WO1993010107A1 - Phenol derivatives as agonists of a cyclic amp dependent protein kinase - Google Patents

Phenol derivatives as agonists of a cyclic amp dependent protein kinase Download PDF

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Publication number
WO1993010107A1
WO1993010107A1 PCT/GB1992/002119 GB9202119W WO9310107A1 WO 1993010107 A1 WO1993010107 A1 WO 1993010107A1 GB 9202119 W GB9202119 W GB 9202119W WO 9310107 A1 WO9310107 A1 WO 9310107A1
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Prior art keywords
compound
formula
group
hereinbefore defined
reacting
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PCT/GB1992/002119
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French (fr)
Inventor
Roderick Alan Porter
Hunter Douglas Prain
Kenneth John Murray
Brian Herbert Warrington
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Smithkline Beecham Plc
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Priority to JP5509095A priority Critical patent/JPH07503235A/en
Priority to EP92923480A priority patent/EP0620815A1/en
Publication of WO1993010107A1 publication Critical patent/WO1993010107A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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
    • 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
    • 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
    • A61P9/06—Antiarrhythmics
    • 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 Table
    • 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 ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or 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)

Definitions

  • the present invention relates to phenol derivatives
  • 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
  • cA-PrK cyclic AMP-dependent protein kinase
  • agonism is thought to be beneficial. They are likely to have anti-proliferative, anti-aggregatory, cholesterol-lowering, smooth muscle relaxant, positive lusitropic, anti-allergic or anti-inflammatory activities. They are likely to be useful in the treatment of
  • diastolic failure cancer, psoriasis, atheroschlerosis, thrombosis, re-stenosis, chronic reversible lung disease such as asthma and bronchitis, allergic disease such as allergic asthma,, allergic rhinitis and urticaria or gut motility disorders such as irritable bowel syndrome.
  • R 0 is OH or a bioprecursor thereof
  • R 1 is A 0 CO 2 H, P(Z) (OH) (OR 2 ), SO 2 H, SO 3 H or 5-tetrazolyl or a bioprecursor thereof
  • a 0 is CH 2 , CHF, CF 2 , CR 3 (OR 4 ) , CO or C (OR 5 ) (OR 6 ) ,
  • 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 1,2- ethanediyl group or 1,3-propanediyl group,
  • Z is O or S
  • Ar is phenyl optionally substituted by one to three groups independently selected from C 1-6 alkyl, C 2-6 alkenyl, C 1-6 alkoxy, C 3-6 alkenyloxy, C 3-6 cycloalkyl,
  • Bioprecursors of the groups R 0 and R 1 are derivatives thereof which are convertible in vivo into the groups R 0 and R 1 .
  • a suitable bioprecursor of the group R 0 is OR 8 wherein R 8 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 substituted phenylsulphonyl or toluenesulphonyl) or C 1-4 alkylsulphonyl
  • R 8 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 substituted phenylsulphonyl or toluenesulphonyl) or C 1-4 alkylsulphonyl
  • R 1 is A 0 CO 2 H
  • a suitable bioprecursor is A 0 CO 2 R 9 wherein R 9 is an ester-forming group.
  • R 1 is P(Z) (OH) (OR 2 )
  • a suitable bioprecursor is
  • Suitable O-protecting groups include pivaloyloxymethyl, propionyloxymethyl and pivalolyloxycarbonyloxymethyl.
  • R 1 is 5-tetrazolyl
  • a suitable biopricursor is a
  • N-protected derivative thereof include pivalolyloxymethyl, propionyloxymethyl and
  • bioprecursors of the groups R 0 and R 1 are those formed when R 1 and R 0 are linked together to form a cyclic structure such that R 1 -R 0 is A 1 CO 2 or A 2 OCH 2 O, in which :
  • a 1 is CH 2 , CHF, CF 2 , CR 3 (OR 4 ), CO or C(OR 5 ) (OR 6 ),
  • a 2 is P(Z)OR 2 or CR 3 (CO2R 9 ), and
  • R 2 to R 6 , R 9 and Z are as hereinbefore defined.
  • R 0 is hydroxy or OR 8 , preferably hydroxy.
  • R 1 is A 0 CO 2 H or A 0 CO 2 R 9 .
  • R 1 is P (Z) (OH) (OR 2 ) or P(Z) (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.
  • Ci-gpolyfluoroalkyl is meant a C 1-6 alkyl group having at least one hydrogen replaced with fluoro, e.g. CF 3 or CF 2 CF 2 H.
  • 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, preferably H or methyl.
  • R 5 and R 6 are independently methyl, ethyl or propyl, preferably together they form a 1,2-ethanediyl group.
  • Z is O.
  • R 9 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 phenyl optionally mono-substituted by a group as hereinbefore defined, for example in the 2,3, or 4
  • Ar is phenyl di-substituted by any groups as
  • Ar is phenyl trisubstituted by any groups as
  • C 2-6 alkenyl, C 1-6 alkoxy or halo examples include methoxy, ethoxy, propoxy, butoxy, or pentyloxy.
  • C 1-6 alkyl examples include methyl, ethyl, propyl, butyl, isobutyl or pentyl.
  • halo examples include fluoro, chloro, bromo or iodo.
  • Particular compounds of this invention include :
  • This invention covers all tautomeric, geometric and optical isomeric forms of compounds of formula (1).
  • Compounds of the formula (1) can form pharmaceutically acceptable base addition salts with metal ions, such as alkali metals for example sodium or potassium, or with an ammonium ion.
  • metal ions such as alkali metals for example sodium or potassium
  • ammonium ion In order to use a compound of the formula (1) or a
  • 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.
  • An oral liquid formulation will generally consist of a suspension or solution of the compound or salt in a liquid carrier for example, ethanol, glycerine or water with a flavouring or colouring agent.
  • a liquid carrier for example, ethanol, glycerine or water with a flavouring or colouring agent.
  • any pharmaceutical carrier routinely used for preparing solid formulations may be used. Examples of such carriers include starch, celluloses, lactose, sucrose and magnesium stearate.
  • any routine encapsulation is suitable, for example using the aforementioned carriers in a hard gelatin capsule shell.
  • any pharmaceutical carrier routinely used for preparing dispersions or suspensions may be
  • 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,
  • 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.
  • 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.
  • 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.
  • 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.
  • bronchodilators such as sympathomimetic amines for example isoprenaline, isoetharine, sulbutamol, phenylephrine and ephedrine or xanthine derivatives for example
  • anti-allergic agents for example disodium cromoglycate, histamine H 1 -antagonists
  • drugs used in the treatment of cancer such as those which inhibit the synthesis of or inactivate DNA, for example methotrexate, fluoracil, cisplatin, actinomycin D, anti- atherschlerotic agents for example cholesterol lowering drugs such as HMGCoA reductase 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.
  • the present invention provides a process for the preparation of compounds of the formula (1) or
  • R 11 is methyl and Ar is as hereinbefore defined. with a compound of the formula (3) :
  • R 12 is CR 3 (OH)CO 2 R 9 and R 3 , R 9 , R 11 , and Ar are as hereinbefore defined and thereafter optionally reacting with a C 1-3 alkylating agent to form the corresponding compound wherein R 12 is CR 3 (OC 1-3 alkyl) CO 2 R 9 , ii) A 0 is CO,
  • CH(OH)CO 2 R 9 and R 9 , R 11 , and Ar are as hereinbefore defined with a fluorinating agent to form the corresponding compound wherein R 12 is CHFCO 2 R 9 , and thereafter optionally : o converting the group OR 11 into OH o converting the group A 0 CO 2 R 9 into AOCO 2 H; or b) for compounds wherein R 1 is CH 2 CO 2 H,
  • R 13 is acetyl and Ar is as hereinbefore defined into the corresponding compound wherein R 13 is CH 2 CO 2 H; or c) for compounds wherein R 1 is CH(OR 4 )CO2H reacting a compound of the formula (4) wherein R 12 is -CH(OH)CN with a C 1-3 alkylating agent and/or converting the group CN into CO 2 H, and optionally converting the group OR 11 into OH; or d) for compounds wherein R 1 is P(O)(OH)(OR 2 ),
  • R 13 is P(O)(OR 2 ) 2 and R 2 , and Ar are as hereinbefore defined; or e) for compounds wherein R 1 is P(S) (OH) (OR 2 ), converting a compound of the formula (6) wherein R 13 is P (O) (NHR 14 ) (OR 2 ) and R 14 is phenyl or C 1-4 alkyl and Ar is as hereinbefore defined into the corresponding compound wherein R 13 is
  • R b is a group R 1 as hereinbefore defined or a precursor thereof and R a is R 0 or OR 11 as hereinbefore defined and L 1 is a leaving group with a compound of the formula (8):
  • a compound of the formula (2) is reacted with a strong base such as lithium diisopropylamide, or a C 1-4 alkyl lithium or aryl lithium such as mesityl lithium in an organic solvent such as tetrahydrofuran, diethylether or
  • the strong base may be formed in situ, for example by the addition of a C 1-4 alkyl lithium e.g. methyllithium followed by a catalytic quantity of diisopropylamine.
  • a suitable compound of the formula (3) is ethylpyruvate, or ethyl glyoxylate or a chemical equivalent thereof and a suitable compound of the formula (5) is diethyloxalate.
  • a compound of the formula (4) wherein R 12 is CR 3 (OH)CO 2 R 9 is suitably reacted with a C 1-3 alkylating agent such as
  • iodomethane, iodopropane or dimethylsulphate in the presence of a base such as sodium hydride or potassium hydroxide in an organic solvent such as dimethylformamide or
  • COCO 2 R 9 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
  • 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
  • a compound of the formula (4) wherein R 12 is COCO 2 R 9 is suitably reacted with a C 1-3 alcohol, 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
  • CHOHCO 2 R 9 is suitably reacted with a fluorinating agent such as diethylaminosulphur trifluoride in an organic solvent such as a halohydrocarbon or an ether such as glyme, or THF at ambient or elevated temperature (e.g. 30-60°C) to form the corresponding compound where R 12 is CF 2 CO 2 R 9 or CHFCO 2 R 9 respectively.
  • a fluorinating agent such as diethylaminosulphur trifluoride
  • organic solvent such as a halohydrocarbon or an ether such as glyme, or THF
  • ambient or elevated temperature e.g. 30-60°C
  • a compound of the formula (4) wherein OR 11 is methoxy can suitably be converted to the corresponding compound wherein OR 11 is hydroxy by reaction with sodium iodide and
  • a compound of the formula (4) wherein R 12 is A 0 CO 2 R 9 can suitably be converted to the corresponding compound wherein R 12 is A 0 CO 2 H by reaction with an aqueous base such as sodium or potassium hydroxide at ambient or elevated temperature (e.g. 40 - 120°).
  • 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 R 0 is methoxy since the OR 11 group is not hydrolysed.
  • Another hydrolysis method utilises aqueous acid such as concentrated
  • hydrochloric acid at an elevated temperature e.g. 40 - 120°C
  • an elevated temperature e.g. 40 - 120°C
  • R 0 is hydroxy
  • R 1 is A 0 CO 2 H
  • a compound of the formula (6) wherein R 13 is acetyl is converted to the corresponding compound where R 13 is CH 2 CO 2 H by reaction with sulphur and morpholine
  • a compound of the formula (4) wherein R 12 is -CH(OH)CN can be prepared by reacting the corresponding compound wherein R 12 is -CHO with a source of cyanide such as potassium cyanide in the presence of an acid such as hydrochloric acid preferably at ambient temperature.
  • a compound of the formula (4) or (6) where R 12 or R 13 is CHO is suitably prepared by reacting the corresponding compound wherein R 12 or R 13 is cyano with a suitable reducing agent such as diisobutylaluminium hydride followed by aqueous acidic work-up.
