[go: up one dir, main page]

WO1992006085A1 - Derives de phenylpyridinol utilises comme medicaments - Google Patents

Derives de phenylpyridinol utilises comme medicaments Download PDF

Info

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
Authority
WO
WIPO (PCT)
Prior art keywords
pyridin
tetrazolyl
methoxy
phenyl
cyano
Prior art date
Application number
PCT/GB1991/001663
Other languages
English (en)
Inventor
Roderick Alan Porter
Kenneth John Murray
Brian Herbert Warrington
Hunter Douglas Prain
Original Assignee
Smith Kline & French Laboratories Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
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/fr

Links

Classifications

    • 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.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Hematology (AREA)
  • Diabetes (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Gynecology & Obstetrics (AREA)
  • Pregnancy & Childbirth (AREA)
  • Endocrinology (AREA)
  • Reproductive Health (AREA)
  • Dermatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pyridine Compounds (AREA)

Abstract

On décrit des dérivés de phénylpyridinol comme médicaments.
PCT/GB1991/001663 1990-09-28 1991-09-26 Derives de phenylpyridinol utilises comme medicaments WO1992006085A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
GB909021184A GB9021184D0 (en) 1990-09-28 1990-09-28 Chemical compounds
GB9021184.8 1990-09-28
GB9117657.8 1991-08-15
GB919117657A GB9117657D0 (en) 1991-08-15 1991-08-15 Chemical compounds

Publications (1)

Publication Number Publication Date
WO1992006085A1 true WO1992006085A1 (fr) 1992-04-16

Family

ID=26297727

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB1991/001663 WO1992006085A1 (fr) 1990-09-28 1991-09-26 Derives de phenylpyridinol utilises comme medicaments

Country Status (9)

Country Link
EP (1) EP0550576A1 (fr)
JP (1) JPH06501254A (fr)
AU (1) AU644016B2 (fr)
CA (1) CA2091989A1 (fr)
IE (1) IE913400A1 (fr)
MX (1) MX9101375A (fr)
NZ (1) NZ239946A (fr)
PT (1) PT99081A (fr)
WO (1) WO1992006085A1 (fr)

Cited By (38)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993010093A1 (fr) * 1991-11-20 1993-05-27 Smithkline Beecham Plc Derives du 2-pyridinol et leur utilisation comme medicaments
WO1993010114A1 (fr) * 1991-11-20 1993-05-27 Smithkline Beecham Plc Derives du 3-pyridinol et leur utilisation comme medicaments
WO1993019754A1 (fr) * 1992-03-27 1993-10-14 Smithkline Beecham Plc Derives de phenol et de pyridinol utilises comme agents lusitropes
WO1994010118A1 (fr) * 1992-10-23 1994-05-11 Celltech Limited Derives du phenyle tri-substitue et procedes pour leur preparation
WO1994012461A1 (fr) * 1992-12-02 1994-06-09 Pfizer Inc. Diethers de pyrocatechine utilises comme inhibiteurs selectifs de la pde¿iv?
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 (fr) * 1996-03-08 1997-09-12 Novartis Ag Composes triaryles
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
US5780477A (en) * 1994-06-22 1998-07-14 Celltech Therapeutics, Limited Trisubstituted phenyl derivatives and processes for their preparation
US5780478A (en) * 1994-06-22 1998-07-14 Celltech Therapeutics, Limited Tetra-substituted phenyl derivatives
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
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
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 (fr) * 1979-10-02 1981-02-02 Meiji Seika Kaisha Composes de penicilline et leurs procedes de preparation
EP0347027A2 (fr) * 1988-04-21 1989-12-20 Smith Kline & French Laboratories Limited Dérivés de phénylpyridine, procédés pour leur préparation et compositions pharmaceutiques les contenant

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 (fr) * 1979-10-02 1981-02-02 Meiji Seika Kaisha Composes de penicilline et leurs procedes de preparation
EP0347027A2 (fr) * 1988-04-21 1989-12-20 Smith Kline & French Laboratories Limited Dérivés de phénylpyridine, procédés pour leur préparation et compositions pharmaceutiques les contenant

