WO1995028400A1 - Novel benzofused 5-membered heterocyclic rings for the treatment of migraine - Google Patents

Novel benzofused 5-membered heterocyclic rings for the treatment of migraine Download PDF

Info

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
Authority
WO
WIPO (PCT)
Prior art keywords
formula
compound
solution
alkyl
ethanol
Prior art date
Application number
PCT/EP1995/001315
Other languages
French (fr)
Inventor
Peter Charles North
Sjoerd Nicolaas Wadman
Mark Ladlow
Original Assignee
Glaxo Group Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Glaxo Group Limited filed Critical Glaxo Group Limited
Priority to AU23439/95A priority Critical patent/AU2343995A/en
Publication of WO1995028400A1 publication Critical patent/WO1995028400A1/en

Links

Classifications

    • 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.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Compounds of formula (Ia), wherein A is O, S, NRa or CH=CH; B is N or CRb; C is a bond or a C¿1-3?alkylene chain; D is a group NR?cRd¿ wherein R?c and Rd¿, which may be the same or different, are hydrogen, C¿1-6?alkyl, C2-6alkenyl, C2-6alkynyl, C3-7cycloalkyl, aryl or aralkyl (wherein the alkyl or aryl group is optionally substituted by one or more halogen, alkyl or aryl); or together form a C3-6alkylene 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 (i), (ii), (iii), (iv) or (v) in which the dotted line represents an optional double bond and R?e¿ is hydrogen, C¿1-6?alkyl, C2-6alkenyl, C2-6alkynyl, phenyl or phen(C1-6)alkyl; E is an optionally substituted 5 or 6 membered heterocyclic ring, optionally linked to the aromatic ring by a C1-3alkylene chain; and R?a and Rb¿, which may be the same or different, are hydrogen or C¿1-6?alkyl; and pharmaceutically acceptable salts and solvates (e.g. hydrates) thereof, pharmaceutical compositions containing such compounds, their use as selective 5HT1-agonists and processes for their preparation.

