EP0674620A1 - Analogues de tryptamine a titre d'agonistes semblables a 5-ht 1? - Google Patents

Analogues de tryptamine a titre d'agonistes semblables a 5-ht 1?

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Publication number
EP0674620A1
EP0674620A1 EP94903794A EP94903794A EP0674620A1 EP 0674620 A1 EP0674620 A1 EP 0674620A1 EP 94903794 A EP94903794 A EP 94903794A EP 94903794 A EP94903794 A EP 94903794A EP 0674620 A1 EP0674620 A1 EP 0674620A1
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EP
European Patent Office
Prior art keywords
indole
pyridyl
chloro
compound
ethyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP94903794A
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German (de)
English (en)
Inventor
Roderick Alan Porter
William John Coates
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SmithKline Beecham Ltd
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SmithKline Beecham Ltd
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Publication date
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Publication of EP0674620A1 publication Critical patent/EP0674620A1/fr
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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • C07D209/16—Tryptamines
    • 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
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to novel tryptamine analogues, processes and intermediates useful in their preparation, pharmaceutical compositions containing them and their use in therapy, in particular for the treatment and/or prophylaxis of disorders characterised by excessive vasodilatation, such as migraine and portal hypertension.
  • the present invention therefore provides, in a first aspect, a compound of structure (I):
  • R! is an optionally substituted 6- to 10-membered aryl or heteroaryl ring
  • R2 is hydrogen, halogen, C ⁇ _4alkyl, CN, NO2 or CF3
  • R4 and R ⁇ are independendy hydrogen or C1.4al.kyl
  • R6 and R 7 are the same or different and are each hydrogen or C ⁇ _4alkyl or together with the nitrogen atom to which they are attached form a ring;
  • R8 is hydrogen, C ⁇ _4alkyl, or C3_6alkenyl;
  • R a is hydrogen and R D is hydrogen or hydroxy, or R a and R ⁇ together represent a bond; and
  • q and m are independently 1 or 2; and pharmaceutically acceptable salts, solvates and hydrates thereof.
  • R ⁇ is an optionally substituted 6- or 10-membered aryl ring such as phenyl or naphthyl.
  • R is an optionally substituted 6- to 10-membered heteroaryl ring containing from 1 to 4 nitrogen atoms.
  • heteroaryl rings include pyridine, pyridazine, pyrimidine, pyrazine, triazine, quinoline, or quinazoline. Particular examples are pyridine, pyridazine, pyrimidine, pyrazine or quinoline.
  • the heteroaryl ring can be linked via a carbon or nitrogen atom of the heteroaryl ring.
  • R* is unsubstituted or substituted by up to 3 groups selected from halo, C alkyl, hydroxy, oxo, C ⁇ _ alkoxy, -CO2 9 , -NHCOR 9 , -CONR ⁇ R 11 , -SO2NR 10 R n , -NHSO 2 R 12 , NO 2 , -NR ⁇ R 1 1, NHCONH 2 , CN, CF3 or CF3O wherein R 9 to R* * are independently hydrogen or Cj ⁇ alkyl and R* 2 is Cj ⁇ alkyl.
  • R 2 is hydrogen, halogen, CMalkyl, CN, NO2 or CF3.
  • R 2 is hydrogen or halogen, in particular hydrogen or chlorine.
  • R 4 and R ⁇ are hydrogen or C ⁇ _4alkyl.
  • R 4 and R ⁇ are both hydrogen or methyl.
  • R ⁇ and R 7 are the same or different and are each hydrogen or CMalky or together with the nitrogen atom to which they are attached form a ring.
  • R" and R7 are both hydrogen or methyl.
  • Suitable rings formed by R ⁇ and R 7 together with the nitrogen atom to which they are attached include for, example, 5- or 6-membered rings such as pyrrolidino and piperidino rings.
  • R 3 is a group
  • C ⁇ _4alkoxy include methyl, ethyl, propyl or butyl which can be straight chain or branched.
  • halo groups include fluoro, bromo, chloro or iodo.
  • Particular compounds of structure (I) include : 4-chloro-3-[2-N,N-(dimethylamino)ethyl]-5-phenylindole,
  • compositions of structure (I) include, for example, those formed with inorganic acids e.g. hydrochloric, sulphuric, methanesulphonic or phosphoric acids and organic acids e.g. succinic, maleic, citric, (D) and (L) tartaric, acetic or fumaric acid.
