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WO1995028400A1 - Nouveaux noyaux heterocycliques a 5 chainons benzocondenses destines au traitement de la migraine - Google Patents

Nouveaux noyaux heterocycliques a 5 chainons benzocondenses destines au traitement de la migraine Download PDF

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Publication number
WO1995028400A1
WO1995028400A1 PCT/EP1995/001315 EP9501315W WO9528400A1 WO 1995028400 A1 WO1995028400 A1 WO 1995028400A1 EP 9501315 W EP9501315 W EP 9501315W WO 9528400 A1 WO9528400 A1 WO 9528400A1
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formula
compound
solution
alkyl
ethanol
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PCT/EP1995/001315
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English (en)
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Peter Charles North
Sjoerd Nicolaas Wadman
Mark Ladlow
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Glaxo Group Limited
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Priority to AU23439/95A priority Critical patent/AU2343995A/en
Publication of WO1995028400A1 publication Critical patent/WO1995028400A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • 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
    • C07D213/24—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 substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/10—1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles
    • C07D271/107—1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles with two aryl or substituted aryl radicals attached in positions 2 and 5
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • This invention relates to benzofuran derivatives, to processes for their preparation, to pharmaceutical compositions containing them and to their medical use, in particular to compounds and compositions of use in the treatment of migraine.
  • the invention provides compounds of formula (l a )
  • B is N or CR b ;
  • C is a bond or a C ⁇ alkylene chain
  • D is a group NR c R d wherein R c and R d , which may be the same or different, are hydrogen, C ⁇ alkyl, C ⁇ alkenyl, C ⁇ alkynyl, C 3 _ 7 cycloalkyl, aryl or aralkyl (wherein the alkyl or aryl group is optionally substituted by one or more halogen, alkyl or aryl); or together form a C 3 ⁇ alkylene group or an aralkylidine group (preferably an arylmethylidene e.g. benzylidene); or together with the nitrogen atom to which they are attached form a saturated monocyclic 4 to 7 membered ring; or D is a group of formula
  • R e is hydrogen, C ⁇ alkyl, C ⁇ alkenyl, C ⁇ alkynyl, phenyl or phen(C 1 ⁇ )alkyl;
  • E is an optionally substituted 5 or 6 membered heterocyclic ring, optionally linked to the aromatic ring by a C- ⁇ alkylene chain;
  • R a and R b which may be the same or different, are hydrogen or C ⁇ alkyl; and pharmaceutically acceptable salts and solvates (e.g. hydrates) thereof.
  • the group E is a 5-membered aromatic heterocyclic ring containing at least one oxygen, sulphur or nitrogen atom.
  • Suitable groups include, for example, furan, thiophen, oxazole, thiazole, isoxazole, isothiazole, oxadiazole, thiadiazole, pyrrole, imidazole, triazole and tetrazole rings, in particular furan (e.g. furan-2-yl), thiazole (e.g. thiazol-4-yl or thiazol-2-yl), oxadiazole (e.g.
  • the group E is a 5-membered saturated heterocyclic ring containing at least one oxygen, sulphur or nitrogen atom.
  • Suitable groups include, for example an imidazolidine (e.g. 2,5- dioxoimidazolidin-4-ylrnethyl) or an oxazolidine (e.g. 2-oxo-1,3-oxazolidin-4- ylmethyl) ring.
  • the group E is a 6-membered aromatic ring containing at least one nitrogen atom, in particular a pyridyl (e.g. pyridin-2- yl, pyridin-3-yl or pyridin-4-yl) ring.
  • a pyridyl e.g. pyridin-2- yl, pyridin-3-yl or pyridin-4-yl
  • A is O
  • B is CH
  • E is an optionally substituted pyridyl ring, in particular a pyridin-3-yl ring.
  • the invention provides compounds of formula (I)
  • R 1 is hydrogen, Chalk !, -AlkOR 3 or -(Alk) n R 4 where Alk is an unsubstituted or substituted C-
  • R 3 is hydrogen or C-
  • R 5 , R 6 , R 10 and R 1 1 which may be the same or different, are hydrogen or C- ⁇ _6alkyl;
  • R 7 and R 8 which may be the same or different, are hydrogen, C*
  • Z is a group of formula -CR 12 R 13 -, -0-, -NR 14 -, -CO- or -S(0)p-;
  • R 9 is hydrogen, (e.g. trifluoromethyl), C-
  • R12 and R 13 which may be the same or different, are hydrogen, hydroxy or
  • R 14 is -S0 2 R 15 , -COR 5 or -COOR 15 ;
  • R 15 is C-
  • an alkyl group may be a straight chain alkyl group, for example a methyl or ethyl group, or a branched chain alkyl group, for example an isopropyl group.
  • alkyl groups are C-]_3alkyl groups, especially methyl.
  • Alk is a C-]_3 alkylene or C2-3alkenylene chain, for example methylene, ethylene or ethenylene, which may be unsubstituted or substituted by one or two C ⁇
  • Preferred compounds of formula (I) are those in which R 1 is -(Alk) n R 4 , in particular -CH2R 4 or -CH 2 CH 2 R 4
  • R 4 is -CONR 7 R 8 , -NR 3 COR 9 -NR 3 COOR 9 -NR 3 SO 2 R 9 or -NR 3 SO 2 NR 7 R 8 .
  • a further preferred class of compounds of formula (I) includes compounds wherein R 2 is -CH 2 CH 2 NR 1 ⁇ R 1 1 .
  • R 10 and R 1 1 are both methyl.
  • R 1 is attached at 5- position of the pyridinyl ring.
  • Typical values of R 1 include
  • R 7 and R 8 which may be the same or different, are C ⁇ _3alkyl or, together with the N-atom to which they are attached, form a saturated 4- to 7- membered ring of formula
  • Z is a group of formula -CR 12 R 13 -, -O-, -NR 14 -;
  • R 10 and R 1 which may be the same or different, are hydrogen or C- ⁇ _3alkyl;
  • R 12 and R 13 which may be the same or different, are hydrogen, hydroxy or C* ⁇ _3alkoxy;
  • R 1 is -SO2R 15 , -COR 15 or -COOR 15 ;
  • R 15 is C ⁇ _3alkyl; and pharmaceutically acceptable salts and solvates thereof.
  • Pharmaceutically acceptable salts of the compounds of formula (I) include those derived from pharmaceutically acceptable inorganic and organic acids.
  • suitable acids include hydrochloric, hydrobromic, sulphuric, nitric, perchloric, fumaric, maleic, phosphoric, glycollic, lactic, salicylic, succinic, toluene-p-sulphonic, tartaric, acetic, citric, methanesulphonic, formic, benzoic, malonic, naphthalene-2-sulphonic and benzenesulphonic acids.
  • Other acids such as oxalic, while not in themselves pharmaceutically acceptable, may be useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable acid addition salts.
  • references hereinafter to a compound according to the invention include both the compounds of formula (I) and their pharmaceutically acceptable salts.
  • Compounds of the invention may be isolated in association with solvent molecules by crystallisation from or evaporation of an appropriate solvent. Such solvates are included within the scope of the present invention.
  • the compounds of formula (I) are selective agonists at 5HT-
  • the compounds of the invention are indicated in the treatment of conditions susceptible to amelioration by agonist activity at 5HT-
  • compounds of the invention are useful in treating certain conditions associated with cephalic pain.
  • the compounds are useful in the treatment of migraine, cluster headache, chronic paroxysmal hemicrania, headache associated with vascular disorders, tension-type headache, headache associated with substances or their withdrawal (e.g. drug withdrawal) and headache associated with meningeal irritation, and in alleviating the symptoms associated therewith.
