according to the procedure of Example 3 (a). (b) Starting from 3-cyano-6- (3-trifluoromethylphenyl) pyridin-2 (1H) -one (1.06 g), after recrystallization from n-butanol, the title compound was prepared (0.93 g) melting point 274-275 ° C, from

According to the procedure of Example 1 (b).

Example 7 6- (3-Ethylphenyl) -3- (5-tetrazolyl) pyridin-2 (1H) -one (a) Starting from 3'-ethylacetophenone (7.4 g) after recrystallization from n-butanol , 3-cyano-6- (3-ethylphenyl) pyridin-2 (1H) -one (3.97 g), melting point 241-242 ° C was prepared according to the procedure of Example 3 (a). ). (b) Starting from 3-cyano-6- (3-ethylphenyl) pyridin-2 (1H) -one (0.89 g), after recrystallization from n-butanol, the title compound (0.37 g ) m.p. 278-279 ° C according to the procedure of Example 1 (b).

Example 8 6- (4-Butoxyphenyl) -3- (5-tetrazolyl) pyridin-2 (1H) -one (a) Starting from 4'-butoxyacetophenone (5.6 g), after recrystallization from ethanol, there was prepared 3-cyano-6- (4-butoxyphenyl) pyridin-2 (1H) -one (1.12 g), melting point 245 ° C according to the procedure of Example 1 (a). (b) A mixture of 3-cyano-6- (4-butoxyphenyl) pyridin-2 (1H) -one (0.3 g), sodium azide (0.098 g), ammonium chloride 08 g) and lithium chloride (0.064 g) in dimethylformamide (15 ml) at 120 ° C for 72 hours. The solvent was removed under reduced pressure, the product precipitated by the addition of 10% aqueous acetic acid (40 ml) and filtered off. The solid was dissolved in 5% potassium hydrogencarbonate and the insoluble material separated by filtration, the filtrate was acidified with concentrated hydrochloric acid, the precipitated product collected by filtration and recrystallized from ethanol to give the title compound (0.05 g ), m.p. 289-292 ° C.

Example 9 6- (4-Isobutylphenyl) pyridin-2 (1H) -one (a) Starting from 4'-isobutylacetophenone (8.8 g), after recrystallization from ethanol, 3-cyano- -iso-butylphenyl) pyridine-2 (1H) -one (6.0 g), melting point 264 ° C,

According to the procedure of Example 3 (a). (b) Starting from 3-cyano-6- (4-isobutylphenyl) pyridin-2 (1H) -one (2.52 g), after recrystallization from dimethylformamide, the title compound (1.54 g) was prepared. melting at 275øC (decomp.) according to the procedure of Example 1 (b), but using dimethylformamide instead of N-methylpyrrolidin-2-one as solvent. Δ NMR δ (DMSO-d 6) 0.89 (d, 6H), 1.81-1.96 (m, 1H), 2.51 (m, 2H), 6.87 (d, 1H) 33 (d, 2H), 7.78 (d, 2H), 8.46 (d, 1H) and 12.63 (br s, 1H).

Example 10 6- (4-Biphenyl) -3- (5-tetrazolyl) pyridin-2 (1H) -one (a) Starting from 4-acetylbiphenyl (19.6 g), after recrystallization from n-butanol, 6- (4-biphenyl) -3-cyanopyrimidin-2 (1H) -one (14.01 g), melting point 312-316 ° C, according to the procedure of Example 1 (a). (b) Starting from 6- (4-biphenyl) -3-cyanopyridin-2 (1H) -one (1.36 g), after recrystallization from dimethylformamide, the title compound (0.84 g) was prepared. melting at 305øC (decomp.), according to the procedure of Example 1 (b). 1H NMR 6 (DMSO-d6) 7.00 (d, 1H), 7.41-7.54 (m, 3H), 7.77 (d, 2H), 7.85 (d, 2H) 98 (d, 2H) and 8.50 (d, 1H).

Example 11 6- (4-Propoxyphenyl) -3- (5-tetrazolyl) pyridin-2 (1H) -one (a) Starting from 4, -propoxyacetophenone (15.4 g) (E. Eckhart and J. Varga, Macryar (3-cyano-6- (4-propoxyphenyl) pyridin-2 (1 H) -one was prepared after recrystallization from dimethylformamide, (1.8 g), mp 262-265øC, according to the procedure of Example 3 (a). (b) Starting from 3-cyano-6- (4-propoxyphenyl) pyridin-2 (1H) -one (1 g), after recrystallization from dimethylformamide, the title compound (0.85 g) 292 ° C (decomp.) According to the procedure of Example 1 (b). 1 H-NMR δ (DMSO-d 6) 0.99

(T, 3H), 1.63-1.84 (m, 2H), 4.02 (t, 2H), 6.81 (d, 1H), 7.07 (d, , 2H), 7.82 (d, 2H), and 8.45 (d, 1H).

Example 12 6- (4-Methoxy-3-propoxyphenyl) -3- (5-tetrazolyl) pyridin-2 (1H) -one (a) Starting from 4-methoxy-3-propoxyacetophenone (12 g) recrystallization from ethanol, 3-cyano-6- (4-methoxy-3-propoxyphenyl) pyridin-2 (1H) -one (14.03 g) was prepared melting at 241 ° C according to the procedure of Example 3 (a). (b) Starting from 3-cyano-6- (4-methoxy-3-propoxyphenyl) pyridin-2 (1H) -one (3.12 g), after recrystallization from n-butanol, the title compound was prepared (1.69 g), m.p. 289-290 ° C, according to the procedure of Example 1 (b).

Example 13 6- (3,4-methylenedioxyphenyl) -3- (5-tetrazolyl) pyridin-2 (1H) -one (a) Starting from 3 ', 4' - (methylenedioxy) acetophenone (16.4 g), then of recrystallization in dimethylformamide, 3-cyano-6- (3,4-methylenedioxyphenyl) pyridine-2 (1H) -one (10.2 g) was prepared melting at < 320 ° C according to the procedure of Example 3 (a). 1 H NMR (DMSOd 6) 6.13 (s, 2H), 6.72 (d, 1H), 7.06 (d, 1H), 7.36-7.42 (m, 2H) 13 (d, 1H) and 12.58 (br s, 1H). (b) Starting from 3-cyano-6- (3,4-methylenedioxyphenyl) pyridin-2 (1H) -one (0.96 g), after recrystallization from ethanol, the title compound (0.1 g) melting point> 325 ° C according to the procedure of Example 1 (b) but using dimethylformamide instead of N-methylpyrrolidione as the solvent. 1 H-NMR δ (DMSO-d6) 6.14 (S, 2H), 6.83 (d, 1H), 7.08 (d, 1H), 7.37-7.46 (m, 2H), 8.43 (d, 1H), 12.55 (br s, 1H) and 13.28 (br s, 1H).

Example 14 6- (3,4-Dichlorophenyl) -3- (5-tetrazolyl) pyridin-2 (1H) -one (a) Starting from 3 '' - dichloroacetophenone (18.9 g), after recrystallization from dimethylformamide , 3-cyano-6- (3,4-dichlorophenyl) pyridine-2 (1H) -one (1.94 g) m.p. 303 ° C was prepared according to the procedure of Example 1 (a). ). 1 H NMR δ 73 118 22052 / Ρ 30140 -26-

(DMSO-d 6) 6.97 (br d, 1H), 7.76-7.87 (m, 2H), 8.15 (s, 1H) and 8.23 (d, 1H). (b) Starting from 3-cyano-6- (3,4-dichlorophenyl) pyridin-2 (1H) -one (1.06 g), after recrystallization from dimethylformamide, the title compound (0.54 g ) melting point 295 ° C (decomp.) according to the procedure of Example 1 (b) but using dimethylformamide instead of N-methylpyrrolidinone as the solvent. ΧΗ NMR δ (DMSO-d 6) 7.02 (d, 1H), 7.76-7.89 (m, 2H), 8.17 (s, 1H) and 8.48 (s, 1H).

Example 15 6- (3,5-Dipropoxyphenyl) -3- (5-tetrazolyl) pyridin-2 (1H) -one (a) Starting from 3 ', 5'-dipropoxyacetophenone (11.82 g), after recrystallization from ethanol was prepared 3-cyano-6- (3,5-dipropoxyphenyl) pyridin-2 (1H) -one (7.1 g) m.p. 209-210 ° C according to the procedure of Example 3 (The). (b) Starting from 3-cyano-6- (3,5-dipropoxyphenyl) pyridin-2 (1H) -one (1.25 g), after recrystallization from n-butanol, the title compound (1, 31 g) mp 224-225 ° C according to the procedure of Example 1 (b).

Example 16 6- (3,5-Diethoxyphenyl) -3- (5-tetrazolyl) pyridin-2 (1H) -one (a) Starting from 3 ', 5'-diethoxyacetophenone (4.16 g), after recrystallization from n-butanol, there was prepared 3-cyano-6- (3,5-diethoxyphenyl) pyridin-2 (1H) -one (1.0 g) m.p. 259-261 ° C according to the procedure of Example 3 (a). (b) Starting from 3-cyano-6- (3,5-diethoxyphenyl) pyridin-2 (1H) -one (0.82 g), after recrystallization from n-butanol, the title compound 57 g), mp 282-283 ° C, according to the procedure of Example 1 (b).

Example 17 6- (3,5-Dibromophenyl) -3- (5-tetrazolyl) pyridin-2 (1H) -one (a) Starting from 3 ', 5'-dibromoacetophenone (M. Tashiro, S. Mataka,

73 118 22052 / Ρ30140 -27- H. Nakamura and K. Nakayama, J. Chem. Soc. Perkin Trans. 1988, 179) (1.11 g), after recrystallization from n-butanol, was prepared 3-cyano-6- (3,5-dibromophenyl) pyridin-2 (1H) -one (0.73 g, g) > 300eC, according to the procedure of Example 3 (a). 1 H NMR δ (DMSO-d6) 7.00 (br d, 1H), 8.02 (s, 1H), 8.09 (s, 2H) and 8.23 (d, 1H). (b) Starting from 3-cyano-6- (3,5-dibromophenyl) pyridin-2 (1H) -one (0.53 g), after recrystallization from n-butanol, the title compound 15 g) mp 295-296 ° C according to the procedure of Example 1 (a). 1 H NMR δ (DMSOd 6) 7.10 (br d, 1H), 8.02 (s, 1H), 8.13 (s, 2H) and 8.47 (d, 1H).

Example 18 6- (2,4-Dipropoxyphenyl) -3- (5-tetrazolyl) pyridin-2 (1H) -one (a) Starting from 2 ', 4'-dipropoxyacetophenone (17.9 g) (P. Chabrier, H. Najer, R. Giudicelli and E. Joannie-Voisinet, Bull Soc. Chim. France, 1958, 1488), after recrystallization from ethanol, 3-cyano-6- (2,4-dipropoxyphenyl) -din-2 (1H) -one (1.69 g), melting point 148 ° C, according to the procedure of Example 3 (a). (b) Starting from 3-cyano-6- (2,4-dipropoxyphenyl) pyridin-2- (1H) -one (1 g), after double recrystallization from ethanol, the title compound (0.60 g ) m.p. 205 ° C, according to the procedure of Example 1 (b).