  • a suitable reducing agent such as diisobutylaluminium hydride followed by aqueous acidic work-up.
  • P(O)(OR 2 ) 2 is hydrolysed by reaction with an aqueous base such as sodium hydroxide optionally in a cosolvent such as a C ⁇ _4alcohol at an elevated temperature (e.g. 40-100°C), preferably at the reflux temperature of the reaction mixture.
  • an aqueous base such as sodium hydroxide
  • a cosolvent such as a C ⁇ _4alcohol
  • an elevated temperature e.g. 40-100°C
  • dimethoxyethane at ambient or elevated temperature (e.g. 40 - 100°C) followed by reaction with carbon disulphide.
  • a compound of the formula (4) wherein R 12 is cyano or a compound of the formula (6) wherein R 13 is cyano is suitably reacted with an azide salt such as ammonium, sodium or aluminium azide in an organic solvent such as
  • diethylformamide, dimethylsulphoxide, N-methylpyrrolidone or tetrahydrofuran at an elevated temperature e.g. 40-200°C, preferably at 100-150°C to form the corresponding
  • OR 1 1 is benzenesulphonyl which can be introduced in standard manner, for example by reacting the corresponding hydroxy compound with benzenesulphonyl chloride in the presence of a base such as triethylamine. This group can be removed in standard manner, for example by reaction with a base such as sodium hydroxide.
  • a compound of the formula (7) is reacted with a compound of the formula (8) in the presence of 1-50 mole %, preferably 2-10 mole %, of a palladium catalyst and a base such as triethylamine, sodium bicarbonate, or aqueous sodium carbonate and optionally lithium chloride in an organic solvent such as dimethylformamide, dimethoxyethane
  • L 1 is halo for example iodo, bromo or chloro or a
  • palladium catalysts examples include: tetrakis(triphenylphosphine)palladium (Pd[PPh 3 ] 4 ),
  • a chemical equivalent of a compound of the formula (8) is meant a reagent that can couple the Ar group onto the pyridyl ring of a compound of the formula (7).
  • aryl stannanes can be used, such as ArSnMe 3 which can suitably be prepared by reacting a suitable aryl halide (such as ArBr or ArI) with a base such as t-butyl lithium followed by reaction with a trimethyl tin halide (e.g. Me 3 SnCl).
  • a suitable aryl halide such as ArBr or ArI
  • a base such as t-butyl lithium
  • a trimethyl tin halide e.g. Me 3 SnCl
  • the aryl halide can be reacted with M ⁇ 3SnSnMe3 in the
  • R 1 An example of a precursor for R 1 is when R D is hydrogen.
  • reaction of a compound of the formula (7) with a compound of the formula (8) or a chemical equivalent thereof results in a compound of the formula (2) or a compound of the formula (6) wherein R 13 is hydrogen.
  • Such compounds can then be converted into a compound of the formula (1) as herein described.
  • R 1 Other precursors for R 1 include CN, CHO or COMe. Reaction of a compound of the formula (7) wherein R b represents such a precursor with a compound of the formula (8) or a chemical equivalent thereof results in a compound of the formula (4) or a compound of the formula (6) wherein R 12 or R 13 is CN,
  • a compound of the formula (1) wherein R 0 is OH can be any compound of the formula (1) wherein R 0 is OH.
  • R 0 is OR 8 by reaction with R 8 L 2 wherein R 8 is as hereinbefore defined and L 2 is a leaving group such as halo e.g. bromo, chloro, iodo.
  • P (Z) (OR 2 ) (OH) can be converted to the corresponding compound wherein R 1 is P (Z) (OR 2 ) (OR 10 ) 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 pivalolyloxymethyl halide.
  • a compound of the formula (1) wherein R 1 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 R 1 -R 0 is 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 with a dehydrating agent such as acetic anhydride, at an elevated temperature (e.g. 40 - 200°C), preferably at the reflux temperature of the
  • a compound of the formula (1) wherein R 1 -R 0 is 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 compound of the formula (2) is suitably prepared by
  • a compound of the formula (6) wherein R 13 is acetyl can also be prepared by reacting a compound of the formula (6) wherein R 13 is cyano with methyl lithium followed by aqueous acidic work up with for example hydrochloric acid.
  • a compound of the formula (6) wherein R 13 is hydrogen can be prepared by reacting a compound of the formula (6) wherein R 13 is cyano with orthophosphoric acid at an elevated temperature (e.g. 40 - 120°C) or with iodomethane and silver carbonate in toluene or chloroform.
  • This method can also be used for converting compounds of the formula (6) into corresponding compounds of the formula (4) and compounds of formula (7) wherein R a is hydroxy into corresponding compounds wherein R a is OR 11 .
  • a compound of the formula (6) wherein R 13 is acetyl can also be prepared by reacting a compound of the formula (6) wherein R 13 is cyano with methyl lithium followed by aqueous acidic work
  • a compound of formula (4) wherein R 12 is cyano is suitably prepared by reacting the anion of a compound of formula (2) wherein Ar and R 11 are as hereinbefore defined with
  • a compound of the formula (6) wherein R 13 is cyano or acetyl and Ar is as hereinbefore defined can be suitably prepared by reaction of a compound of formula (4) wherein R 12 is cyano or acetyl and R 11 and Ar 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
  • a compound of the formula (6) wherein R 13 is P (O) (OR 2 ) 2 can be prepared by treating a compound of the formula (2) wherein R 11 is P(O)(OR 2 ) 2 with a strong base such as lithium
  • a compound of the formula (2) wherein R 11 is P (O) (OR 2 ) 2 is suitably prepared by treating a compound of the formula (6) wherein R 13 is hydrogen with a compound of the formula (9) :
  • L 3 is halo, for example chloro or bromo.
  • a compound of formula (2) wherein R 11 is P (O) (OR 2 ) 2 can also be prepared by treating a compound of the formula (6) wherein R 13 is hydrogen with a compound of the formula (10): HP (O) (OR 2 ) 2 (10) wherein R 2 is as hereinbefore defined in the presence of an amine base such as triethylamine, and carbon tetrachloride.
  • a compound of the formula (6) wherein R 13 is P (O) (OR 2 ) 2 is suitably prepared by treating a compound of the formula (6) wherein R 13 is hydrogen with a compound of the formula (9) in the presence of a strong base such as lithium diisopropylamide in an organic solvent such as
  • a compound of formula (6) wherein R 13 is hydrogen is suitably prepared by demethylating a compound of formula (2) as hereinbefore defined.
  • a compound of formula (2) 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 formula (2) is treated with sodium iodide and chlorotrimethylsilane at ambient or elevated temperature (e.g. 40-80°C) conveniently ambient temperature in a solvent such as acetonitrile or dichloromethane.
  • a compound of the formula (6) wherein R 13 is P (O) (NHR 14 ) (OR 2 ) can be prepared by reaction of a compound of the formula (6) wherein R 13 is P (O) (OH) (OR 2 ) with carbon tetrachloride, triphenylphosphine and aniline or a C 1-4 alkylamine in an organic solvent such as pyridine at ambient temperature or with cooling (e.g. -10 to 5°C).
  • a compound of the formula (6) where R 13 is P (O) (OH) (OR 2 ) can be reacted with dimethylformamide and oxalyl chloride in an organic solvent such as a halo hydrocarbon e.g. dichloromethane at ambient temperature, followed by reaction with aniline or a C 1-4 alkylamine preferably with cooling (-10 to 5°C).
  • R a and L 1 are as hereinbefore defined using similar methods to those described for preparing compounds of the formula (1).
  • a compound of the formula (7) wherein R b is P (O) (OR 2 ) 2 can be prepared by reacting a compound of the formula (11) wherein R a is OH with a compound of the formula (9) or (10) in similar manner to the reaction of a compound of the formula (6) wherein R 13 is hydrogen with a compound of the formula (9) or (10). If desired the group R a can then be converted to OMe.
  • a compound of the formula (11) where R a is OMe can be treated in the presence of a strong base with a compound of the formula (3), a compound of the formula (5) , sulphuryl chloride, sulphur dioxide or dimethylformamide to prepare a compound of the formula (7) wherein R b is CR 3 (OR 4 )CO 2 R 9 , COCO 2 R 9 , SO 3 H, SO 2 H, or CHO respectively in similar manner to the corresponding reaction with a compound of the formula (2) as hereinbefore described.
  • Particularly suitable as a strong base is lithium tetramethyl piperidide.
  • a compound of the formula (8) is suitably prepared by
  • a tri-C 1-4 alkylborate such as trimethyl, tri-isopropyl or tri-n-butyl borate in an organic solvent such as diethyl ether or tetrahydrofuran with cooling (e.g. - 80-10°C).
  • a bromo group may be introduced into a suitably substituted phenyl ring (eg. disubstituted in the 2- and 4-positions by electron-donating groups such as
  • a nitro group can be introduced into a phenyl ring by reaction with a suitable nitrating agent, such as nitronium tetrafluoroborate.
  • a suitable nitrating agent such as nitronium tetrafluoroborate.
  • Such a group can be readily hydrogenated to an amino group which if desired can be converted to a NHCOR 7 group by reaction with LCOR 7 wherein L is a leaving group and R 7 is as hereinbefore defined.
  • Suitable examples of the reagent LCOR include acid halides (L is halo eg. chloro or bromo) or acid anhydrides (L is OCOR 7 ).
  • Suitable functionalisations include the introduction of an allyl group ortho to a hydroxy substituent on a phenyl ring by reaction with an allyl halide, eg. bromide, to form an allyloxy derivative which on heating undergoes a Claisen rearrangement to form an ortho allyl hydroxy derivative.
  • the hydroxy group can in turn be functionalised, eg. by reaction with a C 1-6 alkyl halide to form a C 1-6 alkoxy group.
  • an allyl group can be converted to an E-1-propenyl group by reaction with a strong base, such as sodium
  • An E-1-propenyl group can be cleaved to a formyl group by reaction with an oxidising agent such as
  • N-methylmorpholine-N-oxide in the presence of a catalyst such as osmium tetroxide to form a 1,2,dihydroxypropyl group which on reaction with an oxidising agent such as sodium periodate forms the formyl group.
  • a catalyst such as osmium tetroxide
  • an oxidising agent such as sodium periodate
  • the E-1-propenyl group can be converted directly to a formyl group by reaction with a mixture of osmium tetroxide and sodium periodate or by reaction with ozone.
  • a formyl group can in turn be further functionalised, for example it can be converted to a
  • hydroxymethyl group by reaction with a suitable reducing agent such as sodium borohydride, the hydroxymethyl group then being reacted further, eg. with a C 1-6 alkyl halide to form a C 1-6 alkoxymethyl group.
  • R 7 is as hereinbefore defined.
  • 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.
  • 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
  • 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 Hepes-isotonic saline buffer after a single centrifugation step and adjusted to a concentration of 1.5 ⁇ 10 8 cells/ml. Aliquots of this suspension were pre-incubated with compounds for 5 minutes at 37°C, then challenged with 1.0 ⁇ M U46619. The extent of aggregation after 2 minutes were expressed as a percentage of control and results obtained are expressed as an IC 50
  • the compounds of Examples 1 and 2 had IC 50 values of 20 and 38 ⁇ M respectively.
  • Papillary muscles from the right ventricle of female Albino New Zealand rabbits are mounted in standard organ baths containing oxygenated Krebs solution.
  • One end of the muscle is connected to an isometric transducer which allowed
  • compositions for oral administration are prepared by combining the following :
  • Example 4 A pharmaceutical composition for parenteral administration is prepared by dissolving ethyl 2-hydroxy-4-(2,3-dipropoxyphenyl)phenyl phosphonate (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.