  • inorganic acids e.g. hydrochloric, sulphuric, methanesulphonic or phosphoric acids
  • organic acids e.g. succinic, maleic, citric, (D) and (L) tartaric, acetic or fumaric acid.
  • Other non-pharmaceutically acceptable salts e.g. oxalates may be used for example in the isolation of compounds of formula (I), and are included within the scope of this invention.
  • solvates and hydrates of compounds of formula (I) are also included within the scope of the invention.
  • R 4 is other than hydrogen may contain an asymmetric centre.
  • Such compounds will exis as two (or more) optical isomers (enantiomers). Both the pure enantiomers, racemic mixtures (50% of each enantiomer) and unequal mixtures of the two, are included within the scope of the present invention. Further, all diastereomeric forms possible (pure enantiomers and mixtures thereof) are within the scope of the invention.
  • the compounds of the present invention can be prepared by processes analogous to those known in the art.
  • the present invention therefore provides, in a further aspect, a process for the preparation of a compound of structure (I) or a salt, solvate or hydrate thereof, which comprises:
  • R 3 is a N-protecting group or R& as hereinbefore defined and q and m are as hereinbefore defined, and if required removing the N-protecting group and/or dehydratin to form a compound wherein R a and R D together represent a bond and optionally thereafter hydrogenating to form a compound wherein R a and R ⁇ are both hydrogen;
  • Y may be a group which is converted to
  • Y examples include -C(R 4 )(R 5 )CN; and -C(R 4 )(R 5 )CHO.
  • reaction between a compound of structure (II) and an amine R6R7NH is suitably earned out under reductive animation conditions, for example, catalytic hydrogenation in the presence of the amine R°R7NH and a suitable solvent.
  • Suitable catalysts include, for example, Raney nickel.
  • Suitable solvents include, for example, C j _4alkanols, in particular methanol. The reaction is carried out at ambient temperature or elevated temperature for as long as is necessary for the reaction to be complete.
  • Preferred reaction conditions include, for example for compounds in which R" and R7 are both hydrogen, hydrogenation in methanolic ammonia in the presence of a Raney nickel catalyst; and where R ⁇ and R7 are both Cj_4alkyl, for example methyl, hydrogenation in the presence of dimethylamine in methanol as solvent and Raney nickel as catalyst.
  • Y represents a group -C(R 4 )(R 5 )CH2NO 2 , -C(R 4 )(R 5 )CH 2 N 3 , -COCONR 6 R 7 , or -C(R 4 )(R 5 )CONR 6 R 7
  • the reduction may be effected for example using allane (prepared from lithium aluminium hydride and sulphuric acid) or lithium aluminium hydride in a solvent such as tetrahydrofuran.
  • a group -C(R 4 )(R ⁇ )CH2NO2 may be reduced by catalytic hydrogenation, using for example palladium on charcoal or by treatment with cobalt boride prepared by treating a cobalt (LI) salt such as cobalt chloride with sodium borohydride in a suitable solvent such as methanol.
  • cobalt (LI) salt such as cobalt chloride with sodium borohydride in a suitable solvent such as methanol.
  • Reduction of a group -C(R 4 )(R5)CH2NR6C0R7 may be accomplished using a hydride such as lithium aluminium hydride.
  • the intermediate compounds of structure (II) can be prepared by standard procedures.
  • compounds of structure (IT) wherein Y represents -CH2CN may be prepared from the corresponding gramine (i.e. 3-dimethylaminomethyl) compound by cyanation e.g. using potassium cyanide.
  • the gramine derivative may be obtained by reaction of the 3-unsubstituted indole with bisdimethylaminomethane in the presence of acetyl chloride and in a suitable solvent, such as dichloromethane.
  • the gramine derivative may be obtained by reaction of a compound of structure (DC) :
  • a 3-unsubstituted indole may be prepared from an appropriately substituted nitrotoluene derivative according to the following reaction scheme 1 :
  • a compound of structure (II) may be prepared by reacting a corresponding aminoethyl compound with an acylating agent, for example an anhydride such as acetic or propionic anhydride or a mixture of an acid with an anhydride e.g. formic acid and acetic anhydride.