Description

NOVEL BENZOFUSED 5-MEMBERED HETEROCYCLIC RINGS FOR THE TREATMENT OF MIGRAINE
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 (la)
Figure imgf000003_0001
wherein A is O, S, NRa or CH=CH;
B is N or CRb;
C is a bond or a C^alkylene chain;
D is a group NRcRd wherein Rc and Rd, which may be the same or different, are hydrogen, C^alkyl, C^alkenyl, C^alkynyl, C3_7cycloalkyl, aryl or aralkyl (wherein the alkyl or aryl group is optionally substituted by one or more halogen, alkyl or aryl); or together form a C3^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
Figure imgf000003_0002
in which the dotted line represents an optional double bond and Re is hydrogen, C^alkyl, C^alkenyl, C^alkynyl, phenyl or phen(C1^)alkyl;
E is an optionally substituted 5 or 6 membered heterocyclic ring, optionally linked to the aromatic ring by a C-^alkylene chain; and
Ra and Rb, which may be the same or different, are hydrogen or C^alkyl; and pharmaceutically acceptable salts and solvates (e.g. hydrates) thereof.
In one aspect of the invention 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. 1 ,3,4-oxadiazol-2-yl or 1,2,4-oxadiazol-3-yl), imidazole (e.g. imidazol-2-yl) and triazole (e.g. 1 ,2,4-triazol-3-yl) rings.
In a further aspect of the invention 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.
In a preferred aspect of the invention 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.
In a particularly preferred group of compounds of formula (la) A is O, S or CH=CH and B is CRb (i.e. forming a 3,5-substituted benzofuran or benzothiophene or a 2,8-substituted naphthalene ring system).
In another preferred group of compounds of formula (la) A is O, B is CH and E is an optionally substituted pyridyl ring, in particular a pyridin-3-yl ring.
In one particularly preferred embodiment, the invention provides compounds of formula (I)
Figure imgf000004_0001
wherein R1 is hydrogen, Chalk !, -AlkOR3 or -(Alk)nR4 where Alk is an unsubstituted or substituted C-|_5 alkylene or C2-5alkenylene chain, n is 0 or 1 and R4 is -CN, -COR3, -OCOR3, -COOR3, -S(0)mR3 where m is 0, 1 or 2, -NR7R8, -CONR7R8, -CONR3NR5R6, -OCONR5R6, -NR3COOR9, -NR3COR9, -NR3SO2R9, -SO2NR7R8, -NR3Sθ2NR7R8 or -NR3CONR7R8; R2 is -XNR10R1 1 where X is an unsubstituted or substituted C-|_ 3alkylene chain;
R3 is hydrogen or C-|_6 alkyl or R3 and R8 or R9 together form a linking C2-.5 alkylene chain;
R5, R6, R10 and R1 1, which may be the same or different, are hydrogen or C-ι_6alkyl; R7 and R8, which may be the same or different, are hydrogen, C*|^alk l or C3_6cycloalkyl optionally containing an oxygen atom (e.g. morpholino) or R7 and R8, together with the N-atom to which they are attached, form a saturated 4- to 7-membered ring of formula
Figure imgf000005_0001
where Z is a group of formula -CR12R13-, -0-, -NR14-, -CO- or -S(0)p-; R9 is hydrogen,
Figure imgf000005_0002
(e.g. trifluoromethyl), C-|_6 alkoxy(C-|^)alkyl (e.g. methoxymethyl), phenyl optionally substituted with one or more halogen atoms or carboxy groups (e.g. 4-fluorophenyl or 4-carboxy- phenyl) or phenyl(Cι_3)alkyl (e.g. benzyl);
R12 and R13, which may be the same or different, are hydrogen, hydroxy or
C<|_galkoxy;
R14 is -S02R15, -COR 5 or -COOR15;
R15 is C-|_6 alkyl; and p is 0, 1 or 2; and pharmaceutically acceptable salts and solvates (e.g. hydrates) thereof, with the proviso that when R1 is 3-CH2CONR7R8 wherein R7 and R8, together with the N-atom to which they are attached, form a saturated 4 to 7 membered ring and R2 is -CH2CH2NR10R11, at least one of R10 and R11 is C^alkyl. As used herein, 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. Preferred alkyl groups are C-]_3alkyl groups, especially methyl. In a preferred class of compounds of formula (I) 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<|_3alkyl groups. Preferred compounds of formula (I) are those in which R1 is -(Alk)nR4, in particular -CH2R4 or -CH2CH2R4 Preferably R4 is -CONR7R8, -NR3COR9 -NR3COOR9 -NR3SO2R9 or -NR3SO2NR7R8.
A further preferred class of compounds of formula (I) includes compounds wherein R2 is -CH2CH2NR1θR1 1. Preferably R10 and R1 1 are both methyl.
In a particularly preferred class of compounds of formula (I) R1 is attached at 5- position of the pyridinyl ring. Typical values of R1 include
-CH2CONH2 , -CH2CONHCH2CH3 -CH2CONHCH(CH3)2
Figure imgf000006_0001
SO-CH3
Figure imgf000006_0002
-CH2NHCOCH(CH3)2 -CH2N(CH3)COCH3 t -CH2NHCOCH2OCH3
Figure imgf000006_0003
and / \
-CH-2N, -CH-NHSO- N 0
/ o
A particularly preferred group of compounds of formula (I) is represented by formula (IA)
Figure imgf000007_0001
wherein R7 and R8, which may be the same or different, are Cι_3alkyl or, together with the N-atom to which they are attached, form a saturated 4- to 7- membered ring of formula
Figure imgf000007_0002
where Z is a group of formula -CR12R13-, -O-, -NR14-; R10 and R 1 , which may be the same or different, are hydrogen or C-ι_3alkyl; R12 and R13, which may be the same or different, are hydrogen, hydroxy or C*ι_3alkoxy; R1 is -SO2R15, -COR15 or -COOR15; R15 is Cι_3alkyl; and pharmaceutically acceptable salts and solvates thereof.
Compounds of formula (I) wherein R7 and R8, together with the N-atom to which they are attached, form an azetidine, pyrrolidine, piperidine, hexamethyleneimine, piperazine or morpholine ring are especially preferred.
Pharmaceutically acceptable salts of the compounds of formula (I) include those derived from pharmaceutically acceptable inorganic and organic acids. Examples of 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-|-like receptors and have selective vasoconstrictor activity. This selective 5HT-j-like receptor agonist activity and selective vasoconstrictor activity of the compounds of the invention has been demonstrated in vitro. In addition, compounds of the invention selectively constrict the carotid arterial bed of the anaesthetised dog whilst having negligible effect on blood pressure.
The compounds of the invention are indicated in the treatment of conditions susceptible to amelioration by agonist activity at 5HT-|-like receptors. In particular compounds of the invention are useful in treating certain conditions associated with cephalic pain. In particular 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.
There is thus provided in a further aspect 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.
There is also provided as a further aspect of the invention the use of 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.
In an alternative or further aspect there is provided a method for the treatment of a mammal, including man, 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.
It will be appreciated by those skilled in the art that reference herein to treatment extends to prophylaxis as well as the treatment of established symptoms.
While it is possible that, for use in therapy, 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.
Pharmaceutical formulations 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.
For oral administration, 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). The tablets may be coated by methods well known in the art.
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-β-hydroxybenzoates or sorbic acid).
For buccal administration the 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.
The 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. Alternatively, 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.
For intranasal administration the compounds of the invention may be used, for example, as a liquid spray, as a powder or in the form of drops.
For administration by inhalation 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. In the case of a pressurised aerosol 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.
It will be appreciated that the precise dose administered will depend on the age and condition of the patient, the particular compound used and the frequency and route of administration and will ultimately be at the discretion of the attendant physician. 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.
For oral administration 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.
The combinations referred to above may conveniently be presented for use in the form of a pharmaceutical formulation and thus pharmaceutical formulations 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.
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.
When such combinations are employed the dose of each component of the combination will in general be that employed for each component when used alone.
Compounds of formula (la) 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. Thus, for example, compounds of formula (la) 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. Typically, compounds of formula (la) 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. In the following processes, R , R2, R3, R4, R5 R6, R7 R8, R9, R10,R 1, R 2,R13 R14 R15_ Alk, X, n, m and p are as defined for formula (I) unless otherwise specified.
According to one general process (A) compounds of formula (I) may be prepared by coupling compounds of formula (II)
(ID
Figure imgf000012_0001
with compounds of formula (III)
Figure imgf000013_0001
wherein one of R16 and R17 represents a halogen atom, preferably bromine, and the other is a group of formula -B(OH)2 or -Sn (lower alkyl)3, preferably -Sn(CH3)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 R16 and R17 represents -B(OH)2, a base such as an alkali metal carbonate, eg sodium carbonate. Conveniently the reaction is carried out in 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.
Thus, for example, compounds of formula (II) or formula (III) wherein R16 and R17 are -B(OH)2 may be prepared from the corresponding compounds wherein R16 and R1 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 5θOC, preferably at about -78υC. 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.
Alternatively, compounds of formula (II) or (III), wherein R16 and R17 are -
Sn(lower alkyl)3, may be prepared from the corresponding compounds wherein R16 and R17 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.
Intermediates of formula (II) wherein R16 is a halogen atom may be prepared by reduction of compounds of formula (IV)
Figure imgf000014_0001
(wherein Y represents a nitrile group or the group CONR10R1 1 or CH2CONR10R1 1) using 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. For the preparation of compounds of formula (II) wherein R10 and R1 1 do not both represent hydrogen atoms from compounds of formula (IV) wherein Y represents a nitrile group, the reduction should be carried out in the presence of an amine of formula R10R1 1 H.
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. 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 a temperature of -78 to 100°C.
Intermediates of formula (III) wherein R1 is -(Alk)nCONR7R8 and R17 is a halogen atom may be prepared by reacting a compound of formula (V)
Figure imgf000014_0002
with an amine of formula (VI)
HNR7R8 (VI)
or an acid addition salt thereof in the presence of an amide coupling reagent such as diphenylphosphorylazide and a base such as triethylamine. Conveniently the reaction is carried out in a suitable solvent such as N,N- dimethylformamide at a temperature of -78 to 100°C, for example at about 20°C.
Intermediates of formula (III) wherein R1 is
-CH2CON NR
in which R14 is -SO2R15 or -COOR15 and R17 is a halogen atom may be prepared by sulphonylation or acylation of the corresponding compound of formula (VII)
Figure imgf000015_0001
using 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.
Compounds of formula (IV) may be prepared by reaction of a compound of formula (VIII)
Figure imgf000015_0002
with a phosphorane of formula 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 (R180)2POCH2Y (wherein R18 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 (V), (VI) and (VIII) are known or may be prepared by processes known to those skilled in the art. Compounds of formula (VII) may be prepared by processes analogous to those described for the preparation of compounds of formula (III) wherein R17 represents a halogen atom.
According to another general process (B), compounds of formula (I) wherein R1 is -(Alk)nR4 in which R4 is NR3COR9 or NR3S02R9 and R3 and R9 together form a linking C3_5alk lene chain may be prepared by cyclising the compound of formula (IX)
Figure imgf000016_0001
wherein R 9 is -(Alk)nNHCO(CH2)qZ or -(Alk)nNHSO2(CH2)qZ 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 R1 is -(Alk)nNH2 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 30nC. According to another general process (C), a compound of formula (I) according to the invention may be converted into another compound of the invention using conventional procedures.
Thus a compound of formula (I) wherein one or more of R3, R5, R6, R7, R8, R9, R10 and R1 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. The alkylation reaction is conveniently carried out at a temperature of from 25 to 100°C.
Alternatively, a compound of formula (I) wherein one or more of R5, R6, R10 and R1 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. Alternatively, the alkylation may be performed by heating a compound of formula (I) wherein one or more of R5, R6, R10 and R1 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.
Alternatively a compound of formula (I) wherein R1 is AlkOR3 or AlkR4 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 3θOC.
Alternatively compounds of formula (I) wherein R1 represents a hydroxyalkyl group may be prepared by reduction of a compound of formula (I) wherein R1 represents a group -(Alk)nCOOR3. 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.
Alternatively compounds of formula (I) wherein R1 is a group -(Alk)nOCOR3, -(Alk)nNR3SO2R9 -(Alk)nNR3COR9, -(Alk)nNR3COOR9 or
-(Alk)nNR3SO2NR7R8 may be prepared from compounds of formula (I) in which R1 is -(Alk)nOH or -(Alk)nNHR3 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.
Alternatively compounds of formula (I) wherein R1 is a group -(Alk)nCONR7R8 may be prepared from compounds of formula (I) in which R1 is -(Alk)nCOOH 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).
According to another general process (D) compounds of formula (la) wherein C is a C2.3alkylene chain, especially compounds of formula (la) 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)
Figure imgf000019_0001
For the preparation of compounds of formula (la) wherein Rc and Rd do not both represent hydrogen atoms, the reaction is carried out in the presence of an amine of formula RcRdNH.
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. 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.
Intermediates of formula (X) wherein E is 4H-[1 ,2,4]-triazol-3-yl and A-B is O-CH may be prepared from the compound of formula (XI)
Figure imgf000019_0002
by reaction with the compound of formula (XII)
R— CH- OCH2CH3
(XII)
NH
The reaction is conveniently effected in a suitable reaction medium at a temperature of from "10 to +150υC, 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)
Figure imgf000020_0001
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. The reaction is conveniently effected at a temperature of 0 to 110°C, preferably 50 to 100°C.
The compound of formula (XIII) may be prepared from the compound of formula (XIV)
Figure imgf000020_0002
for example by treatment with the phosphorane of formula (XV)
Ph3P=CHCN (XV)
in 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. Conveniently the reaction is carried at a temperature of 20 to 150°C, preferably at about 140°C.
Other compounds of formula (X) may be prepared by methods analogous to those known in the art.
According to a further general process (E), compounds of formula (la) wherein E is a 1 ,2,4-triazol-3-yl ring, especially those wherein A-B is O-CH, may be prepared by reaction of a compound of formula (XVI)
(XVI)
Figure imgf000020_0003
(wherein Xa represents a nitrile group or a reactive derivative thereof) with a compound of formula (XVII) :
R-|CONHNH2 (XVII)
Compounds of formula (XVI) in which Xa represents a reactive derivative of a nitrile group may include compounds of formula (XVIA)
Figure imgf000021_0001
(wherein L is a readily displaceable atom or group).
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.
Where Xa represents a nitrile group the process is conveniently effected in 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.
When a compound of formula (XVIA) is employed the reaction is conveniently effected in a suitable reaction medium at a temperature of from "10 to +15θOC, optionally in the presence of a base. Suitable solvents and bases include those described for the preparation of compounds of formula (X) above.
Compounds of formula (XVIA) in which L represents an alkoxy group may be prepared from compounds of formula (XVI) wherein Xa represents a nitrile group for example by treatment with the appropriate alkanol in the presence of hydrogen chloride, and conveniently at a temperature of from "10 to +30°C.
Compounds of formula (XVIA) wherein L is an alkylthio group may be prepared from compounds of formula (XVIII) (XVIII)
Figure imgf000022_0001
by reaction with the appropriate alkyl halide, e.g. methyl iodide, in a suitable solvent such as an alcohol e.g. methanol.
Compounds of formula (XVIII) may be prepared from compounds of formula (XVI), wherein Xa represents a nitrile group for example by reaction with hydrogen sulphide in dimethylformamide in the presence of triethylamine.
Compounds of formula (XVI) wherein Xa represents a nitrile group may be prepared by treatment of compounds of formula (XIX)
Figure imgf000022_0002
(wherein Hal represents a halogen atom, for example a bromine or iodine atom) with a metal cyanide, e.g. cuprous cyanide, in a suitable solvent, e.g. N- methylpyrrolidinone or dimethylformamide, at a temperature of 50 to 200°c.
Compounds of formula (XIX) may be prepared by methods analogous to those known in the art.
According to another general process (F), 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.
Thus, at an earlier stage in the preparation of a compound of formula (I) or a salt thereof it may have been necessary and/or desirable to protect one or more sensitive groups in the molecule to prevent undesirable side reactions.
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. Thus, compounds of general formula (I) wherein one or more of the groups R5, R6, R10 and R1 1 represent hydrogen may be prepared by deprotection of a corresponding protected compound.
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.
Removal of any protecting groups present may be achieved by conventional procedures. Thus an aralkyl group such as benzyl, may be cleaved by hydrogenolysis in the presence of a catalyst (e.g. palladium on charcoal); 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.
As will be appreciated, in any of the general processes (A) to (E) described above it may be necessary or desired to protect any sensitive groups in the molecule as just described. Thus, a reaction step involving deprotection of a protected derivative of general formula (I) or a salt thereof may be carried out subsequent to any of the above described processes (A) to (E).
Thus, according to a further aspect of the invention, 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. Where it is desired to isolate 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).
As well as being employed as the last main step in the preparative sequence, 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.
The invention is further illustrated by the following Examples which should not be construed as constituting a limitation thereto. All temperatures are in °C. Ammonia (NH3) or 0.88 NH4OH means aqueous ammonium hydroxide. EtOH means ethanol. THF means tetrahydrofuran. DME means dimethoxyethane. DMF means N,N-dimethylformamide. Dried means dried over anhydrous sodium sulphate (unless otherwise stated). Chromatography was performed on silica (Merck 9385 unless otherwise stated). IPA means iodoplatinic acid. T.l.c. means thin layer chromatography. Detection employed U.V. light and IPA unless otherwise stated.
Intermediate 1
5-Bromo-3-Dyridinemethanamine
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. The crude material was purified by flash chromatography using CH2Cl2: tOH:NH3 (100:8:1) as eluant to yield the amine as a pale yellow oil. T.l.c. Rf 0.31 ; CH2CI2:EtOH:NH3; 100:8:1; Detection U.V., IPA Intermediate 2
