WO1991017987A1 - Phenol and pyridinol derivatives as pharmaceuticals - Google Patents

Phenol and pyridinol derivatives as pharmaceuticals Download PDF

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Publication number
WO1991017987A1
WO1991017987A1 PCT/GB1991/000789 GB9100789W WO9117987A1 WO 1991017987 A1 WO1991017987 A1 WO 1991017987A1 GB 9100789 W GB9100789 W GB 9100789W WO 9117987 A1 WO9117987 A1 WO 9117987A1
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WO
WIPO (PCT)
Prior art keywords
naphthyl
pyridyl
oxo
dihydro
compound
Prior art date
Application number
PCT/GB1991/000789
Other languages
French (fr)
Inventor
Kenneth John Murray
Roderick Alan Porter
Hunter Douglas Prain
Brian Herbert Warrington
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 GB909011274A external-priority patent/GB9011274D0/en
Priority claimed from GB909018919A external-priority patent/GB9018919D0/en
Application filed by Smith Kline & French Laboratories Limited filed Critical Smith Kline & French Laboratories Limited
Publication of WO1991017987A1 publication Critical patent/WO1991017987A1/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
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/08—Bronchodilators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C43/00—Ethers; Compounds having groups, groups or groups
    • C07C43/02—Ethers
    • C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
    • C07C43/205—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring the aromatic ring being a non-condensed ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C65/01—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups
    • C07C65/105—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups polycyclic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C65/21—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing ether groups, groups, groups, or groups
    • C07C65/24—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing ether groups, groups, groups, or groups polycyclic
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    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/76—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
    • C07C69/94—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring of polycyclic hydroxy carboxylic acids, the hydroxy groups and the carboxyl groups of which are bound to carbon atoms of six-membered aromatic rings
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    • 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
    • C07D213/70—Sulfur atoms
    • C07D213/71—Sulfur atoms to which a second hetero atom is attached
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • 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
    • C07D213/79—Acids; Esters
    • C07D213/80—Acids; Esters in position 3
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D257/04—Five-membered rings
    • 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
    • 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
    • C07D401/14—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 three or more hetero rings
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
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    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids RP(=O)(OH)2; Thiophosphonic acids, i.e. RP(=X)(XH)2 (X = S, Se)
    • C07F9/40—Esters thereof
    • C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
    • C07F9/4021—Esters of aromatic acids (P-C aromatic linkage)
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
    • C07F9/576—Six-membered rings
    • C07F9/58—Pyridine rings
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
    • C07F9/6571—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms
    • C07F9/657163—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms the ring phosphorus atom being bound to at least one carbon atom
    • C07F9/657181—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms the ring phosphorus atom being bound to at least one carbon atom the ring phosphorus atom and, at least, one ring oxygen atom being part of a (thio)phosphonic acid derivative

Definitions

  • the present invention relates to fused aryl
  • 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
  • Atheroschlerosis 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.
  • A is N or CH
  • R 0 is OH or a bioprecursor thereof
  • R 1 is A 0 CO 2 H, P(X) (OH) (OR 2 ), SO 2 H, SO 3 H or 5-tetrazolyl or a bioprecursor thereof, A 0 is a single bond, CH 2 , CHF, CF 2 , CR 3 (OR 4 ), CO or
  • R 2 is phenyl, C 3-5 cycloalkyl, C 3-5 cycloalkylC 1-4 alkyl. or C 1-8 alkyl optionally substituted by C 1-4 alkoxy,
  • R 3 is H, methyl or ethyl
  • R 4 is H or C 1-3 alkyl
  • R 5 and R 6 are each C 1-3 alkyl or together form a
  • X is O or S and Ar is 1-naphthyl optionally substituted in the 4-position by hydroxy or C 1-6 alkoxy, 2-naphthyl optionally
  • Bioprecursors of the groups R 0 and R 1 are
  • a suitable bioprecursor of the group R 0 is OR 7 wherein R 7 is 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
  • R 7 can also be C 1-4 alkyl, arylC 1-4 alkyl (for example phenylC 1-4 -alkyl such as benzyl).
  • R 1 is P(X) (OH) (OR 2 )
  • a suitable bioprecursor is P(X) (OR 2 ) 2 wherein X and R 2 are as hereinbefore defined or P(X) (OR 2 ) (OR) wherein R is an O-protecting group.
  • Suitable O-protecting groups include
  • a suitable bioprecursor is a N-protected derivative thereof.
  • Suitable N-protecting groups include pivalolyloxymethyl, propionyloxymethyl and pivaloyloxycarbonyloxymethyl.
  • bioprecursors of the groups R 0 and R 1 are those formed when R 1 and R 0 are linked
  • R 1 -R 0 is A 1 CO 2 or A 2 OCH 2 O, in which :
  • a 1 is CH 2 , CR 3 (OR 4 ), CO or C(OR 5 ) (OR 6 ),
  • a 2 is P(X)OR 2 or CR 3 (CO 2 R 8 ), and
  • R 2 to R 6 , R 8 and X are as hereinbefore defined.
  • R 0 is hydroxy or OR 7 , preferably hydroxy.
  • R 1 is A 0 CO 2 H or A 0 CO 2 R 8 .
  • R 1 is P(X) (OH) (OR 2 ) or P(X) (OR 2 ) 2 .
  • R 1 is SO 2 H, SO 3 H or 5-tetrazolyl.
  • R 1 and R 0 are linked together such that R 1 -R 0 is A 1 CO 2 .
  • R 1 and R 0 are linked together such that R 1 -R 0 is A 2 OCH 2 O.
  • alkyl is meant both straight- and branched- chain alkyl.
  • R 2 is methyl, ethyl, propyl, butyl, pentyl, hexyl, 2-methoxyethyl, phenyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclopropylmethyl.
  • R 3 is H, methyl or ethyl, preferably H or methyl.
  • R 4 is H, methyl, ethyl or propyl
  • R 5 and R 6 are independently methyl, ethyl or propyl, preferably together they form a
  • X is O.
  • R 8 is C 1-4 alkyl optionally substituted by hydroxy, e.g. 2-hydroxyethyl or arylC 1-4 alkyl (for example phenylC 1-4 alkyl such as benzyl).
  • Ar is 1-naphthyl optionally substituted in the 4-position by hydroxy or C 1-6 alkoxy.
  • Ar is 2-naphthyl optionally substituted in the 1-position by hydroxy or C 1-6 alkoxy. Examples of C 1-6 alkoxy
  • Ar is 3-phenanthryl or 9-phenanthryl.
  • Ar is 2-quinolinyl or 4-guinolinyl.
  • Ar is 2-benzofuranyl or 3-thianaphthenyl.
  • Particular compounds of this invention include :
  • This invention covers all tautomeric and optical isomeric forms of compounds of formula (1).
  • R 1 is A 0 CO 2 H, P(X) (OH) (OR 2 ), SO 2 H, SO 3 H or 5-tetrazolyl or R 0 is hydroxy
  • metal ions such as alkali metals for example sodium or potassium, or with an ammonium ion.
  • 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.
  • 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
  • aqueous gums celluloses
  • silicates or oils 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,
  • 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
  • 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.
  • 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 (1) or a pharmaceutically acceptable salt thereof calculated as the free acid.
  • the daily dosage regimen for parenteral administration is suitably about 0.001 mg/Kg to 40 mg/Kg, for example about 0.005 mg/Kg to 10 mg/Kg, of a compound of the formula (1) or a pharmaceutically acceptable salt thereof calculated as the free acid.
  • the active ingredient may be administered as required for example from 1 - 8 times a day or by infusion.
  • the compositions of the invention are agonists of a cA-PrK and are of use in combatting such conditions where such
  • agonism is thought to be beneficial. Such conditions can be treated by administration orally, sublingually
  • 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 any organic compound having the same properties as the compounds of this invention.
  • 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, flouracil, cisplatin,
  • actinomycin D anti-atherschlerotic agents for example cholesterol lowering drugs such as HMGCoA reductase inhibitors, bile acid sequestrants, drugs for the
  • 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 : a) for compounds wherein A is N and R 1 is CO 2 H or CO 2 R 8 in which R 8 is as hereinbefore defined, reacting a compound of the formula (2) :
  • R 8 O 2 CCH 2 CONH 2 (3) wherein Y is a displaceable group and Ar and R 8 are as hereinbefore defined and thereafter optionally converting CO 2 R 8 into CO 2 H; or b) for compounds wherein R 1 is CO 2 H,
  • R 8 is as hereinbefore defined and thereafter optionally reacting with R 8 OH wherein R 8 is as hereinbefore defined.
  • a 0 is CR 3 (OR 4 ),
  • R 8 O 2 CCO 2 R 8 ( ⁇ ) wherein R 8 is as hereinbefore defined to form a compound of the formula (6) wherein R 11 is COCO 2 R 8 and R 8 ,
  • R 10 , A and Ar are as hereinbefore defined, iv) A 0 is CH(OH),
  • R 11 is CH(OH)CO 2 R 8 , or v) A 0 is CH 2 ,
  • R 1 is P(S) (OH) (OR 2 ),
  • R 9 is P(O) (NHR 12 ) (OR 2 ) and R 12 is phenyl or C 1-4 alkyl
  • Y in a compound of the formula (2) is hydroxy or a derivative thereof for example Y is protected hydroxy such as silyloxy, an acid residue (for example C 1-6 alkanoyloxy) or an ether residue (for example
  • Y is a secondary amino group, for example di-C 1-6 alkylamino such as
  • Y is hydroxy or dimethylamino.
  • an alkali metal (e.g. sodium) salt of a compound of the formula (2) wherein Y is hydroxy is treated with a compound of the formula (3) 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 (2) wherein Y is a secondary amino group, for example dimethylamino is treated with a compound of the formula (3) 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
  • a compound of the formula (4) wherein R 9 is cyano can suitably be hydrolysed to a compound of the formula (1) wherein R 1 is CO 2 H by reaction with aqueous
  • a compound of the formula (5) is reacted with a strong base such as lithium diisopropylamide, or a C 1-4 alkyl lithium in an organic solvent such as
  • the strong base may be formed in situ, for example by the addition of a C 1-4 alkyl lithium e.g. methyllithium
  • compound of the formula (7) is ethylpyruvate, or ethyl glyoxylate or a chemical equivalent thereof and a
  • suitable compound of the formula (8) is diethyloxalate.
  • CR 3 (OH)CO 2 R 8 is suitably reacted with a C 1-3 alkyl- ating agent such as iodomethane, iodopropane or dimethyl- sulphate in the presence of a base such as sodium hydride or potassium hydroxide in an organic solvent such as dimethylformamide or dimethylsulphoxide at elevated (e.g. 30 - 80°C) or preferably ambient temperature to form the corresponding compound wherein R 11 is CR 3 (OC 1-3 - alkyl)CO 2 R 8 .
  • a base such as sodium hydride or potassium hydroxide
  • organic solvent such as dimethylformamide or dimethylsulphoxide
  • dimethylformamide or dimethylsulphoxide at elevated (e.g. 30 - 80°C) or preferably ambient temperature to form the corresponding compound wherein R 11 is CR 3 (OC 1-3 - alkyl)CO 2 R 8 .
  • potassium hydroxide is used as base the CO 2 R 8 group may be directly converted
  • COCO 2 R 8 is suitably reacted with a reducing agent such as sodium borohydride, or diisobutylaluminium hydride in an organic solvent such as dichloromethane, a
  • a reducing agent such as sodium borohydride, or diisobutylaluminium hydride in an organic solvent such as dichloromethane, a
  • C 1-4 alcohol e.g. ethanol, or acetic acid or mixtures thereof at ambient or elevated temperature (e.g. 30 - 80°C), or with cooling (e.g. 0 - 5°C) to form the
  • COCO 2 H or COCO 2 R 8 is suitably reacted with a reducing agent such as a zinc amalgam in hydrochloric acid
  • COCO 2 R 8 is suitably reacted with a C 1-3 alcohol
  • R 11 is C(OR 5 ) (OR 6 )CO 2 R 8 .
  • a compound of the formula (6) wherein R 11 is COCO 2 R 8 or CHOHCO 2 R 8 is suitably reacted with a fluorinating agent such as diethylaminosulphur trifluoride in an organic solvent such as a halohydrocarbon or an ether glyme, or THF at ambient or elevated temperature (e.g. 30-60°C) to form the corresponding compound where R 11 is CF 2 CO 2 R 8 or CHFCO 2 R 8 respectively.
  • OR 10 is hydroxy by reaction with sodium iodide and chlorotrimethylsilane in an organic solvent such as acetonitrile, or a halohydrocarbon e.g.
  • ester-forming group R 8 is not hydrolysed under the
  • reaction conditions Another method utilises sodium thiomethoxide in an organic solvent such as dimethyl- formamide at an elevated temperature for example 40 - 120°C.
  • the more forcing conditions of this method are suitable for preparing compounds of formula (1) wherein R 1 is A 0 CO 2 H.
  • a 0 CO 2 R 8 can suitably be converted to the
  • reaction with an aqueous base such as sodium or potassium hydroxide at ambient or elevated temperature (e.g.
  • This method is particularly suitable for preparing compounds of the formula (1) wherein R 0 is methoxy since the OR 10 group is not hydrolysed.
  • Another hydrolysis method utilises aqueous acid such as concentrated hydrochloric acid at an elevated temperature (e.g. 40 - 120°C) which provides directly compounds of the formula (1) wherein R 0 is hydroxy and R 1 is A 0 CO 2 H.
  • a compound of the formula (4) wherein R 9 is acetyl is converted to the corresponding compound where R 9 is CH 2 CO 2 H by reaction with sulphur and
  • aqueous base such as sodium hydroxide optionally in a cosolvent such as a C 1-4 alcohol at an elevated
  • R 11 is SO 3 H or SO 2 H respectively and OR 10 is
  • a compound of the formula (4) wherein R 9 is cyano is suitably reacted with an azide salt such as ammonium, sodium, potassium or aluminium azide in an organic solvent such as dimethylformamide, dimethylsulphoxide, N-methyl- pyrrolidinone or tetrahydrofuran at an elevated
  • a compound of the formula (9) is reacted with a compound of the formula (10) in the presence of 1-50 mole %, preferably 2-10 mole %, of a palladium catalyst and a base such as triethylamine, sodium
  • L 1 is halo for example iodo, bromo or chloro or trifluoromethylsulphonate.
  • the OR 10 group can be converted to hydroxy as hereinbefore described for compounds of formula (6).
  • Examples of palladium catalysts that can be used include: tetrakis (triphenylphosphine)palladium (Pd[PPh 3 ] 4 ),
  • a compound of the formula (1) wherein R 0 is OH can be converted to the corresponding compound where R 0 is OR 7 by reaction with R 7 L 2 wherein R 7 is as
  • L 2 is a leaving group such as halo e.g. bromo, chloro, iodo.
  • a compound of the formula (1) wherein R 1 is P(X) (OR 2 ) (OH) can be converted to the corresponding compound wherein R 1 is P(X) (OR 2 ) (OR) by reaction with a suitable O-protecting agent in standard manner.
  • a suitable O-protecting agent for example the compound can be reacted with a
  • 5-tetrazole can be reacted with a suitable N-protecting agent in standard manner, for example with a
  • a 1 CO 2 is suitably prepared by heating a compound of the formula (1) wherein R 1 is A 1 -CO 2 H and R 0 is OH
  • a dehydrating agent such as acetic anhydride
  • an elevated temperature e.g. 40 - 200°C, preferably at the reflux temperature of the reaction mixture.
  • a 2 OCH 2 O is suitably prepared by reacting a compound of the formula (1) wherein R 1 is A 2 OH and R 0 is OH with a dihalomethane such as diiodo- or dibromomethane in the presence of silver carbonate in an organic solvent such as dimethylformamide at an elevated temperature e.g. 40 - 120°C.
  • a dihalomethane such as diiodo- or dibromomethane
  • L is ethoxy or methoxy.
  • a solution of a compound of the formula (11) and a compound of the formula HCOL 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.
  • the resulting reaction mixture is
  • Y is a secondary amino group (for example
  • HC(OR b ) 2 Y is N,N-dimethylformamide dimethyl or diethyl acetal).
  • a compound of the formula (5) is suitably prepared by reacting a compound of the formula (4) wherein R 9 is hydrogen with an o-methylating agent such as dimethyl- formamide dimethylacetal in dimethylformamide or
  • trimethylphosphite at an elevated temperature e.g. 40 - 120°C or with iodomethane and silver carbonate in toluene or chloroform.
  • a compound of the formula (4) wherein A is N and R 9 is cyano, acetyl or hydrogen is suitably prepared by reaction of a compound of the formula (2) as hereinbefore defined with a compound of the formula (12) :
  • a compound of the formula (4) wherein R 9 is hydrogen can be prepared by reacting a compound of the formula (4) wherein R 9 is cyano with orthophosphoric acid at an elevated
  • a compound of the formula (4) wherein R 9 is acetyl can also be prepared by
  • a compound of the formula (4) wherein A is N or CH and R 9 is cyano or acetyl and Ar is as hereinbefore defined can be suitably prepared by reaction of a compound of formula (6) wherein R 11 is cyano or acetyl and Ar, A and R 10 are as hereinbefore defined with a demethylating agent such as sodium iodide/chlorotrimethylsilane in the absence of solvent or in an organic solvent such as acetonitrile or chloroform at an elevated temperature (e.g. 40 to 100°C) or at ambient temperature.
  • a demethylating agent such as sodium iodide/chlorotrimethylsilane in the absence of solvent or in an organic solvent such as acetonitrile or chloroform at an elevated temperature (e.g. 40 to 100°C) or at ambient temperature.
  • a compound of formula (5) wherein A is CH and Ar is 1-naphthyl can be prepared by reaction of a compound of formula (5) wherein Ar is 3,4-dihydro-1-naphthyl and A and R 10 are as hereinbefore defined with an oxidising agent such as sulphur at elevated temperature e.g. 100-250°C in the absence of a solvent or in the presence of an organic solvent such as diglyme or triglyme.
  • an oxidising agent such as sulphur at elevated temperature e.g. 100-250°C in the absence of a solvent or in the presence of an organic solvent such as diglyme or triglyme.
  • 3,4-dihydro-1-naphthyl and A and R 10 are as hereinbefore defined can be prepared by reacting the Grignard reagent, prepared from a compound of formula (13):
  • L 3 is bromo or chloro and a compound of the formula (13) is reacted with magnesium in an organic solvent such as tetrahydrofuran or diethyl ether followed by 1-tetralone at ambient or elevated temperature, e.g. 40-100°C, preferably at the reflux temperature of the reaction mixture.
  • a compound of formula (5) is suitably prepared by treating in the presence of a palladium catalyst a
  • a compound of formula (6) wherein R 11 is cyano is suitably prepared by reacting the anion of a compound of formula (5) wherein Ar, A and R 10 are as hereinbefore defined with dimethylformamide with cooling (e.g. -80 to 10oC), followed by ambient temperature and aqueous work-up.
  • the resulting compound of formula (6) wherein R 11 is carboxaldehyde is treated with hydroxylamine hydrochloride and sodium acetate in a suitable solvent such as ethanol or methanol at elevated temperature, e.g. 40-100oC, preferably at the reflux temperature of the reaction mixture followed by dehydrating the product obtained for example by heating with acetic anhydride.
  • a compound of the formula (6) wherein R 11 is cyano or acetyl is suitably prepared by reacting in the presence of a palladium catalyst a compound of the formula (14):
  • P(O) (OR 2 ) 2 can be prepared by treating a compound of the formula (5) wherein R 10 is P(O)(OR 2 ) 2 with a
  • P(O) (OR 2 ) 2 is suitably prepared by treating a compound of the formula (4) wherein R 9 is hydrogen with a
  • ZP(O)(OR 2 ) 2 (15) wherein Z is a leaving group and R 2 is as hereinbefore defined with a base such as diisopropylethylamine.
  • Z is halo, for example chloro or bromo.
  • P(O) (OR 2 ) 2 can also be prepared by treating a compound of the formula (4) wherein R 9 is hydrogen with a
  • a compound of the formula (4) wherein R 9 is P(O) (OR 2 ) 2 is suitably prepared by treating a compound of the formula (4) wherein R 9 is hydrogen with a compound of the formula (15) in the presence of a strong base such as lithium diisopropylamide in an organic solvent such as tetrahydrofuran with cooling (e.g.
  • a compound of formula (4) wherein R 9 is hydrogen is suitably prepared by demethylating a compound of formula (5) as hereinbefore defined.
  • a compound of formula (5) is treated with boron tribromide in an organic solvent such as dichloromethane or toluene with cooling (e.g. -80 to 10°C) followed by ambient temperature and aqueous work-up.
  • P(O) (NHR 12 ) (OR 2 ) can be prepared by reaction of a
  • a compound of formula (10) is suitably prepared by reacting the organolithium or Grignard reagent, formed from a compound of formula (17):
  • Ar-L 4 (17) wherein L 4 is bromo or iodo and Ar is as hereinbefore defined with a tri-C 1-4 alkyl borate such as trimethyl, tri-isopropyl or tri-n-butyl borate in an organic solvent such as diethylether or tetrahydrofuran with cooling (e.g. -80 to 10°C).
  • a tri-C 1-4 alkyl borate such as trimethyl, tri-isopropyl or tri-n-butyl borate in an organic solvent such as diethylether or tetrahydrofuran with cooling (e.g. -80 to 10°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
  • 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
  • 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 phospho ⁇ ellulose papers.
  • the concentration of compound required to give 10% phosphotransferase activation is given as the EC 10 ( ⁇ M).
  • the compounds of Examples 1-32, 34-36, 38-46, 49-51, 53-54, 56, 58-61 and 63-65 had EC 10 values in the range 0.04 - 100 ⁇ 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
  • Indicator cells consisting of 3 human colorectal cells lines (SW-620, SW-948 and HT-29) were
  • Trachea were excised from guinea-pigs and, after removal of connective tissue, cut spirally into strips (0.8-1.2 cm). The strips were suspended under 1 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 . The spirals were contracted by the addition of carbachol (final concentration, 1 ⁇ M) to the baths and a steady tension allowed to develop.
  • Test compounds were then added in a cumulative manner to the bath and the experiment was terminated by the addition of sodium nitroprusside (final concentration, 100 ⁇ M).
  • the compounds of Examples 7, 34, 35, 51, 58, 61 and 68 had EC 50 values in the range 19 to 103 ⁇ M.
