WO1993010114A1

WO1993010114A1 - 3-pyridinol derivatives and their use as medicaments

Info

Publication number: WO1993010114A1
Application number: PCT/GB1992/002118
Authority: WO
Inventors: Roderick Alan Porter; Hunter Douglas Prain; Kenneth John Murray; Brian Herbert Warrington
Original assignee: Smithkline Beecham Plc
Priority date: 1991-11-20
Filing date: 1992-11-16
Publication date: 1993-05-27
Also published as: TW221990B; GB9124578D0; AU2930392A; ZA928893B; CA2124002A1; JPH07501070A; PT101072A; EP0613476A1; MX9206710A; NZ245167A

Abstract

Compounds of formula (1), or a pharmaceutically acceptable salt thereof, wherein: R0 is OH or a bioprecursor thereof, R?1 is A0CO¿2H, P(Z)(OH)(OR2), SO2H, SO3H or 5-tetrazolyl or a bioprecursor thereof, A0 is CH¿2?, CHF, CF2, CR?3(OR4¿), CO or C(OR5)(OR6), are described as agonists of a cyclic AMP dependent protein kinase. They are useful as medicaments.

Description

3-PYRIDINOL 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,

R¹ is A⁰CO₂H, P(Z) (OH) (OR²), SO₂H, SO₃H or 5-tetrazolyl or a bioprecursor thereof,

A⁰ is CH₂, CHF, CF₂, CR³(OR⁴), CO or C(OR⁵) (OR⁶), R² is phenyl, C_3-5cycloalkyl, C_3-5cycloalkylCι_4alkyl, or C_1-8alkyl optionally substituted by C_1-4alkoxy, R₃ is H, methyl or ethyl,

R⁴ is H or C_1-3alkyl,

R⁵ and R⁶ are each C_1-3alkyl or together form a 1,2- ethanediyl group or 1,3-propanediyl group,

Z is O or S, and

Ar is phenyl optionally substituted by one to three groups independently selected from C_1-6galkyl, C_2-6 -lkenyl, C_1-6alkoxy, C_3-6alkenyloxy, C_3-6cycloalkyl,

C_3-6cycloalkoxy, C_1-6alkylthio, phenyl, phenylthio, benzyloxy, C_1-6polyfluoroalkyl, C_1-6polyfluoroalkoxy, halo, N(R⁷)2 or NHCOR⁷ wherein R⁷ is H or C_1-6alkyl, or -X(CH₂)_nY- attached to adjacent carbon atoms of the phenyl ring wherein X and Y are independently CH₂ or O and n is 1 to 3, wherein said C_1-6alkyl, C_2-6alkenyl or C_1-6alkoxy groups can be independently substituted by OH, C_1-6alkoxy, C_3-6cycloalkyl, N(R⁷)2, CO₂R⁷ or CON(R⁷)2, or

Ar is 1-naphthyl optionally substituted in the 4-position by hydroxy or C_1-6alkoxy, 2-naphthyl optionally substituted in the 1-position by hydroxy or C_1-6alkoxy,

3-phenanthryl, 9-phenanthryl, 2-quinolinyl, 4-quinolinyl, 3-thianaphthenyl or 2-benzofuranyl.

Bioprecursors of the groups R⁰ and R¹ are derivatives thereof which are convertible in vivo into the groups R⁰ and R¹. A suitable bioprecursor of the group R⁰ is OR⁸ wherein R⁸ is C_1-4alkanoyl (for example acetyl), arylC_1-4alkanoyl (for example phenyl C_1-4alkanoyl such as benzoyl), arylsulphonyl (for example optionally substituted phenylsulphonyl or

toluenesulphonyl) or C_1-4alkylsulphonyl (for example methylsulphonyl) .

When R¹ is A⁰CO₂H a suitable bioprecursor is A⁰CO₂R⁹ wherein R⁹ is an ester-forming group.

When R¹ is P(Z) (OH) (OR²) a suitable bioprecursor is

P(Z) (OR²) 2 wherein Z and R² are as hereinbefore defined or P(Z) (OR²) (OR¹⁰) wherein R¹⁰ is an O-protecting group.

Suitable O-protecting groups include pivaloyloxymethyl, propionyloxymethyl and pivalolyloxycarbonyloxymethyl.

When R¹ is 5-tetrazolyl, a suitable bioprecursor is an

N-protected derivative thereof. Suitable N-protecting groups include pivalolyloxymethyl, propionyloxymethyl and

pivalolyloxycarbonyloxymethyl.

Alternatively bioprecursors of the groups R⁰ and R¹ are those formed when R¹ and R⁰ are linked together to form a cyclic structure such that R¹-R⁰ is A¹C0₂ or A²OCH₂O, in which :

A¹ is CH₂, CHF, CF₂, CR³(OR⁴), CO or C(OR⁵) (OR⁶),

A² is P(Z)OR² or CR³ (CO₂R⁹), and R² to R⁶, R⁹ and Z are as hereinbefore defined.

Suitably R⁰ is hydroxy or OR⁸, preferably hydroxy.

Suitably R¹ is A⁰CO₂H or A⁰CO₂R⁹.

Suitably R¹ is P(Z) (OH) (OR²) or P(Z) (OR²)₂.

Suitably R¹ is SO₂H, SO₃H or 5-tetrazolyl. Suitably R¹ and R⁰ are linked together such that R¹-R⁰ 0s A¹CO₂.

Suitably R¹ and R⁰ are linked together such that R¹-R⁰ is A²OCH₂O. By the term alkyl is meant both straight- and branched- chain alkyl. By the term C_1-6polyfluoroalkyl is meant a C_1-6alkyl group having at least one hydrogen replaced with fluoro, e.g. CF₃ or CF₂CF₂H.

Suitably R² is methyl, ethyl, propyl, butyl, pentyl, hexyl, 2-methoxyethyl, phenyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclopropylmethyl.

Suitably R³ is H, methyl or ethyl, preferably H or methyl. Suitably R⁴ is H, methyl, ethyl or propyl, preferably H or methyl.

Suitably R⁵ and R⁶ are independently methyl, ethyl or propyl, preferably together they form a 1,2-ethanediyl group.