  • an acylating agent for example an anhydride such as acetic or propionic anhydride or a mixture of an acid with an anhydride e.g. formic acid and acetic anhydride.
  • This intermediate provides a convenient method of preparing compounds of structure (I) wherein one of R ⁇ and R7 is hydrogen and the other a C ⁇ _4alkyl group.
  • a compound of structure (II) wherein Y represents -COCONR6R7 may be prepared from an indole of structure (X) :
  • Structure (X) by reaction with oxalyl chloride followed by an amine HNR >R7 and subsequently introducing the group R 2 .
  • R 2 is halogen e.g. iodine this may be introduced by reaction of a compound of structure II where R 2 is H and Y is COCONR6R7 with an appropriate halide e.g. potassium iodide in an acidic medium such as trifluoroacetic acid i the presence of thallium trifluoroacetate.
  • a compound of structure (II) wherein Y represents -C(R 4 )(R ⁇ )CHO may be prepared for example by oxidation of the corresponding alcohol, using an oxidising agent such as pyridinium chlorochromate, or dimethylsulphoxide with oxalylchloride and triethylamine.
  • the alcohol may itself be obtained by a cyclisation analogous to process (b).
  • the alcohol may also be converted to a halide derivative and thence to an azide using standard procedures, to give a compound of structure (II) wherein Y represents -C(R 4 )(R ⁇ )CH2N3.
  • a compound of structure (V) can be prepared by reacting a compound of structure (XI) :
  • Cyclisation according to process (b) is a standard method for preparing indole compounds and may be effected by methods well known in the art, for example by heating a compound of structure (1 ⁇ ) with a compound of structure (IV) in a non-aqueous solvent such as acetic acid or an aqueous or non-aqueous solvent e.g. an alcohol such as methanol in the presence of an acid catalyst such as hydrochloric acid or a Lewis acid such as boron trifluoride, or in the presence of an acidic ion exchange resin.
  • a compound of structure (HI) may be obtained from the corresponding aniline derivative by diazotisation, for example using sodium nitrite and concentrated hydrochloric acid, and subsequent reduction.
  • reaction of a compound of structure (V) with a compound of structure (VI) is suitably performed in the presence of a base e.g. sodium methoxide in an organic solvent such as a C ⁇ alkanol at ambient temperature or elevated temperature e.g.
  • a base e.g. sodium methoxide
  • an organic solvent such as a C ⁇ alkanol
  • both of these products can then be isolated in standard manner.
  • the reaction can be carried out under acidic conditions, e.g. in acetic acid at elevated terperature (e.g. 30-100°C). These acidic conditions are particularly useful whe R 2 is not hydrogen, e.g. when R 2 is Cl.
  • R 3 is a N-protecting group for example tert-butoxycarbonyl this can be removed in standard manner for example by treatment with HC1 in methanol or with trifluoroacetic acid.
  • the dehydrated product can 5 be hydrogenated in standard manner to afford the compound wherein R a and R ⁇ are both hydrogen.
  • suitable leaving groups for X* or X 2 include halo, such as bromo or iodo or trifluoromethanesulphonyloxy.
  • the reaction is suitably performed in the presence of a palladium catalyst such as tetrakis (triphenylphosphine) palladium and a ba
  • a halide salt such as lithium chloride
  • a solvent such as dimethylformamide, acetonitrile, toluene, benzene, tetrahydrofuran, ethanol, dimethoxyethane, water or mixtures thereof, at an elevated temperature (e.g. 30- 150°C), preferably at the reflux temperature of the reaction mixture.
  • Suitable N-protecting groups include trialkylsilyl groups such as triisopropylsilyl which can be removed in standard maner, e.g. by treatment with tetra-n-butylammonium fluoride in a suitable solvent such as tetrahydrofuran or dichloromethane.
