WO1994014770A1 - Tryptamine analogues as 5-ht1-like agonists - Google Patents

Tryptamine analogues as 5-ht1-like agonists Download PDF

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Publication number
WO1994014770A1
WO1994014770A1 PCT/EP1993/003563 EP9303563W WO9414770A1 WO 1994014770 A1 WO1994014770 A1 WO 1994014770A1 EP 9303563 W EP9303563 W EP 9303563W WO 9414770 A1 WO9414770 A1 WO 9414770A1
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Prior art keywords
compound
ethane
indol
mmol
hydrogen
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PCT/EP1993/003563
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French (fr)
Inventor
Roderick Alan Porter
John Gerard Ward
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Smithkline Beecham Plc
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Application filed by Smithkline Beecham Plc filed Critical Smithkline Beecham Plc
Priority to US08/448,544 priority Critical patent/US5637593A/en
Priority to JP6514773A priority patent/JPH08504785A/en
Priority to EP94903793A priority patent/EP0674619A1/en
Publication of WO1994014770A1 publication Critical patent/WO1994014770A1/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
    • C07D401/02—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
    • C07D401/12—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 linked by a chain containing hetero atoms as chain links
    • 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
    • C07D403/12—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 linked by a chain containing hetero atoms as chain links

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.
  • WO-A-93/11106 published after the priority date of the present application describes indole derivatives as serotonin (5HTj) agonists.
  • 5HTj serotonin
  • R! is a 6- to 10- membered aryl or heteroaryl ring optionally substituted by up to 3 groups selected from halo, C ⁇ alkyl, CO2R 9 , NHCOR 9 , CONR ⁇ R 1 *, SO2NR 10 R 1 1, NHSO2R 12 , NO , NR 10 !* 1 !, NHCONH2 or CN,
  • a 1 A 2 is O, S or NH, R 2 is hydrogen and
  • WO-A-93/11106 also specifically discloses as Example 1G a compound wherein R 1 is 3-CF 3 -2-pyridyl, A J A 2 is NH, R 2 is hydrogen and R 3 is CH2CH2NMe2.
  • the present invention provides, in a first aspect, a compound of structure (I):
  • a 1 is O, S(O) n in which n is 0,1 or 2, NR, CH2, or CH(OH);
  • a 2 is a bond or CH2;
  • R is hydrogen or C]_4alkyl
  • R! is an optionally substituted 6- to 10-membered aryl or heteroaryl ring
  • R2 is hydrogen, halogen, Ci ⁇ alkyl, CN, NO2 or CF3;
  • R 4 and R ⁇ are independently hydrogen or Cj_4alkyl
  • R ⁇ and R 7 are the same or different and are each hydrogen or C ⁇ al yl or together with the nitrogen atom to which they are attached form a ring;
  • R8 is hydrogen, C ⁇ _4alkyl, or C3_6alkenyl; the dotted lines represent an optional bond; and q and m are independently 1 or 2; and pharmaceutically acceptable salts, solvates and hydrates thereof.
  • a 1 is O, S, NR or CH2.
  • a 2 is a bond or CH2.
  • R an optionally substituted 6- or 10-membered aryl ring such as phenyl or naphthyl.
  • R 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 and quinoline.
  • the heteroaryl ring can be linked to A* A ⁇ via a carbon or nitrogen atom of the heteroaryl ring.
  • R- is unsubstituted or substituted by up to 3 groups selected from halo, C ⁇ _4alkyl, hydroxy, oxo, Ci ⁇ alkoxy, -CO2R 9 , -NHCOR 9 , -CONR ⁇ R 1 ] ,
  • R 9 toR ⁇ are independently hydrogen or Cj_4alkyl and R* 2 is Cj ⁇ alkyl.
  • R 2 is hydrogen, halogen, Cj ⁇ alkyl, CN, NO2 or CF3.
  • R 2 is hydrogen or halogen, in particular hydrogen or chlorine.
  • R 4 and R ⁇ are hydrogen or C ⁇ _4al yl.
  • R 4 and R ⁇ are both hydrogen or methyl.
  • R ⁇ and R 7 are the same or different and are each hydrogen or C ⁇ al or together with the nitrogen atom to which they are attached form a ring.
  • R and R 7 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
  • Cj ⁇ alkyl groups (alone or as part of another group, e.g. Cj_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 :
  • 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).
  • the compounds of the present invention can be prepared by processes analogou 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 ⁇ 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;
  • Y may be a group which is converted to -C(R 4 )(R 5 )CH2NR 6 R 7 when reduced in the presence of R 6 R 7 NH, in which case examples of Y include -C(R 4 )(R 5 )CN; and -C(R 4 )(R 5 )CHO.
  • reaction between a compound of structure (II) and an amine R°R 7 NH is suitably carried out under reductiv amination conditions, for example, catalytic hydrogenation in the presence of the amine R6R 7 NH and a suitable solvent.
  • Suitable catalysts include, for example, Raney nickel.
  • Suitable solvents include, for example, C ⁇ _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 R 7 are both hydrogen, hydrogenation in methanolic ammonia in the presence of a Raney nickel catalyst; and where R ⁇ and R 7 a both C ⁇ _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 )CH 2 NO 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 usi allane (prepared from lithium aluminium hydride and sulphuric acid) or lithium aluminiu 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 treatment with cobalt boride prepared by treating a cobalt II salt such as cobalt chloride with sodium borohydride in a suitable solvent such as methanol.
  • Reduction of a group -C(R 4 )(R ⁇ )CH2NR ⁇ COR 7 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 (II) 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.
  • a 3-unsubstituted indole may be prepared from an appropriately substituted nitrotoluene derivative accordi to the following reaction scheme 1 : 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 R 7 is hydrogen and the other a C ⁇ _4alkyl group.
  • a compound of structure ( ⁇ ) wherein Y represents -COCONR ⁇ R 7 may be prepared from an indole of structure (VIII) :
  • 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 ( ⁇ ) wherein Y represents -C(R )(R ⁇ )CH2N3.
  • Suitable electrophiles include R ⁇ SSR ⁇ , R ⁇ (CU2)pL ⁇ (wherein p is 1 or 2 and
  • L* is a suitable leaving group such as halo, e.g. bromo or iodo), R ⁇ CHO or
  • reaction with the aldehyde results in compounds wherein A* A 2 is CH(OH) which can be reduced for example by catalytic hydrogenation to CH2.
  • Suitable N-protecting groups include trialkylsilyl groups in particular triisopropylsilyl which can be removed in standard manner, e.g. by treatment with tetra-n- butylammonium fluoride in a suitable solvent such as tetrahydrofuran or dichloromethane.
  • 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 (VIII).
  • a compound of structure (IX) can be suitably prepared by reacting a compound of structure (X) : - ⁇ "
  • L 2 is a suitable leaving group such as halo, e.g. bromo or iodo and R* 4 and R are as hereinbefore defined with a lithiating reagent such as tert-butyl lithium or n-butyl lithium in a solvent such as diethyl ether or tetrahydrofuran at low temperature preferabl -60°C.
  • a lithiating reagent such as tert-butyl lithium or n-butyl lithium in a solvent such as diethyl ether or tetrahydrofuran at low temperature preferabl -60°C.
  • the N-protecting group can be introduced in standard manner, e.g. by treating with triisopropylsilyl chloride in dimethylformamide in the presence of sodium hydride base.
  • a compound of structure (V) wherein A* A 2 is S can be prepared by reacting a compound of structure (XI) :
  • L 3 is a suitable leaving group such as halo, e.g. bromo or iodo, or trifluoromethane sulphonyloxy
  • R ⁇ is as hereinbefore defined and R " ⁇ - hydrogen or a group R* 4 as hereinbefore defined with a compound of the formula R ⁇ SSn(R ⁇ 7 )3 wher R l7 is Ci _4alkyl in the presence of a palladium catalyst such as palladium tetrakistriphenyl phosphine palladium (O) in an organic solvent such as toluene accordin to the method of M. Kosugi et al. Bull Chem Soc Jpn 1985, 58, 3657, and thereafter if required removing the group R and/or converting a group R 5 to a group R 2 .
  • a palladium catalyst such as palladium tetrakistriphenyl phosphine palladium (O) in an organic solvent such as tolu
  • a palladium catalyst such as palladium tetrakistriphenyl phosphine palladiu (O)
  • organic solvent such as tetrahydrofuran at ambient or preferably reflux temperature
  • a compound of structure (V) wherein A ⁇ A 2 is OCH2 SCH2 or NRCH2 can be prepared by reacting a compound of structure (XII) :
  • L 4 is a suitable leaving group such as halo e.g. bromo or iodo, or trifluoromethane sulphonyloxy and R ⁇ and Rl° " are as hereinbefore defined with a compound of formula R*OH, R*SH or R ⁇ NHR in the presence of a suitable base such as potassium carbonate or potassium hydrogen carbonate in an organic solvent such as dimethylsulphoxide or dimethyl formamide at ambient or preferably reflux temperature, and thereafter if required removing the group R ⁇ 4 and/or converting a group R ⁇ to a group R 2 .
  • halo e.g. bromo or iodo, or trifluoromethane sulphonyloxy
  • R ⁇ and Rl° " are as hereinbefore defined with a compound of formula R*OH, R*SH or R ⁇ NHR in the presence of a suitable base such as potassium carbonate or potassium hydrogen carbonate in an organic solvent such as dimethylsulphoxide or dimethyl formamide at ambient or preferably
  • Appropriate electrophiles include R ⁇ L*, R ⁇ SR 1 , RiCHO or R 1 CH2L 1 wherein L 1 is as herebefore defined.
  • a compound of structure (X ⁇ i) can be prepared in standard manner by reacting a compound of structure (XII) wherein L 4 is halo and R ⁇ is a group R ⁇ with magnesium.
  • a compound of structure (V) wherein A A 2 is O, S or NR can be prepared by reacting optionally in the presence of a suitable base such as potassium hydroxide a compound of structure (XIV) :
  • a compound of structure (XV) wherein A ⁇ A 2 is O, S or NR can be prepared by reacting a compound of structure (XVI) wherein D is fluoro with R*OH, R SH or R*NH in a dipolar aprotic solvent such as dimethyl sulphoxide or dimethylformamide in the presence of a base such as potassium carbonate at ambient or preferably elevated temperatures in particular the boiling point of the solvent, and thereafter if required converting a group R ⁇ to a group R 2 .
  • a dipolar aprotic solvent such as dimethyl sulphoxide or dimethylformamide
  • 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 heatin a compound of structure (III) 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 boro trifluoride, or in the presence of an acidic ion exchange resin.
  • a non-aqueous solvent such as acetic acid or an aqueous or non-aqueous solvent e.g. an alcohol such as methanol
  • an acid catalyst such as hydrochloric acid or a Lewis acid such as boro trifluoride
  • a compound of structure (III) 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 Ci _2alkanol at ambient temperature or elevated temperature e.g. 30-50°C, conveniently at the reflux temperature of the reaction mixture.
  • a base e.g. sodium methoxide in an organic solvent such as a Ci _2alkanol
  • an organic solvent e.g. 30-50°C
  • the reaction can be carried out under acidic conditions, e.g. in acetic acid at elevated temperature (e.g. 30-100°C).
  • R* 3 is a N-protecting group for example tert- butoxycarbonyl this can be removed in standard manner for example by treatment with HCI in methanol or with trifluoroacetic acid.
  • a compound of the structure (VII) is suitably reacted with an acid addition salt of aminoguanidine, e.g. the hydrochloride, in a suitable solvent such as a C ⁇ _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 suitable solvent such as a C ⁇ _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 (VII) 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 presenc 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 b 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-lik 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 whi are active when given orally can be formulated as liquids, for example syrups, suspensio 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.
  • suitable pharmaceutical carrier(s) routinely used for preparing solid formulations.
  • suitable pharmaceutical carriers 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, dispersion or suspension can be prepared using any suitable pharmaceutical carriers), fo 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 or sesame oil.
  • a sterile aqueous carrier or parenterally acceptable oil for example polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis or sesame oil.
  • the solution can be lyophilised and then reconstituted with suitable solvent just prior to administration.
  • compositions for nasal administration may conveniently be formulated as aeros drops, gels and powders.
  • Aerosol formulations typically comprise a solution or fine suspension of the active substance in a physiologically acceptable aqueous or non-aqueo solvent and are usually presented in single or multidose quantities in sterile form in a sea container, which can take the form of a cartridge or refill for use with an atomising devi
  • the sealed container may be a unitary dispensing device such as a single do 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 for comprises an aerosol dispenser
  • it will contain a propellant which can be a compressed g 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 and 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 dose 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 th free base, the compound being administered 1 to 4 times per day.
  • the compounds will be administered for a period of continuous therapy, for example for a week or more.
  • the compounds of Examples 1, 2, 3A, 3B, 4A, 8, 10B, 12 and 16 had EC50 values (concentration for half-maximal contraction) in the range 0.025 to 4.2 ⁇ M.
