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WO1994014771A1 - Tryptamine analogues as 5-ht1-like agonists - Google Patents

Tryptamine analogues as 5-ht1-like agonists Download PDF

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Publication number
WO1994014771A1
WO1994014771A1 PCT/EP1993/003564 EP9303564W WO9414771A1 WO 1994014771 A1 WO1994014771 A1 WO 1994014771A1 EP 9303564 W EP9303564 W EP 9303564W WO 9414771 A1 WO9414771 A1 WO 9414771A1
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WO
WIPO (PCT)
Prior art keywords
indole
pyridyl
chloro
compound
ethyl
Prior art date
Application number
PCT/EP1993/003564
Other languages
French (fr)
Inventor
Roderick Alan Porter
William John Coates
Original Assignee
Smithkline Beecham Plc
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 Smithkline Beecham Plc filed Critical Smithkline Beecham Plc
Priority to JP6514774A priority Critical patent/JPH08504786A/en
Priority to AU58119/94A priority patent/AU5811994A/en
Priority to EP94903794A priority patent/EP0674620A1/en
Publication of WO1994014771A1 publication Critical patent/WO1994014771A1/en

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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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  • Indole Compounds (AREA)

Abstract

A compound of structure (I), in which R1 is an optionally substituted 6- to 10-membered aryl or heteroaryl ring; suitably R1 is an optionally substituted 6- or 10-membered aryl ring such as phenyl or naphthyl; suitably R1 is an optionally substituted 6- to 10-membered heteroaryl ring containing from 1 to 4 nitrogen atoms. R2 is hydrogen, halogen, C¿1-4? alkyl, CN, NO2 or CF3; R?3¿ is hydrogen, halogen, C¿1-4? alkyl, CN, NO2 or CF3; R?3 is C(R4)(R5)CH¿2NR6R7, -CH = NNHC(NH)NH¿2? or a; R?4 and R5¿ are independently hydrogen or C¿1-4? alkyl; R?6 and R7¿ are the same or different and are each hydrogen or C¿1-4? alkyl or together with the nitrogen atom to which they are attached form a ring; R?8¿ is hydrogen, C¿1-4? alkyl, or C3-6 alkenyl; R?a¿ is hydrogen and Rb is hydrogen or hydroxy, or R?a and Rb¿ together represent a bond; and q and m are independently 1 or 2; and pharmaceutically acceptable salts, solvates and hydrates thereof. The compounds are 5-HT¿1?-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 to have utility in the treatment or prophylaxis of portal hypertension.

Description

TRYPTAMINE ANALOGUES AS 5-HT1-LIKE AGONISTS
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):
Figure imgf000003_0001
Structure (I) in which
R! is an optionally substituted 6- to 10-membered aryl or heteroaryl ring; R2 is hydrogen, halogen, Cι_4alkyl, CN, NO2 or CF3; R3 is C(R4)(R5)CH2NR6R7, -CH=NNHC(NH)NH2 or
Figure imgf000003_0002
R4 and R^ are independendy hydrogen or C1.4al.kyl;
R6 and R7 are the same or different and are each hydrogen or Cι_4alkyl or together with the nitrogen atom to which they are attached form a ring; R8 is hydrogen, Cι_4alkyl, or C3_6alkenyl; Ra is hydrogen and RD is hydrogen or hydroxy, or Ra and R^ together represent a bond; and q and m are independently 1 or 2; and pharmaceutically acceptable salts, solvates and hydrates thereof.
Suitably R^ is an optionally substituted 6- or 10-membered aryl ring such as phenyl or naphthyl.
Suitably R is an optionally substituted 6- to 10-membered heteroaryl ring containing from 1 to 4 nitrogen atoms. Examples of such 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.
Suitably R* is unsubstituted or substituted by up to 3 groups selected from halo, C alkyl, hydroxy, oxo, Cι_ alkoxy, -CO2 9 , -NHCOR9, -CONR^R11, -SO2NR10Rn, -NHSO2R12, NO2, -NR^R11, NHCONH2, CN, CF3 or CF3O wherein R9 to R* * are independently hydrogen or Cj^alkyl and R*2 is Cj^alkyl.
Suitably, R2 is hydrogen, halogen, CMalkyl, CN, NO2 or CF3. Preferably R2 is hydrogen or halogen, in particular hydrogen or chlorine.
Suitably R3 is C(R4)(R5)CH2NR6R7 or -CH=NNHC(NH)NH2. Suitably, R4 and R^ are hydrogen or C \ _4alkyl. Preferably R4 and R^ are both hydrogen or methyl.
Suitably, R^ and R7 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. Preferably R" and R7 are both hydrogen or methyl. Suitable rings formed by R^ and R7 together with the nitrogen atom to which they are attached include for, example, 5- or 6-membered rings such as pyrrolidino and piperidino rings.
Suitably R3 is a group
Figure imgf000004_0001
Examples of Cj^alkyl groups (alone or as part of another group, e.g.
Cι_4alkoxy) include methyl, ethyl, propyl or butyl which can be straight chain or branched.
Examples of halo groups include fluoro, bromo, chloro or iodo.
Particular compounds of structure (I) include : 4-chloro-3-[2-N,N-(dimethylamino)ethyl]-5-phenylindole,
4-chloro-3-(2-aminoethyl)-5-phenylindole,
4-chloro-3-( 1 -methyl- 1 ,2,3,6-tetrahydro-4-pyridyl)-5-phenylindole,
4-chloro-5-phenylindole-3-carboxaldehyde guanylhydrazone,
3-[2-(dimethylamino)ethyl]-5-phenylindole, 3-(2-aminoethyl)-5-phenylindole,
3-( 1 -methyl- 1 t2,3,6-tetrahydro-4-pyridyl)-5-phenylindole,
5-phenylindole-3-carboxaldehyde guanylhydrazone,
3-[2-(dimethylamino)ethyl]-5-(l-naphthyl)indole,
3-(2-aminoethyl)-5-(l-naphthyl)indole, 3-[2-(dimethylamino)ethyl]-5-(2,6-dimethylphenyl)indole,
3-(2-aminoethyl)-5-(2,6-dimethylphenyl)indole,
4-chloro-3-[2-(dimethylamino)ethyl]-5-(6-methoxy-3-pyridyl)indole,
3-(2-aminoethyl)-4-chloro-5-(6-methoxy-3-pyridyl)indole, 4-chloro-5-(l,2-dihydro-6-oxo-3-pyridyl)-3-[2-(dimethylamino)ethyl]indole,
3-(2-aminoethyl)-4-chloro-5-( 1 ,2-dihydro-6-oxo-3-pyridyl)indole,
5-(l ,4-dihydro-4-oxo- 1 -pyridyl)-3-( 1 -methyl- 1 ,2,3,6-tetrahydro-4-pyridyl)indole,
3-(2-aminoethyl)-5-(2-pyridyl)indole,
3-[2-(dimethylamino)ethyl]-5-(2-pyridyl)indole, 3-[2-(dimethylamino)ethyl]-5-(4-fluorophenyl)indole,
3-(2-aminoethyl)-5-(4-fluorophenyl)indole,
3-(2-aminoethyl)-4-chloro-5-(4-fluorophenyl)indole,
4-chloro-3-[2-(N,N-dimethylamino)ethyl]-5-(4-fluorophenyl)indole,
3-[2-(N,N-dimethylamino)ethyl]-5-(4-methylphenyl)indole, 4-chloro-3- [2- (N,N-dimethylamino)ethyl] -5-(4-methylphenyl)indole,
3-(N-methylpiperidin-4-yl)-5-phenylindole,
5-( 1 ,4-dihydro-4-oxo- 1 -pyridyl)-3-(N-methylpiperidin-4-yl)indole,
5-(2-cyanophenyl)-3-( 1 -methyl- 1 ,2,3,6-tetrahydro-4-pyridyl)indole,
5-(2-cyanophenyl)-3-(N-methylpiperidin-4-yl)indole, 3-( 1 -methyl- 1 ,2,3 ,6-tetrahydro-4-pyridyl)-5-(3-pyridyl)indole,
3-(N-methylpiperidin-4-yl)-5-(3-pyridyl)indole,
5-(4-methoxy-2-pyrimidinyl)-3-( 1 -methyl- 1 ,2,3,6-tetrahydro-4-pyridyl)indole,
5-(4-methoxy-2-pyrimidinyl)-3-(N-methylpiperidin-4-yl)indole,
5-( 1 ,4-dihydro-4-oxo-2-pyrimidinyl)-3-( 1 -methyl- 1 ,2,3,6-tetrahydro-4-pyridyl)indole, 4-chloro-3-[2-(N,N-dimethylamino)ethyl]-5-(4-methoxyphenyl)indole,
3-[2-(N,N-dimethylamino)ethyl]-5-(4-methoxyphenyl)indole,
4-chloro-5-(4-chlorophenyl)-3-[2-(N,N-dimethylamino)ethyl]indole,
5-(4-chlorophenyl)-3-[2-(N,N-dimethylamino)ethyl]indole,
5-(4-chlorophenyl)-3-(2-aminoethyl)indole, 4-chloro-3-[2-(N,N-dimethylamino)ethyl]-5-(4-trifluoromethylphenyl)indole,
3-(2-aminoethyl)-5-(4-trifluoromethylphenyl)indole,
3-[2-(N,N-dimethylamino)ethyl]-5-(4-trifluoromethylphenyl)indole,
3-(2-aminoethyl)-5-( 1 ,4-dihydro-4-oxo- 1 -pyridyl)indole,
5-( 1 ,4-dihydro-4-oxo- 1 -pyridyl)-3- [2- (N,N-dimethylamino)ethyl] -indole, 5-phenyl-3-(l,2,5,6-tetrahydropyridiny-4-yl)indole,
3-[2-(methylamino)ethyl]-5-phenylindole,
4-chloro-3-[2-(methylamino)ethyl]-5-phenylindole,
5-(6-methoxy-3-pyridyl)-3-( 1 -methyl- 1 ,2,3,6-tetrahydro-4-pyridyl)indole, 3-(4-hydroxy-N-methylpiperidin-4-yl)-5-(6-methoxy-3-pyridyl)indole,
4-chloro-3-[2-(dimethylamino)ethyl]-5-(2-methoxy-3-pyridyl)indole,
3-[2-(dimethylamino)ethyl]-4-methyl-5-phenylindole,
3-[2-aminoethyl]-4-methyl-5-phenylindole, 4-chloro-5-(l,2-dihydro-2-oxo-3-pyridyl)-3-f2-(dimethylamino)ethyl]indole,
3-(2-aminoethyl)-4-chloro-5-(2-methoxy-3-pyridyl)indole,
3-(2-aminoethyl)-4-chloro-5-(l,2-dihydro-2-oxo-3-pyridyl)indole,
3-(2-aminoethyl)-4-chloro-5-(4-methoxyphenyl)indole,
3-(2-aminoethyl)-5-(4-methoxyphenyl)indole, 3-(2-aminoethyl)-4-chloro-5-(4-methylphenyl)indole,
3-(2-aminoethyl)-5-(4-methylphenyl)indole,
3-(2-aminoethyl)-4-chloro-5-(4-chlorophenyl)indole, and
3-(2-aminoethyl)-4-chloro-5-(4-trifluoromethylphenyl)indole, and pharmaceutically acceptable salts, solvates or hydrates thereof. Pharmaceutically acceptable acid addition salts of the compounds 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. 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. Also included within the scope of the invention are solvates and hydrates of compounds of formula (I).
