WO1992006085A1 - Phenylpyridinol derivatives as medicaments - Google Patents

Phenylpyridinol derivatives as medicaments Download PDF

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Publication number
WO1992006085A1
WO1992006085A1 PCT/GB1991/001663 GB9101663W WO9206085A1 WO 1992006085 A1 WO1992006085 A1 WO 1992006085A1 GB 9101663 W GB9101663 W GB 9101663W WO 9206085 A1 WO9206085 A1 WO 9206085A1
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WIPO (PCT)
Prior art keywords
pyridin
tetrazolyl
methoxy
phenyl
cyano
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PCT/GB1991/001663
Other languages
French (fr)
Inventor
Roderick Alan Porter
Kenneth John Murray
Brian Herbert Warrington
Hunter Douglas Prain
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Smith Kline & French Laboratories Limited
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Publication date
Priority claimed from GB909021184A external-priority patent/GB9021184D0/en
Priority claimed from GB919117657A external-priority patent/GB9117657D0/en
Application filed by Smith Kline & French Laboratories Limited filed Critical Smith Kline & French Laboratories Limited
Publication of WO1992006085A1 publication Critical patent/WO1992006085A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/64—One oxygen atom attached in position 2 or 6
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/04—Drugs for genital or sexual disorders; Contraceptives for inducing labour or abortion; Uterotonics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/06—Antiarrhythmics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/84—Nitriles
    • C07D213/85—Nitriles in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to pyridinol
  • 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
  • cardiovascular diseases such as congestive heart-failure, cancer,
  • the present invention provides compounds of the formula (1) :
  • R 0 is OH or a bioprecursor thereof
  • R 1 is 5-tetrazolyl or a bioprecursor thereof
  • Ar is phenyl substituted by one to three groups independentl selected from C 1-6 alkyl, C 2-6 alkenyl, C 1-6 alkoxy,
  • R is H or C 1-6 alkyl, or -X(CH 2 ) n Y- attached to adjacent carbon atoms of the phenyl ring wherein and Y are independently CH 2 or O and n is 1 to 3, wherein said C 1-6 alkyl, C 2-6 alkenyl or C 1-6 alkoxy groups can be independently substituted by OH, C 1-6 alkoxy,
  • Ar is not phenyl monosubstituted by 2-C 1-6 alkoxy.
  • Bioprecursors of the group R 0 are derivatives thereof which are convertible in vivo into the group R 0 .
  • a suitable bioprecursor of the group R 0 is OR 2 wherein R 2 is C 1-4 alkyl, arylC 1-4 alkyl (for example phenylC 1-4 - alkyl such as benzyl), C 1-4 alkanoyl (for example acetyl), arylC 1-4 alkanoyl (for example phenyl C 1-4 alkanoyl such as benzoyl), arylsulphonyl (for example optionally substituted phenylsulphonyl or toluenesulphonyl) or C 1-4 alkylsulphonyl (for example methylsulphonyl).
  • arylC 1-4 alkyl for example phenylC 1-4 - alkyl such as benzyl
  • C 1-4 alkanoyl for example acetyl
  • arylC 1-4 alkanoyl for example phenyl C 1-4 alkanoyl such as benzoyl
  • R 0 is hydroxy or OR 2 , preferably hydroxy.
  • a suitable bioprecursor of R 1 is a N-protected
  • N-protecting groups include pivalolyoxymethyl, propionyloxymethyl and
  • alkyl is meant both straight- and branchedchain alkyl.
  • C 1-6 polyfluoroalkyl is meant a C 1-6 alkyl group having at least one hydrogen replaced with fluoro eg. CF 3 , or CF 2 CF 2 H.
  • Ar is phenyl mono-substituted by a group as hereinbefore defined, for example in the 2,3, or 4
  • Ar is phenyl di-substituted by any groups as hereinbefore defined, for example in the
  • 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 2-6 alkenyl, C 1-6 alkoxy or halo.
  • C 1-6 alkoxy examples include methoxy, ethoxy,
  • C 1-6 alkyl examples include methyl, ethyl,
  • halo examples include fluoro, chloro, bromo or iodo, preferably chloro or bromo.
  • Particular compounds of this invention include : 6-(3-methoxyphenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one,
  • 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,
  • 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.
  • a liquid carrier for example, ethanol, glycerine or water with a flavouring or colouring agent.
  • any pharmaceutical carrier routinely used for preparing solid formulations may be used. Examples of such carriers include starch, celluloses, lactose, sucrose and magnesium stearate.
  • 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.
  • composition is in the form of a soft gelatin shell capsule, any pharmaceutical carrier routinely used for preparing dispersions or suspensions may be
  • 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 2-pyrrolidone, cyclodextrin, arachis oil, or sesame oil.
  • a typical suppository formulation comprises a
  • a binding and/or lubricating agent for example polymeric glycols, gelatins, cocoa-butter or other low melting vegetable waxes or fats or their synthetic
  • transdermal formulations comprise a
  • 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.
  • a conventional propellant such as dichlorodifluoromethane or trichlorofluoromethane
  • 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 (l) 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
  • 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
  • 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
  • H 1 -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
  • retinoids for example retinoids, anthralin, anti-inflammatories for example cortiscosteroids,
  • non-steroid anti-inflammatories such as aspirin,
  • antithrombotics for example dipyridamole, or fibrinolytic agents.
  • the present invention provides a process for the preparation of compounds of the formula (1) or pharmaceutically acceptable salts thereof, which
  • process comprises reacting a compound of the formula (2) :
  • a compound of the formula (2) is suitably reacted with an azide salt such as ammonium, sodium, potassium or aluminium azide in an organic solvent such as
  • dimethyIformamide, dimethylsulphoxide, N-methyl- pyrrolidone or tetrahydrofuran at an elevated temperatur e.g. 40 - 200°C, preferably at the reflux temperature of the reaction mixture.
  • a compound of the formula (1) wherein R 0 is OH can be converted to the corresponding compound where R 0 is OR 2 by reaction with R 2 L wherein R 2 is as
  • L is a leaving group such as halo e.g. bromo, chloro, iodo.
  • a compound of the formula (1) can be converted to a N-protected tetrazolyl derivative by reaction with a suitable N-protecting agent in standard manner, for example with a pivalolyoxymethyl halide.
  • L 1 in a compound of the formula (3) is hydroxy or a derivative thereof for example L 1 is
  • protected hydroxy such as silyloxy, an acid residue (for example C 1-6 alkanoyloxy) or an ether residue (for
  • L 1 is a secondary amino group, for example di-C 1-6 alkylamino such as dimethylamino or a cyclic amino group such as piperidino, pyrrolidino or morpholino.
  • L 1 is hydroxy or dimethylamino.
  • an alkali metal (e.g. sodium) salt of a compound of the formula (3) wherein L 1 is hydroxy is treated with a compound of the formula (4) under mildly alkaline aqueous conditions, for example in water in the presence of piperidine and glacial acetic acid, at an elevated temperature e.g. 30 - 200°C, preferably at the reflux temperature of the reaction mixture.
  • a compound of the formula (4) under mildly alkaline aqueous conditions, for example in water in the presence of piperidine and glacial acetic acid, at an elevated temperature e.g. 30 - 200°C, preferably at the reflux temperature of the reaction mixture.
  • dimethylamino is treated with a compound of the formula (4) in a suitable solvent such as dimethylformamide, a C 1-4 alkanol 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.
  • a suitable solvent such as dimethylformamide, a C 1-4 alkanol or pyridine
  • a base such as pyridine or an alkali metal alkoxide, e.g. sodium methoxide.
  • L 2 is ethoxy or methoxy.
  • a solution of a compound of the formula (5) and a compound of the formula HCOL 2 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.
  • a suitable base such as an alkali metal alkoxide, e.g. sodium methoxide at ambient temperature.
  • secondary amino group (e.g. dimethylamino) can suitably be prepared by reacting a compound of the formula (5) with a compound of the formula HC(OR 3 ) 2 L 1 wherein R 3 is
  • L 1 is a secondary amino group (for
  • HC(OR 3 ) 2 L 1 is N,N-dimethylformamide dimethyl or diethyl acetal), or with a compound of the formula HCL where
  • L 1 is a secondary amm. o group (for example HCL 1 3 is
  • Suitable demethylating agents include sodium iodide and chlorotrimethylsilane in an organic solvent such as acetonitrile, or a halohydrocarbon eg. dichloromethane or chloroform at elevated (eg. 30-80°C) or ambient
  • 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 1-6 alkoxy) by reaction with a brominating agent such as N-bromosuccinimide or bromine in a solvent such as dimethyIformamide.
  • a nitro group can be introduced into a phenyl ring by reaction with a suitable nitrating agent, such as nitroniumtetrafluoroborate.
  • Such a group can be readily hydrogenated to an amino group which if desired can be converted to a NHCOR group by reaction with LCOR wherein L is a leaving group and R is as hereinbefore defined.
  • Suitable examples of the reagent LCOR include acid halides (L is halo eg. chloro or bromo) or acid anhydrides (L is OCOR).
  • Other suitable functionalisations include the introduction of an allyl group ortho to a hydroxy
  • allyl halide eg. bromide
  • the hydroxy group can in turn be functionalised, eg. by reaction with a C 1-6 alkyl halide to form a C 1-6 alkoxy group.
  • 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 (5) to a compound of formula (2) 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.
  • an oxidising agent such as N-methylmorpholine-N-oxide
  • a catalyst such as osmium tetroxide
  • 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 C 1-6 alkyl halide to form a C 1-6 alkoxymethyl group.
  • a suitable reducing agent such as sodium borohydride
  • formyl group can be reacted with a suitable Horner Wittig or Wittig reagent such as (R 4 O) 2 P(O) CH 2 CO 2 R 4 or
  • Ph 3 P CHCO 2 R 4 wherein R 4 is C 1-4 alkyl to form a
  • a compound of formula (6) is suitably prepared by reacting a compound of formula (2) wherein Ar is as hereinbefore defined with an O-methylating agent such as dimethylformamide dimethylacetal in dimethylformamide or trimethylphosphite at an elevated temperature (eg.
  • compositions of the formula (1) may be prepared by standard methods, for example by reacting a solution of the
  • Type II cA-PrK was prepared from the cardiac muscle of a cow. The supernatant from a muscle homogenate
  • 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 [ - 32 P]-adenosine triphosphate and a suitable peptide substrate such as malantide (Malencik et al., 1983, Anal. Biochem., 132, 34-40).
  • the reaction was terminated by the addition of hydrochloric acid and the [ 32 P]-phosphopeptide quantified by spotting the reaction mixture onto phosphocellulose papers.
  • the concentration of compound reguired to give 10% phosphotransferase activation is given as the EC 10 ( ⁇ M).
  • the compounds of Examples 1 to 26 had EC 10 values in the range 10 - 130 ⁇ M.
  • Human platelet-rich-plasma was separated from freshly drawn blood (in acid/citrate/dextrose) and treated with 100 ⁇ M acetylsalicylic acid for 15 minutes at 37°C. A washed platelet suspension was then prepared in a
  • the compounds of Examples 2, 4, 5, 11-13, 15, 19-23, and 25-26 had IC 50 values in the range 0.8-300 ⁇ M.
  • DMEM Dulbecco's Modified Eagle's Medium
  • fetal bovine serum 10% fetal bovine serum
  • Indicator cells consisting of 3 human colorectal cells lines (SW-620, NRK-52 and HT-29) were plated at a cell density of 1000 cells in 0.1 ml of DMEM
  • the compounds of Examples 5 and 23 had IC 50 values of 11 and 6.5 ⁇ M respectively.
  • reaction mixture was poured into 10% aqueous acetic acid (150ml), the precipitated solid collected by filtration, washed with water and
  • 3',4'-Dipropoxyacetophenone - yield 95%, 1 H NMR ⁇ (CDCl 3 ) 1.00-1.19(m,6H), 1.78-2.02 (m, 4H), 2.55 (s, 3H), 3.98-4.17 (m, 4H), 6.87 (d, 1H), 7.52 (s, 1H) and 7.54 (d, 1H).
  • 3'-Allyloxyacetophenone - oil, yield 71%, 1 H
  • 6-(4-Biphenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one (a) From 4-acetylbiphenyl (19.6g), 6-(4-biphenyl)-3- cyanopyridin-2(1H)-one (14.01g) m.p. 312-316°C after recrystallisation from n-butanol, was prepared according to the method of Example 1(a). (b) From 6-(4-biphenyl)-3-cyanopyridin-2(1H)-one (1.36g), the title compound (0.84g) m.p. 305°C (decomp) after recrystallisation from dimethylformamide, was prepared according to the method of Example 1(b). 1 H NMR
  • dimethylformamide (12.5g) were boiled in dimethylformamide (100ml) for 3 hours. The solution was diluted with ethyl acetate (500ml), washed with water (6x100ml), dried
  • Example 25 From 3-cyano-6-(3,4-dimethoxyphenyl)pyridin-2(1H)-one (1.02g), the title compound (0.02g) m.p. 293-295°C after recrystallisation from dimethylformamide, was prepared according to the method of Example 1(b).
  • Example 25 From 3-cyano-6-(3,4-dimethoxyphenyl)pyridin-2(1H)-one (1.02g), the title compound (0.02g) m.p. 293-295°C after recrystallisation from dimethylformamide, was prepared according to the method of Example 1(b).
  • 6-(3-allyloxyphenyl)-3-cyanopyridin-2(1H)-one (14.7g) was prepared according to the method of Example 3(a).
  • 1 H NMR ⁇ (d 6 -DMSO) 4.67 (d, 2H), 5.26-5.46 (m, 2H), 5.98-6.20 (m, 1H), 6.80 (d, 1H), 7.13 (m, 1H), 7.33 (m, 3H) and 8.20 (d, 1H).
  • 6-(3-Propionamidophenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one a) To a stirred suspension of sodium methoxide (4.32g) in diethyl ether (50ml) a mixture of 3'- propionamidoacetophenone (5.73g) and ethyl formate (4.44g) in tetrahydrofuran (100ml) was added over 30 minutes. After stirring overnight the mixture was filtered and the residue washed with diethyl ether. The residue was dissolved in water (50ml), the pH adjusted to 9.0 with glacial acetic acid and cyanoacetamide (4.2g) added. The solution obtained was boiled overnight cooled to room temperature and
  • Triethylphosphonoacetate (0.9g) was added dropwise to a suspension of sodium hydride (0.18g, 50% in oil) in
  • Example 1(b) 1 H NMR ⁇ (DMSO-d 6 ) 0.32-0.38 (m, 2H), 0.57- 0.66 (m, 2H), 1.22-1.37 (m, 1H), 3.85 (s, 1H), 3.94 (d, 2H),
  • compositions for oral administration are prepared by combining the following : w/w
  • the formulations are then filled into individual soft gelatin capsules.

Abstract

Phenylpyridinol derivatives are disclosed as medicaments.

Description

PHENYLPYRIDINOL DERIVATIVES
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, lusitropic,
anti-allergic or anti-inflammatory activities. They are likely to be useful in the treatment of cardiovascular diseases such as congestive heart-failure, cancer,
psoriasis, atherosclerosis, thrombosis, chronic reversible lung disease such as asthma and bronchitis, allergic disease such as allergic asthma, allergic rhinitis and urticaria or gut motility disorders such as irritable bowel syndrome. Accordingly the present invention provides compounds of the formula (1) :
Figure imgf000003_0001
or pharmaceutically acceptable salts thereof, wherein : R0 is OH or a bioprecursor thereof,
R1 is 5-tetrazolyl or a bioprecursor thereof, and
Ar is phenyl substituted by one to three groups independentl selected from C1-6alkyl, C2-6alkenyl, C1-6alkoxy,
C3-6alkenyloxy, C3-6cycloalkyl, C3-6cycloalkoxy,
C1-6alkylthio, phenyl, phenylthio, benzyloxy,
C1-6polyfluoroalkyl, C1-6polyfluoroalkoxy, halo, NR2, or NHCOR wherein R is H or C1-6alkyl, or -X(CH2)nY- attached to adjacent carbon atoms of the phenyl ring wherein and Y are independently CH2 or O and n is 1 to 3, wherein said C1-6alkyl, C2-6alkenyl or C1-6alkoxy groups can be independently substituted by OH, C1-6alkoxy,
C3-6cycloalkyl, NR2, CO2R or CONR2; with the proviso
that Ar is not phenyl monosubstituted by 2-C1-6alkoxy.
Bioprecursors of the group R0 are derivatives thereof which are convertible in vivo into the group R0.
A suitable bioprecursor of the group R0 is OR2 wherein R2 is C1-4alkyl, arylC1-4alkyl (for example phenylC1-4- alkyl such as benzyl), C1-4alkanoyl (for example acetyl), arylC1-4alkanoyl (for example phenyl C1-4alkanoyl such as benzoyl), arylsulphonyl (for example optionally substituted phenylsulphonyl or toluenesulphonyl) or C1-4alkylsulphonyl (for example methylsulphonyl).
Suitably R0 is hydroxy or OR2, preferably hydroxy.
A suitable bioprecursor of R1 is a N-protected
tetrazolyl group. Suitable N-protecting groups include pivalolyoxymethyl, propionyloxymethyl and
pivaloyloxycarbonyloxymethyl. By the term alkyl is meant both straight- and branchedchain alkyl.
By the term C1-6 polyfluoroalkyl is meant a C1-6alkyl group having at least one hydrogen replaced with fluoro eg. CF3, or CF2CF2H.
Suitably Ar is phenyl mono-substituted by a group as hereinbefore defined, for example in the 2,3, or 4
positions by C1-6alkyl, C3-6alkenyloxy,
C1-6alkylthio, phenyl, phenylthio, benzyloxy, CF3, halo or NHCOR, or in the 3, or 4-positions with C1-6alkoxy. Suitably Ar is phenyl di-substituted by any groups as hereinbefore defined, for example in the
3, 4-, 3, 5-, 2, 3-, 2, 4- or 2,5-, positions by groups
independently selected from C2-6alkenyl, C1-6alkoxy,
C3-6cycloalkoxy, halo, -X(CH2)nY- or C1-6alkoxy
C1-6 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 C2-6alkenyl, C1-6alkoxy or halo.
Examples of C1-6alkoxy include methoxy, ethoxy,
propoxy, butoxy, or pentyloxy. Examples of C1-6alkyl include methyl, ethyl,
propyl, butyl, isobutyl or pentyl.
Examples of halo include fluoro, chloro, bromo or iodo, preferably chloro or bromo.