Example 19 6- (2,5-Dipropoxyphenyl) -3- (5-tetrazolyl) pyridin-2 (1H) -one (a) Starting from 2 ', 5'-dipropoxyphenylacetophenone (11.8 g), after recrystallization from ethanol, 3-cyano-6- (2,5-di-propoxyphenyl) pyridin-2 (1H) -one (14.36 g) was prepared, melting point 160-162 ° C, according to the procedure of Example 3 (a). 1 H NMR δ (DMSO-d6) 0.92 (t, 3H), 0.97 (t, 3H), 1.61-1.76 (m, 4H), 3.92 (t, 4H) 54 (d, 1H), 7.01-7.06 (m, 3H), 8.18 (d, 1H). (b) Starting from 3-cyano-6- (2,5-dipropoxyphenyl) pyridin-2 (1H) -one (2.5 g), after recrystallization from ethanol, the

The title compound (0.81 g), melting point 188-189Â ° C, was obtained according to the procedure of Example 1 (b).

Example 20 6- (2,3,4-Trichlorophenyl) -3- (5-tetrazolyl) pyridin-2 (1H) -one (a) 2 ', 3', 4'-trichloroacetophenone (22.15 g) and dimethylformamide (12.5 g) in dimethylformamide (100 ml) for 3 hours. The solution was diluted with ethyl acetate (500 mL), washed with water (6 x 100 mL), dried (MgSO4), filtered and the solvent removed under reduced pressure. The residue was triturated with diethyl ether to give 3-N, N-dimethylamino-1- (2,3,4-trichlorophenyl) prop-2-en-1-one (17.5 g). 1 H NMR (DMSOd 6) 2.84 (s, 3H), 3.08 (br s, 3H), 5.17 (d, 1H), 7.1 (br. br d, 1H) and 7.65 (d, 1H). (b) A solution of 3-N, N-dimethylamino-1- (2,3,4-trichlorophenyl) prop-2-en-1-one (9.8 g) and cyanoacetamide (3.18 g ) in dimethylformamide (35 ml) for 48 hours. The reaction mixture was poured into 10% aqueous acetic acid (100 ml), the precipitated product was collected by filtration and recrystallized from ethanol to give 3-cyano-6- (2,3,4-trichlorophenyl) pyridin-2 (1H ) -one (4.4 g). λΉ. NMR (DMSOd 6) 6.52 (d, 1H), 7.58 (d, 1H), 7.79 (d, 1H), 8.24 (d, 1H) and 12.95 (br s, 1H). (c) Starting from 3-cyano-6- (2,3,4-trichlorophenyl) pyridin-2 (1H) -one (1.2 g), after recrystallization from dimethylformamide / water, the title compound was prepared 1.21 g) > 300 " C, according to the procedure of Example 1 (a). NMR δ (DMSO-d6) 6.63 (d, 1H), 7.61 (d, 1H), 7.83 (d, 1H), 8.51 (d, 1H) and 12.98 (br s, 1H).

Example 21 6- (6- (1,2,3,4-tetrahydronaphthyl)] - 3- (5-tetrazolyl) pyridin-2 (1H) -one (a) Starting from 6-acetyltetralin (4.23 g ), after recrystallization from n-butanol, 3-cyano-6- [6- (1,2,3,4-tetrahydronaphthyl)] pyridin-2 (1H) -one (1.27 g ) m.p. 245-246 ° C, according to the procedure of Example 3 (a) .1H NMR δ (DMSO-d6) 1.75 (m, 4H), 2.77 (m, 4H), 6.71 (m, d, 1H), 7.19

(D, 1H), 7.50 (d, 1H), 7.55 (s, 1H) and 8.15 (d, 1H). (b) Starting from 3-cyano-6- [6- (1,2,3,4-tetrahydronaphthyl)] pyridin-2 (1H) -one (1 g), after recrystallization from dimethylformamide / water, the title compound (0.55 g) was prepared, melting point 284-285 ° C according to the procedure of Example 1 (b).

EXAMPLE 22 6- (3-Chlorophenyl) -3- (5-tetrazolyl) pyridin-2 (1H) -one (a) Starting from 3'-chloroacetophenone (15.46 g), after recrystallization from n-butanol, prepared from 6- (3-chlorophenyl) -3-cyanopyridin-2 (1H) -one (17.12 g), melting point 304-305 ° C according to the procedure of Example 3 (a). (b) Starting from 6- (3-chlorophenyl) pyridin-2 (1H) -one (1.2 g), after recrystallization from n-butanol, the title compound was prepared (1.01 g) 301-302 ° C, (decomp.), According to the procedure of Example 1 (b). 1H NMR (DMSO-d6): 6.94 (d, 1H), 7.48-7.62 (m, 2H), 7.81 (d, 1H), 7.96 (s, 1H) 48 (d, 1H) and 12.77 (br s, 1H).

Example 23 6- (3-Phenylthiophenyl) -3- (5-tetrazolyl) pyridin-2 (1H) -one (a) Combined 3-phenylthioacetophenone (2.05 g) (L. Victor, 519 354) and dimethylformamide dimethylacetal (1.19 g) in dimethylformamide (10 ml) at 100 ° C for 18 hours. The reaction mixture was diluted with ethyl acetate (50 ml), washed with water (6 x 30 ml), dried (MgSO4), filtered and the solvent removed under reduced pressure. the residue was chromatographed (silica gel, eluent 5% dichloromethane / dichloromethane) to give 3-N, N-dimethylamino-1- (3-phenylthiophenyl) -prop-2-ene-1- (1.72 g) as a yellow oil. (b) A mixture of 3-N, N-dimethylamino-1- (3-phenylthiophenyl) prop-2-en-1-one (1.72 g), sodium methoxide (0.76 g g) and cyanoacetamide (0.59 g) in dimethylformamide (10 ml) for 1 hour. The reaction mixture was poured into

(100 ml), the product precipitated by filtration and recrystallized from ethanol to give 3-cyano-6- (3-phenylthiophenyl) pyridin-2 (1H) -one ( 1.0 g) m.p. 262-264 ° C. (c) Starting from 3-cyano-6- (3-phenylthiophenyl) pyridin-2 (1H) -one (0.79 g), after recrystallization from n-butanol, the title compound (0.77 g ) melting point 265-266 ° C according to the procedure of Example 1 (b).

Example 24 3,4-Dimethoxyphenyl-3- (5-tetrazolyl) pyridin-2 (1H) -one (a) Starting from 3 ', 4'-dimethoxyacetophenone (18 g), after recrystallization from ethanol, was prepared -cyano-6- (3,4-dimethoxyphenyl) pyridin-2 (1H) -one (9.86 g), mp 269-270 ° C, according to the procedure of Example 1 (a). (b) Starting from 3-cyano-6- (3,4-dimethoxyphenyl) pyridin-2 (1H) -one (1.02 g), after recrystallization from dimethylformamide, the title compound (0.02 g ) melting point 293-295 " C, according to the procedure of Example 1 (b).

Example 25 6- (3-Methylthiophenyl) -3- (5-tetrazolyl) pyridin-2 (1H) -one (a) Starting from 3'-methylthioacetophenone (4.64 g), after recrystallization from ethanol, there was prepared 3-cyano-6- (3-methyl-thiophenyl) pyridin-2 (1H) -one (4.3 g) mp 234-238 ° C according to the procedure of Example 3 (a). (b) Starting from 3-cyano-6- (3-methylthiophenyl) pyridin-2 (1H) -one (1 g), after recrystallization from n-butanol, the title compound (0.85 g) was prepared. melting at 274-276 ° C (decomp.) according to the procedure of Example 1 (b). 1 H NMR δ (DMSOd 6) 2.58 (S, 3H), 6.91 (d, 1H), 7.39-7.63 (m, 3H), 7.68 (s, 1H) 47 (d, 1H). 73 118 22052 / Ρ30140

Example 26 6- (3-Butylthiophenyl) -3- (5-tetrazolyl) pyridin-2 (1H) -one (a) Copper (I) n-butylmercaptet (R. Adams, W. Reijschneider and A (3.34 g) and 3-cyano-6- (3-bromophenyl) pyridin-2 (1H) -one (2.61 g, ) in a mixture of quinoline (10 ml) and pyridine (3 ml) at 160 ° C for 4 hours. The reaction mixture was poured into concentrated hydrochloric acid (30 ml) and ice (100 g) and the precipitated material was collected by filtration. The residue was column chromatographed (silica gel, dichloromethane-dichloromethane / 2% ethanol) to give 3-cyano-6- (3-butylthiophenyl) pyridin-2 (1H) -one (0.35 g) mp 191-193 ° C, after recrystallization from ethanol. (b) Starting from 3-cyano-6- (3-butylthiophenyl) pyridin-2 (1H) -one (0.23 g), after recrystallization from n-butanol, the title compound (0.11 g ) melting point 237-238 ° C according to the procedure of Example 1 (b).

Example 27 6- (3,4-Dipropoxyphenyl) -3- (5-tetrazolyl) pyridin-2 (1H) -one (a) Starting from 3 ', 4'-dipropoxyacetophenone (3.6 g), after recrystallization from ethanol, 3-cyano-6- (3,4-dipro-poxyphenyl) -pyridin-2 (1H) -one (3.21 g) was prepared melting at 249 ° C according to the procedure of Example 3 (The). (b) Starting from 3-cyano-6- (3,4-dipropoxyphenyl) pyridin-2 (1H) -one (1.00 g), after recrystallization from n-butanol, the title compound was obtained, starting from melting at 280 ° C (decomp.), according to the procedure of Example 1 (b). 1 H-NMR (d6-DMSO) 0.97-1.05 (m, 6H), 1.71-1.81 (m, 4H), 4.01 (t, 2H), 4.03 (t, 2H ), 6.88 (d, 1H), 7.09 (d, 1H), 7.43 (d, 1H), 7.46 (s, 1H), 8.44 (d, 1H) and 12.61 (br s, 1H).

Example 28 6- (2,3-Dipropoxyphenyl) -3- (5-tetrazolyl) pyridin-2 (1H) -one (a) Starting from 2,3-dihydroxybenzaldehyde (20 g) -dipropoxybenzaldehyde (18.6 g) isolated as an oil, according to the procedure of Example 2 (a). 1 H NMR (CDCl 3) 1.04

73 118 22052 / Ρ30140 -32-

7.03-7.16 (m, 2H), 7.39 (dd, 1H) and 10.47 (s, 1H). (b) To a solution of 2,3-dipropoxybenzaldehyde (18.6 g) in tetrahydrofuran at -78 " C was added methyl lithium (61 ml, 1.5M in diethyl ether) for 10 minutes. The reaction mixture was stirred at -78 ° C for two hours and at room temperature for 16 hours. After quenching with water, the organic phase was separated, dried (MgSO4) and solvent removed to give 1- (2,3-dipropoxyphenyl) -1-hydroxyethane (20 g) as an oil. 1 H NMR δ (CDCl 3) 1.04 (t, 3H), 1.06 (t, 3H), 1.72-1.93 (m, 4H), 3.89 (t, 2H), 3. , 99 (t, 2H), 5.15 (m, 1H), 6.80 (m, 1H) and 6.95-7.04 (m, 2H). (c) To a solution of 1- (2,3-dipropoxyphenyl) -1-hydroxyethane (20 g) in ice cold dichloromethane (250 ml), powdered molecular sieves (23 g) was added N- methylmorpholine-N-oxide (14.9 g) and tetrapropylammonium perruthenate (1 g). The mixture was stirred for one hour with ice-cooling and at room temperature overnight. After filtration through Hyflo solvent, the solvent was removed under reduced pressure to give 2 '' '- dipropoxyacetophenone (18.3 g). 1 H NMR δ (CDCl 3) 1.03 (t, 3H), 1.08 (t, 3H), 1.72-1.96 (m, 4H), 2.63 (s, 3H) 96 (t, 2H), 4.01 (t, 2H), and 6.99-7.19 (m, 3H). (d) Starting from 2 ', 3' -dipropoxyacetophenone (10 g) was prepared 3-cyano-6- (2,3-dipropoxyphenyl) pyridin-2 (1H) -one (1.87 g) 195-198 ° C according to the procedure of Example 3 (a), omitting the sodium methoxide. NMR (d6 -DMSO) 0.81 (t, 3H), 1.01 (t, 3H), 1.51 (m, 2H), 1.76 (m, 2H), 3.84 (t 2H), 6.43 (d, 1H), 6.97 (d, 1H), 7.10-7.27 (m, 2H) and 8.17 (d, 1H). (e) Starting from 3-cyano-6- (2,3-dipropoxyphenyl) pyridin-2 (1H) -one (1 g), after recrystallization from aqueous ethanol, the title compound (0.47 g) mp 186-187 ° C according to the procedure of Example 1 (b). 73 118 22052 / Ρ30140 -33-