  • Tetra- hydrofuran was removed at reduced pressure, the aqueous phase extracted with dichloromethane (3x100 ml), the combined organic extracts washed with water (100 ml) and brine (100 ml), dried (MgSO4), filtered and solvent removed at reduced pressure. The residue was
  • Example 1 1 n-Butyl [6-(2-naphthyl)-2-oxo-1,2-dihydro-3-pyridyl]- phosphonate (a) Di-n-butyl [6-(2-naphthyl)-2-oxo-1,2-dihydro-3- pyridyl]phosphonate (2 g) was prepared from 6-(2-naphthyl)- pyridin-2(1H)-one (2.2 g) and di-n-butylchlorophosphate (2.2 g) according to the method of Example 10(b);
  • dimethylformamide dimethylacetal (10.71 g) were heated together at 120°C in dimethylformamide (50 ml) for
  • reaction mixture was diluted with ethyl acetate (50 ml), acidified with 2N hydrochloric acid, washed with water (6x50 ml), dried
  • the combined organic material was
  • Ethyl 2-methoxy-2-[6-(2-naphthyl)-2-oxo-1,2-dihydro-3- pyridyl]oropionate (a) Ethyl 2-hydroxy-2-[6-(2-naphthyl)-2-methoxy-3- pyridyl]propionate (0.9 g) was treated with sodium hydride (0.15g, 50% in oil) and iodomethane (0.56 g) according to the method of Example 21(a).
  • Example 40 3-(5-Tetrazolyl)-6-(3-thianaphthenyl)pyridin-2(1H)-one (a) From 3-acetylthianaphthene (5 g), 3-cyano-6-(3- thianaphthenyl)pyridin-2(1H)-one (5.64 g) m.p.
  • Example 41 From 3-cyano-6-(3-thianaphthenyl)pyridin-2(1H)-one (0.92 g), the title compound (0.88 g) m.p. 360°C (decomp) after recrystallisation from n-butanol, was prepared according to the method of Example 1(b) using N-methylpyrrolidinone as solvent.
  • Example 41 From 3-cyano-6-(3-thianaphthenyl)pyridin-2(1H)-one (0.92 g), the title compound (0.88 g) m.p. 360°C (decomp) after recrystallisation from n-butanol, was prepared according to the method of Example 1(b) using N-methylpyrrolidinone as solvent.
  • m.p.105-106°C was prepared from 6-(9-phenanthryl)- pyridin-2(1H)-one (10g) according to the method of Example 18(a).
  • m-Methoxyphenyl magnesium bromide was prepared in the usual way from magnesium (29g) and m-bromoanisole (220g) in tetrahydrofuran (180ml). After the addition of m-bromoanisole was complete the reaction mixture was boiled for 30 minutes added to 1-tetralone (168.12g) in tetrahydrofuran (120mls) and boiled for a further 1 hour. Acetic anhydride (150ml) was then added and the reaction mixture maintained at 60oC for 30 minutes, treated with water (100ml), the organic phase separated and dried.
  • the precipitated material was separated by filtration, dried, suspended in dichloromethane (50ml) at -70°C and treated with boron tribromide (1ml). The reaction was stirred for 2 hours at -70oC and for 2 hours at room temperature. The solution was poured into 25% sodium bicarbonate (100ml), washed with dichloromethane (2x50ml) and acidified with 5N hydrochloric acid. The precipitate obtained was separated by filtration and recrystallised from acetonitrile/water to give the title compound
  • compositions for oral administration are prepared by combining the following : % W/W

Abstract

Fused aryl phenol/pyridinol derivatives are disclosed as medicaments.

Description

Phenol and Pyridinol derivatives as pharmaceuticals
The present invention relates to fused aryl
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, anti-allergic or
anti-inflammatory activities. They are likely to be useful in the treatment of cancer, psoriasis,
atheroschlerosis, 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) :
(1)
Figure imgf000003_0001
or pharmaceutically acceptable salts thereof, wherein : A is N or CH, R0 is OH or a bioprecursor thereof,
R1 is A0CO2H, P(X) (OH) (OR2), SO2H, SO3H or 5-tetrazolyl or a bioprecursor thereof, A0 is a single bond, CH2, CHF, CF2, CR3(OR4), CO or
C(OR5) (OR6),
R2 is phenyl, C3-5cycloalkyl, C3-5cycloalkylC1-4alkyl. or C1-8alkyl optionally substituted by C1-4alkoxy,
R3 is H, methyl or ethyl,
R4 is H or C1-3alkyl, R5 and R6 are each C1-3alkyl or together form a
1,2-ethanediyl group or 1,3-propanediyl group,
X is O or S and Ar is 1-naphthyl optionally substituted in the 4-position by hydroxy or C1-6alkoxy, 2-naphthyl optionally
substituted in the 1-position by hydroxy or C1-6alkoxy, 3-phenanthryl, 9-phenanthryl, 2-quinolinyl, 4-guinolinyl, 3-thianaphthenyl or 2-benzofuranyl.
Bioprecursors of the groups R0 and R1 are
derivatives thereof which are convertible in vivo into the groups R0 and R1. A suitable bioprecursor of the group R0 is OR7 wherein R7 is 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). When A is N, R7 can also be C1-4alkyl, arylC1-4alkyl (for example phenylC1-4-alkyl such as benzyl).
When R1 is A0CO2H a suitable bioprecursor is
A0CO2R8 wherein R8 is an ester-forming group.
When R1 is P(X) (OH) (OR2) a suitable bioprecursor is P(X) (OR2)2 wherein X and R2 are as hereinbefore defined or P(X) (OR2) (OR) wherein R is an O-protecting group. Suitable O-protecting groups include
pivalolyloxymethyl, propionyloxymethyl and pivaloyloxy- carbonyloxymethyl.
When R1 is 5-tetrazolyl, a suitable bioprecursor is a N-protected derivative thereof. Suitable N-protecting groups include pivalolyloxymethyl, propionyloxymethyl and pivaloyloxycarbonyloxymethyl.
Alternatively bioprecursors of the groups R0 and R1 are those formed when R1 and R0 are linked
together to form a cyclic structure such that R1-R0 is A1CO2 or A2OCH2O, in which :
A1 is CH2, CR3(OR4), CO or C(OR5) (OR6), A2 is P(X)OR2 or CR3(CO2R8), and
R2 to R6, R8 and X are as hereinbefore defined.
Suitably R0 is hydroxy or OR7, preferably hydroxy.
Suitably R1 is A0CO2H or A0CO2R8.
Suitably R1 is P(X) (OH) (OR2) or P(X) (OR2)2. Suitably R1 is SO2H, SO3H or 5-tetrazolyl. Suitably R1 and R0 are linked together such that R1-R0 is A1CO2.
Suitably R1 and R0 are linked together such that R1-R0 is A2OCH2O.
By the term alkyl is meant both straight- and branched- chain alkyl. Suitably R2 is methyl, ethyl, propyl, butyl, pentyl, hexyl, 2-methoxyethyl, phenyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclopropylmethyl.
Suitably R3 is H, methyl or ethyl, preferably H or methyl.
Suitably R4 is H, methyl, ethyl or propyl,
preferably H or methyl. Suitably R5 and R6 are independently methyl, ethyl or propyl, preferably together they form a
1,2-ethanediyl group.
Preferably X is O.
Suitably R8 is C1-4alkyl optionally substituted by hydroxy, e.g. 2-hydroxyethyl or arylC1-4alkyl (for example phenylC1-4alkyl such as benzyl). Suitably Ar is 1-naphthyl optionally substituted in the 4-position by hydroxy or C1-6alkoxy. Suitably Ar is 2-naphthyl optionally substituted in the 1-position by hydroxy or C1-6alkoxy. Examples of C1-6alkoxy
include methoxy, ethoxy, propoxy, butoxy or pentyloxy.
Suitably Ar is 3-phenanthryl or 9-phenanthryl. Suitably Ar is 2-quinolinyl or 4-guinolinyl.
Suitably Ar is 2-benzofuranyl or 3-thianaphthenyl. Particular compounds of this invention include :
6-(2-naphthyl)-3-(5-tetrazolyl)pyridin-2(1H)-one,
6-(1-naphthyl)-3-(5-tetrazolyl)pyridin-2(1H)-one,
6-(2-benzofuranyl)-3-(5-tetrazolyl)-pyridin-2(1H)-one,
6-(9-phenanthryl)-3-(5-tetrazolyl)pyridin-2(1H)-one, 6-(3-phenanthryl)-3-(5-tetrazolyl)pyridin-2(1H)-one,
6-(2-quinolinyl)-3-(5-tetrazolyl)pyridin-2(1H)-one,
6-[1-(4-methoxy)naphthyl]-3-(5-tetrazolyl)pyridin-2(1H)- one,
3-carboxy-6-(2-naphthyl)pyridin-2(1H)-one,
3-carboxy-6-(1-naphthyl)pyridin-2(1H)-one, ethyl [6-(2-naphthyl)-2-oxo-1,2-dihydro-3-pyridyl]- phosphonate, n-butyl [6-(2-naphthyl)-2-oxo-1,2-dihydro-3-pyridyl]- phosphonate, n-hexyl [6-(2-naphthyl)-2-oxo-1,2-dihydro-3-pyridyl]- phosphonate, phenyl [6-(2-naphthyl)-2-oxo-1,2-dihydro-3-pyridyl]- phosphonate, ethyl [6-(1-naphthyl)-2-oxo-1,2-dihydro-3-pyridyl]- phosphonate, n-butyl [6-(1-naphthyl)-2-oxo-1,2-dihydro-3-pyridyl]- phosphonate, n-hexyl [6-(1-naphthyl)-2-oxo-1,2-dihydro-3-pyridyl]- phosphonate, ethyl [6-(9-phenanthryl)-2-oxo-1,2-dihydro-3-pyridyl]-phosphonate, ethyl 2-hydroxy-[6-(2-naphthyl)-2-oxo-1,2-dihydro-3- pyridyl]propionate,
2-hydroxy-2-[6-(2-naphthyl)-2-oxo-1,2-dihydro-3-pyridyl]- propionic acid,
2-hydroxy-2-[6-(2-naphthyl)-2-oxo-1,2-dihydro-3-pyridyl]- acetic acid,
2-methoxy-2-[6-(2-naphthyl)-2-oxo-1,2-dihydro-3-pyridyl]- acetic acid, 2-propoxy-2-[6-(2-naphthyl)-2-oxo-1,2-dihydro-3-pyridyl]- acetic acid, ethyl 2-hydroxy-2-[6-(2-naphthyl)-2-oxo-1,2-dihydro-3- pyridyl]acetate,
[6-(2-naphthyl)-2-oxo-1,2-dihydro-3-pyridyl]sulphonic acid,
2-oxo-2-[6-(1-naphthyl)-2-oxo-1,2-dihydro-3-pyridyl]acetic acid, ethyl 2-oxo-2-[6-(1-naphthyl)-2-oxo-1,2-dihydro-3-pyridyl]- acetate,
[6-(2-naphthyl)-2-oxo-1,2-dihydro-3-pyridyl]acetic acid,
[6-(1-naphthyl)-2-oxo-1,2-dihydro-3-pyridyl]acetic acid,
7-aza-6-(1-naphthyl)benzofuran-2-one, 4-ethoxy-4-oxo-1,3,4-dioxyphosphono[5,6-b]-7-(1-naphthyl) pyridine, ethyl [6-(1-naphthyl)-2-oxo-1,2-dihydro-3-pyridyl]- phosphonothioate,
3-methoxycarbonyl-6-(2-naphthyl)pyridin-2(1H)-one, ethyl 2-methoxy-2-[6-(2-naphthyl)-2-oxo-1,2-dihydro-3- pyridy1]propionate,
3-(5-tetrazolyl)-6-[2-(1-propyloxy)naphthyl]pyridin-2 (1H) one,
6-[2-(1-pentyloxy)naphthyl]-3-(5-tetrazolyl)pyridin-2(1H)- one,
[6-(9-phenanthryl)-2-oxo-1,2-dihydro-3-pyridyl]acetic acid,
2-hydroxyethyl 2-[6-(2-naphthyl)-2-oxo-1,2-dihydro-3- pyridyl]-1,3-dioxolane-2-carboxylate,
2-[6-(2-naphthyl)-2-oxo-1,2-dihydro-3-pyridyl]-1,3-dioxo- lane-2-carboxylic acid, n-butyl [6-(9-phenanthryl)-2-oxo-1,2-dihydro-3-pyridyl]- phosphhnate, 3-(5-tetrazolyl)-6-(3-thianaphthenyl)pyridin-2(1H)-one,
6-(4-quinolinyl)-3-(5-(tetrazolyl)pyridin-2(1H)-one, 6-[1-(4-hydroxy)naphthyl]-3-(5-tetrazolyl)pyridin-2(1H)- one,
2-methoxyethyl [6-(2-naphthyl)-2-oxo-1,2-dihydro-3- pyridyl]phosphonate, n-propyl [6-(2-naphthyl)-2-oxo-1,2-dihydro-3-pyridyl]- phosphonate, n-propyl [6-(9-phenanthryl)-2-oxo-1,2-dihydro-3-pyridyl]- phosphonate,
2-hydroxy-2-[6-(9-phenanthryl)-2-oxo-1,2-dihydro-3- pyridyl]acetic acid, ethyl 2-methoxy-2-[6-(2-naphthyl)-2-oxo-1,2-dihydro-3- pyridyl]acetate, ethyl 2-methoxy-2-[6-(1-naphthyl)-2-oxo-1,2-dihydro-3- pyridyl]acetate,
2-ethoxy-2-[6-(2-naphthyl)-2-oxo-1,2-dihydro-3- pyridyl]acetic acid,
3-carboxy-6-(9-phenanthryl)pyridin-2(1H)-one,
6-[1-(4-propoxy)naphthyl]-3-(5-tetrazolyl)pyridin-2(1H)- one, ethyl 2-hydroxy-[6-(9-phenanthryl)-2-oxo-1,2-dihydro-3- pyridyl]acetate, 2-oxo-2-[6-(2-naphthyl)-2-oxo-1,2-dihydro-3-pyridyl]acetic acid,
2-hydroxy-2-[6(1-naphthyl)-2-oxo-1,2-dihydro-3-pyridyl]- acetic acid, n-butyl 2-methoxy-2-[6-(2-naphthyl)-2-oxo-1,2-dihydro-3- pyridyl]acetate, [6-(2-naphthyl)-2-oxo-1,2-dihydro-3-pyridyl]sulphinic acid, ethyl 2,2-difluoro-2-[6-(2-naphthyl)-2-oxo-1,2-dihydro-3- pyridyl]acetate, 2,2-difluoro-2-[6-(2-naphthyl)-2-oxo-1,2-dihydro-3- pyridyl]acetic acid,
4-(1-naphthyl) salicylic acid, ethyl 2-hydroxy-4-(1-naphthyl)phenyl phosphonate,
5-[2-hydroxy-4-(1-naphthyl)phenyl]tetrazole,
4-(2-naphthyl)salicylic acid, ethyl 2-hydroxy-4-(2-naphthyl)phenyl phosphonate, n-butyl 2-hydroxy-4-(2-naphthyl)phenyl phosphonate, ethyl 2-hydroxy-4-(9-phenanthryl)phenyl phosphonate, ethyl 4-(1-naphthyl)salicylate,
6-(1-naphthyl)-3-[5-(2-pivaloyloxymethyl)tetrazolyl]- pyridin-2(1H)-one, and ethyl pivaloyloxymethyl[6-(1-naphthyl)-2-oxo-1,2-dihydro- 3-pyridyl]phosphonate, and pharmaceutically acceptable salts thereof.
This invention covers all tautomeric and optical isomeric forms of compounds of formula (1). In
particular when A is N and R0 is hydroxy the compound can exist in its keto tautomeric form :
Figure imgf000012_0001
Compounds of the formulae (1) wherein R1 is A0CO2H, P(X) (OH) (OR2), SO2H, SO3H or 5-tetrazolyl or R0 is hydroxy can form pharmaceutically acceptable base addition salts with metal ions, such as alkali metals for example sodium or potassium, or with an ammonium ion.
In order to use a compound of the formula (1) or a pharmaceutically acceptable salt thereof for the treatment of humans and other mammals it is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition.
Compounds of formula (1) and their pharmaceutically acceptable salts may be administered in standard manner for the treatment of the indicated diseases, for example orally, sublingually, parenterally, transdermally, rectally, via inhalation or via buccal administration. Compounds of formula (1) and their pharmaceutically acceptable salts which are active when given orally or via buccal administration can be formulated appropriately in dosage forms such as liquids, syrups, tablets, capsules and lozenges. An oral liquid formulation will generally consist of a suspension or solution of the compound or salt in a liquid carrier for example, ethanol, glycerine or water with a flavouring or colouring agent. Where the composition is in the form of a tablet, any pharmaceutical carrier routinely used for preparing solid formulations may be used. Examples of such carriers include starch, celluloses, lactose, sucrose and magnesium stearate.
Where the composition is in the form of a capsule, any routine encapsulation is suitable, for example using the aforementioned carriers in a hard gelatin capsule shell. Where the composition is in the form of a soft gelatin shell capsule, any pharmaceutical carrier routinely used for preparing dispersions or suspensions may be
considered, for example aqueous gums, celluloses,
silicates or oils and are incorporated in a soft gelatin capsule shell.
Typical parenteral compositions consist of a solution or suspension of the compound or salt in a sterile aqueous or non-aqueous carrier optionally containing a parenterally acceptable oil or solubilising agent, for example
polyethylene glycol, polyvinylpyrrolidone, lecithin,
2-pyrrolidone, cyclodextrin, arachis oil, or sesame oil. A typical suppository formulation comprises a
compound of formula (1) or a pharmaceutically acceptable salt thereof which is active when administered in this way, with a binding and/or lubricating agent, for example polymeric glycols, gelatins, cocoa-butter or other low melting vegetable waxes or fats or their synthetic
analogues. Typical transdermal formulations comprise a
conventional aqueous or non-aqueous vehicle, for example a cream, ointment, lotion or paste or are in the form of a medicated plaster, patch or membrane.
Typical compositions for inhalation are in the form of a solution, suspension or emulsion that may be administered in the form of an aerosol using a conventional propellant such as dichlorodifluoromethane or trichlorofluoromethane, or are in the form of a powder for insufflation.
Preferably the composition is in unit dosage form, for example a tablet, capsule or metered aerosol dose, so that the patient may administer to himself a single dose.
Each dosage unit for oral administration contains suitably from 0.001 mg/Kg to 30 mg/Kg, and preferably from 0.005 mg/Kg to 15 mg/Kg, and each dosage unit for
parenteral administration contains suitably from 0.001 mg/Kg to 10 mg/Kg, of a compound of formula (1) or a pharmaceutically acceptable salt thereof calculated as the free acid.
The daily dosage regimen for oral administration is suitably about 0.001 mg/Kg to 120 mg/Kg, of a compound of formula (1) or a pharmaceutically acceptable salt thereof calculated as the free acid. The daily dosage regimen for parenteral administration is suitably about 0.001 mg/Kg to 40 mg/Kg, for example about 0.005 mg/Kg to 10 mg/Kg, of a compound of the formula (1) or a pharmaceutically acceptable salt thereof calculated as the free acid. The active ingredient may be administered as required for example from 1 - 8 times a day or by infusion. The compositions of the invention are agonists of a cA-PrK and are of use in combatting such conditions where such
agonism is thought to be beneficial. Such conditions can be treated by administration orally, sublingually
topically, rectally, parenterally or by inhalation. For administration by inhalation dosages are controlled by a valve, are administered as required and for an adult are conveniently in the range 0.1 - 5.0 mg of a compound of the formula (1) or a pharmaceutically acceptable salt thereof.
The compounds of this invention may be
co-administered with other pharmaceutically active
compounds, for example in combination, concurrently or sequentially. Conveniently the compounds of this
invention and the other active compound or compounds are formulated in a single pharmaceutical composition.
Examples of compounds which may be included in
pharmaceutical compositions with the compounds of the formula (1) are bronchodilators such as sympathomimetic amines for example isoprenaline, isoetharine, sulbutamol, phenylephrine and ephedrine or xanthine derivatives for example theophylline and aminophylline, anti-allergic agents for example disodium cromoglycate, histamine
H1-antagonists, drugs used in the treatment of cancer such as those which inhibit the synthesis of or inactivate DNA, for example methotrexate, flouracil, cisplatin,
actinomycin D, anti-atherschlerotic agents for example cholesterol lowering drugs such as HMGCoA reductase inhibitors, bile acid sequestrants, drugs for the
treatment of psoriasis, for example retinoids, anthralin, anti-inflammatories for example cortiscosteroids,
non-steroid anti-inflammatories such as aspirin,
antithrombotics for example dipyridamole, or fibrinolytic agents.
In another aspect the present invention provides a process for the preparation of compounds of the formula (1) or pharmaceutically acceptable salts thereof, which process comprises : a) for compounds wherein A is N and R1 is CO2H or CO2R8 in which R8 is as hereinbefore defined, reacting a compound of the formula (2) :
ArCOCH=CHY (2) with a compound of the formula (3) :
R8O2CCH2CONH2 (3) wherein Y is a displaceable group and Ar and R8 are as hereinbefore defined and thereafter optionally converting CO2R8 into CO2H; or b) for compounds wherein R1 is CO2H,
hydrolysing a compound of the formula (4) :
(4)
Figure imgf000016_0001
wherein A is N or CH and R9 is cyano and Ar is as hereinbefore defined ; or c) for compounds wherein R1 is A0CO2H or
A0CO2R8 and : i) A0 is a single bond,
reacting in the presence of a strong base a compound of the formula (5) :
(5)
Figure imgf000017_0002
wherein R10 is methyl and Ar and A are as hereinbefore defined with carbon dioxide to form a compound of the formula (6) :
(6)
Figure imgf000017_0001
wherein R11 is carboxy and Ar, A and R10 are as
hereinbefore defined and thereafter optionally reacting with R8OH wherein R8 is as hereinbefore defined. ii) A0 is CR3(OR4),
reacting in the presence of a strong base a compound of the formula (5) as hereinbefore defined with a compound of the formula (7) :
R3COCO2R8 (7) wherein R3 and R8 are as hereinbefore defined to form a compound of the formula (6) wherein R11 is CR3(OH)CO2R8 and R3, R8, R10, A and Ar are as
hereinbefore defined and thereafter optionally reacting with a C1-3alkylating agent to form the corresponding compound wherein R11 is CR3(OC1-3alkyl)CO2R8, iii) A0 is CO,
reacting in the presence of a strong base a compound of the formula (5) as hereinbefore defined with a compound of the formula (8) :
R8O2CCO2R8 (δ) wherein R8 is as hereinbefore defined to form a compound of the formula (6) wherein R11 is COCO2R8 and R8,
R10, A and Ar are as hereinbefore defined, iv) A0 is CH(OH),
reacting a compound of the formula (6) wherein R11 is COCO2R8 and R8, R10, A and Ar are as hereinbefore
defined with a reducing agent to form the corresponding compound wherein R11 is CH(OH)CO2R8, or v) A0 is CH2,
reacting a compound of the formula (6) wherein R11 is COCO2H or COCO2R8 and R8, R10, A and Ar are as
hereinbefore defined with a suitable reducing agent to form the corresponding compound wherein R11 is CH2CO2H, or vi) A0 is C(OR5)(OR6),
reacting a compound of the formula (6) wherein R11 is COCO2R8 and R8, R10, A and Ar are as hereinbefore
defined with a C1-3alcohol, 1,2-ethanediol or
1,3-propanediol to form the corresponding compound wherein R11 is C(OR5) (0R6)CO2R8, vii) A0 is CF2,
reacting a compound of the formula (6) wherein R11 is COCO2R8 and R8, R10, A and Ar are as hereinbefore
defined with a fluorinating agent to form the
corresponding compound wherein R11 is CF2CO2R8, or viii) A0 is CHF,
reacting a compound of the formula (6) wherein R11 is CH(OH)CO2R8 and R8, R10, A and Ar are as
hereinbefore defined with a fluorinating agent to form the corresponding compound wherein R11 is CHFCO2R8, and thereafter optionally : º converting the group OR10 into OH º converting the group A0CO2R8 into A0CO2H; or d) for compounds wherein R1 is CH2CO2H,
converting a compound of the formula (4) wherein R9 is acetyl and Ar and A are as hereinbefore defined into the corresponding compound wherein R9 is CH2CO2H; or e) for compounds wherein R1 is P(O) (OH) (OR2),
hydrolysing a compound of the formula (4) wherein R9 is P(O) (OR2)2 and R2, A and Ar are as hereinbefore
defined; or f) for compounds wherein R1 is P(S) (OH) (OR2),
converting a compound of the formula (4) wherein R9 is P(O) (NHR12) (OR2) and R12 is phenyl or C1-4alkyl
into the corresponding compound wherein R9 is
P(S) (OH) (OR2); or g) for compounds where R1 is SO3H,
reacting in the presence of a strong base a compound of the formula (5) as hereinbefore defined with sulphuryl chloride or a chemical equivalent thereof and optionally converting the group OR10 into OH; or h) for compounds wherein R1 is SO2H,
reacting in the presence of a strong base a compound of the formula (5) as hereinbefore defined with sulphur dioxide and optionally converting the group OR10 into OH; or i) for compounds wherein R1 is 5-tetrazolyl,
reacting a compound of the formula (4) wherein R9 is cyano or a compound of the formula (6) wherein R11 is cyano with an azide salt; or j) for compounds wherein R1 is as defined for
compounds of the formula (1) reacting in the presence of a palladium catalyst a compound of the formula (9):
(9)
Figure imgf000020_0001
wherein R1 and A are as hereinbefore defined and Ra is R0 or OR10 as hereinbefore defined and L1 is a
leaving group with a compound of the formula (10):
ArB(OH)2 (10) wherein Ar is as hereinbefore defined and then, if necessary, converting the group OR10 into OH, and optionally thereafter : º forming a bioprecursor of R0 and/or R1 º forming a pharmaceutically acceptable salt.