Preferably Z is 0.

Suitably R⁹ is C_1-4alkyl optionally substituted by hydroxy, e.g. 2-hydroxyethyl or arylC_1-4alkyl (for example

phenylC_1-4alkyl 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 C_1-6alkyl, C_1-6alkoxy, C_3-6alkenyloxy,

C_1-6alkylthio, phenyl, phenylthio, benzyloxy, CF₃, halo or NHCOR⁷.

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

C_2-6alkenyl, C_1-6alkoxy, C_3-6cycloalkoxy, halo, -X(CH₂)_nY- or C_1-6alkoxyC_1-6 alkoxy. Suitably Ar is phenyl trisubstituted by any groups as hereinbefore defined, for example in the 2,3,4-, 2,3,5-, or 3,4,5-positions by groups independently selected from

C_2-6alkenyl, C_1-6alkoxy or halo.

Suitably Ar is 1-naρhthyl 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_1-6alkoxy.

Suitably Ar is 3-phenanthryl or 9-phenanthryl.

Suitably Ar is 2-quinolinyl or 4-quinolinyl. Suitably Ar is 2-benzofuranyl or 3-thianaphthenyl.

Examples of C_1-6alkoxy include methoxy, ethoxy, propoxy, butoxy, or pentyloxy. Examples of C_1-6alkyl include methyl, ethyl, propyl, butyl, isobutyl or pentyl.

Examples of halo include fluoro, chloro, bromo or iodo. Particular compounds of this invention include : ethyl [5-(2-naphthyl)-3-hydroxy-2-pyridyl]phosphonate, 5-(2,4-dipropoxyphenyl)-2-(5-tetrazolyl)pyridin-3-ol, or

5-(4-methoxy-3-propoxyphenyl)-3-(5-tetrazolyl)pyridin-3-ol, and pharmaceutically acceptable salts thereof. This invention covers all tautomeric, geometric and optical isomeric forms of compounds of formula (1).

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 agonism 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 sympathomimetic amines for example isoprenaline, isoetharine, sulbutamol, phenylephrine and ephedrine or xanthine derivatives for example

theophylline and aminophylline, anti-allergic agents for example disodium cromoglycate, histamine H₁-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 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 R¹ is A⁰CO₂H or A⁰CO₂R⁹ and : i) A⁰ is CR³(OR⁴),

reacting in the presence of a strong base a compound of the formula (2) :

wherein R¹¹ is an O-protecting group and Ar is as

hereinbefore defined, with a compound of the formula (3) :

R³COCO₂R⁹ (3) wherein R³ and R⁹ are as hereinbefore defined to form a compound of the formula (4) :

wherein R¹² is CR³(OH)CO₂R⁹ and R³, R⁹, R¹¹, and Ar are as hereinbefore defined and thereafter optionally reacting with a C_1-3alkylating agent to form the corresponding compound wherein R¹² is CR³ (OC_1-3alkyl) CO₂R⁹, ii) A⁰ 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) :

R⁹O₂CCO₂R⁹ (5) wherein R⁹ is as hereinbefore defined to form a compound of the formula (4) wherein R¹² is COCO2R⁹ and R⁹, R¹¹ and Ar are as hereinbefore defined, iii) A⁰ is CH(OH),

reacting a compound of the formula (4) wherein R¹² is COCO₂R⁹ and R⁹, R¹¹, and Ar are as hereinbefore defined with a reducing agent to form the corresponding compound wherein R¹² is CH(OH)CO₂R⁹, iv) A⁰ is CH₂,

reacting a compound of the formula (4) wherein R¹² is COCO₂H or COCO₂R⁹ and R⁹, R¹¹, and Ar are as hereinbefore defined with a suitable reducing agent to form the corresponding compound wherein R¹² is CH₂CO₂H, v) A⁰ is C(OR⁵)(OR⁶),

reacting a compound of the formula (4) wherein R¹² is COCO₂R⁹ and R⁹, R¹¹, and Ar are as hereinbefore defined with a

C_1-3alcohol, 1,2-ethanediol or 1,3-propanediol to form the corresponding compound wherein R¹² is C(OR⁵) (OR⁶)CO₂R⁹, vi) A⁰ is CF₂,

fluorinating agent to form the corresponding compound wherein R¹¹ is CF₂CO₂R⁹, or vii) A⁰ is CHF,

reacting a compound of the formula (4) wherein R¹² is CH(OH)CO₂R⁹ and R⁹, R¹¹, and Ar are as hereinbefore defined with a fluorinating agent to form the corresponding compound wherein R¹² is CHFCO2R⁹, and thereafter optionally : º converting the group OR¹¹ into OH º converting the group A⁰CO₂R⁹ into A⁰CO₂H; or b) for compounds wherein R¹ is CH₂CO₂H,

converting a compound of the formula (6) :

wherein R¹³ is acetyl and Ar is as hereinbefore defined into the corresponding compound wherein R¹³ is CH₂CO₂H; or c) for compounds wherein R¹ is CH(OR⁴)CO₂H reacting a compound of the formula (4) wherein R¹² is -CH(OH)CN with a C_1-3alkylating agent and/or converting the group CN into CO₂H, and optionally converting the group OR¹¹ into OH; or d) for compounds wherein R¹ is P (O) (OH) (OR²),

hydrolysing a compound of the formula (6) wherein R¹³ is P (O) (OR²)₂ and R², and Ar are as hereinbefore defined; or e) for compounds wherein R¹ is P(S) (OH) (OR²), converting a compound of the formula (6) wherein R¹³ is P (O) (NHR¹⁴) (OR²) and R¹⁴ is phenyl or C_1-4alkyl and Ar is as hereinbefore defined into the corresponding compound wherein R¹³ is

P(S) (OH) (OR²); or f) for compounds where R¹ 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 OR¹¹ into OH; or g) for compounds wherein R¹ 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 OR¹¹ into OH; or h) for compounds wherein R¹ is 5-tetrazolyl, reacting a compound of the formula (4) wherein R¹² is cyano or a compound of the formula (6) wherein R¹³ is cyano with an azide salt and thereafter if necessary converting the group OR¹¹ into OH; or i) for compounds wherein R¹ 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^b is a group R¹ as hereinbefore defined or a

precursor thereof and R^a is a group R⁰ as hereinbefore defined or a precursor thereof 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 R¹ into R¹ and/or converting a precursor of R⁰ into R⁰, and optionally thereafter :