Example 29 6- (3-Cyclopentyloxy-4-methoxyphenyl) -3- (5-tetrazolyl) pyridin-2 (1H) -one A mixture of 3β-hydroxy-4-methoxyacetophenone (20.8 g ), potassium carbonate (24.15 g), cyclopentyl bromide (22.35 g) and potassium iodide (3.32 g) were combined in acetone (250 ml) and boiled for 24 hours. Dimethylformamide (25 ml) was added and the boil continued for another 24 hours. The reaction mixture was cooled to room temperature, filtered and the solvent was removed under reduced pressure. The residue was dissolved in diethyl ether (200 mL), washed with 2N sodium hydroxide (3 x 50 mL) and water, and the solvent was removed under reduced pressure to give 3β-cyclopentyloxy-4-methoxyacetophenone as a oil which solidifies on standing, mp 59-60 ° C. (b) Starting from 3? -cyclopentyloxy-4'-methoxyacetophenone (11.25 g), after digestion with acetonitrile, 3-cyano-6- (3-cyclopentyloxy-4-methoxyphenyl) pyridin-2 (1H) -one (4.07 g), melting point 259-260 ° C, according to the procedure of Example 3 (a), omitting sodium methoxide. (c) Starting from 3-cyano-6- (3-cyclopentyloxyphenyl-4-methoxyphenyl) pyridin-2 (1H) -one (0.8 g), after recrystallization from dimethylformamide, the title compound was prepared 0.6 g), m.p. 286-287Â ° C, (decomp.), According to the procedure of Example 1 (b). 1 H NMR δ (d6 -DMSO) 1.54-2.02 (m, 8H), 3.83 (s, 3H), 5.00 (m, 1H), 6.87 (d, 1H) 10 (d, 1H), 7.43 (s, 1H), 7.46 (d, 1H) and 8.44 (d, 1H).

Example 30 6- (3-Ethoxyphenyl) -3- (5-tetrazolyl) pyridin-2 (1H) -one (a) A mixture of 3-hydroxyacetophenone (6.8 g) and tris (dimethylamino) ) methane (14.5 g) in dimethylformamide (30 ml) at 80 ° C for 4 hours. The reaction mixture was cooled to room temperature, cyanoacetamide (8.4 g) was added and the mixture was boiled for 8 hours. After cooling to room temperature the mixture was poured into 10% aqueous acetic acid (200 ml), filtered and the residue washed with water and ethanol to give 3-cyano- 6- (3-hydroxyphenyl) pyridin-2 (1H) -one. Δ NMR δ (d 6 -DMSO) 6.64 (br.d, 1H), 6.95 (dd, 1H), 7.12 (s, 1H), 7.20 (d, 1H), 7.32 (d, t, 1H), 8.15 (d, 1H), 9.87 (s, 1H) and 12.70 (br.s, 1H). To a suspension of sodium hydride (1 g, 50% in oil) in dimethylformamide (15 ml) was added portionwise 3-cyano-6- (3-hydroxyphenyl) pyridin-2 (1H) -one ( 2.12 g) for 30 minutes. When gas evolution subsided, iodoethane (1.56 g) was added and the mixture was stirred overnight. The mixture was diluted with ethyl acetate (100 ml), washed with 2N hydrochloric acid (2 x 30 ml) and water (4 x 50 ml), dried (MgSO4) and the solvent was removed under reduced pressure. The residue was recrystallized from n-butanol to give 3-cyano-6- (3-ethoxyphenyl) pyridin-2 (1H) -one (0.68 g). 1 H NMR δ (d 6 -DMSO) 1.35 (t, 3H), 4.12 (q, 2H), 6.80 (d, 1H), 7.08 (d, 1H), 7.31-7.70 47 (m, 3H) and 8.18 (d, 1H). (c) Starting from 3-cyano-6- (3-ethoxyphenyl) pyridin-2 (1H) -one (0.5 g), after recrystallization from n-butanol, the title compound (0.44 g ) m.p. 279 ° C (decomp.), according to the procedure of Example 1 (b). 1 H NMR δ (d 6 -DMSO) 1.36 (t, 3H), 4.14 (q, 2H), 6.90 (d, 1H), 7.10 (m, 1H), 7.34- 7.48 (m, 3H) and 8.47 (d, 1H).

Example 31 6- (3,5-Dimethoxyphenyl) -3- (5-tetrazolyl) pyridin-2 (1H) -one (a) Starting from 3β, 5'-dimethoxyacetophenone (4.1 g), after recrystallization from ethanol, 3-cyano-6- (3,5-dimethoxyphenyl) pyridin-2 (1H) -one (2.41 g) was prepared melting point 297 ° C according to the procedure of Example 3 (a). ). (b) Starting from 3-cyano-6- (3,5-dimethoxyphenyl) pyridin-2 (1H) -one (1.4 g), after recrystallization from acetonitrile / dimethylformamide, the title compound was prepared 1.36 g), melting point 338 ° C (decomp.), According to the procedure of Example 1 (b). 1 H NMR δ (d6 -DMSO) 3.86 (s, 6H), 6.66 (m, 1H), 6.95 (d, 1H), 7.02 (m, 2H), 8.47 (d, 1 H) and 12.66 (br.s, 1H).

73 118 22052 / Ρ30140 -35-

Example 32 6- (2-Butylthiophenyl) -3- (5-tetrazolyl) pyridin-2 (1H) -one (a) Starting from 27-bromoacetophenone (19.9 g), after recrystallization from ethanol, 6- (2-bromophenyl) -3-cyanopyridin-2 (1H) -one (11.4 g), mp 245-246øC, according to the procedure of Example 1 (a). (b) Starting from 6- (2-bromophenyl) -3-cyanopyridin-2 (1H) -one (2.61 g), after recrystallization from ethanol, 6- (2-butylthiophenyl) -3-cyanopyridin- 2 (1H) -one (0.83 g), mp 163-165 ° C, according to the procedure of Example 26 (a). (c) Starting from 6- (2-butylthiophenyl) -3-cyanopyridin-2 (1H) -one (0.71 g), after recrystallization from ethanol, the title compound (0.53 g) was prepared. mp 181-182 ° C according to the procedure of Example 1 (b).

Example 33 6- (3-Allyloxyphenyl) -3- (5-tetrazolyl) pyridin-2 (1H) -one (a) Starting from 37-allyloxyacetophenone (15.07 g) was prepared 6- (3-allyloxyphenyl) -3 -cyanopyridin-2 (1H) -one (147 g) according to the procedure of Example 3 (a). 1 H NMR δ (d 6 -DMSO) 4.67 (d, 2H), 5.26-5.46 (m, 2H), 5.98-6.20 (m, 1H), 6.80 (d , 1H), 7.13 (m, 1H), 7.33 (m, 3H) and 8.20 (d, 1H). (b) Starting from 6- (3-allyloxyphenyl) -3-cyanopyridin-2 (1H) -one (1 g), after recrystallization from n-butanol, the title compound (0.34 g) was prepared. melting at 260 ° C (decomp.), according to the procedure of Example 1 (b). % NMR δ (d6 -DMSO) 4.72 (m, 2H), 5.28-5.52 (m, 2H), 6.04-6.20 (m, 1H), 6.94 (d, 1H ), 7.14 (m, 1H), 7.48 (m, 3H) and 8.47 (d, 1H).

Example 34 6- (4-Methoxy-2-pentyloxyphenyl) -3- (5-tetrazolyl) pyridin-2 (1H) -one (a) Starting from 47-methoxy-2-pentyloxyacetophenone (11.8 g), then of recrystallization from ethanol, 3-cyano-6- (4-methoxy-2-pentyloxyphenyl) pyridin-2 (1H) -one (3.4 g) was prepared melting at 143-144 ° C according to the procedure of Example

3 (a). (b) Starting from 3-cyano-6- (4-methoxy-2-pentyloxyphenyl) pyridin-2 (1H) -one (1.25 g), after recrystallization from ethanol, the title compound was prepared 0.65 g), mp 193-194øC, according to the procedure of Example 1 (b).

EXAMPLE 35 6- (3-Iso-butoxy-4-methoxyphenyl) -3- (5-tetrazolyl) pyridin-2 (1H) -one (a) Starting from 3'-iso -butoxy-4'-methoxyacetophenone (7, 6 g), after recrystallization from ethanol, 3-cyano-6- (3-iso-butoxy-4-methoxyphenyl) pyridin-2 (1H) -one (6.02 g) was prepared, melting point 234-235 According to the procedure of Example 3 (a). (b) Starting from 3-cyano-6- (3-iso-butoxy-4-methoxyphenyl) pyridine-2 (1H) -one (1.19 g), after recrystallization from ethanol, the title compound (1.2 g) m.p. 296-297 ° C (decomp.) According to the procedure of Example 1 (b). NMR (DMSO-d6) 1.01 (d, 6H), 2.02-2.16 (m, 1H), 3.85 (s, 3H), 3.89 (d, 2H), 6.89 (d, 1H), 7.12 (d, 1H), 7.41-7.50 (m, 2H) and 8.47 (d, 1H).

Example 36 6- (2-bromo-3,5-diethoxyphenyl) -3- (5-tetrazolyl) pyridin-2 (1H) -one To a solution of 3 ', 5'-diethoxyacetophenone (10.4 g ) in ice-cold dimethylformamide (50 ml) was added portionwise N-bromosuccinimide (9.79 g) for one hour. The mixture was stirred at 0 ° C for 3 hours and kept at room temperature for 48 hours. After dilution with ethyl acetate (200 ml), the mixture was washed with water (5 x 100 ml), dried (MgSO4) and the solvent removed under reduced pressure to give 2'-bromo-3 ', 5'- diethoxyacetophenone (12.53 g) as an oil. 1 H NMR δ (CDCl 3) 1.41 (t, 3H), 1.50 (t, 3H), 2.60 (s, 3H), 4.00 (q, 2H), 4.10 2H), 6.45 (d, 1H) and 6.50 (d, 1H). (b) Starting from 2'-bromo-3 ', 5'-diethoxyacetophenone (4.31 g), after recrystallization from ethanol, 3-cyano-6- (2-bromo-3,5-diethoxyphenyl) pyridine -2 (1H) -one (0.75 g), melting point 234-235 ° C according to the procedure of Example

73 118 -37- 22052 / Ρ30140 3 (a). (c) Starting from 3-cyano-6- (2-bromo-3,5-diethoxyphenyl) pyridin-2 (1H) -one (0.6 g), after recrystallization from ethanol, the title compound, of melting point 276 " C, according to the procedure of Example 1 (b).