It will be appreciated that certain compounds of structure (I) for example where
R4 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:
(a) for compounds in which R3 is C(R4)(R5)CH2NR6R7 reduction of a compound of structure (LT):
Figure imgf000007_0001
Structure (II)
(in which R and R2 are as described for structure Q) and Y is a reducible group) optionally in the presence of a compound of the formula R^R^NH in which R > and R7 are as described for structure (I); or
(b) reaction of a compound of structure (LLT) :
2
NHNH2
Structure (HI)
(wherein R! and R2 are as hereinbefore defined) or a salt thereof, with a compound of structure (IV) :
R CH2CHO Structure (TV)
or a protected derivative (e.g. an acetal or ketal) thereof wherein R3 is as described for structure (I); or
(c) for compounds where R3 is
Figure imgf000007_0002
reaction of a compound of structure (V) :
Figure imgf000007_0003
Structure (V) (wherein R and R2 are as hereinbefore defined) with a compound of structure (VI) :
Figure imgf000008_0001
Structure (VI)
(wherein 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 Ra and RD together represent a bond and optionally thereafter hydrogenating to form a compound wherein Ra and R^ are both hydrogen;
(d) reaction in the presence of a palladium catalyst of a compound of structure (VII) :
Figure imgf000008_0002
Structure (VII) with a compound of formula R^X2, wherein R*4 is hydrogen or an N-protecting group, R*5 is a group R2 as hereinbefore defined or a precursor thereof, R* is as hereinbefore defined and one of X* and X2 is B(OH2) and the other is a suitable leaving group, and thereafter if required removing the N-protecting group and/or converting R ^ to a group
R2;
(e) for compounds wherein R3 is -CH=NNHC(NH)NH2, reaction of a compound of structure (VLTI) :
Figure imgf000008_0003
Structure (VHT) wherein R and R2 are as hereinbefore defined with aminoguanidine or an acid addition salt thereof; and thereafter optionally
• converting a group R* into another group R*;
• converting a group R2 into another group R2;
• forming a pharmaceutically acceptable salt or hydrate thereof. In compounds of structure (II) Y may be a group which is converted to
-C(R )(R5)CH2NR6R7 when reduced in the presence of R6R7NH, in which case examples of Y include -C(R4)(R5)CN; and -C(R4)(R5)CHO. Alternatively Y may be a group which itself can be reduced to -C(R4)(R5)CH2NR6R7, such groups including -C(R4)(R5)CH2NO2, -C(R4)(R5)CH2N3, -COCONR6R7,-C(R4)(R5)CONR6R7, -C(R4)=CHNO2 and -C(R4)(R5)CH2NR6C0R7.
It will be appreciated that the precise method of reduction will depend on the nature of the group Y, such methods being well known in the art.
When Y represents -C(R4)(R5)CHO or -C(R4)(R5)CN the 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.
When Y represents a group -C(R4)(R5)CH2NO2, -C(R4)(R5)CH2N3, -COCONR6R7, or -C(R4)(R5)CONR6R7 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. Alternatively a group -C(R4)(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.
Reduction of a group -C(R4)(R5)CH2NR6C0R7 may be accomplished using a hydride such as lithium aluminium hydride.
It will be appreciated that a variety of other substituents Y and methods of reduction are well-known in tryptamine chemistry, such as those described in GB 2185020A, and may also be employed in process (a).
The intermediate compounds of structure (II) can be prepared by standard procedures.
Thus, 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.
Alternatively the gramine derivative may be obtained by reaction of a compound of structure (DC) :
Figure imgf000010_0001
14
Structure (IX) with a compound of formula R^X2 wherein R , R^4, Rl5, χl and X2 are as hereinbefore defined in analogous manner to process (d).
A 3-unsubstituted indole may be prepared from an appropriately substituted nitrotoluene derivative according to the following reaction scheme 1 :
Scheme 1
Figure imgf000010_0002
Structure (V)
(1) Me2NCH(OEt)2, DMF, pyrrolidine (2) N2H4.H2O, Ni.
Alternatively a 3-unsubstituted indole may be obtained from an appropriately substituted benzaldehyde derivative according to the following reaction scheme 2 : Et
Figure imgf000011_0001
(2)
Figure imgf000011_0002
( )
Figure imgf000011_0003
Structure (V)
(1) Ethyl azidoacetate/sodium ethoxide/ethanol (2) toluene, (reflux) (3) (i) Ethanol/sodium hydroxide (ii) HC1 (4) heating.
When Y represents -C(R4)(R5)CH2NR6COR7 a compound of structure (II) ma 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. This intermediate provides a convenient method of preparing compounds of structure (I) wherein one of R^ and R7 is hydrogen and the other a Cι_4alkyl group.
A compound of structure (II) wherein Y represents -COCONR6R7 may be prepared from an indole of structure (X) :
Figure imgf000011_0004
Structure (X) by reaction with oxalyl chloride followed by an amine HNR >R7 and subsequently introducing the group R2. When R2 is halogen e.g. iodine this may be introduced by reaction of a compound of structure II where R2 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(R4)(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(R4)(R^)CH2N3.
A compound of structure (V) can be prepared by reacting a compound of structure (XI) :
Figure imgf000012_0001
Structure (XI) with a compound of formula R X2, wherein Rl, R 4, R15, χl and X2 are as hereinbefore defined in analogous manner to process (d) .
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 (1Η) 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.
In process (c) the 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.
30-50°C, conveniently at the reflux temperature of the reaction mixture. Under these reaction conditions the compound wherein Ra and RD together represent a bond is formed by dehydration of the intermediate compound wherein Ra is hydrogen and R*5 is hydroxy.
Under suitable conditions both of these products can then be isolated in standard manner. Alternatively 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 R2 is not hydrogen, e.g. when R2 is Cl. When 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. If desired the dehydrated product can 5 be hydrogenated in standard manner to afford the compound wherein Ra and R^ are both hydrogen.
In process (d) suitable leaving groups for X* or X2 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
10 such as triethylamine, barium hydroxide, sodium bicarbonate or sodium carbonate and, when χl or X2 is trifluoromethanesulphonyloxy, a halide salt such as lithium chloride, in 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.
15 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 R2 is hydrogen which is a suitable precursor for halogen as hereinbefore described for the introduction of such a group into
20 compound of structure (X).
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-Cι_4alkylborate such as trimethyl, triisopropyl or tri-n-butyl borate in an organi
25 solvent such as diethyl ether or tetrahydrofuran with cooling (e.g. -80 to 10°C), followed by aqueous work-up.
In a similar manner a compound of structure (XII) :
Figure imgf000013_0001
Structure (XII)
30 wherein R* and R2 are as hereinbefore defined, which is the starting material of scheme can be prepared by reacting a compound of structure (XIH) :
Figure imgf000014_0001
Structure (XIII) with a compound of formula R*X2, where R , R^, X* and X2 are as hereinbefore defined. In process (e) 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.
30-100°C, conveniently at the reflux temperature of the reaction mixture.
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.
Suitable interconversions of R^ groups, and of R2 groups, will be apparent to those skilled in the an and can be carried out by standard procedures. 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-HTι-like receptor and are expected to be useful in treating disease states which require modulation of the 5-HTj-like receptor. In particular 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. In a further aspect, 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. For use in medicine, 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 composition in the form of a tablet can be prepared using any suitable pharmaceutical carrier(s) routinely used for preparing solid formulations. Examples of such carriers include magnesium stearate, starch, lactose, sucrose and cellulose.
A composition in the form of a capsule can be prepared using routine encapsulation procedures. For example, 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. 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. Alternatively, the solution can be lyophilised and then reconstituted with a suitable solvent just prior to administration. 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 Alternatively 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. Where the dosage form comprises an aerosol dispenser, it will contain 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.
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.
Preferably the composition is in unit dose form such as a tablet, capsule or ampoule. Each dosage unit for oral administration contains preferably from 1 to 250 mg
(and for parenteral administration contains preferably from 0.1 to 25 mg) of a compound of the formula (I) or a pharmaceutically acceptable salt thereof calculated as the free base
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. Suitably the compoun will be administered for a period of continuous therapy, for example for a week or more.
BIOLOGICAL DATA
5-HTι-like Receptor Screen RABBIT BASILAR ARTERY Experiments were performed in intracranial arteries from rabbit isolated basilar artery in a similar method to one described previously (Parsons and Whalley, 1989. Eur Pharmacol 174, 189-196.).