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Abstract

Phenol derivatives are described as agonists of a cyclic AMP dependent protein kinase useful as medicaments.

Description

PHENOL DERIVATIVES AS AGONISTS OF A CYCLIC AMP DEPENDENT PROTEIN KINASE
The present invention relates to phenol derivatives,
processes for their preparation, intermediates in their preparation, their use as medicaments and to pharmaceutical compositions comprising them.
The compounds of this invention are agonists of a cyclic AMP- dependent protein kinase (cA-PrK) (see J. Biol. Chem., 1989, 264, 8443 - 8446) and are of use in combatting such
conditions where such agonism is thought to be beneficial. They are likely to have anti-proliferative, anti-aggregatory, cholesterol-lowering, smooth muscle relaxant, positive lusitropic, anti-allergic or anti-inflammatory activities. They are likely to be useful in the treatment of
cardiovascular diseases where there is a component of
diastolic failure, cancer, psoriasis, atheroschlerosis, thrombosis, re-stenosis, chronic reversible lung disease such as asthma and bronchitis, allergic disease such as allergic asthma,, allergic rhinitis and urticaria or gut motility disorders such as irritable bowel syndrome.
Accordingly the present, invention provides compounds of the formula (1) :
Figure imgf000003_0001
or pharmaceutically acceptable salts thereof, wherein :
R0 is OH or a bioprecursor thereof, R1 is A0CO2H, P(Z) (OH) (OR2), SO2H, SO3H or 5-tetrazolyl or a bioprecursor thereof, A0 is CH2, CHF, CF2, CR3 (OR4) , CO or C (OR5) (OR6) ,
R2 is phenyl, 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,
Z is O or S, and
Ar is phenyl optionally substituted by one to three groups independently selected from C1-6alkyl, C2-6alkenyl, C1-6alkoxy, C3-6alkenyloxy, C3-6cycloalkyl,
C3-6cycloalkoxy, C1-6alkylthio, phenyl, phenylthio, benzyloxy, C1-6polyfluoroalkyl, C1-6polyfluoroalkoxy, halo, N(R7)2 or NHCOR7 wherein R7 is H or C1-6alkyl, or -X(CH2)nY- attached to adjacent carbon atoms of the phenyl ring wherein X and Y are independently CH2 or O and n is 1 to 3, wherein said C1-6alkyl, C2-6alkenyl or C1-6alkoxy groups can be independently substituted by OH, C1-6alkoxy, C3-6cycloalkyl, N(R7)2, CO2R7 or CON(R7)2.
Bioprecursors of the groups R0 and R1 are derivatives thereof which are convertible in vivo into the groups R0 and R1.
A suitable bioprecursor of the group R0 is OR8 wherein R8 is 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 R1 is A0CO2H a suitable bioprecursor is A0CO2R9 wherein R9 is an ester-forming group. When R1 is P(Z) (OH) (OR2) a suitable bioprecursor is
P (Z) (OR2)2 wherein Z and R2 are as hereinbefore defined or P(Z) (OR2) (OR10) wherein R10 is an O-protecting group.
Suitable O-protecting groups include pivaloyloxymethyl, propionyloxymethyl and pivalolyloxycarbonyloxymethyl.
When R1 is 5-tetrazolyl, a suitable biopricursor is a
N-protected derivative thereof. Suitable N-protecting groups include pivalolyloxymethyl, propionyloxymethyl and
pivalolyloxycarbonyloxymethyl.
Alternatively bioprecursors of the groups R0 and R1 are those formed when R1 and R0 are linked together to form a cyclic structure such that R1-R0 is A1CO2 or A2OCH2O, in which :
A1 is CH2, CHF, CF2, CR3(OR4), CO or C(OR5) (OR6),
A2 is P(Z)OR2 or CR3(CO2R9), and
R2 to R6, R9 and Z are as hereinbefore defined.
Suitably R0 is hydroxy or OR8, preferably hydroxy. Suitably R1 is A0CO2H or A0CO2R9.
Suitably R1 is P (Z) (OH) (OR2) or P(Z) (OR2)2.
Suitably R1 is SO2H, SO3H or 5-tetrazolyl.
Suitably R1 and R0 are linked together such that R1-R0 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. By the term Ci-gpolyfluoroalkyl is meant a C1-6alkyl group having at least one hydrogen replaced with fluoro, e.g. CF3 or CF2CF2H. Suitably R2 is methyl, ethyl, propyl, butyl, pentyl, hexyl, 2-methoxyethyl, phenyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclopropylmethyl.
Suitably R3 is H, methyl or ethyl, preferably H or methyl.
Suitably R4 is H, methyl, ethyl or propyl, preferably H or methyl.
Suitably R5 and R6 are independently methyl, ethyl or propyl, preferably together they form a 1,2-ethanediyl group.
Preferably Z is O.
Suitably R9 is C1-4alkyl optionally substituted by hydroxy, e.g. 2-hydroxyethyl or arylC1-4alkyl (for example
phenylC1-4alkyl such as benzyl).
Suitably Ar is phenyl optionally mono-substituted by a group as hereinbefore defined, for example in the 2,3, or 4
positions by C1-6alkyl, C1-6alkoxy, C3-6alkenyloxy,
C1-6alkylthio, phenyl, phenylthio, benzyloxy, CF3, halo or NHCOR7.
Suitably Ar is phenyl di-substituted by any groups as
hereinbefore defined, for example in the 3,4-,3,5-,2,3-,2,4- or 2,5-, positions by groups independently selected from
C2-6alkenyl, C1-6alkoxy, C3-6cycloalkoxy, halo, -X(CH2)nY- or C1-6alkoxyC1-6 alkoxy. Suitably Ar is phenyl trisubstituted by any groups as
hereinbefore defined, for example in the 2,3,4-, 2,3,5-, or 3,4,5-positions by groups independently selected from
C2-6alkenyl, C1-6alkoxy or halo. Examples of C1-6alkoxy include methoxy, ethoxy, propoxy, butoxy, or pentyloxy.
Examples of C1-6alkyl include methyl, ethyl, propyl, butyl, isobutyl or pentyl.
Examples of halo include fluoro, chloro, bromo or iodo.
Particular compounds of this invention include :
2-(5-tetrazolyl)-5-(2,3-dipropoxyphenyl)phenol, or ethyl 2-hydroxy-4-(2,3-dipropoxyphenyl)phenyl phosphonate, and pharmaceutically acceptable salts thereof.
This invention covers all tautomeric, geometric and optical isomeric forms of compounds of formula (1). Compounds of the formula (1) can form pharmaceutically acceptable base addition salts with metal ions, such as alkali metals for example sodium or potassium, or with an ammonium ion. In order to use a compound of the formula (1) or a
pharmaceutically acceptable salt thereof for the treatment of humans and other mammals it is normally formulated in
accordance with standard pharmaceutical practice as a
pharmaceutical composition.
Compounds of formula (1) and their pharmaceutically
acceptable salts may be administered in standard manner for the treatment of the indicated diseases, for example orally, sublingually, parenterally, transdermally, rectally, via inhalation or via buccal administration.
Compounds of formula (1) and their pharmaceutically
acceptable salts which are active when given orally or via buccal administration can be formulated appropriately in dosage forms such as liquids, syrups, tablets, capsules and lozenges . An oral liquid formulation will generally consist of a suspension or solution of the compound or salt in a liquid carrier for example, ethanol, glycerine or water with a flavouring or colouring agent. Where the composition is in the form of a tablet, any pharmaceutical carrier routinely used for preparing solid formulations may be used. Examples of such carriers include starch, celluloses, lactose, sucrose and magnesium stearate. Where the composition is in the form of a capsule, any routine encapsulation is suitable, for example using the aforementioned carriers in a hard gelatin capsule shell. Where the composition is in the form of a soft gelatin shell capsule, any pharmaceutical carrier routinely used for preparing dispersions or suspensions may be
considered, for example aqueous gums, celluloses, silicates or oils and are incorporated in a soft gelatin capsule shell.
Typical parenteral compositions consist of a solution or suspension of the compound or salt in a sterile aqueous or non-aqueous carrier optionally containing a parenterally acceptable oil or solubilising agent, for example
polyethylene glycol, polyvinylpyrrolidone, lecithin,
2-pyrrolidone, cyclodextrin, arachis oil, or sesame oil. A typical suppository formulation comprises a compound of formula (1) or a pharmaceutically acceptable salt thereof which is active when administered in this way, with a binding and/or lubricating agent, for example polymeric glycols, gelatins, cocoa-butter or other low melting vegetable waxes or fats or their synthetic analogues.
Typical transdermal formulations comprise a conventional aqueous or non-aqueous vehicle, for example a cream,
ointment, lotion or paste or are in the form of a medicated plaster, patch or membrane.
Typical compositions for inhalation are in the form of a solution, suspension or emulsion that may be administered in the form of an aerosol using a conventional propellant such as dichlorodifluoromethane or trichlorofluoromethane, or are in the form of a powder for insufflation.
Preferably the composition is in unit dosage form, for example a tablet, capsule or metered aerosol dose, so that the patient may administer to himself a single dose.
Each dosage unit for oral administration contains suitably from 0.001 mg/Kg to 30 mg/Kg, and preferably from 0.005 mg/Kg to 15 mg/Kg, and each dosage unit for parenteral
