PYRIDINOL DERIVATIVES AS MEDICAMENTS

Abstract: Trisubstituted pyridinol derivatives are described as agonists of a cyclic AMP-dependent protein kinase useful as medicaments.

Description: PYRIDINOL DERIVATIVES AS MEDICAMENTS The present invention relates to pyridinol derivative 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 combating such conditions where such agonism is thought to be beneficial. They are likely to have anti-proliferative, anti-aggregatory, cholesterol-lowering, smooth muscle relaxant, positive lusitropic, anti-allergic or anti- inflammatory activities. They are likely to be useful in the treatment of cardiovascular diseases where there is component of diastolic failure, cancer, psoriasis, atheroschlerosis, thrombosis, chronic reversible lung disea 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 the formula (1) : Formula (1) or pharmaceutically acceptable salts thereof, wherein R0 is OH or a bioprecursor thereof, R 1 is A°Cθ2H, P(Z) (OH) (OR 2 ) , SO2H, SO3H or 5-tetrazolyl optionally substituted in the 1-position by CH2CO2H or a bioprecursor thereof, A° is CH 2 , CH 2 CH 2 , CHF, CF 2 , CR 3 (OR 4 ) , CO or C(OR 5 ) (OR 6 ), R 2 is phenyl, C3_5Cycloal yl, C3_5cycloalkylC__4alkyl, or C__salkyl optionally substituted by C__4alkoxy, R 3 is H, methyl or ethyl, R 4 is H or C__ 3 alkyl, R^ and R 6 are each C__3alkyl or together form a 1,2- ethanediyl group or 1,3-propanediyl group, Z is 0 or S, R a is halo or x^-Y 1 - X 1 is CH2, 0 or S, Y 1 is C__galkyl or Ar, Ar is phenyl optionally substituted by one to three groups independently selected from halo, C__galkyl, C2-ςalkenyl, C__galkoxy, C__gpolyfluoroalkyl or C__gpolyfluoroalkoxy, or Ar is 1-naphthyl or 2-naphthyl, R is H, C__galkyl or X^r 1 wherein X 2 is a bond or ethenyl and Ar 1 is phenyl optionally substituted by one to three groups independently selected from C^-galkyl, C2-galkenyl, Cχ_galkoxy, C3_galkenyloxy, C2-gcycloalkyl, C2-gcycloalkox C__galkylthio, phenyl, phenylthio, benzyloxy, Cι_gpoly- fluoroalkyl, C__gpolyfluoroalkoxy, halo, N(R 7 )2 or NHCOR 7 wherein R 7 is H or C__galkyl, or -X(CH2) n γ attached to adjacent carbon atoms of the phenyl ring wherein X and Y ar independently CH2 or 0 and n is 1 to 3, wherein said C^-galkyl, C2-galkenyl or C^-galkoxy groups can be independently substituted by OH, C__galkoxy, C2-gcycloalkyl N(R 7 ) 2 , CO2R 7 or C0N(R 7 ) 2 ; or Ar^ is 1-naphthyl optionally substituted in the 4-position hydroxy or C^-galkoxy, 2-naphthyl optionally substituted in the 1-position by hydroxy or C__galkoxy, 3-phenanthryl, 9- phenanthryl, 2-quinolinyl, 4-quinolinyl, 3-thianaphthenyl o 2-benzof ranyl. Bioprecursors of the groups R^ and R^ are derivatives thereof which are convertible in vivo into the groups R^ an Rl. A suitable bioprecursor of the group R^ is OR^ wherei R8 is Cι_ alkyl, aryl C^-^al yl (for example phenyl C^-^alk such as benzyl) , Cι_4al anoyl (for example acetyl) , aryl C__4alkanoyl (for example phenyl Cι_4alkanoyl such as benzoyl) , arylsulphonyl (for example optionally substituted phenylsulphonyl or toluenesulphonyl) or Cι_4alkylsulphonyl (for example methylsulphonyl) . When R 1 is AOCO2H a suitable bioprecursor is A^C02 ^ wherein R^ is an ester-forming group. When R 1 is P(Z) (OH) (OR 2 ) a suitable bioprecursor is P(Z) (OR 2 )2 wherein Z and R 2 are as hereinbefore defined or P(Z) (OR 2 ) (OR 1 ^) wherein R 1 ^ is an 0-ρrotecting group. Suitable O-protecting groups include pivaloyloxymethyl, propionyloxymethyl and pivalolyloxycarbonyloxymethyl. When R 1 is 1-(HO2CCH2)-5-tetrazolyl a suitable bioprecursor is 1-(R 9 θ2CCH2)-5-tetrazolyl wherein R 9 is as hereinbefore defined. When R is 5-tetrazolyl, a suitable bioprecursor is a N-protected derivative thereof. Suitable N-protecting grou include pivaloyloxymethyl, propionyloxymethyl and pivalolyloxycarbonyloxymethyl. Alternatively bioprecursors of the groups R^ and R^ a those formed when B and R^ are linked together to form a cyclic structure such that R^-RO is ^C02 or A 2 OCH2θ, in which : A 1 is CH2, CH 2 CH 2 , CHF, CF 2 , CR 3 (OR 4 ) , CO or C(OR 5 ) (OR 6 ), A 2 is P(Z)OR 2 or CR 3 (CO2R 9 ) , and R 2 to R 6 , R 9 and Z are as hereinbefore defined. Suitably R^ is hydroxy or OR^, preferably hydroxy. Suitably R is H or C__galkyl. Suitably R is X 2 __r^ as hereinbefore defined. Suitably R 1 is A°C02H or A°C02R 9 . Suitably R 1 is P(Z) (OH) (OR 2 ) or P(Z) (OR 2 ) 2 . Suitably R 1 is SO2H, SO3H or 5-tetrazolyl. Suitably R 1 is 1-(H02CCH2)-5-tetrazolyl or 1- (R 9 θ2CCH2)-5-tetrazolyl. Suitably R 1 and R^ are linked together such that R1- is A!C02. Suitably R 1 and R° are linked together such that R 1 - is A 2 OCH2θ. By the term alkyl is meant both straight- and branch chain alkyl. By the term C__gpolyfluoroalkyl is meant a C^-galkyl group having at least one hydrogen replaced with fluoro, e. CF3 or CF2CF2H. Suitably R 2 is methyl, ethyl, propyl, butyl, pentyl, hexyl, 2-methoxyethyl, phenyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclopropylmethyl. Suitably R 3 is H, methyl or ethyl, preferably H or methyl. Suitably R 4 is H, methyl, ethyl or propyl, preferably H or methyl. Suitably R 5 and R 6 are independently methyl, ethyl or propyl, preferably together they form a 1,2-ethanediyl grou Preferably Z is O. Suitably R 9 is C__4alkyl optionally substituted by hydroxy, e.g. 2-hydroxyethyl or aryl Cι_ al yl (for example phenyl Cι_4alkyl such as benzyl) . Suitably R a is halo, for example iodo, bromo, or chloro, preferably bromo. Suitably R a is X 1 Y 1 Suitably Y 1 is C__galkyl, for example methyl, ethyl, propyl, butyl, pentyl or hexyl. Suitably γl is Ar as hereinbefore defined. Suitably Ar is 1-naphthyl or 2-naphthyl or phenyl optionally mono- or di-substituted by chloro. Suitably Ar- 1 - is phenyl optionally mono-substituted by group as hereinbefore defined, for example in the 2,3, or 4 positions by C__galkyl, C__galkoxy, C2-galkenyloxy, C__galkylthio, phenyl, phenylthio, benzyloxy, CF3, halo or NHCOR. Suitably r^ is phenyl di-substituted by any groups a hereinbefore defined, for example in the 3,4-,3,5-,2,3-,2,4 or 2,5-, positions by groups independently selected from C2-galkenyl, C__galkoxy, C2-gcycloalkoxy, halo, -X(CH2) n γ ~ C__galkoxyC__galkoxy. Suitably Ar 1 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 C2-galkenyl, C__galkoxy or halo. Suitably Ar-*- is 1-naphthyl optionally substituted in the 4-position by hydroxy or C__galkoxy. Suitably Ar is 2- naphthyl optionally substituted in the 1-position by hydroxy or C__galkoxy. Suitably Ar^ is 3-phenanthryl or 9-phenanthryl. Suitably Ar 1 is 2-quinolinyl or 4-quinolinyl. Suitably Ar-*- is 2-benzofuran l or 3-thianaphthenyl. Examples of C__galkoxy include methoxy, ethoxy, propoxy, butoxy, or pentyloxy. Examples of C^-galkyl include methyl, ethyl, propyl, butyl, isobutyl or pentyl. Examples of halo include fluoro, chloro, bromo or iodo Particular compounds of this invention include : 6-methyl-5-(2-naphthylthio)-3-(5-tetrazolyl)pyridin-2 (1H)- one, 3-(l-carboxymethyl-5-tetrazolyl)-6-methyl-5-(2-naphthylthio) pyridin-2 (1H)-one, n-propyl-[5-(2-naphthylthio)-2-oxo-l,2-dihydro-3-pyridyl]- phosphonate, 6-methyl-5-phenylthio-3-(5-tetrazolyl)ρyridin-2 (lH)-one, 5-(4-chlorophenylthio)-6-methyl-3-(5-tetrazolyl)pyridin- 2(lH)-one, E-6-(2-phenylethenyl)-5-phenylthio-3-(5-tetrazolyl)pyridin- 2 (lH)-one, 3-carboxymethyl-6-methyl-5-(phenylthio)pyridin-2 (1H)-one, 6-phenyl-5-phenylthio-3-(5-tetrazolyl)pyridin-2 (1H)-one, 5-(3-chlorophenylthio)-6-methyl-3- (5-tetrazolyl)pyridin- 2(lH)-one, 5-(2-chlorophenylthio)-6-methyl-3-(5-tetrazolyl)pyridin- (lH)-one, 5-(3,4-dichlorophenylthio)-6-methyl-3-(5-tetrazolyl) yridin 2(lH)-one, 5-n-butylthio-6-methyl-3-(5-tetrazolyl)pyridin-2 (IH)-one, 5-n-butylthio-6-(4-methoxy-3-propoxyphenyl)-3-(5- tetrazolyl)pyridin-2(IH)-one, 5-benzyl-6-phenyl-3-(5-tetrazolyl)ρyridin-2 (IH)-one, 5-(2-naphthyloxy)-6-phenyl-3-(5-tetrazolyl)pyridin-2(IH)-one 6-(2-naphthyl)-5-ρhenylthio-3-(5-tetrazolyl)pyridin-2(IH)- one, 5-(2-naphthylthio)-6-phenyl-3-(5-tetrazolyl)pyridin-2(IH)- one, 5-n-butylthio-6-(3,4-dimethoxyphenyl)-3-(5-tetrazolyl)- pyridin-2(IH)-one, 3-[6-methyl-5-(2-napthylthio)-2-oxo-l,2-dihydro-3-pyridyl]- propionic acid, 5-phenylthio-6-(4-methoxy-3-propoxyphenyl)-3-(5-tetrazolyl)- pyridin-2(IH)-one, 5-methylthio-6-(4-methoxy-3-propoxyphenyl)-3-(5-tetrazolyl)- pyridin-2(IH)-one, 5-ethylthio-6-(4-methoxy-3-ρropoxyphenyl)-3-(5-tetrazolyl)- pyridin-2(IH)-one, 5-bromo-6-(4-methoxy-3-propoxyphenyl)-3-(5-tetrazolyl)- pyridin-2(IH)-one, 6-(3,4-dimethoxyphenyl)-5-pentyl-3-(5-tetrazolyl)pyridin- 2(lH)-one, 6-(2-naphthyl)-5-phenoxy-3-(5-tetrazolyl)pyridin-2 (IH)-one, 5-n-butylthio-6-[3-(E-1-propenyl)-4-methoxyphenyl]-3-(5- tetrazolyl)pyridin-2 (lH)-one, ethyl (5-phenylthio-2-oxo-l,2-dihydro-3-pyridyl)phosphonate, 5-n-butylthio-6-(4-methoxy-3-n-propylphenyl)-3-(5- tetrazolyl)pyridin-2 (IH)-one, or 5-n-butylthio-6-[3-(E-1-propenyl)-4-methoxyphenyl]-3-(5- tetrazolyl)pyridin-2 (IH)-one, and pharmaceutically acceptable salts thereof. This invention covers all tautomeric, geometric and optical isomeric forms of compounds of formula (1) . In particular when R^ is hydroxy the compound can exist in its keto tautomeric form : 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 o humans and other mammals it is normally formulated in accordance with standard pharmaceutical practice as a 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 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 buccal administration can be formulated appropriately in dosage forms such as liquids, syrups, tablets, capsules and lozenges. An oral liquid formulation will generally consis of a suspension or solution of the compound or salt in a liquid carrier for example, ethanol, glycerine or water with a flavouring or colouring agent. Where the composition is in the form of a tablet, any pharmaceutical carrier routinel used for preparing solid formulations may be used. Example of such carriers include starch, celluloses, lactose, sucros and magnesium stearate. Where the composition is in the form of a capsule, any routine encapsulation is suitable, fo 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 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. 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, 2- pyrrolidone, cyclodextrin, arachis oil, or sesame oil. A typical suppository formulation comprises a compoun of formula (1) or a pharmaceutically acceptable salt thereo which is active when administered in this way, with a bindi and/or lubricating agent, for example polymeric glycols, gelatins, cocoa-butter or other low melting vegetable waxes or fats or their synthetic analogues. 