  • the catalyst was removed by filtration solvent removed at reduced pressure and the residue column chromatographed (silica gel, dichloromethane/10% methanol in ammonia 0 ⁇ 8% eluant) to give the title compound (0.035g) from which the oxalate salt was prepared by the addition of oxalic acid (0.024g) in methanol (1ml) followed by diediyl ether to the cloud point to give the oxalate salt m.p 170-173°C.
  • Triisopropylsilyl chloride (6.87g) was added to the sodium salt prepared from 5- bromoindole (6.35g) and sodium hydride (1.71g, 50% suspension in oil) in dimethylformamide (32ml) and the mixture was stirred at room temperature for 2 hours then poured into ice water (150ml).
  • the crude intermediate obtained by evaporation of th dichloromethane extract was column chromatographed (silica gel, 40-60°C petroleum ether) to give 5-bromo-l-triisopropylsilylindole isolated as an oil.
  • Example 3 l-Amino-2-(S-(4-methoxyphenoxy)indol-3-yl)ethane (3A) and 1-(N,N- dimethylamino)-2-(5-(4-methoxyphenoxy)indol-3-yl)ethane (3B) a) Sodium metal (2.0 lg, 87.43 mmol) cut into small pieces was dissolved in absolute ethanol (67 mL) and the resulting solution cooled to -5°C. A mixture of ethyl azidoacetate (11.32g, 87.67 mmol) and 3-(4-methoxyphenoxy) benzaldehyde (5.0g, 21.91 mmol) was added dropwise over 30 min.
  • N,N,N ⁇ N'-Tetrame ⁇ yldiaminomethane (0.29g, 0.39 mL, 2.82 mmol) was dissolved in CH2CI2 (dry; 8.5 mL) and the stirred solution cooled in an ice-bath.
  • Acetyl chloride (0.23g, 0.21 mL, 2.95 mmol) was added dropwise (syringe) over 10 min, to giv a white suspension.
  • a soluti of 5-(4-methoxyphenoxy)indole 0.5g, 2.09 mmol
  • CH2CI2 7.2 mL
  • Tw products were obtained: (i) l-tert-butoxycarbonylamino-2-(5-(4-methoxyphenoxy)indol yl)ethane; a colourless gum, (0.088g, 21%) which eluted in 60% Et2 ⁇ /hexane, and (ii) 1 (N,N-dimethylamino)-2-(5-(4-methoxyphenoxy)indol-3-yl)eu ⁇ ane; a gum (0.166g, 48% which required the more polar eluant described above.
  • the less polar product was dissolved in MeOH (0.5mL) and treated with ethereal HCI (l.OM, 2 mL).
  • Example 4 l-Amino-2-(5-(4-methylphenoxy)indoI-3-yl)ethane (4A) and l-(N,N-dimethylamino) 2-(5-(4-methylphenoxy)indoI-3-yl)ethane (4B) a)
  • sodium ethoxide was prepared from sodium metal (2.16g, 93.95 mmol) in EtOH (72 mL) and after cooling, a mixture of ethyl azidoacetate (12.17g, 94.25 mmol) and 3-(4-methylphenoxy)benzaldehyde (5.0g, 23.56 mmol) was added.
  • Example 5 ⁇ l-Amino-2-(5-(3-trifluoromethylphe ⁇ oxy)indol-3-yl)ethane (SA) and 1-(N,N- dimethylamino)-2-(5-(3-trifluoromethylphenoxy)indol-3-yl) ethane (SB) a)
  • sodium ethoxide was prepared from sodium metal (1.58g, 68.73 mmol) in EtOH (53 mL) and after cooling, a mixture of ethyl azidoacetat (8.93g, 69.16 mmol) and 3-(3-trifluoromethylphenoxy)benzaldehyde (4.6g, 17.28 mmo was added.
  • Th was dissolved in CH2CI2/THF (1:3; 95 mL) and the solution added dropwise to a stirred, ice cooled solution of 2-amino-2-methyl propan-1-ol in CH2CI2 (185 mL), maintained under an atmosphere of N2.
  • the reaction mixture was stirred at room temperature for ca 16 hr, and was then washed with water (2X) and saturated aqueous NaCl, dried (MgSO4) and evaporated to a gum. This material was cooled (ice-bath) and thionyl chloride (18 m was added dropwise, with stirring. The reaction mixture became warm and vigourous ga evolution was observed. After stirring at room temperature for 0.5 hr, the excess SOCI2 was evaporated in vacuo.
  • the less polar component 1 -(t -butoxycarbonylanrrino)-2-(4-chloro-5-phenoxyindol-3-yl)ethane wa obtained as a gum, 0.012g (10%).
  • the more polar component l-(N,N-dimethylamino) (4-chloro-5-phenoxyindol-3-yl)ed ⁇ ane, also a gum, 0.035g, (35%); was treated witii ox acid (0.02g) in MeOH, followed by addition of Et2 ⁇ , to give: l-(Nfl-dimethylamino)- (4-chloro-5-phenoxyindol-3-yl)ethane oxalate, a white crystalline solid, 0.034g (26%) m. ⁇ . 163-66°C.
  • Example 10 l-Amino-2-(5-(pyrid-3-yloxy)indoI-3-yI)ethane (10A) and l-(N,N-dimethylamino)-2- (5-(pyrid-3-yloxy)indol-3-yl)ethane (10B) a) To a solution of 3-hydroxypyridine (15.0g, 157 mmol) in DMF (60 mL) were added potassium carbonate (15.36g, 110 mmol) and copper powder (1.2g). The mixture was stirred under N2 for 15 min.
  • Example 11 l-Amino-2-(5-(pyrimidin-2-yloxy)indol-3-yl)ethane (11A) and 1-(N,N- dimethylamino)-2-(5-(pyrimidin-2-yloxy)indol-3-yl)ethane (11B) a) A mixture of 5-hydroxyindole (2.50g, 18.7 mmol), 2-chloropyrimidine (4.3g,
  • Example 12 3-(l-MethyI-l,2,5,6-tetrahydropyrid-4-yI)-5-(pyrid-2-yloxy)indole a) 2-Hydroxypyridine (5g, 52 mmol), 5-fluoro-2-nitrotoluene (4.09g, 26.4 mmol), potassium carbonate (7.26g, 52 mmol) and copper powder (0.5g) were heated together in DMF (10 mL), at reflux for 5 hr. After cooling, EtOAc was added and the resulting blac solid precipitate was removed by filtration and discarded. The filtrate was washed with aq. NaOH (IM; 3X), dried (MgSO4) and evaporated to give a dark yellow solid.
  • IM aq. NaOH
  • MgSO4 dried
  • Phenol (73.02g, 780 mmol), 5-fluoro-2-nitrotoluene (60.18g, 390 mmol), potassium carbonate (75.02g, 540 mmol) and copper powder (3.0g) were heated togeth in DMF (150 mL), at reflux for 16 hr. After cooling and work-up, the dark material so obtained, was chromatographed (silica gel; hexane/Et2 ⁇ ; 0-3%), giving: 2-nitro-5- phenoxy toluene, an orange oil, 72.42g (81%).
  • the more polar component: l-(N,N-dimethyl- amino)-2-(5-(4-bromophenoxy)indol-3-yl)ethane was obtained as a gum, 0.084g (ca 25% Further purification was effected by prep, hplc, and the resulting material was treated wit oxalic acid (0.012g, 0.092 mmol) in MeOH/Et2 ⁇ to give: l-(NJ1-dimethylamino)-2-(5- (4-bromophenoxy)indol-3-yl) ethane oxalate, an off- white solid, 0.0 lg (2%), m.p.160- 62° .
  • Tetra-n-butylammonium fluoride solution (l.OM in THF; 30 mL) was added, and after stirring at room temperature for 3 hr, saturated aqueous NaCl was added and the mixture extracted with Et2 ⁇ . The ethereal layer was washed with saturated aqueous NaCl, dried (MgSO4) and evaporated in vacuo. The residue was chromatographed (silica gel; hexane/Et2 ⁇ ; 0-40%) to afford: 5-(pyrid-2 ylthio)indole, as a cream coloured solid, 1.98g (62%).
  • a solution of AIH3 was prepared by addition of C.H2SO4 (1.59g) dropwise to cooled (ice-bath) suspension of LiAlH4 (1.226g) in dry THF (82 mL) over 20 min. Th mixture was them left to stand under dry N2 for 1 hr to allow the solids to settle.
  • a solution of the glyoxamide (0.59g, 1.926 mmol) in THF (1 lOmL) was prepared, and in N2 atmosphere, the AIH3 solution (55 mL) was added over 5 min. The mixture was stirred for 16 hr and then H2O was added dropwise to quench excess reagent, and the T was evaporated in vacuo.
  • 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 the citric acid and the pH slowly adjusted to pH 3.2 with the 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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Abstract

A compound of structure (I), in which A1 is O, S(O)¿n? in which n is 0, 1 or 2, NR, CH2, or CH(OH); A?2¿ is a bond or CH¿2?; or A?1A2¿ is CH = CH; R is hydrogen or C¿1-4?alkyl; R?1¿ 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 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 C3-6alkenyl; the dotted lines represent an optional bond; and q and m are independently 1 or 2; and pharmaceutically acceptable salts, solvates and hydrates thereof. The compounds are 5-HT1-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. WO-A-93/11106 published after the priority date of the present application describes indole derivatives as serotonin (5HTj) agonists. The generic disclosure of this document overlaps with the present application in describing compounds of structure (I) a hereinafter described wherein :
R! is a 6- to 10- membered aryl or heteroaryl ring optionally substituted by up to 3 groups selected from halo, C^alkyl, CO2R9, NHCOR9, CONR^R1 *, SO2NR10R11, NHSO2R12, NO , NR10!*1 !, NHCONH2 or CN, A1A2 is O, S or NH, R2 is hydrogen and
Figure imgf000003_0001
WO-A-93/11106 also specifically discloses as Example 1G a compound wherein R1 is 3-CF3-2-pyridyl, AJA2 is NH, R2 is hydrogen and R3 is CH2CH2NMe2.
The present invention provides, in a first aspect, a compound of structure (I):
Figure imgf000003_0002
Structure (I) in which
A1 is O, S(O)n in which n is 0,1 or 2, NR, CH2, or CH(OH);
A2 is a bond or CH2; or
A 2 is CH=CH,
R is hydrogen or C]_4alkyl,
R! is an optionally substituted 6- to 10-membered aryl or heteroaryl ring;
R2 is hydrogen, halogen, Ci^alkyl, CN, NO2 or CF3;
R3 is C(R4)(R5)CH NR6R7, -CH=NNHC(NH)NH2 or
Figure imgf000004_0001
R4 and R^ are independently hydrogen or Cj_4alkyl;
R^ and R7 are the same or different and are each hydrogen or C^al yl or together with the nitrogen atom to which they are attached form a ring; R8 is hydrogen, Cι_4alkyl, or C3_6alkenyl; the dotted lines represent an optional bond; and q and m are independently 1 or 2; and pharmaceutically acceptable salts, solvates and hydrates thereof. Suitably A1 is O, S, NR or CH2. Suitably A2 is a bond or CH2.
Suitably R s an optionally substituted 6- or 10-membered aryl ring such as phenyl or naphthyl.
Suitably R s 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 and quinoline.
The heteroaryl ring can be linked to A* A^ via a carbon or nitrogen atom of the heteroaryl ring.
Suitably R- is unsubstituted or substituted by up to 3 groups selected from halo, Cι_4alkyl, hydroxy, oxo, Ci^alkoxy, -CO2R9 , -NHCOR9, -CONR^R1 ] ,
-SO NR10R11, -NHSO2R12, NO2, -NR10Rn, -NHCONH2, CN, CF3 or CF3O wherei R9 toR^ are independently hydrogen or Cj_4alkyl and R*2 is Cj^alkyl.
Suitably, R2 is hydrogen, halogen, Cj^alkyl, 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 Cι_4al yl. Preferably R4 and R^ are both hydrogen or methyl.