Example 37 6- (5-Bromo-4-methoxy-2-pentyloxyphenyl) -3- (5-tetraazolyl) pyridin-2 (1H) -one A mixture of 3-cyano-6- (4- methoxy-2-pentyloxyphenyl) pyridine-2 (1H) -one (1.71 g), silver carbonate (1.92 g) and iodomethane in chloroform (30 ml) was stirred in the dark for 48 hours. After filtration (celite pad) the solvent was removed under reduced pressure and the residue was column chromatographed (silica gel, eluent 40% hexane / dichloromethane) to give 3-cyano-2-methoxy-6- ( 4-methoxy-2-pentyloxyphenyl) pyridine (1.45 g), melting point 76-78 ° C. (b) To a solution of 3-cyano-2-methoxy-6- (4-methoxy-2-pentyloxyphenyl) pyridine (1.3 g) in dimethylformamide (10 ml), cooled (ice bath), N-bromosuccinimide (0.71 g) was added portionwise over 30 minutes. The solution was stirred at room temperature overnight, diluted with ethyl acetate (50 mL) and washed with water (5 x 50 mL). The organic phase was dried (MgSO4), the solvent was removed under reduced pressure and the residue recrystallized from ethanol to give 3-cyano-2-methoxy-6- (5-bromo-4-methoxy-2-pentyloxyphenyl) pyridine ( 1.1 g), m.p. 136-137 ° C. (c) 3-cyano-2-methoxy-6- (2-bromo-4-methoxy-2-pentyloxyphenyl) pyridine (1 g) and sodium iodide (1.50 g) (dried at 70 ° C in vacuo for 4 hours) were dissolved in acetonitrile (10 ml) and chlorotrimethylsilane (1.08 g) was added. The reaction mixture was stirred in the dark for 2 hours, diluted with ethyl acetate (50 ml), washed with water (2 x 50 ml), 5% aqueous sodium metabisulfite (30 ml) and water (50 ml). The organic phase was dried (MgSO4), the solvent was removed under reduced pressure, and the organic layer was dried (MgSO4)

The residue was recrystallized from ethanol to give 3-cyano-6- (5-bromo-4-methoxy-2-pentyloxyphenyl) pyridin-2 (1H) -one (0.55 g), m.p. 188-190 ° C. (d) Starting from 3-cyano-6- (5-bromo-4-methoxy-2-pentyloxy-phenyl) pyridin-2 (1H) -one (0.5 g), after recrystallization from ethanol, the title compound (0.38 g), m.p. 246-248 ° C, according to the procedure of Example 1 (b).

Example 38 6- (2-Allyl-4-methoxy-3-propoxyphenyl) -3- (5-tetraazolyl) pyridin-2 (1H) -one (a) A mixture of 3β-allyloxy-4β-methoxyacetophenone (7.76 g) and diethylaniline (5.96 g) was degassed with nitrogen for 15 minutes and heated at 215 ° C for 90 minutes. After cooling to room temperature, the reaction mixture was dissolved in ethyl acetate (100 ml) and washed with 2N hydrochloric acid (3 x 100 ml). The organic phase was dried (MgSO4) and the solvent removed under reduced pressure to give, after recrystallization from ethanol / water, 2'-allyl-3'-hydroxy-4'-methoxyacetophenone (5.1 g), item 81-83 ° C. (b) 2'-Allyl-3'-hydroxy-4'-methoxyacetophenone (5.0 g), potassium carbonate (3.3 g) and iodopropane were heated together in a mixture of dimethylformamide (20 ml) and butanone (30 ml) for 48 hours. The mixture was filtered and the solvent was removed from the filtrate under reduced pressure to give a residue which was dissolved in ethyl acetate (100 ml) and washed with water (5 x 50 ml). The organic phase was dried (MgSO4) and the solvent was removed under reduced pressure to give 2-allyl-4-methoxy-3-propoxyacetophenone (5.0 g) as an oil. Δ (DMSO-d6) 0.98 (t, 3H), 1.62-1.80 (m, 2H), 2.48 (s, 3H), 3.62-3.69 (m, 2H ), 3.79 (t, 2H), 3.85 (s, 3H), 4.82-4.91 (m, 2H), 5.78-5.93 (m, 1H), 6.99 ( d, 1H) and 7.63 (d, 1H). (c) Starting from 2-allyl-4-methoxy-3'-propoxyacetophenone (4.96 g), after recrystallization from ethanol, 3-cyano-6- (2-allyl-4-methoxy-3- -propoxyphenyl) pyridin-2 (1H) -one (1.15 g), m.p. 170-171 ° C, according to the procedure of Example

3 (a), however, omitting sodium methoxide. (d) Starting from 3-cyano-6- (2-allyl-4-methoxy-3-propoxyphenyl) pyridin-2 (1H) -one (0.49 g), after recrystallization from ethanol, the compound of the title (0.24 g), m.p. 210-211 ° C, according to the procedure of Example 1 (b).

Example 39 6- [3- (El-propenyl) -4-methoxyphenyl] -3- (5-tetrazolyl) pyridin-2 (1H) -one (a) Starting from 3-allyl-4-methoxyacetophenone (7, 6 g), after recrystallization from n-butanol, 3-cyano-6- [3- (3-propenyl) -4-methoxyphenyl] pyridin-2 (1H) -one (4 g) was prepared according to the procedure of Example 3 (a). NMR (DMSO-d6) 1.88 (d, 3H), 3.87 (s, 3H), 6.40-6.67 (m, 3H), 6.78 (d, 1H), 7 , 10 (d, 1H), 7.72 (dd, 1H), 7.93 (d, 1H) and 8.14 (d, 1H). (b) Starting from 3-cyano-6- [3- (1-propenyl) -4-methoxyphenyl] pyridin-2 (1H) -one (2.13 g), after recrystallization from dimethylformamide, the title compound of the title (0.8 g), m.p. 291-295 ° C (decomp.), according to the procedure of Example 1 (b). 1 H NMR δ (DMSO-d 6), 1.89 (d, 3H), 3.88 (S, 3H), 6.42-6.71 (m, 3H), 6.90 (d, 1H), 7 , 12 (d, 1H), 7.76 (dd, 1H), 7.97 (d, 1H) and 8.44 (d, 1H).

Example 40 6- (4-methoxy-3-propoxyphenyl) -3- [5- (1-pivaloyloxymethyl) -tetrazoyl] pyridin-2 (1H) -one and 6- (4-methoxy-3-propoxyphenyl) - 3- [5- (2-pivaloyloxymethyl) -tetrazolyl] pyridin-2 (1H) -one.

A mixture of (4-methoxy-3-propoxyphenyl) -3- (5-tetrazolyl) pyridin-2 (1H) -one (1.64 g), pivaloyloxymethyl chloride (0.75 g), sodium hydrogen carbonate 420 mg) and sodium iodide (50 mg) was heated in dimethylformamide (5 ml) at 70 ° C for 24 hours. The mixture was diluted with ethyl acetate (50 ml) and washed with water (6 x 50 ml). The organic phase was dried (MgSO4), filtered and the solvent was removed under reduced pressure. The residue was column chromatographed (silica gel, eluent, 70% hexane-ethyl acetate-hexane / ethyl acetate) to afford: a) 73 118 22052 /

6- (4-methoxy-3-propoxyphenyl) -3- [5- (1-pivaloyloxymethyl) -tetrazolyl] pyridin-2 (1H) -one (0.26 g), mp 169-170 ° C (b) 6- (4-methoxy-3-propoxy-phenyl) -3- (2-pivaloyloxymethyl) -tetrazolyl] -pyridin-2 (1 H) -one (0.35 g), after recrystallization from ethanol, mp 195-196 ° C, after recrystallization from ethanol.

Example 41 6- [3-Ethoxy-5- (2-methoxyethoxy) phenyl] -3- (5-tetrazolyl) pyridin-2 (1H) -one (a) 3 ', 5'-Dihydroxyacetophenone 15.2 g), potassium carbonate (7.59 g) and iodoethane (17.16 g) and heated at reflux for 15 hours. Additional potassium carbonate (2.76 g) and iodoethane (6.2 g) were added and heating was continued for a further 10 hours. The reaction mixture was filtered, the solvent was removed under reduced pressure, the residue was dissolved in ethyl acetate (100 ml) and extracted with 2N sodium hydroxide (3 x 50 ml). The combined basic extracts were washed with ethyl acetate (2 x 50 ml), acidified with 2N hydrochloric acid and extracted with dichloromethane (3 x 100 ml). The combined dichloromethane extracts were washed with water (2 x 50 mL), dried (MgSO4), filtered and the solvent removed under reduced pressure. The residue was column chromatographed (silica gel, eluent dichloromethane) to give 3'-ethoxy-5'-hydroxyacetophenone (4.83 g), m.p. 96-98 ° C. (b) To a suspension of sodium hydride (0.92 g, 60% in oil, washed with hexane) in dimethylformamide (10 ml) was added 3'-ethoxy-5'-hydroxyacetophenone (3.24 g) for 10 minutes. When the gas evolution subsided, chloroethyl methyl ether (1.9 g) and sodium iodide (50 mg) were added and the mixture was heated at 90øC for 18 hours and stirred at room temperature for 24 hours. The mixture was diluted with ethyl acetate (100 mL), washed with 2N sodium hydroxide (3 x 50 mL) and water (3 x 50 mL). The organic phase was dried (MgSO4), filtered and the solvent was removed under reduced pressure to give 3β-ethoxy-5β- (2-methoxyethoxy) acetophenone (4.03 g) as a white solid (738 Λ 22052 / Ρ 30140 ff

-43- JST oil. 1 H NMR (CDCl 3) 1.42 (t, 3H), 2.56 (s, 3H), 3.4 (s, 3H), 3.74-3.78 (m, 2H) (Q, 2H), 4.13-4.17 (m, 2H), 6.68 (m, 1H), and 7.10 (m, 2H). (c) Starting from 3-ethoxy-5 - (2-methoxyethoxy) acetophenone, after recrystallization from ethanol, 3-cyano-6- [3-ethoxy-5- (2-methoxyethoxy) phenyl] pyridin-2 (1H) -one (1.1 g), melting point 199 ° C, according to the procedure of Example 3 (a). (d) Starting from 3-cyano-6- [3-ethoxy-5- (2-methoxyethoxy) phenyl] pyridin-2 (1H) -one (0.94 g), after recrystallization from ethanol, the title compound (0.6 g) m.p. 205-206 ° C according to the procedure of Example 1 (b).

Example 42 6- (3- (2,2-dimethylpropyloxy) -4-methoxyphenyl) -3- (5-tetraazolyl) pyridin-2 (1H) -one (a) Starting from 3 '- (2,2- dimethylpropyloxy) -4-methoxyacetophenone (9.0 g) was prepared 3-cyano-6- [3- (2,2-dimethylpropyloxy) -4-methoxyphenyl] pyridin-2 (1H) -one (3.46 g, g) according to the procedure of Example 3 (a). 1 H NMR δ (DMSO-d6) 1.02 (s, 9H), 3.74 (s, 2H), 3.85 (s, 3H), 6.79 (d, 1H), 7.09 ( d, 1H), 7.42 (s, 1H), 7.43 (d, 1H) and 8.14 (d, 1H). (b) Starting from 3-cyano-6- [3- (2,2-dimethylpropyloxy)

-4-methoxyphenyl] pyridin-2 (1H) -one (1.25 g), after recrystallization from n-butanol, the title compound was prepared (1.28 g) > 300 ° C, according to The title compound was prepared according to the procedure of Example 1 (b). 1 H NMR δ (DMSO-d6) 1.04 (s, 9H), 3.77 (S, 2H), 3.86 (s, 3H), 6.90 (d, 1H), 7.10 ( d, 1H), 7.45 (m, 2H) and 8.44 (d, 1H).

