2-PYRIDINOL DERIVATIVES AND THEIR USE AS MEDICAMENTS

Abstract: Compounds of formula (1) or a pharmaceutically acceptable salt thereof, wherein: R<0> is OH or a bioprecursor thereof, R<1> is A<0>CO2H, P(Z)(OH)(OR<2>), SO2H or SO3H or a bioprecursor thereof, A<0> is CH2, CHF, CF2, CR<3>(OR<4>), CO or C(OR<5>)(OR<6>), are described as agonists of a cyclic AMP-dependent protein kinase. They are useful as medicaments.

Description: 2-PYRIDIN0L DERIVATIVES AND THEIR USE AS MEDICAMENTS. 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, positive lusitropic, anti-allergic or anti-inflammatory activities. They are likely to be useful in the treatment of cardiovascular diseases where there is a component of diastolic failure, cancer, psoriasis, atheroschlerosis, thrombosis, re-stenosis, 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) : or pharmaceutically acceptable salts thereof, wherein R0 is OH or a bioprecursor thereof, R 1 is A°Cθ2H, P(Z) (OH) (OR 2 ) , SO2H or SO3H or a bioprecursor thereof, A 0 is CH 2 , CHF, CF 2 , CR 3 (OR 4 ) , CO or C(OR 5 ) (OR 6 ), R 2 is phenyl, C3_5cycloalkyl, C3_5cycloalkylC _ alkyl, or Ci-gal yl optionally substituted by Cχ_4alkoxy, R 3 is H, methyl or ethyl, R 4 is H or Cχ_ 3 alkyl, R^ and R 6 are each Cχ_3alkyl or together form a 1,2- ethanediyl group or 1,3-propanediyl group, Z is 0 or S, and Ar is phenyl optionally substituted by one to three groups independently selected from Cx-galkyl, C2-galkenyl, Cχ_galkoxy, C^-galkenyloxy, C3_gcycloalkyl, C3_gcycloalkoxy, Ci-galkylthio, phenyl, phenylthio, benzyloxy, Cι_gpolyfluoroalkyl r * C _gpolyfluoroalkoxy, halo, N(R 7 )2 or NHCOR 7 wherein R 7 is H or Cχ_galkyl, or -X(CH2) n Y- 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 Cχ_galkyl, C2-galkenyl or Cχ_galkoxy groups can be independently substituted by OH, Cx-galkoxy, C3_gc cloalkyl, N(R 7 ) 2 , C0 2 R 7 or CON(R 7 ) 2 . Bioprecursors of the groups R^ and R 1 are derivatives thereof which are convertible in vivo into the groups ^ and R 1 . A suitable bioprecursor of the group R^ is OR 5 wherein R^ is C _ al yl, arylCχ_4alkyl (for example phenylCχ_4alkyl such as benzyl) , Cχ_4alkanoyl (for example acetyl) , arylCχ_4alkanoyl (for example phenyl Cχ_4alkanoyl such as benzoyl) , arylsulphonyl (for example optionally substituted phenylsulphonyl or toluenesulphonyl) or Cχ_4alkylsulphonyl (for example methylsulphonyl) . When R 1 is A^C^H a suitable bioprecursor is A u Cθ2 9 wherein R^ is an ester-forming group. When R! 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 10 ) wherein R 10 is an O-protecting group. Suitable O-protecting groups include pivaloyloxymethyl, propionyloxymethyl and pivalolyloxycarbonyloxymethyl. Alternatively bioprecursors of the groups R° and R 1 are those formed when R 1 and R° are linked together to form a cyclic structure such that R 1 -R° is A 1 Cθ2 or A OCH2θ, in which : A 1 is 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 1 is A°Cθ2H or A°C0 2 R 9 . Suitably R 1 is P (Z) (OH) (OR 2 ) or P(Z) (OR 2 ) 2 . Suitably R 1 is SO2H or SO3H. Suitably R 1 and R° are linked together such that R 1 -R° is A 1 Cθ2- Suitably R 1 and R° are linked together such that R 1 -R° is A 2 0CH 2 0. By the term alkyl is meant both straight- and branched- chain alkyl. By the term Cχ_gpolyfluoroalkyl is meant a Cχ_galkyl group having at least one hydrogen replaced with fluoro, e.g. CF3 or CF2C 2H. Suitably R 2 is methyl, ethyl, propyl, butyl, pentyl, hexyl, 2-methoxyethyl, phenyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclopropylmeth l. 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^ and R 6 are independently methyl, ethyl or propyl, preferably together they form a 1,2-ethanediyl group. Preferably Z is 0. Suitably R 9 is Cχ_4alkyl optionally substituted by hydroxy, e.g. 2-hydroxyethyl or arylCχ_4alkyl (for example phenylCχ._4alkyl such as benzyl) . Suitably Ar is phenyl optionally mono-substituted by a group as hereinbefore defined, for -example in the 2,3, or 4 positions by Cχ_galkyl, Cχ_galkoxy, C3_galkenyloxy, Cχ_galkylthio, phenyl, phenylthio, benzyloxy, CF3, halo or NHCOR 7 . 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-galkenyl, Cχ_ςalkoxy, C3_gcycloalkoxy, halo, -X(CH2) n γ ~ or Cχ_galkoxyCχ_5 alkoxy. Suitably Ar is phenyl trisubstituted by any groups as hereinbefore defined, for example in the 2,3,4-, 2,3,5-, or 3, ,5-positions by groups independently selected from C2-galkenyl, Cχ_galkoxy or halo. Examples of Cχ_galkoxy include methoxy, ethoxy, propoxy, butoxy, or pentyloxy. Examples of Cχ_galkyl include methyl, ethyl, propyl, butyl, isobutyl or pentyl. Examples of halo include fluoro, chloro, bromo or iodo. Particular compounds of this invention include : ethyl [6-(3-bromophenyl)-2-oxo-l,2-dihydro-3-pyridyl]- phosphonate, ethyl [6- (4-bromophenyl)-2-oxo-l,2-dihydro-3-pyridyl]- phosphonate, [6-(3,5-diethoxyphenyl)-2-oxo-l,2-dihydro-3-pyridyl]acetic acid, ethyl [6- (2-propoxyphenyl) -2-oxo-l,2-dihydro-3-pyridyl]- phosphonate, ethyl [6-(2,3-dipropoxyphenyl)-2-oxo-l,2-dihydro-3- pyridy1]phosphonate , n-propyl [6- (3-n-propoxyphenyl)-2-oxo-l,2-dihydro-3- pyridyl]phosphonate or {6-[4-methoxy-3- (E-1-propenyl)phenyl]-2-oxo-l,2-dihydro-3- pyridyl}acetic acid, 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 of 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 consist 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 routinely used for preparing solid formulations may be used. Examples of such carriers include starch, celluloses, lactose, sucrose and magnesium stearate. 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 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 compound of formula (1) or a pharmaceutically acceptable salt thereof which is active when administered in this 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. 