Particular compounds of this invention include : 6-(3-methoxyphenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one,
6-(3-propoxyphenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one,
6-(3-butoxyphenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one,
6-(3-benzyloxyphenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one,
6-(3-bromophenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one,
6-(3-trifluoromethyl)-3-(5-tetrazolyl)pyridin-2(1H)-one,
6-(3-ethylphenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one,
6-(4-butoxyphenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one,
6-(4-isobutylphenyl)pyridin-2(1H)-one,
6-(4-biphenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one,
6-(4-propoxyphenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one,
6-(4-methoxy-3-propoxyphenyl)-3-(5-tetrazolyl)pyridin- 2(1H)-one, 6-(3,4-methylenedioxyphenyl)-3-(5-tetrazolyl)pyridin-2(1H) one,
6-(3,4-dichlorophenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one,
6-(3,5-dipropoxyphenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one,
6-(3,5-diethoxyphenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one,
6-(3,5-dibromophenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one,
6-(2,4-dipropoxyphenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one,
6-(2,5-dipropoxyphenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one,
6-(2,3,4-trichlorophenyl)-3-(5-tetrazolyl)pyridin-2(1H)- one, 6-[6-(1,2,3,4-tetrahydronaphthyl)]-3-(5-tetrazolyl)pyridin- 2(1H)-one,
6-(3-chlorophenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one,
6-(3-phenylthiophenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one,
3 ,4-dimethoxyphenyl-3-(5-tetrazolyl)pyridin-2(1H)-one, 6-(3-methylthiophenyl)-3-(5-tetrazolyl)pyridin-2(1H)- one,
6-(3-butylthiophenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one,
6-(3,4-di-n-propoxyphenyl)-3-(5-tetrazolyl)pyridin-2(1H)- one, 6-(2,3-di-n-propoxyphenyl)-3-(5-tetrazolyl)pyridin-2(1H)- one,
6-(3-cyclopentyloxy-4-methoxyphenyl)-3-(5-tetrazolyl)- pyridin-2(1H)-one
6-(3-ethoxyphenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one,
6-(3,5-dimethoxyphenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one,
6-(2-butylthiophenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one, 6-(3-allyloxyphenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one,
6-(4-methoxy-2-pentyloxyphenyl)-3-(5-tetrazolyl)pyridin- 2(1H)-one
6-(3-iso-butoxy-4-methoxyphenyl)-3-(5-tetrazolyl)pyridin- 2(1H)-one,
6-(2-bromo-3,5-diethoxyphenyl-3-(5-tetrazolyl)pyridin- 2(1H)-one, 6- (5-bromo-4-methoxy-2-pentyloxphenyl) -3- (5-tetrazolyl) - pyridin-2 (1H) -one,
6-(2-allyl-4-methoxy-3-propoxyphenyl)-3-(5-tetrazolyl)- pyridin-2(1H)-one,
6-[3-(E-1-propenyl)-4-methoxyphenyl]-3-(5-tetrazolyl)pyridi n-2(1H)-one, 6-(4-methoxy-3-propoxyphenyl)-3-[5-(1-pivaloyloxymethyl)- tetrazolyl)pyridin-2(1H)-one,
6-(4-methoxy-3-propoxyphenyl)-3-[5-(2-pivaloyloxymethyl)- tetrazolyl]pyridin-2(1H)-one,
6-[3-ethoxy-5-(2-methoxyethoxy)phenyl]-3-(5-tetrazolyl)- pyridin-2(1H)-one,
6-[3- (2,2-dimethylpropyloxy)-4-methoxyphenyl]-3-(5- tetrazolyl)pyridin-2(1H)-one,
6-(3-ethoxy-4-methoxyphenyl)-3-(5-tetrazolyl)pyridin-2(1H) one, 6-(3-propionamidophenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one
6-(4-methoxy-3-propylphenyl)-3-(5-tetrazolyl)pyridin-2(1H) one,
6-(3-bromo-4-methoxyphenyl)-3-(5-tetrazolyl)pyridin-2(1H)- one,
6-(3-phenyl-4-methoxyphenyl)-3-(5-tetrazolyl)pyridin-2(1H) one, 6-[4-methoxy-3,5-di(E-1-propenyl)phenyl]-3-(5-tetrazolyl)- pyridin-2(1H)-one,
6-[3-(E-l-propenyl)-4-propoxyphenyl]-3-(5-tetrazolyl)- pyridin-2(1H)-one,
6-(3-bromo-4-methoxy-5-propylphenyl)-3-(5-tetrazolyl)- pyridin-2-(1H)-one, 6-(2-butylthio-3,5-diethoxyphenyl)-3-(5-tetrazolyl)pyridin- 2(1H)-one,
6-(3-bromo-4-N,N-dimethylaminophenyl)-3-(5-tetrazolyl)- pyridin-2(1H)-one,
6-(3-acetamido-4-methoxy-5-propylphenyl)-3-(5-tetrazolyl)- pyridin-2(1H)-one,
6-[3-methoxymethyl-4-methoxy-5-(E-1-propenyl)phenyl]-3-(5- tetrazolyl)pyridin-2(1H)-one,
6-[3-(E-2-carbamoylethenyl)-4-methoxy-5-(E-1-propenyl)- phenyl]-3-(5-tetrazolyl)pyridin-2-(1H)-one, and
6-(3-cyclopropylmethyloxy-4-methoxyphenyl)pyridin-2(1H)-one and pharmaceutically acceptable saltis thereof. This invention covers all tautcmeric, geometric and optical isomeric forms of compounds of formula (1). In particular when R0 is hydroxy the compound can exist in its keto tautomeric form :
Figure imgf000011_0001
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 agueous 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 (l) 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 reacting a compound of the formula (2) :
Figure imgf000014_0001
wherein Ar is as hereinbefore defined with an azide salt, and optionally thereafter :
° forming a bioprecursor of R0 and/or R1
° forming a pharmaceutically acceptable salt.
A compound of the formula (2) is suitably reacted with an azide salt such as ammonium, sodium, potassium or aluminium azide in an organic solvent such as
dimethyIformamide, dimethylsulphoxide, N-methyl- pyrrolidone or tetrahydrofuran at an elevated temperatur e.g. 40 - 200°C, preferably at the reflux temperature of the reaction mixture.
A compound of the formula (1) wherein R0 is OH can be converted to the corresponding compound where R0 is OR2 by reaction with R2L wherein R2 is as
hereinbefore defined and L is a leaving group such as halo e.g. bromo, chloro, iodo.
A compound of the formula (1) can be converted to a N-protected tetrazolyl derivative by reaction with a suitable N-protecting agent in standard manner, for example with a pivalolyoxymethyl halide.
A compound of the formula (2) can suitably be prepared by reacting a compound of the formula (3) : ArCOCH = CHL1 (3) wherein Ar is as hereinbefore defined and L1 is a
displaceable group, with a compound of the formula (4) : H2NCOCH2CN (4)
Suitably L1 in a compound of the formula (3) is hydroxy or a derivative thereof for example L1 is
protected hydroxy such as silyloxy, an acid residue (for example C1-6alkanoyloxy) or an ether residue (for
example methoxy or ethoxy). Alternatively L1 is a secondary amino group, for example di-C1-6alkylamino such as dimethylamino or a cyclic amino group such as piperidino, pyrrolidino or morpholino. Preferably L1 is hydroxy or dimethylamino.
Suitably an alkali metal (e.g. sodium) salt of a compound of the formula (3) wherein L1 is hydroxy is treated with a compound of the formula (4) under mildly alkaline aqueous conditions, for example in water in the presence of piperidine and glacial acetic acid, at an elevated temperature e.g. 30 - 200°C, preferably at the reflux temperature of the reaction mixture.
Alternatively a compound of the formula (3) wherein L1 is a secondary amino group, for example
dimethylamino, is treated with a compound of the formula (4) in a suitable solvent such as dimethylformamide, a C1-4alkanol or pyridine at an elevated temperature e.g. 30 - 200°C, preferably at the reflux temperature of the reaction mixture optionally in the presence of a base such as pyridine or an alkali metal alkoxide, e.g. sodium methoxide.
Compounds of the formula (3) wherein L1 is hydroxy can suitably be prepared by reaction under basic
conditions of a compound of the formula (5) : ArCOCH3 (5) wherein Ar is as hereinbefore defined, with a compound of the formula HCOL2 wherein L2 is a
leaving group.
Suitably L2 is ethoxy or methoxy. Conveniently a solution of a compound of the formula (5) and a compound of the formula HCOL2 in a suitable organic solvent such as diethyl ether is treated with a suitable base such as an alkali metal alkoxide, e.g. sodium methoxide at ambient temperature. The resulting reaction mixture is
preferably extracted with water and the agueous extract which contains the alkali metal salt of a compound of the formula (3) wherein L1 is hydroxy is then treated with a compound of the formula (4) as hereinbefore described.
Compounds of the formula (5) are known or can be prepared by methods known in the art.
Compounds of the formula (3) wherein L1 is a
secondary amino group (e.g. dimethylamino) can suitably be prepared by reacting a compound of the formula (5) with a compound of the formula HC(OR3)2L1 wherein R3 is
C1-4alkyl and L1 is a secondary amino group (for
example HC(OR3)2L1 is N,N-dimethylformamide dimethyl or diethyl acetal), or with a compound of the formula HCL where
L 1 is a secondary amm. o group (for example HCL1 3 is
trisdimethylaminomethane).
Alternatively a compound of formula (2) can be
prepared by demethylation of a compound of formula (6) :
Figure imgf000018_0001
wherein Ar is as hereinbefore defined.
Suitable demethylating agents include sodium iodide and chlorotrimethylsilane in an organic solvent such as acetonitrile, or a halohydrocarbon eg. dichloromethane or chloroform at elevated (eg. 30-80°C) or ambient
temperature or sodium thiomethoxide in an organic solvent such as dimethyIformamide at an elevated temperature, for example 40-120°C. The Ar group in compounds of the formula (2), (5) or (6), preferably (5) or (6) may be appropriately
functionalised by methods of aromatic substitution known in the art. For example, a bromo group may be introduced into a suitably substituted phenyl ring (eg. disubstituted in the 2- and 4-positions by electron-donating groups such as C1-6alkoxy) by reaction with a brominating agent such as N-bromosuccinimide or bromine in a solvent such as dimethyIformamide. Alternatively a nitro group can be introduced into a phenyl ring by reaction with a suitable nitrating agent, such as nitroniumtetrafluoroborate. Such a group can be readily hydrogenated to an amino group which if desired can be converted to a NHCOR group by reaction with LCOR wherein L is a leaving group and R is as hereinbefore defined. Suitable examples of the reagent LCOR include acid halides (L is halo eg. chloro or bromo) or acid anhydrides (L is OCOR). Other suitable functionalisations include the introduction of an allyl group ortho to a hydroxy
subεtituent 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 C1-6alkyl halide to form a C1-6alkoxy 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. This can occur during the conversion of a compound of formula (5) to a compound of formula (2) as hereinbefore described if such a base is used. An E-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 C1-6alkyl halide to form a C1-6alkoxymethyl group. Alternatively a
formyl group can be reacted with a suitable Horner Wittig or Wittig reagent such as (R4O)2P(O) CH2CO2R4 or
Ph3P=CHCO2R4 wherein R4 is C1-4alkyl to form a
CH=CHCO2R4 group which can be optionally hydrolysed to a -CH=CHCO2H group. A -CH=CHCO2R4 group can be
converted to a -CH=CHCONR2 group by reaction with an amine HNR2 or a chemical equivalent thereof wherein R 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 HNR2 or a chemical equivalent thereof. An example of a chemical equivalent is ammonium hydoxide which will form a CH=CHCONH2 group. A compound of formula (6) is suitably prepared by reacting a compound of formula (2) wherein Ar is as hereinbefore defined with an O-methylating agent such as dimethylformamide dimethylacetal in dimethylformamide or trimethylphosphite at an elevated temperature (eg.
40-120°C).
Pharmaceutically acceptable base addition salts of the compounds of the formula (1) may be prepared by standard methods, for example by reacting a solution of the
compound of the formula (1) with a solution of the base.
The following biological test methods, data and
Examples serve to illustrate this invention. Cvclic-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 [ -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]-phosphopeptide quantified by spotting the reaction mixture onto phosphocellulose papers. The concentration of compound reguired to give 10% phosphotransferase activation is given as the EC10 (μM). The compounds of Examples 1 to 26 had EC10 values in the range 10 - 130 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 1.5x108
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 2, 4, 5, 11-13, 15, 19-23, and 25-26 had IC50 values in the range 0.8-300 μM.
Anti-proliferative activity
Compounds under test were dissolved in dimethyl- sulphoxide and diluted 1:10,000 with DMEM (Dulbecco's Modified Eagle's Medium) containing 10% fetal bovine serum to give 12.5, 25, 50 and 100 μM concentrations used in the assay. Indicator cells consisting of 3 human colorectal cells lines (SW-620, NRK-52 and HT-29) were plated at a cell density of 1000 cells in 0.1 ml of DMEM
media in 96 well plates. Cells were incubated for 4 days at 37°C and 10% CO2 atmosphere. On day 5, tetrazolium reagent (50 μg MTT/250 μl total medium volume) was added for 16 - 20 hours. Insoluble formazan was dissolved in 150 μl of dimethylsulphoxide and absorbance
was measured using a microculture plate reader at 560 nm interfaced with an IBM computer. Cell line growth and inhibition were expressed in terms of mean absorbance unit of triplicate samples following subtraction of mean background absorbance. IC50 values (concentration that show 50% growth inhibition) were determined from the dose response curves. (Cancer Res., 48, 589-601, 1988). In the cell line SW-620 the compound of Example 23 had an IC50 value in the range 56 - 90 μM. In the cell line NRK-52 the compound of Example 23 had an IC50 value in the range 46 - 48 μM. In the cell line HT-29 the
compound of Example 23 had an IC50 value in the range of 55 - 66 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). The compounds of Examples 5, 15-17 and 23 had EC50 values in the range 2 - 25 μM. Bronchodilatation - In vitro (Tracheal spiral)
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 lc50(μM).
The compounds of Examples 5 and 23 had IC50 values of 11 and 6.5 μM respectively.
Measurement of cardiac muscle relaxation time in rabbit ventricle Papillary muscles from the right ventricle of female Albino New Zealand rabbits were mounted in standard organ baths containing oxygenated Krebs solution. One end of the muscle was connected to an isometric transducer which allowed recording of contractile force and its first derivative on chart recorders. Test compounds were added to the bath in a cumulative manner. Relaxation time was calculated as the time taken from peak tension to the end of the contraction. At concentrations of 30-100 μM, compounds of Examples 12 and 23 caused a 10-20% decrease in the relaxation time indicating a lusitropic effect of use in the treatment of cardiovascular diseases such as congestive heart failure. Example 1
6-(3-Methoxyphenγl)-3-(5-tetrazolyl)pyridin-2(1H)-one a) 3'-Methoxyacetophenone (15g) and dimethylformamide dimethylacetal (16ml) were heated together at 120°C in dimethyIformamide (80ml) for 6 hours, the deep red
solution was diluted with ethyl acetate (400ml), washed with water (5x100ml), dried (MgSO4) and solvent removed at reduced pressure. The oil obtained was dissolved in dimethylformamide (80ml), cyanoacetamide (10.08g) and sodium methoxide (10.8g) added and the mixture heated at 130°C for 35 minutes. The deep red solution was poured into 5% aqueous acetic acid (400ml), the precipitated product collected by filtration and washed with water, ethanol and diethyl ether. Recrystallisation from
n-butanol gave 3-cyano-6-(3-methoxyphenyl)pyridin- 2(1H)-one (I5.14g) m.p. 251°C as a colourless solid. b) 3-Cyano-6-(3-methoxyphenyl)pyridin-2(1H)-one (1g) sodium azide (0.39g) and ammonium chloride (0.32g) were heated together in N-methylpyrrolidin-2-one (10ml) at
140°C for 2hours. The reaction mixture was poured into 10% aqueous acetic acid (150ml), the precipitated solid collected by filtration, washed with water and
recrystallised from n-butanol to give the title compound (0.93g) m.p. 298°C (decomp). 1H NMR δ (DMSO-d6)
3.87 (s,3H), 6.92 (d,1H), 7.13 (m,1H), 7.41-7.50 (m, 3H) and 8.48 (d,1H).
Example 2
6-(3-Propoxyphenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one (a) 3'-Hydroxyacetophenone (13.6g), iodopropane (10.7ml) and potassium carbonate (13.8g) were heated together in dimethyIformamide (80ml) at 90°C for 20hrs. The reaction mixture was diluted with ethyl acetate (400ml), washed with 2N sodium hydroxide (2x100ml) and water (4x100ml), dried (MgSO4), filtered and solvent removed at reduced pressure to give 3'-propoxyacetophenone (16.46g) as an oil. % NMR δ(DMSO-d6) 0.99 (t,3H), 1.66-1.83 (m, 2H),
2.58 ((s, 3H), 3.98 (t, 3H), 7.19 (dd, 1H) and 7.39-7.57 (m, 3H).
The following compounds were similarly prepared from the appropriate phenol and alkyl iodide.
3'-Butoxyacetophenone:- oil, yield 90%, % NMR δ(DMSO-d6) 0.94 (t, 3H), 1.37-1.52 (m, 2H), 1.66-1.77 (m, 2H), 2.57 (s, 3H), 4.02 (t, 2H), 7.19 (dd, 1H) and 7.39-7.55 (m, 3H).
3'-Benzyloxyacetophenone:- oil, yield 89%, 1H NMR δ(CDCl3) 2.57 (s, 3H), 5.09 (s, 2H), 7.17 (dd, 1H) and
7.29-7.56 (m, 8H).
4' -Methoxy-3'-propoxyacetophenone from 3'-hydroxy-4' methoxyacetophenone:- (A. Brossi et al J. Org. Chem., 1967, 32, 1269) :- oil, yield 71%, 1H NMR δ(CDCl3)
1.05 (t, 3H), 1.87 (m, 2H), 2.56 (s, 3H), 3.93 (s, 1H),
4.04 ((t, 2H), 6.88 (d, 1H), 7.52 (d, 1H), and 7.57 (dd, 1H).
3 ',5'-Dipropoxyacetophenone:- oil, yield 58%, 1H NMR δ(DMSO-d6) 0.98 (t, 6H) 1.66-1.80 (m, 4H), 2.55 (s, 3H), 3.96 (t, 4H), 6.73 (t, 1H) and 7.04 (d, 2H).