Suitably Y in a compound of the formula (2) is hydroxy or a derivative thereof for example Y is protected hydroxy such as silyloxy, an acid residue (for example C1-6alkanoyloxy) or an ether residue (for example
methoxy or ethoxy). Alternatively Y 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 Y is hydroxy or dimethylamino.
Suitably an alkali metal (e.g. sodium) salt of a compound of the formula (2) wherein Y is hydroxy is treated with a compound of the formula (3) 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 (2) wherein Y is a secondary amino group, for example dimethylamino, is treated with a compound of the formula (3) 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. Suitably the compound of the formula (1) wherein R1 is CO2R8 can be hydrolysed to the corresponding compound wherein R1 is CO2H in the presence of an
aqueous acid or base, such as hydrochloric acid or sodium hydroxide. A compound of the formula (4) wherein R9 is cyano can suitably be hydrolysed to a compound of the formula (1) wherein R1 is CO2H by reaction with aqueous
potassium hydroxide or with a mixture of acetic acid and aqueous hydrobromic acid at an elevated temperature, for example at the reflux temperature of the reaction mixture.
Suitably a compound of the formula (5) is reacted with a strong base such as lithium diisopropylamide, or a C1-4alkyl lithium in an organic solvent such as
tetrahydrofuran, diethylether or dimethoxyethane with cooling (-100° - 0ºC) to form the anion thereof. The strong base may be formed in situ, for example by the addition of a C1-4alkyl lithium e.g. methyllithium
followed by diisopropylamine.
The anion of a compound of the formula (5) is
suitably reacted with carbon dioxide, a compound of the formula (7) or a compound of the formula (8) in an organic solvent such as tetrahydrofuran, diethylether or
dimethoxyethane with cooling (-100° to 0°C) to form a compound of the formula (6) wherein R11 is carboxy,
CR3(OH)CO2R8 or COCO2R8 respectively. A suitable
compound of the formula (7) is ethylpyruvate, or ethyl glyoxylate or a chemical equivalent thereof and a
suitable compound of the formula (8) is diethyloxalate.
A compound of the formula (6) wherein R11 is
CR3(OH)CO2R8 is suitably reacted with a C1-3alkyl- ating agent such as iodomethane, iodopropane or dimethyl- sulphate in the presence of a base such as sodium hydride or potassium hydroxide in an organic solvent such as dimethylformamide or dimethylsulphoxide at elevated (e.g. 30 - 80°C) or preferably ambient temperature to form the corresponding compound wherein R11 is CR3 (OC1-3- alkyl)CO2R8. When potassium hydroxide is used as base the CO2R8 group may be directly converted to
carboxy.
A compound of the formula (6) wherein R11 is
COCO2R8 is suitably reacted with a reducing agent such as sodium borohydride, or diisobutylaluminium hydride in an organic solvent such as dichloromethane, a
C1-4alcohol e.g. ethanol, or acetic acid or mixtures thereof at ambient or elevated temperature (e.g. 30 - 80°C), or with cooling (e.g. 0 - 5°C) to form the
corresponding compound wherein R11 is CH(OH)CO2R8.
A compound of the formula (6) wherein R11 is
COCO2H or COCO2R8 is suitably reacted with a reducing agent such as a zinc amalgam in hydrochloric acid
in the absence of a solvent or in a solvent such as ethanol, acetic acid or dioxan and hydrogen chloride gas at ambient or elevated temperature (e.g. 40-100°C) to form the corresponding compound wherein R11 is CH2CO2H.
Under these reaction conditions the CO2R8 group is
converted to carboxy.
A compound of the formula (6) wherein R11 is
COCO2R8 is suitably reacted with a C1-3alcohol,
1,2-ethanediol or 1,3-propanediol in the presence of an acid catalyst such as paratoluenesulphonic acid,
concentrated sulphuric acid or anhydrous hydrogen
chloride, at ambient or elevated temperature to form the corresponding compound wherein R11 is C(OR5) (OR6)CO2R8. A compound of the formula (6) wherein R11 is COCO2R8 or CHOHCO2R8 is suitably reacted with a fluorinating agent such as diethylaminosulphur trifluoride in an organic solvent such as a halohydrocarbon or an ether glyme, or THF at ambient or elevated temperature (e.g. 30-60°C) to form the corresponding compound where R11 is CF2CO2R8 or CHFCO2R8 respectively.
A compound of the formula (6) wherein OR10 is
methoxy can suitably be converted to the corresponding compound wherein OR10 is hydroxy by reaction with sodium iodide and chlorotrimethylsilane in an organic solvent such as acetonitrile, or a halohydrocarbon e.g.
dichloromethane or chloroform at elevated (e.g. 30 - 80°C) or preferably ambient temperature. This method is particularly suitable for preparing compounds of the formula (1) wherein R1 is A0CO2R8 since the
ester-forming group R8 is not hydrolysed under the
reaction conditions. Another method utilises sodium thiomethoxide in an organic solvent such as dimethyl- formamide at an elevated temperature for example 40 - 120°C. The more forcing conditions of this method are suitable for preparing compounds of formula (1) wherein R1 is A0CO2H.
A compound of the formula (6) wherein R11 is
A0CO2R8 can suitably be converted to the
corresponding compound wherein R11 is A0CO2H by
reaction with an aqueous base such as sodium or potassium hydroxide at ambient or elevated temperature (e.g.
40 - 120°). This method is particularly suitable for preparing compounds of the formula (1) wherein R0 is methoxy since the OR10 group is not hydrolysed.
Another hydrolysis method utilises aqueous acid such as concentrated hydrochloric acid at an elevated temperature (e.g. 40 - 120°C) which provides directly compounds of the formula (1) wherein R0 is hydroxy and R1 is A0CO2H. Suitably a compound of the formula (4) wherein R9 is acetyl is converted to the corresponding compound where R9 is CH2CO2H by reaction with sulphur and
morpholine at elevated temperature 50 - 200°C, followed by hydrolysis with an aqueous base such as sodium hydroxide at elevated temperature, preferably at the reflux
temperature of the reaction mixture.
Suitably a compound of the formula (4) wherein R9 is P(O) (OR2) 2 is hydrolysed by reaction with an
aqueous base such as sodium hydroxide optionally in a cosolvent such as a C1-4alcohol at an elevated
temperature (e.g. 40-100°C), preferably at the reflux temperature of the reaction mixture.
Suitably a compound of the formula (4) wherein R9 is P(O) (NHR12) (OR2) is converted to the corresponding compound wherein R9 is P(S) (OH) (OR2) by reaction with a strong base such as sodium hydride in an organic solvent such as dimethoxyethane at ambient or elevated
temperature, e.g. 40 - 100°C followed by reaction with carbon disulphide.
Suitably the anion of a compound of the formula (5) prepared as hereinbefore described is reacted with
sulphuryl chloride or a chemical equivalent thereof or with sulphur dioxide in an organic solvent such as
tetrahydrofuran with cooling (-100° - 0°C) to form after aqueous work-up a compound of the formula (6) wherein
R11 is SO3H or SO2H respectively and OR10 is
methoxy which if desired can be converted to the
corresponding compound wherein OR10 is hydroxy as
hereinbefore described. A compound of the formula (4) wherein R9 is cyano is suitably reacted with an azide salt such as ammonium, sodium, potassium or aluminium azide in an organic solvent such as dimethylformamide, dimethylsulphoxide, N-methyl- pyrrolidinone or tetrahydrofuran at an elevated
temperature e.g. 40 - 200°C, preferably at the reflux temperature of the reaction mixture.
Suitably a compound of the formula (9) is reacted with a compound of the formula (10) in the presence of 1-50 mole %, preferably 2-10 mole %, of a palladium catalyst and a base such as triethylamine, sodium
bicarbonate, or aqueous sodium carbonate and optionally lithium chloride in an organic solvent such as
dimethylformamide, acetonitrile, toluene, tetrahydrofuran, ethanol, or mixtures thereof, at elevated temperature, (e.g. 30-150°C), preferably at the reflux temperature of the mixture. Suitably L1 is halo for example iodo, bromo or chloro or trifluoromethylsulphonate.
Subsequently the OR10 group can be converted to hydroxy as hereinbefore described for compounds of formula (6). Examples of palladium catalysts that can be used include: tetrakis (triphenylphosphine)palladium (Pd[PPh3]4),
bis (triphenylphosphine)palladium dichloride
(Pd[PPh3]2Cl2),
[1,4-bis-(diphenylphosphine)butane]palladium dichloride
(Pd(dppb)Cl2),
[1,3-bis-(diphenylphosphine)propanejpalladium dichloride
(Pd(dppp)Cl2),
[1,2-bis-(diphenylphosphine)ethane]palladium dichloride (Pd(dppe)Cl2),
bis (tri-o-tolylphosphine)palladium diacetate or dichloride
(Pd(totp) (OAc)2 or Pd(totp)Cl2), or
1,1'-bis(diphenylphosphine) ferrocinopalladium diacetate or dichloride (Pd[dppf] (OAc)2 or Pd[dppf]Cl2). If desired a compound of the formula (1) wherein R1 is A0CO2H can be converted to the corresponding
compound wherein R1 is A0CO2R8 by reaction with a compound R8OH wherein R8 is as hereinbefore defined.
A compound of the formula (1) wherein R0 is OH can be converted to the corresponding compound where R0 is OR7 by reaction with R7L2 wherein R7 is as
hereinbefore defined and L2 is a leaving group such as halo e.g. bromo, chloro, iodo.
If desired a compound of the formula (1) wherein R1 is P(X) (OR2) (OH) can be converted to the corresponding compound wherein R1 is P(X) (OR2) (OR) by reaction with a suitable O-protecting agent in standard manner. For example the compound can be reacted with a
pivalolyloxymethyl halide.
A compound of the formula (1) wherein R1 is
5-tetrazole can be reacted with a suitable N-protecting agent in standard manner, for example with a
pivalolyloxymethyl halide.
A compound of the formula (1) wherein R1-R0 is
A1CO2 is suitably prepared by heating a compound of the formula (1) wherein R1 is A1-CO2H and R0 is OH
with a dehydrating agent such as acetic anhydride, at an elevated temperature e.g. 40 - 200°C, preferably at the reflux temperature of the reaction mixture.
A compound of the formula (1) wherein R1-R0 is
A2OCH2O is suitably prepared by reacting a compound of the formula (1) wherein R1 is A2OH and R0 is OH with a dihalomethane such as diiodo- or dibromomethane in the presence of silver carbonate in an organic solvent such as dimethylformamide at an elevated temperature e.g. 40 - 120°C.
Compounds of the formula (2) wherein Y is hydroxy can suitably be prepared by reaction under basic conditions of a compound of the formula (11) :
ArCOCH3 (11) wherein Ar is hereinbefore defined, with a compound of the formula HCOL wherein L is a leaving group. Suitably L is ethoxy or methoxy. Conveniently a solution of a compound of the formula (11) and a compound of the formula HCOL in a suitable organic solvent such as diethyl ether is treated with a suitable base such as an alkali metal alkoxide, e.g. sodium methoxide at ambient temperature. The resulting reaction mixture is
preferably extracted with water and the aqueous extract which contains the alkali metal salt of a compound of the formula (2) wherein Y is hydroxy is then treated with a compound of the formula (3) as hereinbefore described.
Compounds of the formula (2) wherein Y is a secondary amino group (e.g. dimethylamino) can suitably be prepared by reacting a compound of the formula (11) with a compound of the formula HC(ORb)2Y wherein Rb is C1-4alkyl
and Y is a secondary amino group (for example
HC(ORb)2Y is N,N-dimethylformamide dimethyl or diethyl acetal).
A compound of the formula (5) is suitably prepared by reacting a compound of the formula (4) wherein R9 is hydrogen with an o-methylating agent such as dimethyl- formamide dimethylacetal in dimethylformamide or
trimethylphosphite at an elevated temperature e.g. 40 - 120°C or with iodomethane and silver carbonate in toluene or chloroform.
A compound of the formula (4) wherein A is N and R9 is cyano, acetyl or hydrogen is suitably prepared by reaction of a compound of the formula (2) as hereinbefore defined with a compound of the formula (12) :
R13CH2CONH2 (12) wherein R13 is cyano, acetyl or hydrogen respectively, in a similar manner to the reaction of compounds of formulae (2) and (3). Alternatively a compound of the formula (4) wherein R9 is hydrogen can be prepared by reacting a compound of the formula (4) wherein R9 is cyano with orthophosphoric acid at an elevated
temperature, e.g. 50 - 200°C. A compound of the formula (4) wherein R9 is acetyl can also be prepared by
reacting a compound of the formula (4) wherein R9 is cyano with methyl lithium followed by aqueous work up for example with aqueous ammonium chloride. A compound of the formula (4) wherein A is N or CH and R9 is cyano or acetyl and Ar is as hereinbefore defined can be suitably prepared by reaction of a compound of formula (6) wherein R11 is cyano or acetyl and Ar, A and R10 are as hereinbefore defined with a demethylating agent such as sodium iodide/chlorotrimethylsilane in the absence of solvent or in an organic solvent such as acetonitrile or chloroform at an elevated temperature (e.g. 40 to 100°C) or at ambient temperature. A compound of formula (5) wherein A is CH and Ar is 1-naphthyl can be prepared by reaction of a compound of formula (5) wherein Ar is 3,4-dihydro-1-naphthyl and A and R10 are as hereinbefore defined with an oxidising agent such as sulphur at elevated temperature e.g. 100-250°C in the absence of a solvent or in the presence of an organic solvent such as diglyme or triglyme.
A compound of formula (5) wherein Ar is
3,4-dihydro-1-naphthyl and A and R10 are as hereinbefore defined can be prepared by reacting the Grignard reagent, prepared from a compound of formula (13):
(13)
Figure imgf000030_0001
wherein L3 is halo and A and R10 are as hereinbefore defined with 1-tetralone and dehydrating the product obtained, for example by heating with acetic anhydride.
Suitably L3 is bromo or chloro and a compound of the formula (13) is reacted with magnesium in an organic solvent such as tetrahydrofuran or diethyl ether followed by 1-tetralone at ambient or elevated temperature, e.g. 40-100°C, preferably at the reflux temperature of the reaction mixture. A compound of formula (5) is suitably prepared by treating in the presence of a palladium catalyst a
compound of the formula (13) wherein L3 is halo or
trifluoromethylsulphonate and Ar and R10 are as
hereinbefore defined with a compound of the formula (10) in an analogous manner to the reaction of the compounds of formulae (9) and (10). A compound of formula (6) wherein R11 is cyano is suitably prepared by reacting the anion of a compound of formula (5) wherein Ar, A and R10 are as hereinbefore defined with dimethylformamide with cooling (e.g. -80 to 10ºC), followed by ambient temperature and aqueous work-up. The resulting compound of formula (6) wherein R11 is carboxaldehyde is treated with hydroxylamine hydrochloride and sodium acetate in a suitable solvent such as ethanol or methanol at elevated temperature, e.g. 40-100ºC, preferably at the reflux temperature of the reaction mixture followed by dehydrating the product obtained for example by heating with acetic anhydride.
A compound of the formula (6) wherein R11 is cyano or acetyl is suitably prepared by reacting in the presence of a palladium catalyst a compound of the formula (14):
(14)
Figure imgf000031_0001
wherein R14 is cyano or acetyl and R10 and L1 are as hereinbefore defined, with a compound of formula (10) as hereinbefore defined, in analogous manner to the reaction of compounds of formulae (9) and (10).
A compound of the formula (4) wherein R9 is
P(O) (OR2)2 can be prepared by treating a compound of the formula (5) wherein R10 is P(O)(OR2)2 with a
strong base such as lithium diisopropylamide in an organic solvent such as tetrahydrofuran with cooling (e.g.
-100-0°C). A compound of the formula (5) wherein R10 is
P(O) (OR2)2 is suitably prepared by treating a compound of the formula (4) wherein R9 is hydrogen with a
compound of the formula (15):
ZP(O)(OR2)2 (15) wherein Z is a leaving group and R2 is as hereinbefore defined with a base such as diisopropylethylamine.
Suitably Z is halo, for example chloro or bromo.
A compound of formula (5) wherein R10 is
P(O) (OR2)2 can also be prepared by treating a compound of the formula (4) wherein R9 is hydrogen with a
compound of the formula (16):
HP(O)(OR2)2 (16) wherein R2 is as hereinbefore defined in the presence of an amine base such as triethylamine, and carbon
tetrachloride.
Alternatively, a compound of the formula (4) wherein R9 is P(O) (OR2)2 is suitably prepared by treating a compound of the formula (4) wherein R9 is hydrogen with a compound of the formula (15) in the presence of a strong base such as lithium diisopropylamide in an organic solvent such as tetrahydrofuran with cooling (e.g.
-100-0°C) without isolation of the intermediate compound of the formula (5) wherein R10 is P(O) (OR2)2.
A compound of formula (4) wherein R9 is hydrogen is suitably prepared by demethylating a compound of formula (5) as hereinbefore defined. Suitably a compound of formula (5) is treated with boron tribromide in an organic solvent such as dichloromethane or toluene with cooling (e.g. -80 to 10°C) followed by ambient temperature and aqueous work-up.
A compound of the formula (4) wherein R9 is
P(O) (NHR12) (OR2) can be prepared by reaction of a
compound of the formula (4) wherein R9 is
P(O) (OH) (OR2) with carbon tetrachloride, triphenyl- phosphine and aniline or a C1-4alkylamine in an organic solvent such as pyridine at ambient temperature or with cooling (e.g. -10 to 5°C). Alternatively a compound of the formula (4) where R9 is P(O) (OH) (OR2) can be
reacted with dimethylformamide and oxalyl chloride in an organic solvent such as a halohydrocarbon e.g. dichloro- methane at ambient temperature, followed by reaction with aniline or a C1-4alkylamine preferably with cooling (-10 to 5°C).
A compound of formula (10) is suitably prepared by reacting the organolithium or Grignard reagent, formed from a compound of formula (17):
Ar-L4 (17) wherein L4 is bromo or iodo and Ar is as hereinbefore defined with a tri-C1-4alkyl borate such as trimethyl, tri-isopropyl or tri-n-butyl borate in an organic solvent such as diethylether or tetrahydrofuran with cooling (e.g. -80 to 10°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. Cyclic-AMP Protein Kinase (cA-PrK) Agonist Activity
Type II cA-PrK was prepared from the cardiac muscle of a cow. The supernatant from a muscle homogenate (3 mis of 10 mM potassium phosphate, 1 mM EDTA per g tissue) was applied to a column of DEAE-cellulose
equilibrated with the homogenisation buffer and the type II cA-PrK was eluted with homogenisation buffer containing 350 mM sodium chloride (Rannels et al.,
1983, Methods Enzymol., 99, 55-62).
Type II cA-PrK was assayed for phosphotransferase activity by incubating the enzyme at 30°C for 5 minutes with [ -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 phosphoσellulose papers. The concentration of compound required to give 10% phosphotransferase activation is given as the EC10 (μM). The compounds of Examples 1-32, 34-36, 38-46, 49-51, 53-54, 56, 58-61 and 63-65 had EC10 values in the range 0.04 - 100 μM. Inhibition of Platelet Aggregation
Human platelet-rich-plasma was separated from freshly drawn blood (in acid/citrate/dextrose) and treated with 100 μM acetylsalicylic acid for 15 minutes at 37°C. A washed platelet suspension was then prepared in a
Hepes-isotonic saline buffer after a single centrifugation step and adjusted to a concentration of 1.5x108
cells/ml. Aliguots of this suspension were pre-intubated with compounds for 5 minutes at 37°C, then challenged with 1.0 μM U46619. The extent of aggregation after 2 minutes were expressed as a percentage of control and results obtained are expressed as an IC50 (concentration to cause 50% inhibition of platelet aggregation, μM).
The compounds of Examples 1-16, 20, 27-30, 33-36, 38-45, 51, 56, 59-61, 63-64 and 66 had IC50 values in the range 2-192 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, SW-948 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 compounds of Examples 4, 5, 28 and 61 had IC50 values in the range 17 - 82 μM. In the the cell line SW-948 the compounds of Examples 3, 4 and 28 had IC50 values in the range 18 - 46 μM. In the cell line HT-29 the compounds of Examples 4 and 5 had IC50 values of 95 and 31 μM respectively. 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 1,
2 , 4 , 11, 12, 17, 20, 27-31, 35, 36, 42, 47, 51, 59-61, 63 and 64 had EC50 values in the range 1.5 - 210 μM.