administration contains suitably from 0.001 mg/Kg to 10 mg/Kg, of a compound of formula (1) or a pharmaceutically acceptable salt thereof calculated as the free acid. The daily dosage regimen for oral administration is suitably about 0.001 mg/Kg to 120 mg/Kg, of a compound of formula (1) or a pharmaceutically acceptable salt thereof calculated as the free acid. The daily dosage regimen for parenteral administration is suitably about 0.001 mg/Kg to 40 mg/Kg, for example about 0.005 mg/Kg to 10 mg/Kg, of a compound of the formula (1) or a pharmaceutically acceptable salt thereof calculated as the free acid. The active ingredient may be administered as required for example from 1 - 8 times a day or by infusion. The compositions of the invention are agonists of a cA-PrK and are of use in combatting such conditions where such agonism is thought to be beneficial. Such conditions can be treated by administration orally, sublingually topically, rectally, parenterally or by
inhalation. For administration by inhalation dosages are controlled by a valve, are administered as required and for an adult are conveniently in the range 0.1 - 5.0 mg of a compound of the formula (1) or a pharmaceutically acceptable salt thereof. The compounds of this invention may be co-administered with other pharmaceutically active compounds, for example in combination, concurrently or sequentially. Conveniently the compounds of this invention and the other active compound or compounds are formulated in a single pharmaceutical composition. Examples of compounds which may be included in pharmaceutical compositions with the compounds of the formula (1) are bronchodilators such as sympathomimetic amines for example isoprenaline, isoetharine, sulbutamol, phenylephrine and ephedrine or xanthine derivatives for example
theophylline and aminophylline, anti-allergic agents for example disodium cromoglycate, histamine H1-antagonists, drugs used in the treatment of cancer such as those which inhibit the synthesis of or inactivate DNA, for example methotrexate, fluoracil, cisplatin, actinomycin D, anti- atherschlerotic agents for example cholesterol lowering drugs such as HMGCoA reductase inhibitors, bile acid sequestrants, drugs for the treatment of psoriasis, for example retinoids, anthralin, anti-inflammatories for example cortiscosteroids, non-steroid anti-inflammatories such as aspirin,
antithrombotics for example dipyridamole, or fibrinolytic agents.
In another aspect the present invention provides a process for the preparation of compounds of the formula (1) or
pharmaceutically acceptable salts thereof, which process comprises : a) for compounds wherein R1 is A0CO2H or A0CO2R9 and : i) A0 is CR3 (OR4),
reacting in the presence of a strong base a compound of the formula (2) :
Figure imgf000010_0001
wherein R11 is methyl and Ar is as hereinbefore defined. with a compound of the formula (3) :
R3COCO2R9 (3) wherein R3 and R9 are as hereinbefore defined to form a compound of the formula (4) :
Figure imgf000011_0001
wherein R12 is CR3(OH)CO2R9 and R3, R9, R11, and Ar are as hereinbefore defined and thereafter optionally reacting with a C1-3alkylating agent to form the corresponding compound wherein R12 is CR3 (OC1-3alkyl) CO2R9, ii) A0 is CO,
reacting in the presence of a strong base a compound of the formula (2) as hereinbefore defined with a compound of the formula (5) :
R9O2CCO2R9 (5) wherein R9 is as hereinbefore defined to form a compound of the formula (4) wherein R12 is COCO2R9 and R9, R11 and Ar are as hereinbefore defined, iii) A0 is CH(OH),
reacting a compound of the formula (4) wherein R12 is COCO2R9 and R9, R11, and Ar are as hereinbefore defined with a reducing agent to form the corresponding compound wherein R12 is CH(OH)CO2R9, iv) A0 is CH2, reacting a compound of the formula (4) wherein R12 is COCO2H or COCO2R9 and R9, R11, and Ar are as hereinbefore defined with a suitable reducing agent to form the corresponding compound wherein R12 is CH2CO2H, v) A0 is C(OR5) (OR6),
reacting a compound of the formula (4) wherein R12 is COCO2R9 and R9, R11, and Ar are as hereinbefore defined with a
C1-3alcohol, 1,2-ethanediol or 1,3-propanediol to form the corresponding compound wherein R12 is C(OR5) (OR6)CO2R9, vi) A0 is CF2,
reacting a compound of the formula (4) wherein R12 is COCO2R9 and R9, R11, and Ar are as hereinbefore defined with a fluorinating agent to form the corresponding compound wherein R11 is CF2CO2R9, or vii) A0 is CHF,
reacting a compound of the formula (4) wherein R12 is
CH(OH)CO2R9 and R9, R11, and Ar are as hereinbefore defined with a fluorinating agent to form the corresponding compound wherein R12 is CHFCO2R9, and thereafter optionally : º converting the group OR11 into OH º converting the group A0CO2R9 into AOCO2H; or b) for compounds wherein R1 is CH2CO2H,
converting a compound of the formula (6) :
Figure imgf000012_0001
wherein R13 is acetyl and Ar is as hereinbefore defined into the corresponding compound wherein R13 is CH2CO2H; or c) for compounds wherein R1 is CH(OR4)CO2H reacting a compound of the formula (4) wherein R12 is -CH(OH)CN with a C1-3alkylating agent and/or converting the group CN into CO2H, and optionally converting the group OR11 into OH; or d) for compounds wherein R1 is P(O)(OH)(OR2),
hydrolysing a compound of the formula (6) wherein R13 is P(O)(OR2)2 and R2, and Ar are as hereinbefore defined; or e) for compounds wherein R1 is P(S) (OH) (OR2), converting a compound of the formula (6) wherein R13 is P (O) (NHR14) (OR2) and R14 is phenyl or C1-4alkyl and Ar is as hereinbefore defined into the corresponding compound wherein R13 is
P(S) (OH) (OR2); or f) for compounds where R1 is SO3H,
reacting in the presence of a strong base a compound of the formula (2) as hereinbefore defined with sulphury1 chloride or a chemical equivalent thereof and optionally converting the group OR11 into OH; or g) for compounds wherein R1 is SO2H,
reacting in the presence of a strong base a compound of the formula (2) as hereinbefore defined with sulphur dioxide and optionally converting the group OR11 into OH; or h) for compounds wherein R1 is 5-tetrazolyl, reacting a compound of the formula (4) wherein R12 is cyano and R11 is as hereinbefore defined or benzenesulphonyl, or a compound of the formula (6) wherein R12 is cyano with an azide salt and thereafter if necessary converting the group OR11 into OH; or i) for compounds wherein R1 is as defined for compounds of the formula (1) reacting in the presence of a palladium catalyst a compound of the formula (7):
Figure imgf000014_0001
wherein Rb is a group R1 as hereinbefore defined or a precursor thereof and Ra is R0 or OR11 as hereinbefore defined and L1 is a leaving group with a compound of the formula (8):
ArB(OH)2 (8) or a chemical equivalent thereof wherein Ar is as
hereinbefore defined and then, if necessary, converting a precursor of R1 into R1 and/or converting the group OR11 into OH, and optionally thereafter : ° forming a bioprecursor of R0 and/or R1
° forming a pharmaceutically acceptable salt.
Suitably a compound of the formula (2) is reacted with a strong base such as lithium diisopropylamide, or a C1-4alkyl lithium or aryl lithium such as mesityl lithium in an organic solvent such as tetrahydrofuran, diethylether or
dimethoxyethane with cooling (-100° - 0°C) to form the anion thereof. The strong base may be formed in situ, for example by the addition of a C1-4alkyl lithium e.g. methyllithium followed by a catalytic quantity of diisopropylamine.
The anion of a compound of the formula (2) is suitably
reacted with, a compound of the formula (3) or a compound of the formula (5) in an organic solvent such as tetrahydrofuran, diethylether or dimethoxyethane with cooling (-100° to 0°C) to form a compound of the formula (4) wherein R12 is CR3(OH)CO2R9 or COCO2R9 respectively. A suitable compound of the formula (3) is ethylpyruvate, or ethyl glyoxylate or a chemical equivalent thereof and a suitable compound of the formula (5) is diethyloxalate.
A compound of the formula (4) wherein R12 is CR3(OH)CO2R9 is suitably reacted with a C1-3alkylating agent such as
iodomethane, iodopropane or dimethylsulphate in the presence of a base such as sodium hydride or potassium hydroxide in an organic solvent such as dimethylformamide or
dimethylsulphoxide at elevated (e.g. 30 - 80°C) or preferably ambient temperature to form the corresponding compound wherein R12 is CR3 (OC1-3alkyl) CO2R9. When potassium
hydroxide is used as base the CO2R9 group may be directly converted to carboxy. A compound of the formula (4) wherein R12 is COCO2R9 is suitably reacted with a reducing agent such as sodium
borohydride, or diisobutylaluminium hydride in an organic solvent such as dichloromethane, a 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 R12 is
CH(OH)CO2R9.
A compound of the formula (4) wherein R12 is COCO2H or