3',5'-Diethoxyacetophenone:- oil, yield 64%, 1H NMR δ(DMSO-d6) 1.42 (t, 6H), 2.56 (s, 3H), 4.05 (q, 4H),
6.64 (t, 1H) and 7.07 (d, 2H). 2 ',5'-Dipropoxyacetophenone:- oil, yield 64%, 1H
NMR δ(DMSO-d6) 0.96 (t, 3H), 1.04 (t, 3H), 1.62-1.84 (m, 4H), 2.55 (s, 3H), 3.88 (t, 2H), 3.99 (t, 2H) and 7.03-7.11 (m, 3H).
3',4'-Dipropoxyacetophenone:- yield 95%, 1H NMR δ(CDCl3) 1.00-1.19(m,6H), 1.78-2.02 (m, 4H), 2.55 (s, 3H), 3.98-4.17 (m, 4H), 6.87 (d, 1H), 7.52 (s, 1H) and 7.54 (d, 1H). 3'-Allyloxyacetophenone:- oil, yield 71%, 1H
NMRδ (CDCl3) 2.58 (s, 3H), 4.57 (d, 2H), 5.27-5.47 (m, 2H),
5.96-6.15 (m, 1H), 7.12 (dd, 1H), 7.31 (t, 1H) and
7.49-7.55 (m, 2H). 4'-Methoxy-2'-pentyloxyacetophone:-From
4'-methoxy-2'hydroxyacetophenone and iodopentane, yield 92% , % NMR δ (DMSO-d6) 0.86 (t.3H) , 1.20-1.47 (m, 4H) ,
1.74-1.85 (m, 2H), 2.49 (s, 3H), 3.82 (s, 3H), 4.09 (t, 2H),
6.56-6.62 (m, 2H) and 7.66 (d, 1H).
3'-iso-Butoxy-4'-methoxyacetophenone:-From
4'-methoxy-3'-hydroxyacetophenone and iso-butyl bromide using acetone as solvent, yield 68%. 1H NMR
δ(DMSO-d6) 0.99 (d, 6H), 1.96-2.15 (m, 1H), 2.53 (s, 3H),
3.78 (d, 1H), 3.86 (s, 3H), 7.06 (d, 1H), 7.42 (d, 1H) and
7.62 (dd, 1H).
3'-Allyloxy-4'-methoxyacetophenone:-From
4'-methoxy-3'-hydroxyacetophenone and allyl bromide, yield 67%, 1H NMR δ(CDCl3) 2.55 (s, 3H), 3.95 (s, 3H),
4.63-4.68 (m, 2H), 5.29-5.47 (m, 1H), 6.02-6.18 (m, 1H),
6.90 (d, 1H), 7.53 (d, 1H) and 7.60 (dd, 1H).
3'-(2,2,-dimethylpropyloxy)-4'-methoxyacetophenone:-Fr m 4'-methoxy-3'-hydroxyacetophenone and 1-bromo-2,2- dimethylpropane, yield 76%, % NMR δ(CDCl3) 1. 07 (s , 9H) , 2 . 56 (s , 3H) , 3 . 69 (s , 2H) , 6. 88 (d,1H) and
7 . 50-7 . 58 (m , 2H) .
3'-ethoxy-4'-methoxyacetophenone:-from
3'-hydroxy-4'-methoxyacetophenone and iodoethane using acetone as solvent, yield 83%, 1H NMR δ(CDCl3)
1.49 (t, 3H), 2.57 (s, 3K), 3.94 (s, 3H), 4.17 (q, 2H), 6.89 (d, 1H), 7.53 -7.60 (m,2H). 3'-Allyl-4'-methoxyacetophenone:-from
3'-allyl-4'-hydroxyacetophenone, yield 87% as an oil.
1H NMR δ(CDCl3) 2.55 (s, 3H), 3.40 (d, 2H), 3.89 (s, 3H),
5.02-5.10 (m,2H), 5.90-6.04 (m, 1H), 6.88 (d, 1H), 7.77 (d, 1H) and 7.85 (dd, 1H).
(b) From 3'-propoxyacetophenone (9g), 3-cyano-6-(3- propoxyphenyl) pyridin-2 (1H) -one (3.49g) m.p. 240-241°C after recrystallisation from ethanol, was prepared
according to the method of Example 1(a).
(c) From 3-cyano-6-(3-propoxyphenyl)pyridin-2(1H)-one (1g), the title compound (0.61g) m.p. 270-27l°C after recrystallisation from n-butanol, was prepared according to the method of Example 1 (b).
Example 3 6-(3-Butoxyphenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one
(a) 3'-Butoxyacetophenone (17.3g) and dimethylformamide dimethylacetal (11.9g) were boiled together in
dimethyIformamide (90ml) for 15 hours. The deep red
solution was cooled to room temperature, cyanoacetamide (8.3g) and sodium methoxide (10.3g) added and the mixture boiled for a further 3 hours. The reaction mixture was poured into 10% aqueous acetic acid (300ml) the
precipitated product separated by filtration, washed with water and recrystallised from n-butanol to give
3-cyano-6-(3-butoxyphenyl)pyridin-2(1H)-one (10.66g) m.p. 201-202°C.
(b) From 3-cyano-6-(3-butoxyphenyl)pyridin-2(1H)-one (2.15g), the title compound (0.55g) m.p. 259-260°C after recrystallisation from n-butanol, was prepared according to the method of Example 1(b).
Example 4
6-(3-Benzyloxyphenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one
(a) From 3'-benzyloxyphenylacetophenone (20.2g),
3-cyano-6-(3-benzyloxyphenyl)pyridin-2(1H)-one (2.6g) m.p.202-203°C after recrystallisation from ethanol, was prepared according to the method of Example 3(a).
(b) From 3-cyano-6-(3-benzyloxyphenyl)pyridin-2 (1H) -one (1g), the title compound (0.35g) m.p.276°C (decomp) after recrystallisation from dimethylformamide was prepared according to the method of Example 1(b). 1H NMR
δ(DMSO-d6) 5.23 (s, 2H), 6.91 (d, 1H), 7.16-7.20 (m, 1H),
7.31-7.54 (m, 8H), 8.47(d,1H) and 12.67 (br s, 1H).
Example 5 6-(3-Bromophenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one
(a) From 3'-bromoacetophenone (13.2g), 3-cyano-6-(3- bromophenyl)pyridin-2(1H)-one (21.8g) m.p. 309°C (decomp) after recrystallisation from n-butanol, was prepared according to the method of Example 1(a). 1H NMR
δ(DMSO-d6) 6.89 (br s, 1H), 7.48 (t, 1H), 7.75 (d, 1H),
7.83 (d, 1H), 8.06 (s, 1H), 8.21 (d, 1H) and 12.75 (br s, 1H). (b) From 3-cyano-6-(3-bromophenyl)pyridin-2(1H)-one
(1.37g), the title compound (0.39g) m.p. 285-286°C after recrystallisation from dimethylformamide, was prepared according to the method of Example 1(b). Example 6
6-(3-Trifluoromethyl)-3-(5-tetrazolyl)pyridin-2(1H)-one (a) From 3 '-trifluoromethylacetophenone (9.4g), 3-cyano- 6-(3-trifluoromethylphenyl)pyridin-2(1H)-one (11.38g) m.p.255-256°C after recrystallisation from ethanol, was prepared according to the method of Example 3(a). (b) From 3-cyano-6-(3-trifluoromethylphenyl)pyridin- 2(1H)-one (1.06g), the title compound (0.93g)
m.p.274-275°C after recrystallisation from n-butanol, was prepared according to the method of Example 1(b). Example 7
6-(3-Ethylphenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one (a) From 3'-ethylacetophenone (7.4g), 3-cyano-6-(3- ethylphenyl)pyridin-2(1H)-one (3.97g) m.p.241-242°C after recrystallisation from n-butanol, was prepared according to the method of Example 3(a). (b) From 3-cyano-6-(3-ethylphenyl)pyridin-2(1H)-one
(0.89g), the title compound (0.37g) m.p.278-279°C after recrystallisation from n-butanol, was prepared according to the method of Example 1(b).
Example 8
6-(4-Butoxyphenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one
(a) From 4'-butoxyacetophenone (5.6g), 3-cyano-6-(4- butoxyphenyl)pyridin-2(1H)-one (1.12g) m.p. 245°C after recrystallisation from ethanol, was prepared according to the method of Example 1(a).
(b) A mixture of 3-cyano-6-(4-butoxyphenylJpyridin- 2(1H)-one (0.3g), sodium azide (0.098g), ammonium chloride (O.Oδg) and lithium chloride (0.064g) were heated in dimethylformamide (15ml) at 120°C for 72 hours. Solvent was removed at reduced pressure, the product precipitated by the addition of 10% aqueous acetic acid (40ml) and separated by filtration. The solid was dissolved in 5% potassium hydrogen carbonate and insoluble material separated by filtration. The filtrate was acidified with cone, hydrochloric acid, the precipitated product
collected by filtration and recrystallised from ethanol to give the title compound (0.05g) m.p.289-292°C.
Example 9 6-(4-isoButylphenyl)pyridin-2(1H)-one
(a) From 4'-isobutylacetophenone (8.8g), 3-cyano-6-(4- isobutylphenyl)pyridin-2(1H)-one (6.0g) m.p. 264°C after recrystallisation from ethanol, was prepared according to the method of Example 3(a). (b) From 3-cyano-6-(4-isobutylphenyl)pyridin-2(1H)-one (2.52g), the title compound (1.54g) m.p. 275°C (decomp) after recrystallisation from dimethylformamide, was prepared according to the method of Example 1(b) but usin dimethylformamide instead of N-methylpyrrolidin-2-one as solvent. 1H NMR δ(DMSO-d6) 0.89(d,6H), 1.81-1.96
(m, 1H), 2.51 (m, 2H), 6.87 (d, 1H), 7.33 (d, 2H), 7.78 (d, 2H), 8.46 (d, 1H) and 12.63 (br s, 1H). Example 10
6-(4-Biphenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one (a) From 4-acetylbiphenyl (19.6g), 6-(4-biphenyl)-3- cyanopyridin-2(1H)-one (14.01g) m.p. 312-316°C after recrystallisation from n-butanol, was prepared according to the method of Example 1(a). (b) From 6-(4-biphenyl)-3-cyanopyridin-2(1H)-one (1.36g), the title compound (0.84g) m.p. 305°C (decomp) after recrystallisation from dimethylformamide, was prepared according to the method of Example 1(b). 1H NMR
δ(DMSO-d6) 7.00 (d, 1H), 7.41-7.54 (m, 3H), 7.77 (d, 2H),
7.85 (d, 2H), 7.98 (d, 2H) and 8.50 (d, 1H).
Example 11
6-(4-Propoxyphenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one
(a) From 4'-propoxyacetophenone (15.4g) (E. Eckhart and J. Varga, Magyar. Kent. Folyoirat 1961, 67, 509, Chem Abs. 1962, 56, 15557e),
3-cyano-6-(4-propoxyphenyl)pyridin-2(1H)-one (1.8g) m.p. 262-265°C after recrystallisation from dimethylformamide, was prepared according to the method of Example 3(a).
(b) From 3-cyano-6-(4-propoxyphenyl)pyridin-2(1H)-one (1g), the title compound (0.85g) m.p. 292°C (decomp) afte recrystallisation from dimethylformamide, was prepared according to the method of Example 1(b). 1H NMR
δ(DMSO-d6) 0.99 (t, 3H), 1.63-1.84 (m,2H), 4.02(t,2H),
6.81 (d, 1H), 7.07 (d, 2H), 7.82 (d, 2H) and 8.45 (d, 1H).
Example 12
6-(4-Methoxy-3-propoxyphenyl)-3-(5-tetrazolyl)pyridin- 2(1H)-one
(a) From 4'-methoxy-3'-propoxyacetophenone (12g), 3-cyan 6-(4-methoxy-3-propoxyphenyl)pyridin-2(1H)-one (14.03g) m.p. 241°C after recrystallisation from ethanol, was prepared according to the method of Example 3(a).
(b) From 3-cyano-6-(4-methoxy-3-propoxyphenyl)pyridin- 2(1H)-one (3.12g), the title compound (1.69g) m.p.
289-290°C after recrystallisation from n-butanol, was prepared according to the method of Example 1(b).
Example 13
6-(3,4-Methylenedioxyphenyl)-3-(5-tetrazolyl)pyridin- 2(1H)-one
(a) From 3',4'-(methylenedioxy) acetophenone (16.4g), 3-cyano-6-(3,4-methylenedioxyphenyl)pyridin-2(1H)-one (10.2g) m.p. >320°C after recrystallisation from dimethyl formamide, was prepared according to the method of Exampl 3(a). 1H NMR δ(DMSO-d6) 6.13 (s, 2H), 6.72 (d, 1H),
7.06 (d, 1H), 7.36-7.42 (m, 2H), 8.13 (d, 1H) and 12.58 (br s, 1H (b) From 3-cyano-6-(3,4-methylenedioxyphenyl)pyridin- 2(1H)-one (0.96g), the title compound (0.1g) m.p. >325°C after recrystallisation from ethanol, was prepared according to the method of Example 1(b) but using
dimethylformamide instead of N-methylpyrrolidinone as solvent. 1H-NMR δ(DMSO-d6) 6.14 (s, 2H), 6.83 (d, 1H),
7.08 (d, 1H), 7.37-7.46 (m, 2H), 8.43 (d, 1H), 12.55 (br s, 1H) and 13.28 (br s, 1H). Example 14
6-(3,4-Dichlorophenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one (a) From 3' ,4'-dichloroacetophenone (18.9g),
3-cyano-6-(3,4-dichlorophenyl)pyridin-2(1H)-one (1.94g) m.p. >330°C after recrystallisation from dimethylformamide, was prepared according to the method of Example 1(a). 1H NMR δ(DMSO-d6) 6.97 (br d, 1H), 7.76-7.87
(m, 2H), 8.15 (s, 1H) and 8.23 (d, 1H).
(b) From 3-cyano-6-(3,4-dichlorophenyl)pyridin-2(1H)-one (1.06g), the title compound (0.54g) m.p.295°C (decomp) after recrystallisation from dimethylformamide, was prepared according to the method of Example 1(b) but using dimethylformamide instead of N-methylpyrrolidinone as solvent. 1H NMR δ(DMSO-d6) 7.02 (d, 1H) 7.76-7.89
(m, 2H), 8.17 (s, 1H) and 8.48 (s, 1H).
Example 15
6-(3,5-Dipropoxyphenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one
(a) From 3',5'-dipropoxyacetophenone (11.82g), 3-cyano-6- (3,5-dipropoxyphenyl)pyridin-2(1H)-one (7.1g) m.p. 209-210°C after recrystallisation from ethanol, was prepared according to the method of Example 3 (a).
(b) From 3-cyano-6-(3,5-dipropoxyphenyl)pyridin-2(1H)-one (1.25g), the title compound (1.31g) m.p.224-225°C after recrystallisation from n-butanol, was prepared according to the method of Example 1(b).
Example 16 6-(3,5-Diethoxyphenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one
(a) From 3',5'-diethoxyacetophenone (4.16g), 3-cyano-6- (3,5-diethoxyphenyl)pyridin-2(1H)-one (1.0g) m.p.259-261°C after recrystallisation from n-butanol, was prepared according to the method of Example 3(a).
(b) From 3-cyano-6-(3,5-diethoxyphenyl)pyridin-2(1H)-one (0.82g), the title compound (0,57g) m.p. 282-283°C after recrystallisation from n-butanol, was prepared according to the method of Example 1(b).
Example 17 6-(3,5-Dibromophenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one
(a) From 3',5'-dibromoacetophenone (M. Tashiro, S Mataka, H. Nakamura and K Nakayama, J. Chem. Soc. Perkin Trans I., 1988, 179) (1.11g), 3-cyano-6-(3,5-dibromophenyl)pyridin- 2(1H)-one (0.73g) m.p. >300°C after recrystallisation from n-butanol, was prepared according to the method of Example 3(a). 1H NMR δ(DMSO-d6) 7.00 (br d, 1H), 8.02 (s, 1H),
8.09 (s, 2H) and 8.23 (d, 1H). (b) From 3-cyano-6-(3,5-dibromophenyl)pyridin-2(1H)-one (0.53g), the title compound (0.15g) m.p. 295-296°C
(decomp) after recrystallisation from n-butanol was prepared according to the method of Example 1(a). 1H NMR δ(DMSO-d6) 7.10 (br d, 1H), 8.02 (s, 1H), 8.13 (s, 2H) and
8.47 (d, 1H).
Example 18 6-(2,4-Dipropoxyphenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one
(a) From 2',4'-dipropoxyacetophenone (17.9g) (P.
Chabrier, H. Najer, R. Giudicelli and E. Joannie-Voisinet, Bull. Soc. Chim. France, 1958, 1488.), 3-cyano-6-(2,4- dipropoxyphenyl)pyridin-2(1H)-one (1.69g) m.p. 148°C after recrystallisation from ethanol, was prepared according to the method of Example 3(a). (b) From 3-cyano-6-(2,4-dipropoxyphenyl)pyridin-2(1H)-on (1g), the title compound (0.60g) m.p. 205°C after
recrystallisation twice from ethanol, was prepared
according to the method of Example 1(b). Example 19
6-(2,5-Dipropoxyphenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one (a) From 2',5'-dipropoxyphenylacetophenone (11.8g),
3-cyano-6-(2,5-dipropoxyphenyl)pyridin-2(1H)-one (14.36g) m.p. 160-162°C after recrystallisation from ethanol, was prepared according to the method of Example 3(a). 1H NMR δ(DMSO-d6) 0.92 (t, 3H), 0.97 (t, 3H), 1.61-1.76 (m, 4H),
3.92 (t, 4H), 6.54 (d, 1H), 7.01-7.06 (m, 3H), 8.18 (d, 1H). (b) From 3-cyano-6-(2,5-dipropoxyphenyl)pyridin-2(1H)-one (2.5g), the title compound (0.81g) m.p.l88-189°C after recrystallisation from ethanol, was prepared according to the method of Example 1(b).
Example 20
6-(2,3,4-Trichlorophenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one
(a) 2',3',4'-Trichloroacetophenone (22.15g) and
dimethylformamide (12.5g) were boiled in dimethylformamide (100ml) for 3 hours. The solution was diluted with ethyl acetate (500ml), washed with water (6x100ml), dried
(MgSO4), filtered and solvent removed at reduced
pressure. The residue was triturated with diethyl ether to give 3-N,N-dimethylamino-1-(2,3,4-trichlorophenyl)prop- 2-ene-1-one (17.5g). 1H NMR δ(DMSO-d6) 2.84 (s, 3H),
3.08 (br s, 3H), 5.17 (d, 1H), 7.1 (very br, 1H), 7.30 (br d, 1H) and 7.65 (d, 1H).