In brief, rabbits were killed by overdose with anaesthetic (sodium pentobarbitone). The whole brain was quickly removed and immersed in ice cold modified Kreb's solution and the basilar artery removed with the aid of a dissecting microscope. The Krebs solution was of the following composition (mM) Na+ (120); K+ (5); Ca2+ (2.25); Mg2+ (0.5); Cl" (98.5); SO^ (1); EDTA (0.04), equilibrated with 95% O2/5 CO2. The endothelium was removed by a gentle rubbing of the lumen with a fin metal wire. Arteries were then cut into ring segments (ca 4-5 mm wide) and set up for recording of isometric tension in 50 ml tissue baths in modified Krebs solution with the additional supplement of (mM); Na2+ (20); fumarate (10); pyruvate (5); L-glutamate (5) and glucose (10). The arteries were then placed under a resting force of 3-4 mN maintained at 37°C and the solution bubbled with 95% ~I5% CO2.
After tests for initial reactivity with 90 mM KC1 depolarising solution and for lack of acetylcholine-induced relaxation of 5-HT (10 mM) precontraction, cumulative concentration-effect curves (2 nM-60 mM) to 5-HT were constructed in the presence of ascorbate 200 mM, cocaine 6 mM, indomethacin 2.8 mM, ketanserin 1 mM and prazosin mM. Following a 45-60 min wash period, cumulative concentration-effect curves to t test compounds or 5-HT (as a time match control) were constructed in the presence of ascorbate, indomethacin, cocaine, ketanserin and prazosin.
The compounds of Examples 1, 2, 7, 11 A, 11B, 12, 13, 14, 15B, 16, 18, 19, 22, 33, 34A, 38, 42, 43A, 43B, 44, 45A, and 45B had EC50 values (concentration for half maximal contraction) in the range 0.03 to 1.5 μM.
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. The organic phase was separated and solvent removed at reduced pressur The residue was dissolved in diethyl ether (200 ml), filtered and the filtrate evaporated at reduced pressure to give 2-chloro-6-nitro-3-trifluoromethanesulphonyloxytoluene (9.9 g)
!H NMR δ (CDCI3) 2.63(s,3H), 7.39(d,lH) and 7.82(d,lH).
(b) A mixture of 2-chloro-6-nitro-3-trifluoromethanesulphonyloxytoluene (9.7 g), phenylboric acid (3.7 g) tetralds(triphenylphosphine)palladium (0) (1.26 g), lithium chloride (1.77 g), benzene (300 ml) ethanol (30 ml) and aqueous 2N sodium carbonate (37 ml) was boiled for 16 hours. After cooling to room temperature the reaction mixture was extracted with diethyl ether (2 x 200 ml) and the combined organic phases dried (MgSO4) and solvent removed at reduced pressure. The residue was column chromatographed (silica gel, hexane → 5% ethyl acetate/hexane eluant) to give 2-chloro- 6-nitro-3-phenyltoluene (7.04 g).
!H NMR δ (CDCI3) 7.29(d,lH), 7.33-7.5 l(m,5H) and 7.76(d,lH).
(c) A solution of 2-chloro-6-nitro-3-phenyltoluene (7.03 g) in dimethylformamide
(60 ml) containing dimethylformamide diethyl acetal (4.95 g) and pyrrolidine (2.42 g) w heated at 120°C for 18 hours. Additional dimethylformamide diethyl acetal (2.09 g) and pyrrolidine (1.01 g) were added and heating continued for a further 3 hours. Solvent was removed at reduced pressure and the residue dissolved in methanol (50 ml). Raney nickel (one spatula measure) was added followed by hydrazine hydrate (5.17 g) in three portion at 30 minute intervals. After stirring for a further 30 minutes after the addition of the fina portion of hydrazine hydrate the mixture was filtered solvent removed at reduced pressur and the residue column chromatographed (silica gel, ethyl acetate/hexane 0-20%) to give 4-chloro-5-phenylindole (2.49 g)
lϋ NMR δ (d^-dmso) 6.53(m,lH), 7.1 l(d,lH), 7.34-7.52(m,7H) and 11.50(br.s,lH).
(d) To an ice cooled solution of bis (dimethylamino)methane (1.31 g) in dichloromethane (50 ml), acetyl chloride (1.01 g) was added over 10 minutes, the mixture stirred for a further 10 minutes and 4-chloro-5-phenylindole (2.19 g) in dichloromethane (30 ml) added. After stirring for 45 minutes the reaction mixture was basified with 10% sodium hydroxide and water (100 ml) added. The organic phase was separated washed with water (2 x 100 ml) dried (MgSO4) and solvent removed at reduced pressure. The residue was dissolved in dimethylformamide (30 ml), potassium cyanide (2.38 g) and iodomethane (5.41 g) added. The mixture was stirred for 4 hours, diluted with water (100 ml) and extracted with ethyl acetate (3 x 100 ml). The combined organic extracts were washed with water (4 x 100 ml), dried (MgSO4) and solvent removed at reduced pressure to give 4-chloro-3-cyanomethyl-5-phenylindole (1.84 g).
!H NMR δ (d^-dmso) 4.21(s,2H), 7.1 l(d,lH), 7.35-7.61(m,7H) and 11.58(br.s,lH).
(e) A solution of 4-chloro-3-cyanomethyl-5-phenylindole (1.8 g) in methanol (50 ml containing dimethylamine (25 ml) and Raney nickel (one spatula measure) was shaken under an atmosphere of hydrogen (40 psi) for 90 minutes. The mixture was filtered and th filtrate evaporated at reduced pressure. The residue was column chromatographed (silica gel, 10% ammonia in methanol/dichloromethane 0→5%) to give the free base of the title compound (0.446 g) which was converted to the oxalate salt by the addition of oxalic acid (0.28 g) and recrystallisation from methanol/diethyl ether m.p. 197-200°C.
Example 2 4-Chloro-3-(2-aminoethyl)-5-phenylindole
A solution of 4-chloro-3-cyanomethyl-5-phenylindole (0.83 g) in a mixture of methanol (50 ml) and saturated methanolic ammonia (50 ml) was shaken with Raney nickel (0.2 g) under hydrogen (40 psi) for 5 hours. Evaporation of the filtered solution gave the title compound as an oil, which was converted into its oxalate salt, 0.65 g, mp 197-198°C (from methanol). Example 3
4-Chloro-3-(l-methyl-l,2,3,6-tetrahydro-4-pyridyl)-5-phenylindole
Orthophosphoric acid (2.5 ml, 2N) and l-methyl-4-piperidone (0.3 ml) were added to a stirred solution of 4-chloro-5-phenylindole (546 mg) in acetic acid (10 ml) at 85°C. A further five aliquots of l-methyl-4-piperidone were added at 30 minute intervals and after 18 hours the temperature was raised to 100°C for a further 24 hours. The cool mixture was added to ice-ammonia (20 ml) and extracted with ethyl acetate and the extract was in turn extracted with 6N hydrochloric acid. The acid extract was neutralised with sodium bicarbonate and the resultant gum was extracted into ethyl acetate and the extract was evaporated. Recrystallisation of the residue from 2-propanol gave 144 mg of the title compound as its hydrochloride salt mp 255-258°C.
Example 4
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).
(b) A solution of aminoguanidine hydrochloride (267 mg) in methanol (10 ml) was added to a solution of the above aldehyde (617 mg) in methanol (15 ml) and after 1 hour the stirred mixture was heated under reflux for 18 hours. The residue left after evaporation was dissolved in water and treated with sodium bicarbonate (220 mg) to give a sticky solid. This was dissolved in methanol and treated with a solution of maleic acid (280 mg) in methanol. The solid left after evaporation was washed with petroleum ether and ether. Recrystallisation twice from ethyl acetate gave the maleate salt of the title compound as its three quarter hydrate (103 mg, mp 203-205°C).
Example 5
3-[2-(Dimethylamino)ethyl]-5-phenylindole
(a) A stirred mixture of 5-bromoindole (5.88 g), benzeneboronic acid (5.49 g), tetralds(triphenylphosphine)palladium (0.7 g), barium hydroxide (14.2 g), dimethoxyethane (180 ml), and water (45 ml) was heated under reflux for 75 minutes.
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.
(b)(i) In a manner similar to that of Example 1(d), 5-phenylindole (1.55 g) gave 0.77 g of 3-cyanomethyl-5-phenylindole, mp 100-103°C.
(b)(ii) In an alternative procedure the intermediate 5-phenylgramine was prepared by heating a stirred mixture of 5-bromogramine (0.5 g), benzeneboronic acid (0.27 g), sodiu carbonate (0.42 g), tetrakis(triphenylphosphine)palladium (0.05 g), benzene (10 ml), ethanol (3 ml) and water (2 ml) under reflux for 2.5 hours. The filtered mixture was washed with water and then extracted with dilute hydrochloric acid. The extract was neutralised with sodium hydroxide solution and then solid potassium carbonate was adde to give 5-phenylgramine (0.27 g, mp 130-131 °C).
(c) In a manner similar to that of Example 1 (e), hydrogenation of the above nitrile
(0.76 g) gave a 1:1.4 mixture of the amino and dimethylamino products. The crude product in tetrahydrofuran (15 ml) was treated with di-t-butyldicarbonate (145 mg), the solvent was removed, and the residue was purified by flash chromatography (6 to 15% methanol in dichloromethane) to give, after elution of the 3-(2-t- butyloxycarbonylaminoethyl)-5-phenylindole, 0.14 g of 3-[2-(dimethylamino)ethyl)-5- phenylindole as an oil. This was converted into 0.12 g of the oxalate salt, mp 143.5-145° (from 2-propanol).
Example 6 3-(2-AminoethyI)-5-phenylindole
In a manner similar to that of Example 2, 3-cyanomethyl-5-phenylindole (0.77 g) gave 0.65 g of the title compound as its oxalate salt, mp 197-198°C (from methanol).