Example 43 6- (3-Ethoxy-4-methoxyphenyl) -3- (5-tetrazolyl) pyridin-2 (1H) -one (a) Starting from 3-ethoxy-4-methoxyacetophenone (2.91 g), after recrystallization from ethanol, 3-cyano-6- (3-ethoxy-4-methoxyphenyl) pyridin-2 (1H) -one (2.02 g) was prepared melting at 273øC according to The title compound was prepared according to the procedure of Example 1 (a).

(B) Starting from 3-cyano-6- (3-ethoxy-4-methoxyphenyl) pyridin-2 (1H) -one (1.0 g) after recrystallization from n-butanol , the title compound (1.06 g) was prepared melting at 299øC (decomp.) according to the procedure of Example 1 (b). 1 H NMR δ (DMSO-d 6) 1.37 (t, 3H), 3.84 (s, 3H), 4.15 (q, 2H), 6.92 (d, 1H), 7.10 (d, d, 1H), 7.41-7.50 (m, 2H) and 8.43 (d, 1H).

Example 44 6- (3-Propionamidophenyl) -3- (5-tetrazolyl) pyridin-2 (1H) -one (a) To a stirred suspension of sodium methoxide (4.32 g) in diethyl ether (50 ml) was A mixture of 3'-propionamidoacetophenone (5.73 g) and ethyl formate (4.44 g) in tetrahydrofuran (100 ml) was added over 30 minutes. After stirring overnight, the mixture was filtered and the residue washed with diethyl ether. The residue was dissolved in water (50 ml), the pH adjusted to 9.0 with glacial acetic acid and cyanoacetamide (4.2 g) was added. The obtained solution was boiled overnight, cooled to room temperature and the pH adjusted to 5 with glacial acetic acid (U.S. Patent 4,278,681). The precipitated material was collected by filtration, washed carefully (4 x 50 ml) with ethanol and recrystallized from dimethylformamide / water to give 3-cyano-6- (3-propionamidophenyl) pyridin-2 (1H) -one (0.4 g) melting point 328-330 ° C. (b) Starting from 3-cyano-6- (3-propionamidophenyl) pyridin-2 (1H) -one (0.3 g), after recrystallization from dimethylformamide / water, the title compound (0.2 g) mp 291-293øC (decomp.), according to the procedure of Example 1 (b). 1 H NMR δ (DMSO-d6) 1.11 (t, 3H), 2.37 (q, 2H), 6.75 (d, 1H), 7.46 (m, 2H), 7.69 ( m, 1H), 8.09 (m, 1H) and 8.50 (d, 1H).

EXAMPLE 45 6- (4-Methoxy-3-propylphenyl) -3- (5-tetrazolyl) pyridin-2 (1H) -one (SB 20525) (a) A solution of 3'-allyl-4'-methoxyacetophenone ( 20 g) in ethanol (250 ml) containing 10% palladium on charcoal (2 g) was treated with hydrogen at 50 psi until the calculated volume of hydrogen was incorporated. The mixture was filtered 43- 73 118 22052 / Ρ30140

(celite pad) and the solvent was removed under reduced pressure. The residue was dissolved in dichloromethane (100 ml) and manganese dioxide (60 g) was added. The mixture was stirred at room temperature for 48 hours, filtered (celite pad) and the solvent was removed under reduced pressure to give 4'-methoxy-3β-propylacetophenone (15.16 g) as an oil. 1 H NMR (CDCl 3) 0.95 (t, 3H), 1.52-1.79 (m, 2H), 2.55 (s, 3H), 2.61 (t, 2H), 3.88 s, 3H), 6.86 (d, 1H), 7.77 (d, 1H) and 7.82 (dd, 1H). (b) Starting from 4-methoxy-3-propylacetophenone (5.77 g), after recrystallization from butanol, 3-cyano-6- (4-methoxy-3-propylphenyl) pyridin-2 (1H) -one (4.43 g), mp 239øC, according to the procedure of Example 3 (a). (c) Starting from 3-cyano-6- (4-methoxy-3-propylphenyl) pyridin-2 (1H) -one (4.02 g), after recrystallization from ethanol, the title compound 64 g) mp 293-294 ° C (decomp.), According to the procedure of Example 1 (b). Δ NMR (DMSO-d6) 0.93 (t, 3H), 1.51-1.71 (m, 2H), 2.59 (t, 2H), 3.87 (s, 3H) 83 (d, 1H), 7.10 (d, 1H), 7.68-7.74 (m, 2H) and 8.46 (d, 1H).

Example 46 6- (3-Bromo-4-methoxyphenyl) -3- (5-tetrazolyl) pyridin-2 (1H) -one (SB 204617) (a) Starting from 3β-bromo-4-methoxyacetophenone (KW Rosenmund et al., Chem., 1922, 90, 1957) (2.29 g), after recrystallization from ethanol, was prepared 3-cyano-6- (3-bromo-4-methoxyphenyl) 1H) -one (1.42 g), melting point 284-286 ° C, according to the procedure of Example 3 (a). (b) Starting from 3-cyano-6- (3-bromo-4-methoxyphenyl) pyridin-2 (1H) -one (1.22 g), after recrystallization from dimethylformamide, the title compound (1.28 g ), m.p. 292-293Â ° C (decomp.), according to the procedure of Example 1 (b): Î'1 H NMR (DMSO-d 6): 3.94 (s, 3H), 6.90 (d, 1H), 7.27 (d, 1H), 7.90 (dd, 1H), 8.14 (d, 1H) and 8.45 (d, 1H).

Example 47 6- (3-Phenyl-4-methoxyphenyl) -3- (5-tetrazolyl) pyridin-2 (1H) -one (SB 204649) (a) To a suspension of tetrakis (triphenylphosphine) palladium (0) ( 0.5 g) in aqueous sodium hydrogen carbonate (5.04 g in 60 ml of water) were added phenylboronic acid solutions (2.65 g) in dimethoxyethane (100 ml) and 3-bromo-4-methoxyacetophenone ( 4.58 g) in dimethoxyethane (110 ml). The mixture was stirred under reflux for 3 hours, cooled to room temperature and the solvent was removed under reduced pressure. The residue was partitioned between chloroform (200 ml) and water (200 ml), the organic phase separated, dried (MgSO4) and solvent was removed under reduced pressure. The residue was recrystallized from ethanol to give 4'-methoxy-S'-phenylacetophenone (2.87 g), mp 92-93 ° C. (b) Starting from 4'-methoxy-3'-phenylacetophenone (3.3 g), after recrystallization from propan-2-ol, 3-cyano-6- (3-phenyl-4-methoxyphenyl) 2 (1H) -one (2.37 g), melting point 288-291 ° C, according to the procedure of Example 3 (a). (c) Starting from 3-cyano-6 - [(3-phenyl) -4-methoxyphenyl] pyridin-2 (1H) -one (0.91 g), after recrystallization from dimethylformamide / ethanol, The title compound (0.70 g) was obtained, melting point 289-291 ° C, according to the procedure of Example 1 (b). (DMSO-d 6) 3.86 (s, 3H), 6.92 (d, 1H), 7.28 (d, 1H), 7.33-7.48 (m, 3H) , 7.62 (d, 2H), 7.81-7.89 (m, 2H), 8.45 (d, 1H), 11.96 (br.s, 1H) and 12.71 (br.s , 1H).

Example 48 6- [4-methoxy-3,5-di (El-propenyl) phenyl] -3- (5-tetrazolyl) -pyridin-2 (1H) -one (SB 204788) (a) Starting from 3'- allyl-4'-hydroxyacetophenone (17.6 g), 3'-allyl-4'-allyloxyacetophenone (20.7 g) was prepared as an oil according to the procedure of Example 2 (a) using acetone as solvent . 1 H NMR (CDCl 3) 2.55 (s, 3H), 3.44 (d, 2H), 4.61 (m, 2H), 5.04-5.46 (m, 4H), 5.94- 6.10 (m, 2H), 6.86 (d, 1H), 7.78 (d, 1H) and 7.83 (dd, 1H).

(B) Starting from 3'-allyl-4-allyloxyacetophenone (20, prepared 3 ', 5'-diallyl-4'-hydroxyacetophenone (16.3 g) m.p. 83-84 (C) Starting from 3 ', 5'-diallyl-4'-hydroxyacetophenone (16 g), 3', 5'-diallyl-4 '' - methoxyacetophenone (17 g) isolated as an oil according to the procedure of Example 2 (a) .1 H NMR δ (CDCl3) 2.55 (s, 3H), 3.46 (d, 4H), 3 (M, 4H), 5.91 (s, 3H), 5.05-5.14 (m, 4H), 5.91-6.07 (m, 2H) and 7.69 (s, 2H) , 5'-diallyl-4'-methoxyacetophenone (8.5 g), after trituration with hot ethanol, was prepared 3-cyano-6- [4-methoxy-3,5-di (El-propenyl) phenyl] pyridine (E) Starting from 3-cyano-6- [4-methoxy-4-methoxy-2- (1H) -one (6.1 g), melting point 248-250 ° C, according to the procedure of Example 3 (a) (0.46 g), after recrystallization from dimethylformamide / water, the title compound (0.27 g) was prepared, followed by recrystallization from dimethylformamide melting point 285-287 ° C (decomp.) / according to the procedure of Example 1 (b) .1 H NMR δ (DMSO-d6) 1.92 (d, 6H), 3.68 (s, 3H), 6.49-6.68 (m, 4H), 7.00 , 1H), 7.89 (s, 2H) and 8.45 (d, 1H).

Example 49 6- [3- (El-propenyl) -4-propoxyphenyl] -3- (5-tetrazolyl) pyridin-2 (1H) -one (SB 201433) (a) Starting from 3'- (5.28 g), 3-allyl-4-propoxyacetophenone (6.06 g) was prepared as an oil, according to the procedure of Example 2 (a). 1 H NMR (CDCl 3) 1.07 (t, 3H), 1.66-1.92 (m, 2H), 2.55 (S, 3H), 3.41 (d, 2H), 3.99 t, 2H), 5.04-5.12 (m, 2H), 5.90-6.06 (m, 1H), 6.86 (d, 1H), 7.77 (d, 1H), and 7 , 83 (dd, 1H). (b) Starting from 3β-allyl-4-propoxyacetophenone (5.7 g), after recrystallization from butanol, 3-cyano-6- [3- (EI-propenyl) -4-propoxyphenyl] pyridine -2 (1H) -one (2.57 g) mp 240-244 ° C according to the procedure of Example 3 (a). (c) Starting from 3-cyano-6- [3- (E-propenyl) -4-propoxyphenyl] pyrimidin-2 (1H) -one (1.18 g), after recrystallization from butanol, the title compound (0.7 g) was prepared, melting point 290-292 ° C (decomp.) according to the procedure of Example 1 (b). 1 H NMR δ (DMSO-d 6) 1.02 (t, 3H), 1.73-1.86 (m, 2H), 1.90 (d, 3H), 4.04 (t, 2H) (D, 1H), 7.89 (d, 1H), 7.70 (dd, 1H), 7.97 (d, 1H) (d, 1H) and 8.43 (d, 1H).