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 (61)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993010114A1 (fr) * 1991-11-20 1993-05-27 Smithkline Beecham Plc Derives du 3-pyridinol et leur utilisation comme medicaments
WO1993010093A1 (fr) * 1991-11-20 1993-05-27 Smithkline Beecham Plc Derives du 2-pyridinol et leur utilisation comme medicaments
WO1993019754A1 (fr) * 1992-03-27 1993-10-14 Smithkline Beecham Plc Derives de phenol et de pyridinol utilises comme agents lusitropes
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
JPH07502762A (ja) * 1992-10-23 1995-03-23 セルテック　リミテッド 三置換フェニル誘導体およびそれらの製造方法
US6080790A (en) * 1992-10-23 2000-06-27 Celltech Therapeutics, Limited Tri-substituted phenyl derivatives and processes for their preparations
WO1994010118A1 (fr) * 1992-10-23 1994-05-11 Celltech Limited Derives du phenyle tri-substitue et procedes pour leur preparation
US5674880A (en) * 1992-10-23 1997-10-07 Celltech Therapeutics Limited Tri-substituted phenyl derivatives and processes for their preparation
WO1994012461A1 (fr) * 1992-12-02 1994-06-09 Pfizer Inc. Diethers de pyrocatechine utilises comme inhibiteurs selectifs de la pde¿iv?
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
US5780478A (en) * 1994-06-22 1998-07-14 Celltech Therapeutics, Limited Tetra-substituted phenyl derivatives
US6197792B1 (en) 1994-06-22 2001-03-06 Celltech Therapeutics Limited Tetra-substituted phenyl derivatives and processes for their preparation
US5780477A (en) * 1994-06-22 1998-07-14 Celltech Therapeutics, Limited Trisubstituted phenyl derivatives and processes for their preparation
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
US6258843B1 (en) 1996-03-08 2001-07-10 Novartis Ag 4-oxy-3-(aryl)phenyl-arylcarbonyloxy compounds useful as phosphodiesterase inhibitors
US6090817A (en) * 1996-03-08 2000-07-18 Novartis Ag Phenylpyridine derivatives useful as phosphodiesterase inhibitors
RU2194035C2 (ru) * 1996-03-08 2002-12-10 Новартис Аг Триарильные соединения, способ их получения, фармацевтическая композиция на их основе, способ лечения и промежуточные вещества
WO1997032853A1 (fr) * 1996-03-08 1997-09-12 Novartis Ag Composes triaryles
US6288092B1 (en) 1996-03-08 2001-09-11 Novartis Ag Triaryl compounds
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
US6114333A (en) * 1996-10-28 2000-09-05 Celltech Therapeutics Ltd. 2-Pyrimidineamine derivatives 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
US5859034A (en) * 1996-12-04 1999-01-12 Celltech Therapeutics, Limited Tri-substituted phenyl compounds which have useful pharmaceutical activity
US6057329A (en) * 1996-12-23 2000-05-02 Celltech Therapeutics Limited Fused polycyclic 2-aminopyrimidine derivatives
US6599908B1 (en) 1996-12-23 2003-07-29 Celltech R & D Limited Fused polycyclic 2-aminopyrimidine derivatives
US6048866A (en) * 1997-03-14 2000-04-11 Celltech Therapeutics, Limited Substituted 2-anilinopryimidines useful as protein kinase inhibitors
US6337335B1 (en) 1997-03-14 2002-01-08 Celltech Therapeutics Limited Substituted 2-anilinopyrimidines 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

Also Published As

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

Similar Documents

Publication Publication Date Title
WO1992006085A1 (fr) Derives de phenylpyridinol utilises comme medicaments
JPH09510993A (ja) チロシンキナーゼ阻害剤としての水溶性３−アリールイデン−２−オキシインドール誘導体
JPH09502457A (ja) 置換アザインドリリデン化合物及びその製造方法
US20060128757A1 (en) Pyridine derivatives useful as cyclooxygenase inhibitor
IE911704A1 (en) Chemical compounds
EP0334119A1 (fr) Composés pour l'inhibition de la biosynthèse de métabolites de l'acide arachidonique dérivés de la lipoxygénase
US4863933A (en) 3-hydroxypyridines
AU2930392A (en) 3-pyridinol derivatives and their use as medicaments
AU654051B2 (en) Pyridinol derivatives as medicaments
KR102255957B1 (ko) 신규한 디벤조옥사포스피닌 옥사이드 유도체 화합물 및 이를 포함하는 퇴행성 질환의 예방 또는 치료용 약제학적 조성물
HU195651B (en) Process for production of new derivatives of phenil acetic acid and medical compounds containing them
JP2779206B2 (ja) スルフェンアミド誘導体
JPS6025923A (ja) ５−リポキシゲナ−ゼ阻害剤
US6653311B1 (en) 5-lipoxygenase inhibitors: (2-azinylamino) quinone derivatives
AU2927792A (en) 2-pyridinol derivatives and their use as medicaments
AU2927492A (en) Phenol derivatives as agonists of a cyclic amp dependent protein kinase
JP4345509B2 (ja) 医薬組成物
JPH0425268B2 (fr)
KR20050112948A (ko) 1ｈ-피리딘-2-온 유도체
JPH03261765A (ja) ピリドン誘導体及びその製造方法
JPS59110693A (ja) ピリドン誘導体
JPH10316679A (ja) ピリミジン誘導体

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AU CA JP KR US

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FR GB GR IT LU NL SE

WWE Wipo information: entry into national phase

Ref document number: 2091989

Country of ref document: CA

Ref document number: 1991917244

Country of ref document: EP

WWP Wipo information: published in national office

Ref document number: 1991917244

Country of ref document: EP

WWW Wipo information: withdrawn in national office

Ref document number: 1991917244

Country of ref document: EP