Example 7
3-(l-MethyI-l,2,3,6-tetrahydro-4-pyridyl)-5-phenylindole
(a) l-Methyl-4-piperidone (506 mg) was added to a solution of 5-phenylindole (430 mg) in methanol (6 nil) containing 30% w/v sodium methoxide in methanol (2.55 ml) an the solution was stirred under reflux for 3 hours. Filtration of the chilled mixture gave 46 mg of the title compound, mp 225-227°C (from methanol).
(b) In an alternative procedure, a stirred mixture of 5-bromo-3-( 1 -methyl- 1 ,2,3,6- tetrahydro-4-pyridyl)indole (1.0 g), benzeneboronic acid (0.5 g), sodium carbonate (0.72 g), tetralάs(triphenylphosphine)palladium (0.2 g), benzene (30 ml), ethanol (9 ml) and water (4 ml) was heated under reflux for 1.5 hours. The filtered mixture was washed with water and then extracted with dilute hydrochloric acid. The extract was washed with ethe and filtered to give the hydrochloride of the title compound (0.33 g, mp 272-274°C).
Example 8
5-PhenylindoIe-3-carboxaldehyde uanylhydrazone
(a) In a manner similar to that of Example 4(a), 5-phenylindole (1.0 g) gave 5- phenylindole-3-carboxaldehyde (1.1 g, mp 233-235°C).
(b) In a manner similar to that of Example 4(b) the above aldehyde (443 mg) gave 235 mg of the title compound as its maleate salt mp 225.5-226.5°C (from ethanol methanol).
Example 9
3-[2-(Dimethylamino)ethyl]-5-(l-naphthyl)indole (9A), and 3-(2-aminoethyl)-5-(l- naphthyl)indole (9B)
(a) In a manner similar to that of Example 5(a), 1-naphthaleneboronic acid (3.71 g) gave 5-(l-naphthyl)indole as an oil (3.2 g).
(b) In a manner similar to that of Example 1(d), 5-(l-naphthyl)indole (3.1 g) gave 3- cyanomethyl-5-(l-naphthyl)indole as a gum (2.1 g).
(c) In a manner similar to that of Example 1 (e), 3-cyanomethyl-5( 1 -naphthyl)indole (2.1 g) gave 288 mg of 3-[2-(dimethylamino)ethyl]-5-(l-naphthyl)indole, mp 146-148°C
(from toluene). 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. Hydrogen chloride was briefly passed into a solution of this derivative in dichloromethane, and the solution was chilled t give 3-(2-aminoethyl)-5-(l-naphthyl)indole hydrochloride (180 mg, mp 241-243°C).
Example 10 3-[2-(Dimethylammo)ethyl]-5-(2,6-dimethylphenyI)indole (10A), and 3-(2- aminoethyI)-5-(2,6-dimethyIphenyl)indoIe (10B)
(a)(i) A stirred mixture of l-triisopropylsilyl-5-indoleboronic acid (1.6 g), 2,6- dimethylbromobenzene (1.32 ml), barium hydroxide octahydrate (1.6 g), tetrakis(triphenylphosphine)palladium (0.29 g), dimethoxyethane (25 ml), and water (6 ml) was heated under reflux for 2.5 hours. The mixture was filtered, the aqueous solution was extracted with ether, and the combined organic extract was evaporated to an oil. 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 residue after evaporation was dissolved in ether, the solution was washed with water and evaporated to an oil which gave further solid 5-(2,6-dimethylphenyl)indole (0.2 g) when triturated witii petroleum ether. l-Triisopropylsilyl-5-indoleboronic acid was prepared as follows. Triisopropylsilyl chloride (6.87 g) was added to the sodium salt prepared from 5-bromoindole (6.35 g) and sodium hydride (1.71 g, 50% suspension in oil) in dimethylformamide (32 ml) and the mixture was stirred at room temperature for 2 hours then poured into ice water (150 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. Aqueous methanol (4 ml, 50%) was then added dropwise and the temperature was allowed to rise to ambient. After 2 hours the solution was added to water (150 ml) and the mixture was extracted with ether. Evaporation of the washed and dried extract gave l-triisopropyl-5-indoleboronic acid as a glassy solid (3.2 g) which was used without purification.
(a)(ii) In an alternative procedure, a vigorously stirred mixture of 5-bromoindole (4.45 g), 2,6-dimethylbenzeneboronic acid (3.75 g) , barium hydroxide octahydrate (7.89 g), tetrakis(triphenylphosphine)palladium (0.2 g), dimethoxyethane (110 ml) and water (27 ml) was heated under reflux for 8 hours. The cool mixture was filtered, the filtrate evaporated to low volume and the residue was distributed between ethyl acetate (100 ml) and water (75 ml). Hydrochloric acid was added to give a clear two phase system and the organic solution was separated, washed with water and brine, and evaporated to an oil. Flash chromatography on silica with 8:1 petroleum spirit : ether gave 5-(2,6- dimethylphenyl)indole (0.94 g).
(b) In a manner similar to that of Example 1(d), 5-(2,6-dimethylphenyl)indole (0.9 g) gave 3-(cyanomethyl)-5-(2,6-dimethylphenyl)indole as an oil (0.3 g).
(c) In a manner similar to that of Example 1(e), hydrogenation of the above nitrile gave a mixture of the two title compounds. Flash chromatography on silica gel with 200:10:1 dichloromethane:methanol:ammonia gave the less polar 3-[2- (dimethylamino)ethyl]-5-(2,6-dimethylphenyl)indole (80 mg) which was converted into its hemioxalate hydrate (60 mg, mp 237-239°C, from methanol), and the polar 3-(2- aminoethyl)-5-(2,6-dimethylphenyl)indole (50 mg) which was converted into its hemioxalate (30 mg, mp 252-254°C, from methanol-ether).
Example 11 4-Chloro-3-[2-(dimeth ylamino)ethy]]-5-(6-methoxy-3-pyrid vDindole (11 A) and 3-(2- aminoethyl)-4-chloro-5-(6-methoxy-3-pyridyl)indoIe (1 IB)
(a) In a similar manner to that of Example 1(b), 6-methoxy-3-pyridineboronic acid (7.0 g) and 2-chloro-6-nitro-3-trifluoromethanesulphonyloxytoluene (10.0 g) gave 2- chloro-3-(6-methoxy-3-pyridyl)-6-nitrotoluene (3.18 g). iH-nmr (CDCl3)δ 2.63 (s, 3H); 7.39 (d,lH); 7.83 (d, 1H).
(b) In a similar manner to that of Example 1 (c), 2-chloro-3-(6-methoxy-3-pyridyl)-6- nitrotoluene (3.18 g) gave 4-chloro-5-(6-methoxy-3-pyridyl)indole (1.76 g, mp 118-121° C).
(c) In a similar manner to that of Example 1 (d), the above indole ( 1.6 g) gave 4- chloro-3-cyanomethyl-5-(6-methoxy-3-pyridyl)indole (0.76 g, mp 173-177°C).
(d) In a similar manner to that of Example 1(e), the above nitrile gave a mixture of the title compounds. Flash chromatography gave 4-chloro-3-[2-(dimethylamino)ethyl]-5-
(6-methoxy-3-pyridyl)indole (428 mg, mp 140-144°C, after trituration with ether) and the primary amine which was purified further via its t-butyloxycarbonyl derivative (in a similar manner to that in Example 9(a)) to give 3-(2-aminoethyl)-4-chloro-5-(6-methoxy- 3-pyridyl)indole, isolated as its oxalate (130 mg, mp 213-216°C, from methanol).
Example 12 4-Chloro-5-(1^2-dihydro-6-oxo-3-pyridyl)-3-[2-(dimetliylamino)etliyl]indole
Trimethylsilyl chloride (65 mg) was added to 4-chloro-3-[2-(dimetiιylamino)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 13
3-(2-AminoethyI)-4-chloro-5-(l-2-dihydro-6-oxo-3-pyridyI)indole
In a manner similar to that of Example 12, 3-(2-aminoethyl)-4-chloro-5-(6-methoxy-3- pyridyl)indole (90 mg) gave the title compound, isolated as its oxalate salt (37 mg, mp 245-247°C, from methanol).
Example 14
5-(l,4-Dihydro-4-oxo-l-pyridyl)-3-(l-methyl-1^ »6-tetrahydro-4-pyridyl)indole (a) A stirred mixture of 5-aminoindole (2.48 g), 4H-pyran-4-one (2.01 g), hydrochloric acid (1.6 ml) and water (25 ml), was heated under reflux for 4 hours. The cooled mixture was neutralised with dilute sodium bicarbonate solution to deposit a gum which was washed witii water and taken up in ethanol (60 ml). The residue left after evaporation was combined witii the product obtained from a further 1.32 g of 5- aminoindole and purified by flash chromatography (silica, 10:1 dichloromethane:methanol) to give 5-(l,4-dihydro-4-oxo-l-pyridyl)indole (1.48 g, mp 240-241 °C, from ethanol-ether).
(b) A mixture of the above indole (0.7 g), l-methyl-4-piperidone (0.81 ml), methanolic sodium hydroxide (3.7 ml, 30% w/v) and methanol (10 ml), was heated under reflux for 8 hours and then evaporated to 50% of its original volume. The residue was diluted with water (20 ml), dilute hydrochloric acid added to pH 8, and the solution was concentrated to give die title compound as its hydrochloride salt (0.88 g, mp 250-252°C, from aqueous ethanol). Example 15
3-(2-Aminoethyl)-5-(2-pyridyl)indole (15A), and 3-[2-(dimethyIamino)ethyI]-5-(2- pyridyl)indole (15B)
(a) A stirred mixture of l-triisopropyl-5-indoleboronic acid (4.48 g), 2- bromopyridine (4.42 g), sodium carbonate (2.76 g), benzene (80 ml), water (16 ml), ethanol (24 ml) and tetrakis(triphenylphosphine)palladium (0.81 g) was heated under reflux for 4.5 hours and tiien the organic solution was washed witii water and with dilute hydrochloric acid. After evaporation of the organic solvent the crude 5-(2-pyridyl)-l- triisopropylindole was deprotected with 1.0 M tetrabutylammonium fluoride in tetrahydrofuran and d e product subjected to flash chromatography (silica, 0 to 2% methanol in dichloromethane) to give crude 5-(2-pyridyl)indole (1.38 g, mp 125-128°C).
