NZ239946A

NZ239946A - 3-(tetrazol-5-yl)-6-(substituted phenyl)pyridine derivatives and medicaments

Info

Publication number: NZ239946A
Application number: NZ239946A
Authority: NZ
Inventors: Roderick Alan Porter; Kenneth John Murray; Hunter Douglas Prain; Brian Herbert Warrington
Original assignee: Smith Kline French Lab
Priority date: 1990-09-28
Filing date: 1991-09-26
Publication date: 1994-09-27
Also published as: EP0550576A1; WO1992006085A1; AU8543191A; MX9101375A; CA2091989A1; IE913400A1; JPH06501254A; PT99081A; AU644016B2

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number £39946 239 9 4 6 ... .t - 2L&: ■ • ■ I I rin-r-- KHa* ■^-'S>U j •■• • ' .;;Vr'."_ 27 SEP 199^ /3SV . . .. r ■ \ •. 1 ' — NEW ZEALAND PATENTS ACT, 1953 No.: Date: COMPLETE SPECIFICATION CHEMICAL COMPOUNDS K/Wc, SMITH KLINE & FRENCH LABORATORIES LIMITED, Mundells, Welwyn Garden City, Hertfordshire AL7 1EY, England, a British company hereby declare the invention for which we pray that a patent may be granted to>$x$e/us, and the method by which it is to be performed, to be particularly described in and by the following statement:- - 1 -(followed by page la) 5 10 15 20 25 30 2399 4 - la -CHEMICAL COMPOUNDS The present invention relates to pyridinol derivatives, processes for their preparation, intermediates in their preparation, their use as medicaments and to pharmaceutical compositions comprising 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 of use in combatting such conditions where such agonism is thought to be beneficial. They are likely to have anti-proliferative, anti-aggregatory, cholesterol-lowering, smooth muscle relaxant, lusitropic, anti-allergic 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 disease such as asthma and bronchitis, allergic disease such as allergic asthma, allergic rhinitis and urticaria or gut motility disorders such as irritable bowel syndrome. Accordingly the present invention provides compounds of the formula (1) : in any tautomeric, geometric or optical isomeric form thereof, or pharmaceutical^ acceptable salts thereof, wherein : / > / '' 1 t APR ?994 23934 - 2 - R° 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 C1_6alkyl, C2_6alkenyl, C1_6alkoxy, C3_6alkenyl°xy, C3_gcycloalkyl, C3_6cycloalkoxy, Ci-galkylthio, phenyl, phenylthio, benzyloxy, Ci_6P°lyfluoroalkyl, C-^gpolyf luoroalkoxy, halo, NR2 or NHCOR wherein R is H or C-^.galkyl, and -X(CH2)nY- attached to adjacent carbon atoms of the phenyl ring wherein X and Y are independently CH2 or 0 and n is 1 to 3, wherein said C1_6alkyl, C2_6alkenyl or C-^galkoxy groups can be independently substituted by OH, C1_6alkoxy, C3-gCycloalkyl, NR2, C02R or CONR2 wherein R is as hereinbefore defined; with the proviso that Ar is not phenyl monosubstituted by 2-Ci_galkoxy. Bioprecursors of the group R° are derivatives thereof which are convertible in vivo into the group R°. A suitable bioprecursor of the group R° is OR2 wherein R2 is C1_4alkyl, arylC1_4alkyl (for example phenylC1_4-alkyl such as benzyl), C1_4alkanoyl (for example acetyl), arylC^^alkanoyl (for example phenyl C-^alkanoyl such as benzoyl), arylsulphonyl (for example optionally substituted phenylsulphonyl or toluenesulphonyl) or C1_4alkylsulphonyl (for example methylsulphonyl) . Suitably R° is hydroxy or OR2, preferably hydroxy. A suitable bioprecursor of R1 is a N-protected tetrazolyl group. Suitable N-protecting groups include pivalolyoxymethyl, propionyloxymethyl and pivaloyloxycarbonyloxymethyl. i ? -\PR$94- 22052/P30140 3®>99#«B - 3 - By the term alkyl is meant both straight- and branched-chain alkyl. By the term C1-6 polyfluoroalkyl is meant a C1_6alkyl 5 group having at least one hydrogen replaced with fluoro eg. CF3, or CF2CF2H. Suitably Ar is phenyl mono-substituted by a group as hereinbefore defined, for example in the 2,3, or 4 10 positions by C-j_6alkyl, C3_6alkenyloxy, Ci_6alkylthio, phenyl, phenylthio, benzyloxy, CF3, halo or NHCOR, or in the 3, or 4-positions with C-^.galkoxy. 15 Suitably Ar is phenyl di-substituted by any groups as hereinbefore defined, for example in the 3, 4-,3,5-,2,3-,2,4- or 2,5-, positions by groups independently selected from C2_6alkenyl, C-^.galkoxy, C3_6cycloalkoxy, halo, -X(CH2)nY- or C-^galkoxy 20 ci-6 alkoxy. Suitably Ar is phenyl trisubstituted by any groups as hereinbefore defined, for example in the 2,3,4-, 2,3,5-, or 3,4,5-positions by groups independently selected from 25 C2_6alkenyl, C^galkoxy or halo. Examples of C-^galkoxy include methoxy, ethoxy, propoxy, butoxy, or pentyloxy. 30 Examples of C1_6alkyl include methyl, ethyl, propyl, butyl, isobutyl or pentyl. Examples of halo include fluoro, chloro, bromo or iodo, preferably chloro or bromo. 35 Particular compounds of this invention include : 23994 - 4 - 6-(3-methoxyphenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one, 6-(3-propoxyphenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one, 6-(3-butoxyphenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one, 6-(3-benzyloxyphenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one, 6-(3-bromophenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one, 6-(3-trifluoromethylphenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one, 6-(3-ethylphenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one, 6-(4-butoxypheny1)-3-(5-tetrazolyl)pyridin-2(1H)-one, 6-(4-isobutylphenyl)-3-(5-tetrazolyl)pyridin-2(lH)one, 6-(4-biphenyl)-3-(5-tetrazolyl)pyridin-2 (1H)-one, 6-(4-propoxyphenyl)-3-(5-tetrazolyl)pyridin-2(1H) -one, 6-(4-methoxy-3-propoxyphenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one, 4 /• '< V- ''' 11 23994 - 5 - 6-(3,4-methylenedioxyphenyl)-3-(5-tetrazolyl)pyridin-2(1H) one, 6-(3,4-dichloropheny1)-3-(5-tetrazolyl)pyridin-2(1H)-one, 6-(3,5-dipropoxyphenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one, 6-(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)-one, 6-[6-(l,2,3,4-tetrahydronaphthyl)J-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(1H)-one, 6-(3,4-dimethoxyphenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one, ■ vv? J 1 1 AFPv'994: 239 - 6 - 6-(3-methylthiophenyl)-3-(5-tetrazolyl)pyridin-2(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)pyridin-2(1H)-one, 6-(3-cyclopentyloxy-4-methoxyphenyl)-3-(5-tetrazolyl)-pyridin-2(1H)-one 6-(3-ethoxyphenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one, 6-(3,5-dimethoxyphenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one 6-(2-butylthiophenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one, 6-(3-allyloxyphenyl)-3-(5-tetrazolyl)pyridin-2(lH)-one, 6-(4-methoxy-2-pentyloxyphenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one 6-(3-iso-butoxy-4-methoxyphenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one, 6- (2-bromo-3, 5-diethoxyphenyl)-3- (5-tetrazolyl) pyridin-2(1H)-one, 11 '22052 /P30140 239 9 46 - 7 - 6-(5-bromo-4-methoxy-2-pentyloxphenyl)-3-(5-tetrazolyl)-pyridin-2(1H)-one, 6-(2-a1ly1-4-methoxy-3-pr opoxypheny1)-3-(5-1etra z oly1)-5 pyridin-2(1H)-one, 6—[3 —(E-l-propenyl)-4-methoxyphenyl]-3-(5-tetrazolyl)pyridi n-2(1H)-one, 10 6-(4-methoxy-3-propoxyphenyl)-3-[5-(1-pivaloyloxymethyl)-tetrazolyl)pyridin-2(1H)-one, 6-(4-methoxy-3-propoxyphenyl)-3-[5-(2-pivaloyloxymethyl)-tetrazolyl]pyridin-2(1H)-one, 15 6-[3-ethoxy-5-(2-methoxyethoxy)pheny1]-3-(5-1etra z o ly 1) -pyridin-2(1H)-one, 6-[3-(2,2-dimethylpropyloxy)-4-methoxyphenyl]-3-(5-20 tetrazolyl)pyridin-2(IH)-one, 6-(3-ethoxy-4-methoxyphenyl)-3-(5-tetrazolyl)pyridin-2(IH)-one, 25 6-(3-propionamidophenyl)-3-(5-tetrazolyl)pyridin-2(IH)-one, 6-(4-methoxy-3-propyIpheny1)-3-(5-tetrazolyl)pyridin-2(IH)-one, 30 6-(3-bromo-4-methoxyphenyl)-3-(5-tetrazolyl)pyridin-2(IH)-one, 6-(3-pheny1-4-methoxyphenyl)-3-(5-tetrazolyl)pyridin-2(IH)-35 one, 6-[4-methoxy-3,5-di(E-l-propenyl)phenyl]-3-(5-tetrazolyl)-pyridin-2(IH)-one, 6-[3-(E-l-propenyl)-4-propoxyphenyl]-3-(5-tetrazolyl)-pyridin-2(IH)-one, 6-(3-bromo-4-methoxy-5-propylphenyl)-3-(5-tetrazolyl)-pyridin-2-(IH)-one, 6-(2-butylthio-3,5-diethoxyphenyl)-3-(5-tetrazolyl)pyridin-2(IH)-one, 6-(3-bromo—4—N,N-dimethylaminophenyl)-3-(5-tetrazolyl)-pyridin-2(IH)-one, 6-(3-acetamido-4-methoxy-5-propyIpheny1)-3-(5-tetrazolyl)-pyridin-2(IH)-one, 6 - [ 3 -methoxyraethy 1-4 -methoxy-5- (E-l-propenyl) phenyl ]-3-(5-tetrazolyl)pyridin-2(IH)-one, 6-[3-(E-2-carbamoylethenyl)-4-methoxy-5-(E-l-propenyl)-phenyl]-3-(5-tetrazolyl)pyridin-2-(IH)-one, and 6- (3-cyclopropylmethyloxy-4 -methoxyphenyl) -3- (5-tetrazolyl) -pyridin-2(IH)-one and pharmaceutical^ acceptable salts thereof. This invention covers all tautomeric, geometric and optical isomeric forms of compounds of formula (1). In 2052/P30140 239 9 4 6 - 9 - particular when R° is hydroxy the compound can exist in its keto tautomeric form : 10 15 Ar NH R1 Compounds of the formula (1) can 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 the formula (1) or a pharmaceutically acceptable salt thereof for the treatment of humans and other mammals it is normally formulated in accordance with standard pharmaceutical practice as a 2 0 pharmaceutical composition. Compounds of formula (1) and their pharmaceutically acceptable salts may be administered in standard manner for the treatment of the indicated diseases, for example 25 orally, sublingually, parenterally, transdermally, rectally, via inhalation or via buccal administration. Compounds of formula (1) and their pharmaceutically acceptable salts which are active when given orally or via 30 buccal administration can be formulated appropriately 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, glycerine 35 or water with a flavouring or colouring agent. Where the '22052/P3 0140 239946 - 10 - composition is in the form of a tablet, any pharmaceutical carrier routinely used for preparing solid formulations may be used. Examples of such carriers include starch, celluloses, lactose, sucrose and magnesium stearate. 5 Where the composition is in the form of a capsule, any routine encapsulation is suitable, for example using the aforementioned carriers in a hard gelatin capsule shell. Where the composition is in the form of a soft gelatin shell capsule, any pharmaceutical carrier routinely used 10 for preparing dispersions or suspensions may be considered, for example aqueous gums, celluloses, silicates or oils and are incorporated in a soft gelatin capsule shell. 15 Typical parenteral compositions consist of a solution or suspension of the compound or salt in a sterile aqueous or non-aqueous carrier optionally containing a parenterally acceptable oil or solubilising agent, for example polyethylene glycol, polyvinylpyrrolidone, lecithin, 20 2-pyrrolidone, cyclodextrin, arachis oil, or sesame oil. A typical suppository formulation comprises a compound of formula (1) or a pharmaceutically acceptable salt thereof which is active when administered in this 25 way, with a binding and/or lubricating agent, for example polymeric glycols, gelatins, cocoa-butter or other low melting vegetable waxes or fats or their synthetic analogues. 30 Typical transdermal formulations comprise a conventional aqueous or non-aqueous vehicle, for example a cream, ointment, lotion or paste or are in the form of a medicated plaster, patch or membrane. 35 Typical compositions for inhalation are in the form of a solution, suspension or emulsion that may be administered {^p22052/P30140 - 11 - 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. 5 Preferably the composition is in unit dosage form, for example a tablet, capsule or metered aerosol dose, so that the patient may administer to himself a single dose. Each dosage unit for oral administration contains 10 suitably 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 contains suitably from 0.001 mg/Kg to 10 mg/Kg, of a compound of formula (1) or a pharmaceutically acceptable salt thereof calculated as the 15 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 20 calculated as the free acid. The daily dosage regimen for parenteral administration is suitably about 0.001 mg/Kg to 40 mg/Kg, for example about 0.005 mg/Kg to 10 mg/Kg, of a compound of the formula (1) or a pharmaceutically acceptable salt thereof calculated as the free acid. The 25 active ingredient may be administered as required for example from 1-8 times a day or by infusion. The compositions of the invention are agonists of a cA-PrK and are of use in combatting such conditions where such agonism is thought to be beneficial. Such conditions can 30 be treated by administration orally, sublingually topically, rectally, parenterally or by inhalation. For administration by inhalation dosages are controlled by a valve, are administered as required and for an adult are conveniently in the range 0.1 - 5.0 mg of a compound of 35 the formula (1) or a pharmaceutically acceptable salt thereof. 