  • a compound of the invention or a salt thereof for use in therapy, in particular in human medicine. It will be appreciated that use in therapy embraces but is not necessarily limited to use of a compound of the invention or a salt thereof as an active therapeutic substance.
  • a compound of the invention in the preparation of a medicament for use in the treatment of conditions associated with cephalic pain in particular migraine, cluster headache, chronic paroxysmal hemicrania and headache associated with vascular disorders, tension-type headache, headache associated with substances or their withdrawal (e.g. drug withdrawal) and headache associated with meningeal irritation.
  • a method for the treatment of a mammal comprising administration of an effective amount of a compound of the invention or in particular in the treatment of conditions associated with cephalic pain and in alleviating the symptoms associated therewith.
  • a compound of the invention may be administered as the raw chemical it is preferable to present the active ingredient as a pharmaceutical formulation.
  • the invention thus further provides a pharmaceutical formulation comprising a compound of the invention together with one or more pharmaceutically acceptable carriers therefor and, optionally, other therapeutic and/or prophylactic ingredients.
  • the carrier(s) must be 'acceptable' in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • compositions include those suitable for oral, rectal, nasal, buccal, sub-lingual or parenteral (including intramuscular, subcutaneous and intravenous) administration or in a form suitable for administration by inhalation or insufflation.
  • the formulations may, where appropriate, be conveniently presented in discrete dosage units and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing into association the active compound with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.
  • the pharmaceutical compositions may take the form of, for example, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g. lactose, microcrystalline cellulose or calcium phosphate); lubricants (e.g. magnesium stearate, talc or silica); disintegrants (e.g. potato starch or sodium starch glycollate); or wetting agents (e.g. sodium lauryl sulphate).
  • binding agents e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose
  • fillers e.g. lactose, microcrystalline cellulose or calcium phosphate
  • lubricants e.g. magnesium stearate, talc or silica
  • disintegrants e.g. potato starch or sodium starch glycollate
  • Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use.
  • Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g. sorbitol syrup, methyl cellulose or hydrogenated edible fats); emulsifying agents (e.g. lecithin or acacia); non-aqueous vehicles (e.g. almond oil, oily esters or ethyl alcohol); and preservatives (e.g. methyl or propyl- ⁇ -hydroxybenzoates or sorbic acid).
  • suspending agents e.g. sorbitol syrup, methyl cellulose or hydrogenated edible fats
  • emulsifying agents e.g. lecithin or acacia
  • non-aqueous vehicles e.g. almond oil, oily esters or ethyl alcohol
  • preservatives e.g
  • compositions may take the form of tablets or lozenges formulated in conventional manner.
  • the compounds of the invention may be formulated for parenteral administration by injection, conveniently intravenous, intramuscular or subcutaneous injection, for example by bolus injection or continuous intravenous infusion.
  • Formulations for injection may be presented in unit dosage form e.g. in ampoules or in multi-dose containers, with an added preservative.
  • compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising and/or dispersing agents.
  • the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use.
  • the compounds of the invention may also be formulated in rectal compositions such as suppositories or retention enemas, e.g. containing conventional suppository bases such as cocoa butter or other glyceride.
  • Tablets for sub-lingual administration may be formulated in a similar manner.
  • the compounds of the invention may be used, for example, as a liquid spray, as a powder or in the form of drops.
  • the compounds according to the invention are conveniently delivered in the form of an aerosol spray presentation from pressurised packs or a nebuliser, with the use of a suitable propellant, e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • Capsules and cartridges of e.g. gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of a compound of the invention and a suitable powder base such as lactose or starch.
  • the active ingredient may conveniently be presented in unit dose form.
  • a convenient unit dose formulation contains the active ingredient in an amount of from about 0.1 mg to about 200mg.
  • the compound may be administered in single or divided doses and may be administered one or more times, for example 1 to 4 times per day.
  • a proposed dose of the compounds of the invention for oral, sub-lingual parenteral, buccal, rectal or intranasal administration to man (of approximately 70kg bodyweight) for the treatment of migraine is 0.1 to 200mg of the active ingredient per unit dose which could be administered, for example, 1 to 4 times per day.
  • a unit dose will preferably contain from 2 to 200mg of the active ingredient.
  • a unit dose for parenteral administration will preferably contain 0.2 to 5 mg of the active ingredient.
  • Aerosol formulations are preferably arranged so that each metered dose or 'puff delivered from a pressurised aerosol contains 0.2 mg to 2 mg of a compound of the invention, and capsules and cartridges delivered from an insufflator or an inhaler, contain 0.2 mg to 20 mg of a compound of the invention.
  • the overall daily dose by inhalation with an aerosol will be within the range 1 mg to 100 mg. Administration may be several times daily, for example from 2 to 8 times, giving for example 1 , 2 or 3 doses each time. Dosages of the compounds of the invention for rectal, sub-lingual or intranasal administration are similar to those for oral administration.
  • the compounds of the invention may, if desired, be administered in combination with one or more other therapeutic agents, such as analgesics, anti- inflammatory agents and anti-nauseants.
  • compositions comprising a compound of formula (I) together with at least one other therapeutic agent, in particular an analgesic, anti-nauseant or anti-inflammatory agent, and a pharmaceutically acceptable carrier therefore comprise a further aspect of the invention.
  • the compounds When compounds of formula (1) are used in combination with other therapeutic agents, the compounds may be administered either sequentially or simultaneously by any convenient route.
  • each component of the combination will in general be that employed for each component when used alone.
  • compounds of formula (l a ) and pharmaceutically acceptable salts and solvates (e.g. hydrates) thereof may be prepared by methods known in the art for the preparation of analogous compounds.
  • compounds of formula (l a ) wherein E is a 5-membered heterocyclic ring may be prepared by methods known or analogous to those known in the art, for example as described in EP-438230, EP-497512, EP-494774, EP-501568, EP-313397 and W091/18897.
  • compounds of formula (l a ) may be prepared by methods analogous to the preparation of compounds of formula (I) as outlined below. Such processes form a further aspect of the invention.
  • R , R 2 , R 3 , R 4 , R 5 R 6 , R 7 R 8 , R 9 , R 1 0,R 1 , R 2,R1 3 R1 4 R15_ Alk, X, n, m and p are as defined for formula (I) unless otherwise specified.
  • compounds of formula (I) may be prepared by coupling compounds of formula (II)
  • R 16 and R 17 represents a halogen atom, preferably bromine, and the other is a group of formula -B(OH)2 or -Sn (lower alkyl)3, preferably -Sn(CH 3 ) 3 .
  • the reaction is effected in the presence of palladium(O) or an appropriate palladium metal complex, e.g. tetrakis(triphenylphosphine)palladium(0) and, when one of R 16 and R 17 represents -B(OH)2, a base such as an alkali metal carbonate, eg sodium carbonate.
  • a suitable solvent such as water, 1 ,2-dimethoxyethane, N,N-dimethylformamide, tetrahydrofuran, dioxan, xylene, toluene or mixtures thereof.at a temperature of 0 to 160°C, preferably at about 85°C. Where they are not commercially available compounds of formula (II) and (III) may be prepared by methods known from the art.
  • compounds of formula (II) or formula (III) wherein R 16 and R 17 are -B(OH)2 may be prepared from the corresponding compounds wherein R 16 and R 1 represent a halogen atom, preferably bromine, by treatment with a lithiating agent followed by treatment of the lithio derivative with a trialkyl borate ester.
  • Suitable reagents for lithiation include alkali metal alkyls, e.g n-, sec-, or tert-butyl lithium.