Suitably, R^ and R7 are the same or different and are each hydrogen or C^al 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 imgf000005_0001
Examples of Cj^alkyl groups (alone or as part of another group, e.g. Cj_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 :
3-(2-N,N-dimethylaminoethyl)-5-phenoxyindole,
3-(2-N,N-dimethylaminoethyl)-5-phenylthioindole, l-amino-2-(5-(4-methoxyphenoxy)indol-3-yl)ethane, l-(N,N-dimethylamino)-2-(5-(4-methoxyphenoxy)indol-3-yl)ethane, l-amino-2-(5-(4-methylphenoxy)indol-3-yl)ethane, l-(N,N-dimethylamino)-2-(5-(4-methylphenoxy)indol-3-yl)ethane, l-amino-2-(5-(3-trifluoromethylphenoxy)indol-3-yl)ethane, l-(N,N-dimethylamino)-2-(5-(3-trifluoromethylphenoxy)indol-3-yl) ethane, l-(N,N-dimethylamino)-2-(4-chloro-5-phenoxyindol-3-yl)ethane,
3-( 1 -methyl- 1 ^,5,6-tetrahydropyrid-4-yl)-5-(4-methoxyphenoxy)indole, 3-( 1 -methyl- 1 ,2,5,6-tetrahydropyrid-4-yl)-5-phenoxyindole, 3-( 1 -methyl- 1 ,2,5,6- tet-_ahydropyrid-4-yl)-5-phenylthioindole, l-amino-2-(5-(pyrid-3-yloxy)indol-3-yl)ethane, 1 -(N,N-dimethylamino)-2-(5-(pyrid-3-yloxy)indol-3-yl)ethane, l-amino-2-(5-(pyrimidin-2-yloxy)indol-3-yl)ethane, l-(N,N-dimethylamino)-2-(5-(pyrimidin-2-yloxy)indol-3-yl)ethane, 3-(l-methyl-l,2,5,6-tetrahydropyrid-4-yl)-5-(pyrid-2-yloxy)indole, l-(N,N-dimetitιylamino)-2-(5-(4-bromophenoxy)indol-3-yl)ethane, 1 -(N,N-dimethyl_uι_dno)-2-(5-(4-methoxypyrimidin-2-yloxy) indol-3-yl)ethane, 3-(l-methyl-l,2^,6-tetrahydropyrid-4-yl)-5-(pyrid-2-ylthio)indole, 1 -(N,N-dimethylamino)-2-(5-benzylindol-3-yl)ethane, and 4-chloro-3-(2-N,N-dimetiιylaminoethyl)-5-phenylthioindole, 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 exi 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 analogou 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 (II):
Figure imgf000006_0001
Structure (II)
(in which A*, A2, 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 a as described for structure (I); or
(b) reaction of a compound of structure (III) :
Figure imgf000006_0002
Structure (III)
(wherein A*, A2, R^ and R2 are as hereinbefore defined) or a salt thereof, with a compound of structure (IV) : R3CH2CHO
Structure (IV) 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_0001
reaction of a compound of structure (V)
Figure imgf000007_0002
Structure (V)
(wherein A*, A2, R- and R2 are as hereinbefore defined) with a compound of structure (VI) :
Figure imgf000007_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 the N-protecting group; or
(d) for compounds where R3 is -CH=NNHC(NH)NH2, reaction of a compound of structure (VII) :
Figure imgf000007_0004
Structure (VII) where A*, A2, 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(R4)(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)CH2NR°R7, such groups including -C(R4)(R5)CH2NO2, -C(R4)(R5)CH2N3, -COCONR6R7,-C(R4)(R5)CONR6R7, -C(R4)=CHNO2 and -C(R4)(R5)CH2NR°COR7.
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 R°R7NH is suitably carried out under reductiv amination conditions, for example, catalytic hydrogenation in the presence of the amine R6R7NH and a suitable solvent. Suitable catalysts include, for example, Raney nickel. Suitable solvents include, for example, Cι_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 a both Cι_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 usi allane (prepared from lithium aluminium hydride and sulphuric acid) or lithium aluminiu 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 treatment with cobalt boride prepared by treating a cobalt II salt such as cobalt chloride with sodium borohydride in a suitable solvent such as methanol.
Reduction of a group -C(R4)(R^)CH2NR^COR7 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 (II) 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. A 3-unsubstituted indole may be prepared from an appropriately substituted nitrotoluene derivative accordi to the following reaction scheme 1 : Scheme 1
Figure imgf000009_0001
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 imgf000010_0001
(2)
Figure imgf000010_0002
Figure imgf000010_0004
When Y represents -C(R4)(R5)CF_2NR6COR7 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. 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 (ϋ) wherein Y represents -COCONR^R7 may be prepared from an indole of structure (VIII) :
Figure imgf000010_0003
Structure (VIII) by reaction with oxalyl chloride followed by an amine HNR^R7 and subsequently introducing the group R2. When R^ is halogen e.g. iodine this may be introduced by reaction of a compound of structure II where R2 is H and Y is COCONR^R7 w m an appropriate halide e.g. potassium iodide in an acidic medium such as trifluoroacetic acid in 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 (ϋ) wherein Y represents -C(R )(R^)CH2N3.
A compound of structure (V) wherein A1 A2 is S, CH2, CH(OH), CH=CH, CH(OH)CH2 or CH2CH2 can be prepared by reacting a compound of structure (DC) :
Figure imgf000011_0001
Structure (IX) wherein R* is a N-protecting group and R^ is a group R2 as hereinbefore defined or a precursor thereof with an appropriate electrophile and thereafter removing the
N-protecting group and thereafter if necessary converting a group R^ to a group R2. Appropriate electrophiles include R^SSR^, R^(CU2)pL~ (wherein p is 1 or 2 and
L* is a suitable leaving group such as halo, e.g. bromo or iodo), R^CHO or
R1CHCH2 . \ / O
The reaction with the epoxide results in compounds wherein A* A2 is CH(OH)C_H_2 which can be dehydrated in the presence of acid to CH=CH. The reaction with the aldehyde results in compounds wherein A* A2 is CH(OH) which can be reduced for example by catalytic hydrogenation to CH2.
Suitable N-protecting groups include trialkylsilyl groups in particular triisopropylsilyl which can be removed in standard manner, 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 a compound of structure (VIII). A compound of structure (IX) can be suitably prepared by reacting a compound of structure (X) : -~"
Figure imgf000012_0001
Structure (X) wherein L2 is a suitable leaving group such as halo, e.g. bromo or iodo and R*4 and R are as hereinbefore defined with a lithiating reagent such as tert-butyl lithium or n-butyl lithium in a solvent such as diethyl ether or tetrahydrofuran at low temperature preferabl -60°C.
The N-protecting group can be introduced in standard manner, e.g. by treating with triisopropylsilyl chloride in dimethylformamide in the presence of sodium hydride base.
A compound of structure (V) wherein A* A2 is S can be prepared by reacting a compound of structure (XI) :
Figure imgf000012_0002
Structure (XI) wherein L3 is a suitable leaving group such as halo, e.g. bromo or iodo, or trifluoromethane sulphonyloxy, R^ is as hereinbefore defined and R " \- hydrogen or a group R*4 as hereinbefore defined with a compound of the formula R^SSn(R^7)3 wher Rl7 is Ci _4alkyl in the presence of a palladium catalyst such as palladium tetrakistriphenyl phosphine palladium (O) in an organic solvent such as toluene accordin to the method of M. Kosugi et al. Bull Chem Soc Jpn 1985, 58, 3657, and thereafter if required removing the group R and/or converting a group R 5 to a group R2.
A compound of structure (V) wherein A* A2 is CH2? CH=CH or CH2CH2 can prepared by reacting a compound of structure (XI) as hereinbefore defined with a compound of formula R A^ A2ZnX wherein X is halo such as chloro or bromo in the presence of a palladium catalyst such as palladium tetrakistriphenyl phosphine palladiu (O) in an organic solvent such as tetrahydrofuran at ambient or preferably reflux temperature, and thereafter if required removing the group R*4 and/or convening a grou R!5 to a group R2. A compound of structure (V) wherein A A2 is CH=CH or CH2CH2 can be prepared by reacting a compound of structure (XI) as hereinbefore defined with a compound of formula R^CH=CH2 and thereafter if required reducing the product with for example palladium on charcoal under an atmosphere of hydrogen and/or removing the group R^4 and/or converting a group R^ to a group R^.
A compound of structure (V) wherein A^A2 is OCH2 SCH2 or NRCH2 can be prepared by reacting a compound of structure (XII) :
Figure imgf000013_0001
Structure (XII) wherein L4 is a suitable leaving group such as halo e.g. bromo or iodo, or trifluoromethane sulphonyloxy and R^ and Rl°" are as hereinbefore defined with a compound of formula R*OH, R*SH or R^NHR in the presence of a suitable base such as potassium carbonate or potassium hydrogen carbonate in an organic solvent such as dimethylsulphoxide or dimethyl formamide at ambient or preferably reflux temperature, and thereafter if required removing the group R^4 and/or converting a group R^ to a group R2.
A compound of structure (V) wherein A1 A2 is CH2, SCH2, CH(OH)CH2, CH=CH or CH2CH2 can be prepared by reacting a compound of structure (XIII) :
Figure imgf000013_0002
Structure (Xπi) wherein l is halo such as bromo or iodo and R*4 and R1^ are as hereinbefore defined with an appropriate electrophile and thereafter removing the N-protecting group and if required converting a group R^ to a group R2. Appropriate electrophiles include R^L*, R^SR1, RiCHO or R1CH2L1 wherein L1 is as herebefore defined. A compound of structure (Xπi) can be prepared in standard manner by reacting a compound of structure (XII) wherein L4 is halo and R^ is a group R^ with magnesium.
A compound of structure (V) wherein A A2 is O, S or NR can be prepared by reacting optionally in the presence of a suitable base such as potassium hydroxide a compound of structure (XIV) :
Figure imgf000014_0001
Structure (XIV) wherein X is O, S or NR and R*5 and R^" are as hereinbefore defined with a compound of formula R^L* wherein R s as hereinbefore defined and its nature allows nucleophilli aromatic substitution and L* is a suitable leaving group such as halo, and thereafter if required removing the group R*4 and/or converting a group R^ to the group R2-
The chemistry hereinbefore described for preparing a compound of structure (V) can be similarly used for preparing a compound of structure (XV) :
Figure imgf000014_0002
Structure (XV) which is the starting material of Scheme 1, except that instead of the compounds of structure (XI) or (XII) are used compounds of structure (XVI) :
Figure imgf000014_0003
Structure (XVI) wherein D is L3 or L4CH2 and L3, L4 and R 15 are as hereinbefore defined.
A compound of structure (XV) wherein A^ A2 is O, S or NR can be prepared by reacting a compound of structure (XVI) wherein D is fluoro with R*OH, R SH or R*NH in a dipolar aprotic solvent such as dimethyl sulphoxide or dimethylformamide in the presence of a base such as potassium carbonate at ambient or preferably elevated temperatures in particular the boiling point of the solvent, and thereafter if required converting a group R^ to a group R2.
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 heatin a compound of structure (III) 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 boro trifluoride, or in the presence of an acidic ion exchange resin.
A compound of structure (III) 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 Ci _2alkanol at ambient temperature or elevated temperature e.g. 30-50°C, conveniently at the reflux temperature of the reaction mixture. Alternatively the reaction can be carried out under acidic conditions, e.g. in acetic acid at elevated temperature (e.g. 30-100°C). When R*3 is a N-protecting group for example tert- butoxycarbonyl this can be removed in standard manner for example by treatment with HCI in methanol or with trifluoroacetic acid.
In process (d) a compound of the structure (VII) is suitably reacted with an acid addition salt of aminoguanidine, e.g. the hydrochloride, in a suitable solvent such as a Cι_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 (VII) 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 presenc of a base such as sodium hydroxide.
Suitable interconversions of R groups, and of R2 groups, will be apparent to those skilled in the art 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 b 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-lik 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 whi are active when given orally can be formulated as liquids, for example syrups, suspensio 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, dispersion or suspension can be prepared using any suitable pharmaceutical carriers), fo 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 or sesame oil. Alternatively, the solution can be lyophilised and then reconstituted with suitable solvent just prior to administration.
Compositions for nasal administration may conveniently be formulated as aeros drops, gels and powders. Aerosol formulations typically comprise a solution or fine suspension of the active substance in a physiologically acceptable aqueous or non-aqueo solvent and are usually presented in single or multidose quantities in sterile form in a sea container, which can take the form of a cartridge or refill for use with an atomising devi
Alternatively the sealed container may be a unitary dispensing device such as a single do 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 for comprises an aerosol dispenser, it will contain a propellant which can be a compressed g 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 and 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 dose 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 th free base, the compound being administered 1 to 4 times per day. Suitably the compounds will be administered for a period of continuous therapy, for example for a week or more.
BIOLOGICAL DATA
5-HTι-Iike 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 J Pharmacol 174, 189-196.).
In brief, rabbits were killed by overdose with anaesthetic (sodium pentobar itone). 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); SθJ- (1); EDTA (0.04), equilibrated with 95% O2/5% CO2. The endothelium was removed by a gentle rubbing of the lumen with a fine 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% O2/5% CO2.
After tests for initial reactivity with 90 mM KC1 depolarising solution and for lack of acetylcholine-induced relaxation of 5-HT (10 mM) precon traction, cumulative concentration-effect curves (2 nM-60 mM) to 5-HT were constructed in the presence o ascorbate 200 mM, cocaine 6 mM, indomethacin 2.8 mM, ketanserin 1 mM and prazosi mM.
Following a 45-60 min wash period, cumulative concentration-effect curves to 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, 3A, 3B, 4A, 8, 10B, 12 and 16 had EC50 values (concentration for half-maximal contraction) in the range 0.025 to 4.2 μM.