23 239 9 I-22052/P30140 ^ - 12 - 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 5 invention and the other active compound or compounds are formulated in a single pharmaceutical composition. Examples of compounds which may be included in pharmaceutical compositions with the compounds of the formula (1) are bronchodilators such as sympathomimetic 10 amines for example isoprenaline, isoetharine, sulbutamol, phenylephrine and ephedrine or xanthine derivatives for example theophylline and aminophylline, anti-allergic agents for example disodium cromoglycate, histamine H^-antagonists, drugs used in the treatment of cancer 15 such as those which inhibit the synthesis of or inactivate DNA, for example methotrexate, fluoracil, cisplatin, actinomycin D, anti-atherschlerotic agents for example cholesterol lowering drugs such as HMGCoA reductase inhibitors, bile acid sequestrants, drugs for the 20 treatment of psoriasis, for example retinoids, anthralin, anti-inflammatories for example cortiscosteroids, non-steroid anti-inflammatories such as aspirin, antithrombotics for example dipyridamole, or fibrinolytic agents. 25 In another aspect the present invention provides a process for the preparation of compounds of the formula (1) or pharmaceutically acceptable salts thereof, which process comprises reacting a compound of the formula (2) : 30 OH 35 * 2052/P30140 39 9 4 6 - 13 - wherein Ar is as hereinbefore defined with an azide salt, and optionally thereafter : ° forming a bioprecursor of R° and/or R1 5 0 forming a pharmaceutically acceptable salt. A compound of the formula (2) is suitably reacted with an azide salt such as ammonium, sodium, potassium or 10 aluminium azide in an organic solvent such as dimethylformamide, dimethylsulphoxide, N-methyl-pyrrolidone or tetrahydrofuran at an elevated temperature e.g. 40 - 200°C, preferably at the reflux temperature of the reaction mixture. 15 A compound of the formula (l) wherein R° is OH can be converted to the corresponding compound where R° is OR2 by reaction with R2L wherein R2 is as hereinbefore defined and L is a leaving group such as 20 halo e.g. bromo, chloro, iodo. A compound of the formula (1) can be converted to a N-protected tetrazolyl derivative by reaction with a suitable N-protecting agent in standard manner, for 25 example with a pivalolyoxymethyl halide. A compound of the formula (2) can suitably be prepared by reacting a compound of the formula (3) : 30 ArCOCH = CHL1 (3) wherein Ar is as hereinbefore defined and L1 is a displaceable group, 35 with a compound of the formula (4) 2052/P30140 2399 4 - 14 - H2NC0CH2CN (4) Suitably L1 in a compound of the formula (3) is hydroxy or a derivative thereof for example L1 is 5 protected hydroxy such as silyloxy, an acid residue (for example C^.galkanoyloxy) or an ether residue (for example methoxy or ethoxy). Alternatively L1 is a secondary amino group, for example di-C-^galkylamino such as dimethylamino or a cyclic amino group such as 10 piperidino, pyrrolidino or morpholino. Preferably L1 is hydroxy or dimethylamino. Suitably an alkali metal (e.g. sodium) salt of a compound of the formula (3) wherein L1 is hydroxy is 15 treated with a compound of the formula (4) under mildly alkaline aqueous conditions, for example in water in the presence of piperidine and glacial acetic acid, at an elevated temperature e.g. 30 - 200°C, preferably at the reflux temperature of the reaction mixture. 20 Alternatively a compound of the formula (3) wherein L1 is a secondary amino group, for example dimethylamino, is treated with a compound of the formula (4) in a suitable solvent such as dimethylformamide, a 25 C1_4alkanol or pyridine at an elevated temperature e.g. 30 - 200°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, e.g. sodium methoxide. 30 Compounds of the formula (3) wherein L1 is hydroxy can suitably be prepared by reaction under basic conditions of a compound of the formula (5) : 35 ArC0CH3 (5) 2052/P30140 59 9 4 - 15 - wherein Ar is as hereinbefore defined, with a compound of the formula HCOL2 wherein L2 is a leaving group. 5 Suitably L2 is ethoxy or methoxy. Conveniently a solution of a compound of the formula (5) and a compound of the formula HCOL2 in a suitable organic solvent such as diethyl ether is treated with a suitable base such as an 10 alkali metal alkoxide, e.g. sodium methoxide at ambient temperature. The resulting reaction mixture is preferably extracted with water and the aqueous extract which contains the alkali metal salt of a compound of the formula (3) wherein L1 is hydroxy is then treated with a 15 compound of the formula (4) as hereinbefore described. Compounds of the formula (5) are known or can be prepared by methods known in the art. Compounds of the formula (3) wherein L1 is a 20 secondary amino group (e.g. dimethylamino) can suitably be prepared by reacting a compound of the formula (5) with a compound of the formula HC(OR3)2L1 wherein R3 is Ci_4alkyl and L1 is a secondary amino group (for example HC(OR3)2L1 is N,N-dimethylformamide dimethyl or r diethyl acetal), or with a compound of the formula HCL1- where 1 1 . L is a secondary ammo group (for example HCL 3 is trisdimethylaminomethane). Alternatively a compound of formula (2) can be 30 prepared by demethylation of a compound of formula (6) : •|(p22052/P30140 239 9 4 6 - 16 - 10 wherein Ar is as hereinbefore defined. Suitable demethylating agents include sodium iodide and chlorotrimethylsilane in an organic solvent such as acetonitrile, or a halohydrocarbon eg. dichloromethane or 15 chloroform at elevated (eg. 30-80°C) or ambient temperature or sodium thiomethoxide in an organic solvent such as dimethylformamide at an elevated temperature, for example 40-120°C. 20 The Ar group in compounds of the formula (2), (5) or (6), preferably (5) or (6) may be appropriately functionalised by methods of aromatic substitution known in the art. For example, a bromo group may be introduced into a suitably substituted phenyl ring (eg. disubstituted 25 in the 2- and 4-positions by electron-donating groups such as C-j^galkoxy) by reaction with a brominating agent such as N-bromosuccinimide or bromine in a solvent such as dimethylformamide. Alternatively a nitro group can be introduced into a phenyl ring by reaction with a suitable 3 0 nitrating agent, such as nitroniumtetrafluoroborate. Such a group can be readily hydrogenated to an amino group which if desired can be converted to a NHCOR group by reaction with LCOR wherein L is a leaving group and R is as hereinbefore defined. Suitable examples of the reagent 35 LCOR include acid halides (L is halo eg. chloro or bromo) or acid anhydrides (L is OCOR). J22052/P30140 39 9 t t$ - 17 - 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, eg. bromide, to form an allyloxy derivative which 5 on heating undergoes a Claisen rearrangement to form an ortho allyl hydroxy derivative. The hydroxy group can in turn be functionalised, eg. by reaction with a C2_galkyl halide to form a C-^.galkoxy group. If desired, an allyl group can be converted to an E-l-propenyl group by 10 reaction with a .strong base, such as sodium methoxide. This can occur during the conversion of a compound of formula (5) to a compound of formula (2) as hereinbefore described if such a base is used. An E-l-propenyl group can be cleaved to a formyl group by reaction with an 15 oxidising agent such as N-methylmorpholine-N-oxide in the presence of a catalyst such as osmium tetroxide to form a l,2,dihydroxypropyl group which on reaction with an oxidising agent such as sodium periodate forms the formyl group. Alternatively the E-l-propenyl group can be 20 converted directly to a formyl group by reaction with a mixture of osmium tetroxide and sodium periodate or by reaction with ozone. A formyl group can in turn be further functionalised, for example it can be converted to a hydroxymethyl group by reaction with a suitable reducing 25 agent such as sodium borohydride, the hydroxymethyl group then being reacted further, eg. with a C-^galkyl halide to form a C-^galkoxymethyl group. Alternatively a formyl group can be reacted with a suitable Horner Wittig or Wittig reagent such as (R40)2P(0)CH2C02R4 or 30 Ph3P=CHC02R4 wherein R4 is C1-4alkyl to form a CH=CHC02R4 group which can be optionally hydrolysed to a -CH=CHC02H group. A -CH=CHC02R4 group can be converted to a -CH=CHCONR2 group by reaction with an amine HNR2 or a chemical equivalent thereof wherein R is 35 as hereinbefore defined. Alternatively a -CH=CHC02H group can be converted to an acid halide, eg. the acid chloride by reaction with oxalyl chloride, which can then 2052/P30140 399 - 18 - be reacted with an amine HNR2 or a chemical equivalent thereof. An example of a chemical equivalent is ammonium hydoxide which will form a CH=CHCONH2 group. 5 A compound of formula (6) is suitably prepared by reacting a compound of formula (2) wherein Ar is as hereinbefore defined with an O-methylating agent such as dimethylformamide dimethylacetal in dimethylformamide or trimethylphosphite at an elevated temperature (eg. 10 40-120 °C) . Pharmaceutically acceptable base addition salts of the compounds of the formula (1) may be prepared by standard methods, for example by reacting a solution of the 15 compound of the formula (1) with a solution of the base. The following biological test methods, data and Examples serve to illustrate this invention. 20 Cyclic-AMP Protein Kinase fcA-PrK) Agonist Activity Type II cA-PrK was prepared from the cardiac muscle of a cow. The supernatant from a muscle homogenate (3 mis of 10 mM potassium phosphate, 1 mM EDTA per g 25 tissue) was applied to a column of DEAE-cellulose equilibrated with the homogenisation buffer and the type II cA-PrK was eluted with homogenisation buffer containing 350 mM sodium chloride (Rannels et al., 1983, Methods 30 Enzymol., 99, 55-62). Type II cA-PrK was assayed for phosphotransferase activity by incubating the enzyme at 30°C for 5 minutes with -32P]-adenosine triphosphate and a suitable 35 peptide substrate such as malantide (Malencik et al., 1983, Anal. Biochem., 132. 34-40). The reaction was 2052/P30140 2399 - 19 - terminated by the addition of hydrochloric acid and the [32p]-phosphopeptide quantified by spotting the reaction mixture onto phosphocellulose papers. The concentration of compound required to give 10% phosphotransferase 5 activation is given as the EC10 (pM). The compounds of Examples 1 to 26 had EC10 values in the range 10 -130 jiM. Inhibition of Platelet Aggregation 10 Human platelet-rich-plasma was separated from freshly drawn blood (in acid/citrate/dextrose) and treated with 100 yiM acetylsalicylic acid for 15 minutes at 37°C. A washed platelet suspension was then prepared in a 15 Hepes-isotonic saline buffer after a single centrifugation step and adjusted to a concentration of 1.5x10® cells/ml. Aliquots of this suspension were pre-incubated with compounds for 5 minutes at 37°C, then challenged with 1.0 jiM U46619. The extent of aggregation after 2 2 0 minutes were expressed as a percentage of control and results obtained are expressed as an IC50 (concentration to cause 50% inhibition of platelet aggregation, jiM). The compounds of Examples 2, 4, 5, 11-13, 15, 19-23, and 25-26 had IC50 values in the range 0.8-300 pM. 25 Anti-proliferative activity Compounds under test were dissolved in dimethyl-sulphoxide and diluted 1:10,000 with DMEM (Dulbecco's 3 0 Modified Eagle's Medium) containing 10% fetal bovine serum to give 12.5, 25, 50 and 100 pM concentrations used in the assay. Indicator cells consisting of 3 human colorectal cells lines (SW-620, NRK-52 and HT-29) were plated at a cell density of 1000 cells in 0.1 ml of DMEM 35 media in 96 well plates. Cells were incubated for 4 days at 37°C and 10% C02 atmosphere. On day 5, tetrazolium A22052/P30140 239 9 4 6 - 20 - reagent (50 jig MTT/250 yl total medium volume) was added for 16 - 20 hours. Insoluble formazan was dissolved in 150 jil of dimethylsulphoxide and absorbance was measured using a microculture plate reader at 560 nm 5 interfaced with an IBM computer. Cell line growth and inhibition were expressed in terms of mean absorbance unit of triplicate samples following subtraction of mean background absorbance. Icso values (concentration that show 50% growth inhibition) were determined from the dose 10 response curves. (Cancer Res., 48, 589-601, 1988). In the cell line SW-620 the compound of Example 23 had an IC50 value in the range 56 - 90 pM. in the cell line NRK-52 the compound of Example 23 had an IC50 value in the range 46 - 48 yM. In the cell line HT-29 the 15 compound of Example 23 had an IC50 value in the range of 55 - 66 pM. Inhibition of Spontaneous Contraction in Guinea-Pia Colon 20 Segments of isolated guinea-pig colon (2 cm) were suspended under 2 g tension in standard organ baths containing Krebs solution. The tissues were connected at the free end to isometric transducers which allow recording and display of developed tension on chart 25 recorders. On-line computer capture and analysis was used to quantify the effects of test compounds on spontaneous contractions. Inhibitory responses were calculated as % maximum inhibition of spontaneous contraction distance over 3 consecutive pre and post dose 30 2 minute readings. The concentration of compound which caused 50% inhibition of the spontaneous contraction is given as the EC50 (pM) . The compounds of Examples 5, 15-17 and 23 had EC50 values in the range 2-25 pM. 1*22052/P3 0140 239 9 4 6 - 21 - Bronchodilatation - In vitro (Tracheal spiral) Spiral strips of guinea-pig trachea were suspended in standard organ baths containing Krebs solution. The 5 tissues were connected at the free end to isometric transducers