  • the lithiation reaction is conveniently carried out in an inert solvent, such as an ether, eg diethyl ether, tetrahydrofuran or dioxan, or a hydrocarbon, eg cyclohexane, benzene or toluene, at a temperature of -100 to 5 ⁇ OC, preferably at about -78 ⁇ C.
  • Suitable trialkyl borate esters include tri- methyl and tri- isopropylborate.
  • Treatment of the lithio derivative with a trialkyl borate ester is conveniently carried out in an inert solvent such as an ether or a hydrocarbon as described above, at a temperature of -78 to 100°C, preferably at about 23°C.
  • Sn(lower alkyl)3 may be prepared from the corresponding compounds wherein R 16 and R 17 represent a halogen atom, preferably a bromine, by treatment with a hexaalkyldistannane, e.g. hexamethyldistannane, in the presence of a palladium metal complex, e.g. palladium tetrakis(triphenylphosphine).
  • the reaction is conveniently carried out in an inert solvent, e.g. toluene or xylene, at a temperature of 0 - 160°C, preferably at about 150°C.
  • Y represents a nitrile group or the group CONR 10 R 1 1 or CH2CONR 10 R 1 1
  • a suitable reducing agent such as a metal hydride, eg lithium aluminium hydride or diisobutylaluminium hydride, or hydrogen in the presence of a catalyst, in a suitable solvent.
  • a metal hydride eg lithium aluminium hydride or diisobutylaluminium hydride
  • the reduction process may conveniently be carried out in the presence of hydrogen and a metal catalyst, for example, Raney nickel or a nobel metal catalyst such as palladium, platinum, platinum oxide or rhodium, which may be supported, for example, on charcoal.
  • a metal catalyst for example, Raney nickel or a nobel metal catalyst such as palladium, platinum, platinum oxide or rhodium, which may be supported, for example, on charcoal.
  • the reduction may be carried out in a solvent such as an alcohol, e.g. methanol or ethanol, an ether, e.g. dioxan, an ester, e.g. ethyl acetate, or an amide, e.g. dimethylformamide, and conveniently at a temperature of from -10 to +50°C, preferably 20 to 30°C.
  • Suitable solvents for reduction using a metal hydride reducing agent include toluene, tetrahydrofuran, diethyl ether or dioxan, at
  • an amide coupling reagent such as diphenylphosphorylazide and a base such as triethylamine.
  • a suitable solvent such as N,N- dimethylformamide at a temperature of -78 to 100°C, for example at about 20°C.
  • R 14 is -SO2R 15 or -COOR 15 and R 17 is a halogen atom may be prepared by sulphonylation or acylation of the corresponding compound of formula (VII)
  • a suitable sulphonylating or acylating agent such as an acid halide, for example a sulphonyl chloride or a carboxylic acid chloride.
  • the reaction is conveniently effected in a suitable solvent such as dichloromethane, in the presence of a suitable base such as triethylamine and at a temperature of -78 to 100°C, preferably at about 0°C.
  • Ph3P CHY in a suitable inert solvent such as xylene at a temperature of 0 to 130°C, preferably at 130°C, or a phosphonate of formula (R 18 0)2POCH2Y (wherein R 18 is an alkyl group, e.g an ethyl group) in the presence of a suitable base in a compatible solvent.
  • a suitable inert solvent such as xylene at a temperature of 0 to 130°C, preferably at 130°C, or a phosphonate of formula (R 18 0)2POCH2Y (wherein R 18 is an alkyl group, e.g an ethyl group) in the presence of a suitable base in a compatible solvent.
  • Suitable combinations include:alkali metal hydrides, eg sodium hydride or potassium hydride, in an ether, eg diethyl ether, tetrahydrofuran or dioxan, or an amide, eg, dimethylformamide; alkali metal alkoxides, eg sodium ethoxide, sodium methoxide or potassium tert-butoxide, in an alcohol, eg ethanol, methanol or tert-butanol; or alkyllithium, eg butyllithium, in an ether. Conveniently the reaction is carried out at a temperature of -78 to 50°, preferably at 0 to 23°C.
  • compounds of formula (I) wherein R 1 is -(Alk) n R 4 in which R 4 is NR 3 COR 9 or NR 3 S0 2 R 9 and R 3 and R 9 together form a linking C3_5alk lene chain may be prepared by cyclising the compound of formula (IX)
  • R 9 is -(Alk) n NHCO(CH 2 ) q Z or -(Alk) n NHSO 2 (CH2) q Z in which q is 3, 4 or 5 and Z is a suitable leaving group such as a halogen atom, preferably chlorine.
  • Cyclisation may conveniently be effected in an organic solvent such as dimethylformamide in the presence of a base such as an alkali metal hydride e.g. sodium hydride.
  • the cyclisation reaction is conveniently carried out at a temperature in the range of 0 to 100°C, preferably 5 to 50°C.
  • Compounds of formula (IX) may be prepared from compounds of formula (I) wherein R 1 is -(Alk) n NH2 by acylation or sulphonylation.
  • Suitable acylating or sulphonylating agents include acid halides such as carboxylic acid chlorides and sulphonyl chlorides.
  • the reaction is conveniently effected in a solvent such as dichloromethane, preferably in the presence of a base such as pyridine or triethylamine, at a temperature in the range of 10 to 100°C, preferably 20 to 30 n C.
  • a compound of formula (I) according to the invention may be converted into another compound of the invention using conventional procedures.
  • a compound of formula (I) wherein one or more of R 3 , R 5 , R6, R 7 , R 8 , R 9 , R 1 0 and R 1 1 represent a hydrogen atom may be alkylated using conventional techniques.
  • the reaction may be effected using a suitable alkylating agent such as an alkyl halide, an alkyl tosylate or a dialkylsulphate.
  • the alkylation reaction may conveniently be carried out in an organic solvent such as an amide, e.g. dimethylformamide, or an ether, e.g. tetrahydrofuran, preferably in the presence of a base.
  • Suitable bases include, for example, alkali metal hydrides, such as sodium hydride, alkali metal carbonates, such as sodium carbonate, or alkali metal alkoxides such as sodium or potassium methoxide, ethoxide or t-butoxide.
  • alkali metal hydrides such as sodium hydride
  • alkali metal carbonates such as sodium carbonate
  • alkali metal alkoxides such as sodium or potassium methoxide, ethoxide or t-butoxide.
  • a compound of formula (I) wherein one or more of R 5 , R 6 , R 10 and R 1 1 represents a hydrogen atom may be converted to another compound of formula (I) by reductive alkylation.
  • Reductive alkylation with an appropriate aldehyde or ketone may be effected using an alkaline earth metal borohydride or cyanoborohydride.
  • the reaction may be effected in an aqueous or non- aqueous reaction medium, conveniently in an alcohol, e.g. methanol or ethanol or an ether, e.g. dioxan or tetrahydrofuran, optionally in the presence of water.
  • the reaction may conveniently be carried out at a temperature in the range of 0 to 100°C, preferably 5 to 50°C.
  • the alkylation may be performed by heating a compound of formula (I) wherein one or more of R 5 , R 6 , R 10 and R 1 represents a hydrogen atom with the appropriate aldehyde or ketone such as formaldehyde in the presence of an acid such as formic acid at a temperature of 0 to 150°C, preferably at about 90°C.
  • a compound of formula (I) wherein R 1 is AlkOR 3 or AlkR 4 in which Alk is a C2_5alkenylene chain may be converted to another compound of formula (I) wherein Alk is a C2-5alkylene chain by reduction.
  • Reduction may conveniently be effected in the presence of hydrogen and a metal catalyst, for example Raney nickel or a nobel metal catalyst such as palladium, platinum, platinum oxide or rhodium, which may be supported for example on charcoal.