(b) In a manner similar to that of Example 1(d), the above indole (1.37 g) gave 3- (cyanomethyl)-5-(2-ρyridyl)indole (0.26 g, mp 116-121°C, from dichloromethane/hexane).
(c) In a manner similar to that of Example 1 (e), hydrogenation of the above nitrile (0.25 g) gave 3-(2-aminoethyl)-5-(2-pyridyl)indole, isolated as its oxalate (53 mg, mp 186-188°C, from methanol), and 3-[2-(dimethylamino)ethyl]-5-(2-pyridyl)indole isolated as its oxalate (100 mg, m.p. 104-108°C).
Example 16 3-[2-(Dimethylamino)ethyI]-5-(4-fluorophenyI)indole
(a) In a similar manner to that of Example 5(a) 5-bromoindole (3.53 g) and 4- fluorobenzeneboronic acid (3.78 g) gave 5-(4-fluorophenyl)indole (3.09 g, mp 95-96°C).
(b) In a similar manner to that of Example 1(d), the above indole (2.53 g) gave 3- (cyanomethyl)-5-(4-fluorophenyl)indole (1.93 g, mp 143.5-145°C, from ether/petroleum ether).
(c) 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
3-(2-Aminoethyl)-5-(4-fluorophenyI)indole
In a similar manner to that of Example 2, the nitrile from 16(b) above (400 mg) gave the title compound, isolated as its oxalate (120 mg, mp 202-203.5°C, from methanol).
Example 18
3-(2-Aminoethyl)-4-chloro-5-(4-fluorophenyl)indoIe
(a) In a similar manner to that of Example 1(b), 4-fluorobenzeneboronic acid (7.8 g) gave 2-chloro-3-(4-fluorophenyl)-6-nitrotoluene (8.4 g, mp 61.5-62.5°C). (b) In a variation on the method of Example 1 (c), the enamine obtained from 5.7 g of the above nitrotoluene was dissolved in ethanol (15 ml) and die solution was added dropwise during 20 minutes to a stirred mixture of 30% aqueous titanium trichloride (65 ml) and etiianol (15 ml). After 3 hours the mixture was extracted with ether, the extrac was washed with water and sodium carbonate solution, dried, and evaporated. The residue was purified by column chromatography (silica gel, 3:2 petroleum etheπdichloromethane) to give 4-chloro-5-(4-fluorophenyl)indole (1.8 g, mp 93-94°C, from cylcohexane). (c) In a similar manner to that of Example 1 (d), die above indole (3.1 g) gave 4- chloro-3-cyanomethyl-5-(4-fluorophenyl)indole (2.0 g, mp 172-173°C, from cylcohexane- ether). (d) In a similar manner to that of Example 2, the above nitrile (0.46 g) gave the oxalate of the title compound (0.37 g, mp 185.5-187°C, from methanol).
Example 19
4-Chloro-3-[2-(N,N-dimethyIamino)ethyI]-5-(4-fluorophenyI)indole In a similar manner to that of Example 1 (e), 4-chloro-3-cyanomethyl-5-(4- fluorophenyl)indole (0.51 g) gave the oxalate of the title compound (0.21 g, mp 215-216°C, from methanol).
Example 20 3-[2-(N,N-Dimethylamino)ethyl]-5-(4-methylphenyl)indole
A stirred mixture of 5-bromo-3-[2-(N,N-dimetfιylamino)ethyl]indole (0.2 g), 4- methylbenzenebσronic acid (0.21 g), barium hydroxide (0.59 g), tetrakis(triphenylphosphine)palladium (16 mg), dimethoxyethane (6 ml) and water (1 ml) was heated under reflux in an inert atmosphere for 24 hours. The filtered mixture was distributed between water and ethyl acetate and the organic extract was evaporated to an oi (0.23 g). Column chromatography (silica, 100:10:1 dichloromethane:methanol:ammonia) gave the title compound which was isolated as its oxalate (0.04 g, mp 160-162°C, from methanol).
Example 21
4-Chloro-3-[2-(N,N-dimethylamino)ethyl]-5-(4-methylphenyl)indole
(a) In a similar manner to that Example 1 (b), 4-methylbenzenebσronic acid (5.08 g) gave 2-chloro-3-(4-methylphenyl)-6-nitrotoluene (7.57 g, mp 92-94°C).
(b) In a similar manner to that of Example 1(c), the above nitrotoluene (5.95 g) gave 4-chloro-5-(4-methylphenyl)indole (0.45 g, mp °C, from ).
(c) In a similar manner to that of Example 1 (d), the above indole (0.9 g) gave 4- chlσro-3-cyanomethyl-5-(4-methylphenyl)indole as an oil (1.91 g).
(d) In a similar manner to that of Example 1 (e), the above nitrile ( 1.91 g) gave the oxalate of the tide compound (0.15 g, mp 189-191°C, from methanol).
Example 22
3-(N-Methylpiperidin-4-yl)-5-phenyIindole
3-(l -Methyl- l,2,3,6-tetrahydro-4-pyridyl)-5-phenylindole hydrochloride (0.33 g) in ethanol (40 ml) was shaken with 10% palladium on charcoal (0.1 g) under hydrogen at 45 psi until hydrogenation was complete. Evaporation of the filtered solution gave a solid which was recrystallised from 2-propanol and then from ethanol to give the hydrochloride of d e tide compound (0.12 g, mp 247-249°C).
Example 23 5-(l,4-Dihydro-4-oxo-l-pyridyl)-3-(N-methyIpiperidin-4-yl)indole
In a similar manner to that of Example 22, 5-(l,4-dihydro-4-oxo-l-pyridyl)-3-(l-methyl- l,2,3,6-tetrahydro-4-pyridyl)indole hydrochloride (1.03 g) was hydrogenated to give the hydrochloride of the title compound (0.75 g, mp >300°C (decomposition), from ethanol).
Example 24
5-(2-Cyanophenyl)-3-(l-methyl-l.-2 ?6-tetrahydro-4-pyridyl)indole
(a) In a similar manner to that of Example 10(a)(i), 2-bromobenzonitrile (2.73 g) gave 5-(2-cyanophenyl)indole (0.75 g, mp 177-178°C, from cyclohexane).
(b) In a similar manner to that of Example 7(a), the above indole (0.74 g) gave the title compound (0.76 g, mp 225.2-228°C, from methanol). Example 25
5-(2-Cyanophenyl)-3-(N-methylpiperidin-4-yl)indole
In a similar manner to that of Example 23, 5-(2-cyanophenyl)-3-(l-methyl-l,2,3,6- tetrahydro-4-pyridyl)indole hydrochloride (0.35 g) gave the hydrochloride of die tide compound (0.15 g, mp 292-294°C (decomposition), from methanol).
Example 26
3-(l-Methyl-1^ ,6-tetrahydro-4-pyridyl)-5-(3-pyridyl)indole (a) In a similar manner to that of Example 10(a)(i), 3-bromopyridine (2.37 g) gave 5-
(3-pyridyl)indole (0.64 g, mp 157-157.5°C, from acetonitrile).
(b) In a similar manner to that of Example 7(a), the above indole (0.63 g) gave the title compound (0.7 g, mp 231.5-234°C, from methanol).
Example 27
3-(N-Methylpiperidin-4-yl)-5-(3-pyridyl)indole
In a similar manner to that of Example 23, 3-(l-methyl-l,2,3,6-tetrahydro-4-pyridyl)-5-(3- pyridyl)indole (0.47 g) gave the title compound as its dihydrochloride (0.26 g, mp 253- 255°C, from ethanol).
Example 28
5-(4-Methoxy-2-pyrimidinyI)-3-(l-methyl-1^ »6-tetrahydro-4-pyridyl)indole
(a) In a similar manner to that of Example 10(a)(i), 4-benzyloxy-2-chloropyrimidine (3.86 g) gave 5-(4-benzyloxy-2-pyrimidinyl)indole (0.7 g, mp 207-209°C, from acetonitrile). (b) In a similar manner to that of Example 7(a), the above indole (0.69 g) gave die title compound (0.55 g, mp 188-189.5°C, from methanol).
Example 29
5-(4-Methoxy-2-pyrimidinyl)-3-(N-methylpiperidin-4-yl)indole In a similar manner to that of Example 22, 5-(4-methoxy-2-pyrimidinyl)-3-( 1 -methyl- l,2,3,6-tetrahydro-4-pyridyl)indole (0.47 g) gave the title compound (0.3 g, mp 206- 207.5°C, from 2-propanol). Example 30
5-(l,4-Dihydro-4-oxo-2-pyrimidinyl)-3-(l-methyI-l,2,3,6-tetrahydro-4-pyridyl)indole
In a similar manner to that of Example 12, 5-(4-methoxy-2-pyrimidinyl)-3-(l-methyl- l,2,3,6-tetrahydro-4-pyridyl)indole (0.54 g) gave the tide compound isolated as its dihydrochloride salt (0.44 g, mp 238-242°C (decomposition), from ethanol).
Example 31 4-Chloro-3-[2-(N,N-dimethylamino)ethyI]-5-(4-methoxyphenyI)indole
(a) In a similar manner to that of Example 1 (b), 4-methoxybenzenebσronic acid (5.0 g gave 2-chloro-3-(4-medιoxyphenyl)-6-nitrotoluene (7.3 g, mp 87-89°C from dichloromethane/hexane).
(b) In a similar manner to that of Example 1 (c), the above nitrotoluene (7.25 g) gave 4-chlon>5-(4-methoxyphenyl)indole (1.35 g, mp 105-106°C, after trituration with ether/hexane). (c) In a similar manner to that of Example 1(d), d e above indole (1.25 g) gave 4- chloro-3-cyanomethyl-5-(4-methoxyphenyl)indole (0.15 g, mp 131-134°C, from dichloromethane/hexane).