which allow recording and display of developed tension on chart recorders. Tension was allowed to develop spontaneously and concentrations of test compounds added in a cumulative fashion. The concentration of 10 compound which caused 50% inhibition of the spontaneously developed tension is given as the IC50(mM). The compounds of Examples 5 and 23 had IC50 values 15 of 11 and 6.5 jiM respectively. Measurement of cardiac muscle relaxation time in rabbit ventricle 20 Papillary muscles from the right ventricle of female Albino New Zealand rabbits were mounted in standard organ baths containing oxygenated Krebs solution. One end of the muscle was connected to an isometric transducer which allowed recording of contractile force and its first 25 derivative on chart recorders. Test compounds were added to the bath in a cumulative manner. Relaxation time was calculated as the time taken from peak tension to the end of the contraction. At concentrations of 30-100 pM, compounds of Examples 12 and 23 caused a 10-20% decrease 3 0 in the relaxation time indicating a lusitropic effect of use in the treatment of cardiovascular diseases such as congestive heart failure. ^p22052/P30140 3 9 Q - 22 -•Rvantpl p, 1 6-(3-Methoxyphenyl)-3-(5-tetrazolyl)pyridin-2(lH)-one 5 a) 3'-Methoxyacetophenone (15g) and dimethylformamide dimethylacetal (16ml) were heated together at 120°C in dimethylformamide (80ml) for 6 hours, the deep red solution was diluted with ethyl acetate (400ml), washed 10 with water (5x100ml), dried (MgS04) and solvent removed at reduced pressure. The oil obtained was dissolved in dimethylformamide (80ml), cyanoacetamide (10.08g) and sodium methoxide (10.8g) added and the mixture heated at 130°C for 35 minutes. The deep red solution was poured 15 into 5% aqueous acetic acid (400ml), the precipitated product collected by filtration and washed with water, ethanol and diethyl ether. Recrystallisation from n-butanol gave 3-cyano-6-(3-methoxyphenyl)pyridin-2(lH)-one (I5.14g) m.p. 251°C as a colourless solid. 20 b) 3-Cyano-6-(3-methoxyphenyl)pyridin-2(lH)-one (lg) sodium azide (0.39g) and ammonium chloride (0.32g) were heated together in N-methylpyrrolidin-2-one (10ml) at 140°C for 2hours. The reaction mixture was poured into 10% 25 aqueous acetic acid (150ml), the precipitated solid collected by filtration, washed with water and recrystallised from n-butanol to give the title compound (0.93g) m.p. 298°C (decomp) . ■'•H NMR S(DMSO-dg) 3.87(s,3H), 6.92(d,IH), 7.13(m,lH), 7.41-7.50(m,3H) and 30 8.48(d,IH). •Rvamplp 2 6-(3—Propoxyphenyl)-3-(5-tetrazolyl)pyridin-2(IH)-one 35 2052/P30140 239 9 4 6 10 - 23 - (a) 3'-Hydroxyacetophenone (13.6g), iodopropane (10.7ml) arid potassium carbonate (13.8g) were heated together in dimethylformamide (80ml) at 90°C for 20hrs. The reaction mixture was diluted with ethyl acetate (400ml), washed with 2N sodium hydroxide (2x100ml) and water (4x100ml), dried (MgS04), filtered and solvent removed at reduced pressure to give 3'-propoxyacetophenone (16.46g) as an oil. XH NMR S(DMSO-dg) 0.99(t,3H), 1.66-1.83(m,2H), 2.58((s,3H), 3.98(t,3H), 7.19(dd,lH) and 7.39-7.57(m,3H). The following compounds were similarly prepared from the appropriate phenol and alkyl iodide. 3'-Butoxyacetophenone:- oil, yield 90%, 1H NMR 15 6(DMSO-dg) 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,lH) and 7.39-7.55(m,3H). 3'-Benzyloxyacetophenone:- oil, yield 89%, % NMR 20 6(CDCI3) 2.57(s,3H), 5.09(s,2H), 7.17(dd,lH) and 7.29-7.56(m,8H). 4'-Methoxy-3'-propoxyacetophenone from 3'-hydroxy-4'-methoxyacetophenone:- (A. Brossi et al J. Org. Chem., 25 1967, 32, 1269) oil, yield 71%, % NMR 6(CDCI3) 1. 05 (t, 3H) , 1.87 (m, 2H) , 2.56(s,3H), 3.93(s,lH), 4.04((t,2H), 6.88(d,IH), 7.52(d,lH), and 7.57(dd,IH). 3',5'-Dipropoxyacetophenone:- oil, yield 58%, 30 NMR 6(DMSO-dg) 0.98(t,6H) 1.66-1.80(m,4H), 2.55(s,3H), 3.96(t,4H), 6.73(t,IH) and 7.04(d,2H). 35 3',5'—Diethoxyacetophenone:- oil, yield 64%, NMR S(DMSO-dg) 1.42(t,6H), 2.56(s,3H), 4.05(q,4H), 6.64(t,IH) and 7.07(d,2H). #2°52/P30140 2 3 9 6 - 24 - 2', 5'-Dipropoxyacetophenone:- oil, yield 64%, ■'■H NMR 6(DMSO-dg) 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). 5 3' ,4'-Dipropoxyacetophenone:- yield 95%, ^-H NMR 6(CDCI3) 1.00-1. 19 (in, 6H), 1.78-2.02(m,4H), 2.55(S,3H), 3.98-4. 17 (m,4H) , 6.87(d,lH), 7.52(s,lH) and 7.54(d,IH). 10 3'-Allyloxyacetophenone:- oil, yield 71%, 1H NMR6 (CDCI3) 2.58(s,3H), 4.57(d,2H), 5.27-5.47 (m,2H) , 5.96-6.15(m,IH), 7.12(dd,IH), 7.31(t,lH) and 7.49-7.55(m,2H) . 15 4'-Methoxy-2'-pentyloxyacetophone:-From 4'-methoxy-2'hydroxyacetophenone and iodopentane, yield 92%, 1H NMR 6(DMSO-dg)0.86(t.3H), 1.20-1.47(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,IH). 20 3'-iso-Butoxy-4'-methoxyacetophenone:-From 4'-methoxy-3'-hydroxyacetophenone and iso-butyl bromide using acetone as solvent, yield 68%. % NMR 5(DMSO-dg) 0.99(d,6H), 1.96-2.15(m,IH), 2.53(s,3H), 25 3.78(d,IH), 3.86(s,3H), 7.06(d,lH), 7.42(d,lH) and 7.62(dd,IH). 3'-Allyloxy-4'-methoxyacetophenone:-From 4'-methoxy-3'-hydroxyacetophenone and allyl bromide, yield 30 67%, 1H NMR S(CDC13) 2.55(s,3H), 3.95(S,3H), 4.63-4.68(m,2H), 5.29-5.47(m,IH), 6.02-6.18(m,IH), 6.90(d,IH),7.53(d,IH) and 7.60(dd,lH). 35 3 ' -(2, 2,-dimethylpropyloxy)-4'-methoxyacetophenone:-Fr m 4'-methoxy-3'-hydroxyacetophenone and l-bromo-2,2-dimethylpropane, yield 76%, NMR 6(CDC13) 2052/P30140 239 9 4 6 - 25 - 1.07(s,9H), 2.56(s,3H), 3.69(s,2H), 6.88(d,lH) and 7.50-7.58(m,2H). 3'-ethoxy-4'-methoxyacetophenone:-from 3'-hydroxy-4'-methoxyacetophenone and iodoethane using acetone as solvent, yield 83%, NMR S(CDC13) 1.49(t,3H),2.57(s,3H),3.94(S,3H),4.17(q,2H),6.89(d,lH),7.53 -7.60(m,2H) . 3' -Ally1-4'-methoxyacetophenone:-from 3'-ally1-4'-hydroxyacetophenone, yield 87% as an oil. XH NMR 6(CDC13)2.55(s,3H),3.40(d,2H),3.89(s,3H), 5.02-5.10(m,2H), 5.90-6.04(m,IH),6.88(d,IH),7.77(d,IH) and 7.85(dd,IH). (b) From 3'-propoxyacetophenone (9g), 3-cyano-6-(3-propoxyphenyl)pyridin-2(IH)-one (3.49g) m.p. 240-241°C after recrystallisation from ethanol, was prepared according to the method of Example 1(a). (c) From 3-cyano-6-(3-propoxyphenyl)pyridin-2(IH)-one (lg), the title compound (0.61g) m.p. 270-271°C after recrystallisation from n-butanol, was prepared according to the method of Example 1(b) . Rva-mplft 3 6-(3-Butoxypheny1)-3-(5-tetrazolyl)pyridin-2(IH)-one (a) 3'-Butoxyacetophenone (17.3g) and dimethylformamide dimethylacetal (11.9g) were boiled together in dimethylformamide (90ml) for 15 hours. The deep red solution was cooled to room temperature, cyanoacetamide (8.3g) and sodium methoxide (10.3g) added and the mixture boiled for a further 3 hours. The reaction mixture was A 2052/P30140 39 9 4 5 - 26 - poured into 10% aqueous acetic acid (300ml) the precipitated product separated by filtration, washed with water and recrystallised from n-butanol to give 3-cyano-6-(3-butoxyphenyl)pyridin-2(IH)-one (10.66g) m.p. 5 201-202°C. (b) From 3-cyano-6-(3-butoxyphenyl)pyridin-2(IH)-one (2.15g), the title compound (0.55g) m.p. 259-260°C after recrystallisation from n-butanol, was prepared according 10 to the method of Example 1(b). Example 4 6-(3-Benzyloxyphenyl)-3-(5-tetrazolyl)pyridin-2(IH)-one 15 (a) From 3'-benzyloxyphenylacetophenone (20.2g), 3-cyano-6-(3-benzyloxyphenyl)pyridin-2(IH)-one (2.6g) m.p.202-203°C after recrystallisation from ethanol, was 2 0 prepared according to the method of Example 3(a). (b) From 3-cyano-6-(3-benzyloxyphenyl)pyridin-2(IH)-one (lg), the title compound (0.35g) m.p.276°C (decomp) after recrystallisation from dimethylformamide was prepared 25 according to the method of Example 1(b). % NMR 6(DMSO-d6) 5.23(s,2H), 6.91(d,lH), 7.16-7.20(m,IH), 7.31-7.54(m,8H), 8.47(d,lH) and 12.67(br S,IH). 30 Kvample 5 6-(3-Bromophenyl)-3-(5-tetrazolyl)pyridin-2(IH)-one (a) From 3'-bromoacetophenone (13.2g), 3-cyano-6-(3-35 bromophenyl)pyridin-2(IH)-one (21.8g) m.p. 309°C (decomp) after recrystallisation from n-butanol, was prepared 23 - 27 - according to the method of Example 1(a). NMR 6(DMSO-dg) 6.89(br s,IH), 7.48(t,lH), 7.75(d,lH), 7.83(d,IH), 8.06(s,IH), 8.21(d,lH) and 12.75(br s,IH). (b) From 3-cyano-6-(3-bromophenyl)pyridin-2(IH)-one (i.37g), the title compound (0.39g) m.p. 285-286°c after recrystallisation from dimethylformamide, was prepared according to the method of Example 1(b). •Rvamplp 6 6- (3-Trif luoromethylphenyl) -3- (5-tetrazolyl) pyridin-2 (IH) -one (a) From 3'-trifluoromethylacetophenone (9.4g), 3-cyano-6-(3-trifluoromethylphenyl)pyridin-2{IH)-one (11.38g) m.p.255-256°C after recrystallisation from ethanol, was prepared according to the method of Example 3(a). (b) From 3-cyano-6-(3-trifluoromethylphenyl)pyridin-2(lH)-one (i.06g), the title compound (0.93g) m.p.274-275°C after recrystallisation from n-butanol, was prepared according to the method of Example 1(b). Example 7 6-(3-EthyIpheny1)-3-(5-tetrazolyl)pyridin-2(1H)-one (a) From 3'-ethylacetophenone (7.4g), 3-cyano-6-(3-ethylphenyl)pyridin-2(IH)-one (3.97g) m.p.241-242°C after recrystallisation from n-butanol, was prepared according to the method of Example 3(a). (b) From 3-cyano-6-(3-ethylphenyl)pyridin-2(IH)-one (0.89g), the title compound (0.37g) m.p.278-279°C after 11 APR 30 239 - 28 - recrystallisation from n-butanol, was prepared according to the method of Example 1(b). Example 8 5 6- (4-Butoxyphenyl) -3- (5-tetrazolyl) pyridin-2 (IH) -one (a)_ From 4'-butoxyacetophenone (5.6g), 3-cyano-6-(4-10 butoxyphenyl)pyridin-2(IH)-one (l.l2g) m.p. 245°C after recrystallisation from ethanol, was prepared according to the method of Example 1(a). (b) A mixture of 3-cyano-6-(4-butoxyphenyl)pyridin- 15 2(lH)-one (0.3g), sodium azide (0.098g), ammonium chloride (0.08g) and lithium chloride (0.064g) were heated in dimethylformamide (15ml) at 120°C for 72 hours. Solvent was removed at reduced pressure, the product precipitated by the addition of 10% aqueous acetic acid (40ml) and 20 separated by filtration. The solid was dissolved in 5% potassium hydrogen carbonate and insoluble material separated by filtration. The filtrate was acidified with conc. hydrochloric acid, the precipitated product collected by filtration and recrystallised from ethanol to 25 give the title compound (0.05g) m.p.289-292°C. Example 9 6-(4-isoButyIpheny1)-3-(5-tetrazolyl)pyridin-2(IH)-one (a) From 4'-isobutylacetophenone (8.8g), 3-cyano-6-(4-isobutylphenyl)pyridin-2(IH)-one (6.0g) m.p. 264°C after recrystallisation from ethanol, was prepared according to the method of Example 3(a). 35 1 1 >\T2 239 2052/P30140 - 29 - (b) From 3-cyano-6-(4-isobutylphenyl)pyridin-2(IH)-one (2.52g), the title compound (l.54g) m.p. 275°C (decomp) after recrystallisation from dimethylformamide, was prepared according to the method of Example 1(b) but using dimethylformamide instead of N-methylpyrrolidin-2-one as solvent. XH NMR $(DMSO-dg) 0.89(d,6H), 1.81-1.96 (m,lH), 2.51(m,2H), 6.87(d,lH), 7.33(d,2H), 7.78(d,2H), 8.46(d,IH) and 12.63(br s,lH). 0 Example 10 6—(4—Biphenyl)-3-(5-tetrazolyl) pyridin-2(IH)-one 5 (a) From 4-acetylbiphenyl (19.6g), 6-(4-biphenyl)-3-cyanopyridin-2(IH)-one (I4.01g) m.p. 312-316°C after recrystallisation from n-butanol, was prepared according to the method of Example 1(a). 0 (b) From 6-(4-biphenyl)-3-cyanopyridin-2(IH)-one (1.36g), the title compound (0.84g) m.p. 305°C (decomp) after recrystallisation from dimethylformamide, was prepared according to the method of Example 1(b) . -^H NMR 6(DMSO-dg) 7.00(d,IH), 7.41-7.54(m,3H), 7.77(d,2H), 5 7.85(d,2H), 7.98(d,2H) and 8.50(d,IH). Example 11 6- (4 -Propoxyphenyl) -3- (5-tetrazolyl) pyridin-2 (IH) -one (a) From 4'-propoxyacetophenone (15.4g) (E. Eckhart and J. Varga, Magyar. Kem. Folvoirat 1961, 67, 509, Chem Abs. 1962, 56, 15557e), 3-cyano-6-(4-propoxyphenyl)pyridin-2(IH)-one (1.8g) m.p. 262-265°C after recrystallisation from dimethylformamide, 2052/P30140 39 9 4 6 - 30 - was prepared according to the method of Example 3(a). (b) From 3-cyano-6-(4-propoxyphenyl)pyridin-2(IH)-one (lg) , the title compound (0.85g) m.p. 292°C (decomp) after recrystallisation from dimethylformamide, was prepared according to the method of Example 1(b). -^H NMR 6(DMSO-d6) 0.99(t,3H), 1.63-1.84(m,2H), 4.02(t,2H), 6.81(d,IH), 7.07(d,2H), 7.82(d,2H) and 8.45(d,IH). Example 12 6-(4-Methoxy-3-propoxyphenyl) -3-(5-tetrazolyl)pyridin-2 (IH) -one (a) From 4'-methoxy-3'-propoxyacetophenone (12g), 3-cyano-6-(4-methoxy-3-propoxyphenyl)pyridin-2(IH)-one (14.03g) m.p. 24l°C after recrystallisation from ethanol, was prepared according to the method of Example 3(a). (b) From 3-cyano-6-(4-methoxy-3-propoxyphenyl)pyridin-2(lH)-one (3.12g), the title compound (1.69g) m.p. 289-290°C after recrystallisation from n-butanol, was prepared according to the method of Example 1(b). Example 13 6- (3,4-Methylenedioxyphenyl) -3- (5-tetrazolyl)pyridin-2(lH)-one (a) From 3',4'-(methylenedioxy)acetophenone (16.4g), 3-cyano-6-(3,4-methylenedioxyphenyl)pyridin-2(IH)-one (10.2g) m.p. >320°C after recrystallisation from dimethylformamide, was prepared according to the method of Example 3(a). ^-H NMR S(DMSO-dg) 6.13(s,2H), 6.72(d,lH), 7.06(d,IH), 7.36-7.42(m,2H), 8.13(d,lH) and 12.58(br s,lH). 