  • the reaction may be effected in a solvent such as an alcohol, for example ethanol and conveniently at a temperature of from -10 to +50°C, preferably 20 to 3 ⁇ OC.
  • compounds of formula (I) wherein R 1 represents a hydroxyalkyl group may be prepared by reduction of a compound of formula (I) wherein R 1 represents a group -(Alk) n COOR 3 .
  • the reduction may conveniently be carried out using a suitable hydride reducing agent, e.g lithium aluminium hydride or lithium triethylborohydride, in a suitable solvent such as an ether, e.g diethyl ether, tetrahydrofuran or dioxan, or a hydrocarbon such as toluene.
  • the reaction is conveniently conducted at a temperature of -78 to 100°C, preferably at about 0°C.
  • R 1 is a group -(Alk) n OCOR 3 , -(Alk) n NR 3 SO 2 R 9 -(Alk) n NR 3 COR 9 , -(Alk) n NR 3 COOR 9 or
  • R 8 may be prepared from compounds of formula (I) in which R 1 is -(Alk) n OH or -(Alk) n NHR 3 by acylation, sulphonylation or sulphamylation.
  • Suitable acylating or sulphonylating agents which may conveniently be used in the above process include acid halides (for example carboxylic acid chlorides and sulphonyl chlorides), alkyl esters and activated esters (for example diphenylcarbamide anhydride or pivalic anhydride).
  • Suitable sulphamylating agents include sulphamoyl halides (for example dimethylsulphamoyl chloride) or sulphamide.
  • the reaction is conveniently effected in a suitable solvent such as an ether, e.g. diethyl ether, tetrahydrofuran or dioxan, or a hydrocarbon such as toluene and at a temperature of -78 to 100°C, preferably at about 0°C.
  • compounds of formula (I) wherein R 1 is a group -(Alk) n CONR 7 R 8 may be prepared from compounds of formula (I) in which R 1 is -(Alk) n COOH by reaction with an amine of formula (VI) or an acid addition salt thereof under conditions as described for the preparation of compounds of formula (III) from compounds of formula (V).
  • compounds of formula (l a ) wherein C is a C 2.3 alkylene chain especially compounds of formula (l a ) wherein E is a triazole (e.g. 4H-[1 ,2,4]-triazol-3-yl) ring and A-B is O-CH, may be prepared by reduction of the compound of formula (X)
  • the reduction process may conveniently be carried out in the presence of hydrogen and a metal catalyst, for example, Raney nickel or a nobel metal catalyst such as palladium, platinum, platinum oxide or rhodium, which may be supported, for example, on charcoal.
  • a metal catalyst for example, Raney nickel or a nobel metal catalyst such as palladium, platinum, platinum oxide or rhodium, which may be supported, for example, on charcoal.
  • the reduction may be carried out in a solvent such as an alcohol, e.g. methanol or ethanol, an ether, e.g. dioxan, an ester, e.g. ethyl acetate, or an amide, e.g. dimethylformamide, and conveniently at a temperature of from -10 to +50°C, preferably 20 to 30°C.
  • the reaction is conveniently effected in a suitable reaction medium at a temperature of from "10 to +150 ⁇ C, preferably 15 to 90°C, optionally in the presence of a base.
  • suitable solvents include amides, e.g. dimethylformamide, ethers, e.g. dioxan or tetrahydrofuran, nitriles, e.g. acetonitrile, alcohols, e.g. methanol or ethanol, haloalkanes, e.g. dichloromethane or chloroform, water or mixtures thereof.
  • Suitable bases include pyridine, tertiary amines, e.g. triethylamine, alkali metal carbonates, e.g. potassium carbonate, and alkali metal acetates, e.g. sodium acetate. In some cases the base may also act as the reaction solvent.
  • the intermediate of formula (XII) may be prepared from the compound of formula (XIII)
  • reaction by treatment with hydrazine in a suitable solvent such as an alcohol, e.g. ethanol or methanol, an amide, e.g. dimethylformamide, or an ether, e.g. dioxan, tetrahydrofuran or diethyl ether.
  • a suitable solvent such as an alcohol, e.g. ethanol or methanol, an amide, e.g. dimethylformamide, or an ether, e.g. dioxan, tetrahydrofuran or diethyl ether.
  • the compound of formula (XIII) may be prepared from the compound of formula (XIV)
  • a suitable solvent such as a hydrocarbon, e.g. xylene, benzene or cyclohexane, an ether, e.g. diethyl ether, tetrahydrofuran or dioxan, an ester, e.g. ethyl acetate, an amide, e.g. dimethylformamide, or a nitrile, e.g. acetonitrile.
  • a suitable solvent such as a hydrocarbon, e.g. xylene, benzene or cyclohexane, an ether, e.g. diethyl ether, tetrahydrofuran or dioxan, an ester, e.g. ethyl acetate, an amide, e.g. dimethylformamide, or a nitrile, e.g. acetonitrile.
  • the reaction is carried at a temperature of 20 to 150°C, preferably at
  • Compounds of formula (XVI) in which X a represents a reactive derivative of a nitrile group may include compounds of formula (XVIA)
  • Suitable atoms or groups represented by L include halogen atoms, e.g. chlorine, bromine or iodine atoms, alkoxy groups, e.g. methoxy, ethoxy or t-butoxy groups, or alkylthio groups, e.g. methylthio.
  • halogen atoms e.g. chlorine, bromine or iodine atoms
  • alkoxy groups e.g. methoxy, ethoxy or t-butoxy groups
  • alkylthio groups e.g. methylthio.
  • X a represents a nitrile group
  • a suitable reaction medium in the presence of a Lewis acid, e.g. aluminium chloride, at a temperature of 150 to 300°C.
  • Suitable solvents include inert solvents such as diphenylether.
  • reaction is conveniently effected in a suitable reaction medium at a temperature of from “10 to +15 ⁇ OC, optionally in the presence of a base.
  • suitable solvents and bases include those described for the preparation of compounds of formula (X) above.
  • alkyl halide e.g. methyl iodide
  • suitable solvent such as an alcohol e.g. methanol.
  • Compounds of formula (XVIII) may be prepared from compounds of formula (XVI), wherein X a represents a nitrile group for example by reaction with hydrogen sulphide in dimethylformamide in the presence of triethylamine.
  • Hal represents a halogen atom, for example a bromine or iodine atom
  • a metal cyanide e.g. cuprous cyanide
  • a suitable solvent e.g. N- methylpyrrolidinone or dimethylformamide
  • a compound of formula (I) according to the invention, or a salt thereof may be prepared by subjecting a protected derivative of formula (I) or a salt thereof to reaction to remove the protecting group or groups.
  • the protecting groups used in the preparation of compounds of formula (I) may be used in conventional manner. See for example 'Protective Groups in Organic Chemistry' Ed.J.F.W. McOmie (Plenum Press 1973) or 'Protective Groups in Organic Synthesis' by Theodora W Greene (John Wiley and Sons 1981 ).
  • Conventional amino protecting groups may include for example aralkyl groups, such as benzyl, diphenylmethyl or triphenylmethyl groups; and acyl groups such as N-benzyloxycarbonyl or t-butoxycarbonyl.
  • aralkyl groups such as benzyl, diphenylmethyl or triphenylmethyl groups
  • acyl groups such as N-benzyloxycarbonyl or t-butoxycarbonyl.
  • Hydroxy groups may be protected, for example, by aralkyl groups, such as benzyl, diphenylmethyl or triphenylmethyl groups, acyl groups, such as acetyl, silicon protecting groups, such as trimethylsilyl or t-butyl dimethylsilyl groups, or as tetrahydropyran derivatives.