Bronchodilatation - In vivo
Male guinea-pigs of the Dunkin Hartley strain
(500 - 600g) were anaesthetised with Sagatal (pentobarbital sodium) (60 mg/kg). Airway resistance was measured using a modification of the classical Konzett-Rossler technique (J. Pharm. Methods, 13, 309-315, 1985). U46619
(9,11-methaneoepoxy-PGH2) was infused i.v. at a rate of 2.5 nmol/min, this produced a steady state of broncho- constriction (approximately 120% increase from basal airway resistance). The compound under test was
administered by i.v. bolus injection, and the subsequent peak inhibition of bronchoconstriction recorded.
The compounds of Examples 1, 2 and 14 reduced the U46619- induced bronchoconstriction in the range 10 - 35% when given at 10 μmole/kg. Bronchodilatation - In vitro
Trachea were excised from guinea-pigs and, after removal of connective tissue, cut spirally into strips (0.8-1.2 cm). The strips were suspended under 1 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 . The spirals were contracted by the addition of carbachol (final concentration, 1 μM) to the baths and a steady tension allowed to develop.
Test compounds were then added in a cumulative manner to the bath and the experiment was terminated by the addition of sodium nitroprusside (final concentration, 100 μM).
The relaxing effect of different concentrations of test compounds on carbachol induced sustained contraction was expressed as percentage of the relaxation obtained with sodium nitroprusside. The concentration of test compound which gave 50% relaxation is given as EC50.
The compounds of Examples 7, 34, 35, 51, 58, 61 and 68 had EC50 values in the range 19 to 103 μM. The
compounds of Examples 1, 2, 9, 11, 17, 29, 30, 42, 45, 58 and 64 at a concentration of 100 μM gave relaxation in the range 22 to 42%.
Example 1 6-(2-Naphthyl)-3-(5-tetrazolyl)pyridin-2(1H)-one
(a) 2-Acetonaphthone (17 g) and dimethylformamide dimethylacetal (12.5 g) were combined in dimethylformamide
(100 ml) and boiled for 24 hours. The deep red solution was cooled to room temperature, cyanoacetamide (8.4 g) and sodium methoxide (10.8 g) added and the mixture boiled for a further 90 minutes. After cooling to room temperature the reaction mixture was poured into water (300 ml) containing acetic acid (30 ml). The solid product formed was separated by filtration washed thoroughly with water and recrystallised from ethanol to give 3-cyano-6-(2- naphthyl)pyridin-2(1H)-one (12.6 g) m.p. 290-292°C.
(b) 3-Cyano-6-(2-naphthyl)pyridin-2(1H)-one (0.98 g) sodium azide (0.29 g) and ammonium chloride (0.23 g) in dimethylformamide were warmed to 120°C for 18 hours cooled to room temperature and poured into water (150 ml) containing acetic acid (5 ml). The resulting solid was separated by filtration, washed thoroughly with water and recrystallised from dimethylformamide/ethanol to give the title compound (0.51 g) m.p. 298-301°C.
Dimethylformamide can be replaced with advantage by N-methylpyrrolidin-2-one. Exa mpl e 2
6-(1-Naphthyl)-3-(5-tetrazolyl)pyridin-2(1H)-one (a) From 1-acetonaphthone (17 g), 3-cyano-6-(1-naphthyl)- pyridin-2(1H)-one (7.11 g) m.p. 264-266ºC after recrystallisation from ethanol, was prepared according to the method of Example 1(a).
(b) From 3-cyano-6-(1-naphthyl)pyridin-2(1H)-one
(3.69 g), the title compound (0.9 g) m.p. 288-289°C after recrystallisation from dimethylformamide, was prepared according to the method of Example 1 (b).
Example 3 6-(2-Benzofuranyl)-3-(5-tetrazolyl)-pyridin-2(1H)-one
(a) From 2-acetylbenzofuran (8 g) , 6- (2-benzofuranyl) -3- cyanopyridin-2 (1H) -one (3 . 36 g) m.p. >330°C after
recrystallisation from dimethylformamide, was prepared according to the method of Example 1(a); δ(DMSO-d6)
7.02(d,1H), 7.39(t,1H), 7.48(t,1H), 7.69(d,1H),
7.80(d,1H), 7.98(s,1H) and 8.23 (d, 1H).
(b) From 6-(2-benzofuranyl)-3-cyano-pyridin-2(1H)-one (2.36 g) , the title compound (1.34 g) m.p. 248-250°C after recrystallisation from dimethylformamide, was prepared according to the method of Example 1(b); δ(DMSO-d6),
7.17(d,1H), 7.28-7.53 (m, 2H), 7.72(d,1H), 7.81(d,1H), 7.98(s,1H) and 8.53 (d,1H).
Example 4 6-(9-Phenanthryl)-3-(5-tetrazolyl)pyridin-2(1H)-one
(a) From 9-acetylphenanthrene (29.74 g), 3-cyano-6-(9- phenanthryl) pyridin-2(1H)-one (31.93 g) m.p. 305-306°C after recrystallisation from dimethylformamide, was prepared according to the method of Example 1(a). (b) From 3-cyano-6-(9-phenanthryl)pyridin-2(1H)-one
(1 g), the title compound (0.67 g) m.p. 298°C after recrystallisation from dimethylformamide/water, was prepared according to the method of Example 1(b);
δ(DMSO-d6), 6.78(d,1H), 7.69-7.88 (m,4H), 7.93(d,1H),
8.06-8.17(m,2H), 8.59(d,1H), 8.92(d,1H) and 8.99 (d, 1H).
Example 5 6-(3-Phenanthryl)-3-(5-tetrazolyl)pyridin-2(1H)-one
(a) From 3-acetylphenanthrene (25 g), 3-cyano-6-(3- phenanthryl)pyridin-2(1H)-one (18.6 g) m.p. 240ºC (decomp) after recrystallisation from dimethylformamide/water, was prepared according to the method of Example 1(a);
δ(DMSO-d6) 7.08(d,1H), 7.68-8.15 (m,7H), 8.27(d,1H),
9.05(d1H), 9.35(s,1H) and 12.95(br s,1H). (b) From 3-cyano-6-(3-phenanthryl)pyridin-2(1H)-one
(1 g), the title compound (0.58 g) m.p. 294°C (decomp) after recrystallisation from dimethylformamide/water was prepared according to the method of Example 1(b) using N-methylpyrrolidinone as solvent; δ(DMSO-d6),
7.20(d,1H), 7.64-8.17(m,7H), 8.56(d,1H), 9.08 (d,1H) and 9.39(S,1H).
Example 6 6-(2-Ouinolinyl)-3-(5-tetrazolyl)pyridin-2(1H)-one
(a) From 2-acetylquinoline (0.63 g) (Y. Yamamoto nd A.Yanagi, Chem. Pharm. Bull., 1982, 30, 2003),
3-cyano-6-(2-quinolinyl)pyridin-2(1H)-one (0.35 g) m.p. 282-284°C after recrystallisation from ethanol, was prepared according to the method of Example 1(a).
(b) From 3-cyano-6-(2-quinolinyl)pyridin-2(1H)-one
(0.3 g), the title compound (0.06 g) m.p. 291-292°C
(decomp) after recrystallisation from n-butanol was prepared according to the method of Example 1 (b), using N-methylpyrrolidinone as solvent; δ(DMSO-d6),
7.59(d,1H), 7.73(dt,1H), 7.89(dt,1H), 8.09(d,1H),
8.23(d,1H), 8.36(d,1H) and 8.63 (d, 1H).
Example 7 6-[1-(4-Methoxy)naphthyl]-3-(5-tetrazolyl)pyridin-2(1H)-one
(a) From 4-methoxy-1-acetonaphthone (15 g) (E.A.Dixon, A.Fischer and F.P.Robinson, Can. J. Chem., 1981, 59,
2629), 3-cyano-6-[1-(4-methoxy)naphthyl]pyridin-2(1H)-one (16.1 g) m.p. 259-260°C after recrystallisation from n-butanol, was prepared according to the method of Example 1(a).
(b) From 3-cyano-6-[1-(4-methoxy)naphthyl]pyridin- 2(1H)-one (0.55 g) , the title compound (0.35 g) 308-310°C (decomp) after recrystallisation from n-butanol,was
prepared according to the method of Example 1(b) using N-methylpyrrolidinone as solvent; δ(DMSO-d6),
4.05(s,3H), 6.63(d,1H), 7.10(d,1H), 7.57-7.66 (m,3H),
7.88-7.95(m,1H), 8.24-8.30(m,1H) and 8.33 (d,1H). Example 8
3-Carboxy-6-(2-naphthyl)pyridin-2(1H)-one
3-Cyano-6-(2-naphthyl)pyridin-2(1H)-one (10 g) was refluxed in a mixture of acetic acid (250 ml) and 60% hydrobromic acid (250 ml) for 4 hours. The cooled reaction mixture was poured into water (500 ml), the precipitated product separated by filtration, and washed thoroughly with water. Recrystallisation from dimethylformamide/ethanol gave the title compound (7.9 g) m.p. 319-320°C
Example 9 3-Carboxy-6-(1-naphthyl)pyridin-2(1H)-one
The title compound (0.6 g) m.p. 277-279°C after recrystallisation from ethanol, was prepared from
3-cyano-6-(1-naphthyl)pyridin-2(1H)-one (1 g)using the method of example 8.
Example 10
Ethyl [6-(2-naphthyl)-2-oxo-1,2-dihydro-3-Pyridyl]- phosphonate
(a) A mixture of 3-cyano-6-(2-naphthyl)pyridin-2(1H)-one (40.9 g) and 90% orthophosphoric acid (300 ml) were heated to 180°C for 6 hours. The cooled reaction mixture was poured into water (500 ml), to precipitate 6-(2-naphthyl)- pyridin-2(1H)-one (30.8 g) as an off-white solid that was recrystallised from ethanol m.p. 253-255°C.
(b) Lithium diisopropylamide (from diisopropylamine 2.53g and n-butyl lithium 12.5ml of 2.0M in hexanes) was added over 5 minutes to a suspension of 6-(2-naphthyl)pyridin- 2(1H)-one (5.5 g) in tetrahydrofuran (30 ml) at -78ºC under a nitrogen atmosphere. When the addition was complete the reaction mixture was stirred at 0°C for
30 minutes, recooled to -78ºC and treated with diethyl- chlorophosphate (4.3 g). After rewarming to 0°C stirring for 30 minutes, recooling to -78°C and addition of more lithium diisopropylamide (from diisopropylamine 2.53g and n-butyl lithium 12.5ml of 2.0M in hexanes), the reaction mixture was stirred at -78°C for 90 minutes and at 0°C for 30 minutes before quenching with 2N HCl (50 ml). Tetra- hydrofuran was removed at reduced pressure, the aqueous phase extracted with dichloromethane (3x100 ml), the combined organic extracts washed with water (100 ml) and brine (100 ml), dried (MgSO4), filtered and solvent removed at reduced pressure. The residue was
chromatographed (silica gel, ethyl acetate-5%
ethanol/ethyl acetate eluant) to give, after
recrystallisation from ethyl acetate, diethyl
[6-(2-naphthyl)-2-oxo-1,2-dihydro-3- pyridyl]phosphonate (1.8 g) m.p. 148-151°C.
(c) Diethyl [6-(2-naphthyl)-2-oxo-1,2-dihydro-3- pyridyl]phosphonate (1.0 g) and sodium hydroxide (1.2 g) were boiled together in water/ethanol (20ml 1:1) for
12 hours. Solvent was removed at reduced pressure, the residue dissolved in water, cooled to 0°C and concentrated hydrochloric acid added to pH1. The precipitate was separated by filtration and recrystallised from ethanol to give the title compound (0.54 g) m.p. 242-244°C Example 1 1 n-Butyl [6-(2-naphthyl)-2-oxo-1,2-dihydro-3-pyridyl]- phosphonate (a) Di-n-butyl [6-(2-naphthyl)-2-oxo-1,2-dihydro-3- pyridyl]phosphonate (2 g) was prepared from 6-(2-naphthyl)- pyridin-2(1H)-one (2.2 g) and di-n-butylchlorophosphate (2.2 g) according to the method of Example 10(b);
S(DMSO-d6) 0.88(t,6H), 1.30-1.44 (m,4H), 1.55-1.66
(m,4H), 4.04(q,4H), 6.90(dd,1H), 7.59-7.67 (m,2H),
7.89-8.06(m,5H) and 8.47 (s,1H). (b) From di-n-butyl [6-(2-naphthyl)-2-oxo-1,2-dihydro-3- pyridyl]phosphonate (2 g) the title compound (0.12 g) m.p. 216-218°C after recrystallisation from water adjusted to pH1 with concentrated hydrochloric acid, was prepared according to the method of Example 10(c).
Example 12 n-Hexyl [6-(2-naphthyl)-2-oxo-1,2-dihydro-3-pyridyl]- phosphonate
(a) Di-n-hexyl [6-(2-naphthyl)-2-oxo-1,2-dihydro-3- pyridyl]phosphonate (1 g) was prepared from 6-(2- naphthyl)pyridin-2(1H)-one (2.2 g) and di-n-hexyl
chlorophosphate (2.5 g) (B. Colin, N.M.Jones, C.McGuigan and P.A.Riley, Nucleic Acids Res., 1989, 17, 7195)
according to the method of Example 10(b); δ(CDCl3)
0.79(t,6H), 1.13(m,12H), 1.48(m,4H), 3.89-4.09 (m,4H), 6.78(dd,1H), 7.56(m,2H), 7.86-8.00 (m,3H), 8.17(m,1H), 8.24(dd,1H), 8.53(s,1H) and 13.15 (br s,1H).
(b) From di-n-hexyl [6-(2-naphthyl)-2-oxo-1,2-dihydro-3- pyridyl]phosphonate (1 g) the title compound (0.33 g) m.p. 175-178°C after recrystallisation from ethanol, was prepared according to the method of Example 10(c).
Example 13
Phenyl [6-(2-naphthyl)-2-oxo-1,2-dihydro-3-pyridyn- phosphonate
(a) Diphenyl [6-(2-naphthyl)-2-oxo-1,2-dihydro-3- pyridyl]phosphonate (1.1 g) m.p. 200-201°C after
recrystallisation from ethanol, was prepared from
6-(2-naphthyl)pyridin-2(1H)-one (1.1 g) and diphenyl- chlorophosphate (1.34 g) according to the method of Example 10 (b) .
(b) From diphenyl [6-(2-naphthyl)-2-oxo-1,2-dihydro-3- pyridyl]phosphonate (1 g), the title compound (0.27 g) m.p. 236°C after recrystallisation from ethanol, was prepared according to the method of Example 10(c).
Example 14 Ethyl [6- (1-naphthyl) -2-oxo-1,2-dihydro-3-pyridyl]- phosphonate
(a) 6-(1-naphthyl)pyridin-2(1H)-one (41.8 g) m.p.
219-220°C after recrystallisation from sec-butanol, was prepared from 3-cyano-6-(1-naphthyl)pyridin-2(1H)-one (50 g) according to the method of Example 10(a).
(b) Diethyl [6-(1-naphthyl)-2-oxo-1,2-dihydro-3- pyridyl]phosphonate (5.55 g) m.p. 220-222°C after recrystallisation from ethanol/water, was prepared from 6-(1-naphthyl)pyridin-2 (1H)-one (5.5 g) and diethyl chlorophosphate (4.3 g) according to the method of Example 10(b). (c) From diethyl [6-(1-naphthyl)-2-oxo-1,2-dihydro-3- pyridyl]phosphonate (1 g), the title compound (0.28 g) m.p. 257-258°C after recrystallisation from ethanol, was prepared according to the method of Example 10(c).
Example 1 5 n-Butyl [6-(1-naphthyl) -2-oxo-1,2-dihydro-3-pyridyl]- phosphonate
(a) Di-n-butyl [6- (1-naphthyl) -2-oxo-1, 2-dihydro-3- pyridyl]phosphonate (1.45 g) m.p. 161-163°C after
recrystallisation from ethanol, was prepared from
6-(1-naphthyl)pyridin-2(1H)-one (2.21 g) and di-n-butyl chlorophosphate (2.28 g) according to the method of
Example 10 (b).
(b) From di-n-butyl [6-(1-naphthyl)-2-oxo-1,2-dihydro-3- pyridyl]phosphonate (1.45 g) the title compound (0.55 g) m.p. 202-204°C after recrystallisation from ethanol was prepared according to the method of Example 10 (c).
Exampl e 16 n-Hexyl [6-(1-naphthyl)-2-oxo-1,2-dihydro-3-pyridyl]- phosphonate
(a) Di-n-hexyl [6-(1-naphthyl)-2-oxo-1,2-dihydro-3- pyr idyl] phosphonate (2.1 g) isolated as an oil, was prepared from 6-(1-naphthyl)pyridin-2 (1H)-one (2.21 g) and di-n-hexyl chlorophosphate (2.84 g) according to the method of Example 10(b); δ(DMSO-d6) 0.85(t,6H),
1.21-1.45(m,12H), 1.57-1.71(m,4H), 4.04(m,4H), 6.45(m,1H), 7.53-8.11(m,8H) and 11.42 (br s,1H). (b) From di-n-hexyl [6-(1-naphthyl)-2-oxo-1,2-dihydro-3- pyridyl]phosphonate (1.2 g) the title compound (0.35 g) m.p. 189-192ºC after recrystallisation from ethanol, was prepared according to the method of Example 10 (c). Example 17
Ethyl [6-19-phenanthryl)-2-oxo-1,2-dihydro-3-pyridyl]- phosphonate (a) 6-(9-Phenanthryl)pyridin-2(1H)-one (5.98 g) m.p.
278-280°C after recrystallisation from n-butanol, was prepared from 3-cyano-6-(9-phenanthryl)pyridin-2(1H)-one (8 g) according to the method of Example 10(a).
(b) Diethyl [6-(9-phenanthryl)-2-oxo-1,2-dihydro-3- pyridyl]phosphonate (2.46 g) was prepared from
6-(9-phenanthryl)pyridin-2(1H)-one (3 g) and diethyl chlorophosphate (2.27 g) according to the method of
Example 10(b); δ(DMSO-d6) 1.29(t,6H), 4.05-4.21(m,4H), 6.52(m,1H), 7.65-8.13 (m,8H), 8.93(t,2H) and 12.3 (br s, 1H).
(c) From diethyl [6-(9-phenanthryl)-2-oxo-1,2-dihydro-3- pyridyl]phosphonate (2.46 g) the title compound (1.05 g) m.p. 253-255°C after recrystallisation from n-butanol, was prepared according to the method of Example 10(c).
Example 18
Ethyl 2-hydroxy-[6-(2-naphthyl)-2-oxo-1,2-dihydro-3- pyridyl]propionate
(a) 6-(2-Naphthyl)pyridin-2(1H)-one (17.6 g) and
dimethylformamide dimethylacetal (10.71 g) were heated together at 120°C in dimethylformamide (50 ml) for
4 hours. The brown solution was cooled to room
temperature, diluted with ethyl acetate (300 ml) and washed with water (6x100 ml). The residue after removing solvent was column chromatographed (silica gel, hexane-20% dichloromethane/hexane eluant) to give 2-methoxy-6-(2- naphthyl)pyridine (12.4 g) which was recrystallised from ethanol m.p. 91°C
(b) To 2-methoxy-6-(2-naphthyl)pyridine (7.08 g) in tetrahydrofuran (50 ml) under nitrogen at -78ºC methyl lithium (42ml of 1.5M in diethyl ether) was added over 10 minutes, followed by diisopropylamine (0.3 ml). The reaction mixture was stirred for 3 hours at 0°C, trans ferred into a solution of ethyl pyruvate (6.96 g) in tetrahydrofuran at -78°C and stirred for a further 1 hour at -78ºC. After quenching with saturated ammonium chloride, the reaction mixture was diluted with ethyl acetate (250 ml), washed with water (2x100 ml), dried (MgSO4) and solvent removed. The residue was column chromatographed (silica gel, 30% hexane/dichloromethane- dichloromethane eluant) to give ethyl 2-hydroxy-2-[6-(2- naphthyl)-2-methoxy-3-pyridyl]propionate (6.05 g) which was recrystallised from ethanol m.p. 136-137°C
(c) To a solution of ethyl 2-hydroxy-2-[6-(2-naphthyl)-2- methoxy-3-pyridyl]propionate (0.1 g) in acetonitrile
(5 ml) containing sodium iodide (0.75 g) chlorotrimethyl- silane (0.54 g) was added. After stirring for 1 hour the reaction mixture was diluted with ethyl acetate (50 ml), washed with 5% sodium metabisulphite (20 ml) and water (20 ml), dried (MgSO4) and solvent removed at reduced pressure. Recrystallisation of the residue from ethanol gave the title compound (0.06 g) m.p. 162-163°C.
Example 19
2-Hydroxy-2-[6-(2-Naphthyl)-2-oxo-1,2-dihydro-3-pyridyl]- propionic acid
(a) A solution of ethyl 2-hydroxy-2-[6-(2-naphthyl)-2- methoxy-3-pyridyl]propionate in ethano1/2N sodium
hydroxide (1: 1, 8 ml) was boiled for 20 minutes . Solvent was removed at reduced pressure, the residue dissolved in water (50 ml), washed with ethyl acetate (2x30 ml), acidified with 2N hydrochloric acid and extracted with dichloromethane (5x50 ml). The combined extracts were washed with water (2x50 ml), dried (MgSO4) and solvent removed to give 2-hydroxy-2-[6-(2-naphthyl)-2-methoxy-3- pyridyl]propionic acid (300m g) m.p. softens 242-244°C (decomp) ; δ (DMSO-d6) 1.59 (s , 3H) , 4 . 00 (s , 3H) , 7.55
(m, 2H) , 7 . 75 (d, 1H) , 7. 92-8. 07 (m, 4H) , 8.27 (dd, 1H) and 8. 65 (S , 1H) . (b) 2-Hydroxy-2-[6-(2-naphthyl)-2-methoxy-3-pyridyl]- propionic acid (0.4 g) was treated with sodium iodide (1.54 g)and chlorotrimethylsilane (1.08 g) according to the method of Example 18(c) to give after recrystallisation from ethanol the title compound (0.26 g) m.p.
218-222°C (decomp).