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. Typical compositions for inhalation are in the form of a solution, suspension or emulsion that may be administered in the form of an aerosol using a conventional propellant such as dichlorodifluoromethane or trichlorofluoromethane, o are in the form of a powder for insufflation. 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 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 free acid. The daily dosage regimen for oral administration is suitably about 0.001 mg/Kg to 120 mg/Kg, of a compound of formula (1) or a pharmaceutically acceptable salt thereof calculated as the free acid. The daily dosage regimen for parenteral administration is suitably 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 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 combating such conditions where such agonism is thought to beneficial. Such conditions can 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 the range 0.1 - 5.0 mg of a compound of the formula (1) or pharmaceutically acceptable salt thereof. The compounds of this invention may be co-administere with other pharmaceutically active compounds, for example i combination, concurrently or sequentially. Conveniently t compounds of this invention and the other active compound o compounds are formulated in a single pharmaceutical composition. Examples of compounds which may be included i pharmaceutical compositions with the compounds of the formul (1) are bronchodilators such as sympathomimetic amines for example isoprenaline, isoetharine, sulbutamol, phenylephrine and ephedrine or xanthine derivatives for example theophylline and aminophylline, anti-allergic agents for example disodiu cromoglycate, histamine H_-antagonists, drugs used in the treatment of cancer 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 drug such as HMGCoA reductase inhibitors, bile acid sequestrants, drugs for the 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. 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 : a) for compounds wherein R 1 is A^C02H or A^C^R anci : i) A° is CR 3 (0R 4 ) , reacting in the presence of a strong base a compound of the formula (2) : Formula (2) wherein R^ is methyl and R and R a are as hereinbefore defined, with a compound of the formula (3) : R 3 C0C0 2 R 9 (3) wherein R 3 and R 9 are as hereinbefore defined to form a compound of the formula (4) : Formula (4) wherein R 12 is CR 3 (OH)C0 2 R 9 and R, R 3 , R 9 , R 11 , and R a are hereinbefore defined and thereafter optionally reacting wit a C__3alkylating agent to form the corresponding compound wherein R 12 is CR 3 (0C__3alkyl)CO2 9 , ii) A° is CO, reacting in the presence of a strong base a compound of the formula (2) as hereinbefore defined with a compound of the formula (5) : R 9 0 CC02 9 (5) wherein R 9 is as hereinbefore defined to form a compound of the formula (4) wherein R 12 is COCO2R 9 and R, R 9 , R 11 and R a are as hereinbefore defined, iii) A° is CH(OH) , reacting a compound of the formula (4) wherein R^ 2 is COCO2R and R, R 9 , R 11 , and R a are as hereinbefore defined with a reducing agent to form the corresponding compound wherein R^ is CH(OH)C0 2 R 9 , iv) A 0 is CH 2 , reacting a compound of the formula (4) wherein R^ 2 is COCO2H or COCO2R 9 and R, R 9 , R 11 , and R a are as hereinbefore define with a suitable reducing agent to form the corresponding compound wherein R^ 2 is CH2CO2H, v) A° is C(OR 5 ) (OR 6 ) r reacting a compound of the formula (4) wherein R 12 is COCO2R 9 and R, R 9 , R^- 1 , and R a are as hereinbefore defined with a C__3alcohol, 1,2-ethanediol or 1,3-propanediol to form the corresponding compound wherein R^ 2 is C(OR^) (OR 6 )Cθ2R 9 , vi) A 0 is CF 2 , reacting a compound of the formula (4) wherein R^ 2 is COCO2R 9 and R, R 9 , R 11 , and R a are as hereinbefore defined with a fluorinating agent to form the corresponding compound where R 11 is CF2CO2R 9 , or vii) A 0 is CHF, reacting a compound of the formula (4) wherein R 12 is CH(OH)Cθ2R 9 and R, R 9 , R 11 , and R a are as hereinbefore defined with a fluorinating agent to form the corresponding compound wherein R 12 is CHFCO2R 9 , and thereafter optionally : • converting the group OR 11 into OH • converting the group ^C02 9 into OCO2H; or b) for compounds wherein R 1 is CH2CO2H, converting a compound of the formula (6) : Formula (6) wherein R 13 is acetyl and R, and R a are as hereinbefore defined into the corresponding compound wherein R 13 is CH2CO2H; or c) for compounds wherein R 1 is CH2-H2CO2H or CH2CH2-O2R 9 , hydrogenating a compound of the formula (6) wherein R 13 is CH=CHCθ2H or CH=CHCθ2 9 and thereafter optionally converting the group CH2CH2CO2R 9 into CH2CH2CO2H; or d) for compounds wherein R 1 is P (0) (OH) (OR 2 ), hydrolysi a compound of the formula (6) wherein R 13 is P (0) (OR 2 )2 an R, R 2 r and R a are as hereinbefore defined; or e) for compounds wherein R 1 is P(S) (OH) (OR 2 ), convertin compound of the formula (6) wherein R 13 is P (0) (NHR 14 ) (OR 2 ) and R 14 is phenyl or C2-g_-4alkyl and R, and R a are as hereinbefore defined into the corresponding compound wherei R 13 is P(S) (OH) (OR 2 ); or f) for compounds where B?- is SO3H, reacting in the presence of a strong base a compound of the formula (2) as hereinbefore defined with sulphury1 chloride or a chemical equivalent thereof and optionally converting the group OR 1 ! into OH; or g) for compounds wherein R 1 is SO2H, reacting in the presence of a strong base a compound of the formula (2) as hereinbefore defined with sulphur dioxide an optionally converting the group OR 11 into OH; or h) for compounds wherein R 1 is 5-tetrazolyl, reacting a compound of the formula (4) wherein R 12 is cyano or a compound of the formula (6) wherein R 13 is cyano with azide salt; or i) for compounds wherein R 1 is 1-(HO2CCH2) -5-tetrazolyl or l-(R 9 02CCH2)-5-tetrazolyl, reacting a compound of the formula (6) wherein R 13 is 5-tetrazolyl with a compound of the formula (7) : LCH C0 2 R 9 ( 7 ) wherein L is a leaving group and R 9 is as hereinbefore defined and thereafter optionally converting the group CO2R 9 to CO2H; or j) for compounds wherein R a is halo, reacting a compound of the formula (8) : Formula (8) wherein R 1 ^ is a group R^ as hereinbefore defined or a precursor thereof, and R is as hereinbefore defined, with a suitable halogenating agent, and thereafter if necessary converting a precursor of R 1 to R 1 ; and optionally thereafter : • forming a bioprecursor of R^ and/or R 1 » forming a pharmaceutically acceptable salt. Suitably a compound of the formula (2) is reacted wit a strong base such as lithium diisopropylamide, or a Cι_4alkyl lithium or aryl lithium such as mesityl lithium in an organic solvent such as tetrahydrofuran, diethylether or dimethoxyethane with cooling (-100° - 0°C) to form the anion thereof. The strong base may be formed in situ, for exampl by the addition of a Cι_4al yl lithium e.g. methyllithium followed by a catalytic quantity of diisopropylamine. The anion of a compound of the formula (2) is suitably reacted with, a compound of the formula (3) or a compound of the formula (5) in an organic solvent such as tetrahydro- furan, diethylether or dimethoxyethane with cooling (-100° t 0°C) to form a compound of the formula (4) wherein R 12 is CR (OH)C02R 9 or COCO2 9 respectively. A suitable compound of the formula (3) is ethylpyruvate, or ethyl glyoxylate or chemical equivalent thereof and a suitable compound of the formula (5) is diethyloxalate. A compound of the formula (4) wherein R 12 is CR 3 (OH)CO2 9 is suitably reacted with a C__3alkylating agent such as iodomethane, iodopropane or dimethylsulphate in the presence of a base such as sodium hydride or potassium hydroxide in an organic solvent such as dimethylformamide or dimethylsulphoxide at elevated (e.g. 30 - 80°C) or preferabl ambient temperature to form the corresponding compound wherein R 12 is CR 3 (OC__3alkyl)CO2R 9 . When potassium hydroxide is used as base the CO2R 9 group may be directly converted to carboxy. A compound of the formula (4) wherein R 1 is COCO2R 9 i suitably reacted with a reducing agent such as sodium borohydride, or diisobutylaluminium hydride in an organic solvent such as dichloromethane, a C2-g_-4alcohol e.g. ethanol, or acetic acid or mixtures thereof at ambient or elevated temperature (e.g. 30 - 80°C), or with cooling (e.g. 0 - 5°C) to form the corresponding compound wherein R 12 is CH(OH)C0 2 R 9 . A compound of the formula (4) wherein R 12 is COCO2H or COCO2R 9 is suitably reacted with a reducing agent such as a zinc amalgam in hydrochloric acid in the absence of a solvent or in a solvent such as ethanol, acetic acid or dioxan and hydrogen chloride gas at ambient or elevated temperature (e.g. 40-100°C) to form the corresponding compound wherein R 12 is CH2CO2H. Under these reaction conditions the CO2 9 group is converted to carboxy. A compound of the formula (4) wherein R 12 is COCO2R 9 is suitably reacted with a C__3alcohol, 1,2-ethanediol or 1,3- propanediol in the presence of an acid catalyst such as paratoluenesulphonic acid, concentrated sulphuric acid or anhydrous hydrogen chloride, at ambient or elevated temperature to form the corresponding compound wherein R 12 i C(OR 5 ) (OR 6 )C0 2 R 9 . A compound of the formula (4) wherein R 12 is COCO2R 9 or CHOHCO2R 9 is suitably reacted with a fluorinating agent such as diethylaminosulphur trifluoride in an organic solvent suc as a halohydrocarbon or an ether such as glyme, or THF at ambient or elevated temperature (e.g. 30-60°C) to form the corresponding compound where R 12 is CF2CO2 9 or CHFCO2R 9 respectively. A compound of the formula (4) wherein OR 11 is methoxy can suitably be converted to the corresponding compound wherein OR 11 is hydroxy by reaction with sodium iodide and chlorotrimethylsilane in an organic solvent such as acetonitrile, or a halohydrocarbon e.g. dichloromethane or chloroform at elevated (e.g. 30 - 80°C) or preferably ambien temperature. This method is particularly suitable for preparing compounds of the formula (1) wherein R 1 is A^C02R 9 since the ester-forming group R 9 is not hydrolysed under the reaction conditions. Another method utilises sodium thiomethoxide in an organic solvent such as dimethylformamid at an elevated temperature for example 40 - 120°C. The mor forcing conditions of this method are suitable for preparing compounds of formula (1) wherein R 1 is A^C ^H. A compound of the formula (4) wherein R 12 is A 0 CO_»R 9 can suitably be converted to the corresponding compound wherein R 12 is AOCO2H by reaction with an