COCO2R9 is suitably reacted with a reducing agent such as a zinc amalgam in hydrochloric acid in the absence of a solvent or in a solvent such as ethanol, acetic acid or dioxan and hydrogen chloride gas at ambient or elevated temperature
(e.g. 40-100°C) to form the corresponding compound wherein R12 is CH2CO2H. Under these reaction conditions the CO2R9 group is converted to carboxy.
A compound of the formula (4) wherein R12 is COCO2R9 is suitably reacted with a 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 R12 is C(OR5)(OR6)CO2R9.
A compound of the formula (4) wherein R12 is COCO2R9 or
CHOHCO2R9 is suitably reacted with a fluorinating agent such as diethylaminosulphur trifluoride in an organic solvent such as a halohydrocarbon or an ether such as glyme, or THF at ambient or elevated temperature (e.g. 30-60°C) to form the corresponding compound where R12 is CF2CO2R9 or CHFCO2R9 respectively.
A compound of the formula (4) wherein OR11 is methoxy can suitably be converted to the corresponding compound wherein OR11 is hydroxy by reaction with sodium iodide and
chlorotrimethylsilane in an organic solvent such as
acetonitrile, or a halohydrocarbon e.g. dichloromethane or chloroform at elevated (e.g. 30 - 80°C) or preferably ambient temperature. This method is particularly suitable for preparing compounds of the formula (1) wherein R1 is A0CO2R9 since the ester-forming group R9 is not hydrolysed under the reaction conditions. Another method utilises sodium
thiomethoxide in an organic solvent such as dimethylformamide at an elevated temperature for example 40 - 120°C. The more forcing conditions of this method are suitable for preparing compounds of formula (1) wherein R1 is A0CO2H.
A compound of the formula (4) wherein R12 is A0CO2R9 can suitably be converted to the corresponding compound wherein R12 is A0CO2H by reaction with an aqueous base such as sodium or potassium hydroxide at ambient or elevated temperature (e.g. 40 - 120°). This method is particularly suitable for preparing compounds of the formula (1) wherein R0 is methoxy since the OR11 group is not hydrolysed. Another hydrolysis method utilises aqueous acid such as concentrated
hydrochloric acid at an elevated temperature (e.g. 40 - 120°C) which provides directly compounds of the formula (1) wherein R0 is hydroxy and R1 is A0CO2H. Suitably a compound of the formula (6) wherein R13 is acetyl is converted to the corresponding compound where R13 is CH2CO2H by reaction with sulphur and morpholine
at elevated temperature (e.g. 50 - 200°C), followed by hydrolysis with an aqueous base such as sodium hydroxide at elevated temperature, preferably at the reflux temperature of the reaction mixture. Suitably a compound of formula (4) where R12 is -CH(OH)CN is reacted with a C1-3alkylating agent as hereinbefore describe followed by reaction with aqueous mineral acid such as hydrochloric acid at ambient or elevated temperature
preferably at reflux in order to prepare the corresponding compound where R12 is CH(OC1-3alkyl) CO2H. The alkylation can be omitted if the corresponding compound where R12 is CH(OH)CO2H is desired. During the hydrolysis of the CN group the OR11 group may be converted to hydroxy. If not and if desired this group can be converted to hydroxy as
hereinbefore described.
A compound of the formula (4) wherein R12 is -CH(OH)CN can be prepared by reacting the corresponding compound wherein R12 is -CHO with a source of cyanide such as potassium cyanide in the presence of an acid such as hydrochloric acid preferably at ambient temperature.
A compound of the formula (4) or (6) where R12 or R13 is CHO is suitably prepared by reacting the corresponding compound wherein R12 or R13 is cyano with a suitable reducing agent such as diisobutylaluminium hydride followed by aqueous acidic work-up.
Suitably a compound of the formula (6) wherein R13 is
P(O)(OR2)2 is hydrolysed by reaction with an aqueous base such as sodium hydroxide optionally in a cosolvent such as a Cι_4alcohol at an elevated temperature (e.g. 40-100°C), preferably at the reflux temperature of the reaction mixture. Suitably a compound of the formula (6) wherein R13 is
P(O) (NHR14) (OR2) is converted to the corresponding compound wherein R9 is P(S) (OH) (OR2) by reaction with a strong base such as sodium hydride in an organic solvent such as
dimethoxyethane at ambient or elevated temperature, (e.g. 40 - 100°C) followed by reaction with carbon disulphide.
Suitably the anion of a compound of the formula (2) prepared as hereinbefore described is reacted with sulphuryl chloride or a chemical equivalent thereof or with sulphur dioxide in an organic solvent such as tetrahydrofuran with cooling (- 100° - 0°C) to form after aqueous work-up a compound of the formula (4) wherein R12 is SO3H or SO2H respectively and OR11 is methoxy which if desired can be converted to the
corresponding compound wherein OR11 is hydroxy as
hereinbefore described.
A compound of the formula (4) wherein R12 is cyano or a compound of the formula (6) wherein R13 is cyano is suitably reacted with an azide salt such as ammonium, sodium or aluminium azide in an organic solvent such as
diethylformamide, dimethylsulphoxide, N-methylpyrrolidone or tetrahydrofuran at an elevated temperature e.g. 40-200°C, preferably at 100-150°C to form the corresponding
5-tetrazolyl compound. Preferably in a compound of the formula (4) OR1 1 is benzenesulphonyl which can be introduced in standard manner, for example by reacting the corresponding hydroxy compound with benzenesulphonyl chloride in the presence of a base such as triethylamine. This group can be removed in standard manner, for example by reaction with a base such as sodium hydroxide.
Suitably a compound of the formula (7) is reacted with a compound of the formula (8) in the presence of 1-50 mole %, preferably 2-10 mole %, of a palladium catalyst and a base such as triethylamine, sodium bicarbonate, or aqueous sodium carbonate and optionally lithium chloride in an organic solvent such as dimethylformamide, dimethoxyethane
acetonitrile, toluene, tetrahydrofuran, ethanol, or mixtures thereof, at elevated temperature, (e.g. 30-150°C), preferably at the reflux temperature of the mixture. Suitably L1 is halo for example iodo, bromo or chloro or a
trifluoromethanesulphonate. Subsequently the OR11 group can be converted to hydroxy as hereinbefore described for
compounds of formula (4). 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)propane]palladium 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)CI2), or
1,1 -bis(diphenylphosphine)ferrocinopalladium diacetate or dichloride (Pd[dppf](OAc)2 or Pd[dppf]Cl2).
By a chemical equivalent of a compound of the formula (8) is meant a reagent that can couple the Ar group onto the pyridyl ring of a compound of the formula (7). For example aryl stannanes can be used, such as ArSnMe3 which can suitably be prepared by reacting a suitable aryl halide (such as ArBr or ArI) with a base such as t-butyl lithium followed by reaction with a trimethyl tin halide (e.g. Me3SnCl). Alternatively the aryl halide can be reacted with Mβ3SnSnMe3 in the
presence of a palladium catalyst as hereinbefore described to prepare a suitable aryl stannane.
When Rb is a group R1 as hereinbefore defined reaction of a compound of the formula (7) with a compound of the formula (8) results directly in compounds of the formula (1).
An example of a precursor for R1 is when RD is hydrogen. In this situation reaction of a compound of the formula (7) with a compound of the formula (8) or a chemical equivalent thereof results in a compound of the formula (2) or a compound of the formula (6) wherein R13 is hydrogen. Such compounds can then be converted into a compound of the formula (1) as herein described.
Other precursors for R1 include CN, CHO or COMe. Reaction of a compound of the formula (7) wherein Rb represents such a precursor with a compound of the formula (8) or a chemical equivalent thereof results in a compound of the formula (4) or a compound of the formula (6) wherein R12 or R13 is CN,
CHO or COMe. Such compounds can be converted to compounds of the formula (1) as herein described.
If desired a compound of the formula (1) wherein R1 is A0CO2H can be converted to the corresponding compound wherein R1 is A0CO2R9 by reaction with a compound R9OH wherein R9 is as hereinbefore defined.
A compound of the formula (1) wherein R0 is OH can be
converted to the corresponding compound where R0 is OR8 by reaction with R8L2 wherein R8 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 (Z) (OR2) (OH) can be converted to the corresponding compound wherein R1 is P (Z) (OR2) (OR10) by reaction with a suitable O-protecting agent in standard manner. For example the compound can be reacted with a pivalolyloxymethyl halide. A compound of the formula (1) wherein R1 is 5-tetrazole can be reacted with a suitable N-protecting agent in standard manner, for example with a pivalolyloxymethyl halide.