Example 20
2-Hydroxy-2-[6-(2-naphthyl)-2-oxo-1,2-dihydro-3-pyridyl]- acetic acid
(a) Following the method of Example 18(b) 2-methoxy-6- (2-naphthyl)pyridine (2.36 g) was reacted with diethyl oxalate (3.65 g). Work up and column chromatography (silica gel, 70% hexane/dichloromethane-30% hexane/di- chloromethane eluant) gave, after recrystallisation from ethyl acetate/hexane, ethyl 2-oxo-[2-methoxy-6-(2- naphthyl)-3-pyridyl]acetate (2.9 g) m.p 83-85°C. (b) A solution of ethyl 2-oxo-[2-methoxy-6-(2-naphthyl)- 3-pyridyl]acetate (0.61 g) in dichloromethane/ethanol/ acetic acid (5:5:1,11 ml) at 0°C was treated with sodium borohydride (200 mg) in portions over 30 minutes. After stirring for a further 30 minutes, the reaction mixture was diluted with dichloromethane (50 ml), washed with water (3x30 ml), dried (MgSO4) and solvent removed. The residue was column chromatographed (silica gel, 20% hexane/dichloromethane eluant) to give ethyl 2-hydroxy- [2-methoxy-6-(2-naphthyl)-3-pyridyl]acetate (530 mg) m.p. 89-90°C. (c) A solution of ethyl 2-hydroxy-[2-methoxy-6-(2- naphthyl)-3-pyridyl]acetate (530 mg) in ethanol/2N sodium hydroxide (1:1 8 ml) was stirred for 24 hour and boiled for a further 2 hours. Solvent was removed, the residue dissolved in water (50 ml), acidified with 2N hydrochloric acid and extracted with ethyl acetate (4x50 ml). The combined extracts were washed with water (2x50 ml), dried (MgSO4) and solvent removed to give 2-hydroxy-[2-methoxy- 6-(2-naphthyl)-3-pyridyl]acetic acid (480 mg) m.p.
164-165°C.
(d) 2-Hydroxy-[2-methoxy-6-(2-naphthyl)-3-pyridyl]acetic acid (0.46 g) and sodium thiomethoxide (0.5 g) were heated together in dimethylformamide (5 ml) at 100°C for
3 hours. The mixture was cooled (ice bath), water (5 ml) added and adjusted to pH4 with 2N hydrochloric acid. The precipitated solid was separated by filtration, washed (2x10ml 2N hydrochloric acid, 4xl5ml water and 2x20ml diethyl ether) and recrystallised from ethanol to give the title compound (0.23 g) m.p. 239-240°C.
Exampl e 2 1
2-Methoxy-2-[6-(2-naphthyl)-2-oxo-1,2-dihydro-3-pyridyl]- acetic acid
(a) To a solution of ethyl 2-hydroxy-2-[6-(2-naphthyl)-2- methoxy-3-pyridyl]acetate (1.0 g) in dimethylformamide (5 ml) sodium hydride (0.15g,50% in oil) was added. When gas evolution had ceased, iodomethane (0.57 g) was added the reaction mixture stirred for 2 hours, quenched
carefully with water, diluted with ethyl acetate (50 ml), washed with water (6x50 ml), dried (MgSO4) and solvent removed. The residue was column chromatographed (silica gel, 50% hexane/dichloromethane eluant) to give ethyl
2-methoxy-2-[6-(2-naphthyl)-2-methoxy-3-pyridyl]acetate (0.13 g) containing 30% of the corresponding methyl ester; δ(DMSO-d6) 1.18(t,3H), 3.40(s,3H), 4.09(s,3H), 4.14
(q,2H), 5.06(s,1H), 7.52(m,2H), 7.78(m,2H) 7.92-8.09
(m,3H), 8.36(d,1H) and 8.66(s,1H) (for the ethyl ester).
(b) Ethyl 2-methoxy-2-[6-(2-naphthyl)-2-methoxy-3- pyridyl] acetate (0.13 g) was hydrolysed using the method of Example 20(c) to give 2-methoxy-2-[6-(2-naphthyl)-2- methoxy-3-pyridyl] acetic acid (0.12 g); δ(DMSO-d6)
3.36(s,3H), 4.06(s,3H), 7.56(m,2H), 7.79(m,2H), 7.92-8.07 (m,3H), 8.28(dd,1H) and 8.67(s,1H).
(c) Treatment of 2-methoxy-2-[6-(2-naphthyl)-2-methoxy-3- pyridyl] acetic acid (0.12 g) with sodium iodide (1.42 g) and chlorotrimethylsilane (1.3 ml) in acetonitrile
according to the method of example 18(c) gave, after recrystallisation from ethanol the title compound (0.07 g) m.p. 219-220°C (decomp). Example 22
2-Propoxy-2-[6-(2-naphthyl)-2-oxo-1,2-dihydro-3-pyridyl]- acetic acid (a) A suspension of potassium hydroxide (0.45g, crushed pellets) was stirred in dimethylsulphoxide for
5 minutes. Ethyl 2-hydroxy-[6-(2-naphthyl)-2-methoxy- 3-pyridyl) acetate (0.674 g) was then added followed after 3 minutes by iodopropane (0.51 g). Stirring was
continued for 16 hours, water (1 ml) added and stirring continued for a further 3 hours. The reaction mixture was diluted with ethyl acetate (50 ml), acidified with 2N hydrochloric acid, washed with water (6x50 ml), dried
(MgSO4) and solvent removed. The residue was column chromatographed (silica gel, dichloromethane-15%
ethanol/dichloromethane eluant) to give 2-propoxy-2-[6-(2- naphthyl)-2-methoxy-3-pyridyl]acetic acid (0.27 g);
δ(DMSO-d6) 0.87(t,3H), 1.47-1.65 (m,2H), 3.32-3.61
(m,2H), 4.05(s,3H), 5.01(s,1H), 7.51-7.59 (m,2H), 7.78 (2H,ABq), 7.90-8.05(m,3H), 8.27(dd,1H) and 8.65 (s,1H).
(b) Treatment of 2-propoxy-2-[6-(2-naphthyl)-2-methoxy-3- pyridyl]acetic acid (0.25 g) with sodium iodide (1.5 g) and chlorotrimethylsilane (1.08 g) in acetonitrile (5 ml) according to the method of Example 18(c) gave after recrystallisation from ethanol the title compound (0.085 g) m.p. 118-119°C(softens); 6(DMSO-d6) 0.89(t,3H),
1.50-1.63(m,2H), 3.33-3.64 (m,2H), 4.97(s,1H), 6.80(d,1H), 7.55-7.65 (m, 3H), 7.86(dd,1H), 7.94-8.04 (m,3H), 8.38 (S,1H) and 12.47 (br s,1H).
Example 23
Ethyl 2-hydroxy-2-[6-(2-naphthyl)-2-oxo-1,2-dihydro-3- pyridyl]acetate
Treatment of ethyl 2-hydroxy-2-[6-(2-naphthyl)-2- methoxy-3-pyridyl]acetate (0.337 g) with sodium iodide (1.54 g) and chlorotrimethylsilane (1.08 g) in acetonitrile (10 ml) according to the method of Example 18(c) gave after recrystallisation from ethanol the title compound (0.23 g) m.p. 167-168ºC.
Example 24 [6-(2-Naphthyl) -2-oxo-1 , 2-dihyd ro-3-pyridyl]sulphonic acid sodium salt
(a) Following the method of Exxmple 18(b) 2-methoxy-6-(2- naphthyl)pyridine (1.88 g) was reacted with sulphuryl chloride (2.7 g). After the addition of the anion of
2-methoxy-6-(2-naphthyl)pyridine to sulphuryl chloride was complete, the reaction mixture was stirred for a further 10 minutes at -78°C, quenched with 2N hydrochloric acid, diluted with ethyl acetate (200 ml), washed with water (50 ml), dried (MgSO4) and solvent removed. The residue was stirred at room temperature in ethanol/2N sodium hydroxide (2:1 18 ml) for 16 hours and boiled for
2 hours. Acidification with 2N hydrochloric acid gave a solid which was separated by filtration, washed with ethyl acetate (2x20 ml) and recrystallised from ethanol/water to give [6-(2-naphthyl)-2-methoxy-3-pyridyl]sulphonic acid (0.35 g); δ(DMSO-d6) 4.06(s,3H), 7.56(m,2H), 7.70
(d,1H), 7.91-8.09(m,4H), 8.27(dd,1H) and 8.68 (s, 1H).
(b) [6-(2-naphthyl)-2-methoxy-3-pyridyl]sulphonic acid (0.314 g) was heated with sodium thiomethoxide (0.4 g) in dimethylformamide (3 ml) at 100ºC for 3 hours. Water (5 ml) was added followed by 2N hydrochloric acid to pH1, the mixture filtered, water removed at reduced pressure, the residual dimethylformamide refiltered diluted with water (10 ml) and cooled to 0°C for 30 days. The title compound (0.08 g) was separated by filtration m.p. >325°C; δ(DMSO-d6) 7.17(br S,1H), 7.58(m,2H), 7.88-8.05(m-5H) and 8.49 (S,1H). Example 25
2-Oxo-2-[6-(1-naphthyl)-2-oxo-1,2-dihydro-3-pyridyl]acetic acid (a) Treatment of 6-(1-naphthyl)pyridin-2(1H)-one
(17.64 g) with dimethylformamide dimethylacetal (19.04 g) according to the method of Example 18(a) gave after column chromatography (silica gel, 80% hexane/dichloromethane eluant) and recrystallisation from ethyl acetate/hexane, 2-methoxy-6-(1-naphthyl)pyridine (6.81 g) m.p. 56-58°C. Or
A mixture of 6-(1-naphthyl)pyridin-2(1H)-one (4.41 g) and trimethylphosphite (20 ml) was heated at 180°C (oil bath temperature) for 40 minutes. The mixture was cooled to room temperature, diluted with ethyl acetate (100 ml) and washed with water (5x100 ml), dried (MgSO4), and solvent removed at reduced pressure. The residue was column chromatographed (silica gel, 1:1 hexane/dichloro- methane eluant) to give 2-methoxy-6-(1-naphthyl)pyridine.
(b) Following the method of Example 18(b) 2-methoxy-6-(1- naphthyl)pyridine (0.7 g) was reacted with diethyl
oxalate. Work up and column chromatography (80%
hexane/dichloromethane) gave, after recrystallisation from ethyl acetate/hexane ethyl 2-oxo-[2-methoxy-6-(1-naphthyl)- 3-pyridyl] acetate (0.68 g) m.p. 70-72ºC
(c) A solution of ethyl 2-oxo-[2-methoxy-6-(1-naphthyl)-3- pyridyl]acetate (0.4 g) in concentrated hydrochloric acid
(4 ml) was heated to 110°C for 40 minutes. On cooling the precipitated solid was separated by filtration and washed with water to give the title compound (0.21 g) m.p. 228-230°C.
Example 26
Ethyl 2-oxo-2-[6-(1-naphthyl)-2-oxo-1,2-dihydro-3-pyridyl]- acetate
A mixture of ethyl 2-oxo-[2-methoxy-6-(1-naphthyl)-3- pyridyl]acetate (0.6 g) and sodium iodide (2.7 g) were heated together at reflux in chlorotrimethylsilane
(2.3 ml) for 24 hours. The reaction mixture was quenched with 2N hydrochloric acid (10 ml), stirred for 1 hour and filtered. The residue was washed with water (2x20 ml) and ethanol (2x5 ml) and recrystallised from acetone to give the title compound (0.2 g) m.p. 182-186ºC.
Example 27 [6-(2-Naphthyl)-2-oxo-1,2-dihydro-3-pyridyl]acetic acid
(a) To a suspension of 3-cyano-6-(2-naphthyl)pyridin- 2(1H)-one (17 g) in tetrahydrofuran (100 ml) under
nitrogen at -78ºC, methyl lithium (100ml, 1.4M in diethyl ether) was added over 30 minutes. After stirring for a further 20 minutes at -78°C, the reaction mixture was warmed to 0°C and stirring continued for 90 minutes. The reaction was quenched by the careful addition of saturated aqueous ammonium chloride (5 ml), followed by 2N
hydrochloric acid (100 ml). The organic solvents were removed at reduced pressure and the yellow solid separated by filtration to give 3-acetyl-6-(2-naphthyl)pyridin-2 (1H)- one (17.41 g) which was further purified by recrystallisation from acetonitrile/water m.p. 226-230ºC.
Or (b) A solution of 2-acetonaphthone (17.0 g) in dimethylformamide (10 ml) containing dimethylformamide dimethyl- acetal (12 g) was heated at reflux for 4 hours cooled to room temperature and poured into diethyl ether (250 ml). The precipitate was separated by filtration washed with diethyl ether and air dried to give 3-dimethylamino-1-(2- naphthyl)prop-2-ene-1-one 18.75g m.p. 110-112°C.
A mixture of 3-dimethylamino-1-(2-naphthyl)prop-2- ene-1-one (5.73 g), acetoacetamide (2.6 g) and sodium methoxide (2.81 g) in dimethylformεunide (50 ml) was boiled for 8 hours, poured into 1N sodium hydroxide solution (500 ml), washed with ethyl acetate (2x100 ml) and diethyl ether (3x100 ml). The solution was acidified with concentrated hydrochloric acid, filtered and the residue washed with water and dried to give 3-acetyl-6-(2- naphthyl)pyridin-2(1H)-one (1.37 g).
(c) A mixture of 3-acetyl-6-(2-naphthyl)pyridin-2(1H)-one (1.3 g), sulphur (0.23 g) and morpholine (0.64 ml) were heated on an oil bath at 150°C for 5 hours. The dark semi-solid was suspended in water (100 ml), sodium
hydroxide (2 g) added and the mixture boiled for
30 minutes. After filtration, the solution was adjusted to pH5 with acetic acid and the precipitated product separated by filtration and washed with water, to give the title compound (0.47 g) m.p. 280-285ºC.
Example 28
[6-(1-Naphthyl)-2-oxo-1,2-dihydro-3-pyridyl]acetic acid
(a) 3-Acetyl-6-(1-naphthyl)pyridin-2(1H)-one (10.8 g) m.p. 239-240°C after recrystallisation from ethanol, was prepared from 3-cyano-6-(1-naphthyl)pyridin-2(1H)-one (12.3 g) according to the method of Example 27(a).
(b) To a suspension of 3-acetyl-6-(1-naphthyl)pyridin- 2(1H)-one (6.0 g) in morpholine (4mls) sulphur (1.5 g) was added, the mixture was boiled for 4 hours and stood at room temperature overnight. The resultant black mixture was boiled in 2N sodium hydroxide (75 ml) for 4 hours, diluted with water (100 ml), treated with decolourising charcoal and filtered. Addition of carbon dioxide to pH7, refiltration and finally adjustment to pH5 with acetic acid, filtration of the precipitated product and recrystallisation from acetonitrile/water gave the title compound (2.17 g) m.p. 203-207°C.
Example 29 7-Aza-6-(1-naphthyl)benzofuram-2-one
[6-(1-naphthyl)-2-oxo-1,2-dihydro-3-pyridyl]acetic acid (1.56 g) was boiled in acetic anhydride (20mls) until a clear solution was obtained. The solution was
evaporated to dryness, the residue dissolved in diethyl ether (100 ml), washed with 5% sodium bicarbonate solution (3x50 ml), water (50 ml) saturated ammonium chloride solution (50 ml) and dried (MgSO4). Removal of solvent gave a red solid which was continuously extracted with hexane for 16 hours. Concentration of the hexane to a small volume gave the title compound (0.88 g) m.p.
150-153°C.
Example 30
4-Ethoxy-4-oxo-1,3,4-dioxyphosphono[5 ,6-b]-7-(1-naphthyl) pyridine
A mixture of ethyl [6-(1-naphthyl)-2-oxo-1,2- dihydro-3-pyridyl)phosphonate (0.66 g) silver carbonate (1.4 g) and diiodomethane (0.8 g) in dimethylformamide (4 ml) was heated at 100°C for 24 hours in the dark.
More silver carbonate (0.7 g) and diiodomethane (0.4 g) were added and heating continued for a further 24 hours. The reaction mixture was diluted with ethyl acetate
(50 ml), filtered, the filtrate washed with water
(6x50 ml), dried (MgSO4) and solvent removed. The residue was column chromatographed (silica gel, dichloro- methane eluant), the appropriate fractions combined, and solvent removed, to give after recrystallisation twice from ethanol the title compound (0.1 g) m.p. 140-142°C. Exampl e 31
Ethyl [6-(1-naphthyl)-2-oxo-1,2-dihydro-3-pyridyl]- phosphonothioate
(a) To a solution of ethyl [6-(1-naphthyl)-2-oxo-1,2- dihydro-3-pyridyl)phosphonate (0.66 g), carbon tetra- chloride (1.54 g) and aniline (0.93 g) in pyridine (5 ml) under nitrogen at 0°C, triethylphosphine (0.94 g) was added. The reaction mixture was stirred for 24 hours additional carbon tetrachloride (0.77 g) and triethyl- phosphine (0.47 g) added and stirring continued for a further 48 hours. Dilution with ethyl acetate (50 ml), washing with 2N hydrochloric acid (2x50 ml), water
(4x50 ml) drying (MgSO4) and removal of solvent gave a solid (0.18 g). The combined aqueous phases were
extracted with dichloromethane (4x50 ml), the combined dichloromethane extracts washed with water (2x50 ml), dried (MgSO4) and solvent removed. The residue was combined with the solid obtained from the ethyl acetate phase, column chromatographed (silica gel, dichloromethane eluant) the appropriate fractions combined, solvent removed and the residue recrystallised twice from ethanol to give O-ethyl-N-phenyl [6-(1-naphthyl)-2-oxo-1,2- dihydro-3-pyridyl]phosphonoamidate (0.13 g) m.p. 258-260°C
Or
(b) To a suspension of ethyl [6-(1-naphthyl)-2-oxo-1,2- dihydro-3-pyridyl]phosphonate (1.65 g) in dichloromethane
(15 ml), dimethylformamide (0.05 ml) was added followed by oxalyl chloride (2.5 ml). When gas evolution had ceased solvent was removed and the residue redissolved in
dichloromethane (20 ml), cooled (ice bath) and aniline (0.9 g), followed by triethylamine (1.2 g) added. After stirring for 2 hours at 0ºC the reaction mixture was diluted with dichloromethane (50 ml), washed with 2N hydrochloric acid (2x50 ml) and water (2x50 ml), dried (MgSO4) and solvent removed. The residue was
chromatographed (dichloromethane-5% ethanol/dichloro- methane eluant) the appropriate fractions combined, solvent removed and the residue recrystallised twice from ethanol to give O-ethyl-N-phenyl [6-(1-naphthyl)-2-oxo-1,2- dihydro-3-pyridyl]phosphonoamidate (0.4 g). (c) O-Ethyl-N-phenyl [6-(1-naphthyl)-2-oxo-1,2-dihydro-3- pyridyl]phosphonoamidate (0.4 g) was added in portions over 5 minutes to a suspension of sodium hydride (0.2g, 50% in oil washed with hexane) in dimethoxyethane. The mixture was stirred at room temperature for 1 hour and at 50°C for 15 minutes, cooled (ice bath), and carbon
disulphide (0.76 g) added. The mixture was stood at room temperature for 14 days, diluted with ethyl acetate, washed with 2N hydrochloric acid (2x30 ml) and water
(2x30 ml) dried (MgSO4) and solvent removed. The
combined aqueous washes were combined and extracted with dichloromethane (3x50 ml) the combined extracts washed with water (50 ml) dried (MgSO4) solvent removed and the residue combined with the ethyl acetate soluble
material. The combined organic material was
recrystallised twice from ethanol to give the title
compound (0.09 g) m.p. 200-202ºC.
Example 32 3-Methoxycarbonyl-6-(2-naphthyl)pyridin-2(1H)-one
3-Carboxy-6-(2-naphthyl)pyridin-2(1)-one (1 g) was added to thionyl chloride (100 ml) and the mixture boiled for 4 hours. Excess thionyl chloride was removed at reduced pressure and the solid red residue stirred in methanol (50 ml) overnight. The precipitated solid was separated by filtration and recrystallised from methanol to give the title compound (0.55 g) m.p. 223-226°C. E x a m pl e 33
Ethyl 2-methoxy-2-[6-(2-naphthyl)-2-oxo-1,2-dihydro-3- pyridyl]oropionate (a) Ethyl 2-hydroxy-2-[6-(2-naphthyl)-2-methoxy-3- pyridyl]propionate (0.9 g) was treated with sodium hydride (0.15g, 50% in oil) and iodomethane (0.56 g) according to the method of Example 21(a). Purification by column chromatography (silica gel, 20% hexane/dichloromethane eluant) gave ethyl 2-methoxy-2-[6-(2-naphthyl)-2-methoxy-3- pyridyl]propionate (0.76 g) as a pale yellow oil
containing 25 molar% of methyl 2-methoxy-2-[6-(2-naphthyl)- 2-oxo-1,2-dihydro-3-pyridyl]propionate; δ(DMSO-d6)
1.15(t,3H), 1.61(S,3H), 3.25(S,3H), 3.99(S,3H), 4.15
(m,2H), 7.54-7.58(m,2H), 7.78(d,1H), 7.93-8.08 (m,4H), 8.26 (d,1H) and 8.66(s,1H) (for the ethyl ester).
(b) Ethyl 2-methoxy-2-[6-(2-naphthyl)-2-methoxy-3- pyridyl]propionate (0.75 g) was treated with sodium iodide (1.54 g) and chlorotrimethylsilane (1.08 g) according to the method of Example 18(c) to give after recrystallisation from ethanol the title compound (0.42 g) m.p.
softens 141-145°C, melts 166-169°C containing 25 molar% of methyl 2-methoxy-2-[6-(2-naphthyl)-2-methoxy-3-pyridyl]- propionate; δ(DMSO-d6) 1.15(t,3H), 1.56(s,3H), 3.25
(s,3H), 4.09(q,2H), 6.77(d,1H), 7.57-7.60 (m,2H), 7.67
(d,1H), 7.82-8.03 (m,4H), 8.66(s,1H) and 11.98 (br s,1H)
(for the ethyl ester). Example 34
3-(5-Tetrazolyl)-6-[2-(1-propyloxy)naphthyl]pyridin-2(1H)- one
(a) 1-Hydroxy-2-acetonaphthone (9.3 g) 1-iodopropane (17 g) and potassium carbonate (6.9 g) were combined in dimethylformamide (40 ml) and heated to 120°C for
24 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (200 ml), washed with water (6x100 ml), dried (MgSO4) and solvent removed to give 1-propyloxy-2-acetonaphthone (10.9 g) as a brown oil; δ(DMSO-d6) 1.07(t,3H), 1.89(m,2H), 2.70(s,3H),
3.96(t,2H), 7.62-7.69(m,3H), 7.75(d,1H), 7.97(m,1H) and 8.19(m,1H).
(b) 1-Propyloxy-2-acetonaphthone (10.9 g) and dimethylformamide dimethylacetal (6.55 g) were combined in dimethylformamide and heated at 130°C for 18 hours. The deep red solution was cooled to room temperature, cyanoacetamide (4.2 g) added and the solution boiled for
36 hours. The cooled reaction mixture was poured into water (200 ml) containing acetic acid (5 ml) and stirred for 30 minutes, ethanol (100 ml) was then added and stirring continued for a further 30 minutes. The
precipitate was separated by filtration and purified by column chromatography (silica gel, dichloromethane-10% ethanol/dichloromethane) to give after recrystallisation from ethanol, 3-cyano-6-[2-(1-propyloxy)naphthyl]- pyridin-2(1H)-one (0.98 g) m.p. 220-223°C.