2052/P30140 399 4 * - 31 - (b) From 3-cyano-6-(3,4-methylenedioxyphenyl)pyridin-2(lH)-one (0.96g), the title compound (O.lg) m.p. >325°C after recrystallisation from ethanol, was prepared according to the method of Example 1(b) but using dimethylformamide instead of N-methylpyrrolidinone as solvent. 1H-NMR S(DMSO-dg) 6.14(s,2H), 6.83(d,lH), 7.08(d,IH),7.37-7.46(m,2H), 8.43(d,lH), 12.55(br s,IH) and 13.28(br s,IH). Example 14 6- (3,4-Dichlorophenyl) -3- (5-tetrazolyl) pyridin-2 (IH) -one (a) From 3',4'-dichloroacetophenone (18.9g), 3-cyano-6-(3,4-dichlorophenyl)pyridin-2(IH)-one (1.94g) m.p. >330°C after recrystallisation from dimethylformamide, was prepared according to the method of Example 1(a). 1H NMR 6(DMSO-dg) 6.97(br d,IH), 7.76-7.87 (m,2H), 8.15(s,IH) and 8.23(d,lH). (b) From 3-cyano-6-(3,4-dichlorophenyl)pyridin-2(IH)-one (1.06g), the title compound (0.54g) m.p.295°C (decomp) after recrystallisation from dimethylformamide, was prepared according to the method of Example 1(b) but using imethylformamide instead of N-methylpyrrolidinone as solvent. % NMR S(DMSO-dg) 7.02(d,lH) 7.76-7.89 (m,2H), 8.17(s,IH) and 8.48(s,lH). Example 15 6- (3,5-Dipropoxyphenyl) -3- (5-tetrazolyl) pyridin-2 (IH) -one (a) From 3',5'-dipropoxyacetophenone (11.82g), 3-cyano-6-(3,5-dipropoxyphenyl)pyridin-2(IH)-one (7.1g) m.p. ^Pi22052/P30140 239 9 4 6 10 25 - 32 - 209-210°C after recrystallisation from ethanol, was prepared according to the method of Example 3(a). (b) From 3-cyano-6-(3,5-dipropoxyphenyl)pyridin-2(IH)-one (1.25g), the title compound (l.3lg) m.p.224-225°C after recrystallisation from n-butanol, was prepared according to the method of Example 1(b). Example* 16 6-(3,5-Diethoxyphenyl)-3-(5-tetrazolyl)pyridin-2(IH)-one (a) From 3',5'-diethoxyacetophenone (4.16g), 3-cyano-6-15 (3,5-diethoxyphenyl)pyridin-2(IH)-one (l.Og) m.p.259-261°C after recrystallisation from n-butanol, was prepared according to the method of Example 3(a). (b) From 3-cyano-6-(3,5-diethoxyphenyl) pyridin-2(IH)-one 20 (0.82g), the title compound (0,57g) m.p. 282-283°C after recrystallisation from n-butanol, was prepared according to the method of Example 1(b). •Rva-mplf* 17 6- (3,5-Dibromophenyl) -3- (5-tetrazolyl) pyridin-2 (IH) -one (a) From 3',5'-dibromoacetophenone (M. Tashiro, S Mataka, 3 0 H. Nakamura and K Nakayama, J. Chem. Soc. Perkin Trans I.. 1988, 179) (l.llg), 3-cyano-6-(3,5-dibromophenyl)pyridin-2(lH)-one (0.73g) m.p. >300°C after recrystallisation from n-butanol, was prepared according to the method of Example 35 3(a). XH NMR 6(DMSO-dg) 7.00(br d,lH), 8.02(s,lH), 8.09(s,2H) and 8.23(d,lH). 2052/P30140 239946 - 33 - (b) From 3-cyano-6-(3,5-dibromophenyl)pyridin-2(IH)-one (0.53g), the title compound (0.15g) m.p. 295-296°C (decomp) after recrystallisation from n-butanol was prepared according to the method of Example 1(a). -'-H NMR S(DMSO-d6) 7.10 (br d, IH) , 8.02(3,111), 8.13(s,2H) and 8. 47(d,IH). Example* 1 ft 6-(2,4-Dipropoxyphenyl)-3-(5-tetrazolyl)pyridin-2(IH)-one (a) From 2',4'-dipropoxyacetophenone (17.9g) (P. Chabrier, H. Najer, R. Giudicelli and E. Joannie-Voisinet, Bull. Soc. Chim. France. 1958, 1488.), 3-cyano-6-(2,4-dipropoxyphenyl)pyridin-2(IH)-one (1.69g) m.p. 148°C after recrystallisation from ethanol, was prepared according to the method of Example 3(a). (b) From 3-cyano-6-(2,4-dipropoxyphenyl)pyridin-2(IH)-one (lg), the title compound (0.60g) m.p. 205°C after recrystallisation twice from ethanol, was prepared according to the method of Example 1(b). Example 19 6-(2,5-Dipropoxyphenyl)-3-(5-tetrazolyl)pyridin-2(IH)-one (a) From 2',5'-dipropoxyphenylacetophenone (11.8g), 3-cyano-6-(2,5-dipropoxyphenyl)pyridin-2(IH)-one (14.36g) m.p. 160-162°C after recrystallisation from ethanol, was prepared according to the method of Example 3(a). •'■H NMR 6(DMS0-d6) 0.92(t,3H), 0.97(t,3H), 1.61-1.76(m,4H), 3.92(t,4H), 6.54(d,IH), 7.01-7.06(m,3H), 8.18(d,lH). 2052/P30140 - 34 - (b) From 3-cyano-6-(2,5-dipropoxyphenyl)pyridin-2(IH)-one (2.5g), the title compound (0.81g) m.p.188-189°C after recrystallisation from ethanol, was prepared according to the method of Example 1(b). Example* 2Q 6-(2,3,4-Trichloropheny1)-3-(5-tetrazolyl)pyridin-2(IH)-one (a) 2',3',4'-Trichloroacetophenone (22.15g) and dimethylformamide (12.5g) were boiled in dimethylformamide (100ml) for 3 hours. The solution was diluted with ethyl acetate (500ml), washed with water (6x100ml), dried (MgS04), filtered and solvent removed at reduced pressure. The residue was triturated with diethyl ether to give 3-N,N-dimethylamino-1-(2,3,4-trichlorophenyl)prop- 2-ene-l-one (17.5g). IH NMR S(DMSO-dg) 2.84(s,3H), 3.08(br s,3H), 5.17(d,IH), 7.1(very br,lH), 7.30(br d,lH) and 7.65(d,IH). (b) A solution of 3-N,N-dimethylamino-1-(2,3,4-trichlorophenyl)prop-2-ene-l-one (9.8g) and cyanoacetamide (3.18g) in dimethylformamide (35ml) was boiled for 48 hours. The reaction mixture was poured into 10% aqueous acetic acid (100ml), the precipitated product separated by filtration and recrystallised from ethanol to give 3-cyano-6-(2,3,4-trichlorophenyl)pyridin-2(IH)-one (4 . 4g) . XH NMR 6 (DMSO-dg) 6. 52 (d, IH) , 7 .58 (d, IH) , 7.79(d,IH), 8.24 (d,lH) and 12.95(br S,1H). (c) From 3-cyano-6-(2,3,4-trichlorophenyl)pyridin-2(lH)~one (1.2g), the title compound (1.21g) m.p.>300°C after recrystallisation from dimethylformamide/water, was prepared according to the method of Example 1(a). NMR 5(DMSO-dg) 6.63(d,IH), 7.61(d,lH), 7.83(d,lH), 2052/P30140 399 - 35 - 8.51(d,IH) and 12.98(br s,lH). Examnle 21 6—[6-(1,2,3,4-Tetrahydronaphthy1)]-3-(5-tetrazolyl)pyridin-2(IH)-one (a) From 6-acetyltetralin (4.23g), 3-cyano-6-[6-(l,2,3,4-tetrahydronaphthyl)]pyridin-2(IH)-one (1.27g) m.p. 245-246°C after recrystallisation from n-butanol, was prepared according to the method of Example 3(a). IH NMR 5(DMSO-dg) 1.75(m,4H), 2.77(m,4H), 6.71(d,lH), 7.19 (d,IH), 7.50(d,IH), 7.53(s,IH) and 8.15(d,lH). (b) From 3-cyano-6-[6-(l,2,3,4-tetrahydronaphthyl)pyridin-2(lH)-one (lg), the title compound (0.55g) m.p. 284-285°C after recrystallisation from dimethylformamide/water,was prepared according to the method of Example 1(b). •Rvample 22 6—(3-Chlorophenyl)-3-(5-tetrazolyl)pyridin-2(IH)-one (a) From 3'-chloroacetophenone (15.46g), 6-(3-chloro-phenyl)-3-cyanopyridin-2(IH)-one (17.12g) m.p. 304-305°C after recrystallisation from n-butanol, was prepared according to the method of Example 3(a). (b) From 6-(3-chlorophenyl)pyridin-2(IH)-one (1.2g), the title compound (l.Olg) m.p. 301-302°C (decomp) after recrystallisation from n-butanol, was prepared according to the method of Example 1(b). NMR S(DMSO-dg) 6.94(d,IH), 7.48-7.62(m,2H), 7.81(d,lH), 7.96(S,1H), 8.48(d,IH) and 12.77(br s,lH) ? - 2399 4 - 36 - Tgvamplff 9-i 6- (3-Phenylthiophenyl) -3-(5-tetrazolyl)pyridin-2 (IH) -one 5 (a) 3'-Phenylthioacetophenone (2.05g) (L. Victor, Brit. Pat. 1,519,354) and dimethylformamide dimethylacetal (1.19g) were heated together in dimethylformamide (10ml) at 100°C for 18 hours. The reaction mixture was diluted 10 with ethyl acetate (50ml) washed with water (6x30ml), dried (Mgso4) filtered and solvent removed at reduced pressure. The residue was column chromatographed (silica gel, dichloromethane-5% ethanol/dichloromethane eluant) to give 3-N,N-dimethylamino-1-(3-phenylthiophenyl)-15 prop-2-ene-l-one (l.72g) as a yellow oil. (b) A mixture of 3-N,N-dimethylamino-1-(3-phenylthio-phenyl)prop-2-ene-l-one (1.72g), sodium methoxide (0.7 6g) and cyanoacetamide (0.59g) were boiled together in 2 0 dimethylformamide (10ml) for 1 hour. The reaction mixture was poured into 10% aqueous acetic acid (100ml), the precipitated product separated by filtration and recrystallised from ethanol to give 3-cyano-6-(3- 25 phenylthiophenyl)pyridin-2(IH)-one (l.Og) m.p. 262-264°C. (c) From 3-cyano-6-(3-phenylthiophenyl)pyridin-2(IH)-one (0.79g), the title compound (0.77g) m.p.265-266°C after recrystallisation from n-butanol, was prepared according 3 0 to the method of Example 1(b). Example 24 35 6- (3,4-Dimethoxyphenyl)-3-(5-tetrazolyl)pyridin-2(IH)-one (a) From 3',4'-Dimethoxyacetophenone (18g), 3-cyano-6- 11 A°n:?94 2052/P30140 - 37 - (3 ,4-dimethoxyphenyl) pyridin-2 (IH)-one (9.86g) m.p. 269-270°C after recrystallisation from ethanol, was prepared according to the method of Example 1(a). (b) From 3-cyano-6-(3,4-dimethoxyphenyl)pyridin-2(IH)-one (1.02g), the title compound (0.02g) m.p. 293-295°C after recrystallisation from dimethylformamide, was prepared according to the method of Example 1(b). 0 Example 25 6- (3-Methylthiophenyl) -3- (5-tetrazolyl) pyridin-2 (IH) -one 5 (a) From 3'-methylthioacetophenone (4.64g), 3-cyano-6- (3-methylthiophenyl)pyridin-2(IH)-one (4.3g) m.p.234-238°C after recrystallisation from ethanol, was prepared according to the method of Example 3(a). 0 (b) From 3-cyano-6-(3-methylthiophenyl)pyridin-2(IH)-one (lg), the title compound (0.85g) m.p.274-276°C (decomp) after recrystallisation from n-butanol, was prepared according to the method of Example 1(b). NMR 8(DMSO-dg) 2.58 (s,3H), 6.91(d,lH), 7.39-7.63(m,3H), 5 7.68(s,IH) and 8.47(d,lH). Example 26 6-(3-Butylthiophenyl) -3-(5-tetrazolyl)pyridin-2 (IH) -one 0 (a) Copper-(I)-n-butylmercaptide (R. Adams, W. Reijschneider and A. Ferretti, Org, Syn. Coll. Vol., V, pl07) (3.34g) and 3-cyano-6-(3-bromophenyl)pyridin-5 2(lH)-one (2.61g) were heated together in a mixture of quinoline (10ml) and pyridine (3ml) at 160°C for 4 hours. - 239946 ^J|E2052/P30140 - 38 - The reaction mixture was poured onto conc. hydrochloric acid (3Oml) and ice (lOOg) and the precipitated material collected by filtration. The residue was column chromatographed (silica gel, 5 dichloromethane-dichloromethane/2% ethanol) to give 3-cyano-6-(3-butylthiophenyl)pyridin-2(IH)-one (0.35g) m.p. 191-193°C after recrystallisation from ethanol. (b) From 3-cyano-6-(3-butylthiophenyl)pyridin-2(IH)-one 10 (0.23g), the title compound (O.llg) m.p.237-238°C after recrystallisation from n-butanol, was prepared according to the method of Example 1(b). 15 Example 27 6- (3,4-Di-Propoxyphenyl) -3- (5-tetrazolyl) pyridin-2 (IH) • one (a) From 3',4'-di-propoxyacetophenone (3.6g) 20 3-cyano-6-(3,4-dipropoxyphenyl)pyridin-2(IH)-one (3.21g) m.p. 249°C after recrystallisation from ethanol, was prepared according to the method of Example 3(a). (b) From 3-cyano-6-(3,4-di-propoxyphenyl)- 25 pyridin-2(IH)-one (l.OOg) the title compound m.p. 280°C (decomp) after recrystallisation from n-butanol,was prepared according to the method of Example 1(b). -^H NMR Sdg-DMSO) 0.97-1.05(m,6H), 1.71-1.81(m,4H), 4.01(t,2H), 4.03(t,2H), 6.88(d,IH), 7.09(d,lH), 30 7.43(d,IH), 7.46(s,IH) and 8.44(d,IH) and 12.61(br.s,IH). Example 28 35 6-(2,3-di-Propoxyphenyl)-3-(5-tetrazolyl)pyridin-2(IH)-one p2052/P30140 - 39 - (a) From 2,3-dihydroxybenzaldehyde (20g), 2,3-di-propoxy-benzaldehyde (18.6g) isolated as an oil was prepared according to the method of Example 2(a). •'-H-NMR 6(CDC13) 1. 04 (t, 3H) , 1. 09 (t, 3H) , 1. 74-.1. 96 (m, 4H) , 5 3.97(t,2H), 4.15(t,3H), 7. 03-7.16(m,2H) , 7.39(dd,lH) and 10.47(S,1H) (b) To a solution of 2,3-di-propoxybenzaldehyde (18.6g) in tetrahydrofuran at -78°C methyl lithium (61ml, 1.5M in 10 diethyl ether) was added over 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 (MgS04) and solvent removed to give l-(2,3-di-propoxyphenyl)-l-hydroxyethane 15 (20g) as an oil. ^-H-NMR 6(CDC13) 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,IH), 6.80(m,IH) and 6.95-7.04(m,2H). (c) To an ice cooled solution of 1-(2,3-di-propoxy-20 phenyl)-l-hydroxyethane (20g) in dichloromethane (250ml) powdered 4A molecular sieves (23g), N-methylmorpholine-N-oxide (I4.9g) and tetrapropylammonium perruthenate (lg). The mixture was stirred for one hour with ice cooling and at room temperature overnight. After filtration through 25 Hyflo solvent was removed at reduced pressure to give 2',3'-di-propoxyacetophenone (18.3g). 1H-NMR 5(CDC13) 1.03(t,3H), 1.08(t,3H), 1.72-1.96(m,4H), 2.63(s,3H), 3.96(t,2H), 4.01(t,2H) and 6.99-7.19(m,3H). 30 (d) From 23'-dipropoxyacetophenone (lOg), 3-cyano-6-(2,3-di-propoxyphenyl)pyridin-2(IH)-one (l.87g) m.p. 195-198°C was prepared according to the method of Example 3(a), omitting sodium methoxide. *H-NMR (dg-DMSO) 0.81(t,3H), 1.01(t,3H), 1.51(m,2H), 35 1.76(m,2H), 3.84(t,2H), 3.99(t,2H), 6.43(d,lH), 6.97(d,IH), 7.10- 7.27(m,2H) and 8.17(d,IH). £39 9 * 2052/P30140 239 10 - 40 - (e) From 3-cyano-6-(2,3-di-propoxyphenyl)pyridin-2(lH)-one (lg), the title compound (0.47g) m.p. 186-187°C after recrystallisation from aqueous ethanol was prepared according to the method of Example 1(b). Bvatnple 2Q 6— (3 —Cyclopentyloxy—4-methoxyphenyl) -3- (5-tetrazolyl) -pyridin-2(IH)-one (a) A mixture of 3'-hydroxy-4'-methoxyacetophenone (20.8g), potassium carbonate (24.15g), cyclopentyl bromide (22.35g) and potassium iodide (3.32g) were combined in acetone (250ml) and boiled for 24 hours. Dimethylformamide 15 (25ml) was added and boiling continued for a further 24 hours. The reaction mixture was cooled to room temperature, filtered and solvent removed at reduced pressure. The residue was dissolved in diethyl ether (200ml) washed with 2N sodium hydroxide (3x50ml) and water, 20 dried and solvent removed at reduced pressure to give 3'cyclopentyloxy, 4'-methoxyacetophenone as an oil that solidified on standing m.p. 59-60°C. 25 (b) From 3'-cyclopentyloxy-4'-methoxyacetophenone (11.25g), 3-cyano-6-(3-cyclopentyloxy-4-methoxyphenyl)-pyridin-2(IH)-one (4.07g) m.p.259-260°C after digestion with acetonitrile was prepared according to the method of Example 3(a) omitting sodium methoxide. 