Example 50 6- (3-Bromo-4-methoxy-5-propylphenyl) -3- (5-tetrazolyl) pyridin-2 (1H) -one (273/2534) (a) Starting from 4'-methoxy-3- (7.6 g), after column chromatography (silica gel, eluent 50% hexane / dichloromethane), 3R-bromo-4-methoxy-5, -propylacetophenone (4.8 g ) isolated as an oil, according to the procedure of Example 36 (a). 1 H NMR (CDCl 3) 0.98 (t, 3H), 1.57-1.73 (m, 2H), 2.56 (S, 3H), 2.67 (t, 2H), 3.87 (s, 3H), 7.74 (d, 1H) and 7.98 (d, 1H). (b) Starting from 3-bromo-4-methoxy-5-propylacetophenone (3.4 g), after recrystallization from ethanol, 6- (3-bromo-4-methoxy-5-propylphenyl) -3-cyanopyridin-2 (1H) -one (1.2 g) according to the procedure of Example 3 (a). % NMR δ (DMSO-d6) 0.94 (t, 3H), 1.57-1.67 (m, 2H), 2.65 (t, 2H), 3.79 (s, 3H), 6.38 ( br.d, 1H), 7.74 (d, 1H), 7.97 (d, 1H) and 8.18 (d, 1H). (c) Starting from 6- (3-bromo-4-methoxy-5-propylphenyl) -3-cyanopyridin-2 (1H) -one (0.39 g), after recrystallization from ethanol, the title compound was prepared. (0.17 g), melting point 286-287 ° C (decomp.) according to the procedure of Example 1 (a). 1 H NMR δ (DMSO-d6) 0.96 (t, 3H), 1.61-1.70 (m, 2H), 2.67 (t, 2H), 3.81 (s, 3H), 6.94 (d, 1H), 7.76 (d, 1H), 7.99 (d, 1H) and 8.45 (d, 1H).

Example 51 6- (2-Butylthio-3,5-diethoxyphenyl) -3- (5-tetrazolyl) pyridin-2 (1H) -one (a) Starting from 2β-bromo-3β, 5'-diethoxyacetophenone , 53 g), after column chromatography (silica gel, eluent 4: 1 hexane / dichloromethane), 2'-butylthio-3 ', 5'-dietoxyacetophenone (1.96 g) was prepared according to the procedure of Example

73 118 22052 / Ρ 30140 -47- 26 (a). (M, 10H), 2.59 (s, 3H), 2.76 (t, 2H), 4.02 (q, 2H), 4.08 (q, 2H), 6.33 (d, 1H) and 6.46 (d, 1H). (b) Starting from 2-butylthio-3β, 5'-diethoxyacetophenone (1.95 g), after recrystallization from ethanol, 3-cyano-6- (2-butylthio-3,5-diethoxyphenyl) pyridin-2 (1H) -one (0.13 g) according to the procedure of Example 3 (a). 1 H NMR δ (DMSO-d 6) 0.77 (t, 3H), 1.18-1.43 (m, 10H), 2.66 (t, 2H), 4.03-4.18 ( m, 4H), 6.27 (d, 1H), 6.59 (d, 1H), 6.71 (d, 1H) and 8.15 (d, 1H). (c) Starting from 3-cyano-6- (2-butylthio-3,5-diethoxyphenyl) pyridin-2 (1H) -one (0.12 g), after recrystallization from ethanol, the title compound (0.08 g), mp 138-140 ° C, according to the procedure of Example 1 (a). NMR (DMSO-d6) 0.76 (t, 3H), 1.18-1.43 (m, 10H), 2.64 (t, 2H), 4.05-4.19 (m, 4H) , 6.40 (d, 1H), 6.62 (d, 1H), 6.70 (d, 1H), 8.48 (d, 1H) and 12.67 (br.s, 1H).

Example 52 6- (3-Bromo-4- (N-dimethylaminophenyl) -3- (5-tetrazolyl) pyridin-2 (1H) -one (SB 204789) (a) Starting from 4 '- [ dimethylaminoacetophenone (4.9 g), 3'-bromo-4'-Î ±, Î'-dimethylaminoacetophenone (7.0 g) was prepared according to the procedure of Example 36 (a). (CDCl 3) 2.53 (S, 3H), 2.91 (S, 6H), 7.03 (d, 1H), 7.83 (dd, 1H), and 8.13 (d, 1H ). (b) Starting from 3'-bromo-4'-Ν, Ν-dimethylaminoacetophenone (2.42 g) was prepared 3-cyano-6- (3-bromo-4-N, N-dimethylaminophenyl) 2 (1H) -one (2.63 g) according to the procedure of Example 3 (a). 1H NMR δ (DMSO-d6) 2.82 (s, 6H), 6.82 (d, 1H), 7.22 (d, 1H), 7.79 (dd, 1H), 8.08 (d, 1 H), 8.15 (d, 1H) and 12.67 (br. s, 1H). (c) Starting from 3-cyano-6- (3-bromo-4-N, N-dimethylaminophenyl) pyridin-2 (1H) -one (0.8 g), the title compound 57 g), m.p. 275-277Â ° C, according to the procedure of Example 1 (b).

Example 53 6- (3-Acetamido-4-methoxy-5-propylphenyl) -3- (5-tetrazolyl) pyridin-2 (1H) -one (SB 204790) (a) Starting 3'-allyl-4'-benzyloxyacetophenone (23.1 g), isolated as an oil, was prepared according to the procedure of Example 2 (a), using acetone as the solvent. 1 H NMR δ (CDCl 3) 2.55 (s, 3H), 3.47 (d, 2H), 5.04-5.11 (m, 4H), 5.16 (s, 2H) (D, 1H), 7.25-7.41 (m, 5H), 7.81 (s, 1H) and 7.82 (d, 1H) . (b) Starting from 3'-allyl-4'-benzyloxyacetophenone (23 g), after recrystallization from dimethylformamide / water, 6- [4-benzyloxy-3- (1-propenyl) phenyl] -3-cyanopyridine -2 (1H) -one (11.2 g), mp 255-257 ° C, according to the procedure of Example 3 (a). (c) A solution of 6- [4-benzyloxy-3- (E-propenyl) phenyl] -3-cyanopyridin-2 (1H) -one (6.8 g) in dimethylformamide (20 ml) containing dimethylformamide (4.76 g) was heated at 120 ° C for 6 hours. The mixture was diluted with ethyl acetate (200 ml), washed with water (6 x 100 ml), dried (MgSO4) and the solvent was removed under reduced pressure. The residue was chromatographed (silica gel, eluent 1: 1 hexane / dichloromethane) to give 6- [4-benzyloxy-3- (1-propenyl) phenyl] -3-cyano-2-methoxypyridine (6 g) mp 124-125 ° C, after recrystallization from ethanol. (d) A suspension of 6- [4-benzyloxy-3- (1-propenyl) phenyl] -3-cyano-2-methoxypyridine (1.78 g) in ethanol (250 ml) containing 10% palladium / charcoal ( 0.2 g) was hydrogenated at 344.8 kPa (50 psi) until the calculated amount of hydrogen was absorbed. The mixture was filtered (celite pad) and the solvent was removed under reduced pressure. The residue was column chromatographed (silica gel, eluent 1: 1 hexane / dichloromethane-2% ethanol / dichloromethane) to give 3-cyano-6- (4-hydroxy-3-propylphenyl) -2-methoxypyridine (1, 0 g). Δ NMR δ (CDCl 3) 1.01 (t, 3H), 1.65-1.74 (m, 2H), 2.66 (t, 2H), 4.15 (s, 3H), 5.19 ( S, 1H), 6.86 (d, 1H), 7.35 (d, 1H) and 7.81-7.87 (m, 3H). -49- 73 118 22052 / Ρ30140 p

To a stirred suspension of 6- (4-hydroxy-3-propenyl) -3-cyano-2-methoxypyridine (1) was added a solution of nitronium tetrafluoroborate in sulfolane (0.5M, 16 ml) , 88 g) in sulfolane (3 ml) over 5 minutes under ice-cooling. The solution obtained was stirred for 5 hours, more nitronium tetrafluoroborate (0.5M in sulfolane, 2 ml) was added and stirring was continued for a further 3 hours. The solution was diluted with diethyl ether (100 mL), washed with water (8 x 100 mL), dried (MgSO4) and solvent removed under reduced pressure. The residue was recrystallized from ethanol to give 3-cyano-6- (4-hydroxy-3-nitro-5-propylphenyl) -2-methoxypyridine (1.75 g), melting point 160-162 ° C. (f) Starting from 3-cyano-6- (4-hydroxy-3-nitro-5-propylphenyl) -2-methoxypyridine (1.57 g), 3-cyano-6- (4-methoxy- -3-nitro-5-propylphenyl) -2-methoxypyridine (1.53 g), melting point 150-152Â ° C, according to the procedure of Example 2 (a), using as the reaction solvent (1: 1) acetone / dimethylformamide. 1 H NMR δ (CDCl 3) 1.03 (t, 3H), 1.67-1.81 (m, 2H), 2.77 (t, 2H), 3.95 (s, 3H) 17 (S, 3H), 7.42 (d, 1H), 7.96 (d, 1H), 8.07 (d, 1H) and 8.35 (d, 1H). (g) A suspension of 3-cyano-6- (4-methoxy-3-nitro-5-propylphenyl) -2-methoxypyridine (1.4 g) in ethanol (100 ml) containing 10% palladium / mg) was treated with 50 psi hydrogen until absorption of hydrogen was complete. The mixture was filtered (celite pad) and the solvent was removed from the filtrate under reduced pressure. The residue was dissolved in dichloromethane (10 ml) containing triethylamine (1.0 g) added after the addition of acetic anhydride (0.61 g) over 5 minutes. The reaction mixture was stirred for 15 hours, diluted with dichloromethane (100 ml) and washed with 2N hydrochloric acid (2 x 50 ml) and water (50 ml). After drying (MgSO4), the solvent was removed under reduced pressure to give, after recrystallization from ethanol, 6- (3-acetamido-4-methoxy-5-propylphenyl-3-cyano-2-methoxypyridine (1.04 g ) mp 174-175 ° C (h) Starting from 6- (3-acetamido-4-methoxy-5-propylphenyl) -3-cyano-

(0.7 g), 6- (3-acetamido-4-methoxy-5-propylphenyl) -3-cyanopyridin-2 (1H) -one (0.48 g, ) mp 247-249 " C, according to the procedure of Example 37 (c). 1 H-NMR δ (CDCl 3) 1.02 (t, 3H), 1.68-1.83 (m, 2H), 2.27

(br.s, 1H), 7.90 (d, 1H) and 8.62 (d, 1H). (i) Starting from 6- (3-acetamido-4-methoxy-5-propylphenyl) -3-cyano-pyridin-2 (lH) -one (0.4 g), after recrystallization from ethanol, the title compound was prepared. (0.25 g), mp 239-241 ° C, according to the procedure of Example 1 (b).