aqueous base such as sodium or potassium hydroxide at ambient or elevated temperature (e.g. 40 - 120°) . This method is particularly suitable for preparing compounds of the formula (1) wherein R° is methoxy since the OR 11 group is not hydrolysed. Another hydrolysis method utilises aqueous acid such as concentrated hydrochloric acid at an elevated temperature (e.g. 40 - 120°C) which provides directly compounds of the formula (1) wherein 9 is hydroxy and R 1 is AOC ^H. Suitably a compound of the formula (6) wherein R 13 is acetyl is converted to the corresponding compound where R 1 is CH2CO2H by reaction with sulphur and morpholine at elevated temperature (e.g. 50 - 200°C) , followed by hydrolysis with an aqueous base such as sodium hydroxide at elevated temperature, preferably at the reflux temperature the reaction mixture. Suitably a compound of the formula (6) wherein R 13 is CH=CHC02H or CH=CHCθ2 9 is hydrogenated (suitably 1 to 5 atmospheres of hydrogen) in the presence of a suitable catalyst e.g. a rhodium catalyst such as tris(triphenyl- phosphine)rhodium (I) chloride, in a suitable solvent such a C__4alkanol or tetrahydrofuran at ambient or elevated temperature (e.g. 40 - 100°C) , preferably ambient temperature. A compound of the formula (6) wherein R 13 is CH=CHCθ2R is suitably prepared by reacting a compound of formula (6) wherein R 13 is CHO with a suitable Wittig reagent such as (Ph)3P=CHCθ2R 9 in an organic solvent such as toluene, or tetrahydrofuran at an elevated temperature (e.g. 50 - 150°C) conveniently at the reflux temperature of the reaction mixture. If desired the compound of formula (6) wherein R 13 is CH=CHCθ2R can be converted to the corresponding compound where R 13 is CH=CHCθ2H as hereinbefore described. A compound of the formula (6) where R 13 is CHO is suitably prepared by reacting the corresponding compound wherein R 13 is cyano with a suitable reducing agent such as diisobutylaluminium hydride followed by acidic aqueous work- up. Suitably a compound of the formula (6) wherein R 13 is P(0) (OR 2 )2 is hydrolysed by reaction with an aqueous base such as sodium hydroxide optionally in a cosolvent such as Cι_4alcohol at an elevated temperature (e.g. 40-100°C) , preferably at the reflux temperature of the reaction mixtur Suitably a compound of the formula (6) wherein R 13 is P(0) (NHR 14 ) (OR 2 ) is converted to the corresponding compound wherein R 9 is P (S) (OH) (OR 2 ) by reaction with a strong base such as sodium hydride in an organic solvent such as dimethoxyethane at ambient or elevated temperature, (e.g. 4 - 100°C) followed by reaction with carbon disulphide. Suitably the anion of a compound of the formula (2) prepared as hereinbefore described is reacted with sulphury chloride or a chemical equivalent thereof or with sulphur dioxide in an organic solvent such as tetrahydrofuran with cooling (-100° - 0°C) to form after aqueous work-up a compound of the formula (4) wherein R 12 is SO3H or SO2H respectively and OR 11 is methoxy which if desired can be converted to the corresponding compound wherein OR 11 is hydroxy as hereinbefore described. A compound of the formula (4) wherein R 11 is cyano or compound of the formula (6) wherein R^ 3 is cyano is suitabl reacted with an azide salt such as ammonium, sodium, potassium or aluminium azide in an organic solvent such as dimethylformamide, dimethylsulphoxide, N-methylpyrrolidone tetrahydrofuran at an elevated temperature e.g. 40 - 200°C, preferably at 100-150°C to form the corresponding 5- tetrazolyl compound. Suitably a compound of the formula (6) wherein R 13 is 5-tetrazolyl is reacted with a compound of the formula (7) an organic solvent such as dimethylformamide or acetonitrile in the presence of a base such as potassium or sodium bicarbonate at ambient or elevated temperature (e.g. 40- 160°C) . Suitably a compound of the formula (6) wherein R 13 is l-(R 9 02CCH2)-5-tetrazolyl is hydrolysed by reaction with an aqueous base such as sodium hydroxide optionally in a cosolvent such as a C__4alcohol at an elevated temperature (e.g. 40 - 100°C), preferably at the reflux temperature of the reaction mixture. A compound of the formula (8) is suitably reacted wit a halogenating agent, for example a brominating agent such N-bromosuccinimide in an organic solvent such as dimethylformamide or dimethylsulphoxide, at ambient or elevated temperature, e.g. 40-200°C, conveniently at the reflux temperature of the reaction mixture. An example of a bioprecursor of the group R 1 is cyano, which can be converte as hereinbefore described to 5-tetrazolyl. If desired a compound of the formula (1) wherein R 1 is A^C02H can be converted to the corresponding compound wherei R 1 is A°Cθ2R by reaction with a compound R 9 0H wherein R 9 is as hereinbefore defined. A compound of the formula (1) wherein R^ is OH can be converted to the corresponding compound where R^ is OR^ by reaction with R^i wherein R* is as hereinbefore defined an L 1 is a leaving group such as halo e.g. bromo, chloro, iodo. If desired a compound of the formula (1) wherein R 1 is P(Z) (OR 2 ) (OH) can be converted to the corresponding compound wherein R 1 is P(Z) (OR 2 ) (OR 1 ^) by reaction with a suitable 0- protecting agent in standard manner. For example the compound can be reacted with a pivalolyloxymethyl halide. A compound of the formula (1) wherein R 1 is 5-tetrazole can be reacted with a suitable N-protecting agent in a standard manner, for example with a pivalolyloxymethyl halide. A compound of the formula (1) wherein R^-RO is AI-CO2 suitably prepared by heating a compound of the formula (1) wherein R 1 is A^Cθ2H and R^ is OH with a dehydrating agent such as acetic anhydride, at an elevated temperature (e.g. - 200°C) , preferably at the reflux temperature of the reaction mixture. A compound of the formula (1) wherein R 1 -R^ is A 2 OCH2 is suitably prepared by reacting a compound of the formula (1) wherein R 1 is A 2 OH and R^ is OH with a dihalomethane suc as diiodo or dibromomethane in the presence of silver carbonate in an organic solvent such as dimethylformamide . at an elevated temperature (e.g. 40 - 120°C) . A compound of the formula (2) is suitably prepared by reacting a compound of the formula (6) wherein R 13 is hydrogen with an O-methylating agent such as dimethyl¬ formamide dimethylacetal in dimethylformamide or trimethylphosphite at an elevated temperature (e.g. 40 - 120°C) or with iodomethane and silver carbonate in toluene o chloroform. A compound of the formula (6) wherein R is X Ar^, X 2 i ethenyl and R 13 is cyano is suitably prepared by reaction of the corresponding compound wherein R is methyl with Ar^CHO i the presence of a base such as tetrabutylammonium fluoride i an organic solvent such as tetrahydrofuran followed by worku and treatment of the resulting compound with a dehydrating agent such as acetic anhydride in acetic acid at ambient or elevated temperature (e.g. 40 - 150°C) , preferably the reflu temperature of the reaction mixture. A compound of the formula (6) wherein R a is X^Y 1 , R 13 is cyano, acetyl or hydrogen is suitably prepared by reacti of a compound of the formula (9) : with a compound of the formula (10) : R 16 CH 2 CONH 2 (10) wherein R 16 is cyano, acetyl or hydrogen respectively, and is a displaceable group and X 1 , Y 1 and R are as hereinbefor defined. Suitably L 2 in a compound of the formula (9) is hydrox or a derivative thereof for example L 2 is protected hydroxy such as silyloxy, an acid residue (for example C__galkanoyloxy) or an ether residue (for example methoxy or ethoxy) . Alternatively L 2 is a secondary amino group, for example di-C__galkylamino such as dimethylamino or a cyclic amino group such as piperidino, pyrrolidino or morpholino. Preferably L 2 is hydroxy or dimethylamino. Suitably an alkali metal (e.g. sodium) salt of a compound of the formula (9) wherein L 2 is hydroxy is treated with a compound of the formula (10) 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. Alternatively a compound of the formula (9) wherein L 2 is a secondary amino group, for example dimethylamino, is treated with a compound of the formula (10) in a suitable solvent such as dimethylformamide, a C__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. Compounds of the formula (9) wherein L 2 is hydroxy can suitably be prepared by reaction under basic conditions of a compound of the formula (11) : Y 1 X 1 CH 2 COR (11) wherein R, χl and Y 1 are as hereinbefore defined, with a compound of the formula HCOL 3 wherein L 3 is a leaving group. Suitably L 3 is ethoxy or methoxy. Conveniently a solution of a compound of the formula (11) and a compound of the formula HCOL 3 in a suitable organic solvent such as diethyl ether is treated with a suitable base such as an 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 (9) wherein L 2 is hydroxy is then treated with a compound of the formula (10) as hereinbefore described. Compounds of the formula (9) wherein L 2 is a secondary amino group (e.g. dimethylamino) can suitably be prepared by reacting a compound of the formula (11) with a compound of the formula HC(OR 17 )2L 2 wherein R 17 is C__4alkyl and L 2 is a secondary amino group (for example HC(OR 17 )2-> 2 is N,N- dimethylformamide dimethyl or diethyl acetal) . Alternativel a compound of the formula (11) can be reacted with a compoun of the formula HC(L 2 )3 (for example tris dimethylamino- methane) . A compound of the formula (11) wherein X 1 is 0 or S i suitably prepared by reaction of a compound of the formula (12) : Y 1 X 3 H (12) wherein X 3 is 0 or S and Y 1 is as hereinbefore defined with compound of the formula (13) : RC0CH 2 L 4 (13) wherein R is as hereinbefore defined and L 4 is a leaving group such as halo. Suitably a compound of the formula (12) and a compound of the formula (13) in a suitable organic solvent such as dimethylformamide are treated with a base such as potassium carbonate at ambient or elevated temperature (e.g. 40-160°C) A compound of the formula (11) wherein X 1 is S and Y 1 is C__galkyl can also be prepared by reacting a compound of the formula (13) with sodium or potassium thioacetate followed by treatment of the intermediate with a base such a sodium methoxide and an alkylating agent such as a C__galkyl halide, e.g. iodomethane or iodoethane in a solvent such as dimethylformamide or methanol. A compound of the formula (6) wherein R 13 is acetyl can also be prepared by reacting a compound of the formula (6) wherein R 13 is cyano with methyl lithium followed by aqueous work up with for example dilute hydrochloric acid or aqueous ammonium chloride. A compound of the formula (6) wherein R 13 is hydrogen can also be prepared by heating a compound of formula (11) as hereinbefore defined with a C__4alkyl propiolate (such as methyl propiolate) and ammonia in a solvent such as a C__4alkanol in a pressure vessel at elevated temperature (4 200°C) preferably at 100°C. Alternatively a compound of the formula (6) wherein R is hydrogen can be prepared by reacting a compound of the formula (6) wherein R 13 is cyano with orthophosphoric acid an elevated temperature, e.g. 50 - 200°C. Alternatively a compound of the formula (6) wherein X is 0 or S, R is H or Cι_galkyl and R 13 is hydrogen or cyano can be prepared by reaction of a compound of the formula (14) : Formula (14) wherein L^ is halo, for example bromo, A is H or C^-galkyl and B is H or cyano, with a compound of the formula (12) as hereinbefore defined or a chemical equivalent thereof in a solvent such as dimethylformamide or N-methylpyrrolidinone o quinoline in the presence of a base such as potassium carbonate or pyridine at ambient or elevated temperature (e.g. 40 - 160°C) . An example of a chemical equivalent of a compound of the formula (12) is a copper salt such as a bis- (Cι_galkylthio) copper salt. A compound of formula (4) wherein R 12 is cyano is suitably prepared by reacting the anion of a compound of formula (2) wherein R, R a and RH are as hereinbefore define with dimethylformamide with cooling (e.g. -80 to 10°C) , followed by ambient temperature and aqueous work-up. The resulting compound of formula (4) wherein R 12 is carbox- aldehyde is treated with hydroxylamine hydrochloride and sodium acetate in a suitable solvent such as ethanol or methanol at elevated temperature, e.g. 40-100°C, preferably at the reflux temperature of the reaction mixture followed dehydrating the product obtained for example by heating wit acetic anhydride. A compound of the formula (6) wherein R 13 is cyano or acetyl and R, and R a are as hereinbefore defined can be suitably prepared by reaction of a compound of formula (4) wherein R 12 is cyano or acetyl and R, R 11 , and R a , X 1 and Y are as hereinbefore defined with a demethylating agent such as sodium iodide/chlorotrimethyIsilane in the absence of solvent or in an organic solvent such as acetonitrile or chloroform at an elevated temperature (e.g. 40 to 100°C) or at ambient temperature. A compound of the formula (6) wherein R 13 is P(0) (OR 2 ) can be prepared by treating a compound of the formula (2) wherein R 11 is P(0) (OR 2 )2 with a strong base such as lithium diisopropylamide in an organic solvent such as tetra¬ hydrofuran with cooling (e.g. -100-0°C) . A compound of the formula (2) wherein RU is P (0) (OR 2 ) is suitably prepared by treating a compound of the formula (6) wherein R 1 is hydrogen with a compound of the formula (15) : L 6 P(0) (OR 2 ) 2 (15) wherein L 6 is a leaving group and R 2 is as hereinbefore defined with a base such as diisopropylethylamine. Suitably L 6 is halo, for example chloro or bromo. A compound of formula (2) wherein R 11 is P (0) (OR 2 ) 2 c also be prepared by treating a compound of the formula (6) wherein R^ 3 is hydrogen with a compound of the formula (16) HP(0) (OR 2 )2 (16) wherein R 2 is as hereinbefore defined in the presence of an amine base such as triethylamine, and carbon tetrachloride. Alternatively, a compound of the formula (6) wherein R^ 3 is P (0) (OR 2 )2 is suitably prepared by treating a compou of the formula (6) wherein R 13 is hydrogen with a compound o the formula (15) in the presence of a strong base such as lithium diisopropylamide in an organic solvent such as tetrahydrofuran with cooling (e.g. -100-0°C) without isolation of the intermediate compound of the formula (2) wherein R 11 is P (0) (OR 2 )2- A compound of formula (6) wherein R 13 is hydrogen is suitably prepared by demethylating a compound of formula (2) as hereinbefore defined. Suitably a compound of formula (2 is treated with boron tribromide in an organic solvent such as dichloromethane or toluene with cooling (e.g. -80 to 10°C followed by ambient temperature and aqueous work-up. Or a compound of formula (2) is treated with sodium iodide and chlorotrimethylsilane at ambient or elevated temperature (e.g. 40-80°C) conveniently ambient temperature in a solvent such as acetonitrile or dichloromethane. A compound of the formula (6) wherein R^ 3 is P(0) (NHR 14 ) (OR 2 ) can be prepared by reaction of a compound o the formula (6) wherein R 13 is P (0) (OH) (OR 2 ) with carbon tetrachloride, triphenylphosphine and aniline or a C__4alkylamine in an organic solvent such as pyridine at ambient temperature or with cooling (e.g. -10 to 5°C) . Alternatively a compound of the formula (6) where R 13 is P(0) (OH) (OR 2 ) can be reacted with dimethylformamide and oxalyl chloride in an organic solvent such as a halo hydrocarbon e.g. dichloromethane at ambient temperature, followed by reaction with aniline or a C__4alkylamine preferably with cooling (-10 to 5°C) . A compound of the formula (2) wherein R a is SY 1 can b prepared by reaction of a compound of the formula (17) : wherein L 7 is halo such as bromo or iodo, R 11 is methyl and is as hereinbefore defined with a compound of the formula (12) or a chemical equivalent thereof wherein X 3 is S and Y 1 is as hereinbefore defined. An example of a suitable chemical equivalent is a tin complex such as phenyltributyltin sulphide when Y 1 is phenyl which can be reacted with a compound of the formula (17) according to the method of Kosugi et al as noted in Example 27 hereinafter. 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 compound of the formula (1) with a solution of the base. The following biological test methods, data and Examples serve to illustrate this invention. Cyclic-AMP Protein Kinase (cA-PrK) Agonist Activity Type II cA-PrK was prepared from the cardiac muscle o a cow. The supernatant from a muscle homogenate (3 mis of 10 mM potassium phosphate, 1 mM EDTA per g tissue) was applied to a column of DEAE-cellulose equilibrated with the homogenisation buffer and the type II cA-PrK was eluted wit homogenisation buffer containing 350 mM sodium chloride (Rannels et al., 1983, Methods Enzymol., 99, 55-62). Type II cA-PrK was assayed for phosphotransferase activity by incubating the enzyme at 30°C for 5 minutes wit [γ- 32 P]-adenosine triphosphate and a suitable peptide substrate such as malantide (Malencik et al., 1983, Anal. Biochem., 132, 34-40). The reaction was terminated by the addition of hydrochloric acid and the [ 32 P]-phosphopeptide quantified by spotting the reaction mixture onto phosphocellulose papers. The concentration of compound required to give 10% phosphotransferase activation is given as the EC_o (μM) . The compounds of Examples 1 to 27 had EC_Q values in the range 0.09 - 100 μM. Inhibition of Platelet Aggregation Human platelet-rich-plasma was separated from freshly drawn blood (in acid/citrate/dextrose) and treated with 100 μM acetylsalicylic acid for 15 minutes at 37°C. A washed platelet suspension was then prepared in a Hepes- isotonic saline buffer after a single centrifugation step a 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 μM U46619. The extent of aggregation after 2 minutes were expressed as a percentage of control and results obtained are expressed as an IC50 (concentration to cause 50% inhibition of platelet aggregation, μM) . The compounds of Examples 1 to 6, 9, 13, 15, 16, 18 to 21 and 23 to 26 had IC50 values in the range 2 to 300 μM. Inhibition of Spontaneous Contraction in Guinea-Pig Colon 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 recordin and display of developed tension on chart recorders. On¬ line computer capture and analysis was used to quantify th effects of test compounds on spontaneous contractions. Inhibitory responses were calculated as % maximum inhibiti of spontaneous contraction distance over 3 consecutive pre and post dose 2 minute readings. The concentration of compound which caused 50% inhibition of the spontaneous contraction is given as the EC50 (μM) . The compounds of Examples 1 and 4 had EC50 values of 21 and 60 μM respectively. Bronchodilatation - In vitro Spiral strips of guinea-pig trachea were suspended in standard organ baths containing Krebs solution. The tissue were connected at the free end to isometric transducers whi allow recording and display of developed tension on chart recorders. Tension was allowed to develop spontaneously an concentrations of test compounds added in a cumulative fashion. The concentration of compound which caused 50% inhibition of the spontaneously developed tension is given the IC50(μM) . The compounds of Examples 1, 4, 5, 13, 18 and 20 to 2 had IC50 values in the range 9 to 100 μM. Measurement of cardiac muscle relaxation time in rabbit ventricle Papillary muscles from the right ventricle of female Albino New Zealand rabbits are mounted in standard organ baths containing oxygenated Krebs solution. One end of the muscle is connected to an isometric transducer which allows recording of contractile force and its first derivative on chart recorders. Test compounds are added to the bath in a cumulative manner. Relaxation time is calculated as the ti taken from peak tension to the end of the contraction. Compounds which cause a decrease in the relaxation time indicate a positive lusitropic effect of use in the treatme of cardiovascular diseases where there is a component of diastolic failure such as congestive heart failure, angina, hypertension and cardiomyopathy. Example 1 6-Methyl-5-(2-naphthylthio)-3-(5-tetrazolyl)pyridin-2(IH)-o (a) A mixture of chloroacetone (9.3g), 2-naphthalenethiol (16g) and potassium carbonate (13.8g) was stirred in dimethylformamide (100ml) at room temperature for 48 hours. After diluting with ethyl acetate (400ml) , the organic phas was washed with water (6x200ml) , dried (MgS04) filtered and solvent removed at reduced pressure to give l-(2-naρhthyl- thio)ρropan-2-one (20.2g) as an oil. ^-H NMR δ(CDCl3) 2.26(s,3H), 3.74(s,2H), 7.23-7.48(m,3H) and 7.71-7.93(m,4H) (b) l-(2-Naphthylthio)propan-2-one (16.2g) was dissolved dimethylformamide (100ml) containing dimethylformamide dimethylacetal (9.52g) and boiled for 72 hours. The solutio was cooled to room temperature, cyanoacetamide (6.72g) and sodium methoxide (8.64g) added, the solution boiled for a further 1 hour, poured into 10% aqueous acetic acid (300ml) and the precipitated product collected by filtration. Recrystallisation from ethanol gave 3-cyano-6-methyl-5-(2- naphthylthio)pyridin-2(lH)-one (8.24g) m.p. 247-249°C. (c) A mixture of 3-cyano-6-methyl-5-(2-naphthylthio)- pyridin-2(IH)-one (l.Og) ammonium chloride (0.24g) and sodiu azide (0.29g) in N-methylpyrrolidinone was heated at 140°C for 4 hours. The reaction mixture was poured into 10% aqueou acetic acid (50ml) and the precipitated product collected by filtration. Recrystallisation from dimethylformamide gave th title compound (0.53g) m.p.296-297°C. Example 2 3- (l-Carboxymethyl-5-tetrazolyl) -6-methyl-5- (2-naphthylthio pyridin-2 (IH) -one (a) A mixture of 6-methyl-5- (2-naphthylthio) -3- (5- tetrazolyl)pyridin-2 (IH) -one (6.37g), ethyl bromoacetate (3.16g) and sodium bicarbonate (1.74g) were stirred in dimethylformamide (70ml) at room temperature for 10 hrs and at 50°C for 2 hours. The mixture was diluted with ethyl acetate (300ml) washed with water (6x200ml) , dried (MgS04) and solvent removed at reduced pressure. The residue was column chromatographed (silica gel, ethyl acetate eluant) t give in order of elution i) 3- (l-carboethoxymethyl-5- tetrazolyl) -6-methyl-5- (2-naphthylthio)pyridin-2 (IH) -one (0.54g) ii) 3- (2-carboethoxymethyl-5-tetrazolyl) -6-methyl- (2-naphthylthio)pyridin-2 (lH)-one (0.75g) . (b) A solution of 3- (l-carboethoxymethyl-5-tetrazolyl) -6- methyl-5-(2-naphthylthio)ρyridin-2 (lH)-one (0.54g) in IN sodium hydroxide/ethanol (40ml, 1:1) was stirred at room temperature for 4 hours, poured into 2N hydrochloric acid (50ml) and extracted with ethyl acetate (3x50ml) . The combined organic extracts were washed with water, dried (MgS04) and solvent removed. The residue was recrystallised from ethanol to give the title compound (0.2g) m.p. 270°C(decomp) . 