(b) A solution of 3-N,N-dimethylamino-1-(2,3,4- trichlorophenyl)prop-2-ene-1-one (9.8g) and cyanoacetamide (3.18g) in dimethylformamide (35ml) was boiled for 48 hours. The reaction mixture was poured into 10% aqueous acetic acid (100ml), the precipitated product separated by filtration and recrystallised from ethanol to give
3-cyano-6-(2,3,4-trichlorophenyl)pyridin-2(1H)-one
(4.4g). 1H NMR δ(DMSO-d6) 6.52 (d, 1H), 7.58 (d, 1H),
7.79 (d, 1H), 8.24 (d, 1H) and 12.95 (br s, 1H).
(c) From 3-cyano-6-(2,3,4-trichlorophenyl)pyridin- 2(1H)-one (1.2g), the title compound (1.21g) m.p.>300°C after recrystallisation from dimethyIformamide/water, was prepared according to the method of Example 1(a). 1H NMR δ(DMSO-d6) 6.63 (d, 1H), 7.61 (d, 1H), 7.83 (d, 1H), 8.51 (d, 1H) and 12.98 (br s, 1H).
Example 21 6-[6-(1,2,3,4-Tetrahydronaphthyl)]-3-(5-tetrazolyl)pyridin- 2(1H)-one
(a) From 6-acetyltetralin (4.23g), 3-cyano-6-[6-(1,2,3,4- tetrahydronaphthyl)]pyridin-2(1H)-one (1.27g) m.p.
245-246°C after recrystallisation from n-butanol, was prepared according to the method of Example 3(a). 1H NMR δ(DMSO-d6) 1.75 (m,4H), 2.77 (m, 4H), 6.71(d, 1H), 7.19
(d, 1H), 7.50 (d, 1H), 7.53(s,1H) and 8.15 (d, 1H). (b) From 3-cyano-6-[6-(1,2,3,4-tetrahydronaphthyl)pyridin- 2(1H)-one (1g), the title compound (0.55g) m.p. 284-285°C after recrystallisation from dimethylformamide/water,was prepared according to the method of Example 1(b). Example 22
6-(3-Chlorophenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one (a) From 3'-chloroacetophenone (15.46g), 6-(3-chlorophenyl)-3-cyanopyridin-2(1H)-one (17.12g) m.p. 304-305°C after recrystallisation from n-butanol, was prepared according to the method of Example 3(a). (b) From 6-(3-chlorophenyl)pyridin-2(1H)-one (1.2g), the title compound (1.01g) m.p. 301-302°C (decomp) after recrystallisation from n-butanol, was prepared according to the method of Example 1(b). 1H NMR δ(DMSO-d6)
6.94 (d, 1H), 7.48-7.62 (m, 2H), 7.81 (d, 1H), 7.96 (s, 1H),
8.48 (d, 1H) and 12.77 (br s, 1H) Example 23
6-(3-Phenylthiophenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one
(a) 3'-Phenylthioacetophenone (2.05g) (L. Victor, Brit. Pat. 1,519,354) and dimethylformamide dimethylacetal (1.19g) were heated together in dimethylformamide (10ml) at 100°C for 18 hours. The reaction mixture was diluted with ethyl acetate (50ml) washed with water (6x30ml), dried (MgSO4) filtered and solvent removed at reduced pressure. The residue was column chromatographed (silica gel, dichloromethane-5% ethanol/dichloromethane eluant) to give 3-N,N-dimethylamino-1-(3-phenylthiophenyl)- prop-2-ene-1-one (1.72g) as a yellow oil.
(b) A mixture of 3-N,N-dimethylamino-1-(3-phenylthiophenyl)prop-2-ene-1-one (1.72g), sodium methoxide (0.76g) and cyanoacetamide (0.59g) were boiled together in dimethylformamide (10ml) for 1 hour. The reaction mixture was poured into 10% aqueous acetic acid (100ml), the precipitated product separated by filtration and
recrystallised from ethanol to give 3-cyano-6-(3- phenylthiophenyl)pyridin-2(1H)-one (1.0g) m.p. 262-264°C.
(c) From 3-cyano-6-(3-phenylthiophenyl)pyridin-2(1H)-one (0.79g), the title compound (0.77g) m.p.265-266°C after recrystallisation from n-butanol, was prepared according to the method of Example 1(b).
Example 24 3,4-Dimethoxyphenyl-3-(5-tetrazolyl)pyridin-2(1H)-one
(a) From 3',4'-Dimethoxyacetophenone (18g), 3-cyano-6- (3,4-dimethoxyphenyl)pyridin-2(1H)-one (9.86g) m.p.
269-270°C after recrystallisation from ethanol, was prepared according to the method of Example 1(a). (b) From 3-cyano-6-(3,4-dimethoxyphenyl)pyridin-2(1H)-one (1.02g), the title compound (0.02g) m.p. 293-295°C after recrystallisation from dimethylformamide, was prepared according to the method of Example 1(b). Example 25
6-(3-Methylthiophenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one (a) From 3'-methylthioacetophenone (4.64g), 3-cyano-6-
(3-methylthiophenyl)pyridin-2(1H)-one (4.3g) m.p.234-238°C after recrystallisation from ethanol, was prepared
according to the method of Example 3(a). (b) From 3-cyano-6-(3-methylthiophenyl)pyridin-2(1H)-one (1g), the title compound (0.85g) m.p.274-276°C (decomp) after recrystallisation from n-butanol, was prepared according to the method of Example 1(b). 1H NMR
δ(DMSO-d6) 2.58 (s, 3H), 6.91 (d, 1H), 7.39-7.63 (m, 3H),
7.68 (s, 1H) and 8.47 (d, 1H).
Example 26
6- (3-Butylthiophenyl) -3-(5-tetrazolyl)pyridin-2 (1H) -one
(a) Copper-(I)-n-butylmercaptide (R. Adams,
W. Reijschneider and A. Ferretti, Org, Syn. Coll. Vol., V, p107) (3.34g) and 3-cyano-6-(3-bromophenyl)pyridin- 2(1H)-one (2.61g) were heated together in a mixttre of quinoline (10ml) and pyridine (3ml) at 160°C for 4 hours. The reaction mixture was poured onto cone, hydrochloric acid (30ml) and ice (100g) and the precipitated material collected by filtration. The residue was column
chromatographed (silica gel,
dichloromethane-dichloromethane/2% ethanol) to give
3-cyano-6-(3-butylthiophenyl)pyridin-2(1H)-one (0.35g) m.p. 191-193°C after recrystallisation from ethanol.
(b) From 3-cyano-6-(3-butylthiophenyl)pyridin-2(1H)-one (0.23g), the title compound (0.11g) m.p.237-238°C after recrystallisation from n-butanol, was prepared according to the method of Example 1 (b).
Example 27
6-(3 ,4-Di-Propoxyphenyl)-3-(5-tetrazolyl)pyridin-2(1H) one
(a) From 3',4'-di-propoxyacetophenone (3.6g)
3-cyano-6-(3,4-dipropoxyphenyl)pyridin-2(1H)-one (3.21g) m.p. 249 °C after recrystallisation from ethanol, was prepared according to the method of Example 3 (a).
(b) From 3-cyano-6-(3,4-di-propoxyphenyl)- pyridin-2(1H)-one (1.00g) the title compound m.p. 280°C (decomp) after recrystallisation from n-butanol,was prepared according to the method of Example 1(b). 1H NMR δd6-DMSO) 0.97-1.05 (m, 6H), 1.71-1.81 (m, 4H), 4.01 (t, 2H), 4.03 (t, 2H), 6.88 (d, 1H), 7.09 (d, 1H),
7.43 (d, 1H), 7.46 (s, 1H) and 8.44 (d, 1H) and 12.61 (br. s, 1H).
Example 28
6-(2,3-di-Propoxyphenyl)-3-(5-tetrazolyl)pyridin-2(1H)- one (a) From 2,3-dihydroxybenzaldehyde (20g), 2,3-di-propoxy- benzaldehyde (18.6g) isolated as an oil was prepared according to the method of Example 2(a). 1H-NMR
δ(CDCl3) 1.04 (t, 3H), 1.09 (t, 3H), 1.74-1.96 (m, 4H),
3.97 (t, 2H), 4.15 (t, 3H), 7.03-7.16 (m, 2H), 7.39 (dd, 1H) and 10.47 (s, 1H)
(b) To a solution of 2,3-di-propoxybenzaldehyde (18.6g) in tetrahydrofuran at -78°C methyl lithium (61ml, 1.5M in diethyl ether) was added over 10 minutes. The reaction mixture was stirred at -78°C for two hours and at room temperature for 16 hours. After quenching with water the organic phase was separated, dried (MgSO4) and solvent removed to give 1-(2,3-di-propoxyphenyl)-1-hydroxyethane (20g) as an oil. 1H-NMR δ(CDCl3) 1.04 (t, 3H),
1.06 (t, 3H), 1.72-1.93 (m, 4H), 3.89 (t, 2H), 3.99 (t, 2H),
5.15 (m, 1H), 6.80 (m, 1H) and 6.95-7.04 (m, 2H).
(c) To an ice cooled solution of 1-(2,3-di-propoxy- phenyl)-1-hydroxyethane (20g) in dichloromethane (250ml) powdered 4A molecular sieves (23g), N-methylmorpholine- N-oxide (14.9g) and tetrapropylammonium perruthenate (1g). The mixture was stirred for one hour with ice cooling and at room temperature overnight. After filtration through Hyflo solvent was removed at reduced pressure to give 2',3'-di-propoxyacetophenone (18.3g). 1H-NMR δ(CDCl3) 1.03 (t, 3H), 1.08 (t, 3H), 1.72-1.96 (m, 4H), 2.63 (s, 3H),
3.96 (t, 2H), 4.01 (t, 2H) and 6.99-7.19 (m, 3H). (d) From 2',3'-dipropoxyacetophenone (10g),
3-cyano-6-(2,3-di-propoxyphenyl)pyridin-2(1H)-one ( 1.87g) m.p. 195-198°C was prepared according to the method of Example 3(a), omitting sodium methoxide. 1H-NMR
(d6-DMSO) 0.81 (t, 3H), 1.01 (t, 3H), 1.51 (m, 2H),
1.76 (m, 2H), 3.84 (t, 2H), 3.99 (t, 2H), 6.43 (d, 1H),
6.97 (d, 1H), 7.10- 7.27 (m, 2H) and 8.17 (d, 1H). (e) From 3-cyano-6-(2,3-di-propoxyphenyl)pyridin- 2(1H)-one (1g), the title compound (0.47g) m.p. 186-187°C after recrystallisation from aqueous ethanol was prepared according to the method of Example 1(b).
Example 29
6-(3-Cyclopentyloxy-4-meth.ox_yphenyl)-3-(5-tetrazolyl)- pyridin-2(1H)-one
(a) A mixture of 3'-hydroxy-4'-methoxyacetophenone
(20.8g), potassium carbonate (24.15g), cyclopentyl bromide (22.35g) and potassium iodide (3.32g) were combined in acetone (250ml) and boiled for 24 hours. Dimethylformamide (25ml) was added and boiling continued for a further 24 hours. The reaction mixture was cooled to room
temperature, filtered and solvent removed at reduced pressure. The residue was dissolved in diethyl ether
(200ml) washed with 2N sodium hydroxide (3x50ml) and water, dried and solvent removed at reduced pressure to give
3'cyclopentyloxy, 4 '-methoxyacetophenone as an oil that solidified on standing m.p. 59-60°C. (b) From 3'-cyclopentyloxy-4'-methoxyacetophenone
(11.25g), 3-cyano-6-(3-cyclopentyloxy-4-methoxyphenyl)- pyridin-2 (1H)-one (4.07g) m.p.259-260°C after digestion with acetonitrile was prepared according to the method of Example 3(a) omitting sodium methoxide.
(c) From 3-cyano-6-(3-cyclopentyloxyphenyl-4- methoxyphenyl) pyridin-2 (1H) -one (0.8g), the title compound (0.6g) m.p. 286-287°C (decomp) after recrystallisation from dimethylformamide was prepared according to the method of Example 1(b). 1H-NMR δ(d6-DMSO) 1.54-2.02 (m, 8H), 3.83 (s, 3H), 5.00 (m, 1H), 6.87 (d, 1H), 7.10 (d, 1H), 7.43 (s, 1H), 7.46 (d, 1H) and 8.44 (d, 1H).
Example 30 6-(3-Ethoxyphenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one
(a) A mixture of 3-hydroxyacetophenone (6.8g) and
tris (dimethylamino)methane (14.5g) were heated together in dimethylformamide (30ml) at 80°C for 4 hours. The reaction mixture was cooled to room temperature cyanoacetamide (8.4g) added and the mixture boiled for 8 hours. After cooling to room temperature the mixture was poured into 10% aqueous acetic acid (200ml), filtered and the residue washed with water and ethanol to give 3-cyano-6-(3- hydroxyphenyl)pyridin-2(1H)-one. 1H-NMR δ(d6-DMSO)
6.64 (br.d, 1H), 6.95 (dd, 1H), 7.12 (s, 1H), 7.20 (d, 1H),
7.32 (t, 1H), 8.15 (d, 1H), 9.87 (s, 1H) and 12.70 (br. s, 1H).
(b) To a suspension of sodium hydride (lg, 50% in oil) in dimethylformamide (15ml) 3-cyano-6-(3-hydroxy- phenyl)pyridin-2(1H)-one (2.12g) was added in portions over 30 minutes. When gas evolution had ceased
iodoethane (1.56g) was added and the mixture stirred overnight. The mixture was diluted with ethyl acetate (100ml), washed with 2N hydrochloric acid (2x30ml) and with water (4x50ml), dried (MgSO4) and solvent removed at reduced pressure. The residue was recrystallised from n-butanol to give 3-cyano-6-(3-ethoxyphenyl)pyridin-
2(1H)-one (0.68g). 1H-NMR δ(d6-DMSO) 1.35 (t, 3H),
4.12 (q, 2H), 6.80 (d, 1H), 7.08 (d, 1H), 7.31-7.47 (m, 3H) and 8.18 (d, 1H). (c) From 3-cyano-6-(3-ethoxyphenyl)pyridin-2(1H)-one
(0.5g), the title compound (0.44g) m.p.279°C (decomp) after recrystallisation from n-butanol, was prepared according to the method of Example 1(b). 1H-NMR
δ(d6-DMSO) 1.36 (t, 3H), 4.14 (q,2H), 6.90 (d, 1H), 7.10 (m, 1H), 7.34-7.48 (m,3H) and 8.47 (d, 1H).
Example 31
6-(3,5-Dimethoxyphenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one
(a) From 3',5'-dimethoxyacetophenone (4.1g),
3-cyano-6-(3,5-dimethoxyphenyl)pyridin-2(1H)-one (2.41g) m.p. 297°C after recrystallisation from ethanol, was prepared according to the method of Example 3(a).
(b) From 3-cyano-6-(3,5-dimethoxyphenyl)pyridin-2(1H)-one (1.4g), the title compound (1.36g) m.p. 338°C (decomp) after recrystallisation from acetonitrile/dimethyl- formamide was prepared according to the method of Example 1(b). 1H NMR δ(d6-DMSO) 3.86 (s, 6H), 6.66 (m, 1H),
6.95 (d, 1H), 7.02 (m, 2H), 8.47 (d, 1H) and 12.66 (br. s, 1H).
Example 32 6-(2-Butylthiophenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one
(a) From 2'-bromoacetophenone (19.9g), 6-(2-bromophenyl)- 3-cyanopyridin-2(1H)-one (11.4g) m.p. 245-246°C after recrystallisation from ethanol,was prepared according to the method of Example 1(a).
(b) From 6-(2-bromophenyl)-3-cyanopyridin-2(1H)-one (2.61g), 6-(2-butylthiophenyl)-3-cyanopyridin-2(1H)-one (0.83g) m.p.163-165°C after recrystallisation from ethanol, was prepared according to the method of Example 26(a).
(c) From 6-(2-butylthiophenyl)-3-cyanopyridin-2(1H)-one (0.71g), the title compound (0.53g) m.p.18l-182°C after recrystallisation from ethanol, was prepared according to the method of Example 1(b).
Example 33 6-(3-Allyloxyphenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one
(a) From 3'-allyloxyacetophenone (15.07g),
6-(3-allyloxyphenyl)-3-cyanopyridin-2(1H)-one (14.7g) was prepared according to the method of Example 3(a). 1H NMR δ(d6-DMSO) 4.67 (d, 2H), 5.26-5.46 (m, 2H), 5.98-6.20 (m, 1H), 6.80 (d, 1H), 7.13 (m, 1H), 7.33 (m, 3H) and 8.20 (d, 1H).
(b) From 6-(3-allyloxyphenyl)-3-cyanopyridin-2(1H)-one (1g), the title compound (0.34g) m.p.260°C (decomp) after recrystallisation from n-butanol, was prepared according to the method of Example 1(b). 1H NMR δ(d6-DMSO)
4.72 (m, 2H), 5.28-5.52 (m, 2H), 6.04-6.20 (m, 1H), 6.94 (d, 1H), 7.14 (m, 1H), 7.48 (m, 3H) and 8.47 (d, 1H).
Example 34
6-(4-Methoxy-2-pentyloxyphenyl)-3-(5-tetrazolyl)pyridin- 2(1H)-one
(a) From 4'-methoxy-2'-pentyloxyacetophenone (11.8g), 3- cyano-6-(4-methoxy-2-pentyloxyphenyl)pyridin-2(1H)-one (3.4g) m.p. 143-144°C after recrystallisation from ethanol, was prepared according to the method of Example 3 (a). (b) From 3-cyano-6-(4-methoxy-2-pentyloxyphenyl)pyridin- 2(1H)-one (1.25g), the title compound (0.65g) m.p. 193- 194°C after recrystallisation from ethanol was prepared according to the method of Example 1 (b).
Example 35
6-(3-iso-Butoxy-4-methoxyphenyl)-3-(5-tetrazolyl)pyridin- 2(1H)-one
(a) From 3'-iso-butoxy-4'-methoxyacetophenone (7.6g), 3- cyano-6-(3-iso-butoxy-4-methoxyphenyl)pyridin-2(1H)-one (6.02g) m.p.234-235°C after recrystallisation from ethanol, was prepared according to the method of Example 3 (a).