° forming a bioprecursor of R⁰ and/or R¹

° 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_{1 - 4}alkyl 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 C_1-4alkyl 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 R¹² is CR³(OH)CO₂R⁹ or COCO₂R⁹ 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 R¹² is CR³(OH)CO₂R⁹ is suitably reacted with a Cι_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 R¹² is CR³ (OC_1-3alkyl) CO₂R⁹. When potassium

hydroxide is used as base the CO₂R⁹ group may be directly converted to carboxy. A compound of the formula (4) wherein R¹² is COCO₂R⁹ is suitably reacted with a reducing agent such as sodium borohydride, or diisobutylaluminium hydride in an organic solvent such as dichloromethane, a C_1-4alcohol 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 R¹² is

CH(OH) CO₂R⁹. A compound of the formula (4) wherein R¹² is COCO₂H or

COCO₂R⁹ 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 R¹² is CH₂CO₂H. Under these reaction conditions the CO₂R⁹ group is converted to carboxy.

A compound of the formula (4) wherein R¹² is COCO₂R⁹ is suitably reacted with a C_1-3alcohol, 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 R¹² is C(OR⁵) (OR⁶)CO₂R⁹.

A compound of the formula (4) wherein R¹² is COCO₂R⁹ or

CHOHCO₂R⁹ 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 R¹² is CF₂CO₂R⁹ or CHFCO₂R⁹ respectively. Examples of O-protecting groups for R¹¹ include methyl or benzyl. A compound of the formula (4) wherein OR¹¹ is

methoxy can suitably be converted to the corresponding

compound wherein OR¹¹ 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 R¹ is A⁰CO₂R⁹ since the ester-forming group R⁹ 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 R¹ is A⁰CO₂H. Alternatively a compound of the formula (4) wherein OR¹¹ is benzyloxy can be converted to the corresponding compound wherein OR¹¹ is hydroxy in conventional manner, for example catalytic

hydrogenation on palladium on carbon or reacting with sodium in liquid ammonia.

A compound of the formula (4) wherein R¹² is A⁰CO₂R⁹ can suitably be converted to the corresponding compound wherein R¹² is A⁰CO₂H 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 R⁰ is methoxy since the OR¹¹ 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 R⁰ is hydroxy and R¹ is A⁰CO₂H.

Suitably a compound of the formula (6) wherein R¹³ is acetyl is converted to the corresponding compound where R¹³ 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 of the reaction mixture.

Suitably a compound of formula (4) where R¹² is -CH(OH)CN is reacted with a C_1-3alkylating agent as hereinbefore described followed by reaction with aqueous mineral acid such as hydrochloric acid at ambient or elevated temperature, preferably at reflux in order to prepare the corresponding compound where R¹² is CH(OC_1-3alkyl) CO₂H. The alkylation can be omitted if the corresponding compound where R¹² is CH(OH)CO₂H is desired. During the hydrolysis of the CN group the OR¹¹ 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 R¹² is -CH(OH)CN can be prepared by reacting the corresponding compound wherein R¹² 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 R¹² or R¹³ is CHO is suitably prepared by reacting the corresponding compound wherein R¹² or R¹³ is cyano with a suitable reducing agent such as diisobutylaluminium hydride followed by aqueous acidic work-up.

Suitably a compound of the formula (6) wherein R¹³ is

P(O) (OR²)₂ is hydrolysed by reaction with an aqueous base such as sodium hydroxide optionally in a cosolvent such as a C_1-4alcohol 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 R¹³ is

P (O) (NHR¹⁴) (OR²) is converted to the corresponding compound wherein R⁹ is P (S) (OH) (OR²) 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 R¹² is SO₃H or SO₂H respectively and OR¹¹ is as hereinbefore defined which if desired can be converted to the corresponding compound wherein OR¹¹ is hydroxy as hereinbefore described.

A compound of the formula (4) wherein R¹² is cyano or a compound of the formula (6) wherein R¹³ is cyano is suitably reacted with an azide salt such as ammonium, sodium or aluminium azide in an organic solvent such as dimethylformamide, dimethylsulphoxide, N-methylpyrrolidone or

tetrahydrofuran at an elevated temperature e.g. 40-200°C, preferably at 100-150°C to form the corresponding

5-tetrazolyl compound. Preferably in a compound of the formula (4) OR¹¹ is benzyloxy since this group is converted directly to hydroxy under the reaction conditions.

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 L¹ is halo for example iodo, bromo or chloro, preferably L¹ is a trifluoromethanesulphonate. Examples of palladium catalysts that can be used include: tetrakis(triphenylphosphine)palladium (Pd[PPh₃]₄),

bis(triphenylphosphine)palladium dichloride (Pd[PPh₃]₂CI₂), [1,4-bis-(diphenylphosphine)butane]palladium dichloride

(Pd(dppb)Cl₂),

[1,3-bis-(diphenylphosphine)propane]palladium dichloride

(Pd(dppp)Cl₂),

[1,2-bis-(diphenylphosphine)ethane]palladium dichloride

(Pd(dppe)Cl₂),

is (tri-o-tolylphosphine) palladium diacetate or dichloride

(Pd (totp) (OAc) ₂ or Pd (totp) Cl₂) , or 1,1 -bis(diphenylphosphine)ferrocinopalladium diacetate or dichloride (PdCdppf] (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. Me₃SnCl). Alternatively the aryl halide can be reacted with Me3SnSnMe3 in the

presence of a palladium catalyst as hereinbefore described to prepare a suitable aryl stannane. When R^a is a group R⁰ as hereinbefore defined and R^b is a group R¹ 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 R¹ is when R^b is hydrogen.