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, or 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 combatting such conditions where such agonis is thought to be 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 in the range 0.1 - 5.0 mg of a compound of the formula (1) or a pharmaceutically acceptable salt thereof. The compounds of this invention may be co-administered with other pharmaceutically active compounds, for example in combination, concurrently or sequentially. Conveniently the compounds of this invention and 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 sympat omimetic amines for example isoprenaline, isoetharine, sulbutamol, phenylephrine and ephedrine or xanthine derivatives for example theophylline and aminophylline, anti-allergic agents for example disodium cro oglycate, 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 drugs such as H GCoA 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°C02R 9 and : i) A° is CR 3 (OR 4 ) , reacting in the presence of a strong base a compound of the formula (2) : wherein R 11 is methyl and Ar is as hereinbefore defined, with a compound of the formula (3) : R 3 COC0 2 R 9 (3) wherein R 3 and R 9 are as hereinbefore defined to form a compound of the formula (4) : wherein R 12 is CR 3 (OH)Cθ2R 9 and R 3 , R 9 , R 11 , and Ar are as hereinbefore defined and thereafter optionally reacting with a Cχ_3alkylating agent to form the corresponding compound wherein R 12 is CR 3 (OCχ_3al yl)Cθ2R 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 θ2CC0 2 (5) wherein R 9 is as hereinbefore defined to form a compound of the formula (4) wherein R 12 is COCO2 9 and R 9 , R 11 and Ar are as hereinbefore defined, iii) A 0 is CH(OH) , reacting a compound of the formula (4) wherein R 12 is COCO2R 9 and R 9 , R 11 , and Ar are as hereinbefore defined with a reducing agent to form the corresponding compound wherein R 12 is CH(OH)C02R 9 , iv) A 0 is CH2, reacting a compound of the formula (4) wherein R 12 is COCO2H or COCO2R 9 and R 9 , R 11 , and Ar are as hereinbefore defined with a suitable reducing agent to form the corresponding compound wherein R 12 is CH2CO2H, v) A 0 is C(OR 5 ) (OR 6 ), reacting a compound of the formula (4) wherein R 12 is COCO2R 9 and R 9 , R 11 , and Ar are as hereinbefore defined with a Cχ_3alcohol, 1,2-ethanediol or 1,3-propanediol to form the corresponding compound wherein R 12 is C(OR 5 ) (OR )Cθ2R 9 , vi) A 0 is CF 2 , reacting a compound of the formula (4) wherein R 12 is COCO2 and R 9 , R 11 , and Ar are as hereinbefore defined with a fluorinating agent to form the corresponding compound wherein R 11 is CF 2 C0 2 R 9 , or vii) A 0 is CHF, reacting a compound of the formula (4) wherein R 12 is CH(OH)C02R 9 and R 9 , R 11 , and Ar are as hereinbefore defined with a fluorinating agent to form the corresponding compound wherein R 12 is CHFCO2R 9 , and thereafter optionally : 0 converting the group OR 11 into OH ° converting the group A°Cθ2 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 Ar is as hereinbefore defined into the corresponding compound wherein R 13 is CH2CO2H; or c) for compounds wherein R 1 is CH(OR 4 )C02H reacting a compound of the formula (4) wherein R 12 is -CH(OH)CN with a Cχ_3alkylating agent and/or converting the group CN into C0 2 H, and optionally converting the group OR 11 into OH; or d) for compounds wherein R 1 is P(0) (OH) (OR 2 ), hydrolysing a compound of the formula (6) wherein R 13 is (0) (OR 2 )2 and R 2 , and Ar 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 C _ al l and Ar is as hereinbefore defined into the corresponding compound wherein R 1 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-- 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 as defined for compounds of the formula (1) reacting in the presence of a palladium catalyst a compound of the formula (7) : wherein R D is a group R 1 as hereinbefore defined or a precursor thereof and R a is R° or OR 11 as hereinbefore defined and L is a leaving group with a compound of the formula (8) : ArB (OH) 2 (8) or a chemical equivalent thereof wherein Ar is as hereinbefore defined and then, if necessary, converting a precursor of R 1 into R 1 and/or converting the group OR 11 into OH, 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 with a strong base such as lithium diisopropylamide, or a C _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 example by the addition of a Cχ_4alkyl 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 tetrahydrofuran, diethylether or dimethoxyethane with cooling (-100° to 0°C) to form a compound of the formula (4) wherein R 12 is CR 3 (OH)C02R 9 or COCO2R 9 respectively. A suitable compound of the formula (3) is ethylpyruvate, or ethyl glyoxylate or a 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)C0 2 R 9 is suitably reacted with a Cχ_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 preferably ambient temperature to form the corresponding compound wherein R 12 is CR 3 (OCχ_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 12 is COCO2 9 is suitably reacted with a reducing agent such as sodium borohydride, or diisobutylaluminium hydride in an organic solvent such as dichloromethane, a Cχ_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 COC0 2 H or COC0 2 R 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 CH 2 C0 2 H. Under these reaction conditions the C0 2 R 9 group is converted to carboxy. A compound ' of the formula (4) wherein R 1 is C0C0 2 R 9 is suitably reacted with a Cχ_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 is C(0R 5 ) (0R 6 )C0 2 R 9 . A compound of the formula (4) wherein R 12 is C0C0 2 R 9 or CHOHC0 2 R 9 is suitably reacted with a fluorinating agent such as diethylaminosulphur trifluoride in an organic solvent such 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 CF 2 C0 2 R 9 or CHFC0 2 R 9 respectively. A compound of the formula such as 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 ambient temperature. This method is particularly suitable for preparing compounds of the formula (1) wherein R 1 is A°C0 2 R 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 