(d) In a similar manner to that of Example 1 (e), the above nitrile (0.15 g) gave the titl compound (0.04 g, mp 150-153°C, after trituration witii methanol/ether).
Example 32
3-[2-(N,N-Dimethylamino)ethyl]-5-(4-methoxyphenyl)indole
(a) In a similar manner to that of Example 5(a), 4-methoxybenzeneboronic acid (3.2 g gave 5-(4-methoxyphenyl)indole (1,2 g, mp 118-120°C, from dichloromethane/hexane). (b) In a similar manner to that of Example 1 (d), the above indole ( 1.0 g) gave 3- cyanomethyl-5-(4-methoxyphenyl)indole (0.41 g, mp 141-143°C, from dichloromethane/hexane).
(c) In a similar manner to that of Example 1(e), die above nitrile (0.3 g) gave the oxalate of the tide compound (0.06 g, mp 193-195°C, from metiianol/ether).
Example 33
4-Chloro-5-(4-chlorophenyl)-3-[2-(N,N-dimethylamino)ethyl]indole
(a) In a similar manner to that of Example 1(b), 4-chlorobenzeneboronic acid (8.0 g) gave 2-chloro-3-(4-chlorophenyl)-6-nitrotoluene (7.36 g, mp 87-89°C from dichloro- methane/petroleum etiier). (b) In a similar manner to that of Example 18(b), the above nitrotoluene (7.36 g) gave 4-chloro-5-(4-chlorophenyl)indole (2.34 g, mp 79-82°C, from cyclohexane).
(c) 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 34
5-(4-ChIorophenyI)-3-[2-(N,N-dimethylamino)ethyl]indoIe (34A) and 5-(4- chIorophenyl)-3-(2-aminoethyI)indole (34B)
(a) In a similar manner to that of Example 5(a), 4-chlorobenzeneboronic acid (3.94 g) gave 5-(4-chlorophenyl)indole (1.86 g, mp 109-111°C, from toluene-hexane).
(b) In a similar manner to that of Example 1 (d), the above indole (1.82 g) gave 5-(4- chlorophenyl)-3-cyanomethylindole (0.85 g, mp 138-140°C). (c) In a similar manner to that of Example 9(c), the above nitrile (0.85 g) gave the oxalate of 5-(4-chlorophenyl)-3-[2-(N,N-dimedιylamino)ethyl]indole (0.18 g, mp 201- 203°C, from methanol) and die hydrochloride of 5-(4-chlorophenyl)-3-(2-aminoethyl)indole (0.09 g, mp 290°C (decomposition)).
Example 35
4-Chloro-3-[2-(N,N-dimethylamino)ethyl]-5-(4-trifluoromethylphenyl)indole
(a) In a similar manner to that of Example 1 (b), 4-trifluorobenzeneboronic acid (11.11 g) gave 2-chloro-6-nitro-3-(4-trifluorophenyl)toluene (10.61 g, mp 53-63°C).
(b) In a similar manner to that of Example 1(c), the above nitrotoluene (10.5 g) gave 4-chloro-5-(4-trifluorophenyl)indole (2.1 g, mp 123-127°C, from cyclohexane).
(c) In a similar manner to that of Example 1 (d), the above indole (2.0 g) gave 4- chloro-3-cyanomethyl-5-(4-trifluorophenyl)indole (0.5 g, mp 202-205°C, from toluene).
(d) In a similar manner to that of Example 1 (e), the above nitrile (0.5 g) gave the title compound (0.1 g, mp 187-189°C, from toluene).
Example 36
3-(2-AminoethyI)-5-(4-trifluoromethylphenyl)indole
(a) In a similar manner to that of Example 15(a), 4-bromotrifluoromethylbenzene
(3.55 g) and l-triisopropyl-5-indoleboronic (2.5 g) gave 5-(4-trifluoromethylphenyl)indole (1.46 g, mp 148-148.5°C, from dichloromethane-petrol). (b) In a similar manner to that of Example 1(d), the above indole (2.11 g) gave 3- cyanomethyl-5-(4-trifluoromethylphenyl)indole (1.26 g, mp 175-177°C, from dichloromediane-petrol) .
(c) In a similar manner to that of Example 2, the above nitrile (1.1 g) gave the oxalate of the title compound (0.15 g, mp 214-215°C, from acetonitrile).
Example 37
3-[2-(N,N-Dimethylamino)ethyl]-5-(4-trifluoromethylphenyl)indole
In a similar manner to that of Example 20, 4-trifluoromethylbenzeneboronic acid (0.28 g) gave the title compound (75 mg, mp 155-156°C, from toluene).
Example 38 3-(2-AminoethyI)-5-(l,4-dihydro-4-oxo-l-pyridyl)indole
(a) In a similar manner to that of Example 14(a), 5-ammogramine (4.0 g) and 4H- pyran-4-one (2.23 g) gave 5-(l,4-dihydro-4-oxo-l-pyridyl)gramine (3.28 g, mp 208-210°C (decomposition)).
(b) Methyl iodide (3.1 ml) was added to a stirred mixture of the above gramine (3.28 g) and potassium cyanide (3.09 g) in dimethylformamide (50 ml). After 2 hours at room temperature the mixture was evaporated and the residue was chromatographed (silica gel, 100:20:2— > 100:40:3 dichloromethane:methanol:ammonia) and the product was triturated witii acetonitrile to give 3-cyanomethyl-5-(l,4-dihydro-4-oxo-l-pyridyl)indole (1.51g, mp 206-208°C).
(c) In a similar manner to that of Example 2, the above nitrile (0.7 g) gave the oxalate of the title compound (0.52 g, mp 230-232°C (decomposition), from methanol).
Example 39
5-(l,4-Dihydro-4-oxo-l-pyridyl)-3-[2-(N,N-dimethylamino)ethyl]-indole
A mixture of 3-(2-aminoethyl)-5-(l,4-dihydro-4-oxo-l-pyridyl)indole (2.53 g), aqueous formaldehyde (37%, 1.2 ml), sodium cyanoborohydride (1.58 g), acetic acid (2.9 ml) and methanol (100 ml) was stirred at room temperature for 5 hours. The residue left after evaporation was digested with boiling methanol (150 ml) and the material contained in the digest was chromatographed (silica gel, 100:20:2→100:30:3 dichloromethane:methanol:ammonia) to give the title compound as a hydrated salt or complex with HCNBH3 (1.67 g, mp 202-204°C, from ethanol). Example 40
5-Phenyl-3-(l,2,5,6-tetrahydropyridiny-4-yl)indole
A mixture of 5-phenylindole (0.3 g), 4-piperidone hydrochloride hydrate (0.6 g), 30% w/v sodium methoxide in methanol (2 ml) and methanol (6 ml) was heated under reflux for 8 hours. The cool mixture was diluted with water (to 25 ml) and then extracted with ethyl acetate (10 ml) and dien witii ether (30 ml). The organic extract was washed with water and tiien dilute hydrochloric acid (2 ml) was added to give the hydrochloride of the title compound (0.33 g, mp 265-267°C, from aqueous ethanol).
Example 41
3-[2-(Methylamino)ethyI]-5-phenylindole
(a) A solution of 3-(2-aminoethyl)-5-phenylindole (from 0.86 g of the oxalate) in dichloromethane (25 ml) was stirred for 4 hours with triethylamine (0.4 ml) and 3-methyl-2 methylthiobenzothiazolium iodide (0.94 g). The mixture was wshed with water and brine, dried, and evaporated to give crude 3-methyl-2-[2-(5-phenyl-3-indolyl)ethyl]imino-2,3- dihydrobenzothiazole (0.93 g).
(b) The above imino compound (0.92 g) was heated at 100°C under nitrogen with methyl 4-toluenesulphonate (0.67 g) for 1.5 hours The cooled melt was triturated with ethyl acetate/ether to give crude 3-methyl-2-[N-(5-phenyl-3-indolyl)ethyl-N- methyl]benzothiazolium 4-toluenesulphonate ( 1.14 g).
(c) The above quaternary (1.14 g) was stirred for 3 hours with n-butylamine (0.2 ml) in dichloromethane (20 ml). The residue left after evaporation was taken up in ethanol (10 ml) and die solution was stirred with potassium hydroxide (0.56 g). After 2 hours water (15 ml) and brine (20 ml) were added and the mixture was extracted with ethyl acetate. Evaparation of die washed and dried extract gave a gum which was triturated with ether and then chromatographed (silica gel, 100:10:1 dichloromethane:methanol:ammonia) to give the title compound as a gum (0.18 g). The oxalate had mp 226-228°C, from methanol ether.
Example 42
4-Chloro-3-[2-(methylamino)ethyI]-5-phenylindole
(a) In a similar manner to that of Example 41 (a), 3-(2-aminoethyl)-4-chloro-5- phenylindole oxalate (0.87 g) gave 3-methyl-2-[2-(4-chloro-5-phenyl-3-indolyl)ethyl]imino- 2,3-dihydrobenzothiazole (0.71 g, mp 288-289°C, decomposition). (b) In a similar manner to that of Example 41 (b), but using a reaction temperature of 190°C, the above imino compound (0.7 g) gave crude 3-methyl-2-[N-(4-chloro-5-phenyl-3 indolyl)ed yl-N-methyl]benzothiazolium 4-toluenesulphonate (0.88 g).
(c) In a similar manner to that of Example 41(c), the above quternary (0.86 g) gave the title compound (0.17 g) The oxalate had mp 101-103°C, from methanol.
Example 43
5-(6-Methoxy-3-pyridyl)-3-(l-methyM^ ,6-tetrahydro-4-pyridyI)indole (43A) and 3-(4-hydroxy-N-methylpiperidin-4-y])-5-(6-methoxy-3-pyridyl)indole (43B) (a) In a similar manner to that of Example 5(a), 5-bromoindole (4.97 g) and 6- methoxy-3-pyridineboronic acid (5 g) gave 5-(6-methoxy-3-pyridyl)indole (1.89 g, mp 82-
86°C).