Examples of a precursor for R⁰ is when R^a is halo, such as chloro, which can be converted to another precursor OR¹¹, such as methoxy or benzyloxy by reaction with either sodium methoxide or benzyl alcohol and a base such as potassium tert butoxide preferably in the presence of a crown ether such as 18-crown-6 or 15-crown-5. Preferably a compound of the formula (7) wherein R^a is chloro, R^b is hydrogen and L¹ is trifluoromethane sulphonate is reacted with a compound of the formula (8) or a chemical equivalent thereof, followed by conversion of R^a being chloro to R^a being OR¹¹ to form a compound of the formula (2). Such a compound can then be converted into a compound of the formula (1) as herein

described. Other precursors for R¹ include CN, CHO or COMe. Reaction of a compound of the formula (7) wherein R^b represents such a precursor and R^a is OH or OR¹¹ 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 R¹² or R¹³ 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 R¹ is A⁰CO₂ can be converted to the corresponding compound wherein R¹ is A⁰CO₂R⁹ by reaction with a compound R⁹OH wherein R⁹ 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 R⁸L² wherein R⁸ is as hereinbefore defined an L² is a leaving group such as halo e.g. bromo, chloro, iodo.

If desired a compound of the formula (1) wherein R¹ is

P (Z) (OR²) (OH) can be converted to the corresponding compound wherein R¹ is P(Z) (OR²) (OR¹⁰) 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 R¹ is 5-tetrazole can be reacted with a suitable N-protecting agent in standard manner, for example with a pivalolyloxymethyl halide.

A compound of the formula (1) wherein R¹-R⁰ is A¹C_O2 is suitably prepared by heating a compound of the formula (1) wherein R¹ is A¹CO₂H and R⁰ 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 R¹-R⁰ is A²OCH₂O is suitably prepared by reacting a compound of the formula (1) wherein R¹ is A²OH and R⁰ 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 R¹³ 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 or with an O-benzylating agent such as benzyl bromide or chloride in the presence of a base such as

potassium carbonate or sodium hydride. This method can also be used for converting compounds of the formula (6) into corresponding compounds of the formula (4) and compounds of the formula (7) where R^a is hydroxy to corresponding

compounds wherein R^a is OR¹¹.

A compound of the formula (6) wherein R¹³ is acetyl can also be prepared by reacting a compound of the formula (6) wherein R¹³ is cyano with methyl lithium followed by aqueous acidic work up with for example hydrochloric acid.

A compound of the formula (6) wherein R¹³ is hydrogen can be prepared by reacting a compound of the formula (6) wherein R¹³ is cyano with orthophosphoric acid at an elevated

temperature, e.g. 50 - 200°C.

A compound of the formula (6) wherein R¹³ is cyano or acetyl and Ar is as hereinbefore defined can be suitably prepared by reaction of a compound of formula (4) wherein R¹² is cyano or acetyl and R¹¹ and Ar are as hereinbefore defined with a demethylating agent or debenzylating agent as hereinbefore described. A compound of formula (4) wherein R¹² is cyano is suitably prepared by reacting the anion of a compound of formula (2) wherein Ar and R¹¹ 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 R¹² 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 (4) where R¹² is cyano is more suitably prepared by reacting a compound of the formula (9)

wherein Ar and R¹¹ are as hereinbefore defined with a dimethyl carbamoyl halide such as the chloride folowed by reaction with trimethylsilylcyanide, conveniently at ambient temperature in a solvent such as dichloromethane.

A compound of the formula (9) is suitably prepared by reacting a compound of the formula (2) with an oxidising agent such as metachloroperbenzoic acid in an organic solvent such as dichloromethane.

A compound of the formula (6) wherein R¹³ is P (O) (OR²)₂ can be prepared by treating a compound of the formula (2) wherein RH is P (O) (OR²)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 R¹¹ is P (O) (OR²)₂ is suitably prepared by treating a compound of the formula (6) wherein R¹³ is hydrogen with a compound of the formula (10):

L³P(0) (OR²)2 (10) wherein L³ is a leaving group and R² is as hereinbefore defined with a base such as diisopropylethylamine.

Suitably L³ is halo, for example chloro or bromo. A compound of formula (2) wherein R¹¹ is P (O) (OR²)₂ can also be prepared by treating a compound of the formula (6) wherein R¹³ is hydrogen with a compound of the formula (11): HP(O) (OR²)₂ (11) wherein R² 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 R¹³ is P (O) (OR²)₂ is suitably prepared by treating a compound of the formula (6) wherein R¹³ is hydrogen with a compound of the formula (10) 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 R¹¹ is P (O) (OR²)₂.

A compound of formula (6) wherein R¹³ is hydrogen is suitably prepared by demethylating or debenzylating a compound of formula (2) as hereinbefore defined. Suitably a compound of formula (2) wherein OR¹¹ is methoxy 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 R¹³ is P (O) (NHR¹⁴) (OR²) can be prepared by reaction of a compound of the formula (6) wherein R¹³ is P (O) (OH) (OR²) with carbon tetrachloride, triphenylphosphine and aniline or a Cι_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 R¹³ is P (O) (OH) (OR²) 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_1-4alkylamine preferably with cooling (-10 to 5°C).

Compounds of the formula (7) are known or can be prepared in standard manner for example from a compound of the formula (12):

wherein R^a and L¹ 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^b is P (O) (OR²)₂ can be prepared by reacting a compound of the formula (12) wherein R^a is OH with a compound of the formula (10) or (11) in similar manner to the reaction of a compound of the formula (6) wherein R¹³ is hydrogen with a compound of the formula (10) or (11). If desired the group R^a can then be converted to OR¹¹ as hereinbefore described.

Similarly, a compound of the formula (12) where R^a is OR¹¹ 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 PP is

CR³(OR⁴)CO₂R⁹, COCO₂R⁹, SO₃H, SO₂H 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 (12) wherein R^a is chloro and L¹ is trifluoromethanesulphonate is suitably prepared by reacting 3-chloro-5-hydroxy pyridine with trifluoromethane sulphonic anhydride in the presence of a suitable base, e.g. 4-N,N- dimethylaminopyridine in an organic solvent such as

dichloromethane. A compound of the formula (8) is suitably prepared by

reacting the organolithium or Grignard reagent, formed from a compound of the formula (13):

Ar-L⁴ (13) wherein L⁴ is bromo or iodo and Ar is as hereinbefore defined with a tri-C_1-4alkylborate 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) or (13) preferably (2) or (4) 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

C_1-6alkoxy) 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 NHCOR⁷ group by reaction with LCOR⁷ wherein L is a leaving group and R⁷ 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 OCOR⁷).