  • An example of a precursor of the group R 2 is hydrogen which is a suitable precursor for halogen as hereinbefore described for the introduction of such a group into
  • a compound of structure (VII), (IX) or (XI) wherein X is B(OH)2 is suitably prepared by reacting the organolithium or Grignard reagent, formed from the corresponding compound wherein X* is a leaving group such as halo e.g. bromo or iodo, with a tri-C ⁇ _4alkylborate such as trimethyl, triisopropyl or tri-n-butyl borate in an organi
  • R* and R 2 are as hereinbefore defined, which is the starting material of scheme can be prepared by reacting a compound of structure (XIH) : Structure (XIII) with a compound of formula R*X 2 , where R , R ⁇ , X* and X 2 are as hereinbefore defined.
  • a compound of the structure (DC) is suitably reacted with an acid addition salt of aminoguanidine, e.g. the hydrochloride, in a suitable solvent such as a
  • Cj_4alkanol e.g. methanol or ethanol at ambient or preferably elevated temperature, e.g.
  • a compound of the structure (DC) can suitably be prepared by reacting a compound of structure (V) as hereinbefore defined with a Vilsmeier reagent formed from phosphoryl chloride and dimethylformamide followed by aqueous work-up in the presence of a base such as sodium hydroxide.
  • Acid addition salts of compounds (I) can be prepared by standard procedures, for example, by reaction with suitable organic and inorganic acids, the nature of which will be apparent to persons skilled in the art.
  • Compounds of structure (I) have affinity for the 5-HT ⁇ -like receptor and are expected to be useful in treating disease states which require modulation of the 5-HTj-like receptor.
  • the compounds are 5-HTj-like agonists (or partial agonists) and as such are expected to have utility in medicine in the treatment and/or prophylaxis of migraine, and other conditions associated with cephalic pain, such as cluster headache, headache associated with vascular disorders and other neuralgia. They are also expected t have utility in the treatment or prophylaxis of portal hypertension.
  • the invention provides a method of treatment of conditions which require alteration of the 5-HTj-like receptor in particular migraine or portal hypertension which comprises administering to a subject in need thereof an effective amount of a compound of structure (I) or a pharmaceutically acceptable salt, solvate or hydrate thereof.
  • the compounds of the present invention are usually administered in a standard pharmaceutical composition.
  • the present invention therefore provides in a further aspect pharmaceutical compositions comprising a compound of structure (I) or a pharmaceutically acceptable salt, solvate or hydrate thereof and a pharmaceutically acceptable carrier.
  • the compounds of the invention may be administered by any convenient route, for example by oral, parenteral, buccal, sublingual, nasal, rectal or transdermal administration and the pharmaceutical compositions adapted accordingly.
  • the compounds of structure (I) and their pharmaceutically acceptable salts which are active when given orally can be formulated as liquids, for example syrups, suspension or emulsions, tablets, capsules and lozenges.
  • a liquid formulation will generally consist of a suspension or solution of the compound or pharmaceutically acceptable salt in a suitable liquid carrier(s) for example, ethanol, glycerine, non-aqueous solvent, for example polyethylene glycol, oils, or water with a suspending agent, preservative, flavouring or colouring agent.
  • a suitable liquid carrier(s) for example, ethanol, glycerine, non-aqueous solvent, for example polyethylene glycol, oils, or water with a suspending agent, preservative, flavouring or colouring agent.
  • a composition in the form of a tablet can be prepared using any suitable pharmaceutical carrier(s) routinely used for preparing solid formulations.
  • suitable pharmaceutical carrier(s) include magnesium stearate, starch, lactose, sucrose and cellulose.
  • a composition in the form of a capsule can be prepared using routine encapsulation procedures.
  • pellets containing the active ingredient can be prepared using standard carriers and then filled into a hard gelatin capsule; alternatively, a dispersion or suspension can be prepared using any suitable pharmaceutical carrier(s), for example aqueous gums, celluloses, silicates or oils and the dispersion or suspension then filled into a soft gelatin capsule.
  • suitable pharmaceutical carrier(s) for example aqueous gums, celluloses, silicates or oils and the dispersion or suspension then filled into a soft gelatin capsule.
  • Typical parenteral compositions consist of a solution or suspension of the compound or pharmaceutically acceptable salt in a sterile aqueous carrier or parenterally acceptable oil, for example polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oi or sesame oil.
  • compositions for nasal administration may conveniently be formulated as aerosol drops, gels and powders.
