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.

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• 1991
  • 1991-09-26 CA CA002091989A patent/CA2091989A1/en not_active Abandoned
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