Example 1
3-(2-N,N-DimethyIaminoethyl)-5-phenoxyindole
(a) A mixture of 5-fluoro-2-nitrotoluene (9.8g) , phenol ( 11.89g), potassium carbonate (12^2g) and copper bronze (l.Og) was boiled for 16 hours. After cooling to room temperature the mixture was extracted with boiling diethyl ether (2x500ml) and t combined organic phases washed with aqueous IN sodium hydroxide (6x100ml) and w (3x100ml). After drying (MgSO4), solvent was removed at reduced pressure and the residue column chromatographed (silica gel, hexane → 5%diethyl ether/hexane eluant) give 2-nitro-5-phenoxytoluene (2.06g) as an oil.
*H NMR (CDCI3) 2.59(s,3H), 6.81-6.85(m,2H), 7.06(d,2H), 7.23-7.27(m,lH) 7.38- 7.46(m,2H) and 8.04(m,lH).
(b) A solution of 2-nitro-5-phenoxytoluene (2.06g) in dimethylformamide (30ml) containing dimethylformamide diethylacetal (1.57g) and pyrrolidine (0.77g) was heated 120°C for 2 hours. Solvent was removed at reduced pressure and the residue dissolved i methanol. Raney Nickel (one spatula measure) was added followed by hydrazine hydrat (3 x 0.5ml portions, one portion every 30 minutes). The mixture was stirred for a furthe hour after the final portion of hydrazine hydrate was added, the mixture filtered and solvent removed at reduced pressure. The residue was partitioned between water (100m and diethyl ether (100ml), the organic phase separated and dried (MgSO4), solvent removed at reduced pressure and the residue column chromatographed (silica gel, hexa → 10% ethyl acetate/hexane eluant) to give 5-phenoxyindole (0.52g).
*H NMR (d^-DMSO) 6.40(m,lH), 6.80-6.91(m,3H), 7.02(t,lH), 7.20(m,lH), 7.26- 7.44(m,4H) and 11.16(br.s,lH).
(c) To a cooled (ice bath) solution of bis (dimethylamino)methane (0.34g) in dichloromethane (25ml), acetyl chloride was added dropwise over 5 minutes. After stir for 10 minutes, 5-phenoxyindole (0.5 lg) was added and stirring continued for a further one hour at room temperature. The mixture was basified with aqueous 2N sodium hydroxide, brine (50ml) added and the organic phase separated washed with water (2 x 50ml), dried (MgSO4) and the solvent removed at reduced pressure. The residue was dissolved in dimethylformamide (25ml) and potassium cyanide (0.62g) and iodomethane (0.6 lg) added. After stirring for 48 hours, the mixture was diluted with water (50ml) and extracted with ethyl acetate (3 x 50ml). The combined organic phases were washed with water (4 x 50ml), dried (MgSO4) and solvent removed at reduced pressure to give 3- cyanomethyl-5-phenoxyindole (0.57g).
*H NMR (d^-DMSO) 4.01 (s,2H), 6.87-6.92(m,3H), 7.03(t,lH), 7.28-7.45(m,5H)
(d) To a solution of 3-cyanomethyl-5-phenoxyindole {0.57 g) in methanol (25ml) containing dimethylamine (10ml) Raney nickel (one spatula) was added and d e mixture shaken under 45psi hydrogen pressure for 2 hours. The catalyst was removed by filtration solvent removed at reduced pressure and the residue column chromatographed (silica gel, dichloromethane/10% methanol in ammonia 0 →8% eluant) to give the title compound (0.035g) from which the oxalate salt was prepared by the addition of oxalic acid (0.024g) in methanol (1ml) followed by diediyl ether to the cloud point to give the oxalate salt m.p 170-173°C.
Example 2 3-(2-N,N-DimethyIaminoethyl)-5-phenylthioindole
(a) Triisopropylsilyl chloride (6.87g) was added to the sodium salt prepared from 5- bromoindole (6.35g) and sodium hydride (1.71g, 50% suspension in oil) in dimethylformamide (32ml) and the mixture was stirred at room temperature for 2 hours then poured into ice water (150ml). The crude intermediate obtained by evaporation of th dichloromethane extract was column chromatographed (silica gel, 40-60°C petroleum ether) to give 5-bromo-l-triisopropylsilylindole isolated as an oil.
(b) 5-Bromo-l-triisopropylsilylindole (6.74g) was dissolved in tetrahydrofuran (100ml) cooled (CO2/acetone) and tert butyl lithium (40ml, 1.7M in pentane) added over 30 minutes. Stirring of the deep yellow solution was continued for a further 1 hour, diphenyl disulphide (21g) in tetrahydrofuran (30ml) added, the mixture warmed to room temperature overnight, tetrabutylammonium fluoride (50ml, IM in tetrahydrofuran) adde and stirring continued for a further 2 hours. Water (200ml) was added and the mixture extracted with diethyl ether (3 x 100ml). The combined organic phase was washed with brine (100ml) dried (MgSO4) and the solvent removed at reduced pressure. The residue was column chromatographed (silica gel, hexane/diethyl ether 0-40% eluant) appropriat fractions combined, solvent removed and the residue recrystallised from hexane/diethyl ether to give 5-phenylthioindole (2.21g) m.p.97-99°C.
(c) Oxalyl chloride (0.57g) in diethyl ether ((2ml) was added dropwise over 5 minutes to 5-phenylthioindole (0.75g) in diethyl ether (10ml) with ice cooling. After stirring for 1 hour the precipitated solid was collected by filtration dissolved in dichloromethane (40ml) and a saturated solution of dimethylamine in diethyl ether (4ml added. After stirring for 1 hour the mixture was diluted wid dichloromethane (40ml) an washed with 10% aqueous potassium carbonate (2 x 30ml) water (2 x 30ml) and brine (30ml). The organic phase was dried (MgSO4) anc^ me solvent removed at reduced pressure. The residue was triturated with ethyl acetate/diethyl ether to give 3-N,N- dimethylglyoxamido-5-phenylthioindole (0.78g), m.p. 163-166°C.
(d) To a solution of 3-N,N-dimethylglyoxamido-5-phenylUύoindole (0.4g) in tetrahydrofuran (70ml) alane [prepared from lithium aluminium hydride (0.76g) and con sulphuric acid (l.Og) in tetrahydrofuran (50ml)] was added and the mixture stirred for 1 hours. After quenching by the dropwise addition of water the mixture was filtered (celit pad) and solvent removed at reduced pressure. The residue was partitioned between dichloromethane (50ml) and IM hydrochloric acid (50ml). The organic phase was separated, dried (MgSO4) and the solvent removed at reduced pressure. The residue was triturated with diethyl ether/ethyl acetate to give the title compound (0.20g) m.p. softens >162°C.
*H NMRδ (c -DMSO) 2.81(s,6H), 3.12(m,2H), 3.30(m,2H), 7.06(d,2H), 7.12(t,lH), 7.23(m,3H), 7.35(s,lH), 7.46(s,lH), 7.91(s,lH), 10.36(br.s,lH) and 11.32(s,lH).
Example 3 l-Amino-2-(S-(4-methoxyphenoxy)indol-3-yl)ethane (3A) and 1-(N,N- dimethylamino)-2-(5-(4-methoxyphenoxy)indol-3-yl)ethane (3B) a) Sodium metal (2.0 lg, 87.43 mmol) cut into small pieces was dissolved in absolute ethanol (67 mL) and the resulting solution cooled to -5°C. A mixture of ethyl azidoacetate (11.32g, 87.67 mmol) and 3-(4-methoxyphenoxy) benzaldehyde (5.0g, 21.91 mmol) was added dropwise over 30 min. On completion of addition the mixture was stirred at -5°C for 4.5 hr, and then kept at room temperature overnight.The red reaction mixture was poured into saturated aqueous NH4CI solution and extracted (3X) with Et2θ. The ethereal extracts were washed (H2O and then saturated aqueous NaCl), dried (MgSO4) and evaporated to give an orange gum which was chromatographed (sili gel; hexane/Et2θ; 0-15%). The product: ethyl 2-add -3-(3-(4-methoxyphenoxy)- phenyl)propenoate, was thus obtained as a light yellow gum, 5.5g (70%).
b) The vinyl azide (4.40g, 12.97 mmol) was dissolved in dry, redistilled xylene (250 mL) and added dropwise to refluxing xylene (280 mL) under an atmosphere of nitrogen. Once addition was complete, reflux was maintained for 4.5 hr. After cooling, the xylene was evaporated in vacuo and the resulting yellow solid was chromatographed (silica gel; hexane/Et2θ; 0-21%). Two products were obtained: (i) ethyl 7-44-methoxypheιwxy)indote-2*-carboxyl ιte, (Rf = 0.35; hexane/Et2θ) colourless plates ex hexane, 0.957g (24%), and (ii) ethyl 5-(4-methoxypkenoxy) indole- carboxylate, (Rf = 0.19; hexane/Et2θ) colourless needles ex hexane/ toluene (3:1), 1.66 (41%).
c) Ethyl 5-(4-methoxyphenoxy)indole-2-carboxylate (1.60g, 5.14 mmol) was heat in methanolic NaOH (3.2M, 9.1 mL), at reflux for 1 hr. The resulting thick paste was added to water and brought to pH 2 with 5M HCI. The flocculent precipitate of acid thu formed was extracted into EtOAc (3X) and d e combined organic layers washed with saturated aqueous NaCl, dried (MgSO4) and evaporated to give, as an off-white solid: 5- (4-meihoxyphenoxy)indole'2-carboxylic acid, 1.40g (96%).
d) The carboxylic acid (1.3g, 4.59 mmol) was suspended in dry Et2θ, and the mixture cooled in a dry-ice/acetone bath. Pre-condensed liquid ammonia (ca 20 mL) wa added, and the mixture was stirred. The cooling was removed and the mixture allowed t warm to room temperature, while the excess ammonia evaporated. The remaining ether was evaporated in vacuo leaving the ammonium salt as a coating around d e inside of th flask. This was then fitted with an air condenser and, under an atmosphere of N2, the fl was heated over a microburner. The solid melted and darkened, and vigourous gas evolution was observed. After cooling the material was dissolved in CH2CI2 and washe with aq. K2CO3 solution (2X) followed by brine, dried (MgSO4) and evaporated to a da oil which was distilled (kugelrohr, 250°C at ca 0.5 mbar) giving: 5-(4-methoxyphenoxy) indole as a colourless oil which solidified to a crystalline mass on standing, 0.95g (87%)
e) N,N,N\N'-TetrameΛyldiaminomethane (0.29g, 0.39 mL, 2.82 mmol) was dissolved in CH2CI2 (dry; 8.5 mL) and the stirred solution cooled in an ice-bath. Acetyl chloride (0.23g, 0.21 mL, 2.95 mmol) was added dropwise (syringe) over 10 min, to giv a white suspension. After stirring for a further 20 min. with cooling maintained, a soluti of 5-(4-methoxyphenoxy)indole (0.5g, 2.09 mmol) in CH2CI2 (7.2 mL) was added dropwise, over 20 min. The cooling was removed and the resulting clear solution was stirred for 1 hr at room temperature. The solution was then diluted with CH2CI2, wash with 10% aq. NaOH (2X) followed by saturated aqueous NaCl and dried (MgSO4). Evaporation in vacuo gave 3-*{NtN'^methyla-ninomethyl)'5-(4-methoxyphenoxy)ixndol as a gum. This material was dissolved in DMF (dry; 7 mL) and potassium cyanide (0.5 8.0 mmol) was added, followed by methyl iodide (1.19g, 0.52 mL, 8.35 mmol). The mixture became cloudy and eventually opaque. After stirring at room temperature for 3 hr, water was added and the mixture was extracted with Et2θ (2X). The combined organic layers were washed witii H2O (2X) and then with saturated aqueous NaCl, drie (MgSO4) and evaporated to give an almost colourless gum. This was triturated with Et to give: 3-cyanomethyl-5-(4-methoxyphenoxy)indole as a virtually colourless solid, 0.334g (57 %).
f) The cyanomethyl compound (0.3 lg, 1.114 mmol) was dissolved in MeOH
(15 mL) and the solution cooled (dry-ice/acetone bath). Pre-condensed dimethylamine (ca 15 mL) was added, followed by Raney nickel (one spatula). The mixture was hydrogenated at ca 45 psi (room temperature) for 1.5 hr. The catalyst was filtered off, a die filtrate evaporated to a gum. This was dissolved in 1PrOH (10 mL) and treated with ferr-butyl dicarbonate (0.25g, 1.15 mmol). After stirring at room temperature for 1 hr, t mixture was evaporated to a gum, which was chromatographed (silica gel; hexane/Et2θ; 0-60% and then CH2α2 EtOH containing 2% concentrated aqueous NH3; 0-18%). Tw products were obtained: (i) l-tert-butoxycarbonylamino-2-(5-(4-methoxyphenoxy)indol yl)ethane; a colourless gum, (0.088g, 21%) which eluted in 60% Et2θ/hexane, and (ii) 1 (N,N-dimethylamino)-2-(5-(4-methoxyphenoxy)indol-3-yl)euτιane; a gum (0.166g, 48% which required the more polar eluant described above. The less polar product was dissolved in MeOH (0.5mL) and treated with ethereal HCI (l.OM, 2 mL). After standin at ca 4°C for 2hr, the solution was evaporated to dryness. The residue was redissolved i MeOH (0.5 mL) and on addition of Et2θ small, slightly pink plates were obtained of: 1- anύno-2-^5^4-metχhoxypthenoxy)indol-3"yl)et}ιane hydrochloride (3A), 0.054g, (15%), m.p. 207-26°C (decomp.). The more polar column fraction was dissolved in methanol a treated widi oxalic acid (0.1 Og, 1.11 mmol). Addition of Et2θ to the pale yellow soluti gave, as small, slightly off-white crystals: l-(N^f-dimethylamino)-2-(5-(4- methoxyphenoxy)indol-3-yl)ethane oxalate (3B), 0.116g (26%), m.p. 166-70°C.