  • Aerosol formulations typically comprise a solution or fine suspension of the active substance in a physiologically acceptable aqueous or non-aqueous solvent and are usually presented in single or multidose quantities in sterile form in a seale container, which can take the form of a cartridge or refill for use with an atomising device
  • the sealed container may be a unitary dispensing device such as a single dos nasal inhaler or an aerosol dispenser fitted with a metering valve which is intended for disposal once the contents of the container have been exhausted.
  • the dosage form comprises an aerosol dispenser
  • a propellant which can be a compressed gas such as compressed air or an organic propellant such as a fluorochlorohydrocarbon.
  • the aerosol dosage forms can also take the form of a pump-atomiser.
  • compositions suitable for buccal or sublingual administration include tablets, lozenges and pastilles, wherein the active ingredient is formulated with a carrier such as sugar and acacia, tragacanth, or gelatin and glycerin.
  • a carrier such as sugar and acacia, tragacanth, or gelatin and glycerin.
  • compositions for rectal administration are conveniently in the form of suppositories containing a conventional suppository base such as cocoa butter.
  • compositions suitable for transdermal administration include ointments, gels an patches.
  • composition is in unit dose form such as a tablet, capsule or ampoule.
  • dosage unit for oral administration contains preferably from 1 to 250 mg
  • the pharmaceutically acceptable compounds of the invention will normally be administered in a daily dosage regimen (for an adult patient) of, for example, an oral dos of between 1 mg and 500 mg, preferably between 10 mg and 400 mg e.g. between 10 mg and 250 mg, or an intravenous, subcutaneous, or intramuscular dose of between 0.1 mg and 100 mg, preferably between 0.1 mg and 50 mg e.g. between 1 mg and 25 mg, of the compound of the formula (I) or a pharmaceutically acceptable salt thereof calculated as t free base, the compound being administered 1 to 4 times per day.
  • the compoun will be administered for a period of continuous therapy, for example for a week or more.
  • Example 1 4-Chloro-3-[2-N,N-(Dimethylamino)ethyl]-5-phenylindole (a) Trifluoromethanesulphonic anhydride (10 g) was added to a cooled (ice bath) solution of 2-chloro-3-methyl-4-nitrophenol (6.65 g) and 4-N,N-dimethylaminopyridine (8.66 g) in dichloromethane (100 ml) over 30 minutes. After stirring for a further 4 hours the reaction mixture was poured into ice/2M hydrochloric acid (1:1, 100 ml) and stirred for 45 minutes.
  • 4-Chloro-5-phenylindole-3-carboxaIdehyde guanylhydrazone (a) 4-Chloro-5-phenylindole (569 mg) was added to Vilsmeier's reagent (from 0.25 ml phosphoryl chloride and 1.0 ml dimethylformamide) at a temperature ⁇ 10°C. After 1 hour at 10°C the stirred mixture was heated at 35°C for 1 hour. The cool mixture was treated with ice (4 g) and a solution of sodium hydroxide (1.1 g) in water (3 ml) and then heated at the boiling point until evolution of dimethylamine had ceased. Filtration of the chilled mixture gave 4-chloro-5-phenylindole3-carboxaldehyde (627 mg, mp 80-82°C).
  • the volume of the mixture was reduced to about 50 ml by evaporation and the residue was mixed with dichloromethane (200 ml) and water (200 ml) and filtered.
  • the aqueous laye was extracted with dichloromethane (2 x 100 ml) and the combined organic extract was washed with water and brine. Evaporation of the dried solution gave an oil which was purified by flash chromatography (silica, petroleum ether/dichloromethane gradient) to give 4.43 g of 5-phenylindole, mp 63-64.5°C.
  • 3-(2-Aminoethyl)-5-(l-naphthyl)indole was obtained as a more polar component during the chromatographic purification of the above compound.
  • the partiall purified compound (322 mg) was treated with di-t-butyldicarbonate (180 mg) in tetrahydrofuran (5 ml) to give, after, flash chromatography with 30% ethyl acetate in hexane, 245 mg of the t-butyloxycarbonyl derivative.
  • Flas chromatography (silica, petroleum ether then mixtures with ether) gave 0.62 g of 5-(2,6- dimethylphenyl)-l-triisopropylsilylindole as a slowly crystallising oil, and then 0.31 g of 5-(2,6-dimethylphenyl)indole, mp 92-93°C (from cyclohexane).