5-Bromo-3-benzofuranethanamine (i) 5-Bromo-3-(cvanomethyl)benzofuran A suspension .of 5-bromo-3-(2H)-benzofuranone (4.26g) and cyanomethylene triphenylphosphorane (9.06g) in dry xylene (100ml) was heated at reflux for 24h. A further quantity of the phosphorane (450mg) was added and heating continued for a further period of 12h. On cooling to ambient temperature the brown coloured suspension was evaporated to dryness in vacuo. Chromatography of the residue using dichloromethane.hexane (1:3) as eluant afforded a cream coloured product. Recrystallization (from ethanol) of the chromatographed material afforded the title compound as cream flakes, m.p. 120°. T.l.c. Rf 0.73; dichloromethane.
(ii) 5-Bromo-3-benzofuranethanamine
To a stirred solution of the product of stage (i) (0.5g) in dry THF (15ml) at 0°C was added a solution of borane in THF (3.2ml of a 1 M solution). The solution was warmed to room temperature and stirred for 3h, a further quantity of borane in THF (3.2ml of a 1 M solution) was added and the solution stirred overnight. Methanol (5ml) was added after cooling to 0°C, followed by 2N hydrochloric acid (10ml). The solution was refluxed for 1h, cooled, the solvent removed in vacuo, dissolved in 2N hydrochloric acid (20ml) and washed with ether (2x10ml). The aqueous solution was neutralised with solid potassium hydroxide, extracted with dichloromethane (3x20ml), dried and the solvent removed in vacuo. The crude material was purified by flash chromatography using dichloromethane:ethanol:ammonia (50:8:1) to yield the title compound as a pale yellow oil. T.l.c. Rf 0.48, dichloromethane:ethanol:ammonia (50:8:1).
Intermediate 3 r3-(2-Aminoethvπ-5-benzofuranyllboronic acid
(0 2-f2-(5-Bromo-3-benzofuranvnethvn-1.1.3.3-tetramethyl-l .3-disila-2- azacvclopentane Bis(chlorodimethylsilyl)ethane (404mg) in dichloromethane (2ml) was added to a mixture of Intermediate 2 (300mg) and triethylamine (522μl) in dichloromethane (3ml) at 0° under nitrogen. The mixture was allowed to warm to room temperature and stirred overnight. Ether (10ml) was added and the mixture filtered. The filtrate was evaporated, more ether (20ml) added and the mixture filtered. The filtrate was evaporated to leave a yellow oil which was unstable to t.l.c. The product was used without further purification.
(ii) r3-(2-Aminoethyl)-5-benzofuranvnboronic acid s-Butyllithium (1.92ml of 1.3M in cyclohexane) was added dropwise to the intermediate from step (i) (485.6mg) in tetrahydrofuran (20ml) at -100° under nitrogen with stirring. After five minutes triisopropylborate (865μl) was added and the mixture allowed to warm to room temperature with stirring. Water (10ml) was added and the mixture stirred overnight. The solvents were evaporated and the residue purified by column chromatography on silica gel (20g, Merck 7729) eluting with 25:8:1 then 15:8:1 dichloromethane:ethanol:ammonia to give the product as an off-white glass. T.l.c. Siθ2 (50:8:1), Rf 0.05; Detection U.V. and IPA
Intermediate 4 3-f2-(Dimethylamino)ethvn-5-benzofuranylboronic acid (i)5-Bromo-N.N-dimethyl-3-benzofuranacetamide
Dimethyl [2-(dimethylamino)-2-oxoethyl]phosphonate (5g) was added to a stirred suspension of sodium hydride (1.02g of a 60% dispersion in oil) in dry THF (100ml) at 0°C under nitrogen. After stirring for 15 minutes 5-bromo-3- (2H)-benzofuranone (5.0g) in THF (20ml) was added dropwise and stirred at room temperature for 3h. Water (50ml) was added and the mixture extracted with ethyl acetate (3x 50ml), dried and the solvent removed in vacuo. The crude material was purified by flash chromatography using 50% ethyl acetate/hexane as eluant to yield the title compound as a pale yellow solid m.p. 92-94°C. Analysis Found : C.51.26; H.4.28; N.4.75. Ci2H-|3BrN02 requires : C.51.09; H.4.29; N.4.96.
(ii 5-Bromo-N.N-dimethyl-3-benzofuranethanamine
Method A
To a solution of the product of stage(i) (3.3g) in dry toluene (50ml) at 0°C was added 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. The solvent was removed in vacuo and the crude material purified by flash chromatography using dichloromethane:ethanol:ammonia (300:8:1 → 100:8:1) as eluant to yield the title compound as pale yellow oil. T.l.c. Rf 0.1; dichloromethane:ethanol:ammonia (300:8:1).
Method B
Intermediate 2 (1.20g) was stirred with aqueous formaldehyde (1.22ml). Two drops of formic acid were added and the mixture heated to 90°C when CO2 began to be evolved. Further formic acid (1.05ml) was added dropwise over a period of 3h. The reaction was heated for a further 2h, diluted with dilute HCI (2N, 20ml) and then evaporated to dryness. The residual oil was partitioned between aqueous sodium hydroxide (2N) and CH2CI2. The aqueous phase was extracted with CH2CI2 (x2) and the combined organic phases washed with water (x2), dried (MgS04) and evaporated to afford an oil. This was subjected to flash chromatography using CH2Cl2:EtOH:NH3 (100:8:1) to give the product. T.l.c. (silica, CH2Cl2:NH3 300:8:1), Rf 0.36 identical to Method A.
(iii) 3-f2-(Dimethylamino)ethvn-5-benzofuranylboronic acid
To a stirred solution of the product of stage(ii) (0.34g) in dry THF (10ml) at -78°C was added sec-butyllithium (1.5ml of a 1.3M solution in cyclohexane). After 30 minutes triisopropylborate (0.58ml) was added and the solution allowed to warm to room temperature. The solution was stirred overnight, water (10ml) added, the solvent removed in vacuo. ethanol (10ml) added and the solvent again removed in vacuo to yield a white foam which was used without further purification or characterisation.
Intermediate 5 5-f3-[2-(Dimethylamino)ethvn-5-benzofuranyl1-3-pyridinemethanamine A solution of Intermediate 4 (0.6g), Intermediate 1 (0.58g) and tetrakistriphenylphosphine palladium [O] (100mg) in DME (20ml) and 2N sodium carbonate solution (5ml) was heated at reflux for 20h. The solution was allowed to cool, added to 2N sodium carbonate solution (20ml), extracted with ethyl acetate (4x30ml), dried and the solvent removed in vacuo. The crude material was purified by flash chromatography (CH2Cl2:EtOH:NH3, 50:8:1) to yield a pale yellow oil. T.l.c. Rf 0.12; Siθ2; CH2Cl2:EtOH:NH3, 50:8:1
Intermediate 6 5-r3-r2-(Dimethylamino)ethyll-5-benzofuranvn-N-methyl-3-pyridinemethanamine (i) 5-Bromo-N-methyl-3-pyridinemethanamine
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. Siθ2 Rf = 0.56 [CH2Cl2/EtOH/O.88 NH4OH 100:8:1] H n.m.r. in CDCI3: 8.58 (1 H,d), 8.48 (1 H,d), 7.86 (1 H,t), 3.77 (2H,s), 2.45 (3H,s), 1.50 (1 H).
(ii) 5-r3-f2-(Dimethylamino)ethyl1-5-benzofuranyll-N-methyl-3-pyridine- methanamine
A solution of the Intermediate 4 (0.203g), the bromopyridine (0.192g) and tetrakis(triphenylphosphine) palladium (0) (0.06g) in DME (15ml) and 2N sodium carbonate solution (3ml) was heated to reflux for 20h under nitrogen. The solution was allowed to cool, the solvent was removed in vacuo and the residue purified by flash chromatography (Merck silica 9385,
CH2Cl2/EtOH/0.88 NH4OH 100:8:1 ) to yield the product as pale yellow oil. T.l.c. Si02 Rf = 0.29 [CH2CI2 / EtOH / 0.88 NH4OH 100:8:1] H n.m.r. in CDCI3: 8.79 (1 H,d), 8.53 (1 H,d), 7.90 (1 H,t), 7.74 (1 H,s), 7.58- 7.48 (3H,m), 3.86 (2H,s), 2.9-2.6 (4H,m), 2.51 (3H,s)2.33 (6H,s). Example 1
Methyl 5-r3-f2-(Dimethylamino)ethvn-5-benzofuranyl1-3-pyridine carboxylate Intermediate 4 (0.30g), methyl 5-bromo-3-pyridine carboxylate (0.55g), tetrakis(triphenylphosphine)palladium[O] (50mg) in dimethoxyethane (20ml) and 2N sodium carbonate solution (4ml) was refluxed for two hours. Further sodium carbonate solution (20ml) was added and the solution extracted with ethyl acetate (3x 50ml), dried and the solvent removed in vacuo. The crude material was purified by flash chromatography using dichloromethane:ethanol:ammonia (100:8:1) as eluant to yield the title compound as a yellow oil. T.l.c. Rf 0.17; dichloromethane: ethano ammonia (100:8:1).
Example 2 5-r3-f2-(Dimethylamino)ethvn-5-benzofuranvn-3-pyridinemethanol To a stirred solution of lithium aluminium hydride (20mg) in dry THF (2ml) at 0°C under nitrogen was added a solution of the product of Example 1 (0.16g) in THF (1ml). After one hour 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. The crude material was purified by flash chromatography using dichloromethane:ethanol:ammonia (50:8:1) to yield the title compound as pale yellow oil. T.l.c. Rf 0.3; dichloromethane:ethanol:ammonia (50:8:1). δ (CDCI3) 2.36 (6H,s), 2.68 (2H, /2AA'BB'), 2.88 (2H,1/2AA,BB'), 4.83 (2H,s),
7.45-7.56 (3H,m), 7.72 (1 H,d), 7.98 (1H,t), 8.58 (1H,d), 8.77 (1H,d).
Example 3
5-[3-f2-(Dimethylamino)ethyl1-5-benzofuranvn-3-pyridinemethanol oxalate To a stirred solution of oxalic acid (25mg) in ethanol (1ml) was added a solution of the compound of Example 2 (82mg) in ethanol (1ml) and stirred for 2 hours. The resulting solid was filtered off, washed with ethanol and dried in vacuo at room temperature. The product was obtained as a white granular solid mp 187- 188°. T.l.c. Rf 0.3; dichloromethane:ethanol:ammonia (50:8:1) δ (d6-CDCI3), 2.88 (6H,s), 3.10-3.22 (2H, /2AA,BB'), 3.38-3.48 (2H, /2AA'BB'), 4.67 (2H,s), 7.68-7.76 (2H,d+dd), 8.05 (1 H,s), 8.08 (1 H,t), 8.12 (1 H,brs), 8.56 (1 H, brd), 8.89 (1 H,brd).
Example 4
5-r3-(2-Aminoethyl)-5-benzofuranyπ-3-pyridinemethanol (i) f5-rrr(1.1 -Dimethylethyl)dimethylsilylloxy1methvn-3-pyridinyllboronic acid 5-Bromo-3-(tert-buytldimethylsilyloxymethyl)pyridine (8.14g) in ether (200ml) was added dropwise over 20 minutes to a stirred solution of n-butyllithium (25ml of 1.59M) in ether (120ml) at -78° under nitrogen with stirring. After 20 minutes, triisopropylborate (12.3ml) was added and the mixture allowed to warm to room temperature. After stirring for 30 minutes at room temperature, water (120ml) was added and the mixture stirred overnight. The solvents were evaporated to give the crude product as a yellow foam which was used without further purification or characterisation.
(ii)5-r3-(2-Aminoethyl)-5-benzofuranvn-3-pyridinemethanol
A solution of the product of stage (i) (0.15g), Intermediate 3 (0.25g) and tetrakis(triphenylphosphine)palladium[0] (100mg) in dimethoxyethane (5ml) and 2N sodium carbonate solution (1ml) was refluxed under nitrogen for 3h. The solution was diluted with 2N sodium carbonate solution (20ml), extracted with ethyl acetate (3x50ml), washed with brine (20ml), dried and the solvent removed in vacuo. The residue was dissolved in acetic acid:water:THF (10ml of a 6:3:1 mixture) and heated at reflux for 2h, allowed to cool, the solvent removed jn vacuo and purified by flash chromatography using dichloromethane:ethanol:ammonia (50:8:1) as eluant to yield a pale yellow oil. T.l.c. Rf 0.20; dichIoromethane:ethanol:ammonia (50:8:1). δ (CDCI3), 2.65 (2H,vbrs), 2.89 (2H,1/2AA'BB'), 3.09 ^H.^AA'BB'), 4.79 (2H,s), 7.48-7.6 (3H,m), 7.77 (1H,brs), 7.99 (1H,t), 8.57 (1H,d), 8.77 (1H,d).
Example 5
5-f3-(2-Aminoethyl)-5-benzofuranvn-3-pyridinemethanol, oxalate
To a solution of oxalic acid (20mg) in ethanol (1ml) was added a solution of the compound of Example 4 (60mg) in ethanol (1ml). A white solid immediately precipitated which was filtered off and dried in vacuo at room temperature m.p. 120-123°C δ (d6-DMSO) 3.05-3.10 (2H, /2AA'BB'), 3.15-3.25 (2H,1/2AA'BB'), 4.68 (2H,s), 7.68-7.76 (2H, d+dd), 7.99 (1H,s), 8.09 (2H,brs), 8.55 (1H,brd), 8.88 (1H,brd).
Example 6
5-r5-(Methoxymethyl)-3-pyridinvn-3-benzofuranethanamine
(i)3-Bromo-5-(Methoxymethyl)pyridine
To a stirred suspension of sodium hydride (0.50g of a 60% dispersion in oil) in THF (10ml) at 0°C was added a solution of 3-bromo-5-(hydroxymethyl)pyridine (1g) in THF (3ml). After 15 minutes methyl iodide (1ml) was added. After two hours the solution was quenched with water (20ml) and extracted with ethyl acetate (3x50ml), dried and the solvent removed in vacuo to yield a crude oil which was purified by flash chromatography (ethyl acetate hexane, 1:1). The product was obtained as a pale yellow oil.
(ii)5-r5-(Methoxymethyl)-3-pyridinvn-3-benzofuranethanamine
A solution of the product of stage (i) (90mg), Intermediate 3 (60mg) and tetrakis
(triphenylphosphine) palladium (0) (10mg) in dimethoxyethane (5ml) and 2N sodium carbonate solution (1ml) was heated at reflux for 3 hours. The solution was allowed to cool, added to 2N sodium carbonate solution (10ml), extracted with ethyl acetate (3x50ml), dried and the solvent removed in vacuo. The crude material was purified by flash chromatography using dichloromethane: ethanol: ammonia (50:8:1) as eluant to yield the title compound as a pale yellow oil.
Tlc.SiO2; CH2CI2: EtOH:NH3, 50:8:1; Rf 0.30;u.v. IPA
Example 7
5-f5-(Methoxymethyl)-3-pyridinvn-3-benzofuranethanamine. oxalate To a refiuxing solution of oxalic acid (13mg) in ethanol (1ml) was added a solution of the compound of Example 6 (40mg) in ethanol (1ml). The mixture was allowed to cool and the solid was filtered off to give a brown hygroscopic solid m.p. 65-67°C. δ (DMSO-d6) 3.0-3.3(m), 3.39(s, 3H), 4.58(s, 2H),- and 7.7-9.0(m). Example 8
5-(5-Methyl-3-pyridinvπ-3-benzofuranethanamine. oxalate (1 :0.75) (0 (5-Methyl-3-pyridinv0boronic acid 3-Bromo-5-methylpyridine (0.7g) in ether (20ml) was added to n-butyllithium (5.1ml of 1.6M in hexane) in ether (20ml) at -78° under nitrogen with stirring over 75 minutes. After stirring at -78° for 1h, triisopropylborate (2.8ml) was added and the mixture allowed to warm to room temperature. Water (15ml) was added and the mixture stirred overnight. The mixture was evaporated to leave a yellow foam which was used without further purification or characterisation.
(ii) 5-(5-Methyl-3-pyridinyl)-3-benzofuranethanamine. oxalate (1:0.75)
A mixture of the product of step (i) (342mg), Intermediate 2 (308mg), tetrakis
(triphenylphosphine) palladium (0) (25mg) and 2N aqueous sodium carbonate (2ml) in dimethoxyethane (15ml) was heated to reflux with stirring under nitrogen overnight. The mixture was evaporated and the residue purified by column chromatography on silica gel (60g Merck 7729) eluting with 100:8:1 dichloromethane:ethanol:ammonia to give the product as a yellow oil. This was dissolved in ethanol (2ml) and oxalic acid (52.3mg) added in ethanol (1ml). The precipitate formed was collected and recrystallised from methanol to give the product as a pale yellow solid. The mother liquors crystallised on standing to give the product as a white solid m.p. dec. >180°. Analysis Found: C.65.9; H.5.7; N,8.8;
Cl6Hl6N2θ.0.75C2H2O4 requires : C.65.7; H.5.5; N,8.8% T.l.c. Si02 (50:8:1), Rf 0.28; detection U.V. and IPA
Example 9
5-f3-(2-Aminoethyl)-5-benzofuranvn-N-methyl-3-pyridinesulphonamide
(i)5-Bromo-N-methyl-3-pyridinesulphonamide A mixture of pyridine 2-sulphonyl chloride (10.0g) and bromine (3.2ml) was heated at 40-50° for 2 days. The mixture was stood overnight at room temperature and methylamine was condensed into the reaction mixture dropwise. The reaction was extremely exothermic and the flask was cooled in a dry ice bath. Once the vigorous reaction subsided, carbon tetrachloride (10ml) was added and methylamine (10ml) condensed in. The solid slowly dissolved in the methylamine to give an orange solution. After stirring at room temperature for 1h, the solvents were evaporated and the residue treated with water (100ml), extracted with chloroform (3x50ml) and the extracts washed with brine (100ml), dried (MgS04), filtered and evaporated to leave a brown oil. This was purified by column chromatography on silica gel (200g Merck 7729) eluting with 250:8:1 dichloromethane:ethanol:ammonia (twice) to give crude product as a yellow solid. This was further purified by HPLC (55-CN column, eluting with chloroform) to give pure product as a white powder. Analysis Found : C.28.8; H.2.75; N.11.1; C6H7BrN2θ2S requires : C.28.7; H.2.8; N.11.2%
(ii) 5-f3-(2-Aminoethvπ-5-benzofuranvn-N-methyl-3-pyridinesulphonamide
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).
T.l.c. Siθ2 (50:8:1 ,CH2Cl2:EtOH:NH3), Rf 0.23; Detection U.V. and IPA
Example 10 5-r3-(2-Aminoethyl)-5-benzofuranvn-3-pyridinecarboxamide (i) 5-Bromo-3-pyridinecarboxamide
A solution of methyl 5-bromo-3-pyridinecarboxylate (1.6g) in methanolic ammonia (80ml) was heated at 100°C in a Parr autoclave for 16h. The solution was allowed to cool, the solvent removed in vacuo and the resulting solid triturated with ether. The solid was filtered off and the product obtained as a buff crystalline powder m.p. 220-221 °C.
Analysis Found: C.35.87; H.2.46; N.13.57;
Requires : C.35.85; H.2.51; N, 13.94% (ii) 5-f3-(2-Aminoethyl)-5-benzofuranvn-3-pyridinecarboxamide A solution of the Intermediate 3 (0.5g), the product of step (i) (0.74g), tetrakis(triphenylphosphine) palladium [0] (50mg) in dimethoxyethane (10ml) and 2N sodium carbonate solution (2.5ml) was heated at reflux for 6h. The solution was allowed to cool, diluted with 2N sodium carbonate solution (20ml) and extracted with ethyl acetate (3x50ml), dried and the solvent removed ]n vacuo to yield a crude oil which was purified by flash chromatography (CH2Cl2:EtOH:NH3, 25:8:1 ) to yield the product as a pale yellow foam. T.l.c. Rf 0.30; SiO2; CH2CI2: EtOH:NH3, 25:8:1 ; Detection U.V., IPA
Example 11
5-f3-(2-Aminoethyl)-5-benzofuranvn-3-pyridinecarboxamide oxalate (1:1 ) To a solution of oxalic acid (49mg) in ethanol (1ml) at reflux was added a solution of the product of Example 10 (153mg) in ethanol (2ml). The solution was allowed to cool and the resulting solid filtered off, washed with ethanol and dried in vacuo. The product was obtained as a white crystalline solid m.p. 142- 144°C. T.l.c. Rf 0.30; SiO2; CH2Cl2:EtOH:NH3, 25:8:1; Detection U.V., IPA
Example 12 N-fr5-r3-(2-Aminoethyl)-5-benzofuranvn-3-pyridinyllmethvn methanesulphonamide
(i) N-r(5-Bromo-3-pyridinyl)methvnmethanesulphonamide Methanesulphonyl chloride (0.25ml) was added to a solution of the Intermediate 1 (0.25g), in dichloromethane (5ml) and triethylamine (0.74ml) at 0°C under N2. After 2h the solution was added to 2N sodium carbonate solution (20ml) and extracted with dichloromethane (4x20ml), dried and the solvent removed ]n vacuo. The crude material was purified by flash chromatography (CH2Cl2:EtOH:NH3, 100:8:1) to yield the product as a pale yellow oil. T.l.c. Rf 0.37; CH2Cl2:EtOH:NH3, 100:8:1; Detection U.V., IPA δ (MeOH-d4) 3.01 (s, 3H), 3.1 -3.4(m), 4.4(s) and 7.6-8.8(m).
(ii) N-rr5-r3-(2-AminoethvD-5-benzofuranyll-3-pyridinvnmethyl1methane- sulphonamide
A solution of the product of step (i) (0.194g), Intermediate 3 (0.188g), tetrakis(triphenylphosphine) palladium [O] (20mg) in DME (8ml) and 2N sodium carbonate solution (2ml) was heated at reflux for 3h, allowed to cool and the solvent removed in vacuo. The crude material was purified by flash chromatography (CH2Cl2:EtOH:NH3, 25:8:1) to yield a pale oil. T.l.c. Rf 0.28; Si02; CH2Cl2:EtOH:NH3, 50:8:1
Example 13
N-ff5-r3-r2-(Dimethylamino)ethvn-5-benzofuranyl1-3-pyridinvπmethyl1methane- sulphonamide dihvdrochloride
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. Rf 0.69; CH2Cl2:EtOH:NH3, 50:8:1; Detection U.V., KMnO . Example 14 5-f3-(2-Aminoethyl)-5-benzofuranvn-3-pyridinemethanamine A solution of Intermediate 3 (0.18g), Intermediate 1 (0.2g) and tetrakis(triphenylphosphine) palladium [O] (20mg) in dimethoxyethane (8ml) and 2N sodium carbonate solution (2ml) was heated at reflux for 6h. The solution was allowed to cool, the solvent removed in vacuo and purified by flash chromatography (CH2Cl2:EtOH:NH3, 100:8:1) to yield the product as a pale yellow oil. T.l.c. Rf 0.22; Siθ2; CH2Cl2:EtOH:NH3, 25:8:1); Detection U.V., IPA.
Example 15
5-f3-(2-Aminoethyl)-5-benzofuranvn-3-pyridinemethanamine monohvdrochloride To ethanolic HCI at 0°C was added a solution of the product of Example 14 (0.124g) in ethanol (1ml). The solid was filtered off and dried in vacuo to give the product as an off-white solid, m.p. 260-265°C (dec), δ (DMSO-d6) 3.0-3.3(m), 4.31 (q, 2H) and 7.7-9.3(m).
Example 16 N-rf5-r3-(2-Aminoethyl)-5-benzofuranyl1-3-pyridinyl1methyllacetamide oxalate n
(i) N-f(5-Bromo-3-pyridinyl)methyl1acetamide
Intermediate 1 (500mg) was dissolved in dried dichloromethane (20ml) and to the solution was added triethylamine (405mg) followed by acetyl chloride (273mg) dropwise over 5 minutes at 0°C. The mixture was warmed to room temperature over 1h and stirred for a further 1h. The solvents were then evaporated to leave a yellow residue which was purified by flash column chromatography eluting with a mixture of CH2Cl2:EtOH:NH3 (100:8:1) to give the product as a yellow solid.
Analysis Found : C.41.9; H.3.8; N.11.9;
CsHgBr^O requires : C.42.0; H,4.0; N,12.2%
(ii) N-fr5-r3-(2-Aminoethyl)-5-benzofuranvn-3-pyridinvnmethvnacetamide oxalate (1 :1 )