  • aralkyl groups such as benzyl, diphenylmethyl or triphenylmethyl groups
  • acyl groups such as acetyl
  • silicon protecting groups such as trimethylsilyl or t-butyl dimethylsilyl groups, or as tetrahydropyran derivatives.
  • an aralkyl group such as benzyl
  • an acyl group such as N-benzyloxycarbonyl may be removed by hydrolysis with, for example, hydrogen bromide in acetic acid or by reduction, for example by catalytic hydrogenation
  • silicon protecting groups may be removed, for example, by treatment with fluoride ion or by hydrolysis under acidic conditions
  • tetrahydropyran groups may be cleaved by hydrolysis under acidic conditions.
  • the following reactions may, if necessary and/or desired be carried out in any appropriate sequence subsequent to any of the processes (A) to (E) (i) removal of any protecting groups; and (ii) conversion of a compound of formula (I) or a salt thereof into a pharmaceutically acceptable salt thereof.
  • a compound of the invention as a salt, for example as an acid addition salt, this may be achieved by treating the free base of general formula (I) with an appropriate acid, preferably with an equivalent amount, or with creatinine sulphate in a suitable solvent (e.g. aqueous ethanol).
  • the general methods indicated above for the preparation of the compounds of the invention may also be used for the introduction of the desired groups at an intermediate stage in the preparation of the required compound. It should therefore be appreciated that in such multi-stage processes, the sequence of reactions should be chosen in order that the reaction conditions do not affect groups present in the molecule which are desired in the final product.
  • 3-Bromo-5-hydroxymethylpyridine (1.1g) was added to thionyl chloride (5ml) at 0°C under N2 over 5 minutes. The solution was stirred at room temperature for 1h, re-cooled to 0°C and dry ether (40ml) added. The resulting solid was filtered off, washed with ether and added to a stirred solution of ammonia (30ml) in ethanol (40ml) at 0°C. The solution was stirred at room temperature for 20h, the solvent removed in vacuo and the crude material partitioned between 2N sodium hydroxide (30ml) and dichloromethane (4x20ml), dried and the solvent removed in vacuo.
  • diisobutylaluminium hydride 15ml of a 1M solution in toluene. After 1h a further quantity of diisobutylaluminium hydride solution (5ml) was added. After 2h the solution was poured into a stirred mixture of 2M sodium hydroxide solution (50ml) and ether (100ml). The solution was extracted with ether (3x 50ml), the combined extracts were washed with brine (50ml) and dried.
  • Ethanolic methylamine (33%, 12ml) was added to a suspension of the chloromethylpyridine hydrochloride (3.0g) in ethanol (10ml) and the mixture was stirred at room temperature for 3 days. The solvent was removed in vacuo and the residue partitioned between ethyl acetate and saturated aqueous sodium hydrogen carbonate. The organic phase was dried (MgSO4) and evaporated to leave a colourless oil which was chromatographed on silica using a mixture of dichloromethane : ethanol : aqueous ammonia (100:8:1 -» 150:8:1) to give the free base as a colourless oil.T.l.c.
  • Example 2 5-r3-f2-(Dimethylamino)ethvn-5-benzofuranvn-3-pyridinemethanol
  • a solution of the product of Example 1 (0.16g) in THF (1ml).
  • aqueous THF (2ml of 15% water in THF) was added and the reaction mixture poured into a stirred mixture of 2N sodium hydroxide solution (20ml) and ethyl acetate (20ml).
  • the aqueous solution was extracted with ethyl acetate (3x 20ml), dried and the solvent removed in vacuo.
  • Cl6Hl6N2 ⁇ .0.75C 2 H 2 O 4 requires : C.65.7; H.5.5; N,8.8% T.l.c. Si0 2 (50:8:1), Rf 0.28; detection U.V. and IPA
  • step (i) A mixture of the product of step (i) (106.1mg), Intermediate 3 (86.6mg), tetrakistriphenylphosphine palladium (O) (20mg) and 2N aqueous sodium carbonate (0.5ml) was stirred at reflux in dimethoxyethane (5ml) under nitrogen for 6.5h. The mixture was evaporated and the residue purified by column chromatography on silica gel (30g, Merck 7729) eluting with 50:8:1 dichloromethane:ethanol:ammonia to give the product as- a yellow oil. This was triturated with ether/ethyl acetate to give the product as a pale yellow powder m.p. 172-1740 (dec).
  • Example 12 The product of Example 12 (0.15g) was stirred in aqueous formaldehyde (2ml). Formic acid (2 drops) was added and the solution heated to 90°C. Further formic acid (0.5ml) was added over 1h. The solution was allowed to cool, the solvent removed in vacuo and the crude material purified by flash chromatography (CH2Cl2:EtOH:NH3 100:8:1 50:8:1) to give the product. This was converted into the HCI salt by solubilising in ethanol followed by addition of 1M ethanolic HCI. Solvent was removed in vacuo and the product was freeze dried to yield the product as a pale yellow solid, m.p. 80-83°C. T.l.c.
  • N-fr5-r3-r2-(Dimethylamino)ethvn-5-benzofuranv ⁇ -3-pyridinvnmethvnacetamide dihvdrochloride To a solution of the product of Example 17 (0.18g) in dry dimethoxyethane (5ml) and triethylamine (0.17ml) was added acetyl chloride (0.065ml). After 20 hours the solution was partitioned between 2N sodium carbonate solution (20ml) and ether (30ml), extracted with ether (3x30ml), dried (MgSO4) and the solvent removed in vacuo.
  • Example 21 5-f3-(2-Aminoethyl)-5-benzofuranvn-2-pyridinemethanol A mixture of Intermediate 4 (300mg), tetrakis(triphenylphosphine)palladium (O) (25mg), a mixture of 5-bromo-4-hydroxymethylpyridine and 5-bromo-2-hydroxy methylpyridine (413mg), 1 ,2-dimethoxyethane (15ml) and aqueous 2N sodium carbonate (5ml) was refluxed for 10h.
  • Methanesulphonyl chloride (0.19ml) was added to a solution of the product of stage (ii) (0.31 g) in dry dichloromethane (10ml) and triethylamine (0.46ml) at 0° under nitrogen. The solution was allowed to warm to 23° for 1h, poured into aqueous 2N sodium carbonate (20ml), and extracted with dichloromethane (2x20ml). The dried (Na2S ⁇ 4) organic extracts were evaporated and the residue purified by flash chromatography using dichloromethane-ethanol- ammonia (200:8:1) as eluant to yield the product (68%) as a pale yellow solid, m.p. 78-80°. T.l.c. SiO 2 (CH 2 CI 2 :EtOH:NH3, 200:8:1) Rf 0.29; Detection: u.v., KMnO
  • Example 17 (0.1 Og) in dichloromethane (2.0ml) containing pyridine (0.16ml) under nitrogen and then stirred at 23° for 18h. The solvent was evaporated and the residue taken up in toluene (10ml) and triethylamine. The mixture was heated to reflux for 1h, cooled, and evaporated to leave a white solid. This was purified by column chromatography using dichloromethane:ethanol:ammonia
  • Example 28 The product of Example 28 (58mg) was treated with ethanol (2ml) and ethanolic
  • Example 29 The product of Example 29 (54mg) in ethanol (10ml) was stirred with 5% palladium on carbon (8mg) under hydrogen for 22h. The catalyst was filtered off (hyflo) and the filter pad washed with ethanol. The combined solvent and washings were evaporated and the residue (55mg) was purified by flash chromatography using dichloromethane-ethanol-ammonia (50:8:1 ) as eluant to give the free base. This was dissolved in ethanol and ethanolic 1M hydrogen chloride (308 ⁇ l, 1M) was added. The mixture was evaporated and the residue triturated with ether to give a sticky gum. This was redissolved in ethanol, evaporated, and stirred in ether.