  • the crude protected indole (0.6 g) in tetrahydrofuran (10 ml) was treated briefly with 1.0 M tetrabutylammonium fluoride in tetrahydrofuran (1.6 ml).
  • the crude intermediate obtained by evaporation of the dichloromethane extract was purified by flash chromatography (silica, petroleum ether) to give 5-bromo-l- triisopropylindole (10.0 g) as an oil.
  • the latter (3.52 g) in tetrahydrofuran (50 ml) was treated with t-butyl lithium in hexane (12.4 ml, 1.7 M) at -65°C during 15 minutes.
  • the solution was kept at -65°C for 1 hour and then trimethylborate (11.4 ml) was added dropwise during 10 minutes at -65 to -55°C and the solution was kept a further 45 minutes at -65°C.
  • Trimethylsilyl chloride (65 mg) was added to 4-chloro-3-[2-(dimeti ⁇ ylamino)ethyl]-5-(6- methoxy-3-pyridyl)indole (100 mg) and sodium iodide (90 mg) in acetonitrile (2 ml) and the mixture was heated under reflux overnight. The cool mixture was poured into cold water and die residue left after evaporation was recrystallised from water to give the hydroiodide of die tide compound (83 mg, mp 160-165°C).
  • Example 17 In a similar manner to that of Example 1(e), the above nitrile (501 mg) gave an approximately equimolar mixture of the amino and dimethylamino products which was purified in a similar manner to that of Example 5(c) to give the title compound, isolated a its oxalate (170 mg, mp 195-196°C, from ethanol/methanol).
  • Example 17 In a similar manner to that of Example 1(e), the above nitrile (501 mg) gave an approximately equimolar mixture of the amino and dimethylamino products which was purified in a similar manner to that of Example 5(c) to give the title compound, isolated a its oxalate (170 mg, mp 195-196°C, from ethanol/methanol).
  • Example 17 Example 17
  • Example 1 In a similar manner to that of Example 1 (d), the above indole (0.86 g) gave 4- chloro-5-(4-chlorophenyl)-3-cy.anomethylindole (0.4 g, mp 193-195°C). (d) In a similar manner to that of Example 1 (e), the above nitrile (0.4 g) gave the oxalate of the title compound (0.13 g, mp 218-219°C, from methanol).
  • Example 45 In a similar manner to that of Example 1 (d), the above indole (3.0 g) gave 4- chloro-3-cyanomethyl-5-(2-methoxy-3-pyridyl)indole (1.33 g, mp 192-195°C, from ether/hexane). (d) In a similar manner to that of Example 1(e), the above nitrile (0.4 g) gave the title compound (0.16 g, mp 198-200°C, after trituration with methanol/ether).
  • Example 45 In a similar manner to that of Example 1 (e), the above nitrile (0.4 g) gave the title compound (0.16 g, mp 198-200°C, after trituration with methanol/ether).
  • a tablet for oral administration is prepared by combining
  • An injection for parenteral administration is prepared from the following
  • the compound of formula (I) is dissolved in die citric acid and the pH slowly adjusted to pH 3.2 witii die sodium hydroxide solution. The solution is then made up to 100 ml with water, sterilised by filtration and sealed into appropriately sized ampoules and vials.

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  • Plural Heterocyclic Compounds (AREA)

Abstract

Composé présentant la structure (I), dans laquelle R1 représente avantageusement un cycle aryle éventuellement substitué à 6 ou 10 éléments, par exemple phényle ou naphtyle; R1 représente avantageusement un cycle hétéroaryle éventuellement substitué ayant de 6 à 10 éléments, comprenant de 1 à 4 atomes d'azote; R2 représente hydrogène, halogène, alkyle C¿1-4?, CN, NO2 ou CF3; R?3¿ représente hydrogène, halogène, alkyle C¿1-4?, CN, NO2 ou CF3; R?3¿ représente C(R?4)(R5)CH¿2NR6R7, -CH = NNHC(NH)NH¿2? ou (a); R?4 et R5¿, indépendamment l'un de l'autre, représentent hydrogène ou alkyle C¿1-4?; R?6 et R7¿, identiques ou différents, représentent hydrogène ou alkyle C¿1-4? ou forment un cycle conjointement avec l'atome d'azote auquel ils sont liés; R?8¿ représente hydrogène, alkyle C¿1-4? ou alcényle C3-6; R?a¿ représente hydrogène et Rb représente hydrogène ou hydroxy, ou bien Ra et Rb, pris ensemble, représentent une liaison; et q et m, indépendamment l'un de l'autre, valent 1 ou 2; et leurs sels, solvates et hydrates pharmaceutiquement acceptables. Ces composés sont des agonistes (ou agonistes partiels) semblables à 5-HT¿1?, et peuvent, à ce titre, être utilisés en médecine dans le traitement et/ou la prévention de la migraine et d'autres affections associées à la douleur céphalique, par exemple l'algie vasculaire de la face, les céphalées associées aux troubles vasculaires, et d'autres névralgies. Ils sont également utilisables dans le traitement ou la prévention de l'hypertension portale.