A mixture of Intermediate 3 (250mg), the product of stage (i) (354mg), palladium tetrakis(triphenylphosphine) (30mg), dimethoxyethane (8ml) and 2N sodium carbonate (aq) (1ml) was heated at 100° for 19h. The solvent was evaporated in vacuo to leave a brown oil that was purified by flash column chromatography eluting with a mixture of CH2Cl2:EtOH:NH3 (50:8:1) to give the free base as a brown oil.
The oil (101mg) was dissolved in ethanol (0.5ml) and a solution of oxalic acid (29mg) in ethanol (0.5ml) was added dropwise at 5°C with stirring. Diethyl ether (5ml) was added with stirring and the mixture warmed to room temperature and stirred for 30 minutes. The solvents were decanted and the solid product dried in vacuo at 60° for 3h to give the product as a cream solid - m.p.>110° (foams). T.l.c. Siθ2, CH2Cl2:EtOH:NH3 (50:8:1), Rf=0.17, Detection: U.V. and IPA spray δ (DMSO-d6) 1.92(s, 3H), 3.0-3.3(m), 4.38(d, 2H), and 7.6-8.9(m).
Example 17
5-f3-f2-(Dimethylamino)ethyl1-5-benzofuranyl1-3-pyridinemethanamine
A solution of Intermediate 4 (0.6g), Intermediate 1 (0.58g) and tetrakis(triphenylphosphine) palladium [O] (100mg) in dimethoxyethane (20ml) and 2N sodium carbonate solution (5ml) was heated at reflux for 20h. The solution was allowed to cool, added to 2N sodium carbonate solution (20ml), extracted with ethyl acetate (4x30ml), dried and the solvent removed in vacuo. The crude material was purified by flash chromatography (CH2Cl2:EtOH: H3, 50:8:1 ) to yield a pale yellow oil. T.l.c. Rf 0.12; Siθ2; CH2Cl2:EtOH:NH3, 50:8:1
Example 18
N-fr5-r3-r2-(Dimethylamino)ethvn-5-benzofuranvπ-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. The crude material was purified by flash chromatography (CH2Cl2:EtOH:NH3, 50:8:1) to yield a pale oil which was dissolved in ethanol, ethanolic HCI added and the solvent removed in vacuo. The resulting solid was dissolved in water and freeze dried, m.p. 79- 82°C. T.l.c. Rf 0.21; Siθ2; CH2CI2:EtOH:NH3, 50:8:1; Detection U.V., IPA
Example 19
Methyl rf5-f3-f2-(dimethylamino)ethvn-5-benzofuranvn-3-pyridinvn methyllcarbamate dihvdrochloride
To a solution of the product of Example 17 (0.20g) in dichloromethane (5ml) and triethylamine (0.19ml) was added methylchloroformate (0.8ml). After 2h the solution was poured into water (20ml) and extracted with dichloromethane (3x30ml), dried and the solvent removed in vacuo. The crude material was purified by flash chromatography (CH2Cl2:EtOH:NH3, 50:8:1) to yield a pale yellow oil. The oil was dissolved in ethanol, ethanolic HCI added and the solvent removed in vacuo. The residue was dissolved in water and freeze dried to yield a white solid, m.p. 50-54°C. T.l.c. Rf 0.49; Siθ2; CH2Cl2:EtOH:NH3, 50:8:1 ; Detection U.V., IPA
Example 20
5-f3-r2-(Dimethylamino)ethvn-5-benzofuranvn-3-pyridinemethanol acetate - (ester) oxalate (1:1 ) (salt) To a solution of the product of Example 2 (165mg) in dried dichloromethane (4ml) was added triethylamine (113mg) with stirring at 0°. Acetyl chloride (53mg) in dichloromethane (0.5ml) was added dropwise and the mixture warmed to room temperature and stirred for 1 h. The solvent was evaporated in vacuo to leave a brown oil which was purified by flash column chromatography eluting with a mixture of CH2Cl2:EtOH:NH3 (200:8:1 ) to give the free base as a brown oil. The free base (114mg) was dissolved in ethanol (1ml) and a solution of oxalic acid (31 mg) in ethanol (1ml) was added with stirring at 0°C. Diethyl ether (5ml) was added dropwise with stirring and the mixture slowly warmed to room temperature and stirred for a further 1 h. The solvents were decanted and the solid dried in vacuo to give the product as a cream solid, - m.p. 153.4-159.5°. Analysis Found : C,58.9; H.5.5; N.5.8;
C-20H22N2O3I.3C2H2O4.O.45H2O requires C.58.6; H.5.5; N,6.0% Water Analysis contains 1.8%w/w. T.l.c. Siθ2, CH2Cl2:EtOH:NH3 (100:8:1), Rf=0.27, Detection U.V., KMnθ and IPA spray
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. On cooling, the solvents were evaporated and the resultant brown oil was purified by flash chromatography using CH2Cl2:EtOH:NH3 (100:8:1) as eluant to give a brown oil (146mg). A portion of this (120mg) was purified by preparative HPLC, using a 15cm, 53CN column, eluting with a solution of 0.12% v/v trifluoracetic acid and 10% v/v acetonitrile in water to yield the product. T.l.c. Si02 (CH2CI2:EtOH:NH3, 100:8:1 ) Rf 0.34; Detection: u.v., IPA δ (MeOH-d4) 2.9-3.1(m), 4.77(s, 2H) and 7.6-8.8(m).
Example 22
N-rr5-r3-r2-(dimethylamino)ethyl]-5-benzofuranvn-2-pyridinvnmethyll- methanesulphonamide dihvdrochloride (i)5-Bromo-2-(bromomethyl)pyridine hvdrobromide
A solution of the 5-bromo-2-hydroxymethylpyridine (2.0g) in aqueous 40% hydrobromic acid (20ml) was heated at reflux under nitrogen for 20h. The solvent was evaporated to give the product as a pale brown solid which was used directly in the next stage without further purification.
(ii)5-Bromo-2-pyridinemethanamine
Ammonia (10ml) was added to product of stage (i) (1.2g) in ethanol (10ml) and stirred at 23° for 20h. The solvent was evaporated and the residue purified by flash chromatography using dichloromethane-ethanol-ammonia (100:8:1) as eluant to yield the product as a pale yellow oil.
T.l.c. Siθ2 (CH2Cl2:EtOH:NH3, 100:8:1) Rf 0.21; Detection: u.v., IPA
(iii) N-r(5-Bromo-2-pyridinyl)methvnmethanesulphonamide
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 (Na2Sθ4) 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. SiO2 (CH2CI2:EtOH:NH3, 200:8:1) Rf 0.29; Detection: u.v., KMnO
(iv)N-rr5-r3-r2-(Dimethylamino)ethvn-5-benzofuranyl1-2- pyridinvnmethvnmethanesulphonamide dihvdrochloride
A solution of Intermediate 4 (0.28g), the product of stage (iii) (0.27g) and tetrakis(triphenylphosphine)palladium [O] (50mg) in 1 ,2-dimethoxyethane (10ml) and aqueous 2N sodium carbonate (2ml) was heated at reflux under nitrogen for 20h. The solution was allowed to cool, diluted with aqueous 2N sodium carbonate (20ml) and extracted with ethyl acetate (4x30ml). The combined, dried organic extracts were evaporated and the residue was purified by flash chromatography using dichloromethane-ethanol-ammonia (100:8:1 ) as eluant to yield the free base as a pale yellow solid. T.l.c. Siθ2 (CH2Cl2:EtOH:NH3, 100:8:1) Rf 0.12; Detection: u.v., IPA This was purified by preparative HPLC and converted to the hydrochloride salt by dissolution in ethanolic hydrogen chloride followed by freeze drying to give the product, m.p. 118-121 °. δ (MeOH-d ) 3.02(s,6H), 3.23(s, 3H), 3.3(m), 3.58(m), 4.77(s), and 7.6-9.2(m).
Example 23
1-rr5-f3-r2-(dimethylamino)ethyl1-5-benzofuranyl1-3-pyridinvnmethvπ-2- pyrrolidinone
(i) 4-Chloro-N-fr5-r3-r2-(dimethylamino)ethvn-5-benzofuranvn-3- pyridinyllmethvπ- butanamide oxalate
4-Chlorobutyryl chloride (57μi) was added at 0° to a solution of the product of
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
(50:8:1 ) as eluant to give a colourless oil.
T.l.c. Si02 (CH2Cl2:EtOH:NH , 50:8:1 ) Rf 0.51 ; Detection: u.v., IPA.
This was treated with oxalic acid (26mg) in ethanol and the solution evaporated. A solution of the residue in water was freeze-dried to give the product (119mg) as a sticky, hygroscopic foam.
(ii) 1-rf5-[3-r2-(Dimethylamino)ethyll-5-benzofuranvn-3-pyridinyl1methvn-2- pyrrolidinone A mixture of sodium hydride (60% dispersion in oil, 36mg), dimethylformamide, and the product of stage (i) (0.1 Og) was stirred at room temperature for 20h.
Water (2ml) was added and the mixture was evaporated. The residue was taken up in ethanol, filtered, and evaporated. The residue was purified by column chromatography using dichloromethane:ethanol:ammonia (100:8:1 ) as eluant to give the product as a colourless oil.
T.l.c. S1O2 (CH2Cl2:EtOH:NH3, 50:8:1 ) Rf 0.6; Detection: u.v. δ (DMSO-d6) 1.97(m), 2.25(s, 6H), 2.33(t), 2.62(t), 2.87(t), 3.3-3.5(m), 4.52(s,
2H) and 7.2-8.9(m). Example 24
1-fr5-r3-f2-(dimethylamino)ethvn-5-benzofuranvn-3-pyridinvnmethyll-2- pyrrolidinone
(i)N-r(5-Bromo-3-pyridinyl)methyl -4-chlorobutanamide 4-Chlorobutyryl chloride (0.45ml) was added dropwise to a stirred solution of Intermediate 1 (0.56g) in dry dichloromethane (20ml) and pyridine (2ml) cooled in ice under nitrogen. After 10min, stirring was continued at room temperature for 20h. The mixture was partitioned between ethyl acetate and water. The dried (MgSθ4) organic phase was evaporated to leave a yellow oil. This was purified by column chromatography using dichloromethane:ethanol:ammonia (200:8:1 ) as eluant to give the product as a pale yellow solid. T.l.c. Si02 (CH2Cl2:EtOH:NH3, 150:8:1) Rf 0.24; Detection: u.v., IPA.
(ii)1-r(5-Bromo-3-pyridinyl)methvn-2-pyrrolidinone Sodium hydride (60% dispersion in oil, 0.1g) was added in one portion to a solution of the product of stage (i) (0.6g) in dimethylformamide (10ml) at 0° under nitrogen and stirring was continued for 20h at 23°. Water (3ml) was added and the solvent was evaporated. The residue was purified by column chromatography using dichloromethane:ethanol:ammonia (300:8:1 ) as eluant to give the product as a pale yellow solid.
T.l.c. Si0 (CH2CI2:EtOH:NH3, 100:8:1) Rf 0.88; Detection: u.v., IPA.
(iii) 1-ff5-r3-r2-(Dimethylamino)ethvn-5-benzofuranvn-3-pyridinyl1methvn-2- pyrrolidinone dihvdrochloride A mixture of Intermediate 4 (0.1 Og), the product of stage (ii) (0.142g), tetrakis(triphenylphosphine)palladium (O) (50mg), 1,2- dimethoxyethane (5.0ml) and aqueous (6%) sodium carbonate (1.0ml) was heated to reflux under nitrogen for 18h. The solvent was evaporated and the residue taken up in ethanol. This was purified by column chromatography using dichloromethane:ethanol:ammonia (150:8:1) as eluant to give a yellow oil. T.l.c. Siθ2 (CH2Cl2:EtOH:NH3, 100:8:1) Rf 0.3; Detection: u.v., IPA. This was treated with ethanolic hydrogen chloride and evaporated. The residue was treated with isopropanol and evaporated to give the product, δ (DMSO-d6) 2.00(m), 2.27(t), 2.8-3.6(m), 4.64(s, 2H) and 7.7- 9.3(m). Example 25
(E)-2-r5-r3-f2-(Dimethylamino)ethvn-5-benzofuranyl1-3-pyridinvn-N-methyl- ethenesulphonamide dihvdrochloride (i)(E)-2-(5-Bromo-3-pyridinyl)-N-methylethenesulphonamide Mixture of 3,5-dibromopyridine (2.00g), N-methylethene sulphonamide (1.02g), palladium (II) acetate (90mg), tri-(o-tolyl)phosphine (0.25g), triethylamine (1.3ml) and dimethylformamide (12ml) was stirred at 100° (external temperature) under nitrogen for 22h. The reaction mixture was evaporated and the residue eluted through silica with dichloromethane-ethanol-ammonia to give a product (I). The above experiment was repeated exactly as described to give a product (II). A solution of the products (I) and (II) in ethyl acetate was treated with ethanolic 1M hydrogen chloride and the precipitate collected. The precipitate was partitioned between aqueous sodium carbonate and ethyl acetate, and the dried (MgSθ4) organic extract was evaporated to give the product as a white solid, m.p. 143°.
(ii) (E)-2-r5-r3-r2-(Dimethylamino)ethvn-5-benzofuranvπ-3-pyridinvn-N-methyl- ethenesulphonamide dihvdrochloride
A mixture of the product of stage (i) (0.30g), Intermediate 4 (0.26g), tetrakis(triphenylphosphine)palladium (O) (0.13g) and aqueous 1M sodium carbonate (2.5ml) in dimethylformamide (10ml) was heated to 100°C under nitrogen for 20h. The solvent was evaporated and the resultant yellow solid was preabsorbed onto silica gel. Column chromatography using dichloromethane:ethanol:ammonia (100:8:1) as eluant gave the major product (Rf 0.28) as a white solid, with slight impurities. Chromatography was repeated eluting with dichloromethane:ethanol:ammonia (100:8:1 ) to give the pure free base as a white solid. A portion of this material was treated with ethanolic hydrogen chloride and evaporated. A solution of the residue in water was freeze-dried to give the product as a white foam. T.l.c. Siθ2 (CH2Cl2:EtOH:NH3, 100:8:1 ) Rf 0.28; Detection: u.v. δ (DMSO-d6) 2.62(d, 3H), 2.87(d, 6H), 3.2-3.5(m), and 7.3-9.5(m).
Example 26
5-r3-r2-(Dimethylamino)ethyl1-5-benzofuranvn-N-methyl-3-pyridine- ethanesulphonamide dihvdrochloride A solution of the product of Example 25 (0.31 g) in ethanol (30ml) was stirred with 10% palladium oxide-on-carbon under hydrogen for 8h. The catalyst was filtered off (hyflo) and 10% palladium oxide-on-carbon (30mg) was added. The mixture was stirred under hydrogen for a further 18h and the catalyst was then filtered off (hyflo). The solvent was evaporated and the residue purified by column chromatography using dichloromethane: ethanohammonia (200:8:1) as eluant to yield a colourless oil. T.l.c. Siθ2 (CH2Cl2:EtOH:NH3, 100:8:1) Rf 0.32; Detection : u.v.
This was treated with ethanolic hyrogen chloride and evaporated. A solution of the residue in water was freeze-dried to give the product as a white foam, δ (DMSO-d6) 2.67(d, 3H), 2.88(d, 6H), 3.2-3.7(m), and 7.3-9.3(m).
Example 27 2-rf5-r3-r2-(Dimethylamino)ethvn-5-benzofuranyll-3-pyridinyll methylTisothiazolidine-l .1 -dioxide dihvdrochloride
(i)N-f(5-Bromo-3-pyridinyl)methyll-3-chloropropanesulphonamide 3-Chloropropanesulfonyl chloride (0.36ml) was added to a stirred solution of Intermediate 1 (0.5g) in dry dichloromethane (15ml) and triethylamine (0.74ml) under nitrogen at 0°C. The mixture was stirred at room temperature for 20h. The solvent was evaporated and the residue purified by column chromatography using dichloromethane-ethanol-ammonia (200:8:1) as eluant to give the major product as a brown oil. This was converted to the hydrochloride salt with ethanolic hydrogen chloride. A solution of the hydrochloride salt in water was extracted with ether. The aqueous phase was basified with sodium hydroxide pellets and extracted with ethyl acetate (x2). The combined, dried (MgS04) ethyl acetate extracts were evaporated to give the product as a brown oil. T.l.c. S1O2 (CH2Cl2:EtOH:NH3, 100:8:1) Rf 0.58; Detection: u.v.
(ii) 2-[(5-Bromo-3-pyridinyl)methvnisothiazolidine-1.1 -dioxide
Sodium hydride (80mg) was added to a solution of the product of stage (i) (0.56g) in dry dimethylformamide (15ml) and the mixture was stirred at room temperature for 24h. Water was added and the solvent evaporated. The residue was purified by column chromatography using ethyl acetate-hexane (1 : 1 ) as eluant to give the product as a white solid. T.l.c. Siθ2 (Ethyl acetate: hexane, 1 :1 ) Rf 0.32; Detection: u.v., IPA
(iii) 2-[r5-r3-r2-(Dimethylamino)ethvn-5-benzofuranvn-3-pyridinyl1methvniso- thiazolidine-1.1 -dioxide dihvdrochloride A mixture of the product of stage (ii) (105mg), Intermediate 4 (104mg), tetrakis(triphenylphosphine)palladium (O) (46mg), dimethylformamide (5ml) and aqueous 2N sodium carbonate (1 ml) was heated to 100°C under nitrogen for 20h. The solvent was evaporated and the residue purified by column chromatography using dichloromethane:ethanol:ammonia (100:8:1 ) as eluant to give the major product as an impure brown oil. Chromatography was repeated to give the pure free base as a colourless oil.
T.l.c. Si02 (CH2CI2-EtOH-NH3, 100:8:1 ) Rf 0.27; Detection: u.v., IPA. A solution of this in ethanol was treated with ethanolic 1 M hydrogen chloride and evaporated. A solution of the residue in water was freeze-dried to give the product as a white foam. δ (DMSO-d6) 2.30(m), 2.88(d, 6H), 3.2-3.5(m), 4.43(s, 2H), and 7.8- 9.3(m).
Example 28 (E)-3-f5-r3-r2-(Dimethylamino)ethvπ-5-benzofuranvn-3-pyridinyl1-2-propenamide (i)(E)-3-(5-Bromo-3-pyridinyl)-2-propenamide
Nitrogen was bubbled through a suspension of 3,5-dibromopyridine (2.00g), acrylamide (0.600g), palladium acetate (0.20g) and triethylamine (2.35ml) in 1 ,2-dimethoxyethane (100ml). After 10min, tri(o-tolyl)phosphine (0.305g) was added and the mixture was heated under reflux, under nitrogen for 3h. The cooled mixture was filtered (Whatman No. 5 filter paper) and the filtrate evaporated. The residue (4.21 g) was purified by flash chromatography using CH2Cl2:EtOH:NH3 (100:8:1 ) as eluant to give a mixture (0.662g). This was triturated with ether to afford a mixture of the product and acrylamide (38:62). T.l.c. Siθ2 (CH2Cl2:EtOH:NH3, 100:8:1 ) Rf 0.26, Detection: u.v., IPA
(ii)(E)-3-f5-r3-r2-(Dimethylamino)ethyll-5-benzofuranyl1-3-pyridinyl1-2- propenamide
Nitrogen was bubbled through a mixture of Intermediate 4 (0.233g), the impure product of stage (i) (0.182g) and aqueous sodium carbonate (5ml) in 1 ,2- dimethoxyethane (15ml). Tetrakis(triphenylphosphine)palladium (50mg) was added and the reaction mixture heated under reflux for 6h. Further Intermediate 4 (100mg) was added and heating was continued for 16h. The reaction mixture was partitioned between dichloromethane and saturated aqueous sodium bicarbonate. The aqueous phase was extracted with dichloromethane (x3) and the combined organic extracts were washed with water, dried (MgS0 ) and evaporated to dryness. The residue (0.452g) was purified by flash chromatography using CH2Cl2:EtOH:NH3 (100:8:1) as eluant to give firstly impurities followed by the impure product. Chromatography was repeated using CH2Cl2:EtOH:NH3 (80:8:1) as eluant to give the product. T.l.c. Si02 (CH2Cl2:EtOH:NH3, 50:8:1) Rf 0.07, Detection: u.v., IPA δ (MeOH-d4) 2.38(s, 6H), 2.7-3.0(m), and 6.8-8.9(m).
Example 29
(E)-3-r5-r3-r2-(Dimethylamino)ethyll-5-benzofuranyll-3-pyridinvπ-2-propenamide dihvdrochloride
The product of Example 28 (58mg) was treated with ethanol (2ml) and ethanolic
1 M hydrogen chloride (0.35ml). The solution was evaporated and the residue was stirred in ether. This was evaporated to give the product, m.p. >253° (dec).
Analysis Found: C.54.5; H.6.2; N.9.1; Cl.16.1; C20H21 N3O2.2HCI.2H2O requires: C.54.1; H.6.1; N.9.5; Cl,15.9%
Water Analysis: 8.87%w/w = 2.21 mol H2O δ (DMSO-d6) 2.88(d, 6H), 3.2-3.5(m), and 7.0-9.2(m).
Example 30 5-r3-f2-(Dimethylamino)ethvn-5-benzofuranvn-3-pyridinepropanamide dihvdrochloride
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 (308μl, 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. The ether was evaporated to yield the product. T.l.c. Si02 (CH2CI2:EtOH:NH3, 25:8:1) Rf 0.55; Detection: u.v., IPA. δ (MeOH-d4) 2.78(t), 3.03(s, 6H), 3.2-3.7(m), and 7.7-9.2(m).
Example 31 N.N-Dimethyl-5-r5-r(methylsulphinyl)methvn-3-pyridinyll-3-benzofuranethan- amine
(i)3-Bromo-5-(bromomethyl)pyridine hvdrobromide
5-Bromo-3-hydroxymethylpyridine (1.289g) was heated under reflux with hydrobromic acid (130ml, 48%w/v) for 3h. Further hydrobromic acid (10ml, 48%w/v) was added and heating continued for 15h. The reaction mixture was concentrated and ethanol (20ml) was added. The solution was evaporated and the resultant brown solid was triturated with ethanol in an ice-bath. The solid was filtered off, washed with ethanol and dried to give the product. The filtrate was evaporated to afford a further quantity of the product.
(ii)3-Bromo-5-f(methylthio)methvnpyridine
The product of 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.
(iii) 3-Bromo-5-f(methylsulphinyl)methyllpyridine
A stirred solution of the product of stage (ii) (0.325g) in dichloromethane (20ml) was treated with 3-chloroperoxybenzoic acid (55% purity, 0.468g) under nitrogen and stirring continued for 4h. The reaction mixture was partitioned between aqueous sodium bicarbonate and dichloromethane. The aqueous phase was extracted with dichloromethane (x2) and the combined organic extracts washed with water, dried (MgSO4) and evaporated. The residue was purified by flash chromatography using dichloromethane:ethanol:ammonia (100:8:1 ) as eluant to give firstly recovered starting material followed by the impure product. T.l.c. Siθ2 (CH2CI2-EtOH-NH3, 100:8:1) Rf 0.40; Detection: u.v.
(iv) N,N-Dimethyl-5-f5-f(methylsulphinyl)methvn-3-pyridinvn-3-benzofuranethan- amine Intermediate 4 (0.117g), the product of stage (iii) (0.118g), aqueous 2M sodium carbonate (5ml) and dimethylformamide (20ml) were stirred whilst nitrogen was bubbled through the reaction mixture for 1min.
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. δ (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).
Example 32 1-r5-r3-[2-(Dimethylamino)ethyll-5-benzofuranvn-3-pyridinvnethanone dihvdrochloride
Nitrogen was bubbled through a mixture of Intermediate 4 (100mg), 3-acetyl-5- bromopyridine (86mg), aqueous sodium bicarbonate (5ml) and dimethylformamide (20ml) for 1min. Tetrakis(triphenylphosphine)palladium (O) (20mg) was added and the mixture heated under nitrogen for 5h. This reaction mixture was combined with that from a similar reaction carried out in the same way, except that acetonitrile was used instead of dimethylformamide. The combined mixtures were partitioned between water and dichloromethane and the aqueous phase further extracted with dichloromethane. The combined organic phases were washed with water, dried (MgSθ4), and evaporated. The residue was purified by flash chromatography using dichloromethane:ethanol:ammonia (100:8:1) as eluant to give the free base. A solution of this in ethanol (5ml) was treated with 1M ethanolic hydrogen chloride (1.15ml) and evaporated. The resultant solid was washed with ether, filtered off, and dried to give the product. T.l.c. Siθ2 (CH2Cl2:EtOH:NH3, 50:8:1) Rf 0.56; Detection: u.v., IPA. δ (DMSO-d6) 2.78(s, 3H), 2.88(d, 6H), 3.2-3.5(m), and 7.7-9.3(m).