dimethylformamide at an elevated temperature for example 40 - 120°C. The more forcing conditions of this method are suitable for preparing compounds of formula (1) wherein R 1 is A°C0 2 H. A compound of the formula (4) wherein R 12 is A°C0 R 9 can suitably be converted to the corresponding compound wherein R 12 is A°C0 2 H 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 R° is hydroxy and R 1 is A°C0 2 H. Suitably a compound of the formula (6) wherein R 13 is acetyl is converted to the corresponding compound where R 13 is CH 2 C0 2 H 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 of the reaction mixture. Suitably a compound of formula (4) where R 12 is -CH(OH)CN is reacted with a Cχ_3alkylating agent as hereinbefore described followed by reaction with aqueous mineral acid such as 5N hydrochloric acid at ambient or elevated temperature preferably at refux in order to prepare the corresponding compound where R 12 is CH(OCχ_3alkyl) C0 2 H. The alkylation can be omitted if the corresponding compound where R^- 2 is CH(0H)C0 2 H is desired. During the hydrolysis of the CN group the OR 11 group may be converted to hydroxy. If not and if desired this group can be converted to hydroxy as hereinbefore described. A compound of the formula (4) wherein R 12 is -CH(0H)CN can be prepared by reacting the corresponding compound wherein R 12 is -CHO with a source of cyanide such as potassium cyanide in the presence of acid such as hydrochloric acid preferably at ambient temperature. A compound of the formula (4) or (6) where R 1 or R 13 is CHO is suitably prepared by reacting the corresponding compound wherein R 1 or R 13 is cyano with a suitable reducing agent such as diisobutylaluminiu hydride followed by aqueous acidic work-up. Suitably a compound of the formula (6) wherein R 13 is (0) (OR 2 ) 2 is hydrolysed by reaction with an aqueous base such as sodium hydroxide optionally in a cosolvent such as a Cχ_4alcohol at an elevated temperature (e.g. 40-100°C), preferably at the reflux temperature of the reaction mixture. Suitably a compound of the formula (6) wherein R 13 is (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. 40 - 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 sulphuryl 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 S0 2 H respectively and OR 11 is methoxy which if desired can be converted to the corresponding compound wherein OR 11 is hydroxy as hereinbefore described. Suitably a compound of the formula (7) is reacted with a compound of the formula (8) in the presence of 1-50 mole %, preferably 2-10 mole %, of a palladium catalyst and a base such as triethylamine, sodium bicarbonate, or aqueous sodium carbonate and optionally lithium chloride in an organic solvent such as dimethylformamide, dimethoxyethane, acetonitrile, toluene, tetrahydrofuran, ethanol, or mixtures thereof, at elevated temperature, (e.g. 30-150°C) , preferably at the reflux temperature of the mixture. Suitably L 1 is halo for example iodo, bromo or chloro or a trifluoromethane- sulphonate. Subsequently the OR 11 group can be converted to hydroxy as hereinbefore described for compounds of formula (4) . Examples of palladium catalysts that can be used include: tetrakis (triphenylphosphine)palladium (Pd[PPh3]4), bis (triphenylphosphine)palladium dichloride (Pd[PPh3. 2 C1 2 ) , [1,4-bis- (diphenylphosphine)butane]palladium dichloride (Pd(dppb)Cl 2 ), [1,3-bis-(diphenylphosphine)propane]palladium dichloride (Pd(dppp)Cl 2 ), [1,2-bis-(diphenylphosphine)ethane]palladium dichloride (Pd(dppe)Cl 2 ), bis(tri-o-tolylphosphine)palladium diacetate or dichloride (Pd(totp) (OAc) 2 or Pd(totp)Cl2) , or 1,1 -bis(diphenylphosphine) ferrocinopalladium diacetate or dichloride (Pd[dρρf] (OAc)2 or Pd[dppf]Cl2) . By a chemical equivalent of a compound of the formula (8) is meant a reagent that can couple the Ar group onto the pyridyl ring of a compound of the formula (7) . For example aryl stannanes can be used, such as ArSnMe3 which can suitably be prepared by reacting a suitable aryl halide (such as ArBr or Arl) with a base such as t-butyl lithium followed by reaction with a trimethyl tin halide (e.g. Mβ3SnCl) . Alternatively the aryl halide can be reacted with Me3SnSn β3 in the presence of a palladium catalyst as hereinbefore described to prepare a suitable aryl stannane. When R is a group R 1 as hereinbefore defined reaction of a compound of the formula (7) with a compound of the formula (8) results directly in compounds of the formula (1) . An example of a precursor for R is when R 5 is hydrogen. In this situation reaction of a compound of the formula (7) with a compound of the formula (8) or a chemical equivalent thereof results in a compound of the formula (2) or a compound of the formula (6) wherein R 3 is hydrogen. Such compounds can then be converted into a compound of the formula (1) as herein described. Other precursors for R 1 include CN, CHO or COMe. Reaction of a compound of the formula (7) wherein R b represents such a precursor with a compound of the formula (8) or a chemical equivalent thereof results in a compound of the formula (4) or a compound of the formula (6) wherein R 2 or R 3 is CN, CHO or COMe. Such compounds can be converted to compounds of the formula (1) as herein described. If desired a compound of the formula (1) wherein R is A°Cθ2H can be converted to the corresponding compound wherein R is °Cθ2R 9 by reaction with a compound R OH 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 8 by reaction with R 8 L wherein R 8 is as hereinbefore defined and 2 L is a leaving group such as halo e.g. bromo, chloro, iodo. If desired a compound of the formula (1) wherein R is (Z) (OR 2 ) (OH) can be converted to the corresponding compound wherein R 1 is P(Z) (OR 2 ) (OR 10 ) by reaction with a suitable O-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 -R° is A 1 C0 2 is suitably prepared by heating a compound of the formula (1) wherein R 1 is A 1 C0 2 H and R° is OH