(b) From 3-cyano-6-(3-iso-butoxy-4-methoxyphenyl)pyridin- 2(1H)-one (1.19g), the title compound (1.2g) m.p. 296-297°C (decomp) after recrystallisation from ethanol, was prepared according to the method of Example 1(b). 1H NMR δ(DMSO-d6) 1.01 (d, 6H), 2.02-2.16 (m, 1H), 3.85 (s, 3H), 3.89 (d, 2H),
6.89 (d, 1H), 7.12 (d, 1H), 7.41-7.50 (m, 2H) and 8.47 (d, 1H).
Example 36 6-(2-Bromo-3,5-diethoxyphenyl)-3-(5-tetrazolyl)pyridin- 2(1H)-one
(a) To an ice cooled solution of 3',5'-diethoxyacetophenone (10.4g) in dimethylformamide (50ml) N-bromosuccinimide (9.79g) was added in portions over 1 hour. The mixture was stirred at 0°C for 3 hours and stood at room temperature for 48 hours. After diluting with ethyl acetate (200ml) the mixture was washed with water (5x100ml), dried (MgSO4) and solvent removed at reduced pressure to give 2'-bromo-3',5'- diethoxyacetophenone (12.53g) as an oil. H NMR δ(CDCl3)
1.41 (t, 3H), 1.50 (t, 3H), 2.60 (s, 3H), 4.00 (q, 2H), 4.10 (q, 2H), 6.45 (d, 1H) and 6.50 (d, 1H). (b) From 2'-bromo-3',5'-diethoxyacetophenone (4.31g), 3- cyano-6-(2-bromo-3,5-diethoxyphenyl)pyridin-2(1H)-one (0.75g) m.p. 234-235°C after recrystallisation from ethanol, was prepared according to the method of Example 3(a).
(c) From 3-cyano-6-(2-bromo-3,5-diethoxyphenyl)pyridin- 2(1H)-one (0.6g), the title compound m.p. 276°C after recrystallisation from ethanol was prepared according to the method of Example 1 (b).
Example 37 6-(5-Bromo-4-methoxy-2-pentyloxyphenyl)-3-(5-tetrazolyl)- pyridin-2(1H)-one
(a) A mixture of 3-cyano-6-(4-methoxy-2-pentyloxyphenyl)- pyridin-2(1H)-one (1.71g), silver carbonate (1.92g) and iodomethane in chloroform (30ml) were stirred in the dark for 48 hours. After filtration (celite pad) solvent was removed at reduced pressure and the residue column
chromatographed (silica gel, 40%hexane/dichloromehane eluant) to give 3-cyano-2-methoxy-6-(4-methoxy-2- pentyloxyphenyl)pyridine (1.45g) m.p.76-78°C.
(b) To a cooled (ice bath) solution of 3-cyano-2-methoxy-6- (4-methoxy-2-pentyloxyphenyl)pyridine (1.3g) in
dimethylformamide (10ml) N-bromosuccinimide (0.71g) was added in portions over 30 minutes. The solution was stirred at room temperature overnight diluted with ethyl acetate (50ml) and washed with water (5x50ml). The organic phase was dried (MgSO4) solvent removed at reduced pressure and the residue recrystallised from ethanol to give 3-cyano-2- methoxy-6-(5-bromo-4-methoxy-2-pentyloxyρhenyl)pyridine (1.1g) m.p. 136-137°C. (c) 3-Cyano-2-methoxy-6-(2-bromo-4-methoxy-2- pentyloxyphenyl) pyridine (lg) and sodium iodide (1.50g)
(dried at 70°C in vacuo for 4 hours) were dissolved in acetonitrile (10ml) and chlorotrimethylsilane (1.08g) added. The reaction mixture was stirred in the dark for 2 hours, diluted with ethyl acetate (50ml) washed with water (2x50ml), with 5% aqueous sodium metabisulphite (30ml) and water (50ml). The organic phase was dried (MgSO4) solvent removed at reduced pressure and the residue recrystallised from ethanol to give 3-cyano-6-(5-bromo-4-methoxy-2- pentyloxyphenyl)pyridin-2(1H)-one (0.55g) m.p.188-190°C.
(d) From 3-cyano-6-(5-bromo-4-methoxy-2- pentyloxyphenyl)pyridin-2(1H)-one (0.5g), the title
compound (0.38g) m.p.246-248°C after recrystallisation from ethanol, was prepared according to the method of Example 1 (b).
Example 38
6-(2-Allyl-4-methoxy-3-propoxyphenyl)-3-(5-tetrazolyl) pyridin-2(1H)-one
(a) A mixture of 3'-allyloxy-4'-methoxyacetophenone (7.76g) and diethylaniline (5.96g) was degassed with nitrogen for
15 minutes and heated at 215°C for 90 minutes. After cooling to room temperature the reaction mixture was dissolved in ethyl acetate (100ml) and washed with 2N hydrochloric acid (3x100ml). The organic phase was dried (MgSO4) and solvent removed at reduced pressure to give after recrystallisation from ethanol/water 2'-allyl-3'- hydroxy-4'-methoxyacetophenone (5.1g) m.p.81-83°C.
(b) 2'-Allyl-3'-hydroxy-4'-methoxyacetophenone (5.0g), potassium carbonate (3.3g) and iodopropane were heated together in a mixture of dimethylformamide (20ml) and butanone (30ml) for 48 hours. The mixture was filtered and solvent removed from the filtrate at reduced pressure to give a residue which was dissolved in ethyl acetate (100ml) and washed with water (5x50ml). The organic phase was dried (MgSO4) and solvent removed at reduced pressure to give 2'- allyl-4'-methoxy-3'-propoxyacetophenone (5.0g) as an oil. 1H NMR δ(DMSO-d6) 0.98 (t, 3H), 1.62-1.80 (m, 2H), 2.48 (s, 3H), 3.62-3.69 (m, 2H), 3.79 (t, 2H), 3.85 (s, 3H), 4.82-4.91 (m, 2H), 5.78-5.93 (m, 1H), 6.99 (d, 1H and 7.63 (d, 1H). (c) From 2'-allyl-4'-methoxy-3'-propoxyacetophenone (4.96g) 3-cyano-6-(2-allyl-4-methoxy-3-propoxyphenyl)pyridin-2(1H)- one (1.15g) m.p. 170-171°C after recrystallisation from ethanol was prepared according to the method of Example 3(a) with, however, the omission of sodium methoxide.
(d) From 3-cyano-6-(2-allyl-4-methoxy-3- propoxyphenyl)pyridin-2(1H)-one (0.49g), the title compound
(0.24g) m.p. 210-211°C after recrystallisation from ethanol was prepared according to the method of Example 1 (b).
Example 39
6-[3-(E-1-propenyl)-4-methoxyphenyl]-3-(5-tetrazolyl)- pyridin-2(1H)-one
(a) From 3-allyl-4-methoxyacetophenone (7.6g), 3-cyano-6- [3-(E-1-propenyl)-4-methoxyphenyl]pyridin-2(1H)-one (4g) after recrystallisation from n-butanol, was prepared according to the method of Example 3(a). 1H NMR δ(DMSO-d6) 1.88 (d, 3H), 3.87 (s, 3H), 6.40-6.67 (m, 3H), 6.78 (d, 1H),
7.10 (d, 1H), 7.72 (dd, 1H), 7.93 (d, 1H) and 8.14 (d, 1H).
(b) From 3-cyano-6-[3-(E-1-propenyl)-4- methoxyphenyl]pyridin-2(1H)-one (2.13g), the title compound (0.8g) m.p. 291-295°C (decomp) after recrystallisation from dimethylformamide was prepared according to the method of Example 1(b). 1H NMR δ(DMSO-d6) 1.89 (d, 3H), 3.88 (s, 3H), 6.42-6.71 (m, 3H), 6.90 (d, 1H), 7.12 (d, 1H), 7.76 (dd, 1H),
7.97 (d, 1H) and 8.44 (d, 1H).
Example 40
6-(4-Methoxy-3-propoxyphenyl)-3-[5-(1-pivaloyloxymethyl)- tetrazolyl)pyridin-2(1H)-one and 6-(4-methoxy-3- propoxyphenyl)-3-[5-(2-pivaloyloxymethyl)- tetrazolyl]pyridin-2(1H)-one
A mixture of 4-methoxy-3-propoxyphenyl)-3-(5- tetrazolyl)pyridin-2(1H)-one (1.64g), pivaloyloxymethyl chloride (0.75g), sodium hydrogen carbonate (420mg) and sodium iodide (50mg) were heated in dimethylformamide (5ml) at 70°C for 24 hours. The mixture was diluted with ethyl acetate (50ml) and washed with water 6 x 50ml). The organic phase was dried (MgSO4) filtered and solvent removed at reduced pressure. The residue was column chromatographed (silica gel, 70% hexane/ethyl acetate - 30% hexane/ethyl acetate eluant to give:- a) 6-(4-methoxy-3-ρropoxyphenyl)- 3-[5-(1-pivaloyloxymethyl)tetrazolyl]pyridin-2(1H)-one (0.26g) m.p. 169-170°C after recrystallisation from ethanol and b) 6-(4-methoxy-3-propoxyphenyl)-3-[5-(2- pivaloyloxymethyl)tetrazolyl]pyridin-2(1H)-one (0.35g) m.p.l95-196°C after recrystallisation from ethanol.
Example 41
6-[3-Ethoxy-5-(2-methoxyethoxy)phenyl]-3-(5-tetrazolyl)- pyridin-2(1H)-one a) 3',5'-Dihydroxyacetophenone (15.2g), potassium carbonate (7.59g) and iodoethane (17.16g) were combined and heated at reflux for 15 hours. Additional potassium carbonate (2.76g and iodoethane (6.2g) were added and heating was continued for a further 10 hours. The reaction mixture was filtered, solvent removed at reduced pressure, the residue dissolved in ethyl acetate (100ml) and extracted with 2N sodium hydroxide (3x50ml). The combined basic extracts were washed with ethyl acetate (2x50ml), acidified with 2N hydrochloric acid and extracted with dichloromethane (3x100ml). The combined dichloromethane extracts were washed with water (2x50ml), dried (MgSO4), filtered and solvent removed at reduced pressure. The residue was column chromatographed (silica gel, dichloromethane eluant) to give 3'-ethoxy-5'- hydroxyacetophenone (4.83g) m.p. 96-98°C. b) To a suspension of sodium hydride (0.92g, 60% in oil washed with hexane) in dimethylformamide (10ml), 3'-ethoxy- 5'-hydroxyacetophenone (3.24g) was added in portions over 10 minutes. When gas evolution had ceased chloroethylmethyl ether (1.9g) and sodium iodide (50mg) were added and the mixture heated to 90°C for 18 hours and stirred at room temperature for 24 hours. The mixture was diluted with ethyl acetate (100ml), washed with 2N sodium hydroxide (3x50ml) and water (3x50ml). The organic phase was dried (MgSO4), filtered and solvent removed at reduced pressure to give 3'-ethoxy-5'-(2-methoxyethoxy) acetophenone (4.03g) as an oil. 1H NMR δ(CDCl3) 1.42 (t, 3H), 2.56 (s, 3H),
3.46 (s, 3H), 3.74-3.78 (m, 2H), 4.05 (q, 2H), 4.13-4.17 (m, 2H), 6.68 (m, 1H) and 7.10 (m, 2H). c) From 3'-ethoxy-5'-(2-methoxyethoxy) acetophenone, 3- cyano-6-[3-ethoxy-5-(2-methoxyethoxy)phenyl]pyridin-2(1H)- one (1.1g) m.p.199°C after recrystallisation from ethanol, was prepared according to the method of Example 3(a). d) From 3-cyano-6-[3-ethoxy-5-(2- methoxyethoxy)phenyl]pyridin-2(1H)-one (0.94g), the title compound (0.6g) m.p.205-206°C after recrystallisation from ethanol, was prepared according to the method of Example 1 (b). Example 42
6-(3-(2,2-Dimethylpropyloxy)-4-methoxyphenyl)-3-(5- tetrazolyl)pyridin-2(1H)-one a) From 3'-(2,2-dimethylpropyloxy)-4'-methoxyacetophenone (9.0g), 3-cyano-6-[3-(2,2-dimethylpropyloxy)-4- methoxyphenyl]pyridin-2(1H)-one (3.46g) was prepared according to the method of Example 3(a). 1H NMR δ(DMSO d6) 1.02 (s, 9H), 3.74 (s, 2H), 3.85 (s, 3H), 6.79 (d, 1H), 7.09 (d, 1H), 7.42 (s, 1H), 7.43 (d, 1H) and 8.14 (d, 1H). b) From 3-cyano-6-[3-(2,2-dimethylpropyloxy)-4- methoxyphenyl]pyridin-2(1H)-one (1.25g), the title compound (1.28g) m.p. >300°C after recrystallisation from n-butanol, was prepared according to the method of Example 1 (b). 1H NMR δ(DMSO-d6) 1.04 (s, 9H), 3.77 (s, 2H), 3.86 (s, 3H),
6.90 (d, 1H), 7.10 (d, 1H), 7.45 (m, 2H) and 8.44 (d, 1H). Example 43
6-(3-Ethoxy-4-methoxyphenyl)-3-(5-tetrazolyl)pyridin-2(1H)- one
a) From 3'-ethoxy-4'-methoxyacetophenone (2.91g), 3-cyano- 6-(3-ethoxy-4-methoxyphenyl)pyridin-2(1H)-one (2.02g) m.p.273°C after recrystallisation from ethanol was prepared according to the method of Example 1 (a). b) From 3-cyano-6-(3-ethoxy-4-methoxyphenyl)pyridin-2(1H)- one (1.0g), the title compound (1.06g) m.p.299°C (decomp) after recrystallisation from n-butanol, was prepared according to the method of Example 1(b). 1H NMR δ(DMSO-d6) 1.37 (t, 3H), 3.84 (s, 3H), 4.15 (q, 2H), 6.92 (d, 1H), 7.10 (d, 1H), 7.41-7.50 (m, 2H) and 8.43 (d, 1H). Example 44
6-(3-Propionamidophenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one a) To a stirred suspension of sodium methoxide (4.32g) in diethyl ether (50ml) a mixture of 3'- propionamidoacetophenone (5.73g) and ethyl formate (4.44g) in tetrahydrofuran (100ml) was added over 30 minutes. After stirring overnight the mixture was filtered and the residue washed with diethyl ether. The residue was dissolved in water (50ml), the pH adjusted to 9.0 with glacial acetic acid and cyanoacetamide (4.2g) added. The solution obtained was boiled overnight cooled to room temperature and
adjusted to pH 5 with glacial acetic acid (US Patent
4,278,681). The precipitated material was collected by filtration, washed thoroughly (4x50ml) with ethanol and recrystallised from dimethylformamide/water to give 3- cyano-6-(3-propionamidophenyl)pyridin-2(1H)-one (0.4g) m.p. 328-330°C b) From 3-cyano-6-(3-propionamidophenyl)pyridin-2(1H)-one (0.3g) the title compound (0.2g) m.p.291-293°C (decomp) after recrystallisation from dimethylformamide/water, was prepared according to the method of Example 1 (b). 1H NMR δ(DMSO-d6) 1.11 (t, 3H), 2.37 (q, 2H), 6.75 (d, 1H), 7.46 (m, 2H), 7.69 (m, 1H), 8.09 (m, 1H) and 8.50 (d, 1H).
Example 45 6-(4-Methoxy-3-propylphenyl)-3-(5-tetrazolyl)pyridin-2(1H)- one (SB 20525))
(a) A solution of 3'-allyl-4'-methoxyacetophenone (20g) in ethanol (250ml) containing 10% palladium on charcoal (2g) was treated with hydrogen at 50 p.s.i until the calculated volume of hydrogen had been taken up. The mixture was filtered (celite pad) and solvent removed at reduced pressure. The residue was dissolved in dichloromethane (100ml) and manganese dioxide (60g) added. The mixture was stirred at room temperature for 48 hours, filtered (celite pad) and solvent removed at reduced pressure to give 4'- methoxy-3'-propylacetophenone (15.16g) as an oil. 1H NMR δ(CDCl3) 0.95 (t, 3H), 1.52-1.79 (m, 2H), 2.55 (s, 3H),
2.61 (t, 2H), 3.88 (s, 3H), 6.86 (d, 1H), 7.77 (d, 1H) and
7.82 (dd, 1H). (b) From 4'-methoxy-3'-propylacetophenone (5.77g), 3-cyano- 6-(4-methoxy-3-propylphenyl)pyridin-2(1H)-one (4.43g) m.p. 239°C after recrystallisation from butanol, was prepared according to the method of Example 3 (a). (c) From 3-cyano-6-(4-methoxy-3-propylphenyl)pyridin-2(1H)- one (4.02g), the title compound (3.64g) m.p.293-294°C
(decomp) after recrystallisation from ethanol, was prepared according to the method of Example 1(b). 1H NMR δ(DMSO-d6) 0.93 (t, 3H), 1.51-1.71 (m, 2H), 2.59 (t, 2H), 3.87 (s, 3H),
6.83 (d, 1H), 7.10 (d, 1H), 7.68-7.74 (m, 2H) and 8.46 (d, 1H).
Example 46
6-(3-Bromo-4-methoxyphenyl)-3-(5-tetrazolyl)pyridin-2(1H)- one (SB 204617)
(a) From 3'-bromo-4'-methoxyacetophenone (K.W.Rosenmund et. al. Chem. Ber., 1922, 90, 1957) (2.29g), 3-cyano-6-(3- bromo-4-methoxyphenyl)pyridin-2(1H)-one (1.42g) m.p. 284- 286°C after recrystallisation from ethanol, was prepared according to the method of Example 3 (a).
(b) From 3-cyano-6-(3-bromo-4-methoxyphenyl)pyridin-2(1H)- one (1.22g), the title compound (1.28g) m.p. 292-293°C (decomp) after recrystallisation from dimethylformamide, was prepared according to the method of Example 1(b). 1H NMR δ(DMSO-d6) 3.94 (s, 3H), 6.90 (d, 1H), 7.27 (d, 1H),
7.90 (dd, 1H), 8.14 (d, 1H) and 8.45 (d, 1H).