(b) In a similar manner to that of Example 7(a), the above indole (1 g) gave 5-(6- methoxy-3-pyridyl)-3-(l -methyl- l,2,3,6-tetrahydro-4-pyridyl)indole (0.27 g, mp 242°C, decomposition, from methanol/ethyl acetate). Concentration of the crude product mother liquors gave 3-(4-hydroxy-N-methylpiperidin-4-yl)-5-(6-methoxy-3-pyridyl)indole (0.07 g, mp 205°C, decomposition, from methanol).
Example 44 4-Chloro-3-[2-(dimethylamino)ethyI]-5-(2-methoxy-3-pyridyl)indole
(a) In a similar manner to that of Example 1 (b), 2-methoxy-3-pyridineboronic acid (7.2 g) and 2-chloro-6-nitro-4-trifluoromethanesulphonyloxytoluene (20.8 g) gave 2- chloro-5-(2-methoxy-3-pyridyl)-6-nitrotoluene (9.77 g, mp 87-90°C, from ether/hexane).
(b) In a similar manner to that of Example 1(c), the above nitrotoluene (8.36 g) gave 4-chloro-5-(2-methoxy-3-pyridyl)indole (3.9 g, mp 137-139°C, from dichloromethane/hexane).
(c) 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
3-[2-(Dimethylamino)ethyl]-4-methyI-5-phenylindole (45A) and 3-[2-AminoethyI]-4- methyl-5-phenyIindole (45B) a) In a similar manner to that of Example 1 (a), 3-hydroxy-2-methylbenzaldehyde (11.9 g) gave 2-methyl-3- fluoromethanesulphonyloxybenzaldehyde (23 g).
(b) In a similar manner to that of Example 1(a), the above triflate (23 g) gave 2r methyl-3-phenylbenzaldehyde (11.6 g, mp 60-63°C, from petroleum ether).
(c) A mixture of the above aldehyde (11.6 g) and ethyl azidoacetate (30.5 g) in ethan (75 ml) was slowly added to ethanolic sodium ethoxide (from sodium, 5.4 g, and ethanol, 250 ml) maintained at between -15 and -5°C. The mixture was stirred at 0°C for 3 hours and was then allowed to warm up to room temperature overnight. The residue left after evaporation was distributed between ether and saturated aqueous ammonium chloride solution. The washed and dried etiiereal extract was evaporated and die residue chromatographed (silica gel, 10% ether in petroleum ether) gave ethyl 3-(2-methyl-3- biphenyl)-2-azidopropeneoate (5.6 g, mp 66-68°C, from petroleum ether).
(d) The above vinyl azide (7.5 g) in xylene (400 ml) was added dropwise over 1 hour to boiling xylene (1400 ml) in an inert atmosphere. After 3 hours the solution was evaporated to about 50 ml volume and allowed to stand to give ethyl 4-methyl-5- phenylindole-2-carboxylate (5.64 g, mp 161-164°C). (e) The above ester (6.1 g) in a mixture of ethanol (50 ml) and dilute sodium hydroxide solution (25 ml) was heated under reflux for 1 hour. The warm mixture was the acidified with dilute hydrochloric acid to give a solid, which was dissolved in ether. Evaporation of the washed and dried solution gave 4-methyl-5-phenylindole-2-carboxylic acid (5.5 g, mp 250°C). (f) The above acid (5.5 g) was taken in portions and heated (bath temperature 300°) until efffervescence ceased (2-3 minutes). The melts were combined in etiier and the solution evaporated to an oil which crystallised when allowed to stand. Recrystallisation from cyclohexane gave 4-methyl-5-phenylindole (3.45 g, mp 81-82°C). (g) In a similar manner to that of Example 1 (d), die above indole (2.0 g) gave3- cyanomethyl-4-methyl-5-phenylindole (1.5 g, mp 165-170°, from ethyl acetate).
(h) In a similar manner to that of Example 1(e), die above nitrile (1.2 g) gave 3- [2- (dimethylamino)ethyl]-4-methyl-5-phenylindole oxalate (0.42 g, mp 213-216°C, from methanol) and 3-[2-aminoed yl]-4-methyl-5-phenylindole (0.27 g, mp 216-220°C, from methanol). Pharmaceutical formulations
Example A
A tablet for oral administration is prepared by combining
Mg Tablet
Compound of formula (I) 100 lactose 153 starch 33 crospovidone 12 microcrystalline cellulose 30 magnesium stearate 2
22Ω mg into a 9 mm tablet.
Example B
An injection for parenteral administration is prepared from the following
% w:w
Compound of formula (I) 0,50% (w:v) 1M citric acid 30% (v:v) sodium hydroxide (qs) to pH 3.2 water for injection BP to 100 ml
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.

Claims

CLAIMS:
1. A compound of structure (I):
Figure imgf000036_0001
Structure (I) in which
R! is an optionally substituted 6- to 10-membered aryl or heteroaryl ring;
R2 is hydrogen, halogen, Cj^alkyl, CN, NO2 or CF3;
R3 is C(R4)(R5)CH2NR6R7, -CH=NNHC(NH)NH2 or
Figure imgf000036_0002
R4 and R^ are independentiy hydrogen or Cj.4alkyl;
R° and R7 are the same or different and are each hydrogen or Cι_4alkyl or together with the nitrogen atom to which they are attached form a ring; R8 is hydrogen, Cj^alkyl, or C3_6alkenyl;
Ra is hydrogen and RD is hydrogen or hydroxy, or Ra and RD together represent a bond; and q and m are independently 1 or 2; and pharmaceutically acceptable salts, solvates and hydrates thereof.
2. A compound according to claim 1 where R s optionally substituted phenyl or naphthyl.
3. A compound according to claim 1 where R* is an optionally substituted 6- to 10-membered heteroaryl ring containing from 1 to 4 nitrogen atoms.
4. A compound according to any one of claims 1 to 3 wherein R* is unsubstituted or is substituted by 1 to 3 groups selected from halo, Cι_4alkyl, hydroxy, oxo, Cι_4alkoxy, -CO2R9 , -NHCOR9, -CONRIORI I, -SO2NR1()R11, -NHSO R12, NO2, -NRiOR11, NHCONH2, CN, CF3 or CF3O wherein R9 to R11 are independently hydrogen or Cj_4alkyl and R*2 is Cj^alkyl.
5. A compound according to any one of claims 1 to 4 wherein R2 is hydrogen or halogen.
6. A compound according to any one of claims 1 to 5 wherein R3 is
-CH=NNHC(NH)NH2 or C(R4)(R5)CH2NR6R7 and R4 and R5 are both hydrogen or metiiyl.
7. A compound according to any one of claims 1 to 6 wherein R^ and R7 are both hydrogen or metiiyl.
8. A compound according to any one of claims 1 to 5 where R3 is a group
Figure imgf000037_0001
9. A compound of structure (I) selected from : 4-chloro-3-[2-N,N-(dimed ylamino)ethyl]-5-phenylindole,
4-chloro-3-(2-aminoethyl)-5-phenylindole,
4-chloro-3-(l -methyl- 1 ,2,3,6-tetrahydro-4-pyridyl)-5-phenylindole,
4-chloro-5-phenylindole-3-carboxaldehyde guanylhydrazone,
3-[2-(dimetiιylamino)edιyl]-5-phenylindole, 3-(2-aminoethyl)-5-phenylindole,
3-(l-methyl-l,2,3,6-tetrahydro-4-pyridyl)-5-phenylindole,
5-phenylindole-3-carboxaldehyde guanylhydrazone,
3-[2-(dimed ylamino)ethyl]-5-( 1 -naphthyl)indole,
3-(2-aminoethyl)-5-(l-naphdιyl)indole, 3-[2-(dimethylamino)ethyl]-5-(2,6-dimethylphenyl)indole,
3-(2-aminoethyl)-5-(2,6-dimedιylphenyl)indole,
4-chloro-3-[2-(dimethylamino)ethyl]-5-(6-methoxy-3-pyridyl)indole,
3-(2-aminoethyl)-4-chloro-5-(6-methoxy-3-pyridyl)indole,
4-chloro-5-(l,2-dihydro-6-oxo-3-pyridyl)-3-[2-(dimethylamino)ethyl]indole, 3-(2-aminoethyl)-4-chloro-5-( 1 ,2-dihydro-6-oxo-3-pyridyl)indole,
5-(l ,4-dihydro-4-oxo- 1 -pyridyl)-3-( 1 -methyl- 1 ,2,3,6- tetrahydro-4-pyridyl)indole,
3-(2-aminoethyl)-5-(2-pyridyl)indole,
3-[2-(dimethylamino)ethyl]-5-(2-pyridyl)indole,
3-[2-(dimeti ylamino)ethyl]-5-(4-fluorophenyl)indole, 3-(2-aminoethyl)-5-(4-fluorophenyl)indole,
3-(2-aminoethyl)-4-chloro-5-(4-fluorophenyl)indole,
4-chloro-3-[2-(N,N-dimethylamino)ethyl]-5-(4-fluorophenyl)indole,
3- [2- (N,N-dimetiιylamino)ethyl] -5-(4-methylphenyl)indole, 4-chloro-3-[2-(N,N-dimedιylamino)ethyl]-5-(4-methylphenyl)indole,
3-(N-methylpiperidin-4-yl)-5-phenylindole,
5-(l ,4-dihydro-4-oxo- l-pyridyl)-3-(N-medιylpiperidin-4-yl)indole,
5-(2-cyanophenyl)-3-( 1 -methyl- 1 ,2,3,6-tetrahydro-4-pyridyl)indole,
5-(2-cyanophenyl)-3-(N-methylpiperidin-4-yl)indole, 3-(l-medιyl-l,2,3,6-tetrahydro-4-pyridyl)-5-(3-pyτidyl)indole,
3-(N-methylpiperidin-4-yl)-5-(3-pyridyl)indole,
5-(4-methoxy-2-pyrimidinyl)-3-( 1 -methyl- 1 ,2,3,6-tetrahydro-4-pyridyl)indole,
5-(4-methoxy-2-pyrimidinyl)-3-(N-medιylpiperidin-4-yl)indole,
5-(l,4-dihydro-4-oxo-2-pyrimidinyl)-3-(l-methyl-l,2,3,6-tetrahydro-4-pyridyl)indole, 4-chloro-3-[2-(N,N-dimetiιylamino)ethyl]-5-(4-methoxyphenyl)indole,