Example 33 5-r3-r2-(Dimethylamino)ethyl1-5-benzofuranvn-3-pyridinemethanol carbamate ester dihvdrochloride
(i)5-Bromo-3-pyridinemethanol carbamate ester
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. Si02 (CH2Cl2:EtOH:NH3, 200:8:1) Rf 0.27; Detection: u.v.
(ii) 5-r3-f2-(Dimethylamino)ethyll-5-benzofuranvn-3-pyridinemethanol carbamate ester dihvdrochloride
Intermediate 4 (94mg) and the product of stage (i) (100mg) were stirred in 1,2- dimethoxyethane (30ml) with aqueous 1M sodium carbonate (5ml) whilst nitrogen was bubbled through the solution for 10min. Tetrakis(triphenylphosphine)palladium (O) (30mg) was added and the mixture was heated under reflux for 5h. The reaction was partitioned between dichloromethane and water and the aqueous phase was further extracted with dichloromethane (x2). The combined organic phases were washed with water, dried (MgSO4), and evaporated. The resulting black solid was purified three times by flash chromatography using dichloromethane-ethanol-ammonia (25:8:1, then 50:8:1 , then 10:8:1) as eluant to yield the free base as an oil. This was treated with ethereal hydrogen chloride to give the product as an off-white solid. δ (DMSO-d6) 2.88(d, 6H), 3.1-3.5(m), 5.13(s, 2H), and 7.7-9.0(m).
Example 34
(E)-N.N-Dimethyl-5-f5-r2-(methylsulphonyl)ethenvπ-3-pyridinvn-3-benzo- furanethanamine dihvdrochloride (i) (E)-3-Bromo-5-f2-(methylsulphonyl)ethenvnpyridine
Nitrogen was bubbled through a suspension of 2-methylsulphonylethene (0.895g), 3,5-dibromopyridine (2.00g) and triethylamine (2.35ml) in dimethylformamide. After 10min palladium (II) acetate (0.20g) and tri-o- tolylphosphine (0.30g) were added and the mixture heated under reflux for 5h. The cooled mixture was filtered, and the filtrate evaporated to give a brown solid. This was treated with dichloromethane (100ml), and the insoluble white solid filtered off. The filtrate was preabsorbed onto silica gel and this was purified by flash chromatography. Elution with dichloromethane- ethanol- ammonia (200:8:1) gave an impure product. This was further purified by flash chromatography, eluting with ethyl acetate: cyclohexane (3:4) to give the product.
(ii) E)-N.N-Dimethyl-5-f5-f2-(methylsulphonyl)ethenvn-3-pyridinvn-3-benzofuran- ethanamine dihvdrochloride
Nitrogen was bubbled through a mixture of Intermediate 4 (400mg), the product of stage (i) (314mg), dimethylformamide (120ml), and aqueous 2N sodium carbonate (20ml) for 10min. Tetrakis(triphenylphosphine)palladium (O) (130mg) was added and the stirred mixture heated at reflux under nitrogen for 5h. The cooled mixture was partitioned between dichloromethane and water, and the aqueous phase further extracted with dichloromethane (x2). The combined organic phases were washed with water, dried (MgS04), and evaporated. The residue was purified by flash chromatography using dichloromethane:ethanol:ammonia (100:8:1) as eluant to give the pure free base and impure free base. The impure free base was further purified by chromatography as above to give a second batch of pure free base. The pure batches of free base were combined and treated with ethanolic hydrogen chloride to convert them into the product, δ (CDCI3) 2.35(s, 6H), 2.6-3.0(m), 3.10(s, 3H), and 7.0-9.0(m).
Example 35
N,N-Dimethyl-5-f5-f2-(methylsulphonyl)ethyl1-3-pyridinyl1-3-benzo- furanethanamine dihvdrochloride
A solution of the product of Example 34 (192mg) in ethanol (10ml) was stirred with 5% palladium on carbon (25mg) under hydrogen for 24h. The catalyst was filtered off (hyflo), 5% palladium on carbon (30mg) was added, and the solution stirred under hydrogen for 24h. The catalyst was filtered off (hyflo), 5% palladium on carbon (30mg) was added and the solution stirred under hydrogen for 24h. The catalyst was filtered off (hyflo) and the filtrate evaporated. The residual oil was purified three times by flash chromatography using dichloromethane:ethanol:ammonia (100:8:1) as eluant to give the free base. A solution of the free base in ethanol was treated with two equivalents of ethanolic 1 M hydrogen chloride and then triturated with ether to give the product as a white solid. δ (DMSO-d6) 2.88(d, 6H), 3.12(s, 3H), 3.2-3.8(m) and 7.7-9.3(m).
Example 36
(E)-4-r5-r3-r2-(Dimethylamino)ethvn-5-benzofuranvn-3-pyridinvn-3-buten-2-one dihvdrochloride (i) (E)-4-(5-Bromo-3-pyridinyl)-3-buten-2-one
Nitrogen was bubbled through a solution of 3,5-dibromopyridine (2.00g), triethylamine (2.35ml) and tri-o-tolylphosphine (0.30g) in dimethylformamide (100ml). After 10min palladium Qi) acetate (0.20g) was added and the mixture was heated to 60°C. 3-Buten-2-one (0.70ml) was added dropwise over a few hours. Heating was continued for a further 4h and an equivalent of 3-buten-2- one was added. After a few hours, the cooled mixture was evaporated, water was added, and the mixture extracted with ethyl acetate (x3). The combined organic extracts were washed with brine, dried (MgSO4) and evaporated. The resultant yellow brown solid was purified by flash chromatography using ethyl acetate yclohexane (1 :1 ) as eluant to give the product as a pale yellow solid. T.l.c. Siθ2 (Ethyl acetate yclohexane, 1:1 ) Rf 0.40; Detection: u.v.
(ii) (E)-4-r5-r3-r2-(Dimethylamino)ethvn-5-benzofuranvn-3-pyridinyl1-3-buten-2- one dihvdrochloride Intermediate 4 (350mg) and the product of stage (i) (360mg) were stirred in dimethylformamide (100ml) with aqueous 2N sodium carbonate (20ml) for 20min, with nitrogen bubbling through the solution.
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 (MgSθ4) and evaporated. The residue was purified by flash chromatography using dichloromethane:ethanol:ammonia
(100:8:1 ) as eluant to give the pure free base.
T.l.c. Si02 (CH2CI2:EtOH:NH3, 100:8:1) Rf 0.47; Detection: u.v., IPA.
Further elution gave impure free base which was purified by chromatography as above to give pure free base. The combined samples of pure free base were treated with two equivalents of ethanolic hydrogen chloride to give the product as a pale yellow solid. δ (DMSO-d6) 2.42(s, 3H), 2.88(d, 6H), 3.1-3.5(m), 7.2-9.2(m).
Example 37
N-fr5-r3-r2-(Dimethylamino)ethvn-5-benzofuranvn-3-pyridinvnmethvn-N'.N'- dimethylurea dihvdrochloride
(i) N-r(5-Bromo-3-pyridinyl)methvn-N'.N'-dimethylurea A solution of Intermediate 1 (0.50g) in dry dichloromethane (30ml) was treated with triethylamine (1.1ml) followed by JN,N- dimethylcarbamic chloride (0.5ml) at 0°C under nitrogen. After 30min, further N,N-dimethylcarbamic chloride (0.5ml) was added, and the solution allowed to warm to room temperature. Stirring was continued for 20h. The yellow solution was diluted with aqueous 2N sodium carbonate, and extracted with dichloromethane (x4). The combined organic extracts were washed with brine, dried (MgS04) and evaporated. The resultant orange oil was purified by flash chromatography using dichloromethane:ethanol:ammonia (100:8:1) as eluant to yield the product as a yellow oil. T.l.c. Siθ2 (CH2Cl2:EtOH:NH3, 100:8:1) Rf 0.59; Detection: u.v.
(ii) N-rf5-r3-r2-(Dimethylamino)ethyll-5-benzofuranvπ-3-Pyridinvnmethvn-N'.N'- dimethylurea dihvdrochloride
Intermediate 4 (200mg), the product of stage (i) (200mg) and aqueous 2N sodium carbonate (13ml) was stirred in DMF (100ml) for 10 min, with nitrogen bubbling through the solution. Tetrakis(triphenylphosphine)palladium (0) (80mg) was added, and the mixture heated at ca. 100°C for 3h. The cooled mixture was dissolved in water and extracted with ethyl acetate (x3). The combined organic extracts were washed with brine, dried (MgSO4) and evaporated. The residue was purified by flash chromatography using dichloromethane:ethanol:ammonia (50:8:1) as eluant to give the free base as a pale yellow oil. A solution of this in ethanol was treated with 1M ethanolic hydrogen chloride and evaporated. The residue was triturated with ether to give the product as an off- white solid. δ (DMSO-d6) 2.86(s, 6H), 2.88(d, 6H), 3.2-3.5(m), 4.47(d, 2H) and 7.2-9.3(m).
Example 38
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.
(ii) N-ff5-f3-r2-(Dimethylamino)ethyl1-5-benzofuranvn-3-pyridinvπmethvnurea Intermediate 4 (150mg), the product of stage (i) (150mg) and aqueous 2N sodium carbonate (8ml) were stirred in DMF (50ml) for 10min with nitrogen bubbling through the solution. Tetrakis(triphenylphosphine)palladium (O) (70mg) was added and the mixture heated at reflux for 5h. After cooling, the DMF was evaporated, water was added, and the solution extracted with ethyl acetate (x3). The combined organic extracts were washed with brine, dried (MgS04) and evaporated. The resultant white solid was purified by flash chromatography using dichloromethane:ethanol:ammonia (25:8:1) as eluant to give the product. δ (CDCI3) 2.43(s, 6H), 2.7-3.0(m), 4.47(d, 2H), 4.8(br s)m, 5.67(br t) and 7.4- 8.8(m).
Example 39
4-f5-r3-f2-(Dimethylamino)ethvn-5-benzofuranyll-3-pyridinvn-2-butanone dihvdrochloride
A solution of the product of Example 36 (228mg) in ethanol (25ml) was stirred with 5% palladium on carbon (40mg), under an atmosphere of hydrogen for 48h, renewing the catalyst once. The catalyst was filtered off through hyflo, and the filter pad washed with ethanol. The filtrate was evaporated and a solution of the resultant grey oil in ethanol was treated with two equivalents of 1 M ethanolic hydrogen chloride. The solution was evaporated and the residue triturated with ether to give the product as a grey solid. δ (DMSO-d6) 2.17(s, 3H), 2.88(d, 6H), 2.9-3.5(m), and 7.7-9.1 (m).
Example 40
N-ff5-r3-f2-(Dimethylamino)ethyl1-5-benzofuranvn-3-pyridinyllmethyl1-N-methyl- sulphonamide dihvdrochloride (0 N-r(5-Bromo-3-pyridinyl)methvn-N-methyl methanesulphonamide
Sodium, hydride (88mg of a 60% dispersion in oil) was added to a stirred solution of 5-bromo-3-(N-methyl)methyl sulphonamide (551 mg) in dry THF (30ml) under nitrogen at 20°. After 1h, iodomethane (454mg) was added and stirring continued for 3h. The solution was partitioned between ethyl acetate and water. The organic phase was washed with water, followed by brine, dried (MgS04), and evaporated. The residue was purified by flash chromatography using dichloromethane-ethanol-ammonia (100:8:1) as eluant to give the product. T.l.c. Si02 (CH2CI2:EtOH:NH3, 100:8:1) Rf 0.65; Detection: u.v.
(ii) N-fr5-f3-r2-(Dimethylamino)ethvn-5-benzofuranvn-3-pyridinvnmethyl1-N- methyl-sulphonamide dihvdrochloride
Nitrogen was bubbled through a mixture of Intermediate 4 (167mg), the product of stage (i) (202mg), aqueous 2N sodium carbonate (5ml) and dimethylformamide (20ml) for 1min. Tetrakis(triphenylphosphine)palladium (O) (20mg) was added and the stirred mixture heated at 100° under nitrogen for 3h. The 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 residue was purified by flash chromatography using dichloromethane-ethanol-ammonia (100:8:1) as eluant to give impure free base. This was further purified by flash chromatography using dichloromethane:ethanol:ammonia (150:8:1) as eluant to give the pure free base. T.l.c. Siθ2 (CH2Cl2:EtOH:NH3, 50:8:1) Rf 0.52; Detection: u.v., IPA. A solution of the free base in ethanol was treated with 1 M ethanolic hydrogen chloride (0.81ml) and the solution evaporated to dryness. The solid was stirred in ether and then evaporated to give the product. δ (MeOH-d ) 2.87(s), 3.02(s, 6H), 3.07(s), 3.2-3.7(m), 4.69(s, 2H) and 7.6- 9.1(m).
Example 41
5-r3-r2-(Dimethylamino)ethyll-5-benzofuranvπ-3-pyridineacetamide dihyrochloride (i) 5-Bromo-3-pyridineacetamide
5-Bromo-3-pyridineacetonitrile (1g) and amberlite resin IRA-400-OH (ex Aldrich, 1.20g) were heated under reflux in water (50ml) for 2.75h. The reaction mixture was filtered whilst still warm and the filtrate evaporated to dryness. Flash chromatography eluting with CH2Cl2:EtOH:NH4OH 100:8:1 afforded the product as a white solid, m.p. 174-175°.
T.l.c.(Silica, CH2Cl2:EtOH:NH4OH 100:8:1), Rf 0.25
(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.
The reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The aqueous phase was further extracted with ethyl acetate and the combined organic extracts were washed with brine, dried (MgSO4) and evaporated to give an oil. Purification by flash chromatography using dichloromethane: ethanol:ammonia 100:8:1 as the eluant afforded the free base as an oil. This was dissolved in ethanolic hydrogen chloride (containing 2 equivalents of HCI) and the resultant solution was evaporated to a solid. This was triturated with ether, filtered, and dried to give the salt with m.p. 243-246°. T.l.c. (SiO2l CH2CI2:EtOH:NH4OH 25:8:1 ), Rf 0.17 Example 42
5-r3-[2-(Dimethylamino)ethyll-5-benzofuranvπ-N.N-dimethyl-3-pyridine- acetamide. dihvdrochloride (i) 5-Bromo-N,N-dimethyl-3-pyridineacetamide 3-Bromopyridine-5-acetic acid (0.5g) in THF (25ml) and N-methylmorpholine (0.33ml) was cooled to -20°C and isobutylchloroformate (0.33ml) added dropwise. The solution was stirred for 40min at ca. -10°C, warmed to room temperature and partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate, dried and the solvent removed in vacuo. The crude material was purified by flash chromatography (CH2Cl2:EtOH:NH3, 100:8:1 ) to give the product. T.l.c. Rf 0.46; Si02; CH2CI2:EtOH:NH3, 100:8:1 ; Detection U.V., KMn04
(ii) 5-r3-f2-(Dimethylamino)ethyl1-5-benzofuranvn-N.N-dimethyl-3- pyridineacetamide dihvdrochloride
A solution of Intermediate 4 (0.17g), the product from step (i) (0.12g), tetrakis triphenylphosphine palladium [O] (50mg) in DME (10ml) and 2N sodium carbonate solution (3ml) was refluxed under N2* for 2h. The solution was allowed to cool, diluted with sodium carbonate solution (20ml) and extracted with ethyl acetate (3x30ml), washed with brine (30ml), dried and the solvent removed in vacuo. The crude material was purified by flash chromatography (CH2CI2:EtOH:NH3, 50:8:1 ) to yield a pale yellow oil. T.l.c. Rf 0.5; CH2Cl2:EtOH:NH3, 50:8:1 ; Detection U.V., Alk. KMnO4 The free base was dissolved in ethanol, ethanolic HCI added and the solvent removed in vacuo. The resulting oil was dissolved in water and the solution freeze dried to yield a gum. δ (DMSO-d6) 2.86(3H,s), 2.88(3H,s), 2.91 (3H,s) 3.16(3H,s), 3.22(2H,m), 3.47(2H,m), 4.07(2H,s) 7.8-9.3(7H,m) and 10.8(1 H.brs).
Example 43
N-rf5-r3-r2-(Dimethylamino)ethyll-5-benzofuranyll-3-pyridinvnmethvπ-N'.N'- dimethyl-sulphamide dihvdrochloride
A solution of Intermediate 5 (0.1 Og) in dry dichloromethane (5ml) was treated with triethylamine (0.14ml) followed by dimethylsulphamoyl chloride (0.1 ml) at 0°C under N2. After 30min further dimethyl sulphamoyl chloride (0.1 ml) was added and the solution warmed to room temperature. After 2h the solution was diluted with 2N sodium carbonate solution (20ml), extracted with dichloromethane (4x30ml), washed with brine (30ml), dried and the solvent removed in vacuo. The crude material was purified by flash chromatography (CH2Cl2:EtOH:NH3, 50:8:1 ) to yield a pale yellow oil. The oil was dissolved in ethanol, ethanolic HCI added, the solvent removed in vacuo. the salt dissolved in water and freeze dried to yield a pale yellow solid m.p. 97-99°C. T.l.c. Rf 0.28; SiO2; CH2CI2:EtOH:NH3, 50:8:1; Detection U.V., IPA
Example 44
N-rr5-r3-r2-(Dimethylamino)ethyl1-5-benzofuranvn-3-pyridinvnmethyl1sulphamide dihvdrochloride
A solution of Intermediate 5 (91 mg) and sulphamide (60mg) in DME (5ml) was refluxed under N2 for 20h. The solution was allowed to cool, the solvent removed in vacuo and the crude material purified by flash chromatography (CH2Cl2:EtOH:NH3, 25:8:1) to yield a pale yellow oil which was dissolved in ethanol, ethanolic HCI added, the solvent removed in vacuo and the solid dissolved in water and freeze dried. The compound was obtained as a pale brown solid. T.l.c. Rf 0.37; Siθ2; CH2Cl2:EtOH:NH3, 25:8:1; Detection U.V., IPA δ (DMSO-d6) 2.88(3H,s), 2.90(3H,s), 3.22(2H,m), 3.46(2H,m), 4.41 (2H,s), 7.8- 9.3(7H,m) and 10.9(1 H.brs).
Example 45 5-f3-r2-(Dimethylamino)ethyl1-5-benzofuranvn-N-methyl-3-pyridineacetamide. dihvdrochloride
A mixture of Intermediate 4 (103mg), 5-bromo-N-methyl-3-pyridineacetamide (70mg), and tetrakis(triphenylphosphine)palladium (0) (30mg) were stirred in dimethoxyethane (30ml, filtered through alumina (basic)) and aqueous sodium carbonate (5ml, 2N). Nitrogen was bubbled through the solution for 10min prior to the addition of the palladium catalyst. The mixture was heated under reflux under N2 for 5h and then partitioned between water and dichloromethane. After extracting the aqueous phase with dichloromethane, the combined extracts were washed with water and brine, dried (MgSO4) and evaporated to dryness. Purification by flash chromatography eluting with CH2Cl2:EtOH:NH3 50:8:1 afforded the free base. The free base was dissolved in ethanol (1ml), ethanolic HCI was added (0.24ml) and the solution was evaporated to dryness. The residue was triturated with ether and the ether removed by evaporation to afford to give the salt. T.l.c. Silica (CH2CI2:EtOH:NH4θH; 50:8:1) Rf 0.42 δ (DMSO-d6) 2.64(3H,d), 2.87(3H,s), 2.89(3H,s), 3.24(2H,m), 3.47(2H,m), 3.86(2H,s), 7.8-9.3(8H,m) and 10.9(1 H,m).
Example 46 N-rr5-r3-f2-(Dimethylamino)ethvn-5-benzofuranvn-3-pyridinvnmethvn- ethanesulphonamide oxalate
A solution of the product of Example 17 (0.1g) in anhydrous dichloromethane (10ml) containing triethylamine (0.14ml) at 0° (under N2) was treated with freshly distilled ethanesulphonyl chloride (0.064ml) and stirred. Water (5ml) was added and then the mixture evaporated to dryness. The residue was chromatographed on silica using a mixture of dichloromethane:ethanol:aqueous ammonia 200:8:1 100:8:1) to give the free base as a viscous gum. The free base (0.043g) in methanol (0.5ml) was -treated with oxalic acid (10mg) in methanol (0.5ml), and the solution was evaporated to give the salt as a white solid.
T.l.c. SiO2 single spot Rf=0.55 [CH2CI2/EtOH/0.88 NH3 100:8:1] δ (D20) 2.87 (6H,s), 3.2-3.4 (4H,m), 3.58 (2H,m), 4.62 (2H,s), 7.6- 9.0 (7H,m)
Example 47 N.N-fr5-f3-[2-(Dimethylamino)ethvn-5-benzofuranvn-3-pyridinyl1methvn-1- methylethanesulphonamide oxalate
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. T.l.c. Siθ2 (CH2CI2:EtOH:0.88NH3, 100:8:1 ) Rf =0.58; Detection u.v. δ (DMSO-d6) 1.26 (6H,d), 2.73 (6H,s); 3.0-3.3 (5H,m), 4.33 (2H,d), 7.6-9.0 (8H,m).
Example 48 1-[f5-f3-r2-(Dimethylamino)ethvn-5-benzofuranyll-3-pyridinvnmethvn-2-imida- zolidinone
(i) 1 -f (5-Bromo-3-pyridinyl)methyl1-2-imidazolidinone
A mixture of 2-imidazolidinone (1.63g) and sodium hydride (756mg x 60% oil dispersion) in dimethylformamide (20ml) was stirred at 0°C for 0.5h and at +23°C for 1.5h. A solution of the hydrochloride I (1.54g) in dimethylformamide (10ml) was added dropwise at 0°C, and the resulting mixture was allowed to warm to +23°C over 2h. Water (75ml) was added, the aq. solution was extracted with ethyl acetate (3x60ml), and the combined organic extracts were washed with 10% aq. lithium chloride (2x25ml) and brine (1x25ml), dried (MgSO4), and evaporated. The residual orange oil was purified by column chromatography over silica gel (Merck 9385) eluting with a mixture of 5% ammoniacal methanol and dichloromethane (5:95) to give the title compound as a white powder: m.p. = 117-119°C. T.l.c. Siθ2: 5% (5%NH3) MeOH-95% CH2CI2; Detection UV254-IPA; Rf=0.30 N.m.r. (CDCI3; ): 8.61 (1 H,d,CH), 8.46 (1H,d,CH), 7.81 (1 H,trCH), 4.60
(1 H,brs,NH), 4.38 (2H,s,CH2), 3.51-3.30 (4H,AA,BB',2xCH2).
(ii)1-fr5-r3-r2-(Dimethylamino)ethvπ-5-benzofuranyll-3-pyridinyllmethvn-2- imidazolidinone dihvdrochloride A degassed solution of the bromide (i) (70mg), Intermediate 4 (70mg), and palladium tetrakis(triphenylphosphine) (25mg) in a mixture of dimethoxyethane (10ml) and 2N aq. sodium carbonate solution (2.5ml) was heated at reflux with stirring under a nitrogen atmosphere for 5h. The mixture was cooled, diluted with water (30mi) and extracted with dichloromethane (3x30ml). The combined organic extracts were washed with brine (1x20ml), dried (MgSO4), and evaporated to leave a yellow gum which was purified by column chromatography over silica gel (Merck 9385) eluting with a mixture of 5% ammoniacal methanol and dichloromethane (1:9) to give a colourless gum. The gum was further purified by HPLC (BDS-C18: 5μ) eluting with 8% acetonitrile/0.05M ammonium hydrogen phosphate buffer to give an oil which was dissolved in 2M aq. sodium hydroxide (30ml) and extracted with dichloromethane (3x15ml). The combined organic extracts were dried (MgS04), evaporated, and the residual oil was dissolved in ethanol (0.5ml) and treated with 1M ethereal hydrogen chloride (5ml) to give the title compound as a white powder: m.p. =206-208°C. T.l.c. Si02 (free base): 10% (5% NH3) MeOH-90% CH2CI2; Detection: UV254-IPA; Rf=0.25 N.m.r. (DMSO;d6) 10.80 (1 H,brs,NH), 9.20 (1H,d,CH), 8.69 (1 H,brs,CH), 8.60 (1H,brs,CH), 8.40 (1 H,brs,CH), 8.05 (1H,s,CH), 7.80 (2H,m,2xCH), 4.50 (2H,s,CH2), 3.53-3.18 (8H,m,4xCH2), 2.88 (6H,d,NMe2).