Example 47
6-(3-phenyl-4-methoxyρhenyl)-3-(5-tetrazolyl)pyridin-2(1H)- one (SB 204649)
(a) To a suspension of
tetrakis (triphenylphosphine) palladium (0) (0.5g) in aqueous sodium hydrogen carbonate (5.04g in 60ml water), solutions of phenylboronic acid (2.65g) in dimethoxyethane (100ml) and 3'-bromo-4'-methoxyacetophenone (4.58g) in
dimethoxyethane (110ml) were added. The mixture was stirred under reflux for 3 hours cooled to room temperature and solvent removed at reduced pressure. The residue was partitioned between chloroform (200ml) and water (200ml), the organic phase separated dried (MgSO4) and solvent removed at reduced pressure. The residue was recrystallised from ethanol to give 4'-methoxy-3'-phenylacetophenone
(2.87g) m.p. 92-93°C.
(b) From 4'-methoxy-3'-phenylacetophenone (3.3g), 3-cyano- 6-(3-phenyl-4-methoxyphenyl)pyridin-2(1H)-one (2.37g) m.p. 288-291°C after recrystallisation from propan-2-ol, was prepared according to the method of Example 3 (a).
(c) From 3-cyano-6-[(3-phenyl)-4-methoxyphenyl]pyridin- 2(1H)-one (0.91g), the title compound (0.70g) m.p. 289- 291°C after recrystallisation from
dimethylformamide/ethanol, was prepared according to the method of Example 1(b). 1H NMR δ(DMSO-d6) 3.86 (s, 3H),
6.92 (d, 1H), 7.28 (d, 1H), 7.33-7.48 (m, 3H), 7.62 (d, 2H), 7.81- 7.89 (m, 2H), 8.45 (d, 1H), 11.96 (br. s, 1H) and 12.71 (br. s, 1H) Example 48
6-[4-Methoxy-3,5-di(E-1-ρropenyl)phenyl]-3-(5-tetrazolyl)- pyridin-2(1H)-one (SB 204788)
(a) From 3'-allyl-4'-hydroxyacetophenone (17.6g), 3'-allyl- 4'-allyloxyacetophenone (20.7g) isolated as an oil, was prepared according to the method of Example 2 (a) using acetone as solvent. 1H NMR δ(CDCl3) 2.55 (s, 3H), 3.44 (d, 2H), 4.61 (m, 2H), 5.04-5.46 (m, 4H), 5.94-6.10 (m, 2H), 6.86 (d, 1H), 7.78d, 1H) and 7.83 (dd, 1H).
(b) From 3'-allyl-4'-allyloxyacetophenone (20.5g), 3',5'- diallyl-4'-hydroxyacetophenone (16.3g) m.p. 83-84°C was prepared according to the method of Example 38 (a).
(c) From 3',5'-diallyl-4'-hydroxyacetophenone (16g), 3',5'- diallyl-4'-methoxyacetophenone (17g) isolated as an oil, was prepared according to the method of Example 2 (a). 1H NMR δ(CDCl3) 2.55 (s, 3H), 3.46 (d, 4H), 3.77 (s, 3H), 5.05- 5.14 (m, 4H), 5.91-6.07 (m, 2H) and 7.69 (s, 2H).
(d) From 3',5'-diallyl-4'-methoxyacetophenone (8.5g), 3- cyano-6-[4-methoxy-3,5-di(E-1-propenyl)phenyl]pyridin- 2(1H)-one (6.1g) m.p. 248-250°C after trituration with hot ethanol, was prepared according to the method of Example 3(a).
(e) From 3-cyano-6-[4-methoxy-3,5-di(E-1- propenyl)phenyl]pyridin-2(1H)-one (0.46g), the title compound (0.27g) m.p. 285-287°C (decomp) after
recrystallisation from dimethylformamide/water, was prepared according to the method of Example 1 (b). 1H NMR δ(DMSO-d6) 1.92 (d, 6H), 3.68 (s, 3H), 6.49-6.68 (m, 4H),
7.00 (d, 1H), 7.89 (s, 2H) and 8.45 (d, 1H). Example 49
6-[3-(E-1-Propenyl)-4-propoxyphenyl]-3-(5-tetrazolyl)- pyridin-2(1H)-one. (SB 201433)
(a) From 3'-allyl-4'-hydroxyacetophenone (5.28g), 3'-allyl- 4'-propoxyacetophenone (6.06g) isolated as an oil was prepared according to the method of Example 2 (a). 1H NMR δ(CDCl3) 1.07 (t, 3H), 1.66-1.92 (m, 2H), 2.55 (s, 3H),
3.41 (d, 2H), 3.99 (t, 2H), 5.04-5.12 (m, 2H), 5.90-6.06 (m, 1H), 6.86 (d, 1H), 7.77 (d, 1H) and 7.83 (dd, 1H).
(b) From 3'-allyl-4'-propoxyacetophenone (5.7g), 3-cyano-6- [3-(E-1-propenyl)-4-propoxyphenyl]pyridin-2(1H)-one (2.57g) m.p. 240-244°C after recrystallisation from butanol, was prepared according to the method of Example 3(a).
(c) From 3-cyano-6-[3-(E-1-propenyl)-4- propoxyphenyl]pyridin-2 (1H) -one (l.lδg), the title compound (0.7g) m.p.290-292°C (decomp) after recrystallisation from butanol, was prepared according to the method of Example Kb). 1H NMR δ(DMSO-d6) 1.02 (t, 3H), 1.73-1.86 (m, 2H),
1.90 (d, 3H), 4.04 (t, 2H), 6.48-6.61 (dq, 1H), 6.65 (d, 1H),
6.89 (d, 1H), 7.11 (d, 1H), 7.70 (dd, 1H), 7.97 (d, 1H) and
8.43 (d, 1H).
Example 50
6-(3-Bromo-4-methoxy-5-propylphenyl)-3-(5-tetrazolyl)- pyridin-2(1H)-one. (273/2534)
(a) From 4'-methoxy-3'-propylacetophenone (7.6g), 3'-bromo- 4'-methoxy-5'-propylacetophenone (4.8g) isolated as an oil after column chromatography (silica gel, 50%
hexane/dichloromethane eluant) was prepared according to the method of Example 36(a). 1H NMR δ(CDCl3) 0.98 (t, 3H), 1.57-1.73 (m, 2H) , 2.56 (s, 3H) , 2. 67 (t, 2H) , 3. 87 (s, 3H) ,
7 .74 (d, 1H) and 7 . 98 (d, 1H) .
(b) From 3'-bromo-4'-methoxy-5'-propylacetophenone (3.4g), 6-(3-bromo-4-methoxy-5-ρropylphenyl)-3-cyanopyridin-2(1H)- one (1.2g) after recrystallisation from ethanol, was prepared according to the method of Example 3 (a). 1H NMR δ(DMSO-d6) 0.94 (t, 3H), 1.57-1.67 (m, 2H), 2.65 (t, 2H),
3.79 (s, 3H), 6.38 (br.d, 1H), 7.74 (d, 1H), 7.97 (d, 1H) and
8.18 (d, 1H).
(c) From 6-(3-bromo-4-methoxy-5-propylphenyl)-3- cyanopyridin-2(1H)-one (0.39g), the title compound (0.17g) m.p. 286-287 (decomp) after recrystallisation from ethanol, was prepared according to the method of Example 1 (a). 1H NMR δ(DMSO-d6) 0.96 (t, 3H), 1.61-1.70 (m, 2H), 2.67 (t, 2H), 3.81 (s, 3H), 6.94 (d, 1H), 7.76 (d, 1H), 7.99 (d, 1H) and
8.45 (d, 1H). Example 51
6-(2-Butylthio-3,5-diethoxyphenyl)-3-(5-tetrazolyl)pyridin- 2(1H)-one (a) From 2'-bromo-3',5'-diethoxyacetophenone (2.53g), 2'- butylthio-3',5'-diethoxyacetophenone (1.96g) after column chromatography (silica gel, hexane/dichloromethane 4:1 eluant) was prepared according to the method of Example 26(a). 1H NMR δ(CDCl3) 0.87 (t, 3H), 1.25-1.65 (m, 10H),
2.59 (s, 3H), 2.76 (t, 2H), 4.02 (q, 2H), 4.08 (q, 2H), 6.33 (d, 1H) and 6.46 (d, 1H).
(b) From 2'-butylthio-3',5'-diethoxyacetophenone (1.95g), 3-cyano-6-(2-butylthio-3,5-diethoxyphenyl)pyridin-2(1H)-one (0.13g) after recrystallisation from ethanol, was prepared according to the method of Example 3(a). 1H NMR δ(DMSO-d6) 0 .77 (t, 3H) , 1. 18-1. 43 (m, 10H) , 2. 66 (t, 2H) , 4. 03-4. 18 (m, 4H) , 6.27 (d, 1H) , 6.59 (d, 1H) , 6.71 (d, 1H) and 8. 15 (d, 1H) .
(c) From 3-cyano-6-(2-butylthio-3,5-diethoxyphenyl)-3-(5- tetrazolyl)pyridin-2(1H)-one (0.12g), the title compound (0.08g) m.p. 138-140°C after recrystallisation from
ethanol, was prepared according to the method of Example 1(a). 1H NMR δ(DMSO-d6) 0.76 (t, 3H), 1.18-1.43 (m, 10H),
2.64 (t, 2H), 4.05-4.19 (m, 4H), 6.40 (d, 1H), 6.62 (d, 1H),
6.70 (d, 1H), 8.48 (d, 1H) and 12.67 (br. s, 1H).
Example 52
6-(3-Bromo-4-N,N-dimethylaminophenyl)-3-(5-tetrazolyl)- pyridin-2(1H)-one (SB 204789)
(a) From 4'-N,N-dimethylaminoacetophenone (4.9g), 3'-bromo- 4'-N,N-dimethylaminoacetophenone (7.0g) was prepared according to the method of Example 36(a). 1H NMR δ(CDCl3) 2.53 (s, 3H), 2.91 (s, 6H), 7.03 (d, 1H), 7.83 (dd, 1H) and
8.13 (d, 1H).
(b) From 3'-bromo-4'-N,N-dimethylaminoacetophenone (2.42g), 3-cyano-6-(3-bromo-4-N,N-dimethylaminophenyl)pyridin-2(1H)- one (2.63g) was prepared according to the method of Example 3(a). 1H NMR δ(DMSO-d6) 2.82 (s, 6H), 6.82 (d, 1H), 7.22 (d, 1H), 7.79 (dd, 1H), 8.08 (d, 1H), 8.15 (d, 1H) and 12.67 (br. s1H).
(c) From 3-cyano-6-(3-bromo-4-N,N- dimethylaminophenyl)pyridin-2(1H)-one (0.8g), the title compound (0.57g) m.p.275-277°C was prepared according to the method of Example 1 (b). Example 53
6-(3-Acetamido-4-methoxy-5-propylphenyl)-3-(5- tetrazolyl)pyridin-2(1H)-one (SB 204790)
(a) From 3'-allyl-4'-hydroxyacetophenone (17.6g), 3'-allyl- 4'-benzyloxyacetophenone (23. Ig) isolated as an oil was prepared according to the method of Example 2 (a) using acetone as solvent. 1H NMR δ(CDCl3) 2.55 (s, 3H), 3.47 (d, 2H), 5.04-5.11 (m, 4H), 5.16 (s, 2H), 5.93-6.09 (m, 1H), 6.93 (d, 1H), 7.25-7.41 (m, 5H), 7.81 (s, 1H) and 7.82 (d, 1H).
(b) From 3'-allyl-4'-benzyloxyacetophenone (23g), 6-[4- benzyloxy-3-(E-1-propenyl)phenyl]-3-cyanopyridin-2(1H)-one (11.2g) m.p. 255-257°C after recrystallisation from
dimethylformamide/water, was prepared according to the method of Example 3 (a).
(c) A solution of 6-[4-benzyloxy-3-(E-1-propenyl)phenyl]-3- cyanopyridin-2(1H)-one (6.8g) in dimethylformamide (20ml) containing dimethylformamide dimethyl acetal (4.76g) was heated at 120°C for 6 hours. The mixture was diluted with ethyl acetate (200ml), washed with water (6 x 100ml), dried (MgSO4) and solvent removed at reduced pressure. The residue was column chromatographed (silica gel,
hexane/dichloromethane 1:1 eluant) to give 6-[4-benzyloxy- 3-(E-1-propenyl)phenyl]-3-cyano-2-methoxypyridine (6g) m.p. 124-125°C after recrystallisation from ethanol. (d) A suspension of 6-[4-benzyloxy-3-(E-1-propenyl)phenyl]- 3-cyano-2-methoxypyridine (1.78g) in ethanol (250ml) containing 10% palladium/charcoal (0.2g) was hydrogenated at 50 p.s.i until the calculated quantity of hydrogen had been absorbed. The mixture was filtered (celite pad) and solvent removed at reduced pressure. The residue was column chromatographed (silica gel, hexane/dichloromethane 1:1 - 2% ethanol/dichloromethane eluant) to give 3-cyano-6-(4- hydroxy-3-propylphenyl) -2-methoxyρyrιdιne (1 . 0g) . 1H NMR δ (CDCl3) 1.01 (t, 3H) , 1. 65-1.74 (m, 2H) , 2 . 66 (t, 2H) ,
4 . 15 (s, 3H) 5.19 (s, 1H) , 6. 86 (d, 1H) , 7. 35 (d, 1H) and 7. 81-
7 . 87 (m, 3H) .
(e) To a stirred suspension of 6-(4-hydroxy-3- propylphenyl)-3-cyano-2-methoxypyridine (1.88g) in
sulpholane (3ml) a solution of nitronium tetrafluoroborate in sulpholane (0.5M, 16ml) was added over 5 minutes with ice cooling. The solution obtained was stirred for 5 hours, additional nitronium tetrafluoroborate (0.5M in sulpholane, 2ml) added and stirring continued for a further 3 hours. The solution was diluted with diethyl ether (100ml) washed with water (8 x 100ml), dried (MgSO4) and solvent removed at reduced pressure. The residue was recrystallised from ethanol to give 3-cyano-6-(4-hydroxy-3-nitro-5- propylphenyl)-2-methoxypyridine (1.75g) m.p. 160-162°C.
(f) From 3-cyano-6-(4-hydroxy-3-nitro-5-propylphenyl)-2- methoxypyridine (1.57g), 3-cyano-6-(4-methoxy-3-nitro-5- propylphenyl)-2-methoxypyridine (1.53g) m.p. 150-152°C was prepared according to the method of Example 2 (a) using acetone/dimethylformamide (1:1) as reaction solvent. 1H NMR δ(CDCl3) 1.03 (t, 3H), 1.67-1.81 (m, 2H), 2.77 (t, 2H),
3.95 (s, 3H), 4.17 (s, 3H), 7.42 (d, 1H), 7.96 (d, 1H), 8.07 (d, 1H) and 8.35 (d, 1H).
(g) A suspension of 3-cyano-6-(4-methoxy-3-nitro-5- propylphenyl)-2-methoxypyridine (1.4g) in ethanol (100ml) containing 10% palladium/charcoal (200mg) was treated with hydrogen at 50 p.s.i until hydrogen uptake was complete. The mixture was filtered (celite pad) and solvent removed from the filtrate at reduced pressure. The residue was dissolved in dichloromethane (10ml) containing
triethylamine (1.01g) added followed by the addition of acetic anhydride (0.61g) over 5 minutes. The reaction mixture was stirred for 15 hours, diluted with dichloromethane (100ml) and washed with 2N hydrochloric acid (2 x 50ml) and with water (50ml). After drying
(MgSO4), solvent was removed at reduced pressure to give after recrystallisation from ethanol 6-(3-acetamido-4- methoxy-5-propylphenyl-3-cyano-2-methoxypyridine (1.04g) m.p.174-175°C.
(h) From 6-(3-acetamido-4-methoxy-5-propylphenyl)-3-cyano- 2-methoxypyridine (0.7g), 6-(3-acetamido-4-methoxy-5- propylphenyl)-3-cyanopyridin-2(1H)-one (0.48g) m.p.247- 249°C was prepared according to the method of Example
37 (c). 1H NMR δ(CDCl3) 1.02 (t, 3H), 1.68-1.83 (m, 2H),
2.27 (s, 3H), 2.78 (t, 2H), 3.83 (s, 3H), 6.65 (d, 1H), 7.49 (d, 1H), 7.80 (br.s, 1H), 7.90 (d, 1H) and 8.62 (d, 1H).
(i) From 6-(3-acetamido-4-methoxy-5-propylphenyl)-3- cyanopyridin-2(1H)-one (0.4g), the title compound (0.25g) m.p. 239-241°C after recrystallisation from ethanol, was prepared according to the method of Example 1 (b)
Example 54
6-[3-Methoxymethyl-4-methoxy-5-(E-1-propenyl)phenyl]-3-(5- tetrazolyl)pyridin-2(1H)-one (273/2588)
(a) From 3-cyano-6-[4-methoxy-3,5-di(E-1- propenyl)phenyl]pyridin-2(1H)-one (4.59g), 3-cyano-6-[4- methoxy-3,5-di(E-1-propenyl)phenyl]-2-methoxypyridine
(4.1g) m.p. 145°C was prepared according to the method of Example 53 (c). 1H NMR δ(DMSO-d6) 1.93 (d, 6H), 3.67 (s, 3H), 4.11 (s, 3H), 6.42-6.56 (m, 2H), 6.66 (d, 2H), 7.87 (d, 1H),
8.15 (s, 2H) and 8.30 (d, 1H).
(b) To an ice cooled suspension of 3-cyano-6-[4-methoxy- 3,5-di(E-1-proρenyl)phenyl]-2-methoxypyridine (1.6g) in acetone/water (9:1, 100ml) N-methylmorpoline-N-oxide
(0.63g) and osmium tetroxide (2.5% w/w solution in tert- butanol, 0.4ml) were added. The mixture was stirred with ice cooling for 1 hour and at room temperature for 1 hour. Additional N-methylmorpholine-N-oxide (0.1g) was added and stirring continued for an additional 1 hour. The solution was quenched with 5% sodium metabisulphite (5ml) and solvent removed at reduced pressure. The residue was dissolved in ethyl acetate (200ml), washed with water (2 x 100ml)), dried (MgSO4) and solvent removed at reduced pressure. Column chromatography (silica gel,
dichloromethane-5% ethanol/dichloromethane eluant) gave 3- cyano-6-[3-[1-(1,2-dihydroxypropyl)]-4-methoxy-5-(E-1- propenyl)phenyl]-2-methoxypyridine (0.99g). 1Η NMR δ(CDCl3) 1.17 (d, 3H), 1.97 (d, 3H), 2.5 (br. s, 1H), 2.98 (br. s, 1H),
3.82 (s, 3H), 3.94-4.05 (m, 1H), 4.16 (s, 3H), 4.77 (d, 1H), 6.30- 6.42 (m, 1H), 6.66 (d, 1H), 7.41 (d, 1H), 7.90 (d, 1H), 7.93 (d, 1H) and 8.08 (d, 1H).