with a dehydrating agent such as acetic anhydride, at an elevated temperature (e.g. 40 - 200°C) , preferably at the reflux temperature of the reaction mixture. A compound of the formula (1) wherein R 1 -R° is A 2 OCH 0 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 such 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 dimethylformamide dimethylacetal in dimethylformamide or trimethylphosphite at an elevated temperature (e.g. 40 - 120°C) or with iodomethane and silver carbonate in toluene or chloroform. This method can also be used for converting compounds of the formula (6) into corresponding compounds of the formula (4) and compounds of formula (7) where R a is hydroxy to compounds of formula (7) where R a is OR 11 . A compound of the formula (6) wherein R 13 is cyano, acetyl or hydrogen is suitably prepared by reaction of a compound of the formula (9) : ArCOCH=CHL 3 (9) with a compound of the formula (10) : R 15 CH 2 CONH (10) wherein R 15 is cyano, acetyl or hydrogen respectively, and L 3 is a displaceable group and Ar is as hereinbefore defined. Suitably L 3 in a compound of the formula (9) is hydroxy or a derivative thereof for example L 3 is protected hydroxy such as silyloxy, an acid residue (for example Cχ_galkanoyloxy) or an ether residue (for example methoxy or ethoxy) . Alternatively L 3 is a secondary amino group, for example di-Cχ_galkylamino such as dimethylamino or a cyclic amino group such as piperidino, pyrrolidino or morpholino. Preferably L 3 is hydroxy or dimethylamino. Suitably an alkali metal (e.g. sodium) salt of a compound of the formula (9) wherein L 3 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 3 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 Cχ_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 3 is hydroxy can suitably be prepared by reaction under basic conditions of a compound of the formula (11) : ArCOCH 3 (11) wherein Ar is are as hereinbefore defined, with a compound of the formula HCOL 4 wherein L 4 is a leaving group. Suitably L 4 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 3 is hydroxy is then treated with a compound of the formula (10) as hereinbefore described. Compounds of the formula (9) wherein L 3 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 16 ) 2 L 3 wherein R 16 is Cχ_4alkyl and L 3 is a secondary amino group (for example HC(OR 16 ) 2 L 3 is N,N-dimethylformamide dimethyl or diethyl acetal) . Alternatively a compound of the formula (11) can be reacted with a compound of the formula HC(L )3 (for example tris dimethylaminomethane) . 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 acidic work up with for example hydrochloric acid. 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 Cχ_4alkyl propiolate (such as methyl propiolate) and ammonia in a solvent such as a Cχ_4alkanol in a pressure vessel at elevated temperature (40- 200°C) preferably at 100°C. Alternatively a compound of the formula (6) wherein R 13 is hydrogen can be prepared by reacting a compound of the formula (6) wherein R 13 is cyano with orthophosphoric acid at an elevated temperature, e.g. 50 - 200°C. A compound of formula (4) wherein R 12 is cyano is suitably prepared by reacting the anion of a compound of formula (2) wherein Ar and R 11 are as hereinbefore defined 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 carboxaldehyde 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 by dehydrating the product obtained for example by heating with acetic anhydride. A compound of the formula (6) wherein R 13 is cyano or acetyl and Ar is as hereinbefore defined can be suitably prepared by reaction of a compound of formula (4) wherein R 2 is cyano or acetyl and R 11 and Ar are as hereinbefore defined with a demethylating agent such as sodium iodide/chlorotrimethylsilane 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 temperatur . A compound of the formula (6) wherein R 13 is P(0) (OR 2 ) 2 can be prepared by treating a compound of the formula (2) wherein R 1 is (0) (OR 2 ) 2 with a strong base such as lithium diisopropylamide in an organic solvent such as tetrahydrofuran with cooling (e.g. -100-0°C) . A compound of the formula (2) wherein R 11 is P(0) (0R 2 ) 2 is suitably prepared by treating a compound of the formula (6) wherein R 13 is hydrogen with a compound of the formula (12) : ' L 5 P(0) (OR ) 2 (12) wherein L^ is a leaving group and R 2 is as hereinbefore defined with a base such as diisopropylethylamine. Suitably L 5 is halo, for example chloro or bromo. A compound of formula (2) wherein R 11 is P(0) (0R 2 ) 2 can also be prepared by treating a compound of the formula (6) wherein R 13 is hydrogen with a compound of the formula (13) : HP (O) (OR 2 ) 2 (13) 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 13 is P (0) (0R 2 ) is suitably prepared by treating a compound of the formula (6) wherein R 13 is hydrogen with a compound of the formula (12) 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 13 is P (0) (NHR 14 ) (OR 2 ) can be prepared by reaction of a compound of the formula (6) wherein R 13 is P(0) (OH) (OR 2 ) with carbon tetrachloride, triphenylphosphine and aniline or a Cχ_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 Cχ_4alkylamine preferably with cooling (-10 to 5°C) . Compounds of the formula (7) are known or can be prepared from a compound of the formula (14) : wherein R a and L 1 are as hereinbefore defined using similar methods to those described for preparing compounds of the formula (1) . Thus, a compound of the formula (7) wherein R D is P(0) (OR 2 ) 2 can be prepared by reacting a compound of the formula (14) wherein R a is OH with a compound of the formula (12) or (13) in similar manner to the reaction of a compound of the formula (6) wherein R 13 is hydrogen with a compound of the formula (12) or (13) . If desired the group R a can then be converted to OMe. Similarly, a compound of the formula (14) where R a is OMe can be treated in the presence of a strong base with