Example 54 6- [3-methoxymethyl-4-methoxy-5- (E-propenyl) phenyl] -3- (5-tetrazolyl) pyridin-2 (1H) -one (273/2588) (a) Starting from 3- (4-methoxy-3,5-di (1-propenyl) phenyl) pyridine-2 (1H) -one (4.59 g) was prepared 3-cyano-6- [4- 3,5-di (E-1-propenyl) phenyl] -2-methoxypyridine (4.1 g), mp 145 ° C, according to the procedure of Example 53 (c). NMR δ (DMSO-d6) 1.93 (d, 6H), 3.67 (s, 3H), 4.11 (s, 3H), 6.42-6.56 (m, 2H), 6.66 (d, 2H), 7.87 (d, 1H), 8.15 (s, 2H) and 8.30 (d, 1H). (b) To an ice-cooled suspension of 3-cyano-6- [4-methoxy-3,5-di (El-propenyl) phenyl] -2-methoxypyridine (1.6 g) in acetone- was added N-methylmorpholine-N-oxide (0.63 g) and osmium tetroxide (2.5% w / w solution in tert-butanol, 0.4 ml ). The mixture was stirred with ice-cooling for one hour and at room temperature for 1 hour. Further N-methylmorpholine-N-oxide (0.1 g) was added and stirring was continued for an additional 1 hour. The solution was quenched with 5% sodium metabisulfite (5 ml) and the solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate (200 ml), washed with water (2 x 100 ml), dried (MgSO4) and the solvent was removed under reduced pressure. Chromatography (silica gel, eluent dichloromethane - 5% ethanol / dichloromethane) gave 3-cyano-6- [3- [1- (1,2-dihydroxypropyl)] - 4-methoxy-5- ( propanyl) -phenyl] -2-methoxypyridine (0.99 g). NMR δ (CDCl 3) 1.17 (d, 3H), 1.97 (d, 3H), 2.5 (br.s, 1H), 2.98 (br.s, 1H), 3.82 (s , 3H),

73 118 22052 / Ρ30140 -51- 3.94-4.05 (m, 1H), 4.16 (s, 3H), 4.77 (d, 1H), 6.30-6.42 (m, 1H ), 6.66 (d, 1H), 7.41 (d, 1H), 7.90 (d, 1H), 7.93 (d, 1H) and 8.08 (d, 1H). (c) To a solution of 3-cyano-6- [3- [1- (1,2-dihydroxypropyl)] - 4-methoxy-5- (El-propenyl) phenyl] -2-methoxypyridine , 99 g) in tetrahydrofuran (20 ml) was added a solution of sodium metaperioate (0.64 g) in water (3 ml). The mixture was stirred for 2 hours, more sodium metaperiodate (0.1 g) in water (2 ml) was added and stirring was continued for another 2 hours. The mixture was filtered, diluted with ethyl acetate (100 mL), washed with water (2 x 50 mL), dried (MgSO4), and the solvent was removed under reduced pressure. The residue was column chromatographed (silica gel, eluent dichloromethane-5% ethanol / dichloromethane) to give 3-cyano-6- [3-formyl-4-methoxy-5- (El-propenyl) phenyl] - 2-methoxypyridine (0.7 g) m.p. 174Â ° C. 1 H NMR δ (CDCl 3) 2.00 (d, 3H), 3.93 (s, 3H), 4.18 (s, 3H), 6.38-6.53 (m, 1H), 6.69 ( d, 1H), 7.47 (d, 1H), 7.94 (d, 1H), 8.33 (d, 1H), 8.41 (d, 1H) and 10.44 (1H). (d) A solution of 3-cyano-6- [3-formyl-4-methoxy-5- (1-propenyl) phenyl] -2-methoxypyridine (0.65 g) in ethanol (10 ml) was treated with sodium borohydride (100 mg) portionwise over 30 minutes. The solution was stirred for a further 2 hours, the solvent removed under reduced pressure, the residue dissolved in ethyl acetate (100 ml), washed with water (2 x 50 ml), dried (MgSO4) and the solvent was removed under reduced pressure . the residue was dissolved in dimethylsulfoxide (5 ml), potassium hydroxide (0.56 g in crushed pellets) was added, followed by iodomethane (0.6 g) and the mixture was stirred for 30 minutes. After dilution with ethyl acetate (100 ml), the reaction mixture was washed with water (6 x 50 ml), dried (MgSO4) and the solvent was removed under reduced pressure. The residue was column chromatographed (silica gel, 40% hexane / dichloromethane-dichloromethane) to give 3-cyano-6- [3-methoxymethyl-4-methoxy-5- (1-propenyl) phenyl] -2- methoxypyridine (0.54 g) m.p. 81-82 ° C. NMR δ (CDCl 3) 1.96 (d, 3H), 3.47 (s, 3H), 3.79 (s, 3H), 4.17 (s, 3H), 4.56 (s, 2H), 6.30 (d, 1H), 7.42 (d, 1H), 7.88 (d, 1H), 7.92 (d, 1H), and 8.10 (d, 1H).

(E) Starting from 3-cyano-6- [3-methoxymethyl-4-methoxy-5- (1-propenyl) phenyl] -2-methoxypyridine (0.54 g), dichloromethane-2.5% ethanol / dichloromethane), 3-cyano-6- [3-methoxymethyl-4-methoxy-5 (EI-propenyl) phenyl] pyridin-1 (1H) -one (0.33 g), mp 188-190 ° C, according to the procedure of Example 37 (c). Δ NMR δ (CDCl 3) 1.99 (d, 3H), 3.49 (S, 3H), 3.81 (S, 3H), 4.60 (S, 2H), 6.46-6.70 m, 3H), 7.72 (d, 1H), 7.85 (d, 1H), 7.91 (d, 1H) and 12.89 (br.s, 1H). (f) Starting from 3-cyano-6- [3-methoxymethyl-4-methoxy-5 (EI-propenyl) phenyl] pyridin-2 (1H) -one (0.3 g), after recrystallization from ethanol, the title compound (0.22 g) was prepared, melting point 245-246 ° C, according to the procedure of Example 1 (b). NMR (DMSO-d6) 1.92 (d, 3H), 3.61 (s, 3H), 3.83 (s, 3H), 4.81 (s, 2H), 6.26-6.44 (m, 1H), 6.68 (d, 1H), 6.88 (d, 1H), 7.73 (d, 1H), 8.04 (d, 1H), 8.75 (d, 1H) .

Example 55 6- [3- (E-2-carbamoylethtenyl) -4-methoxy-5- (El-propenyl) phenyl] -3- (5-tetrazolyl) pyridin-2- (1H) -one (273/2602 ) (a) Triethylphosphonoacetate (0.9 g) was added dropwise to a suspension of sodium hydride (0.18 g, 50% in oil) in tetrahydrofuran (10 ml). When the gas evolution subsided, a solution of 3-cyano-6- [3-formyl-4-methoxy-5- (El-propenyl) phenyl] -2-methoxypyridine in tetrahydrofuran (10 ml) was added and the mixture was stirred for 4 hours. Ethanol (10 ml) and 2N sodium hydroxide (10 ml) were added and the mixture was boiled for 2 hours. The solvent was removed under reduced pressure, the residue dissolved in water and acidified with 2N hydrochloric acid. The precipitate was collected by filtration to give 3-cyano-6- [3- (E-2-carboxylatoethenyl) -4-methoxy-5- (1-propenyl) phenyl] -2-methoxypyridine (0.9 g) . 1 H NMR (CDCl 3) 1.94 (d, 3H), 3.73 (s, 3H), 4.14 (s, 3H), 6.50-6.62 (m, 1H), 6 , 69 (d, 1H), 6.78 (d, 1H), 7.82 (1H), 7.99 (d, 1H) and 8.33-8.42 (m, 3H). (b) Oxalyl chloride (0.76 g) was added over 5 minutes to an ice-cooled suspension of 3-cyano-6- [3- (E-2-carbo-

3-methoxy-5- (E-1-propenyl) phenyl] -2-methoxypyridine in dichloromethane (20 ml) containing dimethylformamide (0 ml). When the gas evolution subsided (4 hours) the solvent was removed under reduced pressure and the residue redissolved in dichloromethane (20 ml). To the ice-cooled solution, ammonium hydroxide (10 mL, SG 0.88) was added and the solution was stirred at 0øC for 30 minutes and at room temperature for 30 minutes. The precipitated solid was collected by filtration and double recrystallized from ethanol to give 3-cyano-6- [3- (E-2-carbamoylethenyl) -4-methoxy-5- (1-propenyl) phenyl] pyridin-2 (1H ) -one (0.4 g) m.p. 245-246 ° C. 1 H NMR (DMSOd 6): 1.94 (d, 3H), 3.72 (s, 3H), 4.14 (S, 3H), 6.49-6.62 (m, (D, 1H), 7.80 (d, 1H), 7.62 (d, 1H), 7.89 (br. (d, 1H), 8.27 (d, 1H), 8.29 (d, 1H) and 8.34 (d, 1H). (c) Starting from 3-cyano-6- [3- (E-2-carbamoylethtenyl) -4-methoxy-5- (1-propenyl) phenyl] pyridin-2 (1H) -one (0.16 g) , after recrystallization from dimethylformamide / ethanol / water, the title compound (0.08 g) was prepared, melting point 292-294 ° C (decomp.) according to the procedure of Example 1 (b). NMR δ (DMSO-d 6) 1.94 (d, 3H), 3.73 (s, 3H), 6.55-6.72 (m, 2H), 6.83 (d, 1H), 7.00 (d, 1H), 7.63 (br.s, 1H), 7.99 (d, 1H) and 8.48 (d, 1H) d, 1H).

Example 56 6- (3-Cyclopropylmethyloxy-4-methoxyphenyl) pyridin-2 (1H) -one (a) Starting from 3β-hydroxy-4-methoxyacetophenone (3.32 g) was prepared 3β-cyclopropylmethyloxy-4- / -methoxyacetophenone (4.34 g) according to the procedure of Example 2 (a). Δ (CDCl 3) 0.34-0.40 (m, 2H), 0.63-0.70 (m, 2H), 1.28-1.43 (m, 1H), 2.56 (S, 3H), 3.91 (d, 2H), 3.95 (s, 3H), 6.89 (d, 1H), 7.50 (d, 1H) and 7.56 (dd, 1H). (b) Starting from 3-cyclopropylmethyloxy-4'-methoxyacetophenone (3.55 g), after recrystallization from butanol, 3-cyano-6- (3-cyclopropylmethyloxy-4-methoxyphenyl) pyridin-2 (1H) - (1.30 g), melting point 241-242 ° C according to the procedure of Example 3 (a).

(C) Starting from 3-cyano-6- (3-cyclopropylmethyloxy-4-methoxyphenyl) pyridin-2 (1H) -one (0.89 g), after recrystallization from butanol, was obtained The title compound (0.67 g) was prepared, melting point 296-297 ° C (decomp.), according to the procedure of Example 1 (b). 1 H NMR (DMSOd 6) 0.32-0.38 (m, 2H), 0.57-0.66 (m, 2H), 1.22-1.37 (m, 1H), 3.85 (s, 1H), 3.94 (d, 2H), 6.88 (d, 1H), 7.10 (d, 1H), 7.39-7.48 (m, 2H), 8.43 (d, d, 1H) and 12.56 (br.s, 1H).