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 C_1-6alkyl halide to form a C_1-6alkoxy 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. 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 suc as osmium tetroxide to form a 1,2,dihydroxypropyl group whic on reaction with an oxidising agent such as sodium periodate forms the formyl group. Alternatively the E-1-propenyl grou 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 C_1-6alkyl halide to form a C_1-6alkoxymethyl group. Alternatively a formyl group can be reacted with a suitable Horner Wittig or Wittig reagent such as (R¹⁵O)₂P (O) CH₂CO₂R¹⁵ or Ph₃P=CHCO₂R¹⁵ wherein R¹⁵ is C_1-4alkyl to form a CH=CHCO₂R¹⁵ group which can be optionally hydrolysed to a -CH=CHCO₂H group. A -CH=CHCO₂R¹⁵ group can be converted to a -CH=CHC0N(R⁷) ₂ group by reaction with an amine HN(R⁷)₂ or a chemical equivalent thereof wherein R⁷ is as hereinbefore defined. Alternatively a

-CH=CHCO₂H 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(R⁷)₂ or a chemical

equivalent thereof. An example of a chemical equivalent is ammonium hydroxide which will form a CH=CHCONH₂ 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-³²P]-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 [³²P]-phosphoρeptide quantified by spotting the reaction mixture onto

phosphocellulose papers. The concentration of compound required to give 10% phosphotransferase activation is given as the EC₁₀ (μM). The compounds of Examples 1 to 3 had EC₁₀ values in the range 1.8 to 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 and adjusted to a concentration of 1.5×10⁸ 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 3 had IC₅₀ values in the range 6 to 109 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 recording and display of 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 caused 50% inhibition of the spontaneous contraction is given as the EC₅₀ (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). The compound of Example 1 had a IC₅₀ value of 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 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 cardiomyopathy.

Example 1

Ethyl [5-(2-Naphthyl)-3-hydroxy-2-pyridyl]phosphonate

(a) To an ice cooled solution of 3-chloro-5-hydroxypyridine (4.95g) and 4-N,N-dimethylaminopyridine (14g) in

dichloromethane (300mls), trifluoromethanesulphonic anhydride (10g) was added over 30 minutes. When the addition was complete the mixture was stirred for a further 2 hours and poured into 1M hydrochloric acid (300ml). The organic phase was separated, washed with water (2 × 100ml), dried (MgSO₄) and solvent removed at reduced pressure to give 3-chloro-5trifluoromethanesulphonyloxypyridine (8.9g) as an oil that solidified on standing. ¹H NMR δ (CDCI₃) 7.69(m, 1H),

8.52 (m,1H) and 8.65 (m, 1H).

(b) From 2-naphthylboronic acid (2.33g) and 3-chloro-5- trifluoromethanesulphonyloxypyridine (3.4g), 3-chloro-5-(2- naphthyl)pyridine (2.5g) was prepared according to the method of A. Huth, I. Beetz and I. Schumann, Tetrahedron, 1989, 45, 6679. ¹H NMR δ (CDCI₃) 7.52-7.57 (m, 2H), 7.68(dd,1H), 7.84- 8.04(m,5H), 8.58(m,1H) and 8.85 (d, 1H).

(c) A mixture of 3-chloro-5-(2-naphthyl)pyridine (2.0g) and sodium methoxide in dimethylformamide (50ml) was heated at 130°C for 3.5 hours. The mixture was poured onto ice, stirred vigorously for one hour and extracted with diethyl ether

(200ml). The ether extract was washed with water (4 × 100ml), dried (MgSO₄) and solvent removed at reduced pressure. The residue was column chromatographed (silica gel,

dichloromethane eluant) to give 3-methoxy-5-(2-naphthyl)pyridine (1.2g). ¹H NMR δ (CDCI₃) 4.12(s,3H), 7.51-7.62(m,3H), 7.82-8.04 (m, 5H), 8.19(dd,1H) and 8.53 (s, 1H).

(d) A solution of 3-methoxy-5-(2-naphthyl)pyridine (2.07g) in a mixture of acetic acid/hydrobromic acid (250ml, 2:3) was boiled for 65 hours. After cooling to room temperature

solvent was removed at reduced pressure and the residue triturated with water (100ml) to give 3-hydroxy-5-(2- naphthyl)pyridine (1.75g) ¹H NMR δ (DMSO-d₆) 7.50-7.58 (m,3H), 7.86(d,1H), 7.95-8.08 (m,3H), 8.17(d,1H), 8.28(s,1H),

8.52 (d, 1H) and 10.15 (br. s, 1H).

(e) To a solution of 3-hydroxy-5-(2-naphthyl)pyridine (1.75g) in tetrahydrofuran (30ml), lithium diisopropylamide (prepared from n-butyl lithium 3.8mls of 2.5M solution in hexane and diisopropylamine 0.81g) was added at -78°C. When the addition was complete the reaction mixture was warmed to room

temperature stirred for 90 minutes, recooled to -78°C and treated with diethyl chlorophosphate (1.38g). The mixture was warmed to room temperature stirred for 15 minutes recooled to -78°C and treated with additional lithium diisopropylamide (from n-butyl lithium 3.8mls Of 2.5M in hexane and

diisopropylamine 0.81g). After stirring at -78°C for 15 minutes and at room temperature for 20 minutes the reaction mixture was poured into a mixture of ice (100g) and cone, hydrochloric acid (15ml) and stirred overnight.