a compound of the formula (3) , a compound of the formula (5) , sulphuryl chloride, sulphur dioxide or dimethylformamide to prepare a compound of the formula (7) wherein R b is CR 3 (OR 4 )C0 2 R 9 , C0C0 2 R 9 , SO3H, S0 2 H or CHO respectively in similar manner to the corresponding reaction with a compound of the formula (2) as hereinbefore described. Particularly suitable as a strong base is lithium tetramethyl piperidide. A compound of the formula (8) is suitably prepared by reacting the organolithium or Grignard reagent, formed from a compound of the formula (15) : Ar-L 6 (15) wherein L 6 is bromo or iodo and Ar is as hereinbefore defined with a tri-Cχ_4alkylborate such as trimethyl, tri-isopropyl or tri-n-butyl borate in an organic solvent such as diethyl ether or tetrahydrofuran with cooling (e.g. - 80-10°C) . The Ar group in compounds of the formula (2), (4), (6), (11) or (15) preferably (2) , (4) or (11) 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 in the 2- and 4-positions by electron-donating groups such as Cχ_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 nitrating agent, such as nitronium tetrafluoroborate. Such a group can be readily hydrogenated to an amino group which if desired can be converted to a NHCOR 7 group by reaction with LCOR 7 wherein L is a leaving group and R 7 is as hereinbefore defined. Suitable examples of the reagent LCOR include acid halides (L is halo eg. chloro or bromo) or acid anhydrides (L is OCOR 7 ) . 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 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 Cχ_galkyl halide to form a Cχ_galkoxy group. If desired, an allyl group can be converted to an E-1-propenyl group by reaction with a strong base, such as sodium methoxide. This can occur during the conversion of a compound of formula (11) to a compound of formula (6) as hereinbefore described if such a base is used. An E-1-propenyl group can be cleaved to a formyl group by reaction with an oxidising agent such as N-methylmorpholine-N-oxide in the presence of a catalyst such as osmium tetroxide to form a 1,2,dihydroxypropyl group which on reaction with an oxidising agent such as sodium periodate forms the formyl group. Alternatively the E-1-propenyl group can be 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 agent such as sodium borohydride, the hydroxymethyl group then being reacted further, eg. with a Cχ_galkyl halide to form a Cχ_galkoxymethyl group. Alternatively a formyl group can be reacted with a suitable Homer Wittig or Wittig reagent such as (R 17 0) P(0)CH 2 C0 2 R 17 or Ph3P=CHC0 2 R 17 wherein R 17 is Cχ_4alkyl to form a CH=CHC0 2 R 17 group which can be optionally hydrolysed to a -CH=CHC0 2 H group. A -CH=CHC0 2 R 17 group can be converted to a -CH=CHC0N(R 7 ) 2 group by reaction with an amine HN(R 7 ) 2 or a chemical equivalent thereof wherein R 7 is as hereinbefore defined. Alternatively a -CH=CHC0 H group can be converted to an acid halide, eg. the acid chloride by reaction with oxalyl chloride, which can then be reacted with an amine HN(R 7 ) 2 or a chemical equivalent thereof. An example of a chemical equivalent is ammonium hydroxide which will form a CH=CHC0NH 2 group. 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 of 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 with 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 with [γ- 32 P]-adenosine triphosphate and a suitable peptide substrate such as malantide (Malencik et al., 1983, Anal. < - 5 Biochem., 132, 34-40). The reaction was terminated by the addition of hydrochloric acid and the [ P]-phosphopeptide quantified by spotting the reaction mixture onto phosphocellulose papers. The concentration of compound required to give 10% phosphotransferase activation is given 10 as the ECχo (μM) • The compounds of Examples 1 to 7 had ECχo values in the range 1 to 30 μM. Inhibition of Platelet Aggregation 15 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 and adjusted 20 to a concentration of 1.5xlθ8 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 25 (concentration to cause 50% inhibition of platelet aggregation, μM) . The compounds of Examples 3 and 5 had IC50 values of 174 and 73 μM respectivley. Inhibition of Spontaneous Contraction in Guinea-Pig Colon 30 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 35 developed tension on chart 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 2 minute readings. The concentration of compound which cause 50% inhibition of the spontaneous contraction is given as th EC 50 (μM) . Bronchodilatation - In vitro Spiral strips of guinea-pig trachea were suspended 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 recorders. Tension was allowed to develop spontaneously and concentrations of test compounds added in a cumulative fashion. The concentration of compound which caused 50% inhibition of the spontaneously developed tension is given as the IC50(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 allowed 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 time 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 treatment of cardiovascular diseases where there is a component of diastolic failure such as congestive heart failure, angina, hypertension and cardiomyopath . Example 1 Ethyl [6-(3-bromophenyl)-2-oxo-l,2-dihydro-3- pyridyl]phosphonate (a) 6- (3-bromoρhenyl)-3-cyanopyridin-2 (lH)-one (9.6g) was heated in orthophosphoric acid (40ml, 85%) at 170°C for 42 hours, cooled to room temperature and poured into water (200ml) . The precipitated material was separated by filtration, washed with water and recrystallised from n-butanol to give 6-(3-bromophenyl)pyridin-2 (1H)-one (4.18g). l-H-NMR (d6-DMSO) 6.49(d, 1H) , 6.89(d, 1H) , 7.44 (t,lH), 7.56-7.66(m,2H) , 7.84(d,lH) and 8.06(s, 1H) . (b) To a suspension of 6- (3-bromophenyl)ρyridin-2 (1H)-one (1.54g) in tetrahydrofuran (8ml), cooled to -78°C, lithium diisopropylamide (4ml, 1.5M in tetrahydrofuran) was added over 20 minutes. After