A compound of the formula (1) wherein R1-R0 is A1CO2 is suitably prepared by heating a compound of the formula (1) wherein R1 is A1CO2H and R0 is OH with a dehydrating agent such as acetic anhydride, at an elevated temperature (e.g. 40 - 200°C), preferably at the reflux temperature of the
reaction mixture. A compound of the formula (1) wherein R1-R0 is A2OCH2O is suitably prepared by reacting a compound of the formula (1) wherein R1 is A2OH and R0 is OH with a dihalomethane such as diiodo- or dibromomethane in the presence of silver carbonate in an organic solvent such as dimethylformamide at an
elevated temperature (e.g. 40 - 120°C).
A compound of the formula (2) is suitably prepared by
reacting a compound of the formula (6) wherein R13 is
hydrogen with an O-methylating agent such as
dimethylformamide dimethylacetal in dimethylformamide or trimethylphosphite at an elevated temperature (e.g. 40 - 120°C) or with iodomethane and silver carbonate in toluene or chloroform. This method can also be used for converting compounds of the formula (6) into corresponding compounds of the formula (4) and compounds of formula (7) wherein Ra is hydroxy into corresponding compounds wherein Ra is OR11. A compound of the formula (6) wherein R13 is acetyl can also be prepared by reacting a compound of the formula (6) wherein R13 is cyano with methyl lithium followed by aqueous acidic work up with for example hydrochloric acid. A compound of the formula (6) wherein R13 is hydrogen can be prepared by reacting a compound of the formula (6) wherein R13 is cyano with orthophosphoric acid at an elevated
temperature, e.g. 50 - 200°C. A compound of formula (4) wherein R12 is cyano is suitably prepared by reacting the anion of a compound of formula (2) wherein Ar and R11 are as hereinbefore defined with
dimethylformamide with cooling (e.g. -80 to 10°C), followed by ambient temperature and aqueous work-up. The resulting compound of formula (4) wherein R12 is carboxaldehyde is treated with hydroxylamine hydrochloride and sodium acetate in a suitable solvent such as ethanol or methanol at elevated temperature, e.g. 40-100°C, preferably at the reflux
temperature of the reaction mixture followed by dehydrating the product obtained for example by heating with acetic anhydride.
A compound of the formula (6) wherein R13 is cyano or acetyl and Ar is as hereinbefore defined can be suitably prepared by reaction of a compound of formula (4) wherein R12 is cyano or acetyl and R11 and Ar are as hereinbefore defined with a demethylating agent 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 the formula (6) wherein R13 is P (O) (OR2)2 can be prepared by treating a compound of the formula (2) wherein R11 is P(O)(OR2)2 with a strong base such as lithium
diisopropylamide in an organic solvent such as
tetrahydrofuran with cooling (e.g. -100-0°C). A compound of the formula (2) wherein R11 is P (O) (OR2)2 is suitably prepared by treating a compound of the formula (6) wherein R13 is hydrogen with a compound of the formula (9) :
L3p(O) (OR2)2 (9) wherein L3 is a leaving group and R2 is as hereinbefore defined with a base such as diisopropylethylamine.
Suitably L3 is halo, for example chloro or bromo.
A compound of formula (2) wherein R11 is P (O) (OR2)2 can also be prepared by treating a compound of the formula (6) wherein R13 is hydrogen with a compound of the formula (10): HP (O) (OR2)2 (10) wherein R2 is as hereinbefore defined in the presence of an amine base such as triethylamine, and carbon tetrachloride. Alternatively, a compound of the formula (6) wherein R13 is P (O) (OR2) 2 is suitably prepared by treating a compound of the formula (6) wherein R13 is hydrogen with a compound of the formula (9) in the presence of a strong base such as lithium diisopropylamide in an organic solvent such as
tetrahydrofuran with cooling (e.g. -100-0°C) without
isolation of the intermediate compound of the formula (2) wherein R11 is P (O) (OR2)2. A compound of formula (6) wherein R13 is hydrogen is suitably prepared by demethylating a compound of formula (2) as hereinbefore defined. Suitably a compound of formula (2) is treated with boron tribromide in an organic solvent such as dichloromethane or toluene with cooling (e.g. -80 to 10°C) followed by ambient temperature and aqueous work-up. Or a compound of formula (2) is treated with sodium iodide and chlorotrimethylsilane at ambient or elevated temperature (e.g. 40-80°C) conveniently ambient temperature in a solvent such as acetonitrile or dichloromethane.
A compound of the formula (6) wherein R13 is P (O) (NHR14) (OR2) can be prepared by reaction of a compound of the formula (6) wherein R13 is P (O) (OH) (OR2) with carbon tetrachloride, triphenylphosphine and aniline or a 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 (6) where R13 is P (O) (OH) (OR2) can be reacted with dimethylformamide and oxalyl chloride in an organic solvent such as a halo hydrocarbon e.g. dichloromethane at ambient temperature, followed by reaction with aniline or a C1-4alkylamine preferably with cooling (-10 to 5°C).
Compounds of the formula (7) are known or can be prepared from a compound of the formula (11):
Figure imgf000024_0001
wherein Ra and L1 are as hereinbefore defined using similar methods to those described for preparing compounds of the formula (1).
Thus, a compound of the formula (7) wherein Rb is P (O) (OR2)2 can be prepared by reacting a compound of the formula (11) wherein Ra is OH with a compound of the formula (9) or (10) in similar manner to the reaction of a compound of the formula (6) wherein R13 is hydrogen with a compound of the formula (9) or (10). If desired the group Ra can then be converted to OMe.
Similarly, a compound of the formula (11) where Ra is OMe can be treated in the presence of a strong base with a compound of the formula (3), a compound of the formula (5) , sulphuryl chloride, sulphur dioxide or dimethylformamide to prepare a compound of the formula (7) wherein Rb is CR3(OR4)CO2R9, COCO2R9, SO3H, SO2H, or CHO respectively in similar manner to the corresponding reaction with a compound of the formula (2) as hereinbefore described. Particularly suitable as a strong base is lithium tetramethyl piperidide.
A compound of the formula (8) is suitably prepared by
reacting the organolithium or Grignard reagent, formed from a compound of the formula (12):
Ar-L4 (12) wherein L4 is bromo or iodo and Ar is as hereinbefore defined with a tri-C1-4alkylborate such as trimethyl, tri-isopropyl or tri-n-butyl borate in an organic solvent such as diethyl ether or tetrahydrofuran with cooling (e.g. - 80-10°C).
The Ar group in compounds of the formula (2), (4), (6) or (12) preferably (2) or (4) may be appropriately
functionalised by methods of aromatic substitution known in the art. For example, a bromo group may be introduced into a suitably substituted phenyl ring (eg. disubstituted in the 2- and 4-positions by electron-donating groups such as
C1-6alkoxy) by reaction with a brominating agent such as N-bromosuccinimide or bromine in a solvent such as
dimethylformamide. Alternatively a nitro group can be introduced into a phenyl ring by reaction with a suitable nitrating agent, such as nitronium tetrafluoroborate. Such a group can be readily hydrogenated to an amino group which if desired can be converted to a NHCOR7 group by reaction with LCOR7 wherein L is a leaving group and R7 is as hereinbefore defined. Suitable examples of the reagent LCOR include acid halides (L is halo eg. chloro or bromo) or acid anhydrides (L is OCOR7).
Other suitable functionalisations include the introduction of an allyl group ortho to a hydroxy substituent on a phenyl ring by reaction with an allyl halide, eg. bromide, to form an allyloxy derivative which on heating undergoes a Claisen rearrangement to form an ortho allyl hydroxy derivative. The hydroxy group can in turn be functionalised, eg. by reaction with a C1-6alkyl halide to form a C1-6alkoxy group. If desired, an allyl group can be converted to an E-1-propenyl group by reaction with a strong base, such as sodium
methoxide. An E-1-propenyl group can be cleaved to a formyl group by reaction with an oxidising agent such as
N-methylmorpholine-N-oxide in the presence of a catalyst such as osmium tetroxide to form a 1,2,dihydroxypropyl group which on reaction with an oxidising agent such as sodium periodate forms the formyl group. Alternatively the E-1-propenyl group can be converted directly to a formyl group by reaction with a mixture of osmium tetroxide and sodium periodate or by reaction with ozone. A formyl group can in turn be further functionalised, for example it can be converted to a