Tetrahydrofuran was removed at reduced pressure and the aqueous residue extracted with dichloromethane (2 × 100ml). The combined organic extracts were washed with water (2 × 100ml) dried (MgSO₄) and solvent removed at reduced pressure. The residual oil was column chromatographed (silica gel, dichloromethane followed by diethyl ether followed by ethyl acetate/ethanol 4:1 eluant) to give diethyl [3-hydroxy-5-(2- naphthyl)-2-pyridyl]phosphonate (1.86g). ¹H NMR δ (CDCI₃)

1.39(t,6H), 4.15-4.37 (m,4H), 7.53-7.62 (m,3H), 7.71(dd,1H), 7.87-7.95 (m,3H), 8.08(s,1H) and 8.69 (d, 1H). e) A mixture of diethyl [3-hydroxy-5-(2-naphthyl)-2-pyridyl]phosphonate (0.2g) and sodium hydroxide (0.5g) in water/ethanol (11ml, 10:1) was boiled for 12 hours. The solvent was removed at reduced pressure, the residue

dissolved in water (3ml) and acidified with cone,

hydrochloric acid (15ml). The precipitated material was

collected by filtration and recrystallised from ethanol to give the title compound (0.15g) m.p. 252-254°C. ¹H NMR δ

(DMSO-d₆) 1.15 (t,3H), 3.83-3.96 (m,2H), 7.56-7.62 (m,2H), 7.98-8.11(m,3H), 8.19(m,1H), 8.50(s,1H) and 8.73 (s, 1H). Example 2

5-(2,4-Dipropoxyphenyl)-2-(5-tetrazolyl)pyridin-3-ol a) A mixture of 4-bromoresorcinol (25g) potassium carbonate and iodopropane in dimethylformamide was heated in

dimethylformamide at 90° for 18 hours. Solvent was removed at reduced pressure the residue triturated with diethyl ether, filtered, the filtrate adsorbed onto silica gel and column chromatographed (silica gel, petroleum ether/diethyl ether 9:1 eluant) to give l-bromo-2, 4-dipropoxybenzene (11g). ¹H NMR δ (CDCl₃) 1.03(t,3H), 1.06(t,3H), 1.71-1.94 (m, 4H),

3.89(q,2H), 3.92(q,2H), 6.37(dd,1H), 6.46(d,1H) and

7.37 (d, 1H). b) From 2,4-dipropoxyphenyl lithium [prepared by addition of 1-bromo-2,4-dipropoxy-benzene (11.0g) to tert-butyl lithium (48 mis of 1.7M in pentane], (2,4-dipropoxyphenyl)boronic acid (6.1g) was prepared according to the method of

W.J.Thompson and J.Gaudino J. Org. Chem., 1984, 49, 5237. ¹H NMR δ (CDCI₃) 1.14(t,3H), 1.16(t,3H), 1.84-2.04 (m, 4H),

4.06(q,2H), 4.19(q,2H), 6.55 (d,1H), 6.66(dd,1H) and

7.85(d,1H). c) From (2, 4-dipropoxyphenyl)boronic acid (5.0g) and 3- chloro-5-trifluoromethanesulphonyloxypyridine (5.5g), 3-chloro-5-(2,4-dipropoxyphenyl)pyridine (6.47g) was prepared according to the method of Example 1(b). ¹H NMR δ (CDCI₃) 0.99(t,3H), 1.06(t,3H), 1.72-1.89 (m, 4H), 3.93(t,2H),

3.96(q,2H), 6.55-6.59 (m, 2H) , 7.26(d,1H), 7.87(m,1H),

8.45 (d,1H) and 8.62 (d,1H). d) 3-Chloro-5-(2,4-dipropoxyphenyl)pyridine (3.9g), benzyl alcohol (20.0g), potassium tertbutoxide (4.0g) and 18-crown-6 (0.1g) were combined in N-methylpyrrolidinone (20mls) and heated at 130 °C for 48 hours. The mixture was poured into a mixture of ice (100g) and cone, hydrochloric acid (10ml) and extracted with dichloromethane (3 × 100ml). The combined organic extracts were dried (MgSO₄) and solvent removed at reduced pressure. The residue was column chromatographed

(silica gel, petroleum ether/diethyl ether 4:1 eluant) to give 3-benzyloxy-5-(2,4-dipropoxyphenyl)pyridine (1.6g). ¹H NMR δ (CDCI₃) 0.97(t,3H), 1.06(t,3H), 1.65-1.91 (m, 4H),

3.91(t,2H), 3.95 (t,2H), 5.13 (s,2H), 6.51-6.57 (m, 2H), 7.26- 7.49(m,7H), 8.27(d,1H) and 8.37 (d, 1H). e) 3-Chloroperbenzoic acid (2.0g) was added to a solution of 3-benzyloxy-5-(2,4-dipropoxyρhenyl)pyridine (1.6g) and the mixture was stirred for 3 hours. Solvent was removed at reduced pressure and the residue column chromatographed (silica gel, dichloromethane/petroleum etherl:! eluant) to give 3-benzyloxy-5-(2,4-dipropoxyphenyl)pyridine-N-oxide (1.6g). ¹H NMR δ (CDCI₃) 0.99(t,3H), 1.06(t,3H), 1.74- 1.87(m,4H), 3.93(t,2H), 3.95(t,2H), 5.09(s,2H), 6.52- 6.59(m,2H), 7.16-7.20 (m,2H), 7.40(s,5H), 7.96(s,1H) and 8.13 (S,1H). f) From 3-benzyloxy-5-(2,4-diρropoxyphenyl)pyridine-N-oxide (1.6g), 3-benzyloxy-2-cyano-5-(2,4-dipropoxyphenyl)pyridine (0.8g) was prepared according to the method of W. K. Fife, Heterocycles, 1984, 22, 93. ¹H NMR δ (CDCI₃) 0.97 (t,3H), 1.06(t,3H), 1.68-1.91 (m,4H), 3.92(t,2H), 3.96(t,2H),