1 H NMR δ(DMSO-dg) 2.47(s,3H), 5.50(s,2H), 7.33(dd,lH7.41-7.56(m,2H) , 7.65(s,lH), 7.80- .93 (m, 3H) and 7.98 (S-1H) . Example 3 n-Propyl-[5-(2-naphthylthio) -2-oxo-l,2-dihydro-3-pyridyI] - phosphonate sodium salt (a) A mixture of 5-bromopyridin-2 (IH) -one (1.74g), 2- naphthalenethiol (1.6g) and potassium carbonate (1.38g) wer combined in dimethylformamide and heated to 130°C for 3 hours. The green solution was poured into 2N hydrochloric acid (80ml) , ethyl acetate (50ml) and hexane (50ml) added a the mixture stirred for 1 hour. The precipitated solid was separated by filtration, and column chromatographed (silica, dichloromethane-15% ethanol/dichloromethane) to give 5-(2- naphthylthio)pyridin2(lH)-one (0.95g). ^-H NMR (DMSO-dg) 6.41(d,lH), 7.33(dd,lH), 7.42-7.53(m,3H) , 7.64 (s,lH) and 7.76-7.90(m,4H) . (b) To a suspension of 5-(2-naphthylthio)pyridin- 2(lH)-one (0.9g) in tetrahydrofuran (5ml) cooled to -78°C lithium diisopropylamide (1.5M in cyclohexane, 2.7ml) was added over 2 minutes. The mixture was stirred at -78°C for 1 minutes and at 0°C for 30 minutes, recooled to -78°C and di- n-propylphosphorochloridate (0.8g) added. After stirring for a further 15 minutes at -78°C and at 0°C for 30 minutes the solution was recooled to -78°C and, lithium diisopropylamide (1.5M in cyclohexane, 2.7ml) was again added. The solution was stirred for 30 minutes at -78°C and at 0°C for 30 minutes, quenched with 2N hydrochloric acid, diluted with ethyl acetate (50ml) and the organic phase washed with water (2x30ml) , dried (MgS04) , filtered and solvent removed at reduced pressure. The residue was column chromatographed (silica, dichloromethane-10% ethanol/dichloromethane) to give di-n-propyl [5-(2-naphthylthio)-2-oxo-l,2-dihydro-3- pyridyljphosphonate (0.41g). ^-H NMR (DMSO-dg) 0.82 (t,6H), 1.47-1.62(m,4H) , 3.88-3.97 (m, H) , 7.33(dd,lH), 7.44- 7.53(m,2H), 7.66(s,lH), 7.74-7.90 (m,4H) and 8.07(s,IH) . (c) A solution of di-n-propyl [5-(2-naphthylthio)-2-oxo- l,2-dihydro-3-pyridyl]phosphonate (0.37g) in a mixture of n- propanol (3ml) and 2N sodium hydroxide (3ml) was boiled for 10 hours. The solution was stood at room temperature overnight, the precipitated product was separated by filtration and recrystallised from ethanol to give the title compound (0.14g) m.p. >300°C. ^ NMR (0.41g) 6(DMSO-dg) 0.64 (t,3H), 1.31-1.42 (m,2H) , 3. 6-3.60 (m,2H) , 7.19(d,lH), 7.33-7.81 (m,6H) and 7.93 (s, IH) . Example 4 6-Methyl-5-phenylthio-3-(5-tetrazolyl)pyridin-2(IH)-one. (a) A mixture of chloroacetone (19.9ml) thiophenol (25.6m and potassium carbonate (34.5g) was stirred in dimethyl- formamide (200ml) at room temperature for 48 hours. After diluting with ethyl acetate (800ml) the organic phase was washed with water (6x500ml) dried (MgS04) and solvent remov at reduced pressure to give l-phenylthiopropan-2-one (36.6g) as an oil. X H NMR δ(CDCl 3 ) 2.26(s,3H), 3.65(s,2H) and 7.17- 7.47 (m,5H) . Prepared in a similar way from the appropriate thiol or phenol and the 2-haloketone were the following:- 1-(4-chlorophenyl)propan-2-one: oil, yield 93%, 1 H NMR 6(CDCl3) 2.27(s,3H), 3.65(s,2H) and 7.17-7.28 (m, H) ; 1-(3-chlorophenylthio)propan-2-one:- oil, yield 74%, ^H NMR δ(dg-DMSO) 2.23(s,3H), 4.12(s,2H) and 7.20-7.36 (m,4H) ; 1-(2-chlorophenylthio)propan-2-one:- oil, yield 85%, 1 H NMR δ(dg-DMSO) 2.26(s,3H), 4.1 (s,2H), 7.15-7.31 (m,3H) and 7.45(dd,lH) ; 1-(3, 4-dichlorophenylthio)propan-2-one:- oil, yield 85%, ^H NMR δ(dg-DMSO) 2.30(s,3H), 4.16(s,2H), 7.26(dd,lH) and 7.52- 7.56 (m,2H) ; 2-(2-naphthyloxy)acetophenone:- oil, yield 88%, 1 H NMR δ(dg- DMSO) 5.71(s,2H), 7.23-7.88 ( , 10H) , and 8.06-8.10 (m,2H) ; 2-phenylthioacetophenone:- oil, yield 96%, ^-H NMR δ(CDCl3) 4.39(s,2H), 7.25-7.63(m,6H) , 7.85-8.02(m,5H) and 8.42 (s,IH) and 2-(2-naρhthylthio)acetophenone:- oil, yield 80%, ^-H NMR δ(CDCl3) 4.32(s,2H), 7.36-7.97 (m,12H) . (b) l-Phenylthiopropan-2-one (36.6g) was dissolved in dimethylformamide (200ml) containing dimethylformamide dimethylacetal (31.9g) and boiled for 36 hours. The solutio was cooled, cyanoacetamide (18.5g) and sodium methoxide (23.8) added, the mixture boiled for a further 2 hours, poured into water (800ml) containing acetic acid (80ml) and the precipitated product collected by filtration. The produ was recrystallised from ethanol to give 3-cyano-6-methyl-5- ρhenylthiopyridin-2(lH)-one (19.8g) m.p. 252-254°C. (c) A mixture of 3-cyano-6-methyl-5-phenylthiopyridin- 2(lH)-one (1.21g) ammonium chloride (0.8g) and sodium azide (0.98g) in N-methylpyrrolidinone was heated at 130°C for 4 hours. Addition to water (200ml) containing acetic acid (3ml precipitated the product which was recrystallised from ethanol to give the title compound (0.47g) m.p. 300°C(decomp) . Example 5 5-(4-chlorophenylthio)-6-methyl-3-(5-tetrazolyl)pyridin- 2(lH)-one (a) 5-(4-Chlorophenyl)-3-cyano-6-methylpyridin-2(IH)-one (21.6g) m.p. 305°C(decomp) was prepared from l-(4-chloro- thiophenyl)propan-2-one according to the method of Example 4(b). λ Η. NMR δ(DMSO-dg) 2.37 (s,3H), 7.17(d,2H), 7.36(d,2H) and 8.26(s,lH) . (b) From 5- (4-chlorophenylthio) -3-cyano-6-methylpyridin- 2(lH)-one (5.53g) the title compound (2.49g) m.p. 280°C (decomp) was prepared according to the method of Example 4(c) . 1 H NMR δ(DMSO-dg) 2.44 (s,3H), 7.20 (d,2H), 7.37 (d,2H) and 8.34 (s,lH) . Example 6 E-6-(2-Phenylethenyl)-5-phenylthio-3- (5-tetrazolyl)pyridin 2(lH)-one (a) A mixture of 3-cyano-6-methyl-5-phenylthio-pyridin- 2(lH)-one (0.55g), benzaldehyde (0.23g) and tetrabutyl- ammonium fluoride (5ml, 1M in tetrahydrofuran) were boiled together for 6 hours, 4A molecular sieves (lg) were then added and heating continued for a further 50 hours. The reaction mixture was acidified with 2N hydrochloric acid (20ml) and the precipitated product separated by filtration washed with ethanol (30ml) and with diethyl ether (20 ml). The dried product (0.7g) was added to a mixture of acetic anhydride (8ml) acetic acid (4ml) and sodium acetate (lOOmg and boiled for 7 hours. On cooling the yellow product precipitated which was separated by filtration and washed with water (30ml) to give E-3-cyano-6- (2- phenylethenyl)pyridin-2 (lH)-one (0.56g) . 1 H NMR δ(DMSO-dg) 7.16-7.56(m,llH) , 7.84(d,lH) and 8.31 (s, IH) . (b) From E-3-cyano-6- (2-phenylethenyl)pyridin-2 (IH) -one (0.25g), the title compound (0.05 g) m.p. 292°C (decomp) after recrystallisation from n-butanol, was prepared according to the method of Example 4(c) . 1 H NMR δ(DMSO-dg) 7.18-7.61 (m,HH) , 7.88 (d-lH) and 8.38 (s, IH) . Example 7 3-Carboxymethyl-6-methyl-5-(phenylthio)pyridin-2(IH)-one (a) 3-Cyano-6-methyl-5-phenylthiopyridin-2 (IH)-one (5g) wa suspended in tetrahydrofuran (20ml) and cooled to -78°C unde nitrogen. Methyl lithium (32ml, 1.5M in diethyl ether) was added over 10 minutes, the mixture stirred for a further 10 minutes at -78°C and for 4 hours at 0°C. The reaction mixtur was quenched by the addition of saturated ammonium chloride solution (10ml) followed by the addition of 2N hydrochloric acid. After stirring overnight at room temperature the precipitated product was collected by filtration, washed wit water (50ml) and recrystallised from ethanol to give 3- acetyl-6-methyl-5-phenylthiopyridin-2(IH)-one (1.39g) , m.p.203°C. (b) A mixture of 3-acetyl-6-methyl-5-phenylthiopyridin- 2(lH)-one (1.39g), sulphur (0.26g) and morpholine (0.7g) was boiled for 2.5 hours. Sodium hydroxide (2N, 50ml) was added and boiling continued for a further 4 hours. After cooling t room temperature, the reaction mixture was filtered, the filtrate adjusted to pH 4 with cone, hydrochloric acid and the product separated by filtration to give the title compound (0.13g) m.p.217°C (decomp) after recrystallisation from ethanol. R NMR δ(DMSO-dg) 2.31(s,3H), 7.04-7.18(m,3H) , 7.30(t,2H) and 7.41(s,lH) . Example 8 6-Phenyl-5-phenylthio-3-(5-tetrazolyl)pyridin-2(IH)-one (a) From 2-phenylthioacetophenone (11.4g), 3-cyano-6- phenyl-5-phenylthiopyridin-2(IH)-one (7.76g) m.p. 212-213°C after recrystallisation from ethanol, was prepared according to the method of Example 4 (b) . (b) From 3-cyano-6-phenyl-5-phenylthiopyridin-2 (IH) -one (1.22g), the title compound (0.3g) m.p. 276-278°C after recrystallisation from ethanol, was prepared according to t method of Example 4 (c) . Example 9 5- (3-Chlorophenylthio)-6-methyl-3- (5-tetrazolyl)pyridin- 2 (IH) -one (a) From 1- (3-chlorophenylthio)propan-2-one (3.06g), 5- (3- chlorophenylthio) -3-cyano-6-methylpyridin-2 (IH) -one (2.6g) m.p. 245°C after recrystallisation from ethanol, was prepare according to the method of Example (b) . (b) From 5- (3-chlorophenylthio) -3-cyano-6-methylpyridin- 2(lH)-one (lg) the title compound (l.Olg) m.p.277°C after recrystallisation from n-butanol, was prepared according to the method of Example 4(c) . 