  • stage (i) (1.24g) in dimethylformamide (50ml) was added dropwise to - a suspension of sodium thiomethoxide (1.00g) in dimethylformamide (50ml) at 0° under nitrogen. The mixture was allowed to warm to room temperature and stirring was continued for 5d. The dimethylformamide was evaporated and the residue partitioned between dichloromethane and water. The aqueous phase was extracted twice with dichloromethane and the combined organic phases were washed with H2O, dried (MgSO4) and evaporated to give the product.
  • Tetrakis(triphenylphosphine)palladium (O) (20mg) was added and the mixture heated at 100°C (oil bath temperature) under nitrogen for 4h.
  • the cooled reaction mixture was partitioned between ethyl acetate and water.
  • the aqueous phase was extracted with ethyl acetate and the combined organic phases were washed with brine, dried (MgSO4) and evaporated.
  • the crude mixture was purified by flash chromatography using dichloromethane:ethanol:ammonia (100:8:1) as eluant to give firstly recovered bromide and impurities, followed by the product.
  • ⁇ (MeOH-d ) 2.42(s, 6H), 2.67(s, 3H), 2.7-3.1 (m), 4.0-4.4(AB, 2H) and 7.6- 8.9(m).
  • Phenylchloroformate (1.1ml) was added to a stirred solution of 5-bromo-3- hydroxymethylpyridine (0.5g) in pyridine (10ml) at 0°C. The mixture was stirred at 0°C for 0.5h, treated with ammonia (10ml), and allowed to warm to room temperature. After 2h, aqueous 2M hydrochloric acid was added and the mixture extracted with ethyl acetate (x3). The combined organic phases were washed with water, brine, dried (MgSO4), and evaporated. The residue was purified by flash chromatography to give the product. T.l.c. Si0 2 (CH 2 Cl2:EtOH:NH 3 , 200:8:1) Rf 0.27; Detection: u.v.
  • Tetrakis(triphenylphosphine)palfadium (O) was added and the mixture stirred at ca. 100° for 2h. After cooling, the solvent was evaporated, water was added, and the mixture extracted with ethyl acetate (x3). The combined organic extracts were washed with brine, dried (MgS ⁇ 4) and evaporated. The residue was purified by flash chromatography using dichloromethane:ethanol:ammonia
  • N-rr5-r3-r2-(Dimethylamino)ethyl1-5-benzofuranvn-3-pyridinvnmethyl1urea (i) N-r(5-Bromo-3-pyridinyl)methyl1urea
  • a solution of Intermediate 1 (0.50g) in water (2.5ml) and glacial acetic acid (1.3ml) was heated to 35° and a solution of sodium cyanate (350mg) in water (2.5ml) was added dropwise with vigorous stirring. The mixture was stirred for a further 10min and then left to stand at room temperature for 2h. The mixture was cooled to 0° and the precipitate filtered off, washed with water and dried to give the product as a white solid.
  • step (ii) 5-r3-r2-(Dimethylamino)ethyll-5-benzofuranyll-3-pyridineacetamide. dihvdrochloride
  • a mixture of the product of step (i) (0.525g), Intermediate 4 (0.684g), tetrakis(triphenylphosphine) palladium (0) (100mg), aqueous sodium carbonate (10ml, 2N) and dimethoxyethane (50ml, filtered through basic alumina) was refluxed under nitrogen for 7h.
  • a further quantity of the amide was added (0.2g) and the mixture heated for a further 2h.
  • Isopropylsulphonyl chloride (0.11ml) was added to a stirred solution of the product of Example 17 (154mg) in dry dichloromethane (10ml) and triethylamine (1ml) under nitrogen at 0°C. The mixture was then stirred at room temperature for 20h. The solvent was evaporated and the residue purified by column chromatography on silica gel. Elution with dichloromethane-ethanol-0.88 ammonia (100:8:1 ) gave the major product as a brown oil. This was converted to the oxalate salt by treatment with oxalic acid (13mg) in isopropylalcohol. An aqueous solution of the salt was freeze-dried to leave a white foam.
  • Diphenylphosphoryl azide (1.30g) was added at -5° to a stirred solution of 5- bromo-3-pyridineacetic acid (509mg), triethylamine (1.35ml), and N- methylethanamine (0.21ml) in DMF (35ml) under nitrogen and then stirred at +23° for 22h. The mixture was evaporated and the residue purified by flash chromatography over silica gel (100g). Elution with dichloromethane-ethanol- 0.88 ammonia (250:8:1 ) gave a white solid, which was adsorbed from hot ethanol (8ml) onto silica gel (Merck 7734, 6ml).
  • silica was applied as a plug to a flash column of silica gel (Merck 9385, 6cm wide column), and this eluted with ethyl acetate-triethylamine (99:1 ) to give the product as a colourless oil.
  • N.m.r. ( ⁇ ; DMSO): 10.75 (1 H,brs), 9.21 (1 H,d), 8.78-8.70 (2H,m), 8.40 (1 H,brs), 8.30 (1H,t), 8.06 (1H,s), 7.82 (2H,m), 4.41 (2H,d), 3.58 (4H, 1 /2AA'BB'), 3.46 (2H, V2AA'BB'), 3.22 (2H, 1 /2AA'BB'), 3.05 (4H, Yi-AA'BB'), 2.88 (6H,d).
  • Triethylamine 48mg was added to a stirred solution of 5-[5-(aminomethyl) -2- furanyl]-N,N-dimethyl-3-benzofuranethanamine (45mg) in dry dichloromethane (10ml) at below 0°C under nitrogen.
  • Ethanesulphonyl chloride 24mg was added dropwise and the temperature allowed to rise to +23° over 1h. After standing for 20h, the mixture was cooled to 0° and further triethylamine (32mg) followed by ethanesulphonyl chloride (0.023ml, 31 mg) were added.
  • Ethanolic hydrochloric acid (5.8ml) was added to a stirred suspension of the thioamide (1.0g) in methanol (20ml). The resulting yellow solution was evaporated to leave a yellow foam.
  • Dimethylformamide (20ml) and methyl iodide (6ml) were added and the solution was stirred at room temperature under nitrogen for 2.5h then heated gently (45°C) for 30min. The excess methyl iodide was removed by evaporation in vacuo and to the residue were added pyridine (2.0ml) and methanesulphonamidomethyl hydrazide (0.67g). The mixture was heated to 100°C for 20h, cooled and evaporated to leave a brown oil.
  • Example 107 f5-r3-f2-(Dimethylamino)ethyll-1 H-indol-5-v ⁇ -pyridin-3-yll-methanol.
  • oxalate A suspension of lithium aluminium hydride (300mg) in dry ether (20ml) was stirred at 0° under an atmosphere of nitrogen for 10min.