5.25(s,2H), 6.55(s,1H), 6.56(dd,1H), 7.20(d,1H), 7.33- 7.46(m,5H), 7.59(d,1H) and 8.44 (d, 1H). g) A mixture of 3-benzyloxy-2-cyano-5-(2,4- dipropoxyphenyl)pyridine (0.8g), sodium azide (0.54g) and ammonium chloride (1.0g) were heated together in N-methylpyrrolidinone (15ml) at 190°C for 6 hours. Solvent was removed at reduced pressure and the residue triturated with water. The crude product was collected by filtration and chromatographed (C₁₈ reverse phase silica gel,

acetonitrile/0.1% aqueous trifluoroacetie acid 3:2 eluant) to give the title compound (0.13g) m.p. 179-180°C. ¹H NMR δ (DMSO-d₆) 0.95(t,3H), 1.00(t,3H), 1.67-1.84 (m, 4H), 3.99 (t,4H) 6.58-6.68(m,2H), 7.47(d,1H), 7.64(s,1H) and 8.44 (s, 1H). Example 3

5-(4-Methoxy-3-propoxyphenyl)-3-(5-tetrazolyl)pyridin-3-ol a) From 3-hydroxy-4-methoxy-nitrobenzene (25g), 4-methoxy-1- nitro-3-propoxybenzene (31g) was prepared according to the method of Example 2(a). ¹H NMR δ (CDCI₃) 1.07 (t, 3H), 1.82- 1.97(m,2H), 3.97(s,3H), 4.05(t,2H), 6.91(d,1H), 7.74(d,1H) and 7.90 (dd, 1H).

(b) A solution of 4-methoxy-1-nitro-3-propoxybenzene (20g) in acetic acid (150ml) containing 10% palladium on charcoal (2g) was heated at 80°C under an atmosphere of hydrogen (60p.s.i) with shaking for 4 hours. The reaction mixture was filtered under nitrogen into 50% sulphuric acid (300ml) cooled to 0°C and treated with an aqueous solution of sodium nitrite (6.9g in 20ml water) at such a rate that the temperature did not rise above 5°C. When the addition was complete the mixture was stirred for a further 2 hours at 0°C and then poured into a solution of potassium iodide (200g) iodine (40g) and urea (1g) in water (300ml). Dichloromethane (300ml) was added and the mixture stirred vigorously at room temperature until gas evolution ceased (3 hours. Sodium metabisulphite (20g) was added, the organic phase was separated washed with water (2 × 100ml), dried (MgSO₄) and solvent removed at reduced

pressure. The residue was column chromatographed (silica gel petroleum ether/dichloromethane 1:1 eluant) to give 1-iodo-4-methoxy-3-propoxybenzene (17g) ¹H NMR δ (CDCI₃) 1.03(t,3H), 1.77-1.95 (m, 2H) , 3.83(s,3H), 3.93(t,2H), 6.61(d,1H),

7.11 (d,1H) and 7.19 (dd, 1H).

(c) From 1-iodo-4-methoxy-3-propoxybenzene (16.9g), (4-methoxy-3-propoxyphenyl)boronic acid (10.0g) was prepared according to the method of Example 2 (b). ¹H NMR δ (DMSO-d₆) 0.98(t,3H), 1.65-1.79(m,2H), 3.76(s,3H), 3.89(t,2H),

6.91(d,1H), 7.32-7.37 (m,2H) and 7.86 (br.s, 2H).

(d) From (4-methoxy-3-propoxyphenyl)boronic acid (10.0g) and 3-chloro-5-trifluoromethanesulphonyloxypyridine (12.6g), 3- chloro-5-(4-methoxy-3-propoxyphenyl)pyridine (11.0g) was prepared according to the method of Example 1 (b). ¹H NMR δ (CDCl₃) 1.07 (t,3H), 1.83-1.99 (m,2H), 3.92 (s,3H), 4.05 (t,2H), 6.97 (d,1H), 7.06(d,1H), 7.11(dd,1H), 7.81 (m,1H), 8.50 (d,1H) and 8.67 (d, 1H).

(e) From 3-chloro-5-(4-methoxy-3-propoxyphenyl)pyridine

(10.0g}, 3-benzyloxy-5-(4-methoxy-3-propoxyphenyl)pyridine was prepared according to the method of Example 2 (d). The crude material was treated with 3-chloroperbenzoic acid

(10.0g) according to the method of Example 2(e) to give 3- benzyloxy-5-(4-methoxy-3-propoxyphenyl)pyridine-N-oxide

(4.0g) ¹H NMR 1.06 (t,3H), 1.82-1.97 (m,2H), 3.91(s,3H),

4.00(t,2H), 5.13(s,2H), 6.88-7.09 (m, 4H), 7.42(s,5H),

7.98(s,1H) and 8.14 (s,1H).

(f) From 3-benzyloxy-5-(4-methoxy-3-propoxyphenylpyridine-N- oxide (3.8g), 3-benzyloxy-2-cyano-5-(4-methoxy-3- propoxyphenyl)pyridine (2.3g) was prepared according to the method of Example 2(f). ¹H NMR δ (CDCI₃) 1.08 (t, 3H) , 1. 83- 1.98 (m, 2H) , 3.98 (s, 3H) , 4.01(t,2H), 6.94-6.98 (m, 2H),

7.07(dd,1H), 7.38-7.50 (m, 6H) and 8.45 (d, 1H).

(g) From 3-benzyloxy-2-cyano-5- (4-methoxy-3-propoxyphenyl)pyridine (1.55g), the title compound (0.6g) m.p. 229-230°C after reverse phase chromatography (water then 1% aqueous trifluoroacetie acid/acetonitrile 2:3 eluant) was prepared according to the method of Example 2 (g). ¹H NMR 1.01(t,3H), 1.70-1.81 (m,2H), 3.83(s,3H), 4.05(t,2H),

7.10(d,1H), 7.30-7.38(m,2H), 7.77(s,1H) and 8.63(1H). Example 4

Pharmaceutical compositions for oral administration are prepared by combining the following :

% w/w

Ethyl [5-(2-Naphthyl)-3- hydroxy-2-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 5

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

1. A compound of the formula (1) :

or a pharmaceutically acceptable salt thereof, wherein :

R⁰ is OH or a bioprecursor thereof,

R¹ is A⁰CO₂H, P (Z) (OH) (OR².), SO₂H, SO₃H or 5-tetrazolyl or a bioprecursor thereof,

A⁰ is CH₂, CHF, CF₂, CR³ (OR⁴), CO or C(OR⁵) (OR⁶),

R² is phenyl, C_3-5cycloalkyl, C_3-5cycloalkylC_1-4alkyl, or C_1-8alkyl optionally substituted by C_1-4alkoxy,