1 H NMR δ(dg-DMSO) 2.44 (s,3H), 7.11 (d,lH) 7.25(m,2H), 7.33(t,lH) and 8.36 (s, IH) . Example 10 5- (2-Chlorophenylthio)-6-methyl-3- (5-tetrazolyl)pyridin- 2(lH)-one (a) From 1- (2-chlorophenylthio)propan-2-one (3.06g), 5- (2- chlorophenylthio) -3-cyano-6-methylpyridin-2 (IH) -one (2.19g) m.p. 270°C after recrystallisation from ethanol was prepared according to the method of Example (b) . (b) From 5- (2-chlorophenylthio) -3-cyano-6-methylpyridin- 2(lH)-one (lg) , the title compound (0.94g) m.p.289°C after recrystallisation from n-butanol was prepared according to the method of Example 4(c) . Example 11 5- (3, 4-Dichlorophenylthio) -6-methyl-3- (5-tetrazolyl) pyridin 2 (lH) -one. (a) From 1-(3, 4-Dichlorophenylthio)propan-2-one (3.14g), cyano-5-(3,4-dichlorophenylthio) -6-methylpyridin-2 (IH) -one (1.53g) m.p. 255°C after recrystallisation from ethanol, was prepared according to the method of Example 4 (b) . (b) From 3-cyano-5- (3,4-dichlorophenylthio) -6- methylpyridin-2 (IH) -one, (0.75g), the title compound (0.75g) m.p.297°C (decomp) after recrystallisation from n-butanol, was prepared according to the method of Example 4 (c) . ^H NM δ(dg-DMSO) 2.43(s,3H), 7.16(dd,lH), 7.51 (d, IH) , 7.56(d,lH) and 8.36(s,lH) . Example 12 5-n-Butylthio-6-methyl-3-(5-tetrazolyl)pyridin-2(IH)-one (a) To a suspension of 3-cyano-6-methylpyridin-2 (IH) -one (6.7g) in dimethylformamide (50ml), N-bromosuccinimide (8.85g) was added in portions over 10 minutes. The resulting mixture was stirred for 48 hours at room temperature, poured into water (150ml) and the precipitated material collected b filtration. The residue obtained was washed thoroughly with water and dried to give 5-bromo-3-cyano-6-methylpyridin- 2(lH)-one (8.88g) m.p. 254-255°C (decomp) . ^H NMR δ(d6 DMSO) 2.35(s,3H) and 8.35 (s,lH) . (b) A mixture of 5-bromo-3-cyano-6-methylpyridin-2 (IH) -one (2.13g) and bis(butylthio) copper was heated in quinoline (10ml) and pyridine (3ml) at 190°C for 6 hours. The mixture was filtered and poured into 2N hydrochloric acid (100ml) . The precipitated solid was collected by filtration and column chromatographed (silica gel, dichloromethane - 5% ethanol/dichloromethane) to give 5-butylthio-3-cyano-6- methylpyridin-2 (IH)-one (0.12g) m.p. 206-208°C after recrystallisation from ethanol. (c) From 5-butylthio-3-cyano-6-methylpyridin-2 (IH)-one (O.llg) the title compound (0.07g) m.p. 258-259°C after recrystallisation from ethanol, was prepared according to t method of Example 4 (c) . Example 13 5-n-Butylthio-6-(4-methoxy-3-propoxyphenyl)-3-(5- tetrazolyl)pyridin-2(IH)-one (a) A mixture of 3'-hydroxy- '-methoxyacetophenone (A. Brosei, H. Gurien, A. I. Rachlin and S. Teitel, J. Org. Chem., 1967, 32, 1269) (8.31g), iodopropane (17g) and potassium carbonate (9.91g) in acetone (50ml) was boiled for 18 hours. The mixture was cooled to room temperature diluted with ethyl acetate (200ml) and washed with water (200ml), 2N sodium hydroxide (2 x 200ml) and water (2 x 200ml) . The organic phase was dried (MgS04) , and solvent removed at reduced pressure to give '-methoxy-3*-propoxyacetophenone (10.3g) as an oil that solidified on standing m.p. 63-64°C. (b) Copper (II) bromide (13.4g) and 4'-methoxy-3'- propoxyacetophenone (6.25g) were combined in ethyl acetate (60ml) and chloroform (30ml) and the mixture boiled for 90 minutes. The reaction mixture was cooled to room temperature filtered and the residue washed thoroughly with dichloromethane. The combined organic phase was washed with 10% aqueous ammonia (3x50ml) and water (2x50ml) , dried (MgS04) and solvent removed at reduced pressure to give 2- bromo- '-methoxy-3'-propoxyacetophenone (4.94g) m.p. 76-77°C after recrystallisation from aqueous ethanol. (c) From 2-bromo-4'methoxy-3 I -ρroρoxyacetophenone (4.3g), 2-n-butylthio-4 « -methoxy-3•-propoxyacetophenone (2.17g) m. 53-54°C after recrystallisation from ethanol was prepared according to the method of Example 4(a) . (d) From 2-n-butylthio- '-methoxy-3'-propoxyacetophenone (2.52g) , 5-n-butylthio-3-cyano-6-(4-methoxy-3-propoxyphenyl pyridin-2 (IH) -one (2.96g) m.p.l37-138°C after recrystallisation from ethanol, was prepared according to t method of Example 4 (b) . (e) From 5-n-butylthio-3-cyano-6-(4-methoxy-3- propoxyphenyl)pyridin-2 (IH)-one (1.12g), the title compound (0.93g) m.p.l89-190°C after recrystallisation from ethanol was prepared according to the method of Example 4 (c) . Example 14 5-Benzyl-6-phenyl-3-(5-tetrazolyl)pyridin-2(IH)-one (a) From 3-phenylpropiophenone (4.21g), 3-cyano-5- methylphenyl-6-ρhenylpyridin-2(lH)-one (2.15g) m.p. 305°C (decomp) after recrystallisation from ethanol, was prepared according to the method of Example 4(b) . ^-H NMR δ(CDCl3) 3.80 (s,2H), 7.02(dd,2H), 7.20-7.39 (m, 3H) , 7.40-7.60 (m,5H) a 7.71 (s,lH) . (b) From 3-cyano-5-methylphenyl-6-phenylpyridin-2 (IH) -one (0.86g), the title compound (0.64g) m.p. 269°C (decomp) afte recrystallisation from ethanol, was prepared according to th method of Example 4(c) . ^-H NMR δ(dg-DMSO) 3.78 (s,2H), 7.05(d,2H), 7.18-7.30 (m,3H) , 7.51(m,5H) and 8.28 (s,IH) Example 15 5-(2-naphthyloxy)-6-phenyl-3- (5-tetrazolyl)pyridin-2 (IH)-on (a) From 2- (2-naphthyloxy) acetophenone (2.62g), 3-cyano-5 (2-naphthyloxy)-6-phenylpyridin-2 (lH)-one (2.23g) m.p. 272° (decomp) after recrystallisation from ethanol was prepare according to the method of Example 4(b) . 1 H NMR δ(dg-DMSO) 7.28(dd,lH), 7.39-7.92 (m,llH) and 8.31 (s, IH) . (b) From 3-cyano-5- (2-naphthyloxy) -6-phenylpyridin-2 (IH) - one (lg) the title compound (0.93g) m.p.307°C (decomp) afte recrystallisation from n-butanol, was prepared according to the method of Example 4(c) . 1 H NMR δ(dg-DMSO) (7.31 (dd, IH) , 7.37-7.92 (m,llH) and 8.28 (s, IH) . Example 16 6-(2-Naρhthyl)-5-phenylthio-3- (5-tetrazolyl)pyridin-2 (IH)-o (a) From 2- (2-phenylthio) acetonaphthone (13g) , 3-cyano-6- (2-naphthyl)-5-phenylthiopyridin-2 (lH)-one (4.9g) m.p.228°C after recrystallisation from n-butanol, was prepared according to the method of Example (b) . (b) From 3-cyano-6- (2-naphthyl) -5-phenylthiopyridin-2 (IH) one (1.82g), the title compound (1.73g) m.p. 249-250°C after recrystallisation from n-butanol, was prepared according to the method of Example (c) . Example 17 5-(2-Naphthylthio)-6-phenyl-3-(5-tetrazolyl)pyridin-2 (IH)-o (a) From 2- (2-naphthylthio) acetophenone (8g) , 3-cyano-5- (2 naphthylthio)-6-phenylpyridin-2(lH)-one (3.4g) m.p.256-258°C after trituration with water/ethyl acetate, according to t method of Example 4 (b) . (b) From 3-cyano-5-(2-naphthylthio)-6-phenylρyridin-2 (IH) one (3.4g), the title compound (2.7g) m.p.272-274°C after recrystallisation from dimethylformamide/ethanol, was prepared according to the method of Example 4 (c) . Example 18 5-n-Butylthio-6-(3, -dimethoxyphenyl)-3-(5-tetrazolyl)- pyridin-2(IH)-one) (a) From 2-bromo-3' , 4*-dimethoxyacetophenone (3.89g) 2-n- butylthio-3 r , '-dimethoxyacetonphenone (3.87g) isolated as oil was prepared according to the method of Example (a) ^H NMR δ(CDCl 3 ) 0.90 (t,3H), 1.31-1.63 (m, H) , 2.58 (t,2H), 3.75(s,2H), 3.94(s,3H), 3.95(s,3H), 6.89(d,lH), 7.55 (d,lH) and 7.60 (dd, IH) . (b) From 2-n-butylthio-3' ,4'-dimethoxyacetophenone (3.87g 5-n-butylthio-3-cyano-6- (3,4-dimethoxyphenyl)pyridin-2 (IH)- one (1.4g) m.p.l92-193°C after recrystallisation from ethan was prepared according to the method of Example 4 (b) . (c) From 5-n-butylthio-3-cyano-6- (3,4-dimethoxyphenyl)- pyridin-2(lH)-one (1.03g), the title compound ((0.84g) m.p.l97-198°C after recrystallisation from ethanol was prepared according to the method of Example (c) . Example 19 3-[6-Methyl-5-(2-naphthylthio)-2-oxo-l,2-dihydro-3-pyridyl]- propion c acid (a) To a suspension of 3-cyano-6-methyl-5- (2-naphthylthio) pyridin-2(IH) -one (2.64g) in dichloromethane (50ml) at -78°C a solution of diisobutylaluminium hydride (9.1ml, 1M in dichloromethane) was added over 10 minutes. The reaction mixture was warmed to room temperature and stirred for 24 hours. Additional diisobutylaluminium hydride (14ml, 1M in dichloromethane) was added and stirring continued for 24 hours. After cooling to 0°C the mixture was quenched with 2 hydrochloric acid (50ml)and stirred for 3 hours. The organi phase was separated and the aqueous phase extracted with dichloromethane (3x50ml) . The combined organic extracts wer washed with saturated sodium hydrogen carbonate (50ml) , wat (3x50ml) , dried (Na2S04), filtered and solvent removed at reduced pressure. The residue (l.Oδg), and carboethoxy- methylene triphenylphosphorane(1.52g) were heated together reflux in toluene (16ml) for 3 hours. The reaction mixture was cooled to room temperature, diluted with dichloromethan and washed with water (2x50ml) , dried (Na2S04), filtered an solvent removed at reduced pressure to give after column chromatography (silica gel, 20% ethyl acetate/hexane eluant) ethyl E-3-[6-methyl-5- (2-naphthylthio)-2-oxo-l,2-dihydro-3- pyridyl propenoic acid (1.06g) m.p.206°C. ^-H NMR δ(CDCl 3 ) 1.28(t,3H), 2.60(s,3H), 4.21(q,2H), 7.06(d,lH), 7.24(dd,lH), 7.41-7.51 (m,3H) , 7.55(d,lH) and 7.68-7.81 (m,4H) . (b) Ethyl E-3-[6-methyl-5-(2-naphthylthio)-2-oxo-l,2- dihydro-3-pyridyl]propenoate (0.9g) and tris(triphenyl- phosphine)rhodium (I) chloride (0.23g) were stirred in ethanol (40ml) under' 1 atmosphere of hydrogen for 16 hours. Solvent was removed at reduced pressure, the residue dissolved in ethyl acetate (100ml) and washed with 2N hydrochloric acid (50ml) , saturated sodium hydrogen carbona (50ml) and water (2x50ml) . The organic phase was dried ( a2S04) , filtered and solvent removed at reduced pressure t give ethyl 3-[6-methyl-5-(2-naphthylthio)-2-oxo-l,2-dihydro 3-pyridyl]propanoate (0.82g). 1 H NMR δ(CDCl 3 ) 1.14 (t,3H), 2.58-2.73(m,2H) , 2.74-2.89 (m,2H) , 4.05(q,2H), 7.22(dd,lH), 7.32-7.81 (m,7H) and 12.58 (br.s) . (c) A solution of ethyl 3-[6-methyl-5-(2-naphthylthio)-2 oxo-l,2-dihydro-3-pyridyl]propanoate (0.6g) in 2N sodium hydroxide/ethanol (1:1, 20ml) was stirred at room temperat overnight. Solvent was removed at reduced pressure, the residue dissolved in IN sodium hydroxide (60ml) , washed wi dichloromethane (2x50ml) . The aqueous phase was cooled (ic bath) and acidified with 2N hydrochloric acid. The precipitate was collected by filtration washed thoroughly with water and recrystallised from ethyl acetate to give t title compound (0.48g) m.p.l82°C. Example 20 5-Phenylthio-6-(4-methoxy-3-propoxyphenyl)-3-(5-tetrazolyl) pyridin-2(IH)-one a) From 2-bromo- '-methoxy-3'-propoxyacetophenone (2.87 2-phenylthio- '-methoxy-3*-propoxyacetophenone (3.llg) isolated as an oil, was prepared according to the method of Example 4(a). NMR δ(CDCl3) 1.04(t,3H), 1.80-1.94(m,2H) , 3.93(s,3H)3.99(t,2H) , 4.24 (s,2H). 