In a similar manner to that described above for Examples 3A and 3B, the following pair of compounds were synthesised. Example 4 l-Amino-2-(5-(4-methylphenoxy)indoI-3-yl)ethane (4A) and l-(N,N-dimethylamino) 2-(5-(4-methylphenoxy)indoI-3-yl)ethane (4B) a) As previously described, sodium ethoxide was prepared from sodium metal (2.16g, 93.95 mmol) in EtOH (72 mL) and after cooling, a mixture of ethyl azidoacetate (12.17g, 94.25 mmol) and 3-(4-methylphenoxy)benzaldehyde (5.0g, 23.56 mmol) was added. After 4.5 hr the reaction was worked-up, and chromatography (silica gel; hexane/Et2θ; 0-5%) gave the product: ethyl 2-azido-3-(3-(4-methylphenoxy)- phenyl)propenoate as a yellow oil, 4.50g (59%).
b) The azide (3.38g, 10.46 mmol) in xylene (170 mL) was added to refluxing xylen (180 mL) under an atmosphere of N2. After refluxing for 3.5 hr the solution was cooled and evaporated, and the residue was chromatographed (silica gel; hexane/Et2θ) to give two products: (i) ethyl 7-(4-methylphenoxy) indole-2-carboxylate, colourless needles from hexane, 0.797g (20%), and (ii) ethyl S-(4-methylphenoxy)indole-2-carboxylate, colourless crystals from hexane/toluene, 1.752g (43%).
c) Ethyl 5-(4-methylphenoxy)indole-2-cart)oxylate (l.Og, 3.39 mmol) was hydrolysed in methanolic NaOH (3.2M, 6.0 mL) at reflux, for 1 hr. After work-up the product: 5-(4-methylphenoxy)indole-2-carboxylic acid was obtained as an almost white solid, 0.92g (ca 100%).
d) The carboxylic acid (0.72g, 2.69 mmol) was converted to its ammonium salt, which was heated (microbumer) to give a dark oil. This was distilled (kugelrohr, 250°C ca 1 mbar) giving 5-(4-methylphenoxy)indole, a colourless gum, which solidified on storage in the freezer, 0.417g (70%).
e) Treatment of a cooled solution of N,N,N\N'-tetr___methyldiaminomethane (0.24g 0.32 mL, 2.35 mmol) in CH2CI2 (7 mL) with acetyl chloride (0.19g, 0.17 mL, 2.39 mmol) followed by a solution of 5-(4-methylphenoxy)indole (0.39g, 1.74 mmol) in CH2CI2 (6 mL), gave after work-up: 3-^N^-Mmethylaminomethyl)-5-(4-methyl- phenoxy)indole as a gum. This was treated with potassium cyanide (0.43g, 6.6 mmol) an methyl iodide (0.98g, 0.43 mL, 6.9 mmol) in DMF (6 mL) for 16 hr, and after appropriat work-up, 3-cyanomethyl-5-(4*-methylphenoxy)indole was obtained as an off-white crystalline solid 0.338g (74%).
f) The cyanomethyl compound (0.324g, 1.235 mmol) was hydrogenated in MeOH (9 mL) and Me2NH (7 mL) over Raney nickel, at room temperature and 45 psi. After work-up and treatment with BOC2O (excess) in 1PrOH, evaporation gave a gum which was chromatographed (silica gel; hexane/Et2θ; 0-50% and then CH2θ2/EtOH containing 2% concentrated aqueous NH3; 0-14%). Two products were obtained: (i) 1- tert-butoxycarbonylamino-2-(5-(4-methylphenoxy)indol-3-yl) ethane; a gum (0.12g) an (ii) l-(N,N-dimeti ylamino)-2-(5-(4-methylphenoxy) indol-3-yl)ethane; a gum (0.19g). Treatment of the less polar compound with HCl Et2θ in MeOH gave, as a faintly mauv crystalline solid: l**amino-2^5- 4-methylphenoxy)indol-3-yl)ethane hydrochloride (4 0.063g (17%), m.p. 230-34°C. The more polar column fraction, on treatment with oxal acid (0.1 lg) in MeOH (ca 1.5 mL) followed by addition of Et2θ, gave: l- N f- dimethylamino)-2-(5- 4-ntethylphenoxy)indol-3-yl)ethane oxalate (4B), off-white granular crystals, 0.12g (25%), m.p. 148-52°C.
Example 5 \ l-Amino-2-(5-(3-trifluoromethylpheπoxy)indol-3-yl)ethane (SA) and 1-(N,N- dimethylamino)-2-(5-(3-trifluoromethylphenoxy)indol-3-yl) ethane (SB) a) As previously described, sodium ethoxide was prepared from sodium metal (1.58g, 68.73 mmol) in EtOH (53 mL) and after cooling, a mixture of ethyl azidoacetat (8.93g, 69.16 mmol) and 3-(3-trifluoromethylphenoxy)benzaldehyde (4.6g, 17.28 mmo was added. After 16 hr the reaction was worked-up, and chromatography (silica gel; hexane Et2θ; 0-3%) gave the product: ethyl 2-addo-3-(3-(3-trifluoromethyl- phenoxy)phenyl)propenoate as a yellow oil, 3.52g (54%).
b) The azide (3.50g, 9.28 mmol) in xylene (150 mL) was added to refluxing xyle (172 mL) under an atmosphere of N2. After refluxing for 2 hr the solution was cooled evaporated; and the residue was chromatographed (silica gel; hexane/Et2θ) to give two products: (i) ethyl 7'- 3-Mflιwromethylphenoxy)indole-2'Carboxylate, colourless prism from hexane, 0.886g (27%), and (ii) ethyl 5-(3-trifluoromethylphenoxy)indole-2- carboxylate, colourless needles from hexane/toluene, 1.062g (33%).
c) Ethyl 5-(3-trifluoromethylphenoxy)indole-2-carboxylate (0.8g, 2.29 mmol) wa hydrolysed in methanolic NaOH (3.2M, 4.0 mL) at reflux, for 1 hr. After work-up the product: 5-(3-trifluoromethylphenoxy)indole-2'Carboxylic acid was obtained as an almost white solid, 0.73g (ca 100%).
d) The carboxylic acid (0.73g, 2.27 mmol) was converted to its ammonium salt, which was heated (microburner) until tic of the resulting dark oil showed consumption starting material. This oil was distilled (kugelrohr, 225°C at ca 0.8 mbar) giving: 5-(3- trifluoromethylphenoxy)indole, a virtually colourless oil, 0.537g (85%). e) Treatment of a cooled solution of N,N,N',N'-tetramethyldiaminomethane (0.26g 0.34 mL, 2.50 mmol) in CH2CI2 (7.3 mL) with acetyl chloride (0.20g, 0.18 mL, 2.53 mmol) followed by a solution of 5-(3-trifluoromethylphenoxy) indole (0.50g, 1.79 mmol in CH2CI2 (6.2 mL), gave after work-up: 3-(Nfl--timethylaminomethyl)-5-(3-trifluoro- methylphenoxy)indole as a gum. This was treated witii finely ground potassium cyanide (0.45g, 6.9 mmol) and methyl iodide (1.03g, 0.45 mL, 7.26 mmol) in DMF (9 mL) for 1 hr, and after appropriate work-up and chromatography (silica gel; hexane/Et2θ; 0-45%) cyanomethyl-5-(3-trifluoromethylphenoxy)indole was obtained as an almost colourless gum, 0.415g (73%).
f) The cyanomethyl compound (0.4g, 1.27 mmol) was hydrogenated in MeOH (18 mL) and Me2NH (14 mL) over Raney nickel, at room temperature and 40 psi. After work-up and treatment with BOC2O (excess) in 1PrOH, evaporation gave a gum which was chromatographed (silica gel; hexane/Et2θ; 0-60% and then CH2Cl2/EtOH containin 2% ) NH3; 0-22%). Two products were obtained: (i) l-terf-butoxycarbonylamino-2-(5-( trifluoromethylphenoxy) indol-3-yl)edιane; a colourless gum (0.069g) and (ii) 1-(N,N- dimethylamino)-2- (5-(3-trifluoromethylphenoxy)indol-3-yl)ethane; a gum (0.21g). Treatment of the less polar compound with HCl/Et2θ in MeOH gave, as white crystallin powdeπ l-amino-2-(5*^3-Mfl-ωro-nethylphenoxy)indol-3-yl)ethane hydrochloride (5A 0.023g,(5%), m.p. 200-08°C. The more polar column fraction, on treatment with oxalic acid (0.083g) in MeOH, followed by addition of Et2θ, gave small white crystals of: 1~ (N^*^methylχamino)-2-(5-(3-trifluoromethylphenoxy) indol-3-yl)ethane oxalate (5B), 0.151g (27%), m.p. 169-72°C.
Example 6 l-(N^-Dimethylamino)-2-(4-chIoro-5-phenoxyindol-3-yl)ethane a) 3-Phenoxybenzoic acid (20.0g, 93.36 mmol) was added portionwise to thionyl chloride (20 mL) and the resulting mixture was refluxed for 1.5 hr. After cooling, the excess SOCI2 was evaporated in vacuo to give the crude acid chloride as a brown oil. Th was dissolved in CH2CI2/THF (1:3; 95 mL) and the solution added dropwise to a stirred, ice cooled solution of 2-amino-2-methyl propan-1-ol in CH2CI2 (185 mL), maintained under an atmosphere of N2. The reaction mixture was stirred at room temperature for ca 16 hr, and was then washed with water (2X) and saturated aqueous NaCl, dried (MgSO4) and evaporated to a gum. This material was cooled (ice-bath) and thionyl chloride (18 m was added dropwise, with stirring. The reaction mixture became warm and vigourous ga evolution was observed. After stirring at room temperature for 0.5 hr, the excess SOCI2 was evaporated in vacuo. The residue was suspended in water and while cooling in an ic bath, 20% NaOH aq. was added to ca pH 13. The mixture was extracted (2X) with CH2CI2 and the combined extracts were washed with water (2X) and saturated aqueous NaCl, dried (MgSO4) and evaporated to a gum. This was chromatographed (silica gel; hexane/Et2θ) to give two products:
(i) 2-(3-phenoxyphenyl)-4,4-dimethyl-4,5-dihydrooxazole, (Rf = 0.42,
3:1 hexane/Et2θ) a pale yellow oil, 12.72g (51%) and (ii) 2- 3-phenoxybenzamixdo)-2-methylpropylbenzoate. (Rf = 0.26, 3:1 hexane/Et2θ pale yellow viscous gum, 8.98g (20%).
b) 2-(3-Phenoxyphenyl)-4,4-dime yl-4,5-dihydrooxazole (4.5g, 16.83 mmol) wa dissolved in THF (43 mL) and die solution was cooled to -65°C. nBuLi (2.5 M in hexa 9.5 mL) was added (syringe) at an appropriate rate to maintain the temperature below -60°C. The resulting orange-yellow solution was stirred at -65°C for 45 min. and then a solution of N-chlorosuccinimide (2.25g, 16.85 mmol) in THF (35 mL) was added, again ensuring that the temperature did not rise above -60°C. The mixture was allowed to wa gradually to room temperature and stirred overnight After quenching with water and evaporation of the bulk of the THF in vacuo, the biphasic mixture was extracted with Et (2X). The combined ediereal extracts were washed witii H2O and then saturated aqueo NaCl, dried (MgSO4) and evaporated to a gum which was chromatographed (silica gel; hexane/Et2θ; 0-17%) to afford two compounds: firstly, unreacted starting material was recovered, 1.44g (32%); and subsequently, the required product 2-(2-chloro-3- phenoxyphenyl)-4,4-dimethyl-4A3-dihydrooxazole 2.8 lg (55%), was obtained as a visco gum.
c) 2-(2-Chloro-3-phenoxyphenyl)-4,4-dimethyl-4,5-dihydrooxazole (2.80g, 9.28 mmol) was heated with methyl iodide (1.8 mL) in nitromethane (4.0 mL) for 24 hr, (bat temp ca 70°C). The brown solution was allowed to cool and Et2θ was added until a sli cloudiness was observed. Crystallization commenced almost immediately and d e mixt was allowed to stand in the freezer overnight. Large off-white crystals of the product: 2 (2^hloro-3φhenoxyphenyl)-3,4,4~trimethyl-4 -dihydrooxazotium iodide were obtain 3.51g, (85%).
d) The quaternary iodide (3.48g, 7.83 mmol) was stirred in EtOH (34 mL), and sodium borohydride (1.07g, 28.28 mmol) was added portionwise, over ca 1 hr. After stirring for a further 1 hr, HCI (2M; 36 mL) was added with care. This mixture was stir for 1 hr, and after saturating with NaCl, was extracted witii Et2θ (2X). The combined (brownish) extracts were washed with aq. Na2S2θ3, water and tiien saturated aqueous NaCl; dried (MgSO4) and evaporated to a gum. This was dissolved in THF (30 mL) and 5M HCI was added to the point of cloudiness. The mixture was refluxed for 30 min. and after cooling, water was added, followed by solid potassium bicarbonate (carefully) until effervescence ceased. The THF was then removed in vacuo, NaCl added and die mixtur extracted with Et2θ (2X). The combined extracts were washed with H2O and tiien saturated aqueous NaCl, dried (MgSO4) and evaporated to give, as a virtually colourless crystalline solid: 2-chloro-3-phenoxybenzaldehyde, 1.35g (74%).