30 (c) From 3-cyano-6-(3-cyclopentyloxyphenyl-4-methoxyphenyl)pyridin-2(IH)-one (0.8g), the title compound (0.6g) m.p. 286-287°C (decomp) after recrystallisation from dimethylformamide was prepared according to the 35 method of Example 1(b). 1H-NMR S(dg-DMSO) (J^2052/P30140 - 41 - 1.54-2.02(m,8H), 3 . 83 (s, 3H) , 5.00(m,lH), 6.87(d,lH), 7.10(d,IH), 7.43(s,IH), 7.46(d,lH) and 8.44(d,IH). Tftrampli* 30 5 6-(3-Ethoxyphenyl)-3-(5-tetrazolyl) pyridin-2(IH)-one (a) A mixture of 3-hydroxyacetophenone (6.8g) and 10 tris(dimethylamino)methane (14.5g) were heated together in dimethylformamide (30ml) at 80°C for 4 hours. The reaction mixture was cooled to room temperature cyanoacetamide (8.4g) added and the mixture boiled for 8 hours. After cooling to room temperature the mixture was poured into 15 10% aqueous acetic acid (200ml), filtered and the residue washed with water and ethanol to give 3-cyano-6-(3-hydroxyphenyl)pyridin-2(IH)-one. 1H-NMR S(dg-DMSO) 6.64(br.d,IH), 6.95(dd,IH), 7.12(s,lH), 7.20(d,lH), 7.32(t,IH), 8.15(d,IH), 9.87(s,lH) and 12.70(br.s,IH). 20 (b) To a suspension of sodium hydride (lg, 50% in oil) in dimethylformamide (15ml) 3-cyano-6-(3-hydroxy- phenyl)pyridin-2(IH)-one (2.12g) was added in portions over 30 minutes. When gas evolution had ceased 25 iodoethane (1.56g) was added and the mixture stirred overnight. The mixture was diluted with ethyl acetate (100ml), washed with 2N hydrochloric acid (2x30ml) and with water (4x50ml), dried (MgS04) and solvent removed at reduced pressure. The residue was recrystallised from 30 n-butanol to give 3-cyano-6-(3-ethoxyphenyl)pyridin-2(IH)-one (0.68g). 1H-NMR S(dg-DMSO) 1.35(t,3H), 4.12(q,2H), 6.80(d,IH), 7.08(d,lH), 7.31-7.47(m,3H) and 8 .18(d,IH) . 35 (c) From 3-cyano-6-(3-ethoxyphenyl)pyridin-2(IH)-one (0.5g), the title compound (0.44g) m.p.279°C (decomp) 2052/P30140 2399 - 42 - after recrystallisation from n-butanol, was prepared according to the method of Example 1(b). ^-H-NMR 6(dg-DMSO) 1.36(t,3H), 4.14(q,2H), 6.90(d,lH), 7.10(m,lH), 7.34-7.48(m,3H) and 8.47(d,IH). Rva-mpl 31 6- (3,5-Dimethoxyphenyl) -3-(5-tetrazolyl)pyridin-2 (IH) -one (a) From 3',5'-dimethoxyacetophenone (4.lg), 3-cyano-6-(3,5-dimethoxyphenyl)pyridin-2(IH)-one (2.4lg) m.p. 297°C after recrystallisation from ethanol, was prepared according to the method of Example 3(a). (b) From 3-cyano-6-(3,5-dimethoxyphenyl)pyridin-2(lH)-one (1.4g), the title compound (1.36g) m.p. 338°C (decomp) after recrystallisation from acetonitrile/dimethyl-formamide was prepared according to the method of Example 1(b). ^-H NMR 6(d6-DMSO) 3.86(s,6H), 6.66(m,lH), 6.95(d,IH), 7.02(m,2H), 8.47(d,lH) and 12.66(br.S,IH). Rvamplia 32 6- (2-Butylthiophenyl) -3-(5-tetrazolyl)pyridin-2 (IH) -one (a) From 2'-bromoacetophenone (19.9g), 6-(2-bromophenyl)-3-cyanopyridin-2(lH)-one (11.4g) m.p. 245-246°C after recrystallisation from ethanol,was prepared according to the method of Example 1(a). (b) From 6-(2-bromophenyl)-3-cyanopyridin-2(IH)-one (2.61g), 6-(2-butylthiophenyl)-3-cyanopyridin-2 (IH)-one (0.83g) m.p.163-165°C after recrystallisation from ■^2052/P30140 10 - 43 - ethanol, was prepared according to the method of Example 26(a). (c) From 6-(2-butylthiophenyl)-3-cyanopyridin-2(IH)-one (0.7lg), the title compound (0.53g) m.p.181-182°C after recrystallisation from ethanol, was prepared according to the method of Example 1(b). Example 33 6-(3-Allyloxyphenyl) -3-(5-tetrazolyl) pyridin-2 (IH) -one (a) From 3'-allyloxyacetophenone (15.07g), 15 6-(3-allyloxyphenyl)-3-cyanopyridin-2(lH)-one (14.7g) was prepared according to the method of Example 3(a). 1H NMR S(dg-DMSO) 4.67(d,2H), 5.26-5.46(m,2H), 5.98-6.20(m,IH), 6.80(d,IH), 7.13(m,lH), 7.33(m,3H) and 8.20(d,IH). 20 (b) From 6-(3-allyloxyphenyl)-3-cyanopyridin-2(lH)-one (lg), the title compound (0.34g) m.p.260°C (decomp) after recrystallisation from n-butanol, was prepared according to the method of Example 1(b). 1H NMR S(dg-DMSO) 25 4.72(m,2H), 5.28-5.52(m,2H), 6.04-6.20(m,IH), 6.94(d,lH), 7.14(m,IH), 7.48(m,3H) and 8.47(d,lH). Example 34 6-(4-Methoxy-2-pentyloxypheny1)-3-(5-tetrazolyl)pyridin-30 2(IH)-one (a) From 4'-methoxy-2'-pentyloxyacetophenone (11.8g), 3-cyano-6- (4-methoxy-2-pentyloxyphenyl)pyridin-2(IH)-one (3.4g) m.p. 143-144°C after recrystallisation from ethanol, 35 was prepared according to the method of Example 3 (a). # 22052/P30140 10 15 - 44 (b) From 3-cyano-6- (4-methoxy-2-pentyloxyphenyl)pyridin-2(lH)-one (1.259), the title compound (0.65g) m.p. 193-194°C after recrystallisation from ethanol was prepared according to the method of Example 1(b). Example 35 6- (3-iso-Butoxy-4-methoxyphenyl)-3-(5-tetrazolyl)pyridin-2(IH)-one (a) From 3'-iso-butoxy-4'-methoxyacetophenone (7.6g), 3-cyano-6-(3-iso-butoxy-4-methoxyphenyl)pyridin-2(IH)-one (6.02g) m.p.234-235°C after recrystallisation from ethanol, was prepared according to the method of Example 3(a). (b) From 3-cyano-6-(3-iso-butoxy-4-methoxyphenyl)pyridin-2(lH)-one (1.19g), the title compound (1.2g) m.p. 296-297°C (decomp) after recrystallisation from ethanol, was prepared according to the method of Example 1(b). NMR 5(DMSO-dg) 20 1.01 (d, 6H) , 2.02-2.16 (m, IH), 3.85(s,3H), 3.89(d,2H), 6.89(d,IH), 7.12(d,IH), 7.41-7.50(m,2H) and 8.47(d,IH). Example 36 25 6-(2-Bromo-3,5-diethoxyphenyl)-3-(5-tetrazolyl)pyridin-2(IH)-one (a) To an ice cooled solution of 3', 5'-diethoxyacetophenone (10.4g) in dimethylformamide (50ml) N-bromosuccinimide 30 (9.79g) was added in portions over 1 hour. The mixture was stirred at 0°C for 3 hours and stood at room temperature for 48 hours. After diluting with ethyl acetate (200ml) the mixture was washed with water (5x100ml), dried (MgSO^) and solvent removed at reduced pressure to give 2'-bromo-3',5'-35 diethoxyacetophenone (12.53g) as an oil.^H NMR SfCDClg) 1.41 (t,3H), 1.50(t,3H), 2.60 (s,3H), 4.00(q,2H), 4.10(q,2H), 6.45(d,lH) and 6.50(d,IH). 22052/P30140 303 - 45 - (b) From 2'-bromo-3',5'-diethoxyacetophenone (4.31g), 3-cyano-6-(2-bromo-3,5-diethoxyphenyl)pyridin-2 (lH)-one (0.75g) m.p. 234-235°C after recrystallisation from 5 ethanol, was prepared according to the method of Example 3(a) . (c) From 3-cyano-6-(2-bromo-3,5-diethoxyphenyl)pyridin-2(lH)-one (0.6g), the title compound m.p. 276°C after 10 recrystallisation from ethanol was prepared according to the method of Example 1(b). Example 37 15 6- (5 -Bromo-4 -methoxy-2 -penty loxypheny 1) -3- (5-tetrazolyl) -pyridin-2(IH)-one (a) A mixture of 3-cyano-6-(4-methoxy-2-pentyloxyphenyl)-pyridin-2(IH)-one (1.71g), silver carbonate (1.92g) and 20 iodomethane in chloroform (30ml) were stirred in the dark for 48 hours. After filtration (celite pad) solvent was removed at reduced pressure and the residue column chromatographed (silica gel, 40%hexane/dichloromehane eluant) to give 3-cyano-2-methoxy-6-(4-methoxy-2- 25 pentyloxyphenyl)pyridine (1.45g) m.p.76-78°C. (b) To a cooled (ice bath) solution of 3-cyano-2-methoxy-6-(4-methoxy-2-pentyloxyphenyl)pyridine (1.3g) in dimethylformamide (10ml) N-bromosuccinimide (0.71g) was 30 added in portions over 30 minutes. The solution was stirred at room temperature overnight diluted with ethyl acetate (50ml) and washed with water (5x50ml). The organic phase was dried (MgS04) solvent removed at reduced pressure and the residue recrystallised from ethanol to give 3-cyano-2- 35 methoxy-6-(5-bromo-4-methoxy-2-pentyloxyphenyl)pyridine (l.lg) m.p. 136-137°C. 22052/P30140 239 - 46 - (c) 3-Cyano-2-methoxy-6-(2-bromo-4-methoxy-2-pentyloxyphenyl)pyridine (lg) and sodium iodide (1.50g) (dried at 70°C in vacuo for 4 hours) were dissolved in acetonitrile (10ml) and chlorotrimethylsilane (1.08g) 5 added. The reaction mixture was stirred in the dark for 2 hours, diluted with ethyl acetate (50ml) washed with water (2x50ml), with 5% aqueous sodium metabisulphite (30ml) and water (50ml). The organic phase was dried (MgS04) solvent removed at reduced pressure and the residue recrystallised 10 from ethanol to give 3-cyano-6-(5-bromo-4-methoxy-2- pentyloxyphenyl)pyridin-2(IH)-one (0.55g) m.p.l88-190°C. (d) From 3-cyano-6-(5-bromo-4-methoxy-2-pentyloxyphenyl)pyridin-2(IH)-one (0.5g), the title 15 compound (0.38g) m.p.246-248°C after recrystallisation from ethanol, was prepared according to the method of Example Kb) . 20 Example 38 6- (2-Ally 1-4 -methoxy-3 -propoxyphenyl) -3- (5-tetrazolyl) -pyridin-2(IH)-one (a) A mixture of 3'-allyloxy-4'-methoxyacetophenone (7.76g) 25 and diethylaniline (5.96g) 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 (100ml) and washed with 2N hydrochloric acid (3x100ml). The organic phase was dried 30 (MgS04) and solvent removed at reduced pressure to give after recrystallisation from ethanol/water 2'-allyl-3'-hydroxy-4'-methoxyacetophenone (5.1g) m.p.81-83°C. (b) 2' -Allyl-3'-hydroxy-4'-methoxyacetophenone (5.0g), 35 potassium carbonate (3.3g) and iodopropane were heated together in a mixture of dimethylformamide (20ml) and butanone (30ml) for 48 hours. The mixture was filtered and 4f 5 10 15 20 30 22052/P30140 - 47 - solvent removed from the filtrate at reduced pressure to give a residue which was dissolved in ethyl acetate (100ml) and washed with water (5x50ml). The organic phase was dried (MgS04) and solvent removed at reduced pressure to give 2'-allyl-4'-methoxy-3'-propoxyacetophenone (5.0g) as an oil. NMR 5(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, IH), 6.99(d,lH and 7.63(d,lH). (c) From 2'-allyl-4#-methoxy-3'-propoxyacetophenone (4.96g) 3-cyano-6- (2-allyl-4-methoxy-3-propoxyphenyl)pyridin-2 (1H)-one (1.15g) m.p. 170-171°C after recrystallisation from ethanol was prepared according to the method of Example 3(a) with, however, the omission of sodium methoxide. (d) From 3-cyano-6-(2-allyl-4-methoxy-3- propoxyphenyl)pyridin-2(IH)-one (0.49g), the title compound (0.24g) m.p. 210-211°C after recrystallisation from ethanol was prepared according to the method of Example 1 (b) . Example 39 6- [3- (E-l-propenyl) -4-methoxyphenyl] -3- (5-tetrazolyl) -pyridin-2(IH)-one (a) From 3-allyl-4-methoxyacetophenone (7.6g), 3-cyano-6-[3-(E-l-propenyl)-4-methoxyphenyl]pyridin-2(IH)-one (4g) after recrystallisation from n-butanol, was prepared according to the method of Example 3(a). 1H NMR 8(DMSO-dg) 1.88 (d, 3H), 3.87 (s, 3H), 6.40-6. 67 (m, 3H), 6.78(d,lH), 7.10(d,lH), 7.72(dd,IH), 7.93(d,IH) and 8.14(d,IH). (b) From 3-cyano-6-[3-(E-l-propenyl)-4- methoxyphenyl]pyridin-2(IH)-one (2.13g), the title compound (0.8g) m.p. 291-295°C (decomp) after recrystallisation from dimethylformamide was prepared according to the method of Example 1(b). XH NMR 8(DMSO-dg) 1.89(d,3H), 3.88 (s,3H), 10 22052/P30140 - 48 - 233946 6.42-6.71 (m, 3H), 6.90(01,111), 7.12(d,lH), 7.76(dd,lH), 7.97 (d,lH) and 8.44 (d,lH) . Example 40 6-(4-Methoxy-3-propoxyphenyl)-3-[5-(1-pivaloyloxymethyl)-tetrazolyl)pyridin-2(IH)-one and 6-(4-methoxy-3-propoxyphenyl) -3- [5- (2-pivaloyloxymethyl) -tetrazolyl]pyridin-2(IH)-one A mixture of 4-methoxy-3-propoxyphenyl)-3-(5-tetrazolyl)pyridin-2(IH)-one (1.64g), pivaloyloxymethyl chloride (0.75g), sodium hydrogen carbonate (420mg) and sodium iodide (50mg) were heated in dimethylformamide (5ml) 15 at 70°C for 24 hours. The mixture was diluted with ethyl acetate (50ml) and washed with water 6 x 50ml). The organic phase was dried (MgSO^) filtered and solvent removed at reduced pressure. The residue was column chromatographed (silica gel, 70% hexane/ethyl acetate - 30% hexane/ethyl 20 acetate eluant to give:- a) 6-(4-methoxy-3-propoxyphenyl)-3-[5- (1-pivaloyloxymethyl)tetrazolyl]pyridin-2(IH)-one (0.26g) m.p. 169-170°C after recrystallisation from ethanol and b) 6-(4-methoxy-3-propoxyphenyl)-3-[5-(2-pivaloyloxymethyl)tetrazolyl]pyridin-2(IH)-one (0.35g) 25 m.p.195-196°C after recrystallisation from ethanol. Example 41 6-[3-Ethoxy-5-(2-methoxyethoxy)phenyl]-3-(5-tetrazolyl)-30 pyridin-2(IH)-one a) 3',5'-Dihydroxyacetophenone (15.2g), potassium carbonate (7.59g) and iodoethane (17.16g) were combined and heated at reflux for 15 hours. Additional potassium carbonate (2.76g) 35 and iodoethane (6.2g) were added and heating was continued for a further 10 hours. The reaction mixture was filtered, solvent removed at reduced pressure, the residue dissolved 22052/P30140 - 49 - in ethyl acetate (100ml) and extracted with 2N sodium hydroxide (3x50ml). The combined basic extracts were washed with ethyl acetate (2x50ml), acidified with 2N hydrochloric acid and extracted with dichloromethane (3x100ml). The 5 combined dichloromethane extracts were washed with water (2x50ml), dried (MgSO^), filtered and solvent removed at reduced pressure. The residue was column chromatographed (silica gel, dichloromethane eluant) to give 3'-ethoxy-5'-hydroxyacetophenone (4.83g) m.p. 96-98°C. 10 b) To a suspension of sodium hydride (0.92g, 60% in oil washed with hexane) in dimethylformamide (10ml), 3'-ethoxy-5'-hydroxyacetophenone (3.24g) was added in portions over 10 minutes. When gas evolution had ceased chloroethylmethyl 15 ether (1.9g) and sodium iodide (50mg) were added and the mixture heated to 90°C for 18 hours and stirred at room temperature for 24 hours. The mixture was diluted with ethyl acetate (100ml), washed with 2N sodium hydroxide (3x50ml) and water (3x50ml). The organic phase was dried 20 (MgS04), filtered and solvent removed at reduced pressure to give 3'-ethoxy-5'-(2-methoxyethoxy)acetophenone (4.03g) as an oil. 1H NMR 6(CDC13) 1.42(t,3H), 2.56(s,3H), 3.46 (s,3H), 3.74-3.78 (m,2H), 4.05(q,2H), 4.13-4.17(m,2H), 6.68(m,IH) and 7.10(m,2H). 