hydroxymethyl group by reaction with a suitable reducing agent such as sodium borohydride, the hydroxymethyl group then being reacted further, eg. with a C1-6alkyl halide to form a C1-6alkoxymethyl group. Alternatively a formyl group can be reacted with a suitable Horner Wittig or Wittig reagent such as (R15O)2P(O)CH2CO2R15 or Ph3P=CHCO2R15 wherein R15 is C1-4alkyl to form a CH=CHCO2R15 group which can be optionally hydrolysed to a -CH=CHCO2H group. A -CH=CHCO2R15 group can be converted to a -CH=CHCON(R7)2 group by reaction with an amine HN(R7)2 or a chemical equivalent thereof wherein R7 is as hereinbefore defined. Alternatively a
-CH=CHCO2H group can be converted to an acid halide, eg. the acid chloride by reaction with oxalyl chloride, which can then be reacted with an amine HN(R7)2 or a chemical
equivalent thereof. An example of a chemical equivalent is ammonium hydroxide which will form a CH=CHCONH2 group.
Pharmaceutically acceptable base addition salts of the compounds of the formula (1) may be prepared by standard methods, for example by reacting a solution of the compound of the formula (1) with a solution of the base.
The following biological test methods, data and Examples serve to illustrate this invention.
Cyclic-AMP Protein Kinase (cA-PrK) Agonist Activity
Type II cA-PrK was prepared from the cardiac muscle of a cow. The supernatant from a muscle homogenate (3 mis of 10 mM potassium phosphate, 1 mM EDTA per g tissue) was applied to a column of DEAE-cellulose equilibrated with the homogenisation buffer and the type II cA-PrK was eluted with homogenisation buffer containing 350 mM sodium chloride (Rannels et al., 1983, Methods Enzymol., 99, 55-62).
Type II cA-PrK was assayed for phosphotransferase activity by incubating the enzyme at 30°C for 5 minutes with
[γ-32P]-adenosine triphosphate and a suitable peptide substrate such as malantide (Malencik et al., 1983, Anal. Biochem., 132, 34-40). The reaction was terminated by the addition of hydrochloric acid and the [32P]-phosphopeptide quantified by spotting the reaction mixture onto
phosphocellulose papers. The concentration of compound required to give 10% phosphotransferase activation is given as the EC10 (μM). The compounds of Examples 1 and 2 had EC10 values of 2.6 and 1.0 μM respectively. Inhibition of Platelet Aggregation
Human platelet-rich-plasma was separated from freshly drawn blood (in acid/citrate/dextrose) and treated with 100 μM acetylsalicylic acid for 15 minutes at 37°C. A washed platelet suspension was then prepared in a Hepes-isotonic saline buffer after a single centrifugation step and adjusted to a concentration of 1.5×108 cells/ml. Aliquots of this suspension were pre-incubated with compounds for 5 minutes at 37°C, then challenged with 1.0 μM U46619. The extent of aggregation after 2 minutes were expressed as a percentage of control and results obtained are expressed as an IC50
(concentration to cause 50% inhibition of platelet
aggregation, μM). The compounds of Examples 1 and 2 had IC50 values of 20 and 38 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). Bronchodilatation - In vitro
Spiral strips of guinea-pig trachea were suspended in standard organ baths containing Krebs solution. The tissues were connected at the free end to isometric transducers which allow recording and display of developed tension on chart recorders. Tension was allowed to develop spontaneously and concentrations of test compounds added in a cumulative fashion. The concentration of compound which caused 50% inhibition of the spontaneously developed tension is given as the IC50 (μM).
Measurement of cardiac muscle relaxation time in rabbit ventricle
Papillary muscles from the right ventricle of female Albino New Zealand rabbits are mounted in standard organ baths containing oxygenated Krebs solution. One end of the muscle is connected to an isometric transducer which allowed
recording of contractile force and its first derivative on chart recorders. Test compounds are added to the bath in a cumulative manner. Relaxation time is calculated as the time taken from peak tension to the end of the contraction.
Compounds which cause a decrease in the relaxation time indicate a positive lusitropic effect of use in the treatment of cardiovascular diseases where there is a component of diastolic failure such as congestive heart failure, angina, hypertension and cardiomyopathy. Example 1
2-(5-Tetrazolyl)-5-(2,3-di-n-propoxyphenyl)phenol (a) From 1,2-di-n-propoxybenzene (13.8g), 2,3-di-n- propoxyphenylboronic acid (13g) was prepared according to the method of W. J. Thompson and J. Gaudino J. Org. Chem. 1984, 49, 5237. (b) To methyl 2,4-dihydroxybenzoate (5.95g) and 4-N,N- dimethylaminopyridine (8.65g) in dichloromethane at -50°C, trifluoromethanesulphonic anhydride (10.0g) was added over 5mins. The mixture was warmed to room temperature stirred for 1 hour, treated with 2N hydrochloric acid and the organic phase separated, dried (MgSO4) and solvent removed at
reduced pressure. The residue was column chromatographed (silica gel, diethyl ether/petroleum ether eluant) to give methyl 2-hydroxy-4-trifluoromethanesulphonyloxy benzoate (5.0g) 1H NMR (CDCl3) 3.99(s,3H), 7.25(d<1H), 7.44(dd,1H) and 8.23 (d,1H).
(c) From methyl 2-hydroxy-4-trifluoromethanesulphonyloxy benzoate (8.7g) and 2,3-di-n-propoxyphenylboronic acid (7.4g) and using the method of A. Huth, I. Beetz and I. Schumann, Tetrahedron, 1989, 45, 6679, methyl 2-hydroxy-4-(2,3-di-n-propoxyphenyl)benzoate (4.6g) was prepared. 1H NMR (CDCl3) 0.82(t,3H), 1.08(t,3H), 1.48-1.59 (m, 2H), 1.81-1.95 (m, 2H), 3.70(t,2H), 3.96(s,3H), 3.98(t,2H), 6.93(d,2H), 7.07-7.17(m,3H), 7.83(d,1H) and 10.76 (s, 1H).
(d) Methyl 2-hydroxy-4-(2,3-di-n-propoxyphenyl)benzoate (2.2g) in ethanol (15ml) and dioxane (30ml) was treated with sodium borohydride (lg) and stirred at room temperature for 48 hours. Solvent was removed at reduced pressure and the residue column chromatographed (silica gel, dichloromethane eluant) to give 2-hydroxy-4-(2,3-di-n-propoxyphenyl)benzyl alcohol (1.7g). The benzyl alcohol was oxidised according to the method of S. V. Ley et al J. C. S. Chem. Comm., 1987, 1625 to give 2-hydroxy-4-(2,3-di-n-propoxyphenyl)- benzaldehyde (0.78g). 1H NMR (CDCl3) 0.82(t,3H), 1.08(t,3H), 1.41-1.62 (m,2H), 1.84-1.95 (m,2H), 3.72 (t,2H), 3.99(t,2H), 6.91-6.96(m,2H), 7.09(t,1H), 7.18(s,1H), 7.26(dd,1H),
9.92(s,1H) and 11.06 (s,1H).
(e) A solution of 2-hydroxy-4-(2,3-di-n-propoxyphenyl)- benzaldehyde (0.78g) in ethanol (15ml) and saturated aqueous sodium acetate (8ml) containing hydroxylamine hydrochloride (0.23g) was stirred for 16 hours. Solvent was removed at reduced pressure acetic anhydride added and the mixture boiled for 4 hours. Solvent was removed at reduced pressure, the residue dissolved in diethyl ether (50ml) and washed with water (2 × 50ml). The organic layer was dried (MgSO4) and solvent removed at reduced pressure to give 2-hydroxy-4-(2,3- di-n-propoxyphenyl)benzonitrile (0.8g). IR (nujol mull)
2,230cm-1.
(f) A mixture of 2-hydroxy-4-(2,3-di-n-propoxyphenyl)- benzonitrile (0.8g), sodium azide (0.38g) and ammonium chloride (0.35g) in N-methylpyrrolidinone (20ml) was heated at 130°C for 3 hours. The reaction mixture was absorbed onto silica gel and column chromatographed (silica gel, diethyl ether then diethyl ether/methanol 85/15 eluant). Appropriate fractions were combined, solvent removed at reduced pressure and the residue triturated with water to give the title compound (0.26g) m.p. 187-189°C.
Example 2 Ethyl 2-hydroxy-4-(2,3-di-n-propoxyphenyl)phenyl phosphonate
(a) From 3-bromophenol (1.73g) and 2,3-di-n-propoxyphenylboronic acid (2.38g), 3-(2,3-di-n-propoxyphenyl)phenol m.p. 78-80°C after column chromatography (silica gel, diethyl ether/petroleum ether 1:9 eluant) was prepared according to the method of Example 1 (c).
(b) From 3-(2,3-di-n-propoxyphenyl)phenol (1.0g), diethyl 3-(2,3-di-n-propoxyphenyl) phenyl phosphate (1.2g) was prepared according to the method of G. W. Kenner and N. R. Williams J. Chem. Soc. 1955, 522.
(c) Diethyl 3-(2,3-di-n-propoxyphenyl)phenyl phosphate (1.2g) was rearranged to diethyl 2-hydroxy-4-(2,3-di-n- propoxyphenyl)phenyl phosphonate according to the method of L. S. Melvin Tet. Letters, 1981, 22, 3375 and subsequently hydrolysed to the title compound, isolated as an oil, by boiling with 5N aqueous sodium hydroxide (10ml). 1H NMR (DMSO-d6) 0.75(t,3H), 1.05(t,3H), 1.20(6H), 1.43-1.53 (m, 2H), 1.54-1.83(m,2H), 3.72(t,2H, 3.86-3.92 (m, 4H), 4.03(t,2H), 6.88-7.66(m,5H) and 7.46 (dd, 1H).
Example 3
Pharmaceutical compositions for oral administration are prepared by combining the following :
% w/w
2-(5-tetrazolyl)-5- (2,3-dipropoxyphenyl)phenol 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 4 A pharmaceutical composition for parenteral administration is prepared by dissolving ethyl 2-hydroxy-4-(2,3-dipropoxyphenyl)phenyl phosphonate (0.02 g) in polyethylene glycol 300 (25 ml) with heating. This solution is then diluted with water for injections Ph. Eur. (to 100 ml). The solution is then sterilised by filtration through a 0.22 micron membrane filter and sealed in sterile containers.