From this point on the synthesis follows the route described above for Example 3.
e) Sodium ethoxide was prepared from sodium metal (0.50g, 21,75 mmol) in EtO (18 mL) and after cooling, a mixture of ethyl azidoacetate (2.88g, 22.31 mmol) and 2- chloro-3-phenoxybenzaldehyde (1.28g, 5.47 mmol) was added. Afterl.5 hr the reaction was worked-up, and chromatography (silica gel; hexane/Et2θ; 0-10%) gave the product: ethyl 2-azido-3-(2-chloro-3-phenoxy phenyl)propenoate as a yellow oil, 0.913g (49%).
f) The azide (0.904g, 2.63 mmol) in xylene (42 mL) was added to refluxing xylene (49 mL) under an atmosphere of N2. After refluxing for 1 hr the solution was cooled an evaporated, and the residue was chromatographed (silica gel; hexane/Et2θ) to give the product: ethyl 4-chloro-5-phenoxyindole-2-^:arboxylate; small very pale yellow crystals from hexane/toluene, 0.313g (37%).
g) Ethyl 4-chloro-5-phenoxyindole-2-caτboxylate (0.302g, 0.956 mmol) was hydrolysed in methanolic NaOH (3.2M, 1.7 mL) at reflux, for 1.5 hr After work-up, the product: 4-chloro-5-phenoxyindole-2-carboxylic dd was obtained as an almost white solid, 0.275g (ca 100%).
h) The carboxylic acid (0.22g, 0.765 mmol) was heated (Varitemp heat gun,c
400°C) to give a dark oil. This was chromatographed (silica gel; hexane/Et2θ) giving 4- chloro-5-pχhenoxyittdole, as a greenish solid, 0.147g (79%).
i) Treatment of a cooled solution of N,N,N',N'-tetramethyldiaminomethane
(0.083g, 0.11 mL, 0.812 mmol) in CH2CI2 (2.4 mL) with acetyl chloride (0.064g, 0.057 mL, 0.80 mmol) followed by a solution of 4-chloro-5-phenoxy indole (0.14g, 0.574 mmol) in CH2CI2 (2 mL), gave after work-up: 3-(Nfl-dimethylaminomethyl)-4-chloro- 5-phenoxyindole, as an off-white solid. This was treated with potassium cyanide (0.143 2.19 mmol) and methyl iodide (0.0.33g, 0.143 mL, 2.29 mmol) in DMF (1 mL) for 16 hr After appropriate work-up and chromatography (silica gel; hexane/Et2θ; 0-55%), 3- cyanomethyl~4-chloro-5-phenoxyindole was obtained as an off-white crystalline solid 0.094g (58%).
j) The cyanomethyl compound (0.09g, 0.318 mmol) was hydrogenated in MeOH (6 mL) and Me2NH (6 mL) over Raney nickel, at room temperature and 40 psi. After work-up and treatment with BOC2O (0.06g) in 1PrOH (ca 2 mL), for 2hr, evaporation gave a gum which was chromatographed (silica gel; hexane/Et2θ; 0-60% and tiien CH2θ2/EtOH containing 2% concentrated aqueous NH3; 0-15%). The less polar component: 1 -(t -butoxycarbonylanrrino)-2-(4-chloro-5-phenoxyindol-3-yl)ethane wa obtained as a gum, 0.012g (10%). The more polar component: l-(N,N-dimethylamino) (4-chloro-5-phenoxyindol-3-yl)edιane, also a gum, 0.035g, (35%); was treated witii ox acid (0.02g) in MeOH, followed by addition of Et2θ, to give: l-(Nfl-dimethylamino)- (4-chloro-5-phenoxyindol-3-yl)ethane oxalate, a white crystalline solid, 0.034g (26%) m.ρ. 163-66°C.
Example 7
3-(l-Methyl-l ,5,6-tetrahydropyrid-4-yl)-5-(4-methoxyphenoxy)indole
5-(4-Methoxyphenoxy)indole (as prepared above; 0.41 lg, 1.72 mmol) and 1-methyl- piperid-4-one (0.24 mL) were refluxed with sodium metiioxide (0.108g) in MeOH (24 mL) for 16 hr Tic indicated that reaction was not complete and reflux was tiierefore continued over a 24 hr period. Over this period further 4-methylpiperidone (4 X 0.24 and NaOMe (0.108g) were added. After standing at room temperature for 48 hr, the mixture was diluted with water and die MeOH was evaporated in vacuo. The residual mixture was extracted with EtOAc (3X) and die combined extracts were washed with and then saturated aqueous NaCl; dried (MgSO4) ant^ evaporated to a yellow solid, whi was chromatographed (silica gel; CH2θ2/EtOH), giving the product as a pale yellow solid. This was dissolved in MeOH and treated witii oxalic acid (0.15g). On addition o Et2θ, yellow needles were obtained of: 3-(l-methyl-1 ,6"tetrahydropyrid-4-yl)-5-(4 methoxyphenoxy)indole oxalate, 0.283g (39%), m.p. 157-65°C decomp.
Example 8
3-(l-MethyI-l,2,5,6-tetrahydropyrid-4-yl)-5-phenoxyindole
5-Phenoxyindole (0.30g, 1.43 mmol), l-methylpiperid-4-one (0.188g, 0.2 mL, 1.66 m and sodium methoxide (0.09g) were heated at reflux in MeOH (20 mL) for 20 hr. Afte cooling, water was added and most of the MeOH was evaporated in vacuo. The residu mixture was diluted witii water, extracted with EtOAc (2X) and the combined extracts were washed with water, dried (MgSO4) and evaporated to give: 3-(l-methyl- 1,2,5,6- tetrahydropyrid-4-yl) -5-phenoxyindole, a yellow solid 0.243g, (56%). The free base (O.lg) was dissolved in MeOH and treated with fumaric acid (0.057g, 0.49 mmol). Et2θ was added to the point of cloudiness and the mixture was kept at ca 4°C for 48 hr, to afford: 3*^l-methyl-l £,6-tetrahydmpyrid-4-yl)-5-phenoxyindolefumarate, a pale yellow crystalline solid, 0.072g (52%), m.p. 135-37°C.
Example 9 3-(l-Methyl-l,2,5,6-tetrahydropyrid-4-yI)-5-phenylthioindole
This preparation was carried out in a similar manner to that of Example 8.
5-Phenylthioindole (0.50g, 2.22 mmol), l-methylpiperid-4-one (0.292g, 0.32 mL, 2.58 mmol) and sodium methoxide (0.139g) were heated at reflux in MeOH (25 mL) for 20 h After cooling and work-up, 3-(l-mediyl-l,2,5,6-tetrahydropyrid-4-yl)-5-phenylthioindol was obtained as a pale yellow solid, 0.399g, (56%). This free base (0.20g) was treated witii fumaric acid (0.1 lg, 0.94 mmol) in MeOH/Et2θ to give: 3-(l-methyl-l 2J5,6- tetrahydropyrid-4-yl) -S-phenyUhioindole fu morale, 0.124g (46%), m.p. 225-28°C.
Example 10 l-Amino-2-(5-(pyrid-3-yloxy)indoI-3-yI)ethane (10A) and l-(N,N-dimethylamino)-2- (5-(pyrid-3-yloxy)indol-3-yl)ethane (10B) a) To a solution of 3-hydroxypyridine (15.0g, 157 mmol) in DMF (60 mL) were added potassium carbonate (15.36g, 110 mmol) and copper powder (1.2g). The mixture was stirred under N2 for 15 min. and then a solution of 5-fluoro-2-nitrotoluene (12.29g, 79 mmol) in DMF (10 mL) was added dropwise over ca 0.5 hr. The mixture was stirred reflux for 5 hr and then allowed to cool. EtOAc was added and the black solid precipitate produced, was removed by filtration and discarded. NaOH aq. (IM, 100 mL) was added, and the two-phase mixture filtered through Hyflo to remove insoluble tarry material. Th EtOAc layer was then separated, dried (MgSO4) and evaporated to give a dark oil. Chromatography (silica gel;hexane/EtOAc; 0-24%) gave the product: 2-nitro-5-(pyrid-3- yloxy) toluene, a yellow solid, 8.0g (22%).
b) 2-Nitro-5-(pyrid-3-yloxy)toluene (6g, 26 mmol), dimethylformamidedimethyl acetal (5.43g, 45 mmol) and pyrrolidine (3.24g, 45 mmol) were heated in DMF (70 mL) reflux, for 3 hr. The DMF was evaporated in vacuo to leave a deep red oil, which was dissolved in MeOH (200 mL) and the solution cooled in an ice-bath. Raney nickel (3 spatulas) was added, followed by addition of hydrazine hydrate (24 mL; portionwise, to moderate the vigour of the reaction). Once addition was complete, the mixture was stirre for 1 hr at room temp and the Raney nickel residue was then removed by filtration. The filtrate was evaporated and water added to the residue, which was then extracted with EtOAc (2X). The extracts were dried (MgSO4) and evaporated to a gum, which was chromatographed (silica gel; hexane/EtOAc; 0-42%), giving, as a white solid: 5-(pyrid- yloxy)indole, 1.60g (24%).
From this point the preparation follows closely the corresponding stages of the synthesi Example 3.
c) Treatment of a cooled solution of N,N,N',N'-tetramethyldiaminomethane (0.82
1.11 mL, 8.12 mmol) in CH2CI2 (10 mL) with acetyl chloride (0.637g, 0.573 mL, 8.12 mmol) followed by a solution of 5-(pyrid-3-yloxy)indole (1.23g, 5.8 mmol) in CH2CI2 (100 mL), gave after work-up: 3- Nfl-dimethylaminomethyl)-5-(pyrid-3-yloxy)indole a gum. This was treated with finely ground potassium cyanide (1.246g, 19 mmol) and methyl iodide (2.7g, 1.18 mL, 19 mmol) in DMF (70 mL) for 16 hr,and after appropriat work-up and chromatography (silica gel; hexane/EtOAc; 0-60%), 3-cyanomethyl-5- (pyrid-3-yloxy)indole was obtained a gum, which solidified on standing, 0.655g (45%).
d) The cyanomethyl compound (0.655g, 2.6 mmol) was hydrogenated in MeOH (100 mL) and Me2NH (20 mL) over Raney nickel, at room temperature and 50 psi. Aft work-up and treatment with BOC2O (excess) in 1Pι H, evaporation gave a gum which was chromatographed (silica gel; hexane/Et2θ; 0-100% and then CH2Cl2/EtOH containing 2% concentrated aqueous NH3; 0-15%). Two products were obtained: (i) 1- rerr-butoxycarbonylamino-2-(5-(pyrid-3-yloxy)indol-3-yl)ethane, a colourless gum, 0.1 (11%) and (ii) l-(N,N-dimethylamino)-2-(5-(pyrid-3-yloxy) indol-3-yl)ethane; a gum, 0.20g (27%). Treatment of the less polar compound with HCl/Et2θ in MeOH gave, as light brown hygroscopic solid: l-amino-2*{5*ipy--ul-3-yloxy)indol-3-yl)ethane hydrochloride (10A). The more polar column fraction on treatment with oxalic acid in MeOH, followed by addition of Et2θ, gave: 1-(N ,N-dimethylamino)-2-(5-(pyrid-3- yloxy)indol-3-yl) ethane oxalate (10B), m.p 178-80°C.