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Abstract

Composés de la formule (Ia), ainsi que leurs sels et solvates (par exemple des hydrates) pharmacologiquement acceptables, dans laquelle A représente O, S, Nra ou CH=CH; B représente N ou Crb; C est une liaison ou une chaîne alcoylène C¿1-3?; D est un groupe NR?cRd¿ dans lequel Rc et Rd, qui peuvent être semblables ou différents, représentent hydrogène, alcoyle C¿1-6?, alcényle C2-6, alcynyle C2-6, cycloalcoyle C3-7, aryle ou aralcoyle (dans lequel les groupes alcoyle ou aryle sont éventuellement substitués par un ou plusieurs substituants choisis parmi halogène, alcoyle ou aryle), ou bien, ils forment ensemble un groupe alcoylène C3-6 ou un groupe aralcoylidine (de préférence un arylméthylidène, par exemple un benzylidène); ou bien, ensemble avec l'atome d'azote auquel ils sont accolés, ils forment un noyau monocyclique saturé possédant 4 à 7 chaînons; ou D est un groupe de formule (i), (ii), (iii), (iv) ou (v) dans laquelle la ligne en pointillé représente une liaison double éventuelle et R?e¿ représente hydrogène, alcoyle C¿1-6?, alcényle C2-6, alcynyle C2-6, phényle ou phénalcoyle C1-6; E représente un noyau hétérocyclique à 5 ou 6 chaînons éventuellement substitué, lié le cas échéant à un noyau aromatique par une chaîne alcoylène C1-3; et R?a et Rb¿, qui peuvent être semblables ou différents, représentent hydrogène ou alcoyle C¿1-6?. L'invention se rapporte également aux compositions pharmaceutiques contenant de tels composés, à l'utilisation de ceux-ci en tant qu'agonistes sélectifs du 5HT1 ainsi qu'aux procédés de préparation desdits composés.
PCT/EP1995/001315 1994-04-14 1995-04-12 Nouveaux noyaux heterocycliques a 5 chainons benzocondenses destines au traitement de la migraine WO1995028400A1 (fr)

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Cited By (30)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997045426A1 (fr) * 1996-05-24 1997-12-04 Merck Sharp & Dohme Limited Derives de l'azetidine, de la pyrrolidine et de la piperidine utilises comme agonistes des recepteurs 5-ht¿1d?
WO1997045432A1 (fr) * 1996-05-24 1997-12-04 Merck Sharp & Dohme Limited Derives de la piperazine, de la piperidine et de la tetrahydropyridine utilises comme agonistes des recepteurs 5-ht
US5770742A (en) * 1996-05-16 1998-06-23 Allelix Biopharmaceuticals Inc. Thiophene-tryptamine derivatives
WO1998037071A1 (fr) * 1997-02-21 1998-08-27 R.J. Reynolds Tobacco Company Compositions pharmaceutiques comprenant des composes amines olefiniques aryl substitues
WO1999007700A1 (fr) * 1997-08-09 1999-02-18 Smithkline Beecham Plc Composes bicycliques servant de ligands pour les recepteurs 5-ht1
WO1999031062A1 (fr) * 1997-12-17 1999-06-24 Shionogi & Co., Ltd. Nouveaux composes de pyridine
WO2000000487A1 (fr) * 1998-06-30 2000-01-06 Eli Lilly And Company Agonistes de 5-ht¿1f?
WO2000004019A1 (fr) * 1998-07-17 2000-01-27 Allelix Biopharmaceuticals Inc. Composes de 5-bicycloindole
US6274606B1 (en) 1997-02-21 2001-08-14 Targacept, Inc. Methods of treating central nervous system disorders with aryl substituted olefinic amine compounds
US6531606B1 (en) 1997-02-21 2003-03-11 Targacept, Inc. Pharmaceutical compositions incorporating aryl substituted olefinic amine compounds
WO2003068772A1 (fr) * 2002-02-18 2003-08-21 Glaxo Group Limited Composes presentant une affinite avec des recepteurs de type 5ht1 et leur utilisation therapeutique
US7053079B2 (en) * 2001-11-28 2006-05-30 Koei Chemical Company, Limited Dihydroxy (3-pyridyl) borane compounds
US7208513B2 (en) 2000-07-31 2007-04-24 Signal Pharmaceuticals, Llc Indazole compounds and compositions thereof as JNK inhibitors and for the treatment of diseases associated therewith
JP2007510629A (ja) * 2003-10-22 2007-04-26 イーライ リリー アンド カンパニー 新規ｍｃｈ受容体アンタゴニスト
US7211594B2 (en) 2000-07-31 2007-05-01 Signal Pharmaceuticals, Llc Indazole compounds and compositions thereof as JNK inhibitors and for the treatment of diseases associated therewith
DE102008041214A1 (de) 2008-08-13 2010-02-18 Bayer Cropscience Ag N-substituierte Azinylakyl-azincarboxamide und deren Analoge
US7728140B2 (en) 2003-12-24 2010-06-01 Pfizer Italia S.R.L. Pyrrolo[2,3-b]pyridine derivatives active as kinase inhibitors and pharmaceutical compositions comprising them
US7888508B2 (en) 2003-12-24 2011-02-15 Pfizer Italia S.R.L. Pyrrolo[2,3-B]pyridine derivatives active as kinase inhibitors
AU2006254336B2 (en) * 2005-06-01 2012-10-04 Ucb Pharma, S.A. 2 -oxo-I -pyrrolidine derivatives/ processes for preparing them and their therapeutic use on the central nervous system
US8383827B2 (en) 2009-05-15 2013-02-26 Novartis Ag Aryl pyridine as aldosterone synthase inhibitors
CN110551101A (zh) * 2019-08-28 2019-12-10 沈阳药科大学 1、6-二取代-苯并五元杂环类衍生物及其用途
WO2020249799A1 (fr) * 2019-06-14 2020-12-17 Janssen Pharmaceutica Nv Carbamates de pyridine et leur utilisation en tant que modulateurs du récepteur glun2b
US11008302B2 (en) 2018-04-04 2021-05-18 Janssen Pharmaceutica Nv Substituted pyridine and pyrimidines and their use as GluN2B receptor modulators
US11161846B2 (en) 2019-06-14 2021-11-02 Janssen Pharmaceutica Nv Substituted pyrazolo[4,3-b]pyridines and their use as GluN2B receptor modulators
US11207298B2 (en) 2016-10-06 2021-12-28 Janssen Pharmaceutica Nv Substituted 1H-imidazo[4,5-b]pyridin-2(3H)-ones and their use as GLUN2B receptor modulators
US11214563B2 (en) 2019-06-14 2022-01-04 Janssen Pharmaceutica Nv Substituted pyrazolo-pyrazines and their use as GluN2B receptor modulators
US11459336B2 (en) 2019-06-14 2022-10-04 Janssen Pharmaceutica Nv Pyrazine carbamates and their use as GluN2B receptor modulators
US11530210B2 (en) 2019-06-14 2022-12-20 Janssen Pharmaceutica Nv Substituted heteroaromatic pyrazolo-pyridines and their use as GLUN2B receptor modulators
US11618750B2 (en) 2019-06-14 2023-04-04 Janssen Pharmaceutica Nv Substituted pyrazolo-pyridine amides and their use as GluN2B receptor modulators
US12172997B2 (en) 2019-06-14 2024-12-24 Janssen Pharmaceutica Nv Substituted pyrazolo-pyridine amides and their use as GluN2B receptor modulators

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Cited By (47)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5770742A (en) * 1996-05-16 1998-06-23 Allelix Biopharmaceuticals Inc. Thiophene-tryptamine derivatives
US6127388A (en) * 1996-05-24 2000-10-03 Merck Sharp & Dohme Ltd. Azetidine, pyrrolidine and piperidine derivatives as 5-HT1D receptor agonists
WO1997045432A1 (fr) * 1996-05-24 1997-12-04 Merck Sharp & Dohme Limited Derives de la piperazine, de la piperidine et de la tetrahydropyridine utilises comme agonistes des recepteurs 5-ht
WO1997045426A1 (fr) * 1996-05-24 1997-12-04 Merck Sharp & Dohme Limited Derives de l'azetidine, de la pyrrolidine et de la piperidine utilises comme agonistes des recepteurs 5-ht¿1d?