6.87(d,lH) and 7.20- 7.57(m,7H) . b) From 2-phenylthio-4'-methoxy-3'-propoxyaceto- phenone(3.01g) , 3-cyano-5-phenylthio-6-(4-methoxy-3- propoxyphenyl)pyridin-2(lH)-one (1.98g) m.p.210-211° after recrystallisation from ethanol, was prepared according to t method of Example 4(b) . c) From 3-cyano-5-phenylthio-6-(4-methoxy-3- propoxyphenyl)pyridin-2(IH)-one (0.71g), the title compound (0.69g) m.p.191-192° after recrystallisation from ethanol, was prepared according to the method of Example 4(c) . Example 21 5-Methylthio-6-(4-methoxy-3-propoxyρhenyl)-3- (5-tetrazolyl) pyridin-2 (IH)-one (a) Potassium thioacetate (5.02g) was added to a cooled (ice bath) solution of 2-bromo- '-methoxy-3'-propoxy¬ acetophenone (6.3g) in dimethylformamide (120ml) containing 4A molecular sieves (7g) . The mixture was warmed to room temperature and stirred for 18 hours. After diluting with diethyl ether (200ml) the organic phase was washed with IN hydrochloric acid (200ml) , water (4x100ml) , dried (MgS04) a solvent removed at reduced pressure to give 2-acetylthio- ' methoxy-3'-propoxyacetophenone (6.09g) . -^H NMR δ(CDCl3) 1.05(t,3H), 1.79-1.94 (m,2H), 2.40(s,3H), 3.94(s,3H), 4.06(t,2H), 4.36(s,2H), 6.90(d,lH), 7.52(d,lH) and 7.63(dd,lH) . (b) To a solution of 2-acetylthio- '-methoxy-3 '-propoxy- acetophenone (1.12g) in methanol (15ml), a solution of sodi methoxide (0.22g) in methanol (7ml) was added. The solution was stirred for one hour and then treated with iodomethane (0.56g) in methanol (10ml) . The solution was stirred for a further 18 hours to give after removal of solvent 2- methylthio- '-methoxy-3'-propoxyacetophenone (0.51g) . !H NM δ(CDCl3) 1.05(t,3H), 1.81-2.08 (m,2H) , 2.16(s,3H), 3.73(s,2H) 3.94(s,3H), 4.04(t,2H), 6.89(d,lH) and 7.55-7.61 (m, 2H) . (c) From 2-methylthio- '-methoxy-3 '-propoxyacetophenone (0.51g), 3-cyano-5-methylthio-6- (4-methoxy-3-propoxyphenyl) pyridin-2 (lH)-one (0.19g) m.p.212-213° after recrystallisation from ethanol, was prepared according to t method of Example (b) . (d) From 3-cyano-5-methylthio-6- (4-methoxy-3-propoxy- ρhenyl)pyridin-2(lH)-one (0.17g), the title compound (0.10g) m.p.225-226° after recrystallisation from ethanol, was prepared according to the method of Example 4 (c) . Example 22 5-Ethylthio-6-(4-methoxy-3-propoxyphenyl)-3-(5-tetrazolyl) pyridin-2(IH)-one a) From 2-acetylthio-4-'methoxy-3'-propoxyacetophenone (1.12g), 2-ethylthio- *-methoxy-3'-propoxyacetophenone (0.54g) was prepared according to the method of Example 2Kb) . 1H NMR δ(CDCl 3 ) 1.05(t,3H), 1.27 (t,3H), 1.87- 1.99(m,2H), 2.57-2.69 (m,2H) , 3.76(s,2H), 3.93(s,3H), 4.04(t,2H), 6.89(d,lH) and 7.54-7.62 (m,2H) . (b) From 2-ethylthio- '-methoxy-3'-propoxyacetophenone (0.54g) , 3-cyano-5-ethylthio-6-(4-methoxy-3-propoxyphenyl)- pyridin-2 (IH)-one (0.18g) m.p.186-187° after trituration wi ethanol, was prepared according to the method of Example 4 (b) . (c) From 3-cyano-5-ethylthio-6-(4-methoxy-3-propoxyphenyl) pyridin-2(lH)-one (0.17g), the title compound (O.llg) m.p.223-224° after recrystallisation from ethanol, was prepared according to the method of Example 4 (c) . Example 23 5-Bromo-6-(4-methoxy-3-propoxyphenyl)-3-(5-tetrazolyl)- pyridin-2(IH)-one (a) A solution of 3-cyano-6- (4-methoxy-3-propoxyphenyl- pyridin-2(IH) -one (1.42g) and N-bromosuccinimide (0.89g) in dimethylformamide (20ml) was boiled for one hour and dilute with water (300ml) . The precipitated 5-bromo-3-cyano-6-(4- methoxy-3-propoxyphenyl)pyridin-2 (lH)-one (1.73g) m.p.236- 237° was washed with water and diethyl ether. (b) From 5-bromo-6- (4-methoxy-3-propoxyphenyl)pyridin- 2(lH)-one (1.45g), the title compound (1.55g) m.p.238-239° after recrystallisation from dimethylformamide/water, was prepared according to the method of Example (c) . Example 24 6- (3,4-Dimethoxyphenyl) -5-pentyl-3- (5-tetrazolyl)pyridin- 2(lH)-one. (a) To a mixture of heptanoyl chloride (5.3g) and 1,2- dimethoxybenzene (5g) in dichloromethane (50ml) aluminium trichloride (5g) was added portionwise. After the addition was complete the mixture was boiled for one hour, cooled to room temperature and poured into water. The dichloromethane was separated and the aqueous phase extracted with ethyl acetate (3x50ml) . The combined organic phases were dried (MgS04) and solvent removed at reduced pressure to give 3 ' , '-dimethoxyheptanophenone (8.8g) m.p. 35-37°C. (b) From 3 ', 4 '-dimethoxyheptanophenone (5g) , 3-cyano-6- (3, -dimethoxyphenyl) -5-pentylpyridin-2 (IH) -one (0.71g) m.p 182-184°C after recrystallisation from ethanol, was prepare according to the method of Example 4 (b) . (c) From 3-cyano-6- (3, -dimethoxyphenyl) -5-pentylpyridin- 2(lH)-one (0.71g), the title compound (0.6g) m.p. 212-214°C after recrystallisation from ethanol, was prepared accordin to the method of Example 4(c) . Example 25 6- (2-Naphthyl) -5-phenoxy-3- (5-tetrazolyl)pyridin-2 (IH) -one. (a) From 2-bromo-2 '-acetonaphthone (2.25g), 2-phenoxy-2 '- acetonaphthone (2.2g) was prepared according to the method Example 4(a). ^-H NMR δ(CDCl3) 5.39(s,2H), 6.85-7.01(m,3H) , 7.25-7.33(m,2H), 7.54-7.65 (m,2H) 7.87-8.06(m,4H) and 8.54(S,1H) . (b) From 2-phenoxy-2*-acetonaphthone (2.1g), 3-cyano-6-(2 naphthyl)-5-phenoxypyridin-2(lH)-one (0.73g) m.p. 253-254°C after recrystallisation from n-butanol was prepared accordi to the method of Example 4 (b) . (c) From 3-cyano-6-(2-naphthyl)-5-phenoxypyridin-2(IH)-on (0.6g), the title compound (0.49g) m.p. 279°C (decomp) afte recrystallisation from ethanol, was prepared according to t method of Example 4(c) . λ R NMR δ(dg-DMSO) 7.01-7.04(m,3H) , 7.27-7.33(m,2H) , 7.57-7.60 (m,2H) , 7.79(d-lH), 7.91- 7.98(m,3H), 8.23(s,lH) and 8.32(s,IH) . Example 26 5-n-Butylthio-6-[3-(E-1-propenyl)-4-methoxyphenyl]-3-(5- tetrazolyl)pyridin-2(IH)-one. (a) To a suspension of 3-cyano-6-[3-(E-l-propenyl)-4- methoxyρhenyl]pyridin-2(lH)-one (PCT/GB91/01663) (2g) in dimethylformamide (20ml) , N-iodosuccinimide (2g) was added and the mixture stirred in the dark for 24 hours. After diluting with ethyl acetate (100ml) , washing with water (6x50ml) , drying MgSθ4) and removing solvent at reduced pressure 3-cyano-5-iodo-6-[3-(E-1-propenyl)-4- methoxyphenyl]pyridin-2(lH)-one (2.6g) m.p. 233-234°C (decomp) after recrystallisation from ethanol was obtained. (b) From 3-cyano-5-iodo-6-[3-(E-l-propenyl)-4- methoxyphenyl]pyridin-2(lH)-one (lg) , 3-cyano-5-butylthio-6- [3-(E-1-propenyl)-4-methoxyphenyl]pyridin-2(IH)-one (0.065g) was prepared according to the method of Example 12(b) . ^E NM δ(CDCl 3 ) 0.79(t,3H), 1.19-1.36(m,4H) , 1.93(d,3H), 2.54(t,2H), 6 .27-6 . 42 <m, lH) , 6 .71 (d, lH) , 6 . 99 (m, lH) , 7 . 49 (m, lH) , 7 . 67 (s, lH) and 8 . 05 (s, lH) . (c) From 5-butylthio-3-cyano-6- (E-3-prop-l-enyl-4- methoxyphenyl)pyridin-2 (IH) -one (0.065g), the title compoun (0.015g) m.p.225-226°C after recrystallisation from ethanol was prepared according to the method of Example 4 (c) . Example 27 Ethyl (5-phenylthio-2-oxo-l, 2-dihydro-3-pyridyl)phosphonate sodium salt. (a) Using phenyltributyltin sulphide (lOg) and 2-methoxy-5 bromopyridine (4.32g), 2-methoxy-5-phenylthiopyridine (3.8g) was prepared according to the method of Kosugi et al (Bull. Chem. Soc. Jpn., 1985, 58, 3657) . H NMR δ(dg-DMSO) 3.89 (s,3H), 6.91 (d, IH) , 7.16-7.35 ( , 5H) , 7.80 (dd, IH) and 8.30 (d,lH) . (b) A mixture of 2-methoxy-5-phenylthiopyridine (1.74g), chlorotrimethylsilane (2.16g) and sodium iodide (3.0g) were stirred together in acetonitrile (10ml) overnight. The mixture was diluted with ethyl acetate (50ml) and washed wit water (3x50ml) , dried (MgSθ ) and solvent removed at reduced pressure. The residue was suspended in ethyl acetate (20ml) stirred for 20 minutes and filtered to give as the residue 5 phenylthiopyridin-2 (lH)-one (0.87g) m.p.l81-183°C. (c) From 5-phenylthiopyridin-2 (lH)-one (0.61g), diethyl (5- phenylthio-2-oxo-l, 2-dihydro-3-pyridyl)phosphonate (0.21g) m.p.208-209°C after recrystallisation from ethanol, was prepared according to the method of Example 3 (b) . (d) From diethyl (5-phenylthio-2-oxo-l, 2-dihydro-3- pyridyl)phosphonate (0.18g) , the title compound (0.025g) m.p. 280°C (softens) after recrystallisation from ethanol/water. was prepared according to the method of Example 3(c) . ^H NM δ(dg-DMSO) 1.03 (t,3H), 3.60 (m,2H), 6.98-7.30, 7.68 (d,IH) an 7.87 (s,lH) . Example 28 5-n-Butylthio-6-(4-methoxy-3-n-propylphenyl)-3-(5- tetrazolyl)pyridin-2(IH)-one (a) From 4'- methoxy-3'-n-propylacetophenone (5.0g) 2-bromo-4'-methoxy-3'-n-propylacetophenone (5.4g) was prepared according to the method of Example 13(b) .^-H NMR δ(CDC13) 0.95 (t,3H), 1.54-1.69 (m,2H) , 2.61(t,2H), 3.90(s,3H), 4.41(s,2H), 6.89(d,lH) r 7.78(d,lH), 7.86(dd,lH). (b) From 2-bromo-4 ' -methoxy-3 ' -n-propylacetophenone (5.4g) 2-n-butylthio-4 ' -methoxy-3 ' -n-propylacetophenone (4 . 6g) was prepared according to the method of Example 4 (a) . ^-H NMR 0.89 (, 3H) , 0 . 95 (t, 3H) , 1.32-1.48 (m, 2H) , 1.54-1.70 (m, 4H) , 3.74 (s, 2H) , 3. 88 (s, 3H) , 6.86 (d, lH) , 7.77 (d, IH) and 7.84 (dd, lH) . (c) From 2-n-butylthio-4'-methoxy-3'-n-propylacetophenone (4.6g) , 5-n-butylthio-3-cyano-6-(4-methoxy-3-n- propylphenyl)pyridin-2 (IH)-one (0.73g) was prepared accordin to the method of Example 4(b) ^-H NMR δ(DMSO-d6) 0.73 (t,3H), 0.93(t,3H), 1.07-1.31(m,4H) , 1.49-1.64(m,2H) , 3.84(3,3H), 7.05(d,lH), 7.28(d,lH), 7.38(dd,lH) and 8.36(s,IH) . (d) From 5-n-butylthio-3-cyano-6-(4-methoxy-3-n- propylphenyl)pyridin-2(IH)-one (0.7g), the title compound (0.43g) m.p. 210-212°C, after recrystallisation from ethanol, was prepared according to the method of Example 4 (c) . Example 29 5-n-Butylthio-6-[3-(E-1-propenyl)-4-me hoxyphenyl]-3- (5- tetrazolyl)pyridin-2 (IH)-one (a) From 3-cyano-6-[3- (E-1-propenyl) -4-methoxyphenyl]- pyridin-2 (lH)-one (WO 92/06085) (2g) , 3-cyano-5-iodo-6- [3- (E 1-propenyl) -4-methoxyphenyl]pyridin-2 (IH) -one (2.6g) m.p. 233-234°C (decomp), after recrystallisation from ethanol, wa prepared according to the method of Example 23 (a) replacing N-bromosuccinimide with N-iodosuccinimide. (b) From 3-cyano-5-iodo-6-[3- (E-1-propenyl) -4- methoxyphenyl]pyridin-2 (IH) -one (lg) , 5-n-butylthio-3-cyano- 6- [3- (E-1-propenyl) -4-methoxyphenyl]pyridin-2 (lH)-one (0.065g) was prepared according to the method of 12(b) . (c) From 5-n-butylthio-3-cyano-6-[3- (E-1-propenyl) -4- methoxyphenyl]pyridin-2 (IH) -one (0.065g), the title compound (0.66g) m.p. 225-226°C after recrystallisation from ethanol, was prepared according to the method of Example 4(c) . Example 30 Pharmaceutical compositions for oral administration a prepared by combining the following : w/w 6-methyl-5-(2-naphthylthio)-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 gelati capsules. Example 31 A pharmaceutical composition for parenteral administration is prepared by dissolving the title compound of Example 2 (0.02 g) in polyethylene glycol 300 (25 ιr.l) 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.