the addition was complete the mixture was warmed to 0°C, stirred for 30 minutes, recooled to -78°C diethyl chlorophosphate (0.83g) added and the solution rewar ed to 0°C. After 30 minutes the reaction mixture was recooled to -78 C lithium diisopropylamide (4ml, 1.5M in tetrahydrofuran) added, the mixture stirred at -78 C for 30 minutes and at 0°C for 30 minutes. The reaction mixture was quenched with 2N hydrochloric acid (20ml) , diluted with ethyl acetate (200ml) and the organic separated, washed with water (2x50ml) , dried (MgS04) and solvent removed at reduced pressure. Column chromatography (silica, dichloromethane/ethanol 15:1 eluant) of the residue followed by recrystallisation from ethanol gave diethyl [6- (3-bromophenyl)-2-oxo-l,2-dihydro-3-pyridy1]phosphonate (0.37g) m.p.l22-123°C. (c) Diethyl [6- (3-bromophenyl)-2-oxo-l,2-dihydro-3- pyridyl]phosphonate (0.34g) in ethanol (10ml) containing aqueous sodium hydroxide (8ml, 40%) was boiled for 2 hours cooled to room temperature and adjusted to pH 1 with 2N hydrochloric acid. The precipitated material was separated by filtration washed with water and ethanol and recrystallised from ethanol to give the title compound (O.lg) m.p. 228-229°C. Example 2 Ethyl [6-(4-bromophenyl)-2-oxo-l,2-dihydro-3- pyridyl]phosphonate (a) A mixture of '-bromoacetophenone (19.9g) and dimethylformamide dimethylacetal (14.6ml) in dimethylformamide (80ml) was heated at 130°C for 16 hours. The mixture was cooled to room temperature, diluted with ethyl acetate (300ml), washed with water (6 x 200ml), dried (MgSθ4) and solvent removed at reduced pressure. The residue was dissolved in dimethylformamide (80ml) , sodium methoxide (10.8g) and cyanoacetamide (8.4g) added and the mixture heated at 120°C until gas evolution ceased (about 1 hour) . After pouring into 10% aqueous acetic acid (300ml) , the precipitated 6-(4-bromophenyl)-3-cyanopyridin-2(1H)-one (19.8g) m.p. >320°C was collected by filtration, washed with water and ethanol and dried. ^-H NMR (DMSO-dg) 6.82(d,lH), 7.70-7.80 (m,4H) , 8;20(d,lH) and 12.81(br.s,lH) . (b) From 6-(4-bromophenyl)-3-cyanopyridin-2(1H)-one (6.88g), 6-(4-bromophenyl)pyridin-2(1H)-one (6.25g) was prepared according to the method of Example 1(a) . 1 H NMR (d6- DMSO) 6.44 (d,lH), 6.80(d,lH), 7.57(t,lH), 7.67(d,2H) and 7.77(d,2H) . (c) From 6-(4-bromophenyl)-3-cyanopyridin-2(1H)-one (2.00g), diethyl [6-(4-bromophenyl)-2-oxo-l,2-dihydro-3- pyridyl]phosphonate (0.42g) m.p. 136-138°C after recrystallisation from ethanol, was prepared according to the method of Example 1(b) . (d) From diethyl [6-(4-bromophenyl)-2-oxo-l,2-dihydro-3- pyridyl]phosphonate (0.37g), the title compound (0.19g) m.p.240-241°C after recrystallisation from ethanol, was prepared according to the method of Example 1(c) . Example 3 [6-(3,5-Diethoxyphenyl)-2-oxo-l,2-dihydro-3-pyridyl]acetic acid. (a) To a cooled (card ice/acetone bath) suspension of 3- cyano-6- (3,5-diethoxyphenyl)pyridin-2 (lH)-one (2.84g) in tetrahydrofuran (30ml), methyl lithium (18ml of 1.3M in diethyl ether) was added over 10 minutes. When the addition was complete the mixture was warmed to 0°C and stirred for 4 hours giving a deep red solution. The solution was recooled (card ice/acetone) treated with 5N hydrochloric acid (50ml) and stirred at room temperature overnight. The mixture was boiled until all the organic solvent had evaporated cooled to room temperature and the aqueous phase separated by decanting. The residual oily solid was triturated with boiling ethanol to give 3-acetyl-6- (3,5- diethoxyphenyl)pyridin-2(lH)-one (2.3g). 1 H NMR d(DMSO-dg) 1.34(t,6H), 2.58(s,3H), 4.09(q,4H), 6.61(s,lH), 6.83(d,lH), 6.96(s,2H) and 8.07(d,lH). (b) 3-Acetyl-6-(3,5-diethoxyphenyl)pyridin-2 (lH)-one (1.5g), sulphur (0.18g) and morpholine (2ml) were heated together at 140°C for 4 hours. 2N Sodium hydroxide (10ml) was added and the mixture boiled for 3 hours. The solution was cooled to room temperature, filtered (celite pad) and the filtrate washed with ethyl acetate (3 x 30ml) . The aqueous phase was adjusted to pH 7 (carbon dioxide) , filtered (celite pad) , the filtrate adjusted to pH 1 and the product collected by filtration to give the title compound (0.34g) m.p. 245-247°C after recrystallisation from ethanol. 1 H NMR d(DMSO-dg) 1.33(t,6H), 3.38(s,2H), 4.07(q,4H), 6.52(m,lH), 6.58(d,lH), 6.86(d,2H), 7.42(1H) and 12.00 (br.s,2H) . Example 4 Ethyl [6-(2-propoxyphenyl)-2-oxo-l,2-dihydro-3- pyridyl]phosphonate. (a) To a cooled (card ice/acetone) solution of 6-chloro-2- pyridinol (6.48g) in tetrahydrofuran, lithium diisopropylamide (34ml of a 1.5M solution in cyclohexane) was added over 20 minutes. When the addition was complete the temperature was raised to 0°C for 30 minutes, recooled to - 78°C and diethyl chlorophosphate (8.1ml) added. The temperature was again raised to 0°C and the reaction mixture stirred for a further 30 minutes. After recooling to -78°C, additional lithium diisopropylamide (34ml of a 1.5M solution in cyclohexane) was added the mixture stirred at -78°C for 90 minutes and at 0°C for 30 minutes. After quenching with 2N hydrochloric acid (50ml) the aqueous phase was extracted with ethyl acetate (3 x 50ml) . The combined organic extracts were washed with water (3 x 50ml) , dried MgSθ ) and solvent removed at reduced pressure. The residue was column chromatographed (silica gel, dichloromethane ® 7% ethanol/dichloromethane) to give diethyl (6-chloro-2-oxo-l,2- dihydro-3-pyridyl)phosphonate (13.Og) . X H NMR (CDCI3) 1.34(t,6H) ' , 4.07-4.30(m,4H), 6.86(dd,lH) and 7.90(dd,1H) . (b) A mixture of diethyl (6-chloro-2-oxo-l,2-dihydro-3- pyridyl)phosphonate (2.13g), silver carbonate (4.4g) and iodomethane (5.7g) was boiled for 2 hours. The mixture was diluted with dichloromethane (100ml) , filtered (celite pad) and solvent removed at reduced pressure. The residue was column chromatographed (silica gel, 3% ethanol/dichloromethane eluant) to give diethyl (6-chloro-2- methoxy-3-pyridyl)phosphonate (1.2g) . 