25 c) From 3'-ethoxy-5'-(2-methoxyethoxy)acetophenone, 3-cyano-6-[3-ethoxy-5-(2-methoxyethoxy)phenyl]pyridin-2(IH)-one (l.lg) m.p.l99°C after recrystallisation from ethanol, was prepared according to the method of Example 3(a). 30 d) From 3-cyano-6-[3-ethoxy-5-(2- methoxyethoxy)phenyl]pyridin-2(IH)-one (0.94g), the title compound (0.6g) m.p.205-206°C after recrystallisation from ethanol, was prepared according to the method of Example 35 1 (b) . 239 » tfk. m 5 10 15 20 25 30 35 22052/P30140 239 QL « - 50 -Example 42 6- (3- (2,2-Dimethylpropyloxy) -4-methoxyphenyl) -3- (5-tetrazolyl) pyridin-2(IE)-one a) From 3'-(2,2-dimethylpropyloxy)-4' -methoxyacetophenone (9.0g), 3-cyano-6-[3- (2,2-dimethylpropyloxy)-4-methoxyphenyl]pyridin-2(IH)-one (3.46g) was prepared according to the method of Example 3(a) . ■'■H NMR 5(DMS0 dg) 1. 02 (s, 9H), 3.74(s,2H), 3.85(s,3H), 6.79(d,lH), 7.09(d,lH), 7.42 (s, IH), 7.43(d,lH) and 8.14(d,IH). b) From 3-cyano-6-[3-(2,2-dimethylpropyloxy)-4-methoxyphenyl]pyridin-2 (IH) -one (1.25g), the title compound (1.28g) m.p. >300°C after recrystallisation from n-butanol, was prepared according to the method of Example 1(b). *H NMR 5(DMSO-d6) 1. 04 (s, 9H), 3.77(s,2H), 3.86(s,3H), 6.90(d,IH), 7.10(d,IH), 7.45(m,2H) and 8.44 (d,lH). 6- (3-Ethoxy-4-methoxyphenyl) -3- (5-tetrazolyl) pyridin-2 (IH) -one a) From 3'-ethoxy-4f-methoxyacetophenone (2.91g), 3-cyano~ 6-(3-ethoxy-4-methoxyphenyl)pyridin-2(IH)-one (2.02g) m.p.273°C after recrystallisation from ethanol was prepared according to the method of Example 1(a). b) From 3-cyano-6-(3-ethoxy-4-methoxyphenyl)pyridin-2(IH)-one (l.Og), the title compound (1.06g) m.p.299°C (decomp) after recrystallisation from n-butanol, was prepared according to the method of Example 1(b) . NMR 8 (DMSO-dg) 1.37 (t, 3H), 3.84 (s, 3H), 4.15(q,2H), 6.92(d,lH), 7.10(d,lH), 7.41-7.50 (m,2H) and 8.43(d,lH). • * I.' 22052/P30140 239 9 4 6 - 51 -Example 44 6- (3-Propionamidophenyl) -3- (5-tetrazolyl)pyridin-2 (IH) -one 5 a) To a stirred suspension of sodium methoxide (4.32g) in diethyl ether (50ml) a mixture of 3'- propionamidoacetophenone (5.73g) and ethyl formate (4.44g) in tetrahydrofuran (100ml) was added over 30 minutes. After stirring overnight the mixture was filtered and the residue 10 washed with diethyl ether. The residue was dissolved in water (50ml), the pH adjusted to 9.0 with glacial acetic acid and cyanoacetamide (4.2g) added. The solution obtained was boiled overnight cooled to room temperature and adjusted to pH 5 with glacial acetic acid (US Patent 15 4,278,681). The precipitated material was collected by filtration, washed thoroughly (4x50ml) with ethanol and recrystallised from dimethylformamide/water to give 3-cyano-6-(3-propionamidophenyl)pyridin-2(IH)-one (0.4g) m.p. 328-330°C 20 b) From 3-cyano-6-(3-propionamidophenyl)pyridin-2 (IH)-one (0.3g) the title compound (0.2g) m.p.291-293°C (decomp) after recrystallisation from dimethylformamide/water, was prepared according to the method of Example 1(b). NMR 25 8 (DMSO-dg) 1.11 (t, 3H) , 2.37(q,2H), 6.75 (d,lH), 7.46(m,2H), 7.69 (m,IH), 8.09 (m,IH) and 8.50(d,IH). Example 45 30 6-(4-Methoxy-3-propylphenyl) -3-(5-tetrazolyl)pyridin-2(IH)-one (SB 20525)) (a) A solution of 3'-allyl-4'-methoxyacetophenone (20g) in ethanol (250ml) containing 10% palladium on charcoal (2g) 35 was treated with hydrogen at 50 p.s.i until the calculated volume of hydrogen had been taken up. The mixture was filtered (celite pad) and solvent removed at reduced # 22052/P30140 - 52 - 2399 pressure. The residue was dissolved in dichloromethane (100ml) and manganese dioxide (60g) added. The mixture was stirred at room temperature for 48 hours, filtered (celite pad) and solvent removed at reduced pressure to give 4'-5 methoxy-3'-propylacetophenone (15.16g) as an oil. 1H NMR 8(CDC13) 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,lH), 7.77 (d,lH) and 7.82(dd,IH). 10 (b) From 4'-methoxy-3'-propylacetophenone (5.77g), 3-cyano-6-(4-methoxy-3-propylphenyl)pyridin-2(IH)-one (4.43g) m.p. 239°C after recrystallisation from butanol, was prepared according to the method of Example 3(a). 15 (c) From 3-cyano-6-(4-methoxy-3-propylphenyl)pyridin-2 (IH) -one (4.02g), the title compound (3.64g) m.p.293-294°C (decomp) after recrystallisation from ethanol, was prepared according to the method of Example 1(b). 1H NMR 5(DMSO-dg) 0.93(t, 3H), 1.51-1.71(m,2H), 2.59(t,2H), 3.87(s,3H), 20 6.83(d,IH), 7.10 (d,IH), 7.68-7.74 (m,2H) and 8.46(d,IH). Example 46 6- (3-Bromo-4-methoxyphenyl) -3- (5-tetrazolyl)pyridin-2 (IH) -25 one (SB 204617) (a) From 3'-bromo-4'-methoxyacetophenone (K.W.Rosenmund et. al. Chem. Ber., 1922, 90, 1957) (2.29g), 3-cyano-6-(3-bromo-4-methoxyphenyl)pyridin-2(IH)-one (1.42g) m.p. 284- 30 286°C after recrystallisation from ethanol, was prepared according to the method of Example 3(a). (b) From 3-cyano-6-(3-bromo-4-methoxyphenyl)pyridin-2 (IH)-one (1.22g), the title compound (1.28g) m.p. 292-293°C 35 (decomp) after recrystallisation from dimethylformamide, was prepared according to the method of Example 1 (b). 1H 239 9 4 22052/P30140 - 53 - NMR 8 (DMSO-dg) 3 . 94 (s, 3H) , 6.90(d,lH), 7.27(d,lH), 7.90(dd,IH), 8.14(d,lH) and 8.45(d,IH). Example 47 5 6- (3-phenyl-4-methoxyphenyl) -3- (5-tetrazolyl)pyridin-2 (IH) -one (SB 204649) (a) To a suspension of 10 tetrakis(triphenylphosphine)palladium (0) (0.5g) in aqueous sodium hydrogen carbonate (5.04g in 60ml water), solutions of phenylboronic acid (2.65g) in dimethoxyethane (100ml) and 3'-bromo-4'-methoxyacetophenone (4.58g) in dimethoxyethane (110ml) were added. The mixture was stirred 15 under reflux for 3 hours cooled to room temperature and solvent removed at reduced pressure. The residue was partitioned between chloroform (200ml) and water (200ml), the organic phase separated dried (MgS04) and solvent removed at reduced pressure. The residue was recrystallised 20 from ethanol to give 4'-methoxy-3'-phenylacetophenone (2.87g) m.p. 92-93°C. (b) From 4'-methoxy-3'-phenylacetophenone (3.3g), 3-cyano-6-(3-phenyl-4-methoxyphenyl)pyridin-2(IH)-one (2.37g) m.p. 25 288-291°C after recrystallisation from propan-2-ol, was prepared according to the method of Example 3(a). (c) From 3-cyano-6-[ (3-phenyl)-4-methoxyphenyl]pyridin-2(lH)-one (0.91g), the title compound (0.70g) m.p. 289- 30 291°C after recrystallisation from dimethylformamide/ethanol, was prepared according to the method of Example 1(b). NMR S(DMSO-dg) 3.86(s,3H), 6.92(d,IH), 7.28(d,IH), 7.33-7.48(m,3H), 7.62(d,2H), 7.81-7.89(m,2H), 8.45(d,lH), 11.96(br.s,IH) and 12.71(br.s,IH) 35 m 239 9 4 6 22052/P30140 - 54 -Example 48 6- [4-Methoxy-3,5-di (E-l-propenyl) phenyl] -3- (5-tetrazolyl) -pyridin-2(IH)-one (SB 204788) 5 (a) From 3'-ally1-4'-hydroxyacetophenone (17.6g), 3'-allyl-4'-allyloxyacetophenone (20.7g) isolated as an oil, was prepared according to the method of Example 2(a) using acetone as solvent. NMR SfCDClg) 2.55(s,3H), 3.44 (d,2H), 10 4 . 61 (m, 2H) , 5 . 04-5.46 (m, 4H) , 5. 94-6.10 (m, 2H), 6.86(d,lH), 7.78d,IH) and 7.83(dd, IH) . (b) From 3'-allyl~4'-allyloxyacetophenone (20.5g), 3',5'-diallyl-4'-hydroxyacetophenone (16.3g) m.p. 83-84°C was 15 prepared according to the method of Example 38(a). (c) From 3',5'-diallyl-4'-hydroxyacetophenone (16g), 3', 5'-diallyl-4'-methoxyacetophenone (17g) isolated as an oil, was prepared according to the method of Example 2(a). 20 NMR 8(CDC13) 2.55 (s, 3H), 3.46(d,4H), 3.77(s,3H), 5.05-5.14(m,4H), 5.91-6.07(m,2H) and 7.69(s,2H). (d) From 3',5'-diallyl-4'-methoxyacetophenone (8.5g), 3-cyano-6-[4-methoxy-3,5-di(E-l-propenyl)phenyl ] pyridin- 25 2(lH)-one (6.1g) m.p. 248-250°C after trituration with hot ethanol, was prepared according to the method of Example 3(a) . (e) From 3-cyano-6-[4-methoxy-3,5-di(E-l- 30 propenyl)phenyl]pyridin-2(IH)-one (0.46g), the title compound (0.27g) m.p. 285-287°C (decomp) after recrystallisation from dimethylformamide/water, was prepared according to the method of Example 1 (b) . ■LH NMR 8(DMSO-dg) 1.92(d,6H), 3.68(s,3H), 6.49-6.68(m,4H), 35 7.00 (d, IH), 7.89(s,2H) and 8.45(d,lH). 2399 4 6 22052/P30140 - 55 -Example 49 6- [3- (E-l-Propenyl) -4-propoxyphenyl] -3- (5-tetrazolyl) -pyridin-2 (IH) -one. (SB 201433) 5 (a) From 3'-ally1-4'-hydroxyacetophenone (5.28g), 3'-allyl-4'-propoxyacetophenone (6.06g) isolated as an oil was prepared according to the method of Example 2(a). NMR 8(CDC13) 1.07(t,3H), 1.66-1.92 (m, 2H), 2.55(s,3H), 10 3.41(d,2H), 3.99(t,2H), 5.04-5.12 (m,2H), 5.90-6.06 (mfIH), 6.86 (d, IH), 7.77(d,lH) and 7.83 (dd, IH) . (b) From 3'-allyl-4'-propoxyacetophenone (5.7g), 3-cyano-6-[3-(E-l-propenyl)-4-propoxyphenyl]pyridin-2(lH)-one (2.57g) 15 m.p. 240-244°C after recrystallisation from butanol, was prepared according to the method of Example 3 (a). (c) From 3-cyano-6-[3-(E-l-propenyl)-4- propoxyphenyl]pyridin-2 (IH)-one (1.18g), the title compound 20 (0.7g) m.p.290-292°C (decomp) after recrystallisation from butanol, was prepared according to the method of Example 1(b). 1H NMR 8 (DMSO-dg) 1.02(t,3H), 1.73-1.86 (m, 2H), 1.90(d,3H), 4.04(t,2H), 6.48-6.61(dq,IH), 6.65(d,lH), 6.89(d,IH), 7.11(d,IH), 7.70(dd,IH), 7.97(d,lH) and 25 8.43 (d, IH) . Example 50 6- (3-Bromo-4-methoxy-5-propylphenyl) -3- (5-tetrazolyl) -30 pyridin-2(IH)-one. (273/2534) (a) From 4'-methoxy-3'-propylacetophenone (7.6g), 3'-bromo-4'-methoxy-5'-propylacetophenone (4.8g) isolated as an oil after column chromatography (silica gel, 50% 35 hexane/dichloromethane eluant) was prepared according to the method of Example 36(a). NMR StCDClj) 0.98(t,3H), 399 9 22052/P30140 - 56 - 1.57-1.73 (m,2H) , 2.56(s,3H), 2.67(t,2H)/ 3.87(s,3H), 7.74(d,lH) and 7.98(d,IH). (b) From 3'-bromo-4'-methoxy-5'-propylacetophenone (3.4g), 5 6-(3-bromo-4-methoxy-5-propyIpheny1)-3-cyanopyridin-2(IH)- one (1.2g) after recrystallisation from ethanol/ was prepared according to the method of Example 3 (a). NMR 8(DMSO-dg) 0.94(t,3H), 1.57-1.67(m,2H), 2.65(t,2H), 3.79 (s,3H), 6.38(br.d,IH), 7.74(d,lH), 7.97(d,lH) and 10 8.18(d,IH) . (c) From 6-(3-bromo-4-methoxy-5-propylphenyl)-3-cyanopyridin-2 (IH)-one (0.39g), the title compound (0.17g) m.p. 286-287 (decomp) after recrystallisation from ethanol, 15 was prepared according to the method of Example 1 (a). *H NMR 8 (DMSO-dg) 0. 96 (t, 3H), 1. 61-1.70 (m, 2H), 2.67(t,2H), 3.81(s,3H), 6.94(d,IH), 7.76(d,lH), 7.99(d,lH) and 8.45(d,IH). 20 Example 51 6-(2-Butylthio-3,5-diethoxyphenyl)-3-(5-tetrazolyl)pyridin-2(IH)-one 25 (a) From 2'-bromo-3',5'-diethoxyacetophenone (2.53g), 2'-butylthio-3',5'-diethoxyacetophenone (1.96g) after column chromatography (silica gel, hexane/dichloromethane 4:1 eluant) was prepared according to the method of Example 26(a). 1H NMR 8(CDC13) 0.87(t,3H), 1.25-1.65(m,10H), 30 2 .59 (s, 3H) , 2.76 (t,2H), 4.02 (q,2H), 4.08 (q,2H), 6.33 (d,lH) and 6.46(d,IH). (b) From 2'-butylthio-3',5'-diethoxyacetophenone (1.95g), 3-cyano-6- (2-butylthio-3,5-diethoxyphenyl)pyridin-2(IH)-one 35 (0.13g) after recrystallisation from ethanol, was prepared according to the method of Example 3(a). NMR 8(DMSO-dg) 22052/P30140 - 57 - 239946 0.77(t,3H), 1.18-1.43(m,10H), 2.66(t,2H), 4.03-4.18(m,4H), 6.27 (d, IH) / 6.59(d,lH), 6.71(d,lH) and 8.15(d,IH). (c) From 3-cyano-6-(2-butylthio-3,5-diethoxyphenyl)-3-(5-5 tetrazolyl)pyridin-2(IH)-one (0.12g), the title compound (0.08g) m.p. 138-140°C after recrystallisation from ethanol, was prepared according to the method of Example 1(a). ^-H NMR 8(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,lH), 6.62(d,lH), 10 6.70 (d,IH), 8.48(d,IH) and 12.67(br.s,IH). Example 52 6-(3-Bromo-4-N,N-dimethylaminophenyl)-3-(5-tetrazolyl)-15 pyridin-2(IH)-one (SB 204789) (a) From 4'-N,N-dimethylaminoacetophenone (4.9g), 3'-bromo-4' -N,N-dimethylaminoacetophenone (7.0g) was prepared according to the method of Example 36(a). NMR 8(CDCl3) 20 2.53 (s,3H), 2.91 (s,6H), 7.03 (d,lH), 7.83 (dd, IH) and 8.13(d,IH). (b) From 3'-bromo-4'-N,N-dimethylaminoacetophenone (2.42g), 3-cyano-6-(3-bromo-4-N,N-dimethylaminophenyl)pyridin-2(1H)- 25 one (2.63g) was prepared according to the method of Example 3(a). XH NMR 8(DMSO-d6) 2.82 (s,6H), 6.82(d,lH), 7.22 (d,lH), 7.79(dd,IH), 8.08(d,IH), 8.15(d,lH) and 12.67(br.slH). (c) From 3-cyano-6-(3-bromo-4-N,N- 30 dimethylaminophenyl)pyridin-2(IH)-one (0.8g), the title compound (0.57g) m.p.275-277°C was prepared according to the method of Example 1(b) . 