(c) From 3-cyano-6-[2-(1-propyloxy)naphthyl]pyridin- 2(1H)-one (0.6 g), the title compound (0.27 g) m.p. 269°C (decomp) after recrystallisation from n-butanol, was prepared according to the method of Example 1(b) using N-methylpyrrolidinone as solvent; δ(DMSO-d6), 0.93(t,3H), 1.66-1.74 (m,2H), 3.79(t,2H), 6.81(d,1H), 7.62(d,1H), 7.65-7.69(m,2H), 7.85(d,1H), 8.01-8.05 (m, 1H), 8.20-8.24 (m,1H) and 8.57(d,1H). Example 35
6-[2-(1-Pentyloxy)naohthyl]-3-(5-tetrazolyl)pyridin-2(1H)- one (a) 1-Pentyloxy-2-acetonaphthone (11.5 g) was prepared as an oil from 1-hydroxy-2-acetonaphthone (9.3 g) n-pentyl iodide (9.9 g) and potassium carbonate (6.9 g) according to the method of Example 34(a); δ(CDCl3) 0.97(t,3H),
1.36-1.59(m,4H), 1.88-2.01(m, 2H), 2.76(s,3H), 4.02(t,2H), 7.53-7.72(m,4H), 7.83(m,1H) and 8.20 (m, 1H).
(b) 3-Cyano-6-[2-(1-pentyloxy)naphthyl]pyridin-2 (1H)-one (1.41 g) m.p. 141-143°C after recrystallisation from ethanol, was prepared from 1-pentyloxy-2-acetonaphthone (10.24 g), dimethylformamide dimethylacetal (5.24 g), cyanoacetamide (3.36 g) and sodium methoxide (4.32 g) according to the method of Example 1(a).
(c) From 3-cyano-6-[2-(pentyloxy)naphthyl]pyridin- 2(1H)-one (0.99 g) the title compound (0.57 g) m.p.
209-212°C after recrystallisation from ethanol was
prepared according to the method of Example 1(b) using N-methylpyrrolidinone as solvent. Example 36
[6-(9-Phenanthryl)-2-oxo-1,2-dihydro-3-pyridyl]acetic acid (a) 3-Acetyl-6-(9-phenanthryl)pyridin-2(1H)-one (1.63 g) m.p. 239-242°C after recrystallisation from ethanol, was prepared from 3-cyano-6-(9-phenanthryl)pyridin-2(1H)-one (2.96 g) and methyl lithium (13ml, 1.5M in diethyl ether) according to the method of Example 27(a) (b) From 3-acetyl-6-(9-phenanthryl)pyridin-2(1H)-one
(1.5 g) sulphur (0.18 g) and morpholine (4 ml) the title compound (0.16 g) m.p. 301°C after recrystallisation from ethanol, was prepared according to the method of Example 27(c).
Example 37
2-Hydroxyethyl 2-[6-(2-naphthyl)-2-oxo-1,2-dihydro-3- pyridyl]-1,3-dioxolane-2-carboxylate
Ethyl 2-oxo-[2-methoxy-6-(2-naphthyl)-3-pyridyl]- acetate (1.0 g) and p-toluenesulphonic acid (0.1 g) were heated together in 1,2-ethanediol (4 ml) at 120°C for 6 hours. The clear solution was diluted with ethyl acetate (50 ml) washed with water (5x50 ml), dried (MgSO4) and solvent removed at reduced pressure. The residue was column chromatographed (silica gel, dichloromethane - 6% ethanol/dichloromethane eluant), the appropriate fractions combined and solvent removed. Recrystallisation from ethanol gave the title compound (0.24 g) m.p. 212-215°C.
Example 38
2-[6-(2-Naphthyl)-2-oxo-1,2-dihydro-3-pyridyl]-1,3-dioxo- lane-2-carboxylic acid sodium salt
To a solution of 2-hydroxyethyl 2-[6-(2-naphthyl)-2- oxo-1,2-dihydro-3-pyridyl]-1,3-dioxolane-2-carboxylate (0.3 g) in ethanol (25 ml) sodium hydroxide solution (3ml of 2N) was added at room temperature. After 2 hours the precipitated solid was separated by filtration and the residue washed with ethanol (3x10 ml) giving the title compound (0.27 g) m.p. >315°C; δ(DMSO-d6)
3.98-4.19 (m,4H), 6.83 (d,1H), 7.64(m,2H), 7.78(d,1H), 7.88(d,1H), 7.98-8.10(m,3H) and 8.37 (s, 1H).
Example 39 n-Butyl [6-(9-phenanthryl)-2-oxo-1,2-dihydro -3-pyridyl]- phosphonate
(a) Di-n-butyl [6-(9-phenanthryl)-2-oxo-1,2-dihydro-3- pyridyl]phosphonate (0.38 g), was prepared from 6-(9- phenanthryl)pyridin-2 (1H)-one (3 g) and di-n-butyl chlorophosphate (2.8 g) according to the method of Example
10(b); δ(DMSO-d6) 0.91(t,6H), 1.17-1.47 (m,4H), 1.57-
1.67(m,4H), 4.07(q,4H), 6.54(m,1H), 7.67-8.16 (m,8H) and 8.89-8.99(m,2H).
(b) From di-n-butyl [6-(9-phenanthryl)-2-oxo-1,2- dihydro-3-pyridyl]phosphonate (0.38 g) the title compound (0.13 g) m.p. 223-225ºC, after recrystallisation from ethanol, was obtained according to the method of Example 10(c). Example 40 3-(5-Tetrazolyl)-6-(3-thianaphthenyl)pyridin-2(1H)-one (a) From 3-acetylthianaphthene (5 g), 3-cyano-6-(3- thianaphthenyl)pyridin-2(1H)-one (5.64 g) m.p. 302-303°C after recrystallisation from ethanol, was prepared according to the method of Example 1(a). (b) From 3-cyano-6-(3-thianaphthenyl)pyridin-2(1H)-one (0.92 g), the title compound (0.88 g) m.p. 360°C (decomp) after recrystallisation from n-butanol, was prepared according to the method of Example 1(b) using N-methylpyrrolidinone as solvent. Example 41
6-(4-Ouinolinyl)-3-(5-Itetrazolyl)pyridin-2(1H)-one (a) From 4-acetylguinoline (1.02 g) (Y.Yamamoto and
A.Yanagi, Chem. Pharm. Bull., 1982, 30, 2003),
3-cyano-6-(4-guinolinyl)pyridin-2(1H)-one (0.8 g) m.p.
318-320°C after recrystallisation from n-butanol, was prepared according to the method of Example 1(a).
(b) From 3-cyano-6-(4-quinolinyl)pyridin-2 (1H9-one
(0.49 g), the title compound (0.4 g) m.p. 252-254°C after recrystallisation from n-butanol, was prepared according to the method of Example 1(b)
Example 42 6-[1-(4-Hydroxy)naphthyl]-3-(5-tetrazolyl)pyridin-2(1H)-one
(a) A solution of 3-cyano-6-[1-(4-methoxy)naphthyl]- pyridin-2(1H)-one (1.1 g) and sodiiam thiomethoxide (0.5 g) in dimethylformamide (5 ml) was heated at 130°C for
5 hours. The solution was cooled to room temperature acidified with 2N hydrochloric acid and purged with
nitrogen to remove excess methanethiol. The precipitated yellow solid was separated by filtration to give 3-cyano-6- [1-(4-hydroxy)naphthyl]pyridin-2 (1H)-one (0.62 g) m.p.
297-300°C (decomp) after recrystallisation from ethanol. (b) From 3-cyano-6-[1-(4-hydroxy)naphthyl]pyridin- 2(1H)-one (0.52 g) the title compound (0.33 g) m.p.
313-315°C (decomp) after recrystallisation from ethanol, was prepared according to the method of Example (1b) using N-methylpyrrolidinone as solvent.
Example 43
2-Methoxyethyl [6-(2-naphthyl)-2-oxo-1,2-dihydro-3- pyridyl]phosphonate a) To a solution of phosphoryl chloride (5.9 ml) in diethyl ether (30 ml) at 0ºC, a solution of triethylamine (13 ml) and 2-methoxyethanol (9.8 ml) in diethyl ether (30 ml) was added over 30 minutes. The mixture was stirred at room temperature over night, filtered and solvent removed at reduced pressure to give di-2-(methoxyethyl) chlorophosphate (13.7 g) as an oil which was used without further purification δ(DMSO-d6) 3.41(s,6H),
3.59-3.72 (m,4H) and 4.32 (m,4H). b) Di-(2-methoxyethyl) [6-(2-naphthyl)-2-oxo-1,2-dihydro- 3-pyridyl]phosphonate (1.3 g) was prepared from 6-(2- naphthyl)pyridin-2(1H)-one (2.2 g) and di-(2-methoxy- ethyl) chlorophosphate (2.3 g) according to the method of Example 10(b) δ(DMSO-d6) 3.23(s,6H), 3.36(t,4H),
4.04-4.16(m,4H), 6.73(dd,1H), 7.53-7.64 (m,2H),
7.84-8.13 (m,4H), 8.20(dd,1H) and 8.44 (s,1H). c) From di-(2-methoxyethyl) [6-(2-naphthyl)-2-oxo-1,2- dihydro-3-pyridyl]phosphonate (1.3 g) the title compound (0.16 g) m.p. 220-221ºC was prepared according to the method of Example 10(c). Exampl e 44 n-Propyl [6- (2-naphthyl)-2-oxo-1,2-dihydro-3-pyridyl]- phosphonate.
(a) Di-n-propyl [6-(2-naphthyl)-2-oxo-1,2-dihydro-3- pyridyl]phosphonate (1.5g) m.p.130-133°C was prepared from 6-(2-naphthyl)pyridin-2(1H)-one (2.2g) and di-n-propyl chlorophosphate (2.23g) according to the method of Example 10(b).
(b) From di-n-propyl [6-(2-naphthyl)-2-oxo-1,2-dihydro-3- pyridyl]phosphonate (1.5g) the title compound (0.92g) m.p. 238-239°C after precipitation of the sodium salt from aqueous solution with 2N hydrochloric acid, was prepared according to the method of Example 10(c)
Example 45 n-Propyl [6-(9-phenanthryl)-2-oxo-1,2 -dihydro-3-pyridyl]- phosphonate.
(a) Di-n-propyl [6-(9-phenanthryl)-2-oxo-1,2-dihydro-3- pyridyl]phosphonate (0.66g) m.p. 198°C after
recrystallisation from ethanol, was prepared from
6-(9-phenanthryl)pyridin-2(1H)-one (1.08g) and di-n-propyl chlorophosphate (1.00g) according to the method of Example 10(b). (b) From di-n-propyl [6-(9-phenanthryl)-2-oxo-1,2-dihydro- 3-pyridyl]phosphonate (1.04g) the title compound (0.19g) m.p. 244-247°C after recrystallisation from n-propanol was prepared according to the method of Example 10(c). Example 46
2-Hydroxy-2-[6-(9-phenanthryl)-2-oxo-1,2-dihydro-3- pyridyl]acetic acid.
(a) 2-Methoxy-6-(9-phenanthryl)pyridine (3g)
m.p.105-106°C was prepared from 6-(9-phenanthryl)- pyridin-2(1H)-one (10g) according to the method of Example 18(a).
(b) Ethyl 2-oxo-[2-methoxy-6-(9-phenanthryl)-3- pyridyl]acetate (2.5g) isolated as an oil, was prepared from 2-methoxy-6-(9-phenantahryl)pyridine 2.9g) according to the method of Example 20(a). δ(CDCl3)
1.44(t,3H), 4.06(s,3H), 4.46(q,2H), 7.40(d,1H),
7.56-7.71(m,4H), 7.91(S,1H), 7.92(d,1H), 8.22(d,1H),
8.35(d,1H), 8.71(d,1H) and 8.77(d,1H).
(c) Ethyl 2-hydroxy-[2-methoxy-6-(9-phenanthryl)-3- pyridyl]acetate (1.5g) was prepared from ethyl
2-oxo-[2-methoxy-6-(9-phenanthryl)-3-pyridyl]acetate
(2.5g) according to the method of Example 20(b). δ(CDCl3) 1.29(t,3H), 3.68(d,1H), 4.02(s,3H), 4.30(q,2H),
5.33(d,1H), 7.26(d,1H), 7.54-7.74 (m,4H),
7.87(s,1H), 7.93(dd,1H), 8.24(d,1H), 8.71(d,1H) and
8.77 (d,1H).
(d) 2-Hydroxy-2-[2-methoxy-6-(9-phenanthryl)-3-pyridyl]ace tic acid (0.37g) was prepared from ethyl 2-hydroxy- [2-methoxy-6-(9-phenanthryl)-3-pyridyl]acetate (0.50g) according to the method of Example 20(c). δ(d6-DMSO)
3.91(s,3H), 5.29(s,1H), 7.37(d,1H), 7.60-7.81(m,4H),
7.92(d,1H), 7.98(s,1H), 8.06(d,1H), 8.20(d,1H), 8.88(d,1H) and 8.94 (d,1H). (e) From 2-hydroxy-2-[2-methoxy-6-(9-phenanthryl)-3- pyridyl] acetic acid (0.37g), the title compound (0.05g) m.p.206°C (decomp) after precipitation from basic solution with 2N hydrochloric acid, according to the method of Example 18 (c). δ(d6-DMSO) 5.14(s,1H), 6.53(d,1H),
7.64-7.89(m,6H), 7.97(s,1H), 8.07(d,1H), 8.89(d,1H) and 8.95(d,1H).
Example 47
Ethyl 2-methoxy-2-[6-(2-naphthyl)-2-oxo-1,2-dihydro-3- pyridyl]acetate
From ethyl 2-methoxy-2-[6-(2-naphthyl)-2-methoxy-3- pyridyl] acetate (0.75g), the title compound (0.53g) m.p. 177-179°C after recrystallisation from ethanol, was prepared according to the method of Exεimple 18 (c).
Example 48
Ethyl 2-methoxy-2-[6-(1-naphthyl)-2-oxo-1,2-dihydro-3- pyridyl]acetate
(a) From ethyl 2-oxo-[2-methoxy-6-(1-naphthyl)-3- pyridyl]acetate (5.6g), ethyl 2-hydroxy-[2-methoxy-6- (1-naphthyl)-3-pyridyl]acetate (2.4g) was prepared
according to the method of Example 20(b). δ(CDCl3)
1.27(t,3H), 3.67(d,1H), 4.04(s,3H), 4.33(q,2H),
5.31(d,1H), 7.23(d,1H), 7.45-7.92 (m,7H) and
8.27(m,1H).
(b) From ethyl 2-hydroxy-[2-methoxy-6-(1-naphthyl)-3- pyridyl]acetate (2.4g), 2-hydroxy-[2-methoxy-6-(1- naphthyl)-3-pyridyl]acetic acid (2.01g) m.p.148-150°C, was prepared according to the method of Example 20(c). (c) To a solution of 2-hydroxy-[2-methoxy-6-
(1-naphthyl)-3-pyridyl]acetic acid (1g) in 20% aqueous dimethylsulphoxide (5ml), potassium hydroxide (crushed pellets, 0.56g) was added followed by iodomethane (0.85g). The mixture was stirred for 4 hours at room temperature, additional iodomethane (0.8g) added and stirring continued overnight. The reaction mixture was diluted with ethyl acetate (50ml), acidified with 2N hydrochloric acid and the organic phase washed with water (5x50ml). After removal of solvent the residue was boiled in ethanol (5ml) containing 2N sodium hydroxide (5ml) for 3 hours. The mixture was diluted with ethyl acetate and acidified with 2N hydrochloric acid, the organic phase was washed with water (2x30ml) and solvent removed to give
2-methoxy-[2-methoxy-6-(1-naphthyl)-3-pyridyl]acetic acid (0.63g). δ(CDCl3) 3.52(S,3H), 4.04(S,3H),
5.12(S,1H), 7.23(d,1H), 7.49-7.93 (m,7H) and 8.28 (m,1H).
(d) To a solution of 2-methoxy-[2-methoxy-6-(1-naphthyl)- 3-pyridyl]acetic acid (0.61g) in dimethylformamide (4ml) containing potassium carbonate (0.42g), iodoethane was added and the mixture stirred for 8 hours. The reaction mixture was diluted with ethyl acetate (30ml) washed with water (5x30ml) and solvent removed to give ethyl
2-methoxy-[2-methoxy-6-(1-naphthyl)-3-pyridyl]acetate
(0.61g) as a yellow oil. δ(CDCl3) 1.29(t,3H), 3.52(s,3H), 4.02(S,3H), 4.27(q,2H), 5.16(s,1H), 7.22(d,1H),
7.46-7.92 (m,7H) and 8.27 (m,1H). (e) From ethyl 2-methoxy-[2-methoxy-6-(1-naphthyl)-3- pyridyl]acetate (0.6g), the title compound (0.3g)
m.p.171-172°C after recrystallisation from ethanol was prepared according to the method of Example 18 (c). Example 49
Sodium 2-ethoxy-2-[6-(2-naphthyl)-2-oxo-1,2-dihydro -3- pyridyl]acetate
(a) 2-Ethoxy-[2-methoxy-6-(2-naphthyl)-3-pyridyl]acetic acid (0.49g) isolated as an oil after column
chromatography (silica gel, dichloromethane-10%
ethanol/dichloromethane) was prepared from
2-hydroxy-[2-methoxy-6-(2-naphthyl)-3-pyridyl] acetic acid (0.55g) according to the method of Example 48(c) using iodoethane instead of iodomethane.
(b) From 2-ethoxy-[2-methoxy-6-(2-naphthyl)-3- pyridyl]acetic acid (0.47g), the title compound isolated as the sodium salt (0.32g) m.p.300-310°C (decomp) after recrystallisation from aqueous ethanol, was prepared according to the method of example 18 (c).
δ(d6-DMSO) 1.03(t,3H), 3.24-3.45 (m,2H),
4.47(s,1H), 6.76(d,1H), 7.25-8.08(m,7H) and 8.39 (s,1H).
Example 50
3-Carboxy-6-(9-phenanthryl)pyridin -2(1H)-one-
From 3-cyano-6-(9-phenanthryl)pyridin-2(1H)-one (2g), the title compound (0.3g) m.p. >300°C after recrystallisation from ethanol/diethyl ether, was prepared according to the method of Example 8. δ(d6-DMSO) 6.92(d,1H),
7.69-7.93(m,5H), 8.09(s,1H), 8.11(d,1H), 8.52(d,1H), 8.95(d,1H) and 9.00(d,1H). Example 51
6-[1-(4-Propoxy)naphthyl]-3-(5-tetrazolyl)pyridin-2(1H)-one
(a) To a suspension of sodium hydride (60% dispersion in oil, 0.36g) in dimethylformamide (5ml),
3-cyano-6-[1-(4-hydroxy)naphthyl]pyridin-2(1H)-one (0.90g) in dimethylformamide (5ml) was added over 10 minutes. The reaction mixture was stirred until gas evolution ceased, iodopropane (0.35ml) added and stirring continued for 40 minutes. The mixture was diluted with water (30ml) and the precipitated product separated by filtration to give
3-cyano-6-[1-(4-propoxy)naphthyl]pyridin-2(1H)-one (0.63g) m.p.249°C after recrystallisation from ethanol.
(b) From 3-cyano-6-[1-(4-propoxy)naphthyl]pyridin- 2(1H)-one (0.44g) 6-[1-(4-Propoxy)naphthyl]-3- (5-tetrazolyl)pyridin-2(1H)-one (0.46g) m.p. 286-287°C after recrystallisation from n-butanol was prepared
according to the method of Example (1b) using
N-methylpyrrolidinone as solvent.
Example 52
Ethyl 2-hydroxy-[6-(9-phenanthryl)-2-oxo-1,2-dihydro- 3-pyridyl]acetate From ethyl 2-hydroxy-[2-methoxy-6-(9-phenanthryl)-3- pyridyl]acetate (0.74g), the title compound (0.35g) m.p. 170-172°C after recrystallisation from ethanol, was
prepared according to the method of Example 18 (c). Examp le 53
2-oxo-2-[6-(2-naphthyl)-2-oxo-1,2-dihydro-3-pyridyl]acetic acid
From ethyl 2-oxo-[2-methoxy-6-(2-naphthyl)-3- pyridyl]acetate (0.2g) the title compound (0.17g)
m.p.237.5°C (decomp) after precipitation from basic solution with 2N hydrochloric acid, was prepared according to the method of Example 25(c). δ(d6-DMSO) 7.00(d,1H),
7.58-7.72 (m,2H), 7.88-8.13 (m,4H), 8.25(d,1H), 8.52 (s,1H) and 12.82 (br. s,1H). Examp le 54
2-Hydroxy-2-[6(1-naphthyl)-2-oxo-1,2-dihydro-3-pyridyl]- acetic acid
From 2-hydroxy-[2-methoxy-6-(1-naphthyl)-3-pyridyl]acetic acid (0.93g), the title compound (0.63g) m.p.198-199°C
(decomp) after recrystallisation from ethyl acetate, was prepared according to the method of Example 18 (c).
δ(d6-DMSO) 5.13(s,1H), 5.83 (br. s,1H),
6.43(d,1H), 7.53-7.68(m,5H), 7.77-7.83 (m, 1H) and
7.94-8.05(m,2H). Examp le 55 n-Butyl 2-methoxγ-2-[6-(2-naphthyl)-2-oxo-1,2-dihydro-3- pyridyl]acetate
(a) n-Butyl 2-methoxy-[6-(2-naphthyl)-2-methoxy-3- pyridyl]acetate (0.9g) isolated as an oil after column chromatography (silica gel, 50%hexane/dichloromethane eluant) was prepared from 2-methoxy-[6-(2-naphthyl)-2- methoxy-3-pyridyl]acetic acid (0.96g), according to the method of Example 48(d) using iodobutane (0.55g) instead of iodoethane. δ(CDCl3) 0.88(t,3H), 1.22-1.37 (m,2H),
1.54-1.65(m,2H), 3.47(s,3H), 4.14(s,3H), 4.17(t,2H), 5.13(s,1H), 7.48-7.55(m,3H), 7.78-7.96(m,4H),
8.19(dd,1H) and 8.52(s,1H).
(b) From n-butyl 2-methoxy-[6-(2-naphthyl)-2-methoxy-3- pyridyl]acetate (0.85g) the title compound (0.63g) m.p.116-117°C after recrystallisation from ethyl
acetate/hexane, was prepared according to the method of Example 18 (c). Examp le 53 [6-(2-naphthyl)-2-oxo-1,2-dihydro-3-pyridyl]sulphinic acid sodium salt
(a) [6-(2-naphthyl)-2-methoxy-3-pyridyl]sulphinic acid (0.53g) was prepared from 2-methoxy-6-(2-naphthyl)pyridine (1.18g) according to the method of Example 18(b) using a saturated solution of sulphur dioxide in tetrahydrofuran (10ml) instead of ethyl pyruvate to quench the anion.
δ(d6-DMSO) 4.14(s,3H), 7.56-7.60(m,2H),
7.90-8.18(m,5H), 8.17(d,1H), 8.31(dd,1£H) and 8.74 (s,1H).