1 H NMR (DMSO-dg) 1.24(t,6H), 3.94(s,3H), 3.99-4.11(m,4H) , 7.24(dd,lH) and 8.05(dd,lH). (c) To an aqueous solution of sodium bicarbonate (0.54g in ml of water) , [1,4-bis(diphenylphosphino)butane]palladium (II) chloride (0.3g), 2-propoxyphenylboronic acid (0.58g, prepared according to the method of W.J.Thompson and J.Gaudino, J. Org. Chem., 1984, 49, 5237) in dimethoxyethane (6ml) and diethyl (6-chloro-2-methoxy-3-pyridyl)phosphonate (0.56g) in dimethoxyethane (8ml) were added. The mixture was boiled for 4 hours, cooled to room temperature and diluted with water (100ml) and dichloromethane (100ml) . The organic phase was separated and the aqueous phase extracted with dichloromethane (2 x 50ml) . The combined organic extracts were washed with water (2 x 100ml) , dried and solvent removed at reduced pressure. The residue was column chromatographed (silica gel, 5% ethanol/dichloromethane eluant) to give diethyl [6- (2-propoxyphenyl)-2-methoxy-3-pyridyl]phosphonate (0.48g). !H NMR (DMSO-dg) 0.98(t,3H), 1.26(t,6H), 1.66- 1.8 (m,2H), 3.99(s,3H), 3.99-4.11 (m, 6H) , 7.04-7.17 (m,2H) , 7.43(dt,lH), 7.70(dd,lH), 7.94(dd,lH) and 8.05 (dd, 1H) . (d) A mixture of diethyl [6-(2-propoxyphenyl)-2-methoxy-3- pyridyl]phosphonate (0.45g), sodium iodide (0.2g) and chlorotrimethylsilane (0.14g) in chloroform (2ml) was boiled for 45 minutes. After diluting with 2N hydrochloric acid (10ml) the mixture was extracted with ethyl acetate (2 x 20ml) The combined organic extracts were washed with water (20ml) and 10% sodium bicarbonate (2 x 20ml), dried (MgS0 4 ) and solvent removed at reduced pressure. The residue was recrystallised from dichloromethane to give diethyl [6- (2- propoxyphenyl) -2-oxo-l,2-dihydro-3-pyridyl]phosphonate (0.12g) m.p.lll-112°C. NMR (DMSO-dg) 0.94(t,3H), 1.24(t,6H), 1.63-1.78(m,2H), 3.94-4.11 (m, 6H) , 6.43(dd,lH), 7.05(t,lH)7.14(d,lH) , 7.41-7.48 (m,2H) and 7.93 (dd,1H) . (e) From diethyl [6- (2-propoxyphenyl)-2-oxo-l,2-dihydro-3- pyridyl]phosphonate (0.12g), the title compound (0.007g) ,m.p. 182-183°C after recrystallisation from ethanol was prepared according to the method of Example 1 (c) . --E NMR (DMSO-dg) 0.94(t,3H), 1.19(t,3H), 1.64-1.76(m,2H) , 3.91-4.07(m, 4H) , 6.46(dd,lH), 7.03(t,lH), 7.16(d,lH), 7. 0-7.48 (m,2H and 7.92 (dd,1H) . Example 5 Ethyl [6-(2,3-dipropoxyphenyl)-2-oxo-l,2-dihydro-3- pyridyl]phosphonate. (a) From diethyl (6-chloro-2-methoxy-3-pyridyl)phosphonate (l.lg) and 2,3-dipropoxyphenylboronic acid (1.5g), diethyl [6-(2,3-dipropoxyphenyl)-2-methoxy-3-pyridyl]phosphonate (1.3g) was prepared according to the method of Example 4(c) . Treatment of diethyl [6-(2,3-dipropoxyphenyl)-2-methoxy-3- pyridyl]phosphonate (1.05g) with sodium iodide (0.36g) and chlorotrimethylsilane (0.26g) according to the method of Example 4(d) gave diethyl [6-(2,3-dipropoxyphenyl)-2-oxo-l,2- dihydro-3-pyridylIphosphonate (0.14g) m.p.l06-107°C after column chromatography (dichloromethane eluant) . 1 H NMR (DMSO- dg) 0.80(t,3H), 1.02(t,3H), 1.24(t,6H), 1.46-1.60(m,2H) , 1.70-1.83(m,2H) , 3.83(t,2H), 3.96-4.10(m, 6H) , 6.36(br.s,1H) , 6.95(d,lH), 7.08-7.18(m,2H) and 7.93(dd,1H) . (b) From diethyl [6-(2,3-dipropoxyphenyl)-2-oxo-l,2-dihydro— 3-pyridyl]phosphonate (0.07g), the title compound (0.04g) m.p. 129-130°C after recrystallisation from ethyl acetate was prepared according to the method of Example 1(c) . 1 H NMR (DMSO-dg) 0.80 (t,3H), 1.02(t,3H), 1.18 (t,3H), 1.44- 1.59(m,2H), 1.70-1.84(m,2H), 3.82(t,2H), 3.93(t,2H), 3.99(t,2H), 6.44(br.s,lH), 6.98 (d,lH), 7.07-7.68 (2H) and 7.93(dd,1H) . Example 6 n-Propyl [6-(3-n-propoxyphenyl)-2-oxo-l,2-dihydro-3- pyridyl]phosphonate (a) From 3-n-propoxybromobenzene (8.6g), 3-n- propoxyphenylboronic acid (4.8g) m.p. 109-110°C after recrystallisation from ethyl acetate/hexane, was prepared according to the method of W. J. Thompson J. Guadino J. Org. Chem. 1984, 49, 5237. (b) From 3-n-propoxyphenylboronic acid (1.72g) and 2- methoxy-6-chloropyridine (0.86g), 2-methoxy-6- (3-n- propoxyphenyl)pyridine (2.13g) was prepared according to the method of Example 4(c) . 1H NMR (DMS0-d6) 1.00 (t,3H), 1.75(m,2H), 3.95(s,3H), 4.) (t,2H), 6.77 (d,lH), 6.97(dd,lH), 7.36(t,lH), 7.50(d,lH), 7.63(s,lH), 7.66(d,lH) and 7.75 (t,lH) . (c) From 2-methoxy-6- (3-n-propoxyphenyl)pyridine (2.1g), 6- (3-n-propoxyphenyl)pyridin-2 (1H) -one (1.21g) m.p.100-101°C after recrystallisation from ethanol, was prepared according to the method of Example 4 (d) . (d) From 6- (3-n-propoxyphenyl) pyridin-2 (1H) -one (1.15g), di-n-propyl [6- (3-propoxyphenyl) -2-oxo-l, 2-dihydro-3- pyridyl]phosphonate (0.08g) m.p. 128-129°C after recrystal.λisation from ethyl acetate, was prepared according to the method of Example 1 (b) using di-n-propylchloro- phosphate instead of diethyl chlorophosphate. (e) From di-n-propyl [6- (3-propoxyphenyl) -2-oxo-l, 2- dihydro-3-pyridyl]phosphonate (0.06g), the title compound (0.03g) m.p. 160°C after recrystallisation from ethyl acetate, was prepared according to the method of Example 1 (c) . Example 7 {6-[4-methoxy-3-(E-1-propenyl)phenyl]-2-oxo-l,2-dihydro-3- pyridyl}acetic acid (a) From 3-cyano-6- [4-methoxy-3- (E-1-propenyl) phenyl] - pyridin-2 (1H) -one (3.99g) (Patent WO 92/06085), 3-acetyl-6- [4-methoxy-3- (E-1-propenyl)phenyl]pyridin-2 (1H) -one (3.1g) after recrystallisation from dimethylformamide/water, was prepared according to the method of Example 3(a) (b) From 3-acetyl-6- [4-methoxy-3- (E-1-propenyl)phenyl]- pyridin-2 (1H) -one (1.42g), the title compound (0.06g) m.p. 240-242°C , was prepared according to the method of Example 3(b) . Example 8 Pharmaceutical compositions for oral administration are prepared by combining the following : % w/w Ethyl [6-(3-bromophenyl)- 2-oxo-l,2-dihydro3 pyridyl]phosphonate 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. Example 9 A pharmaceutical composition for parenteral administration is prepared by dissolving the title compound of Example 2 (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.