22052/P30140 / 39 9 4 6 - 58 -Example 53 6- (3-Acetamido-4-mathoxy-5 -propy Ipheny 1) -3- (5-tetrazolyl)pyridin-2(IH)-one (SB 204790) 5 (a) From 3'-allyl-4'-hydroxyacetophenone (17.6g), 3'-allyl-4'-benzyloxyacetophenone (23.lg) isolated as an oil was prepared according to the method of Example 2 (a) using acetone as solvent. NMR 8(CDC13) 2.55 (s,3H), 3.47 (d,2H), 10 5.04-5.11(m,4H), 5.16(s,2H), 5.93-6.09(m,IH), 6.93(d,lH), 7.25-7.41(m,5H), 7.81(s,lH) and 7.82(d,IH). (b) From 3'-allyl-4'-benzyloxyacetophenone (23g), 6—[4— benzyloxy-3-(E-l-propenyl)phenyl]-3-cyanopyridin-2(IH)-one 15 (11.2g) m.p. 255-257°C after recrystallisation from dimethylformamide/water, was prepared according to the method of Example 3(a). (c) A solution of 6-[4-benzyloxy-3-(E-l-propenyl)phenyl]-3-20 cyanopyridin-2 (IH)-one (6.8g) in dimethylformamide (20ml) containing dimethylformamide dimethyl acetal (4.76g) was heated at 120°C for 6 hours. The mixture was diluted with ethyl acetate (200ml), washed with water (6 x 100ml), dried (MgSO^) and solvent removed at reduced pressure. The 25 residue was column chromatographed (silica gel, hexane/dichloromethane 1:1 eluant) to give 6-[4-benzyloxy-3-(E-l-propenyl)phenyl]-3-cyano-2-methoxypyridine (6g) m.p. 124-125°C after recrystallisation from ethanol. 30 (d) A suspension of 6-[4-benzyloxy-3-(E-l-propenyl)phenyl]-3-cyano-2-methoxypyridine (1.78g) in ethanol (250ml) containing 10% palladium/charcoal (0.2g) was hydrogenated at 50 p.s.i until the calculated quantity of hydrogen had been absorbed. The mixture was filtered (celite pad) and 35 solvent removed at reduced pressure. The residue was column chromatographed (silica gel, hexane/dichloromethane 1:1 -2% ethanol/dichloromethane eluant) to give 3-cyano-6-(4- 22052/P30140 239946 - 59 - hydroxy-3-propylphenyl)-2-methoxypyridine (l.Og). NMR 8(CDC13) 1.01(t,3H), 1.65-1.74(m,2H), 2.66(t,2H), 4 .15 (s, 3H) 5.19 (sf IH), 6.86(d,lH), 7.35(d,lH) and 7.81-7.87(m,3H) . 5 (e) To a stirred suspension of 6-(4-hydroxy-3-propylphenyl)-3-cyano-2-methoxypyridine (1.88g) in sulpholane (3ml) a solution of nitronium tetrafluoroborate in sulpholane (0.5M, 16ml) was added over 5 minutes with 10 ice cooling. The" solution obtained was stirred for 5 hours, additional nitronium tetrafluoroborate (0.5M in sulpholane, 2ml) added and stirring continued for a further 3 hours. The solution was diluted with diethyl ether (100ml) washed with water (8 x 100ml), dried (MgSO^) and solvent removed 15 at reduced pressure. The residue was recrystallised from ethanol to give 3-cyano-6-(4-hydroxy-3-nitro-5-propyIpheny1)-2-methoxypyridine (1.75g) m.p. 160-162°C. (f) From 3-cyano-6-(4-hydroxy-3-nitro-5-propylphenyl)-2-20 methoxypyridine (1.57g), 3-cyano-6-(4-methoxy-3-nitro-5-propylphenyl)-2-methoxypyridine (1.53g) m.p. 150-152°C was prepared according to the method of Example 2(a) using acetone/dimethylformamide (1:1) as reaction solvent. NMR 8(CDC13) 1.03(t,3H), 1.67-1.81(m,2H), 2.77 (t,2H), 25 3.95 (s,3H), 4.17(s,3H), 7.42 (d,lH), 7.96(d,lH), 8.07(d,IH) and 8.35(d,IH). (g) A suspension of 3-cyano-6-(4-methoxy-3-nitro-5-propylphenyl)-2-methoxypyridine (1.4g) in ethanol (100ml) 30 containing 10% palladium/charcoal (200mg) was treated with hydrogen at 50 p.s.i until hydrogen uptake was complete. The mixture was filtered (celite pad) and solvent removed from the filtrate at reduced pressure. The residue was dissolved in dichloromethane (10ml) containing 35 triethylamine (l.Olg) added followed by the addition of acetic anhydride (0.61g) over 5 minutes. The reaction mixture was stirred for 15 hours, diluted with 15 20 25 22052/P30140 - 60 - 239946 dichloromethane (100ml) and washed with 2N hydrochloric acid (2 x 50ml) and with water (50ml). After drying (MgS04), solvent was removed at reduced pressure to give after recrystallisation from ethanol 6-(3-acetamido-4-5 methoxy-5-propylphenyl-3-cyano-2-methoxypyridine (1.04g) m.p.174-175°C. (h) From 6-(3-acetamido-4-methoxy-5-propylphenyl)-3-cyano-2-methoxypyridine (0.7g), 6-(3-acetamido-4-methoxy-5-10 propylphenyl)-3-cyanopyridin-2(IH)-one (0.48g) m.p.247-249°C was prepared according to the method of Example 37(c). 1H NMR 8(CDC13) 1.02 (t,3H), 1. 68-1. 83 (m, 2H) , 2.27(s,3H), 2 .78 (t,2H), 3.83(s,3H), 6.65(d,lH), 7.49(d,lH), 7.80(br.s,IH), 7.90(d,IH) and 8.62(d,IH). (i) From 6-(3-acetamido-4-methoxy-5-propylphenyl)-3-cyanopyridin-2(IH)-one (0.4g), the title compound (0.25g) m.p. 239-241°C after recrystallisation from ethanol, was prepared according to the method of Example 1 (b) Example 54 6- [3-Methoxymethy 1 -4-methoxy-5- (E-l-propenyl) phenyl] -3- (5-tetrazolyl)pyridin-2(IH)-one (273/2588) (a) From 3-cyano-6-[4-methoxy-3,5-di(E-l- propenyl) phenyl]pyridin-2(IH)-one (4.59g), 3-cyano-6-[4-methoxy-3,5-di (E-l-propenyl)phenyl]-2-methoxypyridine (4.1g) m.p. 145°C was prepared according to the method of 30 Example 53 (c) . 1H NMR 8 (DMSO-dg) 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,lH), 8.15(s,2H) and 8.30(d,lH). (b) To an ice cooled suspension of 3-cyano-6-[4-methoxy-35 3,5-di(E-l-propenyl)phenyl]-2-methoxypyridine (1.6g) in acetone/water (9:1, 100ml) N-methylmorpoline-N-oxide (0.63g) and osmium tetroxide (2.5% w/w solution in tert- 22052/P30140 239946 - 61 - butanol, 0.4ml) were added. The mixture was stirred with ice cooling for 1 hour and at room temperature for 1 hour. Additional N-methylmorpholine-N-oxide (O.lg) was added and stirring continued for an additional 1 hour. The solution 5 was quenched with 5% sodium metabisulphite (5ml) and solvent removed at reduced pressure. The residue was dissolved in ethyl acetate (200ml), washed with water (2 x 100ml)), dried (MgSO^) and solvent removed at reduced pressure. Column chromatography (silica gel, 10 dichloromethane-5% ethanol/dichloromethane eluant) gave 3-cyano-6-[3-[1-(1,2-dihydroxypropyl)]-4-methoxy-5- (E-l-propenyl) phenyl]-2-methoxypyridine (0.99g). ^"H NMR SfCDC^) 1.17(d,3H), 1.97(d,3H), 2.5(br.s,IH), 2.98 (br.s,IH), 3.82(s,3H), 3.94-4.05(m,IH), 4.16(s,3H), 4.77(d,lH), 6.30-15 6.42 (m, IH) , 6.66(d,lH), 7.41(d,lH), 7.90(d,lH), 7.93(d,lH) and 8.08(d,lH). (c) To a solution of 3-cyano-6-[3-[l-(1,2-dihydroxypropyl)]-4-methoxy-5-(E-l-propenyl)phenyl]-2-20 methoxypyridine (0.99g) in tetrahydrofuran(20ml) a solution of sodium metaperiodate (0.64g) in water (3ml) was added. The mixture was stirred for 2 hours, additional sodium metaperiodate (O.lg) in water (2ml) added and stirring continued for a further 2 hours. The mixture was filtered, 25 diluted with ethyl acetate (100ml), washed with water (2 x 50ml), dried (MgS04) and solvent removed at reduced pressure. The residue was column chromatographed (silica gel, dichloromethane- 5% ethanol/dichloromethane eluant) to give 3-cyano-6-[3-formyl-4-methoxy-5- (E-l-propenyl)phenyl]-30 2-methoxypyridine (0.7g) m.p. 174°C. NMR SfCDClg) 2.00(d,3H), 3.93(s,3H), 4.18(s,3H), 6.38-6.53(m,IH), 6. 69 (d, IH) , 7.47 (d,lH), 7.94(d,lH), 8.33(d,lH), 8.41(d,lH) and 10.44 (IH). 35 (d) A solution of 3-cyano-6-[3-formyl-4-methoxy-5-(E-l-propenyl) phenyl]-2-methoxypyridine (0.65g) in ethanol (10ml) was treated with sodium borohydride (lOOmg) in 22052/P30140 239 9 4 6 - 62 - portions over 30 minutes. The solution was stirred for a further 2 hours, solvent removed at reduced pressure, the residue dissolved in ethyl acetate (100ml), washed with water (2 x 50ml) , dried (MgS04) and solvent removed at 5 reduced pressure. The residue was dissolved in dimethyl sulphoxide (5ml), potassium hydroxide (0.56g, crushed pellets) added, followed by iodomethane (0.6g) and the mixture stirred for 30 minutes. After diluting with ethyl acetate (100ml) the reaction mixture was washed with water 10 (6 x 50ml), dried (MgSO^) and solvent removed at reduced pressure. The residue was column chromatographed (silica gel, 40% hexane/dichloromethane - dichloromethane) to give 3-cyano-6-[3-methoxymethyl-4-methoxy-5-(E-l-propenyl) phenyl] -2-methoxypyridine (0.54g) m.p. 81-82°C. 15 NMR 8(CDC13) 1. 96 (d, 3H) , 3.47(s,3H), 3.79(s,3H), 4.17(s,3H), 4.56 (s,2H), 6.306.42 (m,IH), 6.70(d,lH), 7.42(d,lH), 7.88(d,lH), 7.92 (d,lH) and 8.10(d,IH). (e) From 3-cyano-6-[3-methoxymethyl-4-methoxy-5-(E-l- 20 propenyl)phenyl]-2-methoxypyridine (0.54g), 3-cyano-6-[3-methoxymethyl-4-methoxy-5-(E-l-propenyl)phenyl]pyridin-2(lH)-one (0.33g) m.p.188-190°C after column chromatography (silica gel, dichloromethane - 2.5% ethanol/dichloromethane eluant), was prepared according to the method of Example 25 37 (c). 1H NMR 5(CDC13) 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,lH), 7.85(d,lH), 7.91(d,lH) and 12.89(br.s,IH). (f) From 3-cyano-6-[3-methoxymethyl-4-methoxy-5-(E-l- 30 propenyl)phenyl]pyridin-2(IH)-one (0.3g) the title compound (0.22g) m.p. 245-246°C after recrystallisation from ethanol, was prepared according to the method of Example 1(b). 1H NMR 8 (DMSO-dg) 1.92(d,3H), 3.61(s,3H), 3.83(s,3H), 4.81 (s, 2H), 6.26-6.44 (m, IH), 6.68(d,lH), 6.88(d,lH) 35 7.73(d,IH), 8.04(d,lH), 8.75 (d,IH) 22052/P30140 239946 - 63 -Example 55 6- [3- (E-2-Carbamoylethenyl) -4-methoxy-5- (E-l-propenyl) phenyl]-3-(5-tetrazolyl)pyridin-2-(IH)-one 5 (273/2602) (a) Triethylphosphonoacetate (0.9g) was added dropwise to a suspension of sodium hydride (0.18g, 50% in oil) in tetrahydrofuran (10ml). When gas evolution had ceased a 10 solution of 3-cyano-6-[3-formyl-4-methoxy-5-(E-l- propenyl) phenyl]-2-methoxypyridine in tetrahydrofuran (10ml)was added and the mixture stirred for 4 hours. Ethanol (10ml) and 2N sodium hydroxide (10ml) were added and the mixture boiled for 2 hours. Solvent was removed at 15 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-(E-l-propenyl)phenyl]-2-methoxypyridine (0.9g). *1! NMR 8(CDCl3) 1.94 (d,3H), 20 3.73 (s, 3H) , 4.14 (s, 3H), 6.50-6.62 (m, IH) , 6.69(d,lH), 6.7 8(d,lH), 7.82 (IH), 7.99(d,IH) and 8.33-8.42 (m,3H). (b) Oxalyl chloride (0.76g) was added over 5 minutes to an ice cooled suspension of 3-cyano-6-[3-(E-2- 25 carboxylatoethenyl)-4-methoxy-5-(E-l-propenyl)phenyl]-2-methoxypyridine in dichloromethane (20ml) containing dimethylformamide (0.1ml). When gas evolution had ceased (4 hours) solvent was removed at reduced pressure and the residue redissolved in dichloromethane (20ml). To the ice 30 cooled solution ammonium hydroxide (10ml, SG 0.88) was added and the solution stirred at 0°C for 30 minutes and at room temperature for 30minutes. The precipitated solid was collected by filtration and recrystallised twice from ethanol to give 3-cyano-6-[3-(E-2-carbamoylethenyl)-4-35 methoxy-5-(E-l-propenyl)phenyl]pyridin-2(IH)-one (0.4g) m.p. 245-246°C. IH NMR 8(DMSO-dg) 1.94(d,3H), 3.72(s,3H), 4.14 (s, 3H), 6.49-6. 62 (m, IH), 6.66(d,lH), 6.80(d,lH), - 64 - S3 7 .19 (br. s, IH), 7 . 62 (br. s, IH), 7.62(d,lH), 7.89(d,lH), 8.27(d,IH), 8.29(d,IH) and 8.34(d,lH). (c) From 3-cyano-6-[3-(E-2-carbamoylethenyl)-4-methoxy-5- 5 (E-1-propenyl) phenyl]-2-rnethoxypyridine (0.35g), 3-cyano-6-[3-(E-2-carbamoylethenyl)-4-methoxy-5-(E-l-propenyl ) phenyl] pyridin-2 (IH) -one (0.2g) m.p. >300°C after recrystallisation from dimethylformamide/ethanol/water, was prepared according to the method of Example 37(c). 1H NMR 10 8 (DMSO-dg) 1.93(d,3H), 3.71 (s,3H), 6.51-6.71 (m, 2H), 6.91 (br.d, IH), 7.21 (br.s, IH), 7.61(d,lH), 7.62 (br.s, IH), 7.93(S/IH), 7.99(s,IH), 8.20(d,lH) and 12.78 (br.s,IH). (d) From 3-cyano-6-[3-(E-2-carbamoylethenyl)-4-methoxy-5-15 (E-l-propenyl)phenyl]pyridin-2(IH)-one (0.16g), the title compound (0.08g) m.p.292-294°C (decomp) after recrystallisation from dimethylformamide/ethanol/water, was prepared according to the method of Example 1(b) IH NMR 8(DMSO-dg) 1.94(d,3H), 3.73 (s,3H), 6.55-6.72(m,2H), 20 6 . 83 (d, IH), 7.00 (d, IH) , 7.23 (br.s, IH), 7.62(d,lH), 7.66(br.s,IH), 7.99(d,lH) and 8.48 (d,IH). Example 56 25 6- (3-Cyclopropylmethyloxy-4-methoxyphenyl)-3- (5-tetrazolyl) -pyridin-2(1H)-one (a) From 3'-hydroxy-4'-methoxyacetophenone (3.32g), 3'-cyclopropylmethyloxy-4'-methoxyacetophenone (4.34g) was prepared according to the method of Example 2(a). NMR 30 8(CDC13) 0.34-0.40 (m,2H), 0.63-0.70(m,2H), 1.28-1.43m,IH), 2.56 (s, 3H), 3. 91 (d, 2H) , 3.95(s,3H), 6.89(d,lH), 7.50(d,lH) and 7.56(dd,IH). (b) From 3'-cyclopropylmethyloxy-4'-methoxyacetophenone 35 (3.55g), 3-cyano-6-(3-cyclopropylmethyloxy-4- methoxyphenyl)pyridin-2(IH)-one (1.30g) m.p. 241-242°C, - 65 - 239946 after recrystallisation from butanol was prepared according to the method of Example 3(a). (c) From 3-cyano-6-(3-cyclopropylmethyloxy-4-methoxyphenyl)pyridin-2(IH)-one (0.89g), the title compound (0.67g) m.p. 296-297°C (decomp) after recrystallisation from butanol, was prepared according to the method of Example 1(b). 1H NMR 5(DMSO-d6) 0 . 32-0. 38 (m, 2H), 0.57-0.66 (m, 2H) , 1.22-1 . 37 (m, IH) , 3.85(s,lH), 3.94 (d,2H), 6.88 (d, IH) , 7.10(d, IH) , 7 .39-7.4 8 (m, 2H) , 8.43(d,lH) and 12.56 (br. s, IH) . Example 57 6- (2-methoxy-4-propoxyphenyl) -3- (5-tetrazolyl) pyridin-2(IH)-one (a) From 2'-4'-dihydroxyacetophenone (50g), 2'-hydroxy-4'-propoxyacetophenone (6g) was prepared according to the method of Example 2(a), using bromopropane (40g) and acetone as solvent. NMR 8(DMSO-dg) 0.93((t,3H), 1.61-1.72(m,2H), 2 . 38 (s, 3H) , 3.75(t,2H), 5.61(dd,lH), 5.80(d,lH) and 7.40 (d,IH). (b) From 2'-hydroxy-4'-propoxyacetophenone (6g), 2'-methoxy-4'-propyloxyacetophenone (5.18g) was prepared according to the method of Example 2(a) . NMR 8(CDCl3) 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,IH).) (c) From 2'-methoxy-4'-propoxyacetophenone (5g), 3-cyano-6-(2-methoxy-4-propoxyphenyl)pyridin-2 (IH)-one (0.38g) m.p.186-188°C after trituration with diethyl ether was prepared according to the method of Example 3(a). NMR 8 (DMSO-dg) 0. 99 (t, 3H) , 1.72-1.81(m, 2H) , 3.82(s,3H), 4.02 (s,2H), 6.47(d,IH), 6.61-6.67(m,2H), 7.39(d,lH) and 8.11 (d,IH). </div>

