EP0532531A1 - Derives de phenol et de pyridinol comme agents pharmaceutiques - Google Patents

Derives de phenol et de pyridinol comme agents pharmaceutiques

Info

Publication number
EP0532531A1
EP0532531A1 EP91909509A EP91909509A EP0532531A1 EP 0532531 A1 EP0532531 A1 EP 0532531A1 EP 91909509 A EP91909509 A EP 91909509A EP 91909509 A EP91909509 A EP 91909509A EP 0532531 A1 EP0532531 A1 EP 0532531A1
Authority
EP
European Patent Office
Prior art keywords
naphthyl
pyridyl
oxo
dihydro
compound
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP91909509A
Other languages
German (de)
English (en)
Inventor
Kenneth John Smithkline Beecham Pharma. Murray
Roderick Alan Smithkline Beecham Pharma. Porter
Hunter Douglas Smithkline Beecham Pharma. Prain
Brian Herbert Smithkline Beecham Warrington
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Smith Kline and French Laboratories Ltd
Original Assignee
Smith Kline and French Laboratories Ltd
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 and French Laboratories Ltd filed Critical Smith Kline and French Laboratories Ltd
Publication of EP0532531A1 publication Critical patent/EP0532531A1/fr
Withdrawn legal-status Critical Current

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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
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    • 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
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    • 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
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    • 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
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    • 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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    • C07D213/02—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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    • 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
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    • 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
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    • 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
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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
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    • 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)
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • 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 Table
    • 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

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Abstract

Des dérivés de phénol/pyridinol d'aryle fusionné utilisés comme médicaments, sont décrits.
EP91909509A 1990-05-21 1991-05-20 Derives de phenol et de pyridinol comme agents pharmaceutiques Withdrawn EP0532531A1 (fr)

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GB9121651D0 (en) * 1991-10-11 1991-11-27 Smithkline Beecham Plc Chemical compounds
GB9124577D0 (en) * 1991-11-20 1992-01-08 Smithkline Beecham Plc Chemical compounds
GB9124578D0 (en) * 1991-11-20 1992-01-08 Smithkline Beecham Plc Chemical compounds
GB9124579D0 (en) * 1991-11-20 1992-01-08 Smithkline Beecham Plc Chemical compounds
FR2689012A1 (fr) * 1992-03-27 1993-10-01 Beecham Laboratoires Utilisation de composés aryliques dans le traitement d'affections cardio-vasculaires.
DE60238276D1 (de) * 2001-12-13 2010-12-23 Vital Health Sciences Pty Ltd Transdermaler transport von verbindungen
AU2002950713A0 (en) 2002-08-09 2002-09-12 Vital Health Sciences Pty Ltd Carrier
EP1853261B1 (fr) 2005-03-03 2017-01-11 Universität des Saarlandes Inhibiteurs selectifs de synthases de corticoides humaines
JP5221343B2 (ja) 2005-06-17 2013-06-26 バイタル ヘルス サイエンシズ プロプライアタリー リミティド 担体
AU2011213557B2 (en) 2010-02-05 2015-05-07 Phosphagenics Limited Carrier comprising non-neutralised tocopheryl phosphate
RU2553350C2 (ru) 2010-03-30 2015-06-10 Фосфейдженикс Лимитед Трансдермальные пластыри
EP2685992A4 (fr) 2011-03-15 2014-09-10 Phosphagenics Ltd Amino-quinoléines en tant qu'inhibiteurs de kinase
JP2014525453A (ja) * 2011-08-29 2014-09-29 ピーティーシー セラピューティクス， インコーポレイテッド 抗菌化合物および使用方法
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WO2015148314A1 (fr) * 2014-03-25 2015-10-01 3M Innovative Properties Company Adhésif ignifuge sensible à la pression, et composition durcissable
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CN108601732A (zh) 2015-12-09 2018-09-28 磷肌酸有限公司 药物制剂
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