(c) To a solution of 3-cyano-6-[3-[1-(1,2- dihydroxypropyl)]-4-methoxy-5-(E-1-propenyl)phenyl]-2- methoxypyridine (0.99g) in tetrahydrofuran (20ml) a solution of sodium metaperiodate (0.64g) in water (3ml) was added. The mixture was stirred for 2 hours, additional sodium metaperiodate (0.1g) in water (2ml) added and stirring continued for a further 2 hours. The mixture was filtered, diluted with ethyl acetate (100ml), washed with water (2 x 50ml), dried (MgSO4) and solvent removed at reduced
pressure. The residue was column chromatographed (silica gel, dichloromethane- 5% ethanol/dichloromethane eluant) to give 3-cyano-6-[3-formyl-4-methoxy-5-(E-1-propenyl)phenyl]- 2-methoxypyridine (0.7g) m.p. 174°C. 1H NMR δ(CDCl3)
2.00 (d, 3H), 3.93 (s, 3H), 4.18 (s, 3H), 6.38-6.53 (m, 1H),
6.69 (d, 1H), 7.47 (d, 1H), 7.94 (d, 1H), 8.33 (d, 1H), 8.41 (d, 1H) and 10.44 (1H). (d) A solution of 3-cyano-6-[3-formyl-4-methoxy-5-(E-1- propenyl)phenyl]-2-methoxypyridine (0.65g) in ethanol
(10ml) was treated with sodium borohydride (100mg) in portions over 30 minutes. The solution was stirred for a further 2 hours, solvent removed at reduced pressure, the residue dissolved in ethyl acetate (100ml), washed with water (2 x 50ml) , dried (MgSO4) and solvent removed at reduced pressure. The residue was dissolved in dimethyl sulphoxide (5ml), potassium hydroxide (0.56g, crushed pellets) added, followed by iodomethane (0.6g) and the mixture stirred for 30 minutes. After diluting with ethyl acetate (100ml) the reaction mixture was washed with water (6 x 50ml), dried (MgSO4) and solvent removed at reduced pressure. The residue was column chromatographed (silica gel, 40% hexane/dichloromethane - dichloromethane) to give 3-cyano-6-[3-methoxymethyl-4-methoxy-5-(E-1- propenyl)phenyl]-2-methoxyρyridine (0.54g) m.p. 81-82°C. 1H NMR δ(CDCl3) 1.96 (d, 3H), 3.47 (s, 3H), 3.79 (s, 3H),
4.17 (s, 3H), 4.56 (s, 2H), 6.306.42 (m, 1H), 6.70 (d, 1H),
7.42 (d, 1H), 7.88 (d, 1H), 7.92 (d, 1H) and 8.10 (d, 1H).
(e) From 3-cyano-6-[3-methoxymethyl-4-methoxy-5-(E-1- propenyl)phenyl]-2-methoxypyridine (0.54g), 3-cyano-6-[3- methoxymethyl-4-methoxy-5-(E-1-propenyl)phenyl]pyridin- 2(1H)-one (0.33g) m.p.188-190°C after column chromatography (silica gel, dichloromethane - 2.5% ethanol/dichloromethane eluant), was prepared according to the method of Example 37(c). 1H NMR δ(CDCl3) 1.99 (d, 3H), 3.49 (s, 3H), 3.81 (s, 3H), 4.60 (s, 2H), 6.46-6.70 (m, 3H), 7.72 (d, 1H), 7.85 (d, 1H),
7.91 (d, 1H) and 12.89 (br. s, 1H).
(f) From 3-cyano-6-[3-methoxymethyl-4-methoxy-5-(E-1- propenyl)phenyl]pyridin-2(1H)-one (0.3g) the title compound (0.22g) m.p. 245-246°C after recrystallisation from
ethanol, was prepared according to the method of Example 1 (b). 1H NMR δ(DMSO-d6) 1.92 (d, 3H), 3.61 (s, 3H), 3.83 (s, 3H), 4.81 (s, 2H), 6.26-6.44 (m, 1H), 6.68 (d, 1H), 6.88 (d, 1H)
7.73 (d, 1H), 8.04 (d, 1H), 8.75 (d, 1H) Example 55
6-[3-(E-2-Carbamoylethenyl)-4-methoxy-5-(E-1- propenyl)phenyl]-3-(5-tetrazolyl)pyridin-2-(1H)-one
(273/2602)
(a) Triethylphosphonoacetate (0.9g) was added dropwise to a suspension of sodium hydride (0.18g, 50% in oil) in
tetrahydrofuran (10ml). When gas evolution had ceased a solution of 3-cyano-6-[3-formyl-4-methoxy-5-(E-1- propenyl)phenyl]-2-methoxyρyridine in tetrahydrofuran
(10ml)was added and the mixture stirred for 4 hours.
Ethanol (10ml) and 2N sodium hydroxide (10ml) were added and the mixture boiled for 2 hours. Solvent was removed at reduced pressure, the residue dissolved in water and acidified with 2N hydrochloric acid. The precipitate was collected by filtration to give 3-cyano-6-[3-(E-2- carboxylatoethenyl)-4-methoxy-5-(E-1-propenyl)phenyl]-2- methoxypyridine (0.9g). 1H NMR δ(CDCl3) 1.94 (d, 3H),
3.73 (s, 3H), 4.14 (s, 3H), 6.50-6.62 (m, 1H), 6.69 (d, 1H), 6.7 8 (d, 1H), 7.82 (1H), 7.99 (d, 1H) and 8.33-8.42 (m, 3H).
(b) Oxalyl chloride (0.76g) was added over 5 minutes to an ice cooled suspension of 3-cyano-6-[3-(E-2- carboxylatoethenyl)-4-methoxy-5-(E-1-proρenyl)phenyl]-2- methoxypyridine in dichloromethane (20ml) containing dimethylformamide (0.1ml). When gas evolution had ceased (4 hours) solvent was removed at reduced pressure and the residue redissolved in dichloromethane (20ml). To the ice cooled solution ammonium hydroxide (10ml, SG 0.88) was added and the solution stirred at 0°C for 30 minutes and a room temperature for 30minutes. The precipitated solid was collected by filtration and recrystallised twice from ethanol to give 3-cyano-6-[3-(E-2-carbamoylethenyl)-4- methoxy-5-(E-1-propenyl)phenyl]pyridin-2(1H)-one (0.4g) m.p. 245-246°C. 1H NMR δ(DMSO-d6) 1.94 (d, 3H), 3.72 (s, 3H), 4.14 (s, 3H), 6.49-6.62 (m, 1H), 6.66 (d, 1H), 6.80 (d, 1H), 7.19 (br. s, 1H) , 7. 62 (br. s, 1H) , 7 . 62 (d, 1H) , 7. 89 (d, 1H) ,
8.27 (d, 1H) , 8 .29 (d, 1H) and 8 .34 (d, 1H) .
(c) From 3-cyano-6- [3- (E-2-carbamoylethenyl) -4-methoxy-5- (E-1-propenyl) phenyl] -2-methoxypyridine (0.35g) , 3-cyano-6- [3- (E-2-carbamoylethenyl) -4-methoxy-5- (E-1- propenyl) phenyl] pyridin-2 (1H) -one (0.2g) m.p . >300°C after recrystallisation from dimethylf ormamide/ethanol/water, was prepared according to the method of Example 37 (c). 1H NMR δ(DMSO-d6) 1.93 (d, 3H), 3.71 (s, 3H), 6.51-6.71 (m, 2H) ,
6.91 (br.d, 1H), 7.21 (br.s, 1H), 7.61 (d, 1H), 7.62 (br. s, 1H), 7.93 (s, 1H), 7.99 (s, 1H), 8.20 (d, 1H) and 12.78 (br. s, 1H).
(d) From 3-cyano-6-[3-(E-2-carbamoylethenyl)-4-methoxy-5- (E-1-propenyl)phenyl]pyridin-2(1H)-one (0.16g), the title compound (0.08g) m.p.292-294°C (decomp) after
recrystallisation from dimethylformamide/ethanol/water, was prepared according to the method of Example 1 (b) 1H NMR δ(DMSO-d6) 1.94 (d, 3H), 3.73 (s, 3H), 6.55-6.72 (m, 2H),
6.83 (d, 1H), 7.00 (d, 1H), 7.23 (br. s, 1H), 7.62 (d, 1H),
7.66 (br. s, 1H), 7.99 (d, 1H) and 8.48 (d, 1H).
Example 56 6-(3-Cyclopropylmethyloxy-4-methoxyphenyl)pyridin-2(1H)-one
(a) From 3'-hydroxy-4'-methoxyacetophenone (3.32g), 3'- cyclopropylmethyloxy-4'-methoxyacetophenone (4.34g) was prepared according to the method of Example 2 (a). 1H NMR δ(CDCl3) 0.34-0.40 (m, 2H), 0.63-0.70 (m, 2H), 1.28-1.43m, 1H), 2.56 (s, 3H), 3.91 (d, 2H), 3.95 (s, 3H), 6.89 (d, 1H), 7.50 (d, 1H) and 7.56 (dd, 1H).
(b) From 3 ' -cyclopropylmethyloxy-4 ' -methoxyacetophenone (3.55g) , 3-cyano-6- (3-cyclopropylmethyloxy-4- methoxyphenyl) pyridin-2 (1H) -one (1.30g) m.p . 241-242°C after recrystallisation from butanol was prepared according to the method of Example 3 (a).
(c) From 3-cyano-6-(3-cyclopropylmethyloxy-4- methoxyphenyl)pyridin-2(1H)-one (0.89g), the title compound (0.67g) m.p. 296-297°C (decomp) after recrystallisation from butanol, was prepared according to the method of
Example 1(b). 1H NMR δ(DMSO-d6) 0.32-0.38 (m, 2H), 0.57- 0.66 (m, 2H), 1.22-1.37 (m, 1H), 3.85 (s, 1H), 3.94 (d, 2H),
6.88 (d, 1H), 7.10 (d, 1H), 7.39-7.48 (m, 2H), 8.43 (d, 1H) and 12.56 (br. s, 1H).
Example 57 6-(2-methoxy-4-propoxyphenyl)-3-(5-tetrazolyl)pyridin- 2(1H)-one
(a) From 2'-4'-dihydroxyacetophenone (50g), 2'-hydroxy-4'- propoxyacetophenone (6g) was prepared according to the method of Example 2(a), using bromopropane (40g) and acetone as solvent. 1H NMR δ(DMSO-d6) 0.93 ((t, 3H), 1.61- 1.72 (m, 2H), 2.38 (s, 3H), 3.75 (t, 2H), 5.61 (dd, 1H), 5.80 (d, 1H) and 7.40 (d, 1H). (b) From 2'-hydroxy-4'-propoxyacetophenone (6g), 2'- methoxy-4'-propyloxyacetophenone (5.18g) was prepared according to the method of Example 2(a). 1H NMR δ(CDCl3) 1.05 (t, 3H), 1.74-1.91 (m, 2H), 2.57 (s, 3H), 3.89 (s, 3H),
3.97 (t, 2H), 6.46-6.53 (m, 2H) and 7.80 (d, 1H).)
(c) From 2'-methoxy-4'-propoxyacetophenone (5g), 3-cyano-6- (2-methoxy-4-propoxyphenyl)pyridin-2(1H)-one (0.38g) m.p.l86-188°C after trituration with diethyl ether was prepared according to the method of Example 3 (a). 1H NMR δ(DMSO-d6) 0.99 (t, 3H), 1.72-1.81 (m, 2H), 3.82 (s, 3H),
4.02 (s, 2H), 6.47 (d, 1H), 6.61-6.67 (m, 2H), 7.39 (d, 1H) and 8.11 (d, 1H). (d) From 3-cyano-6-(2-methoxy-4-propoxyphenyl)pyridin- 2(1H)-one (0.36g), the title compound (0.04g) m.p. >300°C after recrystallisation from ethanol and trituration with diethyl ether, was prepared according to the method of Example 1(b). 1H NMR δ(DMSO-d6 at 370K) 1.00 (t, 3H), 1.69- 1.82 (m, 2H), 3.83 (s, 3H), 4.02 (t, 2H), 6.61-6.66 (m, 2H),
6.98 (unresolved, 1H), 7.55 (unresolved, 1H) and
8.44 (unresolved, 1H).
Example X
Pharmaceutical compositions for oral administration are prepared by combining the following : w/w
6-(3-methoxyphenyl)-3-
(5-tetrazolyl)pyridin-2(1H)-one 0.5 3.0 7.14
2% w/w Soya lecithin in soya
bean oil 90.45 88.2 84.41
Hydrogenated vegetable
shortening and beeswax 9.05 8.8 8.45
The formulations are then filled into individual soft gelatin capsules.
Example Y
A pharmaceutical composition for parenteral
administration is prepared by dissolving the title
compound of Example 23 (0.02 g) in polyethylene glycol 300 (25 ml) with heating. This solution is then diluted with water for injections Ph. Eur. (to 100 ml). The solution is 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) :
Figure imgf000069_0001
or a pharmaceutically acceptable salt thereof, wherein
R0 is OH or a bioprecursor thereof,
R1 is 5-tetrazolyl, or a bioprecursor thereof and
Ar is phenyl substituted by one to three groups
independently selected from C1-6alkyl,
C2-6alkenyl, C1-6alkoxy, C3-6alkenyloxy,
C3-6cycloalkyl, C3-6σycloalkoxy, C1-6alkylthio,
phenyl, phenylthio, benzyloxy, C1-6polyfluoroalkyl, C1-6polyfluoroalkoxy, halo, NR2, or NHCOR wherein R is H or C1-6alkyl, or -X(CH2)nY- attached to adjacent
carbon atoms of the phenyl ring wherein X and Y are independently CH2 or 0 and n is 1 to 3, wherein said C1-6alkyl, C2-6alkenyl or C1-6alkoxy groups can be independently substituted by OH, C1-6alkoxy,
C3-6cycloalkyl, NR2, CO2R or CONR2 ; with the
proviso that Ar is not phenyl monosubstituted by
2-C1-6alkoxy.
2. A compound according to claim 1 wherein R0 is OH or OR2 in which R2 is C1-4alkyl, arylC1-4alkyl,
C1-4alkanoyl, arylsulphonyl or C1-4alkylsulphonyl.
3. A compound according to claim 1 or 2 wherein Ar is phenyl mono-substituted by a group as defined in claim 1.
4. A compound according to claim 1 or 2 wherein Ar is phenyl di-substituted by any two groups as defined in claim 1.
5. A compound according to claim 1 or 2 wherein Ar is phenyl trisubstituted by any three groups as defined in claim 1.
6. A compound according to claim 1 which is :
6- (3-methoxyphenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one, 6-( 3-propoxyphenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one, 6-(3-utoxyphenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one, 6-(3-benzyloxyphenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one,
6- (3-bromophenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one,
6- (3-trifluoromethyl)-3-(5-tetrazolyl)pyridin-2(1H)-one,
6- (3-ethylphenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one, 6-( 4-butoxyphenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one,
6- (4-isobutylphenyl)pyridin-2(1H)-one,
6-( 4-biphenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one,
6- ( 4-propoxyphenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one, 6- (4-methoxy-3-propoxyphenyl) -3- ( 5-tetrazolyl) pyridin- 2 (1H) -one,
6-(3,4-methylenedioxyphenyl)-3-(5-tetrazolyl)pyridin-2(1H)- one,
6-(3,4-dichlorophenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one,
6-(3,5-dipropoxyphenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one,
6-(3,5-diethoxyphenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one,
6-(3,5-dibromophenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one, 6-(2,4-dipropoxyphenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one,
6-(2,5-dipropoxyphenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one,
6-(2,3,4-trichlorophenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one,
6-[6-(1,2,3,4-tetrahydronaphthyl)]-3-(5-tetrazolyl)pyridin- 2 (1H)-one,
6-(3-chlorophenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one,
6-(3-phenylthiophenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one,
3,4-dimethoxyphenyl-3-(5-tetrazolyl)pyridin-2(1H)-one, 6-(3-methylthiophenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one,
6-(3-butylthiophenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one, 6-(3,4-di-n-propoxyphenyl)-3-(5-tetrazolyl)pyridin-2(1H)- one,
6-(2,3-di-n-propoxyphenyl)-3-(5-tetrazolyl)pyridin-2(1H)- one,
6-(3-cyclopentyloxy-4-methoxyphenyl)-3-(5-tetrazolyl)- pyridin-2(1H)-one, 6-(3-ethoxyphenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one,
6-(3,5-dimethoxyphenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one,
6-(2-butylthiophenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one,
6-(3-allyloxyphenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one,
6-(4-methoxy-2-pentyloxyphenyl)-3-(5-tetrazolyl)pyridin- 2(1H)-one, 6-(3-iso-butoxy-4-methoxyphenyl)-3-(5-tetrazolyl)pyridin- 2(1H)-one,
6-(2-bromo-3,5-diethoxyphenyl-3-(5-tetrazolyl)pyridin- 2(1H)-one,
6-(5-bromo-4-methoxy-2-pentyloxyphenyl)-3-(5-tetrazolyl)- pyridin-2(1H)-one,
6-(2-allyl-4-methoxy-3-propoxyphenyl)-3-(5-tetrazolyl)- pyridin-2(1H)-one, 6-[3-(E-1-propenyl)-4-methoxyphenyl]-3-(5-tetrazolyl)pyridin -2(1H)-one,
6-(4-methoxy-3-propoxyphenyl)-3-[5-(1-pivaloyloxymethyl)- tetrazolyl]pyridin-2(1H)-one,
6-(4-methoxy-3-propoxyphenyl)-3-[5-(2-pivaloyloxymethyl)- tetrazolyl]pyridin-2(1H)-one, 6-[3-ethoxy-5-(2-methoxyethoxy)phenyl]-3-(5-tetrazolyl)- pyridin-2(1H)-one,
6-[3-(2,2-dimethylpropyloxy)-4-methoxyphenyl]-3-(5- tetrazolyl)pyridin-2(1H)-one,
6-(3-ethoxy-4-methoxyphenyl)-3-(5-tetrazolyl)pyridin-2(1H)- one,
6-(3-propionamidophenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one,
6-(4-methoxy-3-propylphenyl)-3-(5-tetrazolyl)pyridin-2(1H)- one, 6-(3-bromo-4-methoxyphenyl)-3-(5-tetrazolyl)pyridin-2(1H)- one,
6-(3-phenyl-4-methoxyphenyl)-3-(5-tetrazolyl)pyridin-2(1H)- one,
6-[4-methoxy-3,5-di(E-1-propenyl)phenyl]-3-(5-tetrazolyl)- pyridin-2(1H)-one,
6-[3-(E-1-propenyl)-4-propoxyphenyl]-3-(5-tetrazolyl)- pyridin-2(1H)-one, 6- (3-bromo-4-methoxy-5-propylphenyl) -3- (5-tetrazolyl) - pyridin-2- (1H) -one,
6-(2-butylthio-3,5-diethoxyphenyl)-3-(5-tetrazolyl)pyridin- 2(1H)-one,
6-(3-bromo-4-N,N-dimethylaminophenyl)-3-(5-tetrazolyl)- pyridin-2(1H)-one, 6-(3-acetamido-4-methoxy-5-propylphenyl)-3-(5-tetrazolyl)- pyridin-2(1H)-one,
6-[3-methoxymethyl-4-methoxy-5-(E-1-propenyl)phenyl]-3-(5- tetrazolyl)pyridin-2(1H)-one,
6-[3-(E-2-carbamoylethenyl)-4-methoxy-5-(E-l-propenyl)- phenyl]-3-(5-tetrazolyl)pyridin-2-(1H)-one, or
6-(3-cyclopropylmethyloxy-4-methoxyphenyl)pyridin-2(1H)- one or a pharmaceutically acceptable salt thereof.