Claims

<div class="application article clearfix printTableText" id="claims"> m - 66 - 239946 (d) From 3-cyano-6-(2-methoxy-4-propoxyphenyl)pyridin-2(lH)-one (0.36g), the title compound (0.04g) m.p. >300°C after recrystallisation from ethanol and trituration with diethyl ether, was prepared according to the method of Example 1(b). 1H NMR 8(DMSO-dg 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,IH), 7.55(unresolved,IH) and 8.44(unresolved, IH) . Example X Pharmaceutical compositions for oral administration are prepared by combining the following : % w/w 6-(3-methoxyphenyl)-3- (5-tetrazolyl)pyridin-2(IH) -one 0.5 3.0 7.14 2% w/w Soya lecithin in soya bean oil 90.45 88.2 84.41 Hydrogenated vegetable shortening and beeswax 9.05 8.8 8.45 The formulations are then filled into individual soft gelatin capsules. Evample 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 then sterilised by filtration through a 0.22 micron membrane filter and sealed in sterile containers. WHAT WE CLAIM IS: - 67 - 239 4

1. A compound of the formula (1) : 5 in any tautomeric, geometric or optical isomeric form thereof, or a pharmaceutically acceptable salt thereof, wherein : R° is OH or a bioprecursor thereof, 15 R1 is 5-tetrazolyl, or a bioprecursor thereof and Ar is phenyl substituted by one to three groups independently selected from C1_6alkyl, 20 c2_6alkenyl, c^galkoxy, C3_6alkenyloxy, C3_6cycloalkyl, C3_gcycloalkoxy, C1_6alkylthio, phenyl, phenylthio, benzyloxy, C-^gpolyfluoroalkyl, Ci_6p°lyfluoroalkoxy, halo, NR2 or NHCOR wherein R is H or C-^galkyl, and -X(CH2)nY- attached to adjacent 25 carbon atoms of the phenyl ring wherein X and Y are independently CH2 or 0 and n is 1 to 3, wherein said C-j^galkyl, C2_galkenyl or C1-6alkoxy groups can be independently substituted by OH, C^-galkoxy, C3_6cycloalkyl, NR2, C02R or C0NR2 wherein R is as 30 hereinbefore defined; with the proviso that Ar is not phenyl monosubstituted by 2-Ci_{jalkoxy.

2. A compound according to claim 1 wherein R° is OH or OR2 in which R2 is C1_4alkyl, arylC-j^alkyl, 35 C1_4alkanoyl, arylsulphonyl or C1_4alkylsulphonyl. <*' " > " ' 1 1 APR 1TA;2399 4 6;- 68 -;

3. A compound according to claim 1 or 2 wherein Ar is phenyl mono-substituted by a group as defined in claim 1.;

4. A compound according to claim 1 or 2 wherein Ar is phenyl di-substituted by any two groups as defined in claim 1.;

5. A compound according to claim 1 or 2 wherein Ar is phenyl trisubstituted by any three groups as defined in claim 1.;

6. A compound according to claim 1 which is : 6-(3-methoxyphenyl)-3-(5-tetrazolyl)pyridin-2(IH)-one, 6-(3-propoxyphenyl)-3-(5-tetrazolyl)pyridin-2(IH)-one, 6-(3-butoxyphenyl)-3-(5-tetrazolyl)pyridin-2(IH)-one,;6-(3-benzyloxyphenyl)-3-(5-tetrazolyl)pyridin-2(IH)-one,;6-(3-bromophenyl)-3-(5-tetrazolyl)pyridin-2(IH)-one,;6-(3-trifluoromethylphenyl)-3-(5-tetrazolyl)pyridin-2(IH)-one,;6-(3-ethyIpheny1)-3-(5-tetrazolyl)pyridin-2(IH)-one,;6-(4-butoxyphenyl)-3-(5-tetrazolyl)pyridin-2(IH)-one,;6-(4-isobutyIpheny1)-3-(5-tetrazolyl)pyridin-2(IH)-one,;6-(4-biphenyl)-3-(5-tetrazolyl)pyridin-2(IH)-one,;6-(4-propoxyphenyl)-3-(5-tetrazolyl)pyridin-2(IH)-one,;1 1 APR '.994;23994;- 69 -;6- (4 -methoxy-3 -propoxyphenyl) -3- (5-tetrazolyl) pyridin-2(IH)-one,;6- (3,4-methylenedioxyphenyl) -3- (5-tetrazolyl) pyridin-2 (IH) -one,;6-(3,4-dichlorophenyl) -3-(5-tetrazolyl)pyridin-2 (IH) -one,;6- (3,5-dipropoxyphenyl) -3-(5-tetrazolyl) pyridin-2 (IH) -one,;6-(3,5-diethoxyphenyl) -3-(5-tetrazolyl)pyridin-2 (IH) -one,;6- (3,5-dibromophenyl) -3- (5-tetrazolyl) pyridin-2 (IH) -one,;6- (2,4-dipropoxyphenyl) -3-(5-tetrazolyl)pyridin-2 (IH) -one,;6-(2,5-dipropoxyphenyl)-3-(5-tetrazolyl)pyridin-2(IH)-one,;6-(2,3,4-trichlorophenyl)-3-(5-tetrazolyl)pyridin-2(IH)-one,;6-[6-(1,2,3,4-tetrahydronaphthyl)]-3-(5-tetrazolyl)pyridin-2(IH)-one,;6-(3-chlorophenyl)-3- (5-tetrazolyl)pyridin-2(IH)-one, 6-(3-phenylthiophenyl)-3-(5-tetrazolyl) pyridin-2(IH)-one, 6-(3,4-dimethoxyphenyl)-3-(5-tetrazolyl)pyridin-2(IH)-one, 6-(3-methylthiophenyl)-3-(5-tetrazolyl) pyridin-2(IH)-one, 6-(3-butylthiophenyl) -3-(5-tetrazolyl)pyridin-2 (IH) -one,;1 1;239946;- 70 -;6-(3,4-di-n-propoxyphenyl)-3-(5-tetrazolyl)pyridin-2(IH)-one,;6-(2,3-di-n-propoxyphenyl)-3-(5-tetrazolyl)pyridin-2(IH) -5 one,;6-(3-cyclopentyloxy-4-methoxyphenyl)-3-(5-tetrazolyl)-pyridin-2(IH)-one,;10 6-(3-ethoxyphenyl)-3-(5-tetrazolyl)pyridin-2(IH)-one,;6-(3,5-dimethoxyphenyl)-3-(5-tetrazolyl)pyridin-2(IH)-one,;15;6-(2-butylthiophenyl)-3-(5-tetrazolyl)pyridin-2(IH)-one, 6-(3-allyloxyphenyl)-3-(5-tetrazolyl)pyridin-2(IH)-one,;20;6-(4-methoxy-2-pentyloxyphenyl)-3-(5-tetrazolyl)pyridin-2(IH)-one,;25 6-(3-iso-butoxy-4-methoxyphenyl)-3-(5-tetrazolyl)pyridin-2(IH)-one,;6- (2-bromo-3 , 5-diethoxyphenyl)-3- (5-tetrazolyl) pyridin-2(IH)-one,;30;6-(5-bromo-4-methoxy-2-pentyloxyphenyl)-3-(5-tetrazolyl)-pyridin-2(IH)-one,;6-(2-ally1-4-methoxy-3-propoxyphenyl)-3-(5-tetrazolyl)-3 5 pyridin-2(IH)-one,;V;11 APS 394;2052/P30140;239946;- 71 -;6- [ 3- (E-l -propenyl) -4 -methoxyphenyl ] - 3 - (5 -tetra z o ly 1) pyr idin -2(IH)-one,;6- (4-methoxy-3-propoxypheny1)-3-[5-(1-piva1oy1oxymethy 1) -tetrazolyl]pyridin-2(IH)-one,;6- (4-methoxy-3-propoxyphenyl) -3-[5-(2-pivaloyloxymethyl) -tetrazolyl]pyridin-2(IH) -one,;6-[3-ethoxy-5- (2-methoxyethoxy)phenyl]-3- (5-tetrazolyl) -pyridin-2(IH)-one,;6- [ 3 - (2,2-dimethylpropyloxy) -4-methoxyphenyl]-3- (5-tetrazolyl)pyridin-2(IH)-one,;6- (3-ethoxy-4-methoxyphenyl)-3-(5-tetrazolyl)pyridin-2 (IH) -one,;6- (3-propionamidophenyl) -3- (5-tetrazolyl) pyridin-2 (IH) -one,;6- (4-methoxy-3-propyIpheny 1)-3-(5-tetrazolyl)pyridin-2 (IH) -one,;6- (3-bromo-4 -methoxyphenyl) -3- (5-tetrazolyl) pyr idin-2 (IH) -one,;6- (3-pheny 1-4-methoxyphenyl) -3- (5-tetrazolyl)pyridin-2 (IH) -one,;6- [4-methoxy-3 ,5-di (E-l-propenyl)phenyl]-3- (5-tetrazolyl) -pyridin-2(IH)-one,;6-[3-(E-l-propenyl) -4-propoxyphenyl]-3- (5-tetrazolyl) -pyridin-2(IH)-one,;- 72 -;6-(3-bromo-4-methoxy-5-propylphenyl)-3-(5-tetrazolyl) -pyridin-2-(IH)-one,;6-(2-butylthio-3,5-diethoxyphenyl)-3-(5-tetrazolyl)pyridin-5 2(IH)-one,;6-(3-bromo-4-N,N-dimethylaminophenyl)-3-(5-tetrazolyl) -pyridin-2(IH)-one,;10 6-(3-acetamido-4-methoxy-5-propyIpheny1)-3-(5-tetrazolyl) -pyridin-2(IH)-one,;6-[3-methoxymethyl-4-methoxy-5-(E-l-propenyl)phenyl]—3 — (5— tetrazolyl)pyridin-2(IH)-one,;15;6-[3-(E-2-carbamoylethenyl)-4-methoxy-5-(E-l-propenyl) -pheny1]-3-(5-tetrazolyl)pyridin-2-(IH)-one, or;6- (3-cyclopropylmethyloxy-4-methoxyphenyl)-3-(5-tetrazolyl )-2 0 pyridin-2 (IH) -one or a pharmaceutically acceptable salt thereof.;

7. A compound according to any one of claims l to 6 25 for use as a medicament.;

8. A pharmaceutical composition which comprises a compound according to any one of claims 1 to 6 and a pharmaceutically acceptable carrier.;30;239946;- 73 -;

9. A process for preparing a compound of the formula (1) as defined in claim 1 or a pharmaceutically acceptable salt thereof which process comprises reacting a compound of the formula (2) :;10;NC;OH;ipr;Ar;(2);15 wherein Ar is as defined in claim 1 with an azide salt, and optionally thereafter :;° forming a bioprecursor of R° and/or R1;20 ° forming a pharmaceutically acceptable salt.;25

10. A process for preparing a compound of the formula (1) as defined in claim 1 or a pharmaceutically acceptable salt thereof, substantially as hereinbefore described with reference to any one of the foregoing Examples 1 to 57.;DATED THIS I;A. J. P;Vil If;'■V * 1 1 APR </div>