EP94903794A 1992-12-21 1993-12-14 Analogues de tryptamine a titre d'agonistes semblables a 5-ht 1? Withdrawn EP0674620A1 (fr)

Applications Claiming Priority (3)

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GB929226537A GB9226537D0 (en) 1992-12-21 1992-12-21 Compounds
GB9226537 1992-12-21
PCT/EP1993/003564 WO1994014771A1 (fr) 1992-12-21 1993-12-14 Analogues de tryptamine a titre d'agonistes semblables a 5-ht¿1?

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EP (1) EP0674620A1 (fr)
JP (1) JPH08504786A (fr)
CN (1) CN1092765A (fr)
AU (1) AU5811994A (fr)
GB (1) GB9226537D0 (fr)
WO (1) WO1994014771A1 (fr)
ZA (1) ZA939456B (fr)

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JP2002519348A (ja) 1998-06-30 2002-07-02 イーライ・リリー・アンド・カンパニー ５−ｈｔ１ｆアゴニスト
WO2001005768A1 (fr) * 1999-07-19 2001-01-25 Shionogi & Co., Ltd. Composes tricycliques porteurs de pendants acyloxymethoxycarbonyle
WO2001032621A1 (fr) * 1999-10-29 2001-05-10 Wakunaga Pharmaceutical Co., Ltd. Nouveaux derives d'indole, et medicaments contenant lesdits derives comme principe actif
WO2001034146A1 (fr) * 1999-11-08 2001-05-17 Smithkline Beecham Corporation Anti-infectieux
DE19963178A1 (de) 1999-12-27 2001-07-05 Gruenenthal Gmbh Substituierte Indol-Mannichbasen
US6429001B1 (en) 2000-01-26 2002-08-06 Chiron Corporation Recombinant AAV packaging systems
MXPA04001203A (es) * 2001-08-08 2004-05-20 Pharmacia & Upjhon Company 1-h-pirido[4,3-b] indoles terapeuticos.
DE10209520A1 (de) * 2002-03-04 2003-09-25 4Sc Ag Neue Modulatoren von Kaliumkanälen
US6906095B2 (en) 2002-05-10 2005-06-14 Wyeth Indolylalkylidenehydrazine-carboximidamide derivatives as 5-hydroxytryptamine-6 ligands
US6951881B2 (en) 2002-05-10 2005-10-04 Wyeth (1-substituted-indol-3-yl) alkylidenehydrazinecarboximidamide derivatives as 5-hydroxytryptamine-6 ligands
US7423044B2 (en) * 2002-09-05 2008-09-09 Wyeth Pyrimidine derivatives useful in the treatment of insulin resistance and hyperglycemia
CN1729174B (zh) 2002-12-20 2015-10-21 西巴特殊化学品控股有限公司 胺的合成以及用于合成胺的中间体
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JP2012503620A (ja) * 2008-09-26 2012-02-09 エフ．ホフマン−ラ ロシュ アーゲー Ｈｃｖを処置するためのピリンまたはピラジン誘導体
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GB9226537D0 (en) 1993-02-17
AU5811994A (en) 1994-07-19
ZA939456B (en) 1995-06-19
CN1092765A (zh) 1994-09-28
WO1994014771A1 (fr) 1994-07-07
JPH08504786A (ja) 1996-05-21

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