7. A compound according to any one of claims 1 to 6 for use as a medicament.
8. A pharmaceutical composition which comprises a compound according to any one of claims 1 to 6 and a pharmaceutically acceptable carrier.
9. A process for preparing a compound of the formula (1) as defined in claim 1 or a pharmaceutically acceptable salt thereof which process comprises reacting a compound of the formula (2) :
Figure imgf000075_0001
wherein Ar is as hereinbefore defined with an azide salt, and optionally thereafter :
° forming a bioprecursor of R0 and/or R1 ° forming a pharmaceutically acceptable salt.
10. A compound of the formula (2) as defined in claim 9.
PCT/GB1991/001663 1990-09-28 1991-09-26 Phenylpyridinol derivatives as medicaments WO1992006085A1 (en)

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Cited By (38)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993010093A1 (en) * 1991-11-20 1993-05-27 Smithkline Beecham Plc 2-pyridinol derivatives and their use as medicaments
WO1993010114A1 (en) * 1991-11-20 1993-05-27 Smithkline Beecham Plc 3-pyridinol derivatives and their use as medicaments
WO1993019754A1 (en) * 1992-03-27 1993-10-14 Smithkline Beecham Plc Phenol and pyridinol derivatives as lusitropic agents
WO1994010118A1 (en) * 1992-10-23 1994-05-11 Celltech Limited Tri-substituted phenyl derivatives and processes for their preparation
WO1994012461A1 (en) * 1992-12-02 1994-06-09 Pfizer Inc. Catechol diethers as selective pdeiv inhibitors
US5580888A (en) * 1992-12-23 1996-12-03 Celltech Therapeutics Limited Styryl derivatives as anti-inflammatory agents
US5608070A (en) * 1993-12-22 1997-03-04 Celltech Therapeutics Limited Enantioselective process for the preparation of chiral triaryl derivatives and chiral intermediates for use therein
US5622977A (en) * 1992-12-23 1997-04-22 Celltech Therapeutics Limited Tri-substituted (aryl or heteroaryl) derivatives and pharmaceutical compositions containing the same
US5633257A (en) * 1993-03-10 1997-05-27 Celltech Therapeutics Limited Cyclo(alkyl and alkenyl)phenyl-alkenylyl(aryl and heteroaryl)compounds and pharmaceutical compositions containing them
WO1997032853A1 (en) * 1996-03-08 1997-09-12 Novartis Ag Triaryl compounds
US5693659A (en) * 1994-06-23 1997-12-02 Celltech Therapeutics Limited Substituted oxime derivatives and processes for their preparation
US5739144A (en) * 1993-03-10 1998-04-14 Celltech Therapeutics Limited Trisubstituted phenyl derivatives
US5780478A (en) * 1994-06-22 1998-07-14 Celltech Therapeutics, Limited Tetra-substituted phenyl derivatives
US5780477A (en) * 1994-06-22 1998-07-14 Celltech Therapeutics, Limited Trisubstituted phenyl derivatives and processes for their preparation
US5786354A (en) * 1994-06-21 1998-07-28 Celltech Therapeutics, Limited Tri-substituted phenyl derivatives and processes for their preparation
US5798373A (en) * 1995-12-21 1998-08-25 Celltech Therapeutics, Limited Tri-substituted phenyl derivatives useful as PDE IV inhibitors
US5814651A (en) * 1992-12-02 1998-09-29 Pfizer Inc. Catechol diethers as selective PDEIV inhibitors
US5849770A (en) * 1995-12-21 1998-12-15 Celltech Therapeutics Ltd. Tri-substituted phenyl derivatives useful as PDE IV inhibitors
US5859034A (en) * 1996-12-04 1999-01-12 Celltech Therapeutics, Limited Tri-substituted phenyl compounds which have useful pharmaceutical activity
US5866593A (en) * 1993-12-22 1999-02-02 Celltech Therapeutics Ltd. Trisubstituted phenyl derivatives and processes for their preparation
US5922741A (en) * 1996-04-24 1999-07-13 Celltech Therapeutics Ltd. 5-aminopyrazoles useful as tyrosine kinase inhibitors
US5958935A (en) * 1995-11-20 1999-09-28 Celltech Therapeutics Limited Substituted 2-anilinopyrimidines useful as protein kinase inhibitors
US5958837A (en) * 1995-01-13 1999-09-28 Basf Aktiengesellschaft Substituted 2-phenylpyridines
US6048866A (en) * 1997-03-14 2000-04-11 Celltech Therapeutics, Limited Substituted 2-anilinopryimidines useful as protein kinase inhibitors
US6057329A (en) * 1996-12-23 2000-05-02 Celltech Therapeutics Limited Fused polycyclic 2-aminopyrimidine derivatives
US6093716A (en) * 1996-09-16 2000-07-25 Celltech Therapeutics, Limited Substituted 2-pyrimidineamines and processes for their preparation
US6096747A (en) * 1992-06-15 2000-08-01 Celltech Therapeutics Limited Phenylaminocarbonyl derivatives and processes for their preparation
US6114333A (en) * 1996-10-28 2000-09-05 Celltech Therapeutics Ltd. 2-Pyrimidineamine derivatives and processes for their preparation
US6133257A (en) * 1997-06-20 2000-10-17 Celltech Therapeutics Limited Fused polycyclic 2-aminopyrimidine derivatives
US6245774B1 (en) 1994-06-21 2001-06-12 Celltech Therapeutics Limited Tri-substituted phenyl or pyridine derivatives
US6579983B1 (en) 1999-06-18 2003-06-17 Celltech R&D Limited 5-cyano-2-aminopyrimidine derivatives
US6600037B1 (en) 1999-10-20 2003-07-29 Celltech R & D Limited 4,5-disubstituted-2-aminopyrimidines
US6770661B2 (en) 2001-09-07 2004-08-03 Euro-Celtique S.A. Aryl substituted pyridines and their use
US6867210B2 (en) 2000-03-10 2005-03-15 Euro-Celtique S.A. Aryl substituted pyrimidines
US7105549B2 (en) 2001-09-07 2006-09-12 Euro-Celtique S.A. Aryl substituted pyridines and the use thereof
US7235561B2 (en) 2001-05-29 2007-06-26 Schering Ag Compound and a composition including such a compound
US8013001B2 (en) * 2001-12-21 2011-09-06 Exelixis, Inc. Modulators of LXR
US11149027B2 (en) 2016-03-31 2021-10-19 Sumitomo Chemical Company, Limited Heterocyclic compound

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BE885484A (en) * 1979-10-02 1981-02-02 Meiji Seika Kaisha PENICILLIN COMPOUNDS AND PROCESSES FOR THEIR PREPARATION
EP0347027A2 (en) * 1988-04-21 1989-12-20 Smith Kline & French Laboratories Limited Phenylpyridone derivatives,processes for their preparation and pharmaceutical compositions containing them.

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB8923131D0 (en) * 1989-10-13 1989-11-29 Smith Kline French Lab Chemical compounds

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BE885484A (en) * 1979-10-02 1981-02-02 Meiji Seika Kaisha PENICILLIN COMPOUNDS AND PROCESSES FOR THEIR PREPARATION
EP0347027A2 (en) * 1988-04-21 1989-12-20 Smith Kline & French Laboratories Limited Phenylpyridone derivatives,processes for their preparation and pharmaceutical compositions containing them.

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
Chemical Abstracts, volume 86, no. 17, 1977 (Columbus, Ohio, US) J. Liebscher et al.: "Chemistry of activated vinyl halides. Synthesis and reaction behavior of 3-(beta-chlorovinyl)acrylonitriles", see page 513, abstract 120947m, & J. Prakt. Chem., 1976, 318(5), 705-30 *
Chemical Abstracts, volume 95, no. 9, 1981, (Columbus, Ohio, US) see page 788, abstract 80943j, & BE, A, 885484 (MEIJI SEIKA KAISHA, LTD) 2 February 1981 *
Chemical Pharmacological Bulletin, volume 30, no. 12, 1982 (Tokyo, JP) Y. Honma et al.: "Studies on antiallergic agents. I. Phenyl-substituted heterocycles with a 5-tetrazolyl or N-(5-tetrazolyl)carbamoyl group", pages 4314-4324, see page 4318, compound 57 *
Registry Handbook, number section, 1987, supplement, registry numbers 107982-26-3 through 110170-82-6, Chemical Abstracts Service, (Columbus, Ohio, US) see page 1208, registry numbers 107487-93-4; 107487-94-5, 107487-95-6; 107488-00-6; 107488-01-7; 107488-02-8 *

Cited By (60)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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US6096747A (en) * 1992-06-15 2000-08-01 Celltech Therapeutics Limited Phenylaminocarbonyl derivatives and processes for their preparation
US5491147A (en) * 1992-10-23 1996-02-13 Celltech, Limited Tri-substituted phenyl derivatives and their use in pharmaceutical compositions and methods of treatment
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US6080790A (en) * 1992-10-23 2000-06-27 Celltech Therapeutics, Limited Tri-substituted phenyl derivatives and processes for their preparations
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US5674880A (en) * 1992-10-23 1997-10-07 Celltech Therapeutics Limited Tri-substituted phenyl derivatives and processes for their preparation
WO1994012461A1 (en) * 1992-12-02 1994-06-09 Pfizer Inc. Catechol diethers as selective pdeiv inhibitors
AU673569B2 (en) * 1992-12-02 1996-11-14 Pfizer Inc. Catechol diethers as selective PDE-IV inhibitors
US5814651A (en) * 1992-12-02 1998-09-29 Pfizer Inc. Catechol diethers as selective PDEIV inhibitors
US5580888A (en) * 1992-12-23 1996-12-03 Celltech Therapeutics Limited Styryl derivatives as anti-inflammatory agents
US5622977A (en) * 1992-12-23 1997-04-22 Celltech Therapeutics Limited Tri-substituted (aryl or heteroaryl) derivatives and pharmaceutical compositions containing the same
US5739144A (en) * 1993-03-10 1998-04-14 Celltech Therapeutics Limited Trisubstituted phenyl derivatives
US5962483A (en) * 1993-03-10 1999-10-05 Celltech Therapeutics, Limited Trisubstituted phenyl derivatives and processes for their preparation
US5962492A (en) * 1993-03-10 1999-10-05 Celltech Therapeutics Limited 2 cyclo(alkyl and alkenyl) phenyl-alkenylyl heteroaryl compounds and pharmaceutical compositions containing same
US5633257A (en) * 1993-03-10 1997-05-27 Celltech Therapeutics Limited Cyclo(alkyl and alkenyl)phenyl-alkenylyl(aryl and heteroaryl)compounds and pharmaceutical compositions containing them
US5723460A (en) * 1993-03-10 1998-03-03 Celltech Therapeutics Limited Cyclo (alkyl and alkenyl) phenyl-alkenylyl heteroaryl compounds and pharmaceutical compositions containing same
US5866593A (en) * 1993-12-22 1999-02-02 Celltech Therapeutics Ltd. Trisubstituted phenyl derivatives and processes for their preparation
US5608070A (en) * 1993-12-22 1997-03-04 Celltech Therapeutics Limited Enantioselective process for the preparation of chiral triaryl derivatives and chiral intermediates for use therein
US6077854A (en) * 1994-06-21 2000-06-20 Celltech Therapeutics, Limited Tri-substituted phenyl derivatives and processes for their preparation
US5786354A (en) * 1994-06-21 1998-07-28 Celltech Therapeutics, Limited Tri-substituted phenyl derivatives and processes for their preparation
US6245774B1 (en) 1994-06-21 2001-06-12 Celltech Therapeutics Limited Tri-substituted phenyl or pyridine derivatives
US6297264B1 (en) 1994-06-22 2001-10-02 Celltech Therapeutics Limited Trisubstituted phenyl derivatives and process for their preparation
US5780477A (en) * 1994-06-22 1998-07-14 Celltech Therapeutics, Limited Trisubstituted phenyl derivatives and processes for their preparation
US6197792B1 (en) 1994-06-22 2001-03-06 Celltech Therapeutics Limited Tetra-substituted phenyl derivatives and processes for their preparation
US5780478A (en) * 1994-06-22 1998-07-14 Celltech Therapeutics, Limited Tetra-substituted phenyl derivatives
US5693659A (en) * 1994-06-23 1997-12-02 Celltech Therapeutics Limited Substituted oxime derivatives and processes for their preparation
US5958837A (en) * 1995-01-13 1999-09-28 Basf Aktiengesellschaft Substituted 2-phenylpyridines
US5958935A (en) * 1995-11-20 1999-09-28 Celltech Therapeutics Limited Substituted 2-anilinopyrimidines useful as protein kinase inhibitors
US6235746B1 (en) 1995-11-20 2001-05-22 Celltech Therapeutics, Limited Substituted 2-anilinopyrimidines useful as protein kinase inhibitors
US5849770A (en) * 1995-12-21 1998-12-15 Celltech Therapeutics Ltd. Tri-substituted phenyl derivatives useful as PDE IV inhibitors
US5798373A (en) * 1995-12-21 1998-08-25 Celltech Therapeutics, Limited Tri-substituted phenyl derivatives useful as PDE IV inhibitors
US6410547B1 (en) 1996-03-08 2002-06-25 Novartis Ag Phenylpyridine derivatives useful as phosphodiesterase inhibitors
US6090817A (en) * 1996-03-08 2000-07-18 Novartis Ag Phenylpyridine derivatives useful as phosphodiesterase inhibitors
WO1997032853A1 (en) * 1996-03-08 1997-09-12 Novartis Ag Triaryl compounds
US6288092B1 (en) 1996-03-08 2001-09-11 Novartis Ag Triaryl compounds
US6258843B1 (en) 1996-03-08 2001-07-10 Novartis Ag 4-oxy-3-(aryl)phenyl-arylcarbonyloxy compounds useful as phosphodiesterase inhibitors
US5922741A (en) * 1996-04-24 1999-07-13 Celltech Therapeutics Ltd. 5-aminopyrazoles useful as tyrosine kinase inhibitors
US6093716A (en) * 1996-09-16 2000-07-25 Celltech Therapeutics, Limited Substituted 2-pyrimidineamines and processes for their preparation
US6552029B1 (en) 1996-10-28 2003-04-22 Celltech R&D Limited 2-pyrimidineamine derivatives and processes for their preparation
US6114333A (en) * 1996-10-28 2000-09-05 Celltech Therapeutics Ltd. 2-Pyrimidineamine derivatives and processes for their preparation
US5859034A (en) * 1996-12-04 1999-01-12 Celltech Therapeutics, Limited Tri-substituted phenyl compounds which have useful pharmaceutical activity
US6599908B1 (en) 1996-12-23 2003-07-29 Celltech R & D Limited Fused polycyclic 2-aminopyrimidine derivatives
US6057329A (en) * 1996-12-23 2000-05-02 Celltech Therapeutics Limited Fused polycyclic 2-aminopyrimidine derivatives
US6337335B1 (en) 1997-03-14 2002-01-08 Celltech Therapeutics Limited Substituted 2-anilinopyrimidines useful as protein kinase inhibitors
US6048866A (en) * 1997-03-14 2000-04-11 Celltech Therapeutics, Limited Substituted 2-anilinopryimidines useful as protein kinase inhibitors
US6133257A (en) * 1997-06-20 2000-10-17 Celltech Therapeutics Limited Fused polycyclic 2-aminopyrimidine derivatives
US6579983B1 (en) 1999-06-18 2003-06-17 Celltech R&D Limited 5-cyano-2-aminopyrimidine derivatives
US6600037B1 (en) 1999-10-20 2003-07-29 Celltech R & D Limited 4,5-disubstituted-2-aminopyrimidines
US6867210B2 (en) 2000-03-10 2005-03-15 Euro-Celtique S.A. Aryl substituted pyrimidines
US7235561B2 (en) 2001-05-29 2007-06-26 Schering Ag Compound and a composition including such a compound
US7291624B2 (en) 2001-05-29 2007-11-06 Bayer Schering Pharma Ag CDK-inhibitory pyrimidines, their production and use as pharmaceutical agents
US6770661B2 (en) 2001-09-07 2004-08-03 Euro-Celtique S.A. Aryl substituted pyridines and their use
US7105549B2 (en) 2001-09-07 2006-09-12 Euro-Celtique S.A. Aryl substituted pyridines and the use thereof
US7579367B2 (en) 2001-09-07 2009-08-25 Purdue Pharma L.P. Aryl substituted pyridines and the use thereof
US7943643B2 (en) 2001-09-07 2011-05-17 Purdue Pharma L.P. Aryl substituted pyridines and the use thereof
US8013001B2 (en) * 2001-12-21 2011-09-06 Exelixis, Inc. Modulators of LXR
US11149027B2 (en) 2016-03-31 2021-10-19 Sumitomo Chemical Company, Limited Heterocyclic compound

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PT99081A (en) 1992-08-31
AU644016B2 (en) 1993-12-02
CA2091989A1 (en) 1992-03-29
EP0550576A1 (en) 1993-07-14
AU8543191A (en) 1992-04-28
IE913400A1 (en) 1992-04-08
JPH06501254A (en) 1994-02-10
NZ239946A (en) 1994-09-27
MX9101375A (en) 1992-05-04

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