Example 49
N-ff5-f3-r2-(Dimethylamino)ethvn-5-benzofuranvn-3-pyridinvnmethvn-N.2-di- methylpropanamide dihvdrochloride
A mixture of Intermediate 6 (100mg), isobutyryl chloride (50μl), pyridine (6.0ml), and dichloromethane (10ml) was stirred at +23°C under nitrogen for 17h. The mixture was evaporated, and the residual oil was purified by column chromatography over silica gel (Merck 9385) eluting with a mixture of dichloromethane-ethanol-0.880 ammonia (100:8:1) to give an oil. The oil was dissolved in ethanol (2ml), treated with 1.0M ethanolic hydrogen chloride (0.5ml), and the solution was evaporated and the residue triturated with diethyl ether to give the title compound as a white powder: m.p. 197-199°C. T.l.c. (free base) Siθ2: 100/8/1: CH Cl2/EtOH/NH3; Detection: UV254; Rf=0.20N.m.r. (DMSO;d6) 10.80 (1 H,brs,H+), 9.21 (1 H,d,CH), 8.60 (2H,m,2xCH), 8.40 (1 H,s,CH), 8.05 (1 H,s,CH), 7.80 (2H,s,2xCH), 4.73 (2H,s,CH2), 3.5-3.38 (2H,1/2AA'BB',CH2), 3.3-3.15 (5H,y2AA,BB'+s,CH+CH2), 2.99 (1 H,m,CH), 2.85
(6H,d,NMe2), 1.05 (6H,d,2xCH3).
Example 50 N-ff5-f3-f2-(Dimethylamino)ethyl1-5-benzofuranvn-3-pyridinyl]methvn- benzoylamide dihvdrochloride
A solution of Intermediate 5 (0.15g) in anhydrous dichloromethane (10ml) containing triethylamine (0.167ml) under nitrogen at room temperature was treated with benzoyl chloride (0.071ml) and stirred. The mixture evaporated to dryness and the residue was chromatographed on silica using a mixture of dichloromethane : ethanol : aqueous ammonia (100:8:1 ) to give the free base as a yellow oil (0.145g). The free base (0.145g) in isopropyl alcohol (10ml) was treated with ethanolic hydrochloric acid (1M, 2ml) and the solution was evaporated to dryness to give the salt as a yellow solid.T.l.c. Siθ2 Rf = 0.33 [CH2CI2 / EtOH / 0.88 NH4OH 100:8:1] Melting point = 179°C (decomposes) Assay: Found: C.59.3; H.6.2; N,7.9%
1H n.m.r. in D6-DMSO : 10.8(1 H,s), 9.5(1 H,t), 9.23 (1 H,d), 8.93 (1 H,s), 8.8 (1 H,d), 8.44 (1H,s), 8.06 (1 H,s), 7.99 (2H,m), 7.86 (1 H,dd), 7.80 (1H,d), 7.6- 7.45 (3H,m), 4.74 (2H,d), 3.53-3.36 (4H,m), 2.87 (6H,d).
Example 51
1-ff5-r3-[2-(Dimethylamino)ethyl1-5-benzofuranvn-3-pyridinvπmethvn-2- oxazolidinone
(i) 1 -f(5-Bromo-3-pyridinyl)methvn-2-oxazolidinone
A solution of 2-oxazolidinone (1.74g) in dimethylformamide (10ml) was added dropwise over 5min to a cold (0-5°C), stirring suspension of sodium hydride (2.00g x 60% oil dispersion) in dimethylformamide (30ml). After 0.5h, a solution of 3-chloromethyl-5-bromopyridine hydrochloride (5.00g) in dimethylformamide (30ml) was added dropwise over 10min, and the mixture was stirred at +23°C for 4h. The mixture was diluted with water (100ml), extracted with ethyl acetate (3x150ml), and the combined organic extracts were washed with 10% aq. lithium chloride solution (2x80ml), brine (1x80ml), dried (MgSO4), and evaporated to leave a brown oil. The oil was purified by column chromatography over silica gel (Merck 9385) eluting with a mixture of 5% ammoniacal methanol and ethyl acetate (2:98) to give the title compound as a white powder: m.p. = 75-77°C.
T.l.c. Siθ2: 2% (5%NH3) MeOH - 98% EtOAc; Detection UV254-IPA; Rf=0.30 Assay: CgHgBrN2θ2 requires: C,42.05; H.3.53; N, 10.90; Found: C.41.98; H.3.51; N, 10.84%
(ii)1-rr5-r3-r2-(Dimethylamino)ethyl1-5-benzofuranyll-3-pyridinyl1methyll-2- oxazolidinone dihvdrochloride
A degassed solution of the bromide (i) (208mg), Intermediate 4 (200mg), and palladium tetrakis(triphenylphosphine) (40mg) in a mixture of 1 ,2- dimethoxyethane (20ml) and 2.N aq. sodium carbonate solution (5ml) was heated at reflux with stirring under a nitrogen atmosphere for 3h. The mixture was cooled, diluted with 2N aq. sodium carbonate solution (20ml), and extracted with ethyl acetate (3x20ml). The combined organic extracts were washed with brine (1x15ml), dried (MgS04), and evaporated to leave a yellow gum which was purified by column chromatography over silica gel (Merck 9385) eluting with a mixture of 5% ammoniacal methanol and dichloromethane (8:92) to give a colourless oil. The oil was dissolved in ethanol (2ml) and treated successively with 1 M ethereal hydrogen chloride (2ml) and then diethyl ether (20ml) to give the title compound as a white powder: m.p.=188-189°C. T.l.c.Siθ2 (free base): 8% (5% NH3) MeOH-92% CH2CI2; Detection UV254 IPA; Rf=0.25Assay:C2i H23N3θ3.2HCI.0.9H2O Requires: C.55.49; H.5.94; N,9.24; Found: C.55.59; H.6.05; N,9.08% MS: Found MH+=366; Required MH+=366
Example 52
N-rf5-r3-r2-(Dimethylamino)ethvn-5-benzofuranvn-3-pyridinyl1methyll-2-methoxy- acetamide dihvdrochloride
A solution of methoxyacetyl chloride (38μl) in dichloromethane (1ml) was added dropwise to a cold (0-5°C), stirring solution of Intermediate 5 (112mg) and triethylamine (80μl) in dichloromethane (3ml). The mixture was stirred at +23°C for 3h, diluted with water (20ml) and extracted with dichloromethane (3x15ml).
The combined organic extracts were washed with brine (1x5ml), dried
(MgSO4), and evaporated to leave a yellow gum. The gum was purified by column chromatography over silica gel (Merck 9385) eluting with a mixture of 5% ammoniacal methanol and dichloromethane (7:93) to give a colourless oil which was dissolved in ethanol (0.5ml) and treated with 1M ethereal hydrogen chloride to give the title compound as a white powder: m.p. = 177-179°C. T.l.c.
Siθ2 (free base): 7% (5%NH3) MeOH-93% CH2CI2; Detection UV254-IPA;
Rf=0.30 Assay: C21 H25N3O3.2HCI.I .4H2O requires: C.54.17; H.6.45; N.9.02; Found: C.54.11 ; H.5.98; N,8.99%
MS: Found MH+ = 368; Required MH+ = 368
Example 53
5-r3-f2-(Dimethylamino)ethyl1-'5-benzofuranvn-N-(1-methylethyl)-3- pyridineacetamide (0 Ethyl 5-bromo-3-pyridineacetate
A mixture of 3-cyanomethyl-5-bromopyridine (8.08g), concentrated sulphuric acid (55ml), water (10ml), and ethanol (160ml) was heated at reflux under nitrogen for 16h. The mixture was cooled, evaporated, adjusted to ca. pH8 with 2N aq. sodium carbonate, and extracted with ethyl acetate (3x500ml). The combined organic extracts were dried (MgS04) and evaporated to leave an oil which was purified by column chromatography over silica gel (Merck 9385) eluting with a mixture of ethyl acetate and cyclohexane (1:41:3) to give the title compound as a pale yellow oil. T.l.c. SiO2: 967/30/3: CH2CI2/EtOH/NH3; Detection: UV254; Rf=0.44 Assay: CgH-jnBrNO2Requires:C,43.80; H.4.30; N.5.70; Br,32.4; Found: C.44.60; H.4.30; N.6.00; Br,32.5%
(ii) 5-Bromo-N-(1-methylethyl)-3-pyridineacetamide A mixture of the ester (i) (1.00g) and 1-methylethyiamine (1.00ml) was stirred at 95°C in a reacti-vial for 48h. The mixture was cooled and purified by column chromatography over silica gel (Merck 9385) eluting with a mixture of dichloromethane-ethanol-0.880 ammonia (967:30:3) to give the title compound which crystallised as fine, white needles from ethanol m.p. = 160-162°C. T.l.c. (free base) Siθ2: 967/30/3: CH2Cl2/EtOH/NH3; Detection UV254; Rf=0.10 Assay: C-|oHn BrN2θ Requires: C, 47.10; H.5.20; N.10.9; Found: C.46.70; H.5.10; N,10.9%
(iii) 5-r3-r2-(Dimethylamino)ethvn-5-benzofuranvn-N-(1-methylethyl)-3-pyridine- acetamide dioxalate
A mixture of the bromide (ii) (208mg), Intermediate 4 (200mg), sodium carbonate (273mg), palladium tetrakis(triphenylphosphine) (40mg), water (5ml), and dimethylformamide (10ml) was heated at reflux with stirring under a nitrogen atmosphere for 4h. The mixture was cooled, evaporated, diluted with water (30ml), and extracted with ethyl acetate (4x60ml). The combined organic extracts were dried (MgSO4), evaporated, and the residual oil was purified by column chromatography over silica gel (Merck 7729) eluting with a mixture of dichloromethane-ethanol-0.88 ammonia (967:30:3 → 934:60:6) to give the free base as an oil. A solution of the free base (173mg) in hot ethanol (5ml) was 95/28400 PO7EP95/01315
61
treated with a solution of oxalic acid dihydrate (180mg) in ethanol (2ml) to give, upon cooling, the title compound as white crystals: m.p. = 148 - 150°C.
T.l.c. (free base) SiO2: 89/10/1: CH2CI2/EtOH/NH3; Detection: UV254; Rf=0.23 Assay: C22H27 3O2.2C2H2O4.0.69H2ORequires:C,56.0; H.5.85; N,7.5; Found: C.55.8; H.5.8; N,7.4%
Example 54 N-Methyl.ff5-r3r2-(dimethylamino)ethvn-5-benzofuranvn-3-pyridinyl1- methyllethanamide dihvdrochloride
A solution of Intermediate 6 (0.1 g) in anhydrous tetrahydrofuran (10ml) containing pyridine (0.080ml) under nitrogen at room temperature was treated with acetic anhydride (0.040ml) and stirred. Ethanol (1ml) was added and the mixture evaporated to dryness. The residue was chromatographed on silica using a mixture of dichloromethane : ethanol : aqueous ammonia (100:8:1) to give the free base as a colourless oil (0.096g). The free base (0.096g) in ethanol (10ml) was treated with ethanolic hydrochloric acid (1M, 2ml) and the solution was evaporated to dryness to give the salt as a white solid. T.l.c. SiO2 Rf = 0.35 [CH2CI2 / EtOH / 0.88 NH4OH 100:8:1] Melting point = 172°C (decomposes)
1H n.m.r. in D6-DMSO : 11.1 (1H,s), 9.32 (1H,s), 8.87 (1H,s), 8.72 (1H,s), 8.53 (1H,s), 8.08 (1H,s), 7.89 (1H,dd), 7.81 (1 H,d), 4.78 (2H,s), 3.52-3.2 (4H,m), 3.14 (3H,s), 2.9 (6H,s), 2.12 (3H,s).
Example 55
N-rf5-r3-f2-(Dimethylamino)ethvn-5-benzofuranvn-3-pyridinvnmethvn-2-methyl- propanamide dihvdrochloride
A solution of Intermediate 5 (0.1 g) in anhydrous dichloromethane (10ml) containing pyridine (0.081ml) under nitrogen at room temperature was treated with isobutyryl chloride (0.046ml) and stirred. Ethanol (5ml) was then added and the mixture evaporated to dryness. The residue was chromatographed on silica using a mixture of dichloromethane : ethanol : aqueous ammonia (200:8:1 ) to give the free base as a colourless gum (0.095g). The free base (0.095g) in ethanol (10ml) was treated with ethanolic hydrochloric acid (1 M, 2ml) and the solution was evaporated to dryness to give the salt as a white solid. T.l.c. Si02 Rf = 0.37 [CH2CI2/EtOH/0.88 NH4OH 100:8:1] Melting point = 208°C
1 H n.m.r. δ in D-6 DMSO: 10.7 (1 H,s), 9.12 (1 H,d), 8.7-8.55 (3H,m), 8.35 (1 H,s), 8.04 (1 H,s), 7.79 (2H,s), 4.48 (2H,d), 3.55-3.10 (4H,m), 2.88 (6H,d), 2.50 (1 H,m), 1.05 (6H,d).
Example 56
N-rr5-f3-r2-(Dimethylamino)ethvn-5-benzofuranvn-3-pyridinyl1methvnbenzene- sulphonamide oxalate A solution of Intermediate 5 (0.1g) in anhydrous dichloromethane (10ml) containing triethylamine (0.14ml) under nitrogen at O^C was treated with benzenesulphonyl chloride (0.086ml) and stirred. Water (5ml) was then added and the mixture evaporated to dryness. The residue was chromatographed on silica using a mixture of dichloromethane:ethanol:aqueous ammonia (200:8: 1- 150:8:1) to give the free base as a yellow gum. The free base (0.017g) in ethanol (1ml) was treated with oxalic acid (0.0036g) and the solution was evaporated to dryness. An aqueous solution of the residue was freeze-dried to afford the salt as a white solid. T.l.c. SiO2 Rf = 0.50 [CH2Cl2/EtOH/0.88 NH4OH 100:8:1] 1 H n.m.r. in D6-DMSO : 8.82 (1H,d), 8.42 (1H,d), 8.35 (1H,t), 8.05-7.5 (10H,m),
4.18 (2H,d), 3.4-3.05 (4H,m), 2.8 (6H,s).
Example 57 5-r3-r2-(Dimethylamino)ethvπ-5-benzofuranvn-N-ethyl-N-methyl-3- pyridineacetamide a) 5-Bromo-N-ethyl-N-methyl-3-pyridineacetamide
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). The resultant 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.
T.l.c. Si02 (EtOAc-Et3N, 99:1) Rf 0.22, u.v., IPA δ (CDCI3) (Rotameric mixture) 8.58 (1 H,d), 8.4 (1 H,d), 7.82 (1 H,m), 3.68, 3.66 (2H,2xs), 3.50-3.35 (2H,m(2xq)), 3.03, 2.97 (3H,2xs), 1.2, 1.12 (3H,2xt)
b) 5-r3-f2-(Dimethylamino)ethvn-5-benzofuranyl1-N-ethyl-N-methyl-3-pyridine acetamide
A mixture of the intermediate of step (a) (332mg), Intermediate 4 (400mg), sodium carbonate (546mg), tetrakis(triphenylphosphine)palladium (0) (79mg), DMF (38ml) and water (24ml) was purged with nitrogen for 5min and then stirred at 100° under nitrogen for 1 h. The mixture was evaporated, treated with water (40ml), and extracted with ethyl acetate (4x80ml). The combined, dried organic extracts were evaporated and the residue purified by flash chromatography over silica gel (4.5cm wide column). Gradient elution with dichloromethane-ethanol- 0.88 ammonia (967:30:3 923:70:7) afforded an oil. This was purified by short path chromatography over silica gel (Merck 7729, 90g, 6.5cm wide column), eluting with diehloromethane-ethanol-0.88 ammonia (967:30:3 945:50:5) to give the product as a red oil. T.l.c. Si02 (CH2Cl2-EtOH-0.88NH3, 89:10:1) Rf 0.32, u.v. δ (CDCI3) (Rotameric mixture) 8.78 (1H,d), 8.46 (1H,d), 8.87 (1H,m), 7.73 (1 H,brs), 7.58-7.45 (3H,d,brs,dd), 3.78 (2H,2xs), 3.45 (2H,2xq), 3.06, 2.97 (3H,2xs), 2.9 (2H,1 AA'BB'), 2.67 (2H,1/ VBB'), 2.35 (6H,s), 1.2, 1.13 (3H,2xt).
Example 58
5-f3-r2-(Dimethylamino)ethvn-5-benzofuranyl1-N-ethyl-3-pyridineacetamide dihvdrochloride a) 5-Bromo-N-ethyl-3-pyridineacetamide
Diphenylphosphoryl azide (1.00ml) was added dropwise under nitrogen to a stirred solution of 5-bromo-3-pyridine acetic acid (500mg) in DMF (30ml) containing ethylamine (0.15ml) and triethylamine (1.29ml) at +23°. After stirring for 20h the mixture was evaporated and the residual oil purified by flash chromatography over silica gel (5.0cm wide column). Elution with dichloromethane-ethanol-0.88 ammonia (967:30:3) afforded the product as fine white crystals, m.p. 120-120.5°. Found:C,44.7; H,4.6; N,11.5;
CgH1 1 BrN20 requires: C.44.5; H.4.6; N,11.5%
T.l.c. Si02 (CH2CI2-EtOH-0.88NH3, 89:10:1 ) Rf 0.19; U.V.
b) 5-r3-f2-(Dimethylamino)ethvn-5-benzofuranvn-N-ethyl-3-pyridineacetamide dihvdrochloride
A mixture of the intermediate of step (a) (231 mg), Intermediate 4 (300mg), tetrakis(triphenylphosphine)palladium (0) (59mg), sodium carbonate (409mg), DMF (36ml), and water (18ml) was purged with nitrogen for 5min and then stirred at 100° under nitrogen for 5h. The cooled mixture was evaporated, treated with water (50ml) and extracted with ethyl acetate (5x50ml). The combined, dried organic extracts were evaporated and the residue purified by flash chromatography over silica gel (6.0cm wide column). Gradient elution with dichloromethane-ethanol-0.88 ammonia (967:30:3 923:70:7) afforded a pure gum I followed by impure gum II. The impure gum II was purified by short path chromatography over silica gel (Merck 7729, 80g, 6.0cm wide column), eluting with dichloromethane-ethanol-0.88 ammonia (967:30:3 945:50:5) to give a pure gum III. Gums I and III were combined to give gum IV and a solution of this in hot ethyl acetate (5ml) acidified to pH1 by the addition of ethereal hydrogen chloride. The precipitate was filtered off to give the product as fine white crystals.
T.l.c. SiO2 (CH2Cl2-EtOH-0.88NH3, 89:10:1 ) Rf 0.17; U.V. δ (DMSO-d6) 10.5 (1 H,brs), 9.18 (1 H,d), 8.72-8.68 (2H,2xm), 8.42-8.37 (2H,brs+m), 8.06 (1 H,s), 7.82 (2H,m), 3.76 (2H,s), 3.42 ^H.Y-AA'BB'), 3.22 (2H,1/2AA'BB')1 3.12 (2H,m), 2.88 (6H,d), 1.06 (3H,t)
Example 59
N-f5-f3-(2-Pyrrolidin-1-yl-ethyl)-benzofuran-5-vnpyridin-3- ylmethvDmethanesulphonamide dihvdrochloride Methanesulphonyl chloride (30μl) was added to a solution of 5-[3-(2-pyrrolidin-
1-yl-ethyl)-benzofuran-5-yl]pyridin-3-yl-methylamine (100mg) in dichloromethane (15ml) and triethylamine (0.5ml), and the mixture stirred for 2h.
Ethanol (1 ml) was added and the solvent evaporated in vacuo. The residue was purified by flash column chromatography on silica. Elution with dichloromethane/ethanol/ammonia 100:8:1 gave a colourless oil (0.141mg). The hydrochloride salt was prepared using ethanolic HCI. Evaporation of the solvent gave a white solid (159mg).
T.l.c. (Free base) SiO2, (Dichloromethane/ethanol/ammonia 100:8:1 ), Rf 0.30 N.m.r. (250MHz; DMSO; δ): 11.05 (1H,brd s), 9.28 (1H,d), 8.90 (IH.brd t), 8.80 (1H,d), 8.44 (1H,brd s), 8.05 (2H,s+t), 7.84 (2H,d+dd), 4.49 (2H,d), 3.59 (4H,m), 3.06-3.29 (4H,m), 3.04 (3H,s), 1.85-2.13 (4H,m).
Example 60 (5-r3-(1-Methyl-ρyrrolidin-3-yl)-benzofuran-5-vnpyridin-3-yl)methanol. dihvdrochloride
A solution of 5-bromo-[3-(1-methyl-3-pyrrolidinyl)-5-benzofuran (140mg), 3- [(1,1'-dimethylethyl)dimethyl silyloxymethyl]pyridine-5-boronic acid (B) (200mg) and tetrakis triphenylphosphine palladium [o] (20mg) in DME (7.5ml) and 2N sodium carbonate solution (2.5ml) was heated at reflux for 2h. The solution was allowed to cool, diluted with 2N sodium carbonate solution (20ml) and extracted with ethyl acetate (4x30ml), dried (Na2S04) and the solvent removed in vacuo. The residue was dissolved in acetic acid, water, THF (10ml of 6:3:1 solution) and refluxed for 21/_>h. The solvent was removed in vacuo and the crude material purified by flash chromatography (Merck 9385 silica; CH2CI2:EtOH:NH3, 50:8:1→25:8:1) to yield a pale oil which was dissolved in ethanol (2ml), ethanolic HCI (0.39ml, 1eq) added and the solvent removed jn vacuo. The resulting foam was dissolved in water and freeze dried. The salt was obtained as an off-white solid (0.12g), m.p. 70-72°C. T.l.c.Si02; CH2CI2:EtOH:NH3, 50:8:1, Rf 0.17
Example 61
N-(6-f3-(2-Dimethylamino-ethyl)-benzofuran-5-vn-pyridin-2- ylmethvDmethanesulfonamide
To a cold (0°) stirred solution of 6-[3-(2-Dimethylamino-ethyl)-benzofuran-5-yl]- pyridine-2-methylamine (100mg) in dry CH2CI2 (6ml) containing triethylamine (0.14ml) was added methanesulfonyl chloride (0.057ml) under N2. After 2h, water (2ml) was added and the mixture was evaporated to dryness. The residue was chromatographed on silica gel (Merck 9385). Gradient elution with CH2CI2 →CH2CI2:EtOH:NH3; 100:8:1 gave a beige semi-solid (55mg). Purification of this material by conversion to its oxalate salt, followed by regeneration of the free base gave a colourless gum (12mg). T.l.c.(Si02) CH2CI2:EtOH:NH3; 50:8:1 , Rf 0.7 b) 5-f3-[2-(Dimethylamino)ethyl1-5-benzofuranvπ-N-ethyl-3-pyridineacetamide dihvdrochloride
A mixture of the intermediate of step (a) (231 mg), Intermediate 4 (300mg), tetrakis(triphenylphosphine)palladium (0) (59mg), sodium carbonate (409mg), DMF (36ml), and water (18ml) was purged with nitrogen for 5min and then stirred at 100° under nitrogen for 5h. The cooled mixture was evaporated, treated with water (50ml) and extracted with ethyl acetate (5x50ml). The combined, dried organic extracts were evaporated and the residue purified by flash chromatography over silica gel (6.0cm wide column). Gradient elution with dichloromethane-ethanol-0.88 ammonia (967:30:3 923:70:7). afforded a pure gum I followed by impure gum II. The impure gum II was purified by short path chromatography over silica gel (Merck 7729, 80g, 6.0cm wide column), eluting with dichloromethane-ethanol-0.88 ammonia (967:30:3 945:50:5) to give a pure gum III. Gums I and III were combined to give gum IV and a solution of this in hot ethyl acetate (5ml) acidified to pH1 by the addition of ethereal hydrogen chloride. The precipitate was filtered off to give the product as fine white crystals.
T.l.c. Si0 (CH2Cl2-EtOH-0.88NH3, 89:10:1) Rf 0.17; U.V. δ (DMSO-d6) 10.5 (I H.brs), 9.18 (1 H,d), 8.72-8.68 (2H,2xm), 8.42-8.37 (2H,brs+m), 8.06 (1 H,s), 7.82 (2H,m), 3.76 (2H,s), 3.42 (2H,1/2AA'BB'), 3.22 (2H,1/2AA'BB'), 3.12 (2H,m), 2.88 (6H,d), 1.06 (3H,t)
Examples 62 - 80
The compounds of examples 62 to 80 were prepared in a manner analogous to Examples 1 to 61 using appropriate intermediate compounds to give the following compounds of formula (I):
62. N-[r5-r3-f2-(Dimethylamino)ethyl1-5-benzofuranyl1-3-pyridinyllmethvn-4-mor- pholinesulfonamide dihvdrochloride
Assay: C22H28N4O4S.2HCI Requires: C.51.1 ; H.5.8; N.10.8; Found: C,50.5; H.5.8; N,10.4%
N.m.r. (δ; 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).
63. 2-r5-r3-(1-Methyl-pyrrolidin-3-yl)-benzofuran-5-vn-pyridin-3-vn-acetamide dihvdrochloride
T.l.c. CH2CI2: EtOH: NH3 (50:8:1) Rf 0.06.
64. N-r5-r3-(2-Dimethylamino-ethyl)-benzofuran-5-vn-pyridin-3-ylmethyl1-C.C.C- trifluoromethanesulfonamide
65. N-f5-r3-(1-Methyl-pyrrolidin-3-yl)-benzofuran-5-yl1-pyridin-3-ylmethyll- methanesulfonamide dihvdrochloride T.l.c. CH2CI2: EtOH: NH3 (50:8:1) Rf = 0.34.
66. N-Methyl-N-f5-f3-(2-pyrrolidin-1-yl-ethyl)-benzofuran-5-yl1-pyridin-3- -ylmethyll-methanesulfonamide hydrochloride
T.l.c. CH2CI2: EtOH: NH3 (25:8:1) Rf = 0.5.