Example 57 6- (2-Methoxy-4-propoxyphenyl) -3- (5-tetrazolyl) pyridin-2 (1H) -one a) Starting from 2 ', 4'-dihydroxyacetophenone (50 g) 4-propoxyacetophenone (6 g) according to the procedure of Example 2 (a) using bromopropane (40 g) and acetone as solvent. 1 H-NMR (DMSOd 6) 0.93 (t, 3H), 1.61-1.72 (m, 2H), 2.38 (s, 3H), 3.75 (t, 2H) (B) Starting from 2'-hydroxy-4'-propoxyacetophenone (6 g) was prepared 2-methoxy -4-propyloxyacetophenone (5.18 g) according to the procedure of Example 2 (a). 1 H NMR δ (CDCl 3), 1.05 (t, 3H), 1.74-1.91 (m, 2H), 2.57 (s, 3H), 3.89 (s, 3H), 3.97 (t, 2H), 6.46-6.53 (m, 2H) and 7.80 (d, 1H). c) Starting from 2'-methoxy-4'-propoxyacetophenone (5 g) after trituration with diethyl ether, 3-cyano-6- (2-methoxy-4-propoxyphenyl) pyridin-2 (1H) -one 0.38 g), mp 186-188 ° C according to the procedure of Example 3 (a). 1 H-NMR δ (DMSO-d6) 0.99 (t, 3H), 1.72-1.81 (m, 2H), 3.82 (s, 3H), 4.02 (s, 2H), 6.47 (d, 1H), 6.61-6.67 (m, 2H), 7.39 (d, 1H) and 8.11 (d, 1H). d) Starting from 3-cyano-6- (2-methoxy-4-propoxyphenyl) pyridin-2 (1H) -one (0.36 g), after recrystallization from ethanol and trituration with diethyl ether, the title compound was prepared. title (0.04 g) mp> 300 ° C according to the procedure of Example 1 (b). 1 H NMR δ (DMSO-d 6 at 370K) 1.00 (t, 3H), 1.69-1.82 (m, 2H), 3.83 (s, 3H), 4.02 (t, 2H ), 6.61-6.66 (m, 2H), 6.98 (unresolved, 1H), 7.55 (unresolved, 1H) and 8.44 (unresolved, 1H). -55- 73 118 22052 / Ρ30140

Example X

Pharmaceutical compositions for oral administration are prepared by the combination of the following:

% P / P 6- (3-methoxyphenyl) -3- (5-tetrazolyl) pyridin-2 (1H) -one 0.5 3.0 7.14

Soybean Lecithin 2% w / w Soybean Oil 90.45 88.2 84.41

Hydrogenated vegetable fat and beeswax 9.05 8.8 8.45

The formulations are then filled into individual soft gelatin capsules.

Example Y

A pharmaceutical composition for parenteral administration is prepared by dissolving the title compound of Example 23 (0.02 g) in polyethylene glycol 300 (25 ml) with heating. This solution is then diluted with water for injections Ph. Eur. (To 100 ml). The solution is sterilized by filtration through a 0.22 micron membrane filter and sealed in sterile containers. i

Claims (8)

A process for the preparation of a compound of formula (1): (D) or a pharmaceutically acceptable salt thereof, wherein: R1 is OH or a bioprecursor thereof R1 is 5-tetrazolyl or a bioprecursor thereof and Ar is phenyl substituted by one to three groups independently selected from C2-6 alkenyloxy, C3-6 alkenyloxy, C3-6 cycloalkyl, C3-6 cycloalkoxy, C1-6 alkylthio, phenyl, phenylthio, benzyloxy, polyfluoroC1-6 alkyl, polyfluoroC1-6 alkoxy, halo, NR2 or NHCOR where R is H or Or X (CH2) n Y- attached to the adjacent carbon atoms of the phenyl ring wherein X and Y are each independently CH2 or O3a, wherein said C1-6 alkyl, C2-8 alkenyl or alkoxy groups may are independently substituted by OH, C1-6 alkoxy, C3-6 cycloalkyl, NR2, CO2 R2 or CONR2, with the proviso that Ar is not a phenyl group monosubstituted by 2-C1-6 alkoxy characterized in that the process comprises the reaction with a compound of formula (2): in which Ar is as defined above, with an azide salt, and then optionally - the formation of a bioprecursor of R ° and / or R1 - the formation of a pharmaceutically acceptable salt. 73 118 22052 / Ρ30140 -57- 2. A compound according to claim 1 wherein R 1 is OH or OR 2 in which R 2 is C 1-4 alkyl, C 1-4 alkyl aryl, C 1 -C 4 alkanoyl arylsulfonyl or C 1-4 alkylsulfonyl. A process as claimed in claim 1 or 2, wherein Ar is phenyl monosubstituted by a group as defined in claim 1. A process as claimed in claim 1 or 2, wherein Ar is phenyl disubstituted by any two groups as defined in claim 1. A process according to claim 1 or 2, wherein Ar is a phenyl group trisubstituted by any three groups as defined in claim 1. A process according to claim 1, characterized in that it is prepared; 6- (3-propoxyphenyl) -3- (5-tetrazolyl) pyridin-2 (1H) -one, 6- (3-methoxyphenyl) -3- (5-tetrazolyl) pyridin-2 (1H) 6- (3-benzyloxyphenyl) -3- (5-tetrazolyl) pyridin-2 (1H) -one, 6- (3-butoxyphenyl) -3- (5-tetrazolyl) pyridin-2 (1H) (1H) -one, 6- (3-trifluoromethyl) -3- (5-tetrazolyl) pyridin-2 (1H) -one, 6- (3-ethylphenyl) ) -6- (4-butoxyphenyl) -3- (5-tetrazolyl) pyridin-2 (1H) -one, 6- (4-isobutylphenyl) pyridine -2 (1H) -one, 6- (4-propoxyphenyl) -3- (5-tetrazolyl) pyridin-2 (1H) -one, 6- (4-biphenyl) -3- (5-tetrazolyl) (1H) -one, 6- (3,4-methylenedioxyphenyl) -3- (5-tetrazolyl) pyridine-2 (1H) -one, 6- (4-methoxy-3-propoxyphenyl) -3- (5-tetrazolyl) ) pyridin-2 (1H) -one, 6- (3,4-dichlorophenyl) -3- (5-tetrazolyl) pyridin-2 (1H) -one, 6- (3,5-dipropoxyphenyl) -3- (5- (3,5-diethoxyphenyl) -3- (5-tetrazolyl) pyridin-2 (1H) -one, 6- (3,5-dibromophenyl) -3- (5-tetrazolyl) pyridin-2 (1H) -one, 6- (2,4-dipropoxyphenyl) -3- (5-tetrazolyl) pyridin-2 (1H) -one, 6- (2- , 5-dipropoxyphenyl) -3- (5-tetrazolyl) pyridin-2 (1H) -one, 6- (2,3,4-trichlorophenyl) -3- (5-tetrazolyl) pyridin-2 (1H) 73 118 22052 / Ρ30140 6- [6- (1,2,3,4-tetrahydronaphthyl)] - 3- (5-tetrazolyl) pyridin-2 (1H) -one, 6- (3-chlorophenyl) -3- (5-Tetrazolyl) pyridin-2 (1H) -one, 6- (3-phenylthiophenyl) -3- (5-tetrazolyl) pyridin-2 (1 H) -one, 3,4-dimethoxyphenyl) -3- (5- tetrazolyl) pyridine-2 (1H) -one, 6- (3-butylthiophenyl) -3- (5-tetrazolyl) pyridine-2 (1H) -one, 6- (3,4-di-n-propoxyphenyl) -3- (5-tetrazolyl) pyridin-2 (1H) -one, 6- (2,3- propoxyphenyl) -3- (5-tetrazolyl) pyridin-2 (1H) -one, 6- (3-cyclopentyloxy-4-methoxyphenyl) -3- (5-tetrazolyl) pyridin-2 (1H) -one, 6- (3-ethoxyphenyl) -3- (5-tetrazolyl) 6- (2-butylthiophenyl) -3- (5-tetrazolyl) pyridin-2 (1H) -one, 6- (3,5-dimethoxyphenyl) -3- (5-tetrazolyl) 6- (4-methoxy-2-pentyloxyphenyl) -3- (5-tetrazolyl) pyridin-2 (1H) -one, 6- (3-allyloxyphenyl) -3- (5-tetrazolyl) 1H) -one, 6- (3-iso-butoxy-4-methoxyphenyl) -3- (5-tetrazolyl) pyridin-2 (1H) -one, 6- (2-bromo-3,5-diethoxyphenyl) -3- 2- (1H) -one, 6- (5-bromo-4-methoxy-2-pentyloxyphenyl) -3- (5-tetrazolyl) pyridin-2- (2-allyl-4-methoxy-3-propoxyphenyl) -3- (5-tetrazolyl) pyridin-2 (1H) -one, 6- [3- (El-propenyl) -4-methoxyphenyl] -3- ( 5-tetrazolyl) pyridin-2 (1H) -one, 6- (4-methoxy-3-propoxyphenyl) -3- [5- (1-pivaloyloxymethyl) tetrazolyl) pyridin-2 (1H) -one, 6- (4-methoxy- - (2-pivaloyloxymethyl) tetrazolyl) pyridin-2 (1H) -one, 6- [3-ethoxy-5- (2-methoxyethoxy) phenyl] -3- (5-tetrazolyl) pyridin-2 (1H) - 6- (3-ethoxy-4-methoxyphenyl) -3-methoxyphenyl] -3- (5-tetrazolyl) pyridin-2 (1H) -one, 6- [3- (2,2-dimethylpropyloxy) (5-Tetrazolyl) -pyridin-2 (1H) -one, 6- (4-methoxy-3-propylphenyl) -piperidin-2 (1H) -one, 6- (3-propionamidophenyl) -3- (5-tetrazolyl) 3- (5-Tetrazolyl) pyridin-2 (1H) -one, 6- (3-bromo-4-methoxyphenyl) -3- (5-tetrazolyl) pyridin-2 (1H) -one, 6- (3- -4-methoxyphenyl) -3- (5-tetrazolyl) pyridin-2 (1H) -one, 6- [4-methoxy-3,5-di (El-propenyl) phenyl] -3- (5-tetrazolyl) pyridine 6- [3- (El-propenyl) -4-propoxyphenyl] -3- (5-tetrazolyl) pyridin-2- (1H) -one, 6 - (3-bromo-4-methoxy-5-propylphenyl) -3- (5-tetrazolyl) pyridin-2 (1H) -one, 6- (2-butylthio-3,5-diethoxyphenyl) -3- (5- -tetrazolyl) pyridin-2 (1H) -one, 6- (3-bromo-4-N, N-dimethylaminophenyl) -3- (5- (3-acetamido-4-methoxy-5-propylphenyl) -3- (5-tetrazolyl) pyridin-2 (1H) -one / 6- [3- methoxy-5- (1-propenyl) phenyl] -3- (5-tetrazolyl) pyridin-2 (1H) -one, 6- [3- (E-2-carbamoylethenyl) -4-methoxy-5- - (1-propenyl) phenyl] -3- (5-tetrazolyl) pyridin-2 (1H) -one, or 6- (3-cyclopropylmethyloxy-4-methoxyphenyl) pyridin-2 (1H) pharmaceutically acceptable salt. 7. A process for the preparation of a pharmaceutical composition which comprises associating a compound according to any one of claims 1 to 6 with a pharmaceutically acceptable carrier. A process for the preparation of a compound of formula (2) as defined in claim 1, comprising reacting a compound of formula (3): wherein Ar is as previously defined and L 1 is a displaceable group, with a compound of formula (4): H 2 CNCONH 2 CN (4). Lisbon, 26. $ 1 1991 By SMITH KLINE & FRENCH LABORATORIES LIMITED