Claims

Claims
1. A compound of the formula (1)
Figure imgf000033_0001
or a pharmaceutically acceptable salt thereof, wherein :
R0 is OH or a bioprecursor thereof,
R1 is A0CO2H, P(Z) (OH) (OR2), SO2H, SO3H or 5-tetrazolyl or a bioprecursor thereof,
A0 is CH2, CHF, CF2, CR3(OR4), CO or C(OR5) (OR6),
R2 is phenyl, 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.
Z is O or S, and Ar is phenyl optionally substituted by one to three groups independently selected from C1-6alkyl, C2-6alkenyl, C1-6alkoxy, C3-6alkenyloxy, C3-6cycloalkyl,
C3-6cycloalkoxy, C1-6alkylthio, phenyl, phenylthio, benzyloxy, C1-6polyfluoroalkyl, C1-6polyfluoroalkoxy, halo, N(R7)2 or NHCOR7 wherein R7 is H or C1-6alkyl, or -X(CH2)nY- attached to adjacent carbon atoms of the phenyl ring wherein X and Y are independently CH2 or 0 and n is 1 to 3, wherein said C1-6alkyl, C2-6alkenyl or C1-6alkoxy groups can be independently substituted by OH, C1-6alkoxy, C3-6cycloalkyl, N(R7)2, CO2R7 or CON(R7)2.
2. A compound according to claim 1 wherein R1 is AOCO2H or A0CO2R9 in which R9 is an ester-forming group.
3. A compound according to claim 1 wherein R1 is P(Z) (OH) (OR2) or P(Z) (OR2)2.
4. A compound according to claim 1 wherein R1 is SO2H, SO3H or 5-tetrazolyl.
5. A compound according to claim 1 wherein R1 and R0 are linked together such that R1-R0 is A1CO2
in which A1 is CH2, CHF, CF2, CR3(OR4), CO or C(OR5) (OR6).
6. A compound according to claim 1 wherein R1 and R0 are linked together such that R1-R0 is A2OCH2O in which A2 is P (Z) (OR2) or CR3(CO2R9) and R9 is an ester-forming group.
7. A compound according to claim 1 which is :
2-(5-tetrazolyl)-5-(2,3-dipropoxyphenyl)phenol, or ethyl 2-hydroxy-4-(2,3-dipropoxyphenyl)phenyl phosphonate, or a pharmaceutically acceptable salt thereof.
8. A compound according to any one of claims 1 to 7 for use as a medicament.
9. A pharmaceutical composition which comprises a compound according to any one of claims 1 to 7 and a
pharmaceutically acceptable carrier.
10. A process for preparing a compound of the formula (1) as defined in claim 1 or a pharmaceutically acceptable salt thereof which process comprises : a) for compounds wherein R1 is A0CO2H or A0CO2R9 and : i) A0 is CR3(OR4),
reacting in the presence of a strong base a compound of the formula (2) :
Figure imgf000035_0001
wherein R11 is methyl and Ar is as defined in claim 1, with a compound of the formula (3) :
R3COCO2R9 (3) wherein R3 is as defined in claim 1 and R9 is an esterforming group to form a compound of the formula (4) :
Figure imgf000035_0002
wherein R12 is CR3(OH)CO2R9 and R3, R9, R11, and Ar are as hereinbefore defined and thereafter optionally reacting with a C1-3alkylating agent to form the corresponding compound wherein R12 is CR3 (OC1-3alkyl)CO2R9, ii) A0 is CO,
reacting in the presence of a strong base a compound of the formula (2) as hereinbefore defined with a compound of the formula (5) :
R9O2CCO2R9 (5) wherein R9 is as hereinbefore defined to form a compound of the formula (4) wherein R12 is COCO2R9 and R9, R11 and Ar are as hereinbefore defined, iii) A0 is CH(OH),
reacting a compound of the formula (4) wherein R12 is COCO2R9 and R9, R11, and Ar are as hereinbefore defined with a reducing agent to form the corresponding compound wherein R12 is CH(OH)CO2R9, iv) A0 is CH2,
reacting a compound. of the formula (4) wherein R12 is COCO2H or COCO2R9 and R9, R11, and Ar are as hereinbefore defined with a suitable reducing agent to form the corresponding compound wherein R12 is CH2CO2H, v) A0 is C(OR5) (OR6),
reacting a compound of the formula (4) wherein R^2 is COCO2R9 and R9, R11, and Ar are as hereinbefore defined with a
Cl-3alcohol, 1,2-ethanediol or 1,3-propanediol to form the corresponding compound wherein R12 is C(OR5) (OR6)CO2R9, vi) A0 is CF2,
reacting a compound of the formula (4) wherein R12 is COCO2R9 and R9, R11, and Ar are as hereinbefore defined with a
fluorinating agent to form the corresponding compound wherein R11 is CF2CO2R9, or vii) A0 is CHF, reacting a compound of the formula (4) wherein R12 is
CH(OH)CO2R9 and R9, R11, and Ar are as hereinbefore defined with a fluorinating agent to form the corresponding compound wherein R12 is CHFCO2R9, and thereafter optionally :
° converting the group OR11 into OH ° converting the group A0CO2R9 into A0CO2H; or b) for compounds wherein R1 is CH2CO2H,
converting a compound of the formula (6) :
Figure imgf000037_0001
wherein R13 is acetyl and Ar is as hereinbefore defined into the corresponding compound wherein R13 is CH2CO2H; or c) for compounds wherein R1 is CH(OR4)CO2H reacting a compound of the formula (4) wherein R12 is -CH(OH)CN with a C1-3alkylating agent and/or converting the group CN into CO2H, and optionally converting the group OR11 into OH; or d) for compounds wherein R1 is P (O) (OH) (OR2), hydrolysing a compound of the formula (6) wherein R13 is P (O) (OR2)2, R2 is as defined in claim 1 and Ar is as hereinbefore defined; or e) for compounds wherein R1 is P(S) (OH) (OR2), converting a compound of the formula (6) wherein R13 is P (O) (NHR14) (OR2) and R14 is phenyl or C1-4alkyl and Ar is as hereinbefore defined into the corresponding compound wherein R13 is
P(S) (OH) (OR2); or f) for compounds where R1 is SO3H,
reacting in the presence of a strong base a compound of the formula (2) as hereinbefore defined with sulphuryl chloride or a chemical equivalent thereof and optionally converting the group OR11 into OH; or g) for compounds wherein R1 is SO2H,
reacting in the presence of a strong base a compound of the formula (2) as hereinbefore defined with sulphur dioxide and optionally converting the group OR11 into OH; or h) for compounds wherein R1 is 5-tetrazolyl, reacting a compound of the formula (4) wherein R12 is cyano and R11 is as hereinbefore defined or benzenesulphonyl, or a compound of the formula (6) wherein R12 is cyano with an azide salt and thereafter if necessary converting the group OR11 into OH; or i) for compounds wherein R1 is as defined for compounds of the formula (1) reacting in the presence of a palladium catalyst a compound of the formula (7):
Figure imgf000038_0001
wherein Rb is a group R1 as defined in claim 1 or a precursor thereof and Ra is R0 or OR11 as hereinbefore defined and L1 is a leaving group with a compound of the formula (8) :
ArB(OH)2 (8) or a chemical equivalent thereof wherein Ar is as
hereinbefore defined and then, if necessary, converting a precursor of R1 into R^ and/or converting the group OR11 into OH, and optionally thereafter :
° forming a bioprecursor of R0 and/or R1 ° forming a pharmaceutically acceptable salt.
PCT/GB1992/002119 1991-11-20 1992-11-16 Phenol derivatives as agonists of a cyclic amp dependent protein kinase WO1993010107A1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
JP5509095A JPH07503235A (en) 1991-11-20 1992-11-16 Phenol derivatives as cyclic AMP-dependent protein kinase agonists
EP92923480A EP0620815A1 (en) 1991-11-20 1992-11-16 Phenol derivatives as agonists of a cyclic amp dependent protein kinase

Applications Claiming Priority (2)

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GB9124579.5 1991-11-20
GB919124579A GB9124579D0 (en) 1991-11-20 1991-11-20 Chemical compounds

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GB (1) GB9124579D0 (en)
MX (1) MX9206709A (en)
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TW (1) TW221812B (en)
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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1230958A (en) * 1967-10-06 1971-05-05
WO1991017987A1 (en) * 1990-05-21 1991-11-28 Smith Kline & French Laboratories Limited Phenol and pyridinol derivatives as pharmaceuticals

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1230958A (en) * 1967-10-06 1971-05-05
WO1991017987A1 (en) * 1990-05-21 1991-11-28 Smith Kline & French Laboratories Limited Phenol and pyridinol derivatives as pharmaceuticals

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ZA928894B (en) 1994-05-18
JPH07503235A (en) 1995-04-06
AU2927492A (en) 1993-06-15
TW221812B (en) 1994-03-21
EP0620815A1 (en) 1994-10-26
PT101073A (en) 1994-02-28
MX9206709A (en) 1993-05-01
GB9124579D0 (en) 1992-01-08
CA2124003A1 (en) 1993-05-27

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