US5998416A (en) * 1996-05-24 1999-12-07 Merck Sharp & Dohme Ltd. Piperazine, piperidine and tetrahydropyridine derivatives as 5-HT receptor agonists
WO1998037071A1 (fr) * 1997-02-21 1998-08-27 R.J. Reynolds Tobacco Company Compositions pharmaceutiques comprenant des composes amines olefiniques aryl substitues
US6531606B1 (en) 1997-02-21 2003-03-11 Targacept, Inc. Pharmaceutical compositions incorporating aryl substituted olefinic amine compounds
US6274606B1 (en) 1997-02-21 2001-08-14 Targacept, Inc. Methods of treating central nervous system disorders with aryl substituted olefinic amine compounds
US6391891B1 (en) 1997-08-09 2002-05-21 Smithkline Beecham Plc Bicyclic compounds as ligands for 5-HT1 receptors
WO1999007700A1 (fr) * 1997-08-09 1999-02-18 Smithkline Beecham Plc Composes bicycliques servant de ligands pour les recepteurs 5-ht1
WO1999031062A1 (fr) * 1997-12-17 1999-06-24 Shionogi & Co., Ltd. Nouveaux composes de pyridine
WO2000000487A1 (fr) * 1998-06-30 2000-01-06 Eli Lilly And Company Agonistes de 5-ht¿1f?
US6358972B1 (en) 1998-06-30 2002-03-19 Eli Lilly And Company 5-HT1F agonists
WO2000004019A1 (fr) * 1998-07-17 2000-01-27 Allelix Biopharmaceuticals Inc. Composes de 5-bicycloindole
AU767274B2 (en) * 1998-07-17 2003-11-06 Nps Allelix Corp. 5-bicycloindole compounds
US7211594B2 (en) 2000-07-31 2007-05-01 Signal Pharmaceuticals, Llc Indazole compounds and compositions thereof as JNK inhibitors and for the treatment of diseases associated therewith
US7208513B2 (en) 2000-07-31 2007-04-24 Signal Pharmaceuticals, Llc Indazole compounds and compositions thereof as JNK inhibitors and for the treatment of diseases associated therewith
US7053079B2 (en) * 2001-11-28 2006-05-30 Koei Chemical Company, Limited Dihydroxy (3-pyridyl) borane compounds
EP1460079A4 (fr) * 2001-11-28 2007-03-28 Koei Chemical Co Composes dihydroxy(3-pyridyl)borane
WO2003068772A1 (fr) * 2002-02-18 2003-08-21 Glaxo Group Limited Composes presentant une affinite avec des recepteurs de type 5ht1 et leur utilisation therapeutique
US7244726B2 (en) 2002-02-18 2007-07-17 Glaxo Group Limited Heterocyclic compounds possessing affinity at 5HT1 -type receptors and use thereof in therapy
JP2007510629A (ja) * 2003-10-22 2007-04-26 イーライ リリー アンド カンパニー 新規ｍｃｈ受容体アンタゴニスト
US7728140B2 (en) 2003-12-24 2010-06-01 Pfizer Italia S.R.L. Pyrrolo[2,3-b]pyridine derivatives active as kinase inhibitors and pharmaceutical compositions comprising them
US7888508B2 (en) 2003-12-24 2011-02-15 Pfizer Italia S.R.L. Pyrrolo[2,3-B]pyridine derivatives active as kinase inhibitors
US8106069B2 (en) 2003-12-24 2012-01-31 Pfizer Italia S.R.L. Pyrrolo[2,3-b]pyridine derivatives active as kinase inhibitors and pharmaceutical compositions comprising them
US8198298B2 (en) 2003-12-24 2012-06-12 Pfizer Italia S.R.L. Pyrrolo[2,3-b]pyridine derivatives active as kinase inhibitors
AU2006254336B9 (en) * 2005-06-01 2013-02-28 Ucb Pharma, S.A. 2 -oxo-I -pyrrolidine derivatives/ processes for preparing them and their therapeutic use on the central nervous system
AU2006254336B2 (en) * 2005-06-01 2012-10-04 Ucb Pharma, S.A. 2 -oxo-I -pyrrolidine derivatives/ processes for preparing them and their therapeutic use on the central nervous system
DE102008041214A1 (de) 2008-08-13 2010-02-18 Bayer Cropscience Ag N-substituierte Azinylakyl-azincarboxamide und deren Analoge
US8519142B2 (en) 2009-05-15 2013-08-27 Novartis Ag Aryl pyridine as aldosterone synthase inhibitors
US8809545B2 (en) 2009-05-15 2014-08-19 Novartis Ag Aryl pyridine as aldosterone synthase inhibitors
US8383827B2 (en) 2009-05-15 2013-02-26 Novartis Ag Aryl pyridine as aldosterone synthase inhibitors
US11759455B2 (en) 2016-10-06 2023-09-19 Janssen Pharmaceutica Nv Substituted 1H-imidazo[4,5-b]pyridin-2(3H)-ones and their use as GLUN2B receptor modulators
US11207298B2 (en) 2016-10-06 2021-12-28 Janssen Pharmaceutica Nv Substituted 1H-imidazo[4,5-b]pyridin-2(3H)-ones and their use as GLUN2B receptor modulators
US11008302B2 (en) 2018-04-04 2021-05-18 Janssen Pharmaceutica Nv Substituted pyridine and pyrimidines and their use as GluN2B receptor modulators
US11459336B2 (en) 2019-06-14 2022-10-04 Janssen Pharmaceutica Nv Pyrazine carbamates and their use as GluN2B receptor modulators
US11161846B2 (en) 2019-06-14 2021-11-02 Janssen Pharmaceutica Nv Substituted pyrazolo[4,3-b]pyridines and their use as GluN2B receptor modulators
WO2020249799A1 (fr) * 2019-06-14 2020-12-17 Janssen Pharmaceutica Nv Carbamates de pyridine et leur utilisation en tant que modulateurs du récepteur glun2b
US11214563B2 (en) 2019-06-14 2022-01-04 Janssen Pharmaceutica Nv Substituted pyrazolo-pyrazines and their use as GluN2B receptor modulators
CN114007691A (zh) * 2019-06-14 2022-02-01 詹森药业有限公司 吡啶氨基甲酸酯及其作为GluN2B受体调节剂的用途
US11447503B2 (en) 2019-06-14 2022-09-20 Janssen Pharmaceutica Nv Pyridine carbamates and their use as GLUN2B receptor modulators
US11530210B2 (en) 2019-06-14 2022-12-20 Janssen Pharmaceutica Nv Substituted heteroaromatic pyrazolo-pyridines and their use as GLUN2B receptor modulators
US11618750B2 (en) 2019-06-14 2023-04-04 Janssen Pharmaceutica Nv Substituted pyrazolo-pyridine amides and their use as GluN2B receptor modulators
US11993587B2 (en) 2019-06-14 2024-05-28 Janssen Pharmaceutica Nv Substituted pyrazolo-pyrazines and their use as GluN2B receptor modulators
US12172997B2 (en) 2019-06-14 2024-12-24 Janssen Pharmaceutica Nv Substituted pyrazolo-pyridine amides and their use as GluN2B receptor modulators
CN110551101B (zh) * 2019-08-28 2020-11-24 沈阳药科大学 1、6-二取代-苯并五元杂环类衍生物及其用途
CN110551101A (zh) * 2019-08-28 2019-12-10 沈阳药科大学 1、6-二取代-苯并五元杂环类衍生物及其用途

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