Claims: Claims 1. A compound of the formula (1) : or a pharmaceutically acceptable salt thereof, wherein : 10 R° is OH or a bioprecursor thereof, R 1 is A°C0 2 H, P(Z) (OH) (OR 2 ), S0 2 H or S0 3 H or a bioprecursor thereof, 15 A° is CH 2 , CHF, CF , CR 3 (OR 4 ), CO or C(OR 5 ) (OR 6 ), R 2 is phenyl, C3_5Cycloalkyl, C3_5cycloalkylCχ_4alkyl, or Cχ_8alkyl optionally substituted by Cχ._4alkoxy, 20 R 3 is H, methyl or ethyl, R 4 is H or Cχ_3alkyl, 25 R5 and R 6 are each Cχ_3alkyl or together form a 1,2- ethanediyl group or 1,3-propanediyl group, Z is 0 or S ( and 30 Ar is phenyl optionally substituted by one to three groups independently selected from Cχ_galkyl, C 2 _galkenyl, Cχ_galkoxy, C3_galkenyloxy, C3_gcycloalkyl, C3_gcycloalkoxy, Cχ_galkylthio, phenyl, phenylthio, benzyloxy, Cχ_gpolyfluoroalkyl, Cι_gpolyfluoroalkoxy, halo, N(R 7 ) 2 or 35 NHCOR 7 wherein R 7 is H or Cχ_galkyl, or -X(CH2) n Y- attached to adjacent carbon atoms of the phenyl ring wherein X and Y are independently CH 2 or 0 and n is 1 to 3, wherein said Cχ_galkyl, C 2 _galkenyl or Cχ_galkoxy groups can be independently substituted by OH, Cχ_galkoxy, C3_gcycloalkyl, N(R 7 ) 2 , C0 2 R 7 or CON(R 7 ) 2 . 2. A compound according to claim 1 wherein R 1 is A°C0 2 H or A°C0 R 9 in which R 9 is an ester-forming group. 3. A compound according to claim 1 wherein R 1 is P(Z) (OH) (OR 2 ) or P(Z) (0R 2 ) 2 . 4. A compound according to claims 1 wherein R 1 is S0 H or SO3H. 5. A compound according to claim 1 wherein R 1 and R° are linked together such that R 1 -R° is A C0 in which A 1 is CH 2 , CHF, CF 2 , CR 3 (OR 4 ), CO or C(0R 5 ) (OR 6 ). 6. A compound according to claim 1 wherein R 1 and R° are linked together such that R 1 -R° is A 2 OCH 2 0 in which A 2 is P(Z) (OR 2 ) or CR 3 (C0 2 R 9 ) and R 9 is an ester-forming group. 7. A compound according to claim 1 which is : ethyl [6-(3-bromophenyl)-2-oxo-l,2-dihydro-3-pyridyl]- phosphonate, ethyl [6-(4-bromophenyl)-2-oxo-l,2-dihydro-3-pyridyl]- phosphonate, [6-(3,5-diethoxyphenyl)-2-oxo-l,2-dihydro-3-pyridyl]acetic acid, ethyl [6-(2-propoxyphenyl)-2-oxo-l,2-dihydro-3-pyridyl]- phosphonate, ethyl [6-(2,3-dipropoxyphenyl)-2-oxo-l,2-dihydro-3- pyridyl]phosphonate, n-propyl [6- (3-n-propoxyphenyl) -2-oxo-l,2-dihydro-3- pyridyl]phosphonate, or {6-[4-methoxy-3-(E-1-propenyl)phenyl]-2-oxo-l,2-dihydro-3- <=. 5 pyridyl}acetic acid, or a pharmaceutically acceptable salt thereof. 8. A compound according to any one of claims 1 to 7 for use as a medicament. 10 9. A pharmaceutical composition which comprises a compound according to any one of claims 1 to 7 and a pharmaceutically acceptable carrier. 15 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°C0 2 H or A°C0 2 R 9 and : 20 i) A 0 is CR 3 (OR 4 ) , reacting in the presence of a strong base a compound of the formula (2) : 25 wherein R 11 is methyl and Ar is as defined in claim 1, 30 with a compound of the formula (3) : R3 C 0C0 2 R 9 (3) 35 wherein R 3 is as defined in claim 1 and R 9 is an ester- forming group to form a compound of the formula (4) : wherein R 12 is CR 3 (0H)C0 2 R 9 and R 3 , R 9 , R 11 , and Ar are as hereinbefore defined and thereafter optionally reacting with a Cχ_3alkylating agent to form the corresponding compound wherein R 12 is CR 3 (0Cχ_3alkyl)C0 2 R 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 CCθ2R 9 (5) wherein R 9 is as hereinbefore defined to form a compound of the formula (4) wherein R 12 is COC0 2 R 9 and R 9 , R 11 and Ar are as hereinbefore defined, iii) A 0 is CH(OH), reacting a compound of the formula (4) wherein R 12 is COC0 2 R 9 and R 9 , R 11 , and Ar are as hereinbefore defined with a reducing agent to form the corresponding compound wherein R 12 is CH(0H)C0 2 R 9 , iv) A° is CH 2 , reacting a compound of the formula (4) -wherein R 12 is C0C0 2 H or COC0 2 R 9 and R 9 , R 11 , and Ar are as hereinbefore defined with a suitable- reducing agent to form the corresponding compound wherein R 2 is CH C0 2 H, v) A 0 is C(0R 5 ) (0R 6 ), reacting a compound of the formula (4) wherein R 12 is C0C0 2 R 9 and R 9 , R 11 , and Ar are as hereinbefore defined with a Cl-3alcohol, 1,2-ethanediol or 1,3-propanediol to form the corresponding compound wherein R 12 is C(OR^) (OR 6 )C0 2 R 9 , vi) A 0 is CF 2 , reacting a compound of the formula (4) wherein R 2 is COC0 2 R 9 and R 9 , R 11 , and Ar are as hereinbefore defined with a fluorinating agent to form the corresponding compound wherein R 11 is CF2CO2R 9 , or vii) A 0 is CHF, reacting a compound of the formula (4) wherein R 12 is CH(0H)C02R 9 and R 9 , R 11 , and Ar 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 Ar is as hereinbefore defined into the corresponding compound wherein R 13 is CH2CO2H; or c) for compounds wherein R 1 is CH(OR 4 )C0 2 H reacting a compound of the formula (4) wherein R12 is -CH(OH)CN with a Cχ_3alkylating agent and/or converting the group CN into CO2H, and optionally converting the group OR 11 into OH; or d) for compounds wherein R 1 is (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 Ar is 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 Cχ_4alkyl and Ar is 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 S0 2 H, 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 1 is as defined for compounds of the formula (1) reacting in the presence of a palladium catalyst a compound of the formula (7) : wherein R is a group R 1 as defined in claim 1 or a precursor thereof and R a is R° or OR 11 as hereinbefore defined and L 1 is a leaving group with a compound of the formula (8) : ArB (OH) 2 (8) or a chemical equivalent thereof wherein Ar is as hereinbefore defined and then, if necessary, converting a precursor of R into R and/or converting the group OR 11 into OH, 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 HUNTER DOUGLAS, WARRINGTON BRIAN HERBERT, MURRAY, KENNETH, JOHN, PORTER, RODERICK, ALAN, PRAIN, HUNTER, DOUGLAS, WARRINGTON, BRIAN, HERBERT
Applicants: SMITHKLINE BEECHAM PLC
Application year: 1992
Main classification: A61K31
IPC codes: A61K31, A61P7, A61P9, A61P11, A61P43, C07D213, C07F9