Claims: Claims A compound of the formula (1) Formula (1) or a pharmaceutically acceptable salt thereof, wherein : RO is OH or a bioprecursor thereof, R 1 is A°C0 2 H, P(Z) (OH) (OR 2 ), S0 2 H, S0 3 H or 5-tetrazolyl optionally substituted in the 1-position by CH2CO2H or a bioprecursor thereof, A 0 is CH2, CH2CH2, CHF, CF 2 , CR 3 (OR 4 ), CO or C(0R 5 ) (0R 6 ), R 2 is phenyl, C3_5cycloalkyl, C3_5cycloal yl C__4alkyl, or Cχ_8al yl optionally substituted by C _4alkoxy, R 3 is H, methyl or ethyl, R 4 is H or C _3alkyl, R^ and R 6 are each C__3alkyl or together form a 1,2- ethanediyl group or 1,3-propanediyl group, Z is 0 or S, R a is halo or X^-Y 1 , X 1 is α_2, 0 or S, Y 1 is C__galkyl or Ar, Ar is phenyl optionally substituted by one to three groups independently selected from halo, C__galkyl, C2-galkenyl, C__galkoxy, C__gpolyfluoroalkyl or C__gpolyfluoroalkoxy, or Ar is 1-naphthyl or 2-naphthyl, R is H, C__galkyl or X 2 Ar! wherein X 2 is a bond or ethenyl and Ar 1 is phenyl optionally substituted by one to three groups independently selected from C__galkyl, C2-galkenyl, C__galkoxy, C3_galkenyloxy, C2-gcycloalkyl, C2-gcycloalkoxy, C__galkylthio, phenyl, phenylthio, benzyloxy, C__gpolyfluoroalkyl, C__gpolyfluoroalkoxy, halo, N(R 7 >2 or NHCOR 7 wherein R 7 is H or C__galkyl, or -X(CH ) n Y attached adjacent carbon atoms of the phenyl ring wherein X and Y ar independently CH2 or 0 and n is 1 to 3, wherein said C__galkyl, C2-galkenyl or Cχ_galkoxy groups can be independently substituted by OH, C__galkoxy, C2-gcycloalkyl, N(R 7 )2, CO2 7 or CON(R 7 ) 2 ; or Ar 1 is 1-naphthyl optionally substituted in the 4-position b hydroxy or C__galkoxy, 2-naphthyl optionally substituted in the 1-position by hydroxy or C__galkoxy, 3-phenanthryl, 9- phenanthryl, 2-quinolinyl, 4-quinolinyl, 3-thianaphthenyl or 2-benzofuranyl. 2. A compound according to claim 1 wherein R is X 2 Ar 1 . 3. A compound according claim 1 or 2 wherein R 1 is A^C02H or Aθcθ2R 9 in which R 9 is an ester-forming group. . A compound according to claim 1 or 2 wherein R^- is P(Z) (OH) (OR 2 ) or P(Z) (OR 2 ) 2 . 5. A compound according to claim 1 or 2 wherein R is SO2H, SO3H or 5-tetrazolyl . 6. A compound according to any one of claims 1 to 5 wherein R a is χ!γl. 7. A compound according to claim 1 which is : 6-methyl-5- (2-naphthylthio)-3-(5-tetrazolyl)pyridin-2 (IH)- one, 3-(l-carboxymethyl-5-tetrazolyl)-6-methyl-5-(2-naphthylthio)- pyridin-2 (IH)-one, n-propyl-[5-(2-naphthylthio)-2-oxo-l,2-dihydro-3-pyridyl]- phosphonate. 6-methyl-5-phenylthio-3-(5-tetrazolyl)pyridin-2 (IH)-one, 5-(4-chlorophenylthio)-6-methyl-3-(5-tetrazolyl)pyridin- 2 (lH)-one, E-6-(2-phenylethenyl)-5-phenylthio-3-(5-tetrazolyl)pyridin- 2(lH)-one, 3-carboxymethyl-6-methyl-5-(phenylthio)pyridin-2 (IH)-one, 6-phenyl-5-phenylthio-3-(5-tetrazolyl)pyridin-2 (IH)-one. 5-(3-chlorophenylthio)-6-methyl-3-(5-tetrazolyl)pyridin- 2(lH)-one, 5- (2-chlorophenylthio) -6-methyl-3- (5-tetrazolyl) pyridin- 2 (lH) -one, 5- (3, 4-dichlorophenylthio) -6-methyl-3- (5-tetrazolyl) pyridin 2 (IH) -one, 5-n-butylthio-6-methyl-3- (5-tetrazolyl) pyridin-2 (IH) -one, 5-n-butylthio-6- (4-methoxy-3-propoxyphenyl) -3- (5-tetrazolyl) pyridin-2 (IH) -one, 5-benzyl-6-ρhenyl-3- (5-tetrazolyl) pyridin- 2 (IH) -one, 5-(2-naphthyloxy)-6-phenyl-3-(5-tetrazolyl)ρyridin-2 (IH)-one 6-(2-naphthyl)-5-phenylthio-3-(5-tetrazolyl)pyridin-2(IH)- one, 5-(2-naρhthylthio)-6-ρhenyl-3-(5-tetrazolyl)pyridin-2(IH)- one, 5-n-butylthio-6-(3,4-dimethoxyphenyl)-3-(5-tetrazolyl)- pyridin-2(IH)-one, 3-[6-methyl-5-(2-napthylthio)-2-oxo-l,2-dihydro-3-pyridyl]- propionic acid, 5-phenylthio-6-(4-methoxy-3-propoxyphenyl)-3-(5-tetrazolyl)- pyridin-2(IH)-one, 5-methylthio-6-(4-methoxy-3-propoxyphenyl)-3-(5-tetrazolyl)- pyridin-2(IH)-one, 5-ethylthio-6-(4-methoxy-3-propoxyphenyl)-3-(5-tetrazolyl)- pyridin-2(IH)-one, 5-bromo-6-(4-methoxy-3-propoxyphenyl)-3-(5-tetrazolyl)- pyridin-2 (IH)-one, 6-(3,4-dimethoxyphenyl)-5-pentyl-3-(5-tetrazolyl)pyridin- 2(lH)-one, 6-(2-naphthyl)-5-phenoxy-3-(5-tetrazolyl)pyridin-2 (IH)-one, 5-n-butylthio-6-[3-(E-1-propenyl)-4-methoxyphenyl]-3-(5- tetrazolyl)pyridin-2 (IH)-one, ethyl (5-phenylthio-2-oxo-l,2-dihydro-3-pyridyl)phosphonate, 5-n-butylthio-6-(4-methoxy-3-n-propylphenyl)-3-(5- tetrazolyl)pyridin-2 (IH)-one, or 5-n-butylthio-6-[3-(E-1-propenyl)-4-methoxyphenyl]-3-(5- tetrazolyl)pyridin-2 (IH)-one, or a pharmaceutically acceptable salt thereof. 8. A compound according to any one of claims 1 to 7 for use as a medicament. 9. A pharmaceutical composition which comprises a compound according to any one of claims 1 to 7 and a pharmaceutically acceptable carrier. 10. A process for preparing a compound of the formula (1) as defined in claim 1 or a pharmaceutically acceptable salt thereof which process comprises : a) for compounds wherein R 1 is A°Cθ2H or A°Cθ2R 9 and : i) A 0 is CR 3 (OR 4 ), reacting in the presence of a strong base a compound of the formula (2) : Formula (2) wherein R 11 is methyl and R, and R a are as defined in claim 1- with a compound of the formula (3) : R 3 COC02R S (3) wherein R3 is as defined in claim 1 and R 9 is an ester- forming group to form a compound of the formula (4) : Formula (4) wherein R 12 is CR 3 (OH)CO2R 9 and R, R 3 , R 9 , R 11 , and R a are a hereinbefore defined and thereafter optionally reacting with a C__3alkylating agent to form the corresponding compound wherein R 12 is CR 3 (0C__3alkyl)CO2R 9 , ii) A 0 is CO, reacting in the presence of a strong base a compound of the formula (2) as hereinbefore defined with a compound of the formula (5) : R 9 0 2 CC0 2 R 9 (5) wherein R 9 is as hereinbefore defined to form a compound of the formula (4) wherein R 12 is COCO2R 9 and R, R 9 , R 11 and R a are as hereinbefore defined, iii) A 0 is CH(OH) , reacting a compound of the formula (4) wherein R 12 is COCO2R and R, R 9 , R 11 , and R a are as hereinbefore defined with a reducing agent to form the corresponding compound wherein R 1 is CH(OH)C0 2 R 9 , iv) A 0 is CH 2 , reacting a compound of the formula (4) wherein R 12 is COCO2H or COCO2R 9 and R, R 9 , R 11 , and R a are as hereinbefore defined with a suitable reducing agent to form the corresponding compound wherein R^ 2 is CH2CO2H, v) A° is C(OR 5 ) (OR 6 ), reacting a compound of the formula (4) wherein R^ 2 is COCO2R and R, R 9 , R 11 , and R a are as hereinbefore defined with a Cι_3alcohol, 1,2-ethanediol or 1,3-ρropanediol to form the corresponding compound wherein R 12 is C(OR^) (OR )Cθ2R , vi) A 0 is CF2, reacting a compound of the formula (4) wherein R^ 2 is COCO2R 9 and R, R 9 , R 11 , and R a are as hereinbefore defined with a fluorinating agent to form the corresponding compound wherein R 11 is CF2CO2R 9 , or vii) A° is CHF, reacting a compound of the formula (4) wherein R 12 is CH(OH)C02R 9 and R, R 9 , R 11 , and R a are as hereinbefore defined with a fluorinating agent to form the corresponding compound wherein R 12 is CHFCO2R 9 , and thereafter optionally : ° converting the group OR 11 into OH ° converting the group A°Cθ2R 9 into A°Cθ2H; or b) for compounds wherein R 1 is CH2CO2H, converting a compound of the formula (6) : wherein R 13 is acetyl and R, and R a are as hereinbefore defined into the corresponding compound wherein R 13 is CH2CO2H; or c) for compounds wherein R 1 is CH2CH2CO2H or CH2CH2CO2R 9 , hydrogenating a compound of the formula (6) wherein R 13 is CH=CHCθ2H or CH=CHC02R 9 and thereafter optionally converting the group CH2CH2CO2R 9 into CH2CH2CO2H; or d) for compounds wherein R 1 is P(0) (OH) (OR 2 ), hydrolysing a compound of the formula (6) wherein R 13 is P (0) (OR 2 )2, R 2 is as defined in claim 1 and R- and R a are as hereinbefore defined; or e) for compounds wherein R 1 is P (S) (OH) (OR 2 ), converting a compound of the formula (6) wherein R 13 is P(0) (NHR 14 ) (OR 2 ) and R 14 is phenyl or C2- χ-4alkyl and R, and R a are as hereinbefore defined into the corresponding compound wherein R 13 is P(S) (OH) (OR 2 ); or f) for compounds where R 1 is SO3H, reacting in the presence of a strong base a compound of the formula (2) as hereinbefore defined with sulphuryl chloride or a chemical equivalent thereof and optionally converting the group OR 11 into OH; or g) for compounds wherein R 1 is SO2H, reacting in the presence of a strong base a compound of the formula (2) as hereinbefore defined with sulphur dioxide and optionally converting the group OR 11 into OH; or h) for compounds wherein R is 5-tetrazolyl, reacting a compound of the formula (4) wherein R 12 is cyano or a compound of the formula (6) wherein R 13 is cyano with an azide salt; or i) for compounds wherein R 1 is 1- (HO2CCH2) -5-tetrazolyl or 1- (R 9 θ2CCH2) -5-tetrazolyl, reacting a compound of the formula (6) wherein R 13 is 5-tetrazolyl with a compound of the formula (7) : LCH 2 C0 2 R 9 (7) wherein L is a leaving group and R 9 is as hereinbefore defined and thereafter optionally converting the group CO2R 9 to CO2H; or j) for compounds wherein R a is halo, reacting a compound of the formula (8) : Formula (8) wherein R 1 ^ is a group R 1 as hereinbefore defined or a precursor thereof, and R is as hereinbefore defined, with a suitable halogenating agent, and thereafter if necessary converting a precursor of R 1 to R 1 ; and optionally thereafter : ° forming a bioprecursor of R^ and/or R 1 ° forming a pharmaceutically acceptable salt,

Inventors: MURRAY KENNETH JOHN, PORTER RODERICK ALAN, PRAIN HUTER DOUGLAS, WARRINGTON BRIAN HERBERT, MURRAY, KENNETH, JOHN, PORTER, RODERICK, ALAN, PRAIN, HUTER, DOUGLAS, WARRINGTON, BRIAN, HERBERT
Applicants: SMITHKLINE BEECHAM PLC
Application year: 1992
Main classification: C07D213
IPC codes: A61K31, A61P7, A61P9, A61P17, A61P29, C07D213, C07D401, C07F9