R³ is H, methyl or ethyl,

R⁴ is H or C_1-3alkyl,

R⁵ and R⁶ are eachC_1-3alkyl or together form a 1,2- ethanediyl group or 1,3-propanediyl group,

Z is O or S, and

Ar is phenyl optionally substituted by one to three groups independently selected from C_1-6alkyl, C_2-6alkenyl,

C_1-6alkoxy, C_1-6alkenyloxy, C_3-6cycloalkyl,

C_3-6cycloalkoxy, C_1-6alkylthio, phenyl, phenylthio, benzyloxy, C^-gpolyfluoroalkyl, C_1-6polyfluoroalkoxy, halo, N(R⁷)2 or NHCOR⁷ wherein R⁷ is H or C_1-6alkyl, or -X(CH₂)_nY- attached to adjacent carbon atoms of the phenyl ring wherein X and Y are independently C_H2 or O and n is 1 to 3, wherein said C_1-6alkyl, C_2-6alkenyl or C_1-6alkoxy groups can be independently substituted by OH, C_1-6alkoxy, C_3-6cycloalkyl, N(R⁷)₂, CO₂R⁷ or CON(R⁷)₂; or

3_phenanthryl, 9-phenanthryl, 2-quinolinyl, 4-quinolinyl, 3-thianaphthenyl or 2-benzofuranyl.

2. A compound according to claim 1 wherein R¹ is

A⁰CO₂H or A⁰CO₂R⁹ in which R⁹ is an ester-forming group.

3. A compound according to claim 1 wherein R¹ is

P(Z) (OH) (OR²) or P(Z) (OR²)₂.

4. A compound according to claim 1 wherein R¹ is SO₂H, SO₃H or 5-tetrazolyl.

5. A compound according to claim 1 wherein Rl and R^ are linked together such that R¹-R⁰ is A¹CO₂

in which A¹ is CH₂, CHF, CF₂, CR³(OR⁴), CO or C(OR⁵) (OR⁶).

6. A compound according to claim 1 wherein R-- and R^ are linked together such that R¹-R⁰ is A²OCH₂O in which A² is P(Z) (OR²) or CR³(CO₂R⁹) and R⁹ is an ester-forming group.

7. A compound according to claim 1 which is : ethyl [5-(2-naphthyl)-3-hydroxy-2-pyridyl]phosphonate, 5-(2,4-dipropoxyphenyl)-2-(5-tetrazolyl)pyridin-3-ol, or 5-(4-methoxy-3-propoxyphenyl)-3-(5-tetrazolyl)pyridin-3-ol, 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 R¹ is A⁰CO₂H or A⁰CO₂R⁹ and : i) A⁰ is CR³ (OR⁴),

reacting in the presence of a strong base a compound of the formula (2) :

wherein R¹¹ is an O-protecting group and Ar is as defined in claim 1, with a compound of the formula (3) :

R³COCO₂R⁹ (3) wherein R³ is as defined in claim 1 and R⁹ is an ester-forming group to form a compound of the formula (4) :

R⁹O₂CCO₂R⁹ (5) wherein R⁹ is as hereinbefore defined to form a compound of the formula (4) wherein R¹² is C0C0₂R⁹ and R⁹, R¹¹ and Ar are as hereinbefore defined, iii) A⁰ is CH(OH) ,

reacting a compound of the formula (4) wherein R¹² is COCO₂H or COCO₂R⁹ and R⁹, R¹¹, and Ar are as hereinbefore defined with a suitable reducing agent to form the corresponding compound wherein R¹² is CH₂CO₂H, v) A⁰ is C(OR⁵) (OR⁶),

C1-3alcohol, 1,2-ethanediol or 1,3-propanediol to form the corresponding compound wherein R¹² is C(OR⁵) (OR⁶)CO₂R⁹, vi) A⁰ is CF2,

reacting a compound of the formula (4) wherein R¹² is COCO₂R⁹ and R⁹, R¹¹, and Ar are as hereinbefore defined with a fluorinating agent to form the corresponding compound wherein R¹¹ is CF₂CO₂R⁹, or vii) A⁰ is CHF,

reacting a compound of the formula (4) wherein R¹² is

CH(OH)CO₂R⁹ and R⁹, R¹¹, and Ar are as hereinbefore defined with a fluorinating agent to form the corresponding compound wherein R¹² is CHFCO₂R⁹, and thereafter optionally : º converting the group OR¹¹ into OH º converting the group A⁰CO₂R⁹ into A⁰CO₂H; or b) for compounds wherein R¹ is CH₂CO₂H,

converting a compound of the formula (6) :

(6)

wherein R¹³ is acetyl and Ar is as hereinbefore defined into the corresponding compound wherein R¹³ is CH₂CO₂H; or c) for compounds wherein R¹ is CH (OR⁴) CO₂H reacting a compound of the formula (4) wherein R12 is -CH(OH)CN with a C_1-3alkylating agent and/or converting the group CN into CO₂H, and optionally converting the group OR¹¹ into OH; or d) for compounds wherein R¹ is P (O) (OH) (OR²), hydrolysing a compound of the formula (6) wherein R¹³ is P (O) (OR²)₂, R² is as defined in claim 1 and Ar is as hereinbefore defined; or e) for compounds wherein R¹ is P(S) (OH) (OR²), converting a compound of the formula (6) wherein R¹³ is P (O) (NHR¹⁴) (OR²) and R14 is phenyl or C_1-4alkyl and Ar is as hereinbefore defined into the corresponding compound wherein R¹³ is P(S) (OH) (OR²); or f) for compounds where R¹ 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 OR¹¹ into OH; or g) for compounds wherein R¹ is SO₂H,

wherein R^b is a group R¹ as defined in claim 1 or a precursor thereof and R^a is a group R⁰ or as defined in claim 1 or a precursor thereof and L¹ 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 R¹ into R¹ and/or converting a precursor of R⁰ into OH, and optionally thereafter : º forming a bioprecursor of R⁰ and/or R¹ º forming a pharmaceutically acceptable salt.