(b) From [6-(2-naphthyl-2-methoxy-3-pyridyl]sulphinic acid (0.5g), [6-(2-naphthyl)-2-oxo-1,2-dihydro-3- pyridyl]sulphinic acid (0.33g) was prepared according to the method of Example 21(d). The sodium salt was prepared by dissolving [6-(2-naphthyl)-2-oxo-1,2-dihydro-3- pyridyl]sulphinic acid (0.33g) in water (5ml) containing sodium carbonate (0.053g)and subsequently removing solvent at reduced pressure. The residue was recrystallised from aqueous ethanol to give the title compound (0.3g) m.p. foams at 190°C. δ(d6-DMSO) 7.40-7.62 (m,4H),
7.92-8.14 (m,4H) and 8.55 (s,1H) Example 57
Ethyl 2,2-difluoro-2-[6-(2-naphthyl)-2-oxo-1,2-dihydro-3- pyridyl]acetate
(a) Diethylaminosulphur trifluoride (0.69g) was added to a solution of ethyl 2-oxo-[2-methoxy-6-(2-naphthyl)-3- pyridyl]acetate (1g) in dichloromethane (30ml) the mixture was stirred at room temperature for 3 hours and poured onto ice (100g). The mixture was diluted with more
dichloromethane (70ml), the organic phase separated, dried (MgSO4) and solvent removed. The residue was column
chromatographed (silica gel, 10% diethyl ether/petroleum ether eluant) to give ethyl 2,2-difluoro-2-[2-methoxy-6-(2- naphthyl)-3-pyridyl]acetate (0.93g) as an oil.δ(CDCl3) 1.33(t,3H), 4.11(s,3H), 4.37(q,2H), 7.458.14 (m,8H) and 8.53(s,1H).
(b) From ethyl 2,2-difluoro-[2-methoxy-6-(2-naphthyl)-3- pyridyl]acetate (0.63g) the title compound (0.205g), m.p.196-197ºC after column chromatography (silica gel, dichloromethane eluant), was prepared according to the method of Example 18 (c). Example 58
2,2-difluoro-2-[6-(2-naphthyl)-2-oxo-1,2-dihydro-3- pyridyl]acetic acid (a) 2-Oxo-[2-methoxy-6-(2-naphthyl)-3-pyridyl]acetic acid (1.3g) was prepared from ethyl 2-oxo-[2-methoxy-6-(2- naphthyl)-3-pyridyl]acetate (1.5g) according to the method of Example 20(c). δ(CDCl3) 3.96(s,3H), 7.25-7.39(m,2H), 7.47(d,1H), 7.61-7.80(m,3H),
7.98-8.10(m,3H) and 8.36(s,1H). (b) Benzyl 2-oxo-[2-methoxy-6-(2-naphthyl)-3- pyridyl]acetate (1.6g) was prepared from 2-oxo-[2-methoxy- 6-(2-naphthyl)-3-pyridyl] acetic acid (1.3g) according to the method of Example 48(d) using benzyl bromide (0.86g) instead of iodoethane. δ(CDCl3) 3.87(s,3H), 5.39(s,2H),
7.37-7.65(m,8H), 7.83-8.03 (m,3H), 8.17(dd,1H), 8.28(d,1H) and 8.55(s,1H).
(c) Benzyl 2,2-difluoro-[2-methoxy-6-(2-naphthyl)-3- pyridyl]acetate (1.2g) was prepared from benzyl
2-oxo-[2-methoxy-6-(2-naphthyl)-3-pyridyl]acetate (1.6g) according to the method of Example 57(a). δ(CDCl3)
3.87(s,3H), 5.32(s,2H), 7.36(s,5H), 7.49-7.60 (m,3H),
7.82-7.99 (m,4H), 8.15 (dd,1H) and
8.51(s,1H).
(d) Benzyl 2,2-difluoro-2-[6-(2-naphthyl)-2-oxo-1,2- dihydro-3-pyridyl]acetate (0.8g) was prepared from benzyl 2,2-difluoro-[2-methoxy-6-(2-naphthyl)-3-pyridyl]acetate (1.2g) according to the method of Example 18(c). δ(CDCl3) 4.99(s,2H), 6.80(d,1H), 7.18(s,5H), 7.52-7.64 (m,2H),
7.77-8.12 (m,5H) and 8.26(s,1H).
(e) A solution of benzyl 2,2-difluoro-2-[6-(2-naphthyl)-2- oxo-1,2-dihydro-3-pyridyl]acetate (0.6g) in ethanol/ dichloromethane (25ml, 4:1)was stirred for 2 hours at 15°C with 10% palladium on charcoal (0.1g) under hydrogen at atmospheric pressure. The reaction was filtered (celite pad), solvent removed at reduced pressure and the residual oil dissolved in 2N sodium hydroxide. The title compound (0.24g) m.p. 208°C (decomp) was obtained by acidification of the basic solution with cone, hydrochloric acid.
δ(d6-DMSO) 6.87(d,1H), 7.59-7.63 (m,2H), 7.84-8.07 (m,5H) and 8.43(s,1H). Example 59
4-(1-Naphthyl)salicylic acid (a) m-Methoxyphenyl magnesium bromide was prepared in the usual way from magnesium (29g) and m-bromoanisole (220g) in tetrahydrofuran (180ml). After the addition of m-bromoanisole was complete the reaction mixture was boiled for 30 minutes added to 1-tetralone (168.12g) in tetrahydrofuran (120mls) and boiled for a further 1 hour. Acetic anhydride (150ml) was then added and the reaction mixture maintained at 60ºC for 30 minutes, treated with water (100ml), the organic phase separated and dried.
Distillation of the organic phase gave 3,4-dihydro-1- (3-methoxyphenyl)naphthalene (178g) bp 159-162°C/0.3mmHg.
(b) A mixture of 3,4-dihydro-1-(3-methoxyphenyl)- naphthalene (178g) and sulphur (27g) was heated at 250°C until evolution of gas ceased/ Vacuum distillation gave a brown oil bp 156-160°C/0.4mmHg that was recrystallised from hexane to give 3-(1-naphthyl)anisole (102g)
mp 40-44ºC.
(c) To a solution of 3-(1-naphthyl) anisole (7.03g) in tetrahydrofuran (100ml) at -78ºC under an inert atmosphere sec-butyl lithium (30ml 1.3M in cyclohexane) was added over 30 minutes. After the addition was complete the reaction mixture was stirred for a further 90 minutes then poured over solid carbon dioxide (200g) in tetrahydrofuran (500ml). The mixture was warmed to room temperature and treated with diethyl ether (100ml) and 5M hydrobromic acid (100ml). The organic phase was separated washed with water (2x100ml) dried (MgSO4) and solvent removed to give 2-methoxy-4-(1-naphthyl) benzoic acid (6.6g) mp
152-155ºC. (d) A mixture of 2-methoxy-4-(1-naphthyl)benzoic acid glacial acetic acid (100ml) and 48% hydrobromic acid
(500ml) was boiled for 5 hours and then evaporated to dryness under reduced pressure. The residue was dissolved in 20% sodium bicarbonate (100ml), filtered and adjusted with 2N hydrochloric acid to pH4. The solid product was separated by filtration and recrystallised from
acetonitrile/water to give the title compound (3.58g), mp 187-190°C. Example 60
Ethyl 2-hydroxy-4-(1-naphthyl)phenyl phosphonate sodium salt
(a) To a solution of 3-(1-naphthyl) anisole (7.03g) in dichloromethane (100ml) at -78°C boron tribromide (1ml) was added, the mixture stirred at -78ºC for 1 hour and then warmed to room temperature. After addition to saturated sodium acetate solution (100mls) the organic phase was separated and washed with water (50ml),
saturated sodium bicarbonate solution (50ml) and saturated ammonium chloride solution (50ml) and dried
(MgSO4). The filtered solution was treated with
triethylamine (6.0ml)and diethylchlorophosphate (5.8ml) and stirred at room temperature overnight. The solution was washed with water (50ml), saturated sodium
bicarbonate (50ml) and saturated ammonium chloride (50ml) dried (MgSO4) and solvent removed. The residue was dissolved in tetrahydrofuran (50ml) and added to a mixture of lithium diisopropylamide (18ml 1.5M in hexane) and tetrahydrofuran (50ml) at -78ºC. The mixture was stirred for 10 minutes at -78ºC and 25 minutes at 0°c, quenched with acetic acid (1ml) and saturated ammonium chloride solution (25ml) diluted with diethyl ether
(100ml) the organic phase separated and washed with water (2x50ml), dried (MgSO4) and solvent removed. The
colourless solid obtained was recrystallised from diethyl ether/hexane to give diethyl 2-hydroxy-4-(1-naphthyl)- phenyl phosphonate (4.76g) mp 170-173°C.
(b) A suspension of diethyl 2-hydroxy-4-(1-naphthyl)- phenyl phosphonate (2.0g) in 1N sodium hydroxide (40ml) was boiled for 4 hours cooled to room temperature and filtered. The filtrate was adjusted to pH5 with acetic acid the precipitated product separated by filtration and washed with water to give the title compound (1.84g) mp 168-170°C. Example 61 5-[2-Hydroxy-4-(1-naphthyl)phenyl]tetrazole
(a) To a solution of 3-(1-naphthyl) anisole (7.04g) in tetrahydrofuran (40ml) at -78°C sec-butyl lithium (25ml 1.3M in cyclohexane) was added followed after 45 minutes by dimethylformamide (2.6ml). The solution was stirred at -78°C for a further 15 minutes and at room temperature for 30 minutes. The reaction was quenched with saturated ammonium chloride diluted with diethyl ether, the organic phase washed with saturated ammonium chloride, dried
(MgSO4) and solvent removed. The residue obtained was dissolved in ethanol (50ml), hydroxylamine hydrochloride (2.5g) and saturated sodium acetatle (25ml) added and the mixture heated on the steam bath for 2 hours. The
precipitate formed on cooling was separated by filtration washed with water and boiled in acetic anhydride (50ml) for 4 hours. The solution was poured into water (200ml) stirred for 1 hour and extracted with diethyl ether
(4x150ml). The combined extracts were washed with water (50ml), 5% sodium bicarbonate solution (50ml) and
saturated ammonium chloride (50ml), dried (MgSO4) and solvent removed. The residue was recrystallised from diethyl ether/hexane to give 2-cyano-5-(1-naphthyl)- anisole (4.74g) mp 100-103°C. (b) To a solution of 2-cyano-5-(1-naphthyl) anisole
(2.59g) in dimethylformamide (10ml) sodium azide (1.3g) and ammonium chloride (1.1g) were added. The mixture was boiled for 24 hours additional sodium azide (1.3g) and ammonium chloride (1.1g) added and heating continued for a further 48 hours. The mixture was poured into water (100ml) adjusted to pH10 with ammonium hydroxide and washed with diethyl ether (4x50ml). The aqueous solution was filtered and acidified with 2N hydrochloric acid.
The precipitated material was separated by filtration, dried, suspended in dichloromethane (50ml) at -70°C and treated with boron tribromide (1ml). The reaction was stirred for 2 hours at -70ºC and for 2 hours at room temperature. The solution was poured into 25% sodium bicarbonate (100ml), washed with dichloromethane (2x50ml) and acidified with 5N hydrochloric acid. The precipitate obtained was separated by filtration and recrystallised from acetonitrile/water to give the title compound
(0.15g) mp 258-262°C. Example 62
4-(2-Naphthyl)salicylic acid
(a) tert-Butyl lithium (100ml,1.5M in pentane) was added over 20 minutes to a solution of 2-bromonaphthalene
(13.8g) in tetrahydrofuran (300ml) at -78°C under
nitrogen. The mixture was stirred for a further 90 minutes at -78ºC after the addition was complete and then transferred into a solution of triisopropylborate (37.6g) in tetrahydrofuran (50ml) at -78ºC. The reaction mixture was stirred for 30 minutes at -78°C after the transfer was complete, quenched with 2N hydrochloric acid, diluted with ethyl acetate (300ml), the organic phase washed with water (2x200ml), dried (MgSO4) and solvent removed.
Recrystallisation of the residue from ethyl
acetate/hexane gave 2-naphthylboronic acid (6.6g)
mp 243-246°C as a colourless solid.
(b) Palladium acetate (0.134g) and 1,1'-bis(diphenylphosphino) ferrocene (0.443g) were warmed together in dimethylformamide (15ml) at 50°C for 30 minutes. To the orange solution 2-naphthylboronic acid (3.76g),
3-bromoanisole (3.74g) and triethylamine (4.0ml) were added and the mixture heated at 100°C for 4 hours. The cooled mixture was filtered through a celite pad the filtrate diluted with ethyl acetate (200ml) and washed with water (5x100ml) dried (MgSO4) and solvent
removed. The residue was chromatographed
(hexane-50%hexane/dichloromethane eluant) the appropriate fractions combined, solvent removed and the residue recrystallised from a small volume of ethanol to give 3-(2-naphthyl)anisole (2.21g), mp 78-79°C.
(c) 2-Methoxy-4-(2-naphthyl)benzoic acid (0.78g) isolated as a pale buff solid mp 126-128°C was prepared according to the method of Example 59(c) from
3-(2-naphthyl) anisole (1.17g).
(d) The title compound (0.3g), isolated as a colourless solid mp 253-254°C after recrystallisation from ethanol, was prepared according to the method of Example 59(d) from 2-methoxy-4-(2-naphthyl)benzoic acid (0.5g) Example 63
Ethyl 2-hydroxy-4-(2-naphthyl)phenyl phosphonate sodium salt
(a) Diethyl 2-hydroxy-4-(2-naphthyl)phenyl phosphonate (1.4g) isolated as a pale yellow oil after column
chromatography (silica gel, 1:1 hexane dichloromethane), was prepared according to the method of Example 60(a) from 3-(2-naphthyl) anisole (2.3g). δ(DMSO-d6) 1.26(t,6H), 4.06(m,4H), 7.32(dd,1H), 7.37(m,1H), 7.54-7.59 (m,2H), 7.66(dd,1H), 7.81(dd,1H), 7.94-8.06(m,3H) and 8.23(s,1H). (b) From diethyl 2-hydroxy-4-(2-naphthyl)phenyl
phosphonate (0.64g) the title compound (0.35g) isolated as a colourless solid, mp 297-299°C after recrystallisation from water, was prepared according to the method of
Example 60 (b).
Example 64 n-Butyl 2-hydroxy-4-(2-naphthyl)phenyl phosphonate sodium salt
(a) Di-n-butyl 2-hydroxy-4-(2-naphthyl)phenyl phosphonate (0.85g) isolated as a colourless oil after column
chromatography (silica gel, 3:2 hexane/dichloromethane eluant) was prepared according to the method of Example 60(a) from 3-(2-naphthyl)anisole (1.49g) and di-n-butyl chlorophosphate. δ(DMSO-d6) 0.88(t,6H), 1.32-1.41(m,4H), 1.55-1.63(m,4H), 3.92-4.09 (m,4H), 7.31-7.42 (m,2H),
7.53-7.60(m,2H), 7.65(dd,1H), 7.81(dd,1H), 7.94-8.07 (m,3H) and 8.22(s,1H). (b) From di-n-butyl 2-hydroxy-4-(2-naphthyl)phenyl phosphonate (0.83g) the title compound (0.35g) isolated as a colourless solid mp darkens above 250°C after
recrystallisation from water was prepared according to the method of Example 60(b). δ(DMSO-d6) 0.79(t,3H),
1.19-1.31 (m,2H), 1.38-1.48(m,2H), 3.57-3.68 (m, 2H),
7.16(dd,1H), 7.25(dd,1H), 7.48-7.61 (m, 3H), 7.85(dd,1H), 7.92-8.07(m,3H) and 8.24 (s, 1H). Example 65
Ethyl 2-hydroxy-4-(9-phenanthryl)phenyl phosphonate sodium salt (a) 9-Phenanthrylboronic acid, a colourless solid,
mp >300°C after recrystallisation from ethyl acetate, was prepared from 9-bromophenanthrene according to the method of Example 62(a). δ(DMSO-d6) 7.60-7.72 (m,4H),
7.97(dd,1H), 8.04(s,1H), 8.37-8.41(m,1H), 8.48(s,2H) and 8.78-8.84(m,2H)
(b) To a solution of 3-methoxyphenol (2.48g) and
diisopropylethylamine (3.23g) in dichloromethane (40ml) phenyltrifluoromethanesulphonimide (7.14g) was added in one portion. The reaction mixture was stirred at room temperature overnight, washed with water (2x50ml),
saturated ammonium chloride (50ml) and saturated sodium chloride (50ml), dried (MgSO4) and solvent removed to give 3-methoxyphenyl trifluoromethanesulphonate (4.3g) as a colourless oil. δ(CDCl3) 3.81(s,3H), 7.02-7.11(m,3H) and 7.50(t,1H).
(c) 3-Methoxyphenyl trifluoromethanesulphonate (1.2g)
9-phenanthryl boronic acid (1.33g), lithium chloride
(0.46g) and tetrakis(triphenylphosphine)palladium[0]
(0.22g) in a mixture of ethanol (22ml), toluene (54ml) and aqueous sodium carbonate (2M,7ml), were heated together at 95°C for 2 hours. The mixture was filtered through celite, the organic phase separated, dried (MgSO4) and solvent removed. Column chromatography (silica gel, petroleum ether/dichloromethane eluant) gave
3-(9-phenanthryl)anisole 1.01g mp 95-96°C after
recrystallisation from ethanol as a colourless oil.
δ(CDCl3) 3.86(s,3H), 6.94-7.14 (m, 3H), 7.33-7.74 (m, 6H), 7.82-7.99(m,2H) and 8.57-8.78 (m,2H).
(d) To a solution of 3-(9-phenanthryl) anisole (0.945g) in dichloromethane (10ml) at -78°c, boron tribromide (1.5g) was added. The reaction mixture was stirred at -78°C for 1 hour and at 0°C for 2 hours. After quenching with water the organic phase was washed with water (2x20ml), dried (MgSO4) filtered and solvent removed to give
3-(9-phenanthryl) phenol (0.9g) as a colourless oil. (d) δ(CDCl3) 4.97(s,1H), 6.93(dd,1H), 7.00-7.24 (m,3H),
7.38(t,1H), 7.50-7.69(m,4H),
7.87-7.95(m,2H), 8.72 (d,1H) and 8.77 (d, 1H).
(e) A solution of 3-(9-phenanthryl) phenol (0.85g), diethyl phosphite (0.48g) and triethylamine (0.353g) in carbon tetrachloride (20ml) was stirred at room temperature overnight. The reaction mixture was washed with 2N hydrochloric acid (1x20ml), 2N sodium hydroxide solution (3x20ml) and water (1x20ml), dried (MgSO4) and solvent removed at reduced pressure to give diethyl
3-(9-phenanthryl) phenyl phosphate (0.91g) as a colourless oil. δ(CDCl3) 1.37(t,6H), 4.19-4.31 (m, 4H),
7.21-7.71 (m,9H), 7.89(d,2H), 8.71(d,1H) and 8.78 (d,1H).
(f) A solution of diethyl 3-(9-phenanthryl) phenyl
phosphonate (0.9g) in tetrahydrofuran (5ml) was added to lithium diisopropylamide (prepared from diisopropylamine (0.40g) and n-butyllithium (2M in hexane, 2ml)) in tetrahydrofuran (5ml) at -78°C. The reaction mixture was stirred for 20 minutes at -78°C and for 1 hour at 0°C during which a colourless precipitate formed. The reaction mixture was quenched with saturated ammonium chloride solution, diluted with diethyl ether (50ml), washed with water (2x30ml), the organic phase dried
(MgSO4) filtered and solvent removed at reduced pressure. Column chromatography (silica gel, 5% ethyl
acetate/hexane-25% ethyl acetate/hexane) and
recrystallisation from ethyl acetate/hexane gave diethyl 2-hydroxy-4-(9-phenanthryl)phenyl phosphonate (0.5g) mp 143-146°C as a colourless solid. δ(DMSO-d6)
1.30(t,6H), 4.01-4.19(m,4H), 7.04-7.16 (m,2H),
7.59-7.90(m,7H), 8.07(dd,1H), 8.88 (d,1H) and 8.98 (d, 1H).
(g) The title compound (0.055g) isolated as a pale buff solid, mp >300°C after recrystallisation from water, was prepared from diethyl 2-hydroxy-4-(9-phenanthryl)- phosphonate (0.67g) according to the method of Example 60(b). δ(DMSO-d6) 1.08(t,3H), 3.66(m,2H), 6.77(dd,1H), 6.86(dt,1H) 7.48(dd,1H), 7.57-7.77(m,5H), 7.92(d,1H), 8.04(dd,1H), 8.87(d,1H) and 8.93 (d, 1H).
Example 66 Ethyl 4-(1-naphthyl)salicylate
A solution of 4-(1-naphthyl)salicylic acid (3.29g) in absolute ethanol (50ml) was saturated with hydrogen chloride and refluxed for 5 hours. Solvent was removed at reduced pressure, the residual oil dissolved in diethyl ether, washed with water (2x50ml), saturated sodium hydrogen carbonate (50ml) and saturated ammonium chloride (50ml), dried (MgSO4) and solvent removed at reduced pressure. The oil obtained was recrystallised from hexane and then from aqueous ethanol to give the title compound (0.35g) mp 64-66°C as a colourless solid.
Examp!e 67
6-(1-Naphthyl)-3-[5-(2-pivaloyloxymethyl)tetrazolyll- pyridin-2(1H)-one
A mixture of 6-(1-naphthyl)-3-(5-tetrazolyl)pyridin- 2(lH)-one (1.39g), pivaloyloxymethyl chloride (0.75g) sodium bicarbonate (0.42g) and sodium iodide (0.05g) were combined in dimethylformamide (5ml) and warmed at 80°C for 16 hours. The reaction mixture was diluted with ethyl acetate (50ml), washed with water (6x50ml), dried
(MgSO4) and solvent removed. The residue was column chromatographed (silica gel, dichloromethane-5%
dichloromethane/ethanol eluant) to give the title compound (0.6g) m.p. 171-172°C after recrystallisation from
propan-2-ol.
Ex ampl e 68
Ethyl pivaloyloxymethyl[6-(1-naphthyl)-2-oxo-1,2-dihydro- 3-pyridyl]phosphonate
From ethyl[6-(1-naphthyl)-2-oxo-1,2-dihydro-3- pyridyl]phosphonate (0.69g) the title compound (0.23g) m.p. 197-198°C after recrystallisation from ethyl
acetate/hexane was prepared according to the method of Example 67.