3-[2-(N,N-dimethylamino)ethyl]-5-(4-methoxyphenyl)indole,
4-chloro-5-(4-chlorophenyl)-3-[2-(N,N-dimetiιylamino)ethyl]indole,
5-(4-chlorophenyl)-3-[2-(N,N-dimed ylamino)ethyl]indole,
5-(4-chlorophenyl)-3-(2-aminoethyl)indole, 4-chloro-3-[2-(N,N-dimedιylamino)ethyl]-5-(4-trifluoromethylphenyl)indole,
3-(2-aminoethyl)-5-(4-trifluoromedιylphenyl)indole,
3-[2-(N,N-dimedιylamino)edιyl]-5-(4-trifluoromethylphenyl)indole,
3-(2-aminoethyl)-5-( 1 ,4-dihydro-4-oxo- 1 -pyridyl)indole,
5-(l,4-dihydro-4-oxo-l-pyridyl)-3-[2-(N,N-dimeti ylamino)ethyl]-indole, 5-phenyl-3-(l,2,5,6-tetrahydropyridiny-4-yl)indole,
3-[2-(methylamino)ethyl]-5-phenylindole,
4-chloro-3-[2-(methylamino)ethyl]-5-phenylindole,
5-(6-methoxy-3-pyridyl)-3-(l -methyl- 1 ,2,3,6-tetrahydro-4-pyridyl)indole,
3-(4-hydroxy-N-medιylpiperidin-4-yl)-5-(6-methoxy-3-pyridyl)indole, 4-chloro-3-[2-(dimethylamino)ethyl]-5-(2-methoxy-3-pyridyl)indole,
3-[2-(dimethylamino)ed yl]-4-methyl-5-phenylindole,
3- [2-aminoethyl] -4-methyl-5-phenylindole,
4-chloro-5-(l,2-dihydro-2-oxo-3-pyridyl)-3-[2-(dimethylamino)ethyl]indole,
3-(2-aminoethyl)-4-chloro-5-(2-methoxy-3-pyridyl)indole, 3-(2-aminoethyl)-4-chloro-5-(l,2-dihydro-2-oxo-3-pyridyl)indole,
3-(2-aminoethyl)-4-chloro-5-(4-methoxyphenyl)indole,
3-(2-aminoethyl)-5-(4-methoxyphenyl)indole,
3-(2-aminoethyl)-4-chloro-5-(4-methylphenyl)indole, 3-(2-aminoethyl)-5-(4-methylphenyl)indole, 3-(2-aminoethyl)-4-chloro-5-(4-chlorophenyl)indole, or 3-(2-aminoethyl)-4-chloro-5-(4-trifluoromethylphenyl)indole, or a pharmaceutically acceptable salt, solvate or hydrate thereof.
10. A process for the preparation of a compound of structure (I) or a salt, solvate or hydrate diereof, which comprises :
(a) for compounds in which R3 is C(R4)(R5)CH2NR6R7 reduction of a compound of structure (II):
Figure imgf000039_0001
Structure (II)
(in which R* and R2 arc as described for structure (I) and Y is a reducible group) optionally in the presence of a compound of the formula R^R7NH in which R > and R7 are as described for structure (I); or
(b) reaction of a compound of structure (III) :
2
F
1
R
NHNH2
Structure (HI)
(wherein R* and R2 are as hereinbefore defined) or a salt thereof, with a compound of structure (TV) :
R3CH2CHO
Structure (TV) or a protected derivative (e.g. an acetal or ketal) thereof wherein R3 is as described for structure (I); or (c) for compounds where R3 is
Figure imgf000040_0001
reaction of a compound of structure (V)
Figure imgf000040_0002
Structure (V)
(wherein R and R2 are as hereinbefore defined) with a compound of structure (VI) :
Figure imgf000040_0003
Structure (VI)
(wherein R^ is a N-protecting group or R^ as hereinbefore defined and q and m are as hereinbefore defined), and if required removing die N-protecting group and/or dehydratin to form a compound wherein Ra and RD together represent a bond and optionally thereafter hydrogenating to form a compound wherein Ra and R^ are both hydrogen;
(d) reaction in die presence of a palladium catalyst of a compound of structure (VII) :
Figure imgf000040_0004
Structure (VII) with a compound of formula R X2, wherein R*4 is hydrogen or an N-protecting group, Rl5 is a group R2 as hereinbefore defined or a precursor thereof, R* is as hereinbefore defined and one of X* and X2 is B(OH2) and d e otiier is a suitable leaving group, and thereafter if required removing the N-protecting group and/or converting R^ to a group R2;
(e) for compounds wherein R3 is -CH=NNHC(NH)NH2, reaction of a compound of structure (VIII) :
Figure imgf000041_0001
Structure (VHI) wherein R and R2 are as hereinbefore defined with aminoguanidine or an acid addition salt thereof; and thereafter optionally
• converting a group R into another group R ;
• converting a group R2 into another group R2;
• forming a pharmaceutically acceptable salt or hydrate tiiereof.
11. A compound of structure (I) as defined in claim 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof for use as a medicament.
12. A pharmaceutical composition comprising a compound of structure (I) as defined in claim 1 or a pharmaceutically acceptable salt, solvate or hydrate tiiereof and a pharmaceutically acceptable carrier.
13. A method of treatment of a condition which requires modulation of the 5-HTι-like receptor which comprises administering to a subject in need thereof an effective amount of a compound of structure (I) as defined in claim 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof.
PCT/EP1993/003564 1992-12-21 1993-12-14 Tryptamine analogues as 5-ht1-like agonists WO1994014771A1 (en)

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AU58119/94A AU5811994A (en) 1992-12-21 1993-12-14 Tryptamine analogues as 5-ht1-like agonists
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WO2000000487A1 (en) * 1998-06-30 2000-01-06 Eli Lilly And Company 5-ht1f agonists
WO2001005768A1 (en) * 1999-07-19 2001-01-25 Shionogi & Co., Ltd. Tricyclic compounds bearing acyloxymethoxycarbonyl pendants
WO2001032621A1 (en) * 1999-10-29 2001-05-10 Wakunaga Pharmaceutical Co., Ltd. Novel indole derivatives and drugs containing the same as the active ingredient
WO2001034146A1 (en) * 1999-11-08 2001-05-17 Smithkline Beecham Corporation Novel anti-infectives
WO2001047885A1 (en) * 1999-12-27 2001-07-05 Grünenthal GmbH Substituted indole mannich bases
US6429001B1 (en) 2000-01-26 2002-08-06 Chiron Corporation Recombinant AAV packaging systems
WO2003014118A1 (en) * 2001-08-08 2003-02-20 Pharmacia & Upjohn Company THERAPEUTIC 1H-PYRIDO[4,3-b]INDOLES
WO2003074047A1 (en) * 2002-03-04 2003-09-12 4Sc Ag Indole derivatives as modulators of potassium channels
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
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US7189753B1 (en) 1997-11-06 2007-03-13 Cady Roger K Preemptive prophylaxis of migraine
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
WO2001005768A1 (en) * 1999-07-19 2001-01-25 Shionogi & Co., Ltd. Tricyclic compounds bearing acyloxymethoxycarbonyl pendants
US6765096B1 (en) 1999-07-19 2004-07-20 Shionogi & Co., Ltd. Tricyclic compound having acyloxymethoxycarbonyl side chain
WO2001032621A1 (en) * 1999-10-29 2001-05-10 Wakunaga Pharmaceutical Co., Ltd. Novel indole derivatives and drugs containing the same as the active ingredient
WO2001034146A1 (en) * 1999-11-08 2001-05-17 Smithkline Beecham Corporation Novel anti-infectives
WO2001047885A1 (en) * 1999-12-27 2001-07-05 Grünenthal GmbH Substituted indole mannich bases
US7091220B2 (en) 1999-12-27 2006-08-15 Gruenenthal Gmbh Substituted indole Mannich bases
US6429001B1 (en) 2000-01-26 2002-08-06 Chiron Corporation Recombinant AAV packaging systems
WO2003014118A1 (en) * 2001-08-08 2003-02-20 Pharmacia & Upjohn Company THERAPEUTIC 1H-PYRIDO[4,3-b]INDOLES
US6849640B2 (en) 2001-08-08 2005-02-01 Pharmacia & Upjohn Company Therapeutic 1H-pyrido [4,3-b] indoles
WO2003074047A1 (en) * 2002-03-04 2003-09-12 4Sc Ag Indole derivatives as modulators of potassium channels
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
US7645886B2 (en) * 2002-12-20 2010-01-12 Ciba Specialty Corporation Synthesis of amines and intermediates for the synthesis thereof
US7968730B2 (en) 2002-12-20 2011-06-28 Basf Se Synthesis of amines and intermediates for the synthesis thereof
US8710093B2 (en) * 2002-12-20 2014-04-29 BASF SE Ludwigshafen Synthesis of amines and intermediates for the synthesis thereof
US8822702B2 (en) 2002-12-20 2014-09-02 Basf Se Synthesis of amines and intermediates for the synthesis thereof
WO2006019831A1 (en) * 2004-07-14 2006-02-23 Ptc Therapeutics, Inc. Methods for treating hepatitis c
US7973069B2 (en) 2004-07-14 2011-07-05 Ptc Therapeutics, Inc. Methods for treating hepatitis C
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