Example 11 l-Amino-2-(5-(pyrimidin-2-yloxy)indol-3-yl)ethane (11A) and 1-(N,N- dimethylamino)-2-(5-(pyrimidin-2-yloxy)indol-3-yl)ethane (11B) a) A mixture of 5-hydroxyindole (2.50g, 18.7 mmol), 2-chloropyrimidine (4.3g,
37.6 mmol) and powdered KOH (1.049g, 18.7 mmol) was warmed in DMSO (50 mL) a 40°C for 5 hr, under an atmosphere of N2. The dark solution was cooled and poured int saturated aqueous NaCl and the mixture was extracted with EtOAc (3X). The extracts were dried and evaporated, and the residue was chromatographed (silica gel; hexane/EtOAc; 0-70%),giving, as a white solid: 5-(pyrimidin-2-yloxy)indole, 1.12g (28%).
From this point the preparation follows closely the corresponding stages of the synthesis Example 3.
b) Treatment of a cooled solution of N,N,N',N'-tetramethyldiaminomethane (0.854 1.14 mL, 8.36 mmol) in CH2Cl2 (10 mL) with acetyl chloride (0.657g, 0.59 mL, 8.36 mmol) followed by a solution of 5-(pyrimidin-2-yloxy)indole (1.268g, 6.00 mmol) in CH2CI2 (110 mL), gave after work-up: 3-(Nfl* imethyLaminomethyl)-5-(pyrimidin-2- yloxy)indole as a yellow solid. This was treated with finely ground potassium cyanide (1.37g, 21 mmol) and methyl iodide (2.94g, 1.28 mL, 21 mmol) in DMF (70 mL) for 16 hr, and after appropriate work-up, 3-cyanomethyl-5-(pyrimidin-2-yloxy)indole was obtained as a light yellow solid, 0.98g (65%).
c) The cyanomethyl compound (0.98g, 3.9 mmol) was hydrogenated in MeOH (15 mL) and Mβ2NH (20 mL) for 1 hr, over Raney nickel, at room temperature and 50 psi. After removal of the catalyst by filtration, evaporation gave a gum which was chromatographed (silica gel; CH2θ2/MeOH containing 10% concentrated aqueous NH3 0-10%). Two products were obtained: (i) l-(N,N-dimethylamino)-2-(5-(pyrimidin-2- yloxy)indol-3-yl)ethane, a gum, 0.32g (29%) and (ii) l-amino-2-(5-(pyrimidin-2- yloxy)indol-3-yl)ethane, also a gum, 0.072g (7%). Both free bases were converted into their respective oxalate salts by treatment with oxalic acid in MeOH/Et2θ. The former amine gave: l*>(Nfl- methyUmιinθ'2*-(5-4py--unidin-2-yloxy)i-ιdote oxalate
(1 IA), a white crystalline solid, m.p. 174-76°C. The more polar amine gave: l-amino-2 (5-ipyrimidin-2-yloxy)indol-3-yl) ethane oxalate (11B), an off-white solid m.p. 178-80°
Example 12 3-(l-MethyI-l,2,5,6-tetrahydropyrid-4-yI)-5-(pyrid-2-yloxy)indole a) 2-Hydroxypyridine (5g, 52 mmol), 5-fluoro-2-nitrotoluene (4.09g, 26.4 mmol), potassium carbonate (7.26g, 52 mmol) and copper powder (0.5g) were heated together in DMF (10 mL), at reflux for 5 hr. After cooling, EtOAc was added and the resulting blac solid precipitate was removed by filtration and discarded. The filtrate was washed with aq. NaOH (IM; 3X), dried (MgSO4) and evaporated to give a dark yellow solid. This w chromatographed (silica gel; hexane/EtOAc; 0-100% and then EtOAc/MeOH; 0-5%) giving: 2-nitro-S-(pyrid-2-yloxy)toluene, a light yellow solid, 1.50g (12%). b) 2-Nitro-5-(pyrid-2-yloxy)toluene ( 1.11 g, 4.82 mmol), dimethylformamide dimethylacetal (1.018g, 8.54 mmόl) and pyrrolidine (0.6g, 84.36 mmol) were heated in DMF (25 mL) at reflux, for 3 hr. The DMF was evaporated in vacuo to leave a deep re oil, which was dissolved in MeOH (80 mL) and the solution cooled in an ice-bath. Ran nickel (2 spatulas) was added, followed by addition of hydrazine hydrate (4 mL; portionwise, to moderate the vigour of the reaction). Once addition was complete, the mixture was stirred for 1.5 hr at room temp.and the Raney nickel residue was tiien removed by filtration (Hyflo). The filtrate was evaporated and water added to the resid giving a brown solid, which was collected by filtration and chromatographed (silica gel hexane/ EtOAc; 0-100% and then EtOAc/MeOH 0-3%) to afford, as a light yellow soli 5-(pyrid-2-yloxy)indole, 0.22g (23%).
The remaining stage of this preparation was carried out in a similar manner to that of Example 8.
c) 5-(Pyrid-2-yloxy)indole (0.22g, 1.04 mmol), l-methylpiperid-4-one (0.235g, mmol) and sodium methoxide (0.337 g) were heated at reflux in MeOH (20 mL) for 48 over activated molecular sieves. After cooling and work-up, the residue was chromatographed (silica gel; CH2Cl2/MeOH; 0-25%) to give 3-(l-methyl-l,2,5,6- tetrahydropyrid-4-yl)-5-(pyrid-2-yloxy)indole, a gum, 0.083g (26%). This free base w treated with oxalic acid in MeOH/Et2θ to give: 3-(l-methyl-ly2^,6-tetrahydropyrid-4- 5-(pyrid-2-yloxy)indole oxalate, m.p. 240-45°C.
Example 13 l-(N^S-Dimethylamino)-2-(5-(4-bromophenoxy)indoI-3-yl)ethane
This preparation was carried out by adaptation of those of Examples 3 and 8.
a) Phenol (73.02g, 780 mmol), 5-fluoro-2-nitrotoluene (60.18g, 390 mmol), potassium carbonate (75.02g, 540 mmol) and copper powder (3.0g) were heated togeth in DMF (150 mL), at reflux for 16 hr. After cooling and work-up, the dark material so obtained, was chromatographed (silica gel; hexane/Et2θ; 0-3%), giving: 2-nitro-5- phenoxy toluene, an orange oil, 72.42g (81%).
b) 5-Phenoxy-2-nitrotoluene (2.0g, 8.72 mmol) and N-bromosuccinimide (2.33g, 13.09 mmol) were stirred at 70°C in DMF (30 mL) over a period of 64 hr. Over this period additional NBS (total 1.87g, 10.48 mmol) was added in four portions. The mixt was cooled and then partitioned between H2θ/EtOAc. The organic extract was washed (H2O), dried (MgSO4) and evaporated to give: 5-(4-bromophenoxy)-2-nitrotoluene as yellow oil, (2.86g) slightly contaminated with starting material, but sufficiently pure to b carried through to the next stage.
c) 5-(4-Bromophenoxy)-2-nitrotoluene (3.12g), dimethylformamidediethyl acetal (1.77g, 2.1 mL, 12.02 mmol) and pyrrolidine (0.863g, 1.01 mL, 12.13 mmol) were heate in DMF (30 mL) at 120°C for 2 hr. The DMF was evaporated in vacuo to leave a deep oil. This was dissolved in MeOH (30 mL), and after cooling, Raney nickel (1 spatula) wa added, followed by addition of hydrazine hydrate (1.8 mL; portionwise). After ca 1 hr th Raney nickel was removed by filtration and the filtrate evaporated. The residue was worked-up (Et2θ/sat.aq.NaCl) and chromatographed (silica gel; hexane EtOAc; 0-10%) afford, as a greenish solid: 5-(4-bromophenoxy)indole, 0.394g (ca 13%; containing trace contaminants)
d) Treatment of a cooled solution of N,N,N',N'-tetramethyldiaminomethane (0.186 0.25 mL, 1.83 mmol) in CH2CI2 (10 mL) with acetyl chloride (0.143g, 0.13 mL, 1.83 mmol) followed by a solution of 5-(4-bromophenoxy)indole (0.394g, 1.37 mmol) in CH2CI2 (5 mL), gave after woτ -up3^N -dimethykwύ-wmethyl)-5^4-bromo~ phenoxy)indole as a brown gum. This was treated with finely ground potassium cyanide (0.34g, 5.21 mmol) and methyl iodide (0.77 g, 0.34 mL, 5.44 mmol) in DMF (30 mL) for 16 hr, and after appropriate work-up, 3-cyano~nethyl-5-(4-bromophenoxy)indole was obtained as a brown gum 0.29g, (ca 65%; carried through to next stage without further purification).
e) The cyanomethyl compound (0.29g) was hydrogenated for 1 hr in MeOH (20 mL) and Mβ2NH (15 mL) over Raney nickel, at room temperature and 40 psi. After work-up and treatment with BOC2O (excess) in 1PrOH, evaporation gave a gum which was chromatographed (silica gel; CH2Cl2/MeOH; 0-20%). The less polar component w not obtained pure and was discarded. The more polar component: l-(N,N-dimethyl- amino)-2-(5-(4-bromophenoxy)indol-3-yl)ethane was obtained as a gum, 0.084g (ca 25% Further purification was effected by prep, hplc, and the resulting material was treated wit oxalic acid (0.012g, 0.092 mmol) in MeOH/Et2θ to give: l-(NJ1-dimethylamino)-2-(5- (4-bromophenoxy)indol-3-yl) ethane oxalate, an off- white solid, 0.0 lg (2%), m.p.160- 62° .
Example 14 l-(N,N-Dimethylamino)-2-(5-(4-methoxypyrimidin-2-yloxy) indol-3-yl)ethane
This preparation was carried out in a similar manner to that described above for Example 11. a) 5-Hydroxyindole (8.6g, 64 mmol), 2-chloro-6-methoxypyrimidine (9.9g, 68 mmol) and powdered KOH (3.59g, 64 mmol) were heated together in DMSO
(70 mL) at 80°C for 5 hr. After cooling and work-up, chromatography (hexane/EtOAc; 27%) gave: 5-(4-methoxypyrimidin-2-yl)indole, 3.0g, (18%).
b) Treatment of a cooled solution of N,N,N',N'-tetramethyldiaminomethane (1.18 1.58 mL, 11.5 mmol) in CH2CI2 (10 mL) with acetyl chloride (0.90g, 0.81 mL, 11.5 mmol) followed by a solution of 5-(4-methoxypyrimidin- 2-yloxy)indole (2.0g, 8.2 mm in CH2CI2 (100 mL), gave after work-up: 3-(Nfl-dimethylaininomethyl)-5-(4- methoxypyrimidin-2-yloxy)indole as a white solid. This was treated with finely ground potassium cyanide (1.75g, 26.8 mmol) and methyl iodide (3.80g, 1.65 mL, 26.8 mmol) i DMF (130 mL) for 16 hr, and after appropriate work-up, 3-cyanomethyl-5-(4- methoxypyrimidin-2-yloxy)indole was obtained as a white solid, 2.20g (96%).
c) The cyanomethyl compound (2.20g, 7.8 mmol) was hydrogenated in MeOH (2 mL) and Me2NH (30 mL) for 2 hi- over Raney nickel; at room temperature and 50 psi. After removal of the catalyst by filtration, evaporation gave a solid residue (1.8g) which was treated widi BOC2O (2.2g, ca 10 mmol) in DMF (60 mL), at room temperature for hr. Work-up (EtOAc/H2θ) followed by chromatography (silica gel; hexane/EtOAc; 0-
50% and then CH2Cl2/MeOH; 0-40%) gave two products:
(i) l-rerr-butoxycartκ)nylamino-2-(5-(4-methoxypyrimidin-2-yloxy)indol-3-yl) ethane, a white solid, 0.23g (8%) and
(ii) l-(N,N-dimethyl_umno)-2-(5-(4-methoxypyrimidin-2-yloxy)indol-3-yl)ethane, gum, 0.08g (3%). The latter product was treated with oxalic acid in MeOH/Et2θ to giv l^Nfl^methyltιnύno)-2*^5-(4-methoxypyrin Mn-2*y ethane oxalate, white solid, m.p.203-04°C. The less polar (tBOC) product of the hydrogenation was unstable in the presence of acid.
Example 15
3-(l-Methyl-l s6-tetrahydropyrid-4-yl)-5-(pyrid-2-ylthio)indole a) 5-Bromo-l-triisopropylsilylindole (5.0g, 14.19 mmol) was dissolved in THF (d
60 mL) and, under an atmosphere of dry N2, the solution was cooled to -65°C. tert- Butyllithium solution (1.7M in pentane; 30 mL, 50.37 mmol) was added over ca 0.5 hr t give a yellow solution which was stirred at -65°C for a further 1 hr. A solution of 2,2'- dipyridyldisulphide (15.72g, 71.37 mmol) in THF (30 mL) was then added over a perio of 20 min. and after a further 20 min at -65°C, the mixture was allowed to warm slowly room temperature and stirred for ca 16 hr. Tetra-n-butylammonium fluoride solution (l.OM in THF; 30 mL) was added, and after stirring at room temperature for 3 hr, saturated aqueous NaCl was added and the mixture extracted with Et2θ. The ethereal layer was washed with saturated aqueous NaCl, dried (MgSO4) and evaporated in vacuo. The residue was chromatographed (silica gel; hexane/Et2θ; 0-40%) to afford: 5-(pyrid-2 ylthio)indole, as a cream coloured solid, 1.98g (62%).