67. N-Methyl-N-r5-f3-(1-methyl-pyrrolidin-3-yl)-benzofuran-5-vn-pyridin-3- ylmethyll-methanesulfonamide dihvdrochloride
T.l.c. CH2CI2: EtOH: NH3 (50:8:1) Rf = 0.14.
68. r5-r3-(2-Dimethylaminoethyl)-benzofuran-5-vn-pyridin-3-vπ-acetonitrile T.l.c. CH2CI2: EtOH: NH3 (89:10:1) Rf 0.32.
69. 1-r5-f3-(2-Dimethylaminoethyl)-benzofuran-5-vπ-pyridin-3-ylmethvn-3- methyl-imidazolidin-2-one dihvdrochloride T.l.c. 7% (5% NH3) MeOH 93% CH2CI2 Rf = 0.3. m.p. 217-220°C.
70 2-r5-f3-(2-Dimethylamino-ethyl)-benzofuran-5-vn-pyridin-3-yl1-acetic acid hvdrazide
T.l.c. Si02: CH2CI2: EtOH: NH3 (78:20:2): Rf = 0.12. m.p. = 113-117°C. 71 Dimethyl-r2-(5-r5-f2-(morpholine-4-sulfonyl)-vinyl1-pyridin-3-vn-benzofuran-
3-vD-ethvπ-amine dihvdrochloride
T.l.c. Si02: CH2CI2: EtOH: NH3 (100:8:1): Rf = 0.33. m.p. = 159°C.
72 Ethanesulfonic acid r2-f3-(2-dimethylamino-ethyl)-benzofuran-5-vn-pyridin- 4-ylmethyll-amide dihvdrochloride T.l.c. SiO2: CH2CI2: EtOH: NH3 (89:10:1 ): Rf = 0.20. m.p. = 175-184°C.
73 1-Azetidin-1-yl-2-r5-r3-(2-dimethylamino-ethyl)-benzofuran-5-vn-pyridin-3- yll-ethanone oxalate
T.l.c. Si02: 5% NH3/MeOH: CH2CI2 (8:92): Rf = 0.30. m.p. = 115-117°C.
74 Ethanesulfonic acid f5-f3-(1 -methyl-piperidin-4-yl)-benzofuran-5-vn-pyridin- 3-ylmethyll-amide dihvdrochloride T.l.c. SiO2: 5% NH3/MeOH: CH2CI2 (1:9): Rf = 0.20. m.p. = 204-206°C.
75 Ethanesulfonic acid r5-r3-(2-pyrrolidin-1 -yl-ethyl)-benzofuran-5-yl1-pyridin-3- ylmethvn-amide dihvdrochloride
T.l.c. SiO2: 5% NH3/MeOH: CH2CI2 (5:95): Rf = 0.20. m.p. = 200-202°C.
76 N-f5-f3-(2-Dimethylamino-ethyl)-benzofuran-5-vn-pyridin-3-ylmethvn-4- fluoro-benzenesulfonamide dihvdrochloride
T.l.c. SiO2: CH2CI2: EtOH: NH3 (100:8:1 ): Rf = 0.50. m.p. = 236-238°C.
77 (2-f5-f5-(1 ,1-Dioxo-thiomorpholin-4-ylmethyl)-pyridin-3-yl1-benzofuran-3-yl1- ethvD-dimethyl-amine dihvdrochloride T.l.c. Si02: CH2CI2: EtOH: NH3 (100:8:1): Rf = 0.19. m.p. = 198X.
78 2-r5-r3-(2-Dimethylamino-ethyl)-benzofuran-5-vn-pyridin-3-yl1-N-(tetrahvdro- pyran-4-yl)-acetamide dihvdrochloride
T.l.c. Si02: 5% NH3/MeOH: CH2CI2 (13:87): Rf = 0.30.
79 4-ff5-f3-(2-Dimethylamino-ethyl)-benzofuran-5-yl1-pyridin-3-ylmethvπ- sulfamovD-benzoic acid dihvdrochloride T.l.c. SiO2: CH2CI2: EtOH: NH3 (20:8:1): Rf = 0.25. m.p. = 223-226°C. 80 [3-(2-Dimethylamino-ethyl)-benzofuran-5-yl)-pyridin-3-yll-methyl-carbamic acid ethyl ester dihvdrochloride
T.l.c. Si02: CH2CI2: EtOH: NH3 (100:8:1): Rf = 0.20. m.p. = 172°C.
Example 81 r5-r3-(2-Aminoethyl)-benzofuran-5-vn-4H-π .2.41-triazol-3-vπ-methanol. dihvdrochloride i) Methyl 3-(cvanomethyl)benzofuran-5-carboxylate A mixture of methyl 3-(2H)-benzofuranone-5-carboxylate (1.5g), cyanomethylene triphenylphosphorane (3.0g) and xylene (100ml) was heated under reflux for 20h. A further 1.5g of cyanomethylene triphenylphosphorane was added after the first 2.5h. The dark brown solution was concentrated to low volume and absorbed onto Merck Kieselgel 60 (70g). Elution with cyclohexane (300ml) and cyclohexane ethyl acetate (9:1 , 100ml; 4:1 , 100ml) gave fractions which were discarded. Further elution with ethyl acetate-cyclohexane (1:1 , 700ml), afforded the title compound still contaminated with triphenylphosphine as a buff solid (2.69g). This material was absorbed from ethyl acetate (10ml) and cyclohexane (10ml) onto a second column of Kieselgel 60 (75g). Elution with ethyl acetate-cyclohexane (1 :4, 1500ml) afforded the title compound (1.52g); m.p. 127-129°. C12H9NO2 requires C.67.0; H.4.2; N.6.5. Found C.67.0; H.4.1; N,6.4%. ii) 3-(Cvanomethyl)-5-benzofurancarboxylic acid hvdrazide Methyl 3-(cyanomethyl)benzofuran-5-carboxylate (1.03g) was stirred with hydrazine hydrate (20ml) in ethanol (30ml) at reflux under nitrogen for 5h. The solvents were evaporated to leave a white solid. This was dissolved in methanol, absorbed onto silica gel and purified by column chromatography eluting with 100:8:1 dichloromethane: ethanoLammonia to give the title compound as a white powder (749mg). M.p. 195-196°.
Analysis Found: C.61.2; H.4.1; N,19.2.
Ci -|HgN3O2 requires C.61.4; H.4.2; N, 19.5%. iii) f5-r(3-Cvanomethyl)benzofuran-5-vn-4H-ri.2.41-triazol-3-yl1methanol Ethyl hydroxyacetimidate (292mg) and the product of (ii) (300mg) were stirred in ethanol (40ml) at room temperature with triethylamine (0.583ml) under nitrogen. After stirring for 2 days the mixture was heated to reflux for 48h. The solvents were evaporated to leave a white solid. This was purified by column chromatography on silica gel eluting with 100:8:1 then 50:8:1 dichloromethane:ethanol:ammonia to give the title compound as a white powder (0.20g). M.p. 214-218°. T.l.c. Siθ2(50:8:1 CH2Cl2:EtOH:ammonia) Rf 0.28. iv) r5-f3-(2-Aminoethyl)-benzofuran-5-yl1-4H-ri.2.41-triazol-3-vn-methanol. dihvdrochloride
A solution of [5-[(3-cyanomethyl)-benzofuran-5-yl]-4H-[1 ,2,4]-triazol-3-yl]- methanol (0.72g) in methanol (20ml), ethanol (60ml) and concentrated hydrochloric acid (4ml) was hydrogenated in the presence of 10% palladium oxide on carbon (0.7g of a 50% paste in H2O). After 2.5h, the catalyst was filtered off and the solvent evaporated to leave a sandy-fawn solid (0.92g). Crystallisation from absolute alcohol/ethyl acetate afforded the dihydrochloric salt as a yellow powder (0.3285g), m.p. 256-8°C. T.l.c.SiO2 CH2CI2:EtOH:NH4OH (10:8:1), UV254-IPA, Rf=0.25
Example 82
N-fr5-r3-f2-(Dimethylamino)ethyll-5-benzofuranvn-2-furanyllmethyl 1 ethanesulphonamide i) 5-f3-r2-(Dimethylamino)ethvn-5-benzofuranyl1-2-furancarboxamide A solution of 5-bromo-2-furancarboxamide (479mg), Intermediate 4 (600mg) and aqueous 2N sodium carbonate (20ml) in dimethylformamide (100ml) was stirred whilst bubbling nitrogen through the solution for 1 min. Tetrakis(triphenylphosphine)palladium (0) (78mg) was added and the mixture stirred under reflux under nitrogen for 6h. The mixture was evaporated and the residue partitioned between 8% aqueous sodium bicarbonate (70ml) and ethyl acetate (75ml). The aqueous phase was extracted with ethyl acetate (5 x 75ml) and the combined, dried (MgSθ4) organic phases were evaporated to leave a brown oil. This was purified by flash chromatography over silica gel (50g) eluting with dichloromethane: ethanol:0.88 ammonia (100:8:1) to give an impure brown gum. This was purified by short path chromatography over silica gel, (Merck 7729, 100g), eluting with dichloromethane:ethanol:0.88 ammonia
(200:8:1 ) to give the product as a brown gummy oil.
T.l.c. SiO2 (CH2Cl2-EtOH-0.88 NH3, 100:8:1 ) Rf 0.16; detection u.v., IPA.
ii) 5-f5-(Aminomethyl)-2-furanyl1-N,N-dimethyl-3-benzofuranethanamine
A solution of 5-[3-[2-(dimethylamino)ethyl]-5-benzofuranyl]-2-furancarboxamide (169mg) in anhydrous tetrahydrofuran (5ml) was added to lithium aluminium hydride (74mg) under nitrogen and the mixture stirred at reflux for 3.5h. Diisobutylaluminium hydride (1.0M solution in cyclohexane, 2.3ml) was added to the cooled mixture and stirring at reflux continued for 3h. Further diisobutylaluminium hydride (2.3ml) was added to the cooled reaction mixture and stirring at reflux continued for 3h. After cooling, water (0.1ml) was slowly added, followed by 5M aqueous sodium hydroxide (0.1ml) and, then, water (0.3ml). The mixture was filtered and the precipitate washed with THF (30ml) and water (20ml). The combined filtrate and washings were evaporated and the orange residue was purified by short path chromatography over silica gel (Merck 7729, 50g). Elution with dichloromethane: ethanol:0.88 ammonia (100:8:1) gave an impure product, which was further purified by short path chromatography over silica gel (Merck 7729, 50g). Elution with dichloromethane: ethanol:0.88 ammonia (967:30:3) gave the product as a brown gummy oil. T.l.c. Si02 (CH2Cl2-EtOH-0.88 NH3, 100:8:1) Rf 0.23; detection u.v., KMnO^
iii) N-[r5-f3-r2-(Dimethylamino)ethvn-5-benzofuranvn-2-furanyl1methvn ethanesulphonamide
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. The mixture was allowed to warm to +23° over 4.25h and then partitioned between aqueous 8% sodium bicarbonate (20ml) and dichloromethane (10ml). The aqueous phase was extracted with dichloromethane (3 x 10ml) and the combined, dried organic phases were evaporated. The residue was purified by flash chromatography over silica gel (25g) eluting with dichloromethane:ethanol:0.88 ammonia (967:30:3) to give the product as a yellow powdery solid m.p. 131-
135°.
T.l.c. SiO2 (CH2Cl2-EtOH-0.88 NH3, 100:8:1) Rf 0.54; detection u.v., IPA.
Examples 83 to 88
The compounds of Examples 83 to 88 were prepared in a manner analogous to Examples 81 and 82 using appropriate intermediate compounds to give the following compounds of formula (I):
83. f5-f3-(2-Methylamino-ethyl)-benzofuran-5-vn-4H-f1.2.41triazol-3-yl)- methanol
T.l.c. CH2CI2:EtOH:NH4OH (10:8:1) Rf 0.25, m.p. 105-110°C.
84. 2-f5-(5-Methyl-2H-π.2.41triazol-3-yl)-benzofuran-3-yll-ethylamine T.l.c. CH2CI2: EtOH: NH3 (25:8:1) Rf 0.25. m.p. 183.5-186.7°C.
85. 4-r3-(2-Dimethylamino-ethyl)-benzofuran-5-vn-thiazole-2-carboxylic acid amide oxalate T.l.c. 5% NH3/MeOH: CH2CI2 (1 :9) UV254 - IPA: Rf = 0.25. m.p. = 196-198°C.
86. N-(4-r5-r3-(2-Dimethylamino-ethyl)-benzofuran-5-yll-π .2.41oxadiazol-3- ylmethvπ-phenvD-methanesulfonamide hydrochloride
T.l.c. 5% NH3/MeOH: CH2CI2 (6:94) UV254 - IPA: Rf = 0.30. m.p. = 242-243°C.
87. Ethanesulfonic acid r2-f3-(2-dimethylamino-ethyl)-benzofuran-5-yll-3H- imidazol-4-ylmethvπ-amide
T.l.c. Si02: CH2CI2: EtOH: NH3 (89:10:1 ) UV254 - IPA: Rf 0.16. m.p. 56-58°C.
88. Ethanesulfonic acid f2-r3-(2-dimethylamino-ethyl)-benzofuran-5-vn-thiazol- 4-ylmethvn-amide dihvdrochloride T.l.c. 5% NH3/MeOH: CH2CI2 (7:93) UV254 - IPA: Rf = 0.30. m.p. = 172-174°C. Example 89
(5-f3-(2-Amino-ethyl)-benzofb1thiophen-5-vnpyridin-3-yl)-methanol hydrochloride
A mixture of 5-bromo-2-(2-aminoethyl)benzo[b]thiophene (150mg), 3-[(1,1'- dimethylethyl)dimethyl silyloxymethyl]pyridine-5-boronic acid (500mg), palladium tetrakis triphenylphosphine (25mg), dimethoxyethane (8ml) and 2N aq. sodium carbonate (2ml) was refluxed at 100° for 3h. The solvent was evaporated in vacuo to leave a black residue which was dissolved in a mixture of acetic acid:water (8:2) (10ml) and refluxed for 30min. On cooling to room temperature, the acidic reaction mixture was poured into 2N sodium carbonate (aq) (25ml), and the aqueous layer then extracted with ethyl acetate (2x50ml). The organic layers were washed (brine), dried (Na2S04), filtered and evaporated to leave a brown residue which was purified by flash column chromatography eluting with a mixture of CH2CI2:EtOH:NH3 (100:8:1) to give the free base as a brown oil (73mg). The free base (73mg) was dissolved in ethanol (1ml) and a solution of hydrogen chloride in ethanol (0.5ml; 1 equiv.) was added followed by the dropwise addition of diethyl ether (5ml) at 0°. The mixture stirred for 15min, and the solvent was decanted to leave a cream solid which was dried in vacuo to leave the title compound as a cream solid (68mg), m.p. 202-206°.
T.l.c. SiO2 (Dichloromethane/ethanol/ammonia 50:8:1), Rf 0.4 Assay Found: C.59.9; H.5.3; N.8.2;
C16H16N2O2S.HCI Requires: C.59.9; H.5.3; N,8.7%
Example 90 r5-f8-r2-(Dimethylamino)ethvn-napthalen-2-vH-pyridin-3-vn-methanol. dihvdrochloride
To a suspension of [5-[8-(2-aminoethyl)-naphthalen-2-yl]-pyridin-3-yl]-methanol
(143mg) in a mixture of methanol (5ml) and water (5ml) was added 2M hydrochloric acid dropwise until a solution was obtained. Formaldehyde (0.5ml of a 37% w/v solution in water) was added followed portionwise by sodium borohydride (0.5g). The pH of the solution was then readjusted to -4 and the above addition of formalin (0.5ml) and sodium borohydride (0.5g) repeated. After a further 20min 2M hydrochloric acid was added dropwise until the pH of the solution was ~2. After stirring for 10-15min the pH of the mixture was adjusted to -12 with 2M sodium hydroxide solution and the resulting emulsion saturated with solid sodium chloride and extracted with dichloromethane (2x50ml). The combined organic layers were washed with brine (1x50ml) and evaporated in vacuo to leave a syrupy liquid. This residue was purified by column chromatography (Merck 9385) eluting with a mixture of dichloromethane, ethanol and 0.88 ammonia (100:8: 1-V75: 8:1) to give a colourless, viscous liquid. This liquid was taken up into ethanol (4.0ml) and cone, hydrochloric acid (4 drops) added. The resulting clear solution was diluted dropwise with ether (4.0ml), and the suspension stirred for 10min. The solid was collected by filtration, washed with ether (2ml) and dried in vacuo to give the dihvdrochloride (II) as a white powder (152mg), m.p. 201-211°. T.l.c.Si02 [CH2CI2:EtOH:0.88NH3; 50:8:1], Rf 0.35; Detection by u.v. and IPA
Example 91 2-(5-r8-(2-Dimethylamino-ethyl)-naphthalen-2-vn-pyridin-3-ylV-1-morpholin-4-yl- ethanone. dihvdrochloride
A mixture of 2-[8-(2-Dimethylamino-ethyl)-naphthalene]boronic acid (510mg), 2- (5-bromo-pyridin-3-yl)-1-morpholin-4-yl ethanone (660mg), tetrakis(triphenylphosphine)palladium° (134mg) and 2N sodium carbonate (5ml) in dimethoxyethane (30ml) was heated to reflux under N2 for 18h.
The solvents were evaporated and the residue chromatographed on silica gel (Merck 9385). Elution with CH2CI2:EtOH:NH3; 100:8:1 gave a yellow oil (680mg). On treatment with ethanolic HCI a yellow solid was obtained (750mg), m.p. 202°. T.l.c. (Si02) CH2CI2:EtOH:NH3; 50:8:1 , Rf 0.58
Example 92
(5-f8-(2-Amino-ethyl)-naphthalen-2-yl1-f1.3.41oxadiazol-2-yl>-methanol
A solution of {5-[8-(2-Dibenzylamino-ethyl)-naphthalen-2-yl]-[1,3,4]oxadiazol-2- yl}-methanol (379mg) in ethanol (25ml) was hydrogenated at 20° and atmospheric pressure over palladium catalyst (10% on C, 50%w w H2O, 800mg) for 36h. The catalyst was removed by filtration through hyflo. The filtrate was evaporated and the residue chromatographed on silica gel (Merck 9385, 15g). Elution with CH2CI2:EtOH:NH3; 50:8:1 gave an impure sample of the titie compound. Chromatography (as above) was repeated and the yellow waxy solid obtained was triturated with chloroforrrrhexane 3:1 (ca. 1.5ml) giving a white solid (13mg), m.p. 154-7°.
T.l.c.(SiO2) CH2CI2:EtOH:NH3; 25:8:1 , Rf 0.25
Example 93
N-(5-r8-(2-Dimethylamino-ethyl)-naphthalen-2-yll-4H-ri.2.41trizol-3-vimethylV methanesulphonamide dihvdrochloride
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. Column chromatography on silica gel. Eluting with CH2CI2:EtOH:NH3 = 100:8:1 , then 50:8:1 followed by preparative HPLC gave a colourless solid which was dissolved in aqueous ethanol and oxalic acid (0.26g) added. The solvent was evaporated and the residual solid recrystallised from isopropanol to give a solid (398mg).
N.m.r. (250MHz; DMSO+DCI; δ): 9.01 (1 H,s), 8.20 (1H,d), 8.14 (1H,d), 7.96 (1 H,dd), 7.59 (2H,t+d), 4.46 (2H,s), 3.61 (2H,m), 3.46 (2H,m), 3.04 (3H,s), 2.94 (6H,s)
Examples 94 to 106
The compounds of examples 94 to 106 were prepared in a manner analogous to examples 90 to 93 using appropriate intermediate compounds to give the following compounds of formula (I):
94. f5-r8-(2-Amino-ethyl)-naphthalen-2-vH-pyridin-3-vn-methanol dihvdrochloride T.l.c. CH2CI2: EtOH: NH3 (25:8:1) Rf 0.20. m.p. 268-270°C.
95. r5-r8-(2-Amino-ethyl)-naphthalen-2-yll-4H-f1.2.4ltriazol-3-yll-methanol dihvdrochloride T.l.c. CH2CI2: EtOH: NH3 (25:8:1 ) Rf 0.14.
96. N-r5-r8-(2-Dimethylamino-ethyl)-naphthalen-2-yll-pyridin-3-ylmethvn- methanesulfonamide T.l.c. CH2CI2: EtOH: NH3 (75:8:1) Rf 0.55.
97. N-f5-r8-(2-Dimethylamino-ethyl)-naphthalen-2-vn-pyridin-3-vn-N'.N'- dimethyl-sulfuric diamide oxalate
T.l.c. CH2CI2: EtOH: NH3 (50:8:1) Rf 0.75.
98. N-f5-r8-(2-Dimethylamino-ethyl)-naphthalen-2-yl1-pyridin-3-ylmethyll- acetamide oxalate
T.l.c. CH2CI2: EtOH: NH3 (100:8:1) Rf 0.4.
99. N-r5-f8-(2-Dimethylamino-ethyl)-naphthalen-2-vn-pyridin-3-yl)-sulfuric diamide dihvdrochloride T.l.c. CH2CI2: EtOH: NH3 (50:8:1) Rf 0.2. m.p. 237-243°C.
100. f5-f8-(2-Dimethylamino-ethyl)-naphthalen-2-vn-pyridin-3-ylmethvn-urea T.l.c. CH2CI2: EtOH: NH3 (50:8:1 ) Rf 0.31.
101. Ethanesulfonic acid r5-r8-(2-dimethylamino-ethyl)-naphthalen-2-yl1-pyridin- 3-ylmethyll-amide
T.l.c. CH2CI2: EtOH: NH3 (100:8:1) Rf = 0.15.
102. N-r5-r8-(2-Dimethylamino-ethyl)-naphthalen-2-yll-pyridin-3-ylmethyll- isobutyramide dihvdrochloride
T.l.c. CH2CI2: EtOH: NH3 (100:8:1 ) Rf = 0.28. m.p. 180°C.
103. f5-f8-(2-dimethylamino-ethyl)-naphthalen-2-vπ-pyridin-3-ylmethvn-amide dihvdrochloride T.l.c. CH2CI2: EtOH: NH3 (100:8:1 ) Rf = 0.46. m.p. 158-160°C.
104. N-f5-r8-(2-Dimethylamino-ethyl)-naphthalen-2-yl1-pyridin-3-ylmethyl1-4- fluoro-benzenesulfonamide dihvdrochloride T.l.c. CH2CI2: EtOH: NH3 (100:8:1 ) Rf 0.52.
105. (2-r7-f5-(1.1-Dioxo-thiomorpholin-4-ylmethyl)-pyridin-3-vπ-naphthalen-1- yl)-ethyl)dimethyl-amine dihvdrochloride T.l.c. CH2CI2: EtOH: NH3 (100:8:1 ) Rf = 0.2.
106. 3-r5-r8-(2-Dimethylamino-ethyl)-naphthalen-2-yll-pyridin-3-ylmethvn- oxazolidin-2-one
T.l.c. 8% (5% NH3) MeOH 92% CH2CI2 Rf = 0.30. m.p. 199-201 °C.
Example 107 f5-r3-f2-(Dimethylamino)ethyll-1 H-indol-5-vπ-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. A solution of methyl 5- [3-[2-(dimethylamino)ethyl]-1 lH-indol-5-yI]-pyridine-3-carboxylate (325mg) in dry tetrahydrofuran (30ml) was added dropwise to the cold suspension and the mixture was stirred for 15min. Saturated potassium carbonate solution (20ml) was added and the resultant two phases were separated. The aqueous phase was extracted with ethyl acetate (2x50ml) and the combined organic solutions were evaporated in vacuo to afford a pale brown foam. Purification by column chromatography on silica gel (Merck Art 9385) eluting with CH2CI2:EtOH:NH3 (aq) (50:8:1 ) gave an off-white foam (200mg, 68%). The foam was dissolved in isopropanol (2ml) and treated with a solution of oxalic acid (58mg) in isopropanol (0.5ml). Excess ether (40ml) was added to the resultant white precipitate. The solvent was removed by filtration and the solid was dried under vacuum at 40° for 20h to give the title compound as a fine white solid (197mg) m.p. 175-176° (dec).
T.l.c.SiO2 CH2CI2:EtOH:NH3 (aq) (50:8:1 ), Rf 0.17, Detection u.v., IPA Analysis Found: C.62.6; H.6.2; N.10.8; C18H21N3O.C2H204 Requires: C,62.3; H.6.0; N,10.9%
Example 108
5-f3-(1-Methyl-4-piperidinyl)-1H-indol-5-yl1-3-pyridinemethanol A solution of methyl 5-[3-(1-methyl-4-piperidinyl)-1 H-indol-5-yl]-3-pyridine carboxylate (500mg) in tetrahydrofuran (40ml) was added dropwise over 15min to a stirring suspension of lithium aluminium hydride (430mg) in diethyl ether (30ml) maintained at 0°C. After 10min saturated potassium carbonate solution (40ml) was added. The mixture was stirred for 15min, diluted with ethyl acetate (100ml) and the organic phase was separated. The saturated aq. phase was extracted with hot ethanol (150ml) and the combined org. solutions were preabsorbed onto silica gel (Merck 9385) and purified by column chromatography (SiO2: Merck 9385) eluting with a mixture of dichloromethane, ethanol and ammonia (50:8:1) to give a white solid (213mg). The solid was dissolved in hot methanol (20ml) and treated with a solution of oxalic acid (60mg) in methanol (0.5ml). The solvent was evaporated in vacuo. and the residue was triturated with diethyl ether to give the oxalate as a pale yellow solid (230mg): m.p. = 86-88°C.
T.l.c.SiO2: CH2CI2-EtOH-NH3 (50:8:1); UV254-IPA; Rf=0.23 Assay: Found: C,61.3; H.6.7; N.9.4; C20H23N3O.C2H2O4.1.2H2O Requires: C.61.0; H.6.4; N,9.7%
Examples 109 to 116
The compounds of examples 109 to 116 were prepared in a manner analogous to examples 107 and 108 using appropriate intermediate compounds to give the following compounds of formula (I):
109. 5-f3-(2-Dimethylamino-ethyl)-1 H-indol-5-yl1-nicotinamide T.l.c. CH2CI2: EtOH: NH3 (50:8:1) Rf = 0.12. m.p. 223-224°C.
110. 5-f3-(1-Methyl-piperidin-4-yl)-1H-indol-5-yl1-nicotinic acid methyl ester
T.l.c. CH2CI2: EtOH: NH3 (75:8:1) Rf = 0.59. m.p. 207-209°C.
111. 5-f3-(1 -Methyl-piperidin-4-yl)-1 H-indol-5-vπ-nicotinamide T.l.c. CH2CI2: EtOH: NH3 (aq) (25:8:1 ) Rf 0.4. m.p. 266-272°C.
112. 3-(1-Methyl-1.2.3.6-tetrahvdro-ρyridin-4-yl)-5-pyridin-3-yl-1H-indole dihvdrochloride
T.l.c. Si02: EtOAc: 'PrOH: H2O: NH3 (25:15:8:2): Rf 0.25. m.p. 252-254°C.
113. 2-(5-Pyridin-3-yl-1 H-indol-3-yl)-ethylamine dihvdrochloride T.l.c. SiO2: CH2CI2: EtOH: NH3 (20:8:1 ): Rf 0.46. m.p. 170-180°C.
114. Dimethyl-f2-(5-pyridin-3-yl-1H-indol-3-yl)-ethyl1-amine oxalate T.l.c. SiO2: CH2CI2: EtOH: NH3 (50:8:1): Rf 0.64. m.p. 145.5-148°C.
115. Dimethyl-r2-(5-pyridin-4-yl-1 H-indol-3-yl)-ethyll-amine oxalate T.l.c. Si02: CH2CI2: EtOH: NH3 (50:8:1 ): Rf 0.33. m.p. 193.5-195.5°C.
116. 5-f3-(2-Dimethylamino-ethyl)-1 H-indol-5-yl-nicotinic acid methyl ester oxalate
T.l.c. Si02: CH2CI2: EtOH: NH3 (50:8:1): Rf 0.36. m.p. 101-102°C (dec).