Example 69
Pharmaceutical compositions for oral administration are prepared by combining the following : % W/W
6-(9-phpnanthryl)-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 70
A pharmaceutical composition for parenteral
administration is prepared by dissolving the title
compound of Example 17 (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

Clai ms
1. A compound of the formula (1) :
(1)
Figure imgf000088_0001
or a pharmaceutically acceptable salt thereof, wherein :
A is N or CH
R0 is OH or a bioprecursor thereof,
R1 is A0CO2H, P(X) (OH) (OR2), SO2H, SO3H or
5-tetrazolyl or a bioprecursor thereof,
A0 is a single bond, CH2, CHF, CF2, CR3(OR4), CO
or C(OR5) (OR6),
R2 is phenyl, C3-5cycloalkyl, C3-5cycloalkyl- C1-4alkyl, or C1-8alkyl optionally substituted by
C1-4alkoxy,
R3 is H, methyl or ethyl, R4 is H or C1-3alkyl,
R5 and R6 are each C1-3alkyl or together form a 1,2- ethanediyl group or 1,3-propanediyl group, X is O or S and Ar is 1-naphthyl optionally substituted in the 4-position by hydroxy or C1-6alkoxy, 2-naphthyl optionally
substituted in the 1-position by hydroxy or C1-6alkoxy, 3-phenanthry1, 9-phenanthryl, 2-quinolinyl, 4-quinolinyl, 3-thianaphthenyl or 2-benzofuranyl.
2. A compound according to claim 1 wherein R0 is OH or OR7 in which R7 is C1-4alkyl, arylC1-4alkyl,
C1-4alkanoyl, arylsulphonyl or C1-4alkylsulphonyl.
3. A compound according to claim 1 or 2 wherein R1 is A0CO2H or A0CO2R8 in which R8 is an
ester-forming group.
4. A compound according to claim 1 or 2 wherein R1 is P(X) (OH) (OR2) or P(X) (OR2)2.
5. A compound according to claim 1 or 2 wherein
R1 is 5-tetrazolyl, SO2H or SO3H.
6. A compound according to claim 1 wherein R1 and R0 are linked together such that R1-R0 is A1CO2 is which A1 is CH2, CR3(OR4), CO or C(OR5)(OR6).
7. A compound according to claim 1 wherein R1 and R0 are linked together such that R1-R0 is
A2OCH2O in which A2 is P(X) (OR2) or CR3(CO2R8)
and R8 is an ester-forming group.
8. A compound according to any one of claims 1 to 7 wherein Ar is 1-naphthyl optionally substituted in the 4-position by hydroxy or C1-6alkoxy.
9. A compound according to any one of claims 1 to 7 wherein Ar is 2-naphthyl optionally substituted in the 1-position by hydroxy or C1-6alkoxy.
10. A compound according to any one of claims 1 to 7 wherein Ar is 3-phenanthryl or 9-phenanthryl.
11. A compound according to any one of claims 1 to 7 wherein Ar is 2-quinolinyl or 4-quinolinyl.
12. A compound according to any one of claims 1 to 7 wherein Ar is 2-benzofuranyl or 3-thianaphthenyl.
13. A compound according to claim 1 which is :
6-(2-naphthyl)-3-(5-tetrazolyl)pyridin-2(1H)-one,
6-(1-naphthyl)-3-(5-tetrazolyl)pyridin-2(1H)-one,
6-(2-benzofuranyl)-3-(5-tetrazolyl)-pyridin-2(1H)-one,
6-(9-phenanthryl)-3-(5-tetrazolyl)pyridin-2(1H)-one, 6-(3-phenanthryl)-3-(5-tetrazolyl)pyridin-2(1H)-one,
6-(2-quinolinyl)-3-(5-tetrazolyl)pyridin-2(1H)-one,
6-[1-(4-methoxy)naphthyl]-3-(5-tetrazolyl)pyridin-2(1H)- one,
3-carboxy-6-(2-naphthyl)pyridin-2(1H)-one,
3-carboxy-6-(1-naphthyl)pyridin-2(1H)-one, ethyl [6-(2-naphthyl)-2-oxo-1,2-dihydro-3-pyridyl]- phosphonate, n-butyl [6-(2-naphthyl)-2-oxo-1,2-dihydro-3-pyridyl]- phosphonate. n-hexyl [6-(2-naphthyl)-2-oxo-1,2-dihydro-3-pyridyl]- phosphonate, phenyl [6-(2-naphthyl)-2-oxo-1,2-dihydro-3-pyridyl]- phosphonate, ethyl [6-(1-naphthyl)-2-oxo-1,2-dihydro-3-pyridyl]- phosphonate, n-butyl [6-(1-naphthyl)-2-oxo-1,2-dihydro-3-pyridyl]- phosphonate, n-hexyl [6-(1-naphthyl)-2-oxo-1,2-dihydro-3-pyridyl]- phosphonate, ethyl [6-(9-phenanthryl)-2-oxo-1,2-dihydro-3-pyridyl]- phosphonate, ethyl 2-hydroxy-[6-(2-naphthyl)-2-oxo-1,2-dihydro-3- pyridyl]propionate,
2-hydroxy-2-[6-(2-naphthyl)-2-oxo-1,2-dihydro-3-pyridyl]- propionic acid, 2-hydroxy-2-[6-(2-naphthyl)-2-oxo-1,2-dihydro-3-pyridyl]- acetic acid,
2-methoxy-2-[6-(2-naphthyl)-2-oxo-1,2-dihydro-3-pyridyl]- acetic acid,
2-propoxy-2-[6-(2-naphthyl)-2-oxo-1,2-dihydro-3-pyridyl]- acetic acid, ethyl 2-hydroxy-2-[6-(2-naphthyl)-2-oxo-1,2-dihydro-3- pyridyl]acetate, [6-(2-naphthyl)-2-oxo-1,2-dihydro-3-pyridyl]sulphonic acid,
2-oxo-2-[6-(1-naphthyl)-2-oxo-1,2-dihydro-3-pyridyl]acetic acid, ethyl 2-oxo-2-[6-(1-naphthyl)-2-oxo-1,2-dihydro-3-pyridyl]- acetate.
[6-(2-naphthyl)-2-oxo-1,2-dihydro-3-pyridyl]acetic acid,
[6-(1-naphthyl)-2-oxo-1,2-dihydro-3-pyridyl]acetic acid,
7-aza-6-(1-naphthyl)benzofuran-2-one, 4-ethoxy-4-oxo-1,3,4-dioxyphosphono[5,6-b]-7-(1-naphthyl)- pyridine, ethyl [6-(1-naphthyl)-2-oxo-1,2-dihydro-3-pyridyl]- phosphonothioate,
3-methoxycarbonyl-6-(2-naphthyl)pyridin-2(1H)-one, ethyl 2-methoxy-2-[6-(2-naphthyl)-2-oxo-1,2-dihydro-3- pyridyl]propionate,
3-(5-tetrazolyl)-6-[2-(1-propyloxy)naphthyl]pyridin-2(1H)- one,
6-[2-(1-pentyloxy)naphthyl]-3-(5-tetrazolyl)pyridin-2(1H)- one,
[6-(9-phenanthryl)-2-oxo-1,2-dihydro-3-pyridyl]acetic acid,
2-hydroxyethyl 2-[6-(2-naphthyl)-2-oxo-1,2-dihydro-3- pyridyl]-1,3-dioxolane-2-carboxylate, 2-[6-(2-naphthyl)-2-oxo-1,2-dihydro-3-pyridyl]-1,3-dioxo- lane-2-carboxylic acid, n-butyl [6-(9-phenanthryl)-2-oxo-1,2-dihydro-3-pyridyl]- phosphonate,
3-(5-tetrazolyl)-6-(3-thianaphthenyl)pyridin-2(1H)-one,
6-(4-quinolinyl)-3-(5-(tetrazolyl)pyridin-2(1H)-one,
6-[1-(4-hydroxy)naphthyl]-3-(5-tetrazolyl)pyridin-2(1H)- one,
2-methoxyethyl [6-(2-naphthyl)-2-oxo-1,2-dihydro-3- pyridyl]phosphonate, n-propyl [6-(2-naphthyl)-2-oxo-1,2-dihydro-3-pyridyl]- phosphonate, n-propyl [6-(9-phenanthryl)-2-oxo-1,2-dihydro-3-pyridyl]- phosphonate,
2-hydroxy-2-[6-(9-phenanthryl)-2-oxo-1,2-dihydro-3- pyridyl]acetic acid, ethyl 2-methoxy-2-[6-(2-naphthyl)-2-oxo-1,2-dihydro-3- pyridyl]acetate, ethyl 2-methoxy-2-[6-(1-naphthyl)-2-oxo-1,2-dihydro-3- pyridyl]acetate,
2-ethoxy-2-[6-(2-naphthyl)-2-oxo-1,2-dihydro-3- pyridyl]acetic acid, 3-carboxy-6-(9-phenanthryl)pyridin-2(1H)-one. 6-[1-(4-propoxy)naphthyl]-3-(5-tetrazolyl)pyridin-2(1H)- one, ethyl 2-hydroxy-[6-(9-phenanthryl)-2-oxo-1,2-dihydro-3- pyridyl]acetate,
2-oxo-2-[6-(2-naphthyl)-2-oxo-1,2-dihydro-3-pyridyl]acetic acid, 2-hydroxy-2-[6(1-naphthyl)-2-oxo-1,2-dihydro-3-pyridyl]- acetic acid, n-butyl 2-methoxy-2-[6-(2-naphthyl)-2-oxo-1,2-dihydro-3- pyridyl]acetate,
[6-(2-naphthyl)-2-oxo-1,2-dihydro-3-pyridyl]sulphinic acid, ethyl 2,2-difluoro-2-[6-(2-naphthyl)-2-oxo-1,2-dihydro-3- pyridyl]acetate,
2,2-difluoro-2-[6-(2-naphthyl)-2-oxo-1,2-dihydro-3- pyridyl]acetic acid.
4-(1-naphthyl)salicylic acid, ethyl 2-hydroxy-4-(1-naphthyl)phenyl phosphonate, 5-[2-hydroxy-4-(1-naphthyl)phenyl]tetrazole, 4-(2-naphthyl)salicylic acid, ethyl 2-hydroxy-4-(2-naphthyl)phenyl phosphonate, n-butyl 2-hydroxy-4-(2-naphthyl)phenyl phosphonate, ethyl 2-hydroxy-4-(9-phenanthryl)phenyl phosphonate, ethyl 4-(1-naphthyl)salicylate,
6-(1-naphthyl)-3-[5-(2-pivaloyloxymethyl)tetrazolyl]- pyridin-2(1H)-one, or ethyl pivaloyloxymethyl[6-(1-naphthyl)-2-oxo-1,2-dihydro- 3-pyridyl]phosphonate, or a pharmaceutically acceptable salt thereof.
14. A compound according to any one of claims 1 to 13 for use as a medicament.
15. A pharmaceutical composition which comprises a compound according to any one of claims 1 to 13 and a pharmaceutically acceptable carrier.
16. A process for preparing a compound of the formula (1) as defined in claim 1 or a pharmaceutically acceptable salt thereof which process comprises : a) for compounds wherein A is N and R1 is CO2H or
CO2R8 in which R8 is an ester-forming group, reacting a compound of the formula (2) :
ArCOCH=CHY (2) with a compound of the formula (3) : R8O2CCH2CONH2 (3) wherein Y is a displaceable group and Ar is as defined in claim 1 and R8 is as hereinbefore defined and thereafter optionally converting CO2R8 into CO2H; or b) for compounds wherein R1 is CO2H,
hydrolysing a compound of the formula (4) :
(4)
Figure imgf000096_0002
wherein A is N or CH and R9 is cyano and Ar is as hereinbefore defined; or c) for compounds wherein R1 is A0CO2H or A0CO2R8 and : i) A0 is a single bond,
reacting in the presence of a strong base a compound of the formula (5) :
(5)
Figure imgf000096_0001
wherein R10 is methyl, and Ar and A are as hereinbefore defined with carbon dioxide to form a compound of the formula (6) : (6)
Figure imgf000097_0001
wherein R11 is carboxy and Ar, A and R10 are as
hereinbefore defined and thereafter optionally reacting with R8OH, wherein R8 is as hereinbefore defined, ii) A0 is CR3(OR4),
reacting in the presence of a strong base a compound of the formula (5) as hereinbefore defined with a compound of the formula (7) :
R3COCO2R8 (7)
wherein R3 is as defined in claim 1 and R8 is as
hereinbefore defined to form a compound of the formula (6) wherein R11 is CR3(OH)CO2R8 and R3, R8, R10, A and Ar are as hereinbefore defined and thereafter optionally reacting with a C1-3alkylating agent to form the
corresponding compound wherein R11 is
CR3 (OC1-3alkyl) CO2R8, iii) A0 is CO,
reacting in the presence of a strong base a compound of the formula (5) as hereinbefore defined with a compound of the formula (8) : R8O2CCO2R8 (8) wherein R8 is as hereinbefore defined to form a compound of the formula (6) wherein R11 is COCO2R8 and R8,
R10, A and Ar are as hereinbefore defined, iv) A0 is CH(OH),
reacting a compound of the formula (6) wherein R11 is
COCO2R8 and R8, R10, A and Ar are as hereinbefore defined with a reducing agent to form the corresponding compound
wherein R11 is CH(OH)CO2R8, or v) A0 is CH2,
reacting a compound of the formula (6) wherein R11 is
COCO2H or COCO2R8 and R8, R10, A and Ar are as
hereinbefore defined with a suitable reducing agent to form the corresponding compound wherein R11 is CH2CO2H, or vi) A0 is C(OR5)(OR6),
reacting a compound of the formula (6) wherein R11 is
COCO2R8 and R8, R10, A and Ar are as hereinbefore
defined with a C1-3alcohol, 1,2-ethanediol or
1,3-propanediol to
form the corresponding compound wherein R11 is
C(0R5) (OR6)CO2R8, vii) A0 is CF2,
reacting a compound of the formula (6) wherein R11 is
COCO2R8 and R8, R10, A and Ar are as hereinbefore
defined with a fluorinating agent to form the
corresponding compound wherein R11 is CF2CO2R8, or viii) A0 is CHF,
reacting a compound of the formula (6) wherein R11 is
CH(OH)CO2R8 and R8, R10, A and Ar are as
hereinbefore defined with a fluorinating agent to form the corresponding compound wherein R11 is CHFCO2R8, and thereafter optionally :
° converting the group OR10 into OH ° converting the group A0CO2R8 into A0CO2H; or d) for compounds wherein R1 is CH2CO2H,
converting a compound of the formula (4) wherein R9 is acetyl and Ar and A are as hereinbefore defined into the corresponding compound wherein R9 is CH2CO2H; or e) for compounds wherein R1 is P(O) (OH) (OR2),
hydrolysing a compound of the formula (4) wherein R9 is P(O) (OR2)2 and R2 is as defined in claim 1 and A and Ar are as hereinbefore defined; or f) for compounds wherein R1 is P(S) (OH) (OR2),
converting a compound of the formula (4) wherein R9 is P(O) (NHR12) (OR2) and R12 is phenyl or C1-4alkyl into the corresponding compound wherein R9 is P(S) (OH) (OR2); or g) for compounds where R1 is SO3H,
reacting in the presence of a strong base a compound of the formula (5) as hereinbefore defined with sulphuryl chloride or a chemical equivalent thereof and optionally converting the group OR10 into OH; or h) for compounds wherein R1 is SO2H,
reacting in the presence of a strong base a compound of the formula (5) as hereinbefore defined with sulphur dioxide and optionally converting the group OR10 into OH; or i) for compounds wherein R1 is 5-tetrazolyl,
reacting a compound of the formula (4) wherein R9 is cyano or a compound of the formula (6) wherein R11 is cyano with an azide salt; or j) for compounds wherein R1 is as defined for
compounds of the formula (1) reacting in the presence of a palladium catalyst a compound of the formula (9):
(9)
Figure imgf000100_0001
wherein R1 and A are as hereinbefore defined and Ra is R0 or OR10 as hereinbefore defined and L1 is a
leaving group with a compound of the formula (10):
ArB(OH)2 (10) wherein Ar is as hereinbefore defined and then, if
necessary, converting the group OR10 into OH, and optionally thereafter : ° forming a bioprecursor of R0 and/or R1
° forming a pharmaceutically acceptable salt.
PCT/GB1991/000789 1990-05-21 1991-05-20 Phenol and pyridinol derivatives as pharmaceuticals WO1991017987A1 (en)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993010107A1 (en) * 1991-11-20 1993-05-27 Smithkline Beecham Plc Phenol derivatives as agonists of a cyclic amp dependent protein kinase
WO1993010114A1 (en) * 1991-11-20 1993-05-27 Smithkline Beecham Plc 3-pyridinol derivatives and their use as medicaments
WO1993010093A1 (en) * 1991-11-20 1993-05-27 Smithkline Beecham Plc 2-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
WO2003049774A1 (en) * 2001-12-13 2003-06-19 Vital Health Sciences Pty Ltd Transdermal transport of compounds
WO2006092430A1 (en) * 2005-03-03 2006-09-08 Universität des Saarlandes Selective inhibitors of human corticosteroid synthases
US8841342B2 (en) 2002-08-09 2014-09-23 Vital Health Sciences Pty. Ltd. Carrier
EP2750504A4 (en) * 2011-08-29 2015-03-11 Ptc Therapeutics Inc Antibacterial compounds and methods for use
WO2015148314A1 (en) * 2014-03-25 2015-10-01 3M Innovative Properties Company Flame retardant, pressure-sensitive adhesive, and curable composition
US9168216B2 (en) 2005-06-17 2015-10-27 Vital Health Sciences Pty. Ltd. Carrier comprising one or more di and/or mono-(electron transfer agent) phosphate derivatives or complexes thereof
US9314527B2 (en) 2010-03-30 2016-04-19 Phosphagenics Limited Transdermal delivery patch
US9561243B2 (en) 2011-03-15 2017-02-07 Phosphagenics Limited Composition comprising non-neutralised tocol phosphate and a vitamin A compound
US9650395B2 (en) 2011-08-29 2017-05-16 Ptc Therapeutics, Inc. Antibacterial compounds and methods for use
US10071030B2 (en) 2010-02-05 2018-09-11 Phosphagenics Limited Carrier comprising non-neutralised tocopheryl phosphate
US10266496B2 (en) 2015-09-02 2019-04-23 Sunshine Lake Pharma Co., Ltd. Carboxy substituted (hetero) aromatic ring derivatives and preparation method and uses thereof
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Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB9121651D0 (en) * 1991-10-11 1991-11-27 Smithkline Beecham Plc Chemical compounds
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3703582A (en) * 1970-04-20 1972-11-21 Merck & Co Inc Aryl pyridine carboxylic acids in the treatment of inflammation
EP0308020A2 (en) * 1987-09-18 1989-03-22 Merck & Co. Inc. 5-(aryl and heteroaryl)-6-(aryl and heteroaryl)-1,2-dihydro-2-oxo 3-pyridinecarboxylic acids and derivatives thereof
EP0347027A2 (en) * 1988-04-21 1989-12-20 Smith Kline & French Laboratories Limited Phenylpyridone derivatives,processes for their preparation and pharmaceutical compositions containing them.

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3703582A (en) * 1970-04-20 1972-11-21 Merck & Co Inc Aryl pyridine carboxylic acids in the treatment of inflammation
EP0308020A2 (en) * 1987-09-18 1989-03-22 Merck & Co. Inc. 5-(aryl and heteroaryl)-6-(aryl and heteroaryl)-1,2-dihydro-2-oxo 3-pyridinecarboxylic acids and derivatives thereof
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 (1)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, vol. 96, no. 15, 1982, page 680, abstract no. 122589b, (Columbus, Ohio, US), A. ESSAWY et al.: "Synthesis and some reactions of 3-cyano-4-phenyl-6-[1-(2-methoxynaphthalenyl)]-2-pyridone", & REV. ROUM. CHIM. 1981, 26(8), 1141-8, see 1,2-dihydro-6-(2-methoxy-1-naphthalenyl)-2-oxo-4-phenyl-3-pyridinecarboxylic acid, RN=81188-58-1 *

Cited By (24)

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Publication number Priority date Publication date Assignee Title
WO1993010107A1 (en) * 1991-11-20 1993-05-27 Smithkline Beecham Plc Phenol derivatives as agonists of a cyclic amp dependent protein kinase
WO1993010114A1 (en) * 1991-11-20 1993-05-27 Smithkline Beecham Plc 3-pyridinol derivatives and their use as medicaments
WO1993010093A1 (en) * 1991-11-20 1993-05-27 Smithkline Beecham Plc 2-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
WO2003049774A1 (en) * 2001-12-13 2003-06-19 Vital Health Sciences Pty Ltd Transdermal transport of compounds
US8841342B2 (en) 2002-08-09 2014-09-23 Vital Health Sciences Pty. Ltd. Carrier
US9271963B2 (en) 2005-03-03 2016-03-01 Universitat Des Saarlandes Selective inhibitors of human corticosteroid synthases
WO2006092430A1 (en) * 2005-03-03 2006-09-08 Universität des Saarlandes Selective inhibitors of human corticosteroid synthases
US9168216B2 (en) 2005-06-17 2015-10-27 Vital Health Sciences Pty. Ltd. Carrier comprising one or more di and/or mono-(electron transfer agent) phosphate derivatives or complexes thereof
US10071030B2 (en) 2010-02-05 2018-09-11 Phosphagenics Limited Carrier comprising non-neutralised tocopheryl phosphate
US9314527B2 (en) 2010-03-30 2016-04-19 Phosphagenics Limited Transdermal delivery patch
US9561243B2 (en) 2011-03-15 2017-02-07 Phosphagenics Limited Composition comprising non-neutralised tocol phosphate and a vitamin A compound
US10188670B2 (en) 2011-03-15 2019-01-29 Phosphagenics Limited Composition
AU2012301953B2 (en) * 2011-08-29 2016-05-12 Ptc Therapeutics, Inc. Antibacterial compounds and methods for use
AU2012301953C1 (en) * 2011-08-29 2016-11-03 Ptc Therapeutics, Inc. Antibacterial compounds and methods for use
US9409905B2 (en) 2011-08-29 2016-08-09 Ptc Therapeutics, Inc. Antibacterial compounds and methods for use
US9650395B2 (en) 2011-08-29 2017-05-16 Ptc Therapeutics, Inc. Antibacterial compounds and methods for use
EP2750504A4 (en) * 2011-08-29 2015-03-11 Ptc Therapeutics Inc Antibacterial compounds and methods for use
CN106459490A (en) * 2014-03-25 2017-02-22 3M创新有限公司 Flame retardant, pressure-sensitive adhesive, and curable composition
US9926473B2 (en) 2014-03-25 2018-03-27 3M Innovative Properties Company Flame retardant, pressure-sensitive adhesive, and curable composition
WO2015148314A1 (en) * 2014-03-25 2015-10-01 3M Innovative Properties Company Flame retardant, pressure-sensitive adhesive, and curable composition
US10266496B2 (en) 2015-09-02 2019-04-23 Sunshine Lake Pharma Co., Ltd. Carboxy substituted (hetero) aromatic ring derivatives and preparation method and uses thereof
US10973761B2 (en) 2015-12-09 2021-04-13 Phosphagenics Limited Pharmaceutical formulation
US11753435B2 (en) 2016-12-21 2023-09-12 Avecho Biotechnology Limited Process

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PT97722A (en) 1992-02-28

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