Claims

Claims
1. Compounds of formula (la)
Figure imgf000082_0001
wherein A is 0, S, NRa or CH=CH;
B is N or CRb;
C is a bond or a C-^alkylene chain;
D is a group NRcRd wherein Rc and Rd, which may be the same or different, are hydrogen, C^alkyl, C^alkenyl, C2^alkynyl, C3_7cycloalkyl, 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^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
Figure imgf000082_0002
in which the dotted line represents an optional double bond and Re is hydrogen,
C^alkyl, C2^alkenyl, C2^alkynyl, phenyl or phen(C1^)alkyl;
E is an optionally substituted 5 or 6 membered heterocyclic ring, optionally linked to the aromatic ring by a C-^alkylene chain; and
Ra and Rb, which may be the same or different, are hydrogen or C1^alkyl;
and pharmaceutically acceptable salts and solvates (e.g. hydrates) thereof.
2. A compound of formula (la) as claimed in Claim 1 wherein group E is a 5- membered aromatic heterocyclic ring containing at least one oxygen, sulphur or nitrogen atom.
3. A compound of formula (la) as claimed in Claim 1 or Claim 2 wherein E is a furan, thiazole, oxadiazole, imidazole or triazole ring.
4. A compound of formula (la) as claimed in Claim 1 wherein group E is a 5- membered saturated heterocyclic ring containing at least one oxygen, sulphur or nitrogen atom.
5. A compound of formula (la) as claimed in Claim 4 wherein group E is an imidazolidine or an oxazolidine ring.
6. A compound of formula (la) as claimed in Claim 1 wherein group E is a 6- membered aromatic ring containing at least one nitrogen atom.
7. A compound of formula (la) as claimed in Claim 6 wherein group E is a pyridyl ring.
8. A compound of formula (la) as claimed in any one of Claims 1 to 7 wherein A is O, S or CH=CH and B is CRb.
9. A compound of formula (la) as claimed in Claim 1 wherein A is 0, B is CH and E is an optionally substituted pyridyl ring.
10. A compound of formula (I)
Figure imgf000083_0001
wherein R1 is hydrogen,
Figure imgf000083_0002
-AlkOR3 or -(Alk)nR4 where Alk is an unsubstituted or substituted Cι.5alkylene or C2.5alkenylene chain, n is 0 or 1 and R4 is -CN, -COR3, -OCOR3, -COOR3, -SiO)mR3 where m is 0, 1 or 2, -NR7R8, -
CONR7R8, -CONR3NR5R6, -OCONR5R6, -NR3COOR9, -NR3COR9, -NR3S02R9,
-S02NR7R8, -NR3S02NR7R8 or -NR3CONR7R8:
R2 is -XNR10R11 where X is an unsubstituted or substituted Cι.3alkylene chain;
R3 is hydrogen or Ci-ealkyl or R3 and R8 or R9 together form a linking C2.5 alkylene chain; 5/28400
82
R5, R6, R10 and R11, which may be the same or different, are hydrogen or
C^alkyl;
R7 and R8, which may be the same or different, are hydrogen, d-ealkyl or
C^cycloalkyl optionally containing an oxygen atom (e.g. morpholino) or R7 and
R8, together with the N-atom to which they are attached, form a saturated 4- to
7-membered ring of formula
Figure imgf000084_0001
where Z is a group of formula -CR12R13-, -0-, -NR14-, -CO- or -S(O)p-; R9 is hydrogen, C^alkyl, halogenated C^alkyl (e.g. trifluoromethyl), d-e alkoxy(Cι-6)alkyl (e.g. methoxymethyl), phenyl optionally substituted with one or more halogen atoms or carboxy groups (e.g. 4-fluorophenyl or 4-carboxy- phenyl) or phenyl(Cι.3)alkyl (e.g. benzyl);
R12 and R13, which may be the same or different, are hydrogen, hydroxy or Ci-ealkoxy;
R14 is -S02R15, -COR15 or -COOR15;
R15 is Ci-ealkyl; and p is 0, 1 or 2; and pharmaceutically acceptable salts and solvates (e.g. hydrates) thereof, with the proviso that when R1 is 3-CH2CONR7R8 wherein R7 and R8, together with the N-atom to which they are attached, form a saturated 4 to 7 membered ring and R2 is -CH2CH2NR10R11, at least one of R10 and R11 is C^alkyl.
11. A compound of formula (I) as claimed in Claim 10 wherein R is -(Alk)„R4.
12. A compound of formula (I) as claimed in Claim 10 or Claim 11 wherein R4 is -CONR7R8, -NR3COR9, -NR3COOR9, -NR3SO2R9 or -NR3S02NR7R8.
13. A compound of formula (I) as claimed in any one of Claims 10 to 12 wherein R2 is -CH2CH2NR10R11.
14. A compound of formula (I) as claimed in any one of Claims 10 to 13 wherein R1 is attached at the 5-position of the pyridinyl ring.
15. A compound of formula (IA)
Figure imgf000085_0001
wherein R7 and R8, which may be the same or different, are Cι-3alkyl or, together with the N-atom to which they are attached, form a saturated 4- to 7-membered ring of formula
Figure imgf000085_0002
where Z is a group of formula -CR12R13-, -O-, -NR14-;
R10 and R11, which may be the same or different, are hydrogen or Cι.3alkyl;
R12 and R13, which may be the same or different, are hydrogen, hydroxy or
Cι-3alkoxy;
R14 is -SO2R15, -COR15 or -COOR15;
,15
R13 is Cι.3alkyl; and pharmaceutically acceptable salts and solvates thereof.
16. A compound of formula (IA) as claimed in Claim 15 wherein R7 and R8, together with the N-atom to which they are attached, form an azetidine, pyrrolidine, piperidine, hexamethyleneimine, piperazine or morpholine ring.
17. A pharmaceutical formulation comprising a compound as claimed in any one of Claims 1 to 16 together with one or more pharmaceutically acceptable carriers therefor and, optionally, other therapeutic and/or prophylactic ingredients.
18. The use of a compound as claimed in any one of Claims 1 to 16 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.
19. A method for the treatment of a mammal, including man, comprising administration of an effective amount of a compound as claimed in any one of Claims 1 to 16 in particular in the treatment of conditions associated with cephalic pain and in alleviating the symptoms associated therewith.
20. A process for preparing a compound as claimed in any one of Claims 1 to 16 which comprises:
(A) coupling a compound of formula (II)
Figure imgf000086_0001
with a compound of formula (III)
Figure imgf000086_0002
wherein one of R16 and R17 represents a halogen atom, preferably bromine, and the other is a group of formula -B(OH)2 or -Sn (lower alkyl)3;
(B) for the preparation of compounds of formula (I) wherein R1 is -(Alk)nR4 in which R4 is NR3COR9 or NR3SO2R9 and R3 and R9 together form a linking Cs-salkylene chain, cyclising the compound of formula (IX)
Figure imgf000086_0003
wherein R19 is -(Alk)nNHCO(CH2)qZ or -(Alk)nNHS02(CH2)qZ in which q is 3, 4 or 5 and Z is a suitable leaving group;
(C) converting a compound of formula (I) into another compound of formula (I);
(D) for the preparation of compounds of formula (la) wherein C is a C2.3alkylene chain reducing the compound of formula (X)
Figure imgf000087_0001
(E) for the preparation of compounds of formula (la) wherein E is a 1 ,2,4-triazol- 3-yl ring, reacting a compound of formula (XVI)
Figure imgf000087_0002
(wherein Xa represents a nitrile group or a reactive derivative thereof) with a compound of formula (XVII) :
R^ONHNHz (XVII); and subsequent to any of the processes (A) to (E), if necessary and/or desired
i)removing any protecting groups; and
ii)converting a compound of formula (I) or a salt thereof into a pharmaceutically acceptable salt thereof.
PCT/EP1995/001315 1994-04-14 1995-04-12 Novel benzofused 5-membered heterocyclic rings for the treatment of migraine WO1995028400A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU23439/95A AU2343995A (en) 1994-04-14 1995-04-12 Novel benzofused 5-membered heterocyclic rings for the treatment of migraine

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9407447.3 1994-04-14
GB9407447A GB9407447D0 (en) 1994-04-14 1994-04-14 Chemical compounds

Publications (1)

Publication Number Publication Date
WO1995028400A1 true WO1995028400A1 (en) 1995-10-26

Family

ID=10753551

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1995/001315 WO1995028400A1 (en) 1994-04-14 1995-04-12 Novel benzofused 5-membered heterocyclic rings for the treatment of migraine

Country Status (3)

Country Link
AU (1) AU2343995A (en)
GB (1) GB9407447D0 (en)
WO (1) WO1995028400A1 (en)

Cited By (30)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997045426A1 (en) * 1996-05-24 1997-12-04 Merck Sharp & Dohme Limited Azetidine, pyrrolidine and piperidine derivatives as 5-ht1d receptor agonists
WO1997045432A1 (en) * 1996-05-24 1997-12-04 Merck Sharp & Dohme Limited Piperazine, piperidine and tetrahydropyridine derivatives as 5-ht receptor agonists
US5770742A (en) * 1996-05-16 1998-06-23 Allelix Biopharmaceuticals Inc. Thiophene-tryptamine derivatives
WO1998037071A1 (en) * 1997-02-21 1998-08-27 R.J. Reynolds Tobacco Company Pharmaceutical compositions incorporating aryl substituted olefinic amine compounds
WO1999007700A1 (en) * 1997-08-09 1999-02-18 Smithkline Beecham Plc Bicyclic compounds as ligands for 5-ht1 receptors
WO1999031062A1 (en) * 1997-12-17 1999-06-24 Shionogi & Co., Ltd. Novel pyridine compounds
WO2000000487A1 (en) * 1998-06-30 2000-01-06 Eli Lilly And Company 5-ht1f agonists
WO2000004019A1 (en) * 1998-07-17 2000-01-27 Allelix Biopharmaceuticals Inc. 5-bicycloindole compounds
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 (en) * 2002-02-18 2003-08-21 Glaxo Group Limited Heterocyclic compounds possessing affinity at 5ht1-type receptors and use thereof in therapy
EP1460079A1 (en) * 2001-11-28 2004-09-22 Koei Chemical Co., Ltd. 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 (en) * 2003-10-22 2007-04-26 イーライ リリー アンド カンパニー Novel MCH receptor antagonist
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 (en) 2008-08-13 2010-02-18 Bayer Cropscience Ag New N-substituted azinylalkyl-azincarboxamide compounds useful e.g. in plant protection, for combating animal pests, arthropods, nematodes and plant diseases, and for protecting industrial materials against attack and destruction by insect
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 (en) * 2019-08-28 2019-12-10 沈阳药科大学 1. 6-disubstituted-benzo five-membered heterocyclic derivative and application thereof
WO2020249799A1 (en) * 2019-06-14 2020-12-17 Janssen Pharmaceutica Nv Pyridine carbamates 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
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
US11993587B2 (en) 2020-06-12 2024-05-28 Janssen Pharmaceutica Nv Substituted pyrazolo-pyrazines and their use as GluN2B receptor modulators

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE1963205A1 (en) * 1968-12-20 1970-07-09 Labaz Lab Benzo [b] benzofurano [2,3-e] oxepine derivatives
DE1670105A1 (en) * 1966-07-08 1970-12-10 Byk Gulden Lomberg Chem Fab Process for the preparation of benzofuryl (3) -alkylamines and their salts
EP0313397A1 (en) * 1987-10-23 1989-04-26 The Wellcome Foundation Limited Therapeutic heterocyclic compounds
WO1994008993A1 (en) * 1992-10-16 1994-04-28 Glaxo Group Limited Benzofuran derivatives as 5-ht1-like receptor antagonists

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE1670105A1 (en) * 1966-07-08 1970-12-10 Byk Gulden Lomberg Chem Fab Process for the preparation of benzofuryl (3) -alkylamines and their salts
DE1963205A1 (en) * 1968-12-20 1970-07-09 Labaz Lab Benzo [b] benzofurano [2,3-e] oxepine derivatives
EP0313397A1 (en) * 1987-10-23 1989-04-26 The Wellcome Foundation Limited Therapeutic heterocyclic compounds
WO1994008993A1 (en) * 1992-10-16 1994-04-28 Glaxo Group Limited Benzofuran derivatives as 5-ht1-like receptor antagonists

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
H. NAKAI ET. AL.: "New Potent Antagonists of Leukotrienes C4 and D4.", J. MED. CHEM., vol. 31, no. 1, 1988, pages 84 - 91 *
L. J. STREET ET. AL.: "Synthesis and Serotonergic Activity of 5-(Oxadiazolyl)tryptamines", J. MED. CHEM., vol. 36, no. 11, 1993, pages 1529 - 1538 *

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
WO1997045432A1 (en) * 1996-05-24 1997-12-04 Merck Sharp & Dohme Limited Piperazine, piperidine and tetrahydropyridine derivatives as 5-ht receptor agonists
WO1997045426A1 (en) * 1996-05-24 1997-12-04 Merck Sharp & Dohme Limited Azetidine, pyrrolidine and piperidine derivatives as 5-ht1d receptor agonists
US5998416A (en) * 1996-05-24 1999-12-07 Merck Sharp & Dohme Ltd. Piperazine, piperidine and tetrahydropyridine derivatives as 5-HT receptor agonists
US6127388A (en) * 1996-05-24 2000-10-03 Merck Sharp & Dohme Ltd. Azetidine, pyrrolidine and piperidine derivatives as 5-HT1D receptor agonists
US6274606B1 (en) 1997-02-21 2001-08-14 Targacept, Inc. Methods of treating central nervous system disorders with aryl substituted olefinic amine compounds
WO1998037071A1 (en) * 1997-02-21 1998-08-27 R.J. Reynolds Tobacco Company Pharmaceutical compositions incorporating aryl substituted olefinic amine compounds
US6531606B1 (en) 1997-02-21 2003-03-11 Targacept, Inc. Pharmaceutical compositions incorporating aryl substituted olefinic amine compounds
WO1999007700A1 (en) * 1997-08-09 1999-02-18 Smithkline Beecham Plc Bicyclic compounds as ligands for 5-ht1 receptors
US6391891B1 (en) 1997-08-09 2002-05-21 Smithkline Beecham Plc Bicyclic compounds as ligands for 5-HT1 receptors
WO1999031062A1 (en) * 1997-12-17 1999-06-24 Shionogi & Co., Ltd. Novel pyridine compounds
US6358972B1 (en) 1998-06-30 2002-03-19 Eli Lilly And Company 5-HT1F agonists
WO2000000487A1 (en) * 1998-06-30 2000-01-06 Eli Lilly And Company 5-ht1f agonists
WO2000004019A1 (en) * 1998-07-17 2000-01-27 Allelix Biopharmaceuticals Inc. 5-bicycloindole compounds
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
EP1460079A1 (en) * 2001-11-28 2004-09-22 Koei Chemical Co., Ltd. Dihydroxy(3-pyridyl)borane compounds
US7053079B2 (en) * 2001-11-28 2006-05-30 Koei Chemical Company, Limited Dihydroxy (3-pyridyl) borane compounds
EP1460079A4 (en) * 2001-11-28 2007-03-28 Koei Chemical Co Dihydroxy(3-pyridyl)borane compounds
US7244726B2 (en) 2002-02-18 2007-07-17 Glaxo Group Limited Heterocyclic compounds possessing affinity at 5HT1 -type receptors and use thereof in therapy
WO2003068772A1 (en) * 2002-02-18 2003-08-21 Glaxo Group Limited Heterocyclic compounds possessing affinity at 5ht1-type receptors and use thereof in therapy
JP2007510629A (en) * 2003-10-22 2007-04-26 イーライ リリー アンド カンパニー Novel MCH receptor antagonist
US8198298B2 (en) 2003-12-24 2012-06-12 Pfizer Italia S.R.L. Pyrrolo[2,3-b]pyridine derivatives active as kinase inhibitors
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
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
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
DE102008041214A1 (en) 2008-08-13 2010-02-18 Bayer Cropscience Ag New N-substituted azinylalkyl-azincarboxamide compounds useful e.g. in plant protection, for combating animal pests, arthropods, nematodes and plant diseases, and for protecting industrial materials against attack and destruction by insect
US8383827B2 (en) 2009-05-15 2013-02-26 Novartis Ag Aryl pyridine as aldosterone synthase inhibitors
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
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
US11214563B2 (en) 2019-06-14 2022-01-04 Janssen Pharmaceutica Nv Substituted pyrazolo-pyrazines 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 (en) * 2019-06-14 2020-12-17 Janssen Pharmaceutica Nv Pyridine carbamates and their use as glun2b receptor modulators
CN114007691A (en) * 2019-06-14 2022-02-01 詹森药业有限公司 Pyridine carbamates and their use as GluN2B receptor modulators
US11447503B2 (en) 2019-06-14 2022-09-20 Janssen Pharmaceutica Nv Pyridine carbamates 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
CN110551101B (en) * 2019-08-28 2020-11-24 沈阳药科大学 1. 6-disubstituted-benzo five-membered heterocyclic derivative and application thereof
CN110551101A (en) * 2019-08-28 2019-12-10 沈阳药科大学 1. 6-disubstituted-benzo five-membered heterocyclic derivative and application thereof
US11993587B2 (en) 2020-06-12 2024-05-28 Janssen Pharmaceutica Nv Substituted pyrazolo-pyrazines and their use as GluN2B receptor modulators

Also Published As

Publication number Publication date
AU2343995A (en) 1995-11-10
GB9407447D0 (en) 1994-06-08

Similar Documents

Publication Publication Date Title
WO1995028400A1 (en) Novel benzofused 5-membered heterocyclic rings for the treatment of migraine
US6200978B1 (en) Compounds as delta opioid agonists
EP1531812B1 (en) Fused heteroaryl derivatives for use as p38 kinase inhibitors in the treatment of i.a. rheumatoid arthritis
US5496833A (en) Piperidine tachykinin receptor antagonists
AU763356B2 (en) Fused-ring compounds and use thereof as drugs
EP0652866B1 (en) Azacyclic compounds
US6514975B1 (en) Anti-inflammatory piperazinyl-benzyl-tetrazole derivatives and intermediates thereof
AU712315B2 (en) Cyclic amidino agents useful as nitric oxide synthase inhibitors
US20060247439A1 (en) Mchir antagonists
US20040087798A1 (en) Novel amide compounds
WO1993021181A1 (en) Azacyclic compounds
KR19990007942A (en) Their use as modulators of benzimidazole compounds and gamma-aminobutyl acid receptor complexes
US6376490B1 (en) Quinoxalinediones
US7709469B2 (en) P2X7 receptor antagonists and methods of use
EP3107898B1 (en) 1,2-substituted cyclopentanes as orexin receptor antagonists
JP2009143904A (en) Benzamide derivative
CZ20031941A3 (en) Substituted triazole diamine derivatives functioning as kinase inhibitors
PH12014502775B1 (en) TRIAZOLONE COMPOUNDS AS mPGES-1 INHIBITORS
EP0634402A1 (en) Isochinolinone derivatives, their production and use
EP0501322B1 (en) 3-Piperidinylmethylcarboxylate substituted indoles
JP2007538068A (en) Novel fused heterocycles and their use
JP2014521595A (en) Substituted sulfonamides useful as anti-apoptotic Bcl inhibitors
CA2143744A1 (en) Diaryl piperazinoacetamide compounds as antimuscarinic agents
CA2602383A1 (en) Substituted triazole derivatives as oxytocin antagonists
JP3218045B2 (en) Novel thiophene derivative and pharmaceutical composition thereof

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AM AT AU BB BG BR BY CA CH CN CZ DE DK EE ES FI GB GE HU IS JP KE KG KP KR KZ LK LR LT LU LV MD MG MN MW MX NO NZ PL PT RO RU SD SE SG SI SK TJ TM TT UA US UZ VN

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): KE MW SD SZ UG AT BE CH DE DK ES FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN ML MR NE SN TD TG

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: CA