The final stage of this preparation was carried out in a similar manner to that of Example 8.
b) 5-(Pyrid-2-ylthio)indole (0.347g, 1.53 mmol), l-methylpiperid-4-one (0.347g,
0.38 mL, 3.06 mmol), sodium methoxide (0.497 g) and some finely ground molecular sieves were heated in refluxing MeOH (20 mL) for 24 hr. After work-up and chromatography (silica gel; CH2θ2/MeOH; 0-15%), 3-(l-methyl-l,2,5,6-tetrahydropyri 4-yl)-5-(pyrid-2-ylti io)indole was obtained as a yellow solid (0.35g).This was treated wi fumaric acid (0.189g, 1.6 mmol) in MeOH Et2θ to give, as a pale yellow crystalline soli 3^1'methyl 2 ,6-4etrn-hydropy--\ '4^ (34%), m.p. 226-28°C
Example 16 l-(N^J-Dimethylamino)-2-(5-benzylindol-3-yl)ethane a) 5-Bromo-l-triisopropylsilylindole (2.0g, 5.68 mmol) was dissolved in THF (dry
30 mL) and the solution cooled to -70°C. rert-Butyllithium (1.7M in hexane; 10.7 mL, 18.2 mmol) was added, and by the time addition was complete, a permanent yellow coloration had been produced. After a further 1 hr at -65°C benzaldehyde (0.658g, 6.20 mmol) was added and the mixture stirred at ca -65°C for 1 hr before warming gradually t room temperature H2O and NaCl were added to the mixture which was then extracted (3X) witii Et2θ,and the extracts were combined, washed (H20, 3X and then saturated aqueous NaCl) and dried (MgSO4). Evaporation gave a gum which was chromatographe (silica gel; hexane/Et2θ; 0-30%). Recovered starting material, 0.437g (22%) eluted first followed by the product: phenyl(l-triisopropylsilylindol-5-yl)methanol, a gum which solidified on standing, 0.61g (28%; several fractions containing contaminated product were subsequently obtained). The pure product (0.6g, 1.58 mmol) was dissolved in THF (10 mL) and treated with tetra-n-butylammonium fluoride solution (l.OM in THF; 3.0 m at room temperature. The mixture was stirred for 1.5 hr and then partitioned between Et2θ and saturated aqueous NaCl. After re-extracting the aqueous layer (Et2θ; 2X), the combined ethereal layers were washed with saturated aqueous NaCl, dried (MgSO4) and evaporated to a gum which was chromatographed (silica gel; hexane Et2θ; 0-50%), giving: phenyl(indol-5-yl)methanol, as an almost colourless gum, 0.347g (98%). This material was hydrogenated in EtOH (25 L) over Pd-C (5%; a total of 0.30g was adde over the reaction χ>eriod, in two portions), at 45 psi, for ca 40 hr. The catalyst was filte off, and the filtrate evaporated to a gum which was chromatographed (silica gel; hexane/Et2θ; 0-50%). The required product: 5-benzylindole, was obtained as an off w solid, 0.135g (44%), as well as 5-benzylindoline 0.03g, (10%) and unreacted starting material, 0.013g (4%).
b) 5-Benzylindole (0.563g, 2.716 mmol) was dissolved in dry Et2θ (8 mL) and t solution cooled in an ice-bath. A solution of oxalyl chloride (0.47g, 0.32 mL, 3.67 mm in dry Et2θ (6 mL) was added over ca 15 min. An orange precipitate was observed an after standing at ca 4°C for 16 hr, this solid was collected by filtration, and blown dry a current of dry N2. This acid chloride was immediately suspended in dry CH2CI2 (35 mL), and while cooling (ice-bath) and stirring, a solution of Me2NH in Et2θ was added (1.6M; 4.5 mL; freshly prepared) over 5 min. The starting material dissolved to give a very pale yellow solution which was stirred at ice-bath temperature for 1 hr and then allowed to warm to room temperature. This solution was then diluted with CH2CI washed successively with aq. K2CO3, H2O and saturated aqueous NaCl, and dried (MgSO4). Evaporation gave a solid which was triturated with t2θ to afford as a white powder 3^Nfl-dimethylglyoxamido)-5-benzylindole, 0.604g (90%).
c) A solution of AIH3 was prepared by addition of C.H2SO4 (1.59g) dropwise to cooled (ice-bath) suspension of LiAlH4 (1.226g) in dry THF (82 mL) over 20 min. Th mixture was them left to stand under dry N2 for 1 hr to allow the solids to settle. A solution of the glyoxamide (0.59g, 1.926 mmol) in THF (1 lOmL) was prepared, and in N2 atmosphere, the AIH3 solution (55 mL) was added over 5 min. The mixture was stirred for 16 hr and then H2O was added dropwise to quench excess reagent, and the T was evaporated in vacuo. The residue was partitioned between IM HCI/CH2G2 and af re-extraction of the aqueous layer (2X; CΗ2O2). the combined organic layers were washed witii IM HCI and then saturated aqueous NaCl, dried (MgSO4) and evaporated a solid. Chromatography (silica gel; CH2Cl2/EtOH containing 2% concentrated aqueou NH3; 0-12%), gave the free base: l-(N,N-dimethylamino)-2-(5-benzylindol-3-yl)ethane as a gum, 0.246g (46%). This was treated with oxalic acid (0.07g) in MeOH (2 mL) an Et2θ added until crystallisation commenced. The product: l-(Nfl-dimethylamino)-2-( benzylindol-3-yl)ethane oxalate, was obtained as white granular crystals, 0.191g (27%) m.p.l58-9°C. 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
22Q 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)
IM 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 the citric acid and the pH slowly adjusted to pH 3.2 with the 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 imgf000038_0001
Structure (I) in which
A1 is O, S(O)n in which n is 0,1 or 2, NR, CH2, or CH(OH); A2 is a bond or CH2; or A1A2 is CH=CH; R is hydrogen or C^alkyl;
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 imgf000038_0002
R4 and R^ are independently hydrogen or C1_.4a._kyl;
R and R7 are the same or different and are each hydrogen or C1.4al.kyl or together wi the nitrogen atom to which they are attached form a ring; R8 is hydrogen, C^alkyl, or C3_6alkenyl; the dotted lines represent an optional 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 with the proviso that R- is not a 6-
10- membered aryl or heteroaryl ring optionally substituted by up to 3 groups selected from halo, Cι.4alkyl, CO2R9, NHCOR9, CONR^R11, SO2NR10R11, NHSO2R12, NO2, NRWR1 K NHCONH2 or CN, when A1 A2 is O, S or NH, R2 is hydrogen and
Figure imgf000039_0001
and with the further proviso that R is not 3-CF3-2-pyridyl, when A*A2 is NH, R2 is hydrogen and R3 is CH2CH2NMe2.
3. A compound according to claim 1 or 2 where A* is O, S, NR or CH2 and 5 A2 is a bond or CH2.
4. A compound according to any one of claims 1 to 3 where R* is optionally substituted phenyl or naphthyl.
10 5. A compound according to any one of claims 1 to 3 wherein R is an optionally substituted 6- to 10-membered heteroaryl ring containing from 1 to 4 nitrogen atoms.
6. A compound according to any one of claims 1 to 5 wherein R* is 15 unsubstituted or is substituted by 1 to 3 groups selected from halo, C^al yl, hydroxy, oxo, Cι_4alkoxy, -CO2R9 , -NHCOR9, -CONR^R11, -SO2NR10R11, -NHSO2R12, NO2, -NRWR11, -NHCONH2, CN, CF3 or CF3O wherein R9 to R1 - are independently hydrogen or Cι_4_dkyl and R is C1.4a_.kyl.
20 7. A compound according to any one of claims 1 to 6 wherein R2 is hydroge or halogen.
8. A compound according to any one of claims 1 to 7 wherein R3 is -CH=NNHC(NH)NH2 or C(R4)(R5)CH2NR6R7 and R4 and R5 are both hydrogen or
25 methyl.
9. A compound according to any one of claims 1 to 8 wherein R" and R7 are both hydrogen or methyl.
30 10. A compound according to any one of claims 1 to 7 where R3 is a group
Figure imgf000040_0001
11. A compound of structure (I) selected from : pharmaceutically acceptable salt, solvate or hydrate thereof. 3-(2-N,N-dimethylaminoethyl)-5-phenoxyindole,
3-(2-N,N-dimethylaminoethyl)-5-phenylthioindole, l-amino-2-(5-(4-methoxyphenoxy)indol-3-yl)ethane,
1 -(N,N-dimethy lamino)-2-(5-(4-methoxyphenoxy)indol-3-yl)ethane, l-amino-2-(5-(4-methylphenoxy)indol-3-yl)ethane, l-(N,N-dimethylamino)-2-(5-(4-riιethylphenoxy)indol-3-yl)ethane, l-amino-2-(5-(3-trifluoromethylphenoxy)indol-3-yl)ethane, l-(N,N-dimethylamino)-2-(5-(3-trifluoromethylphenoxy)indol-3-yl) ethane, l-(N,N-dimethylamino)-2-(4-chloro-5-phenoxyindol-3-yl)ethane,
3-(l-methyl-l,2,5,6-tetrahydropyrid-4-yl)-5-(4-methoxyphenoxy)indole, 3-(l-methyl-l^,5,6-tetrahydropyrid-4-yl)-5-phenoxyindole,
3-(l-methyl-l^,5,6-tetrahydropyrid-4-yl)-5-phenylthioindole, l-amino-2-(5-(pyrid-3-yloxy)indol-3-yl)ethane, l-(N,N-dimethylamino)-2-(5-(pyrid-3-yloxy)indol-3-yl)ethane, l-aιnino-2-(5-(pyrimidin-2-yloxy)indol-3-yl)ethane, 1 -(N,N-dimetiιylamino)-2-(5-(pyrimidin-2-yloxy)indol-3-yl)ethane,
3-(l -methyl- 1 ,2,5,6-tetrahydropyrid-4-yl)-5-(pyrid-2-yloxy)indole, l-(N,N-d__methylamino)-2-(5-(4-bromophenoxy)indol-3-yl)ethane, l-(N,N-dimethylamino)-2-(5-(4-methoxypyriιnidin-2-yloxy) indol-3-yl)ethane,
3-(l-methyl-l,2,5,6-tetrahydropyrid-4-yl)-5-(pyrid-2-ylthio)indole, l-(N,N-dimethylamino)-2-(5-benzylindol-3-yl)ethane, or
4-cWoro-3-(2-N,N-dimethylaminoethyl)-5-phenylthioindole, or pharmaceutically acceptable salt, solvate or hydrate thereof.
12. A process for the preparation of a compound of structure (I) as defined i claim 1 or a salt, solvate or hydrate thereof, which comprises :
(a) for compounds in which R3 is C(R4)Q . )CH2NR<3R reduction of a compoun structure (II):
Figure imgf000041_0001
Structure (II)
(in which A*, A2, R and R2 are 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 a as described for structure (I); or
(b) reaction of a compound of structure (HI)
Figure imgf000041_0002
Structure (HI) (wherein A*, A2, R* and R2 are as hereinbefore defined) or a salt thereof, with a compound of structure (TV) :
R3CH2CHO
Structure (IV) 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 imgf000041_0003
reaction of a compound of structure (V) :
Figure imgf000041_0004
Structure (V) (wherein A , A2, R and R^ are as hereinbefore defined) with a compound of structure (VI) :
Figure imgf000042_0001
Structure (VI)
(wherein R is a N-protecting group or R^ as hereinbefore defined and q and m are a hereinbefore defined), and if required removing the N-protecting group; or
(d) for compounds where R3 is -CH=NNHC(NH)NH2, reaction of a compound o structure (VII) :
Figure imgf000042_0002
Structure (VII) wherein A^, A2, R\ and R2 are as hereinbefore defined with aminoguanidine or an aci 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.
13. A compound of structure (I) as defined in claim 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof for use as a medicament.
14. A pharmaceutical composition comprising a compound of structure (I) a defined in claim 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof and pharmaceutically acceptable carrier.
15. 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.
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Cited By (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995030655A1 (en) * 1994-05-06 1995-11-16 Allelix Biopharmaceuticals Inc. Tryptamine derivatives as 5-ht-1d receptor ligands
WO1996009288A1 (en) * 1994-09-22 1996-03-28 Pierre Fabre Medicament Aromatic ethers derived from indols such as 5ht1-like ligands
WO1996011685A2 (en) * 1994-10-12 1996-04-25 Pfizer Limited Use of indole derivatives for the treatment of various diseases
EP0733628A1 (en) * 1995-03-20 1996-09-25 Eli Lilly And Company 5-Substituted-3-(1,2,3,6-tetrahydropyridin-4-yl)- and 3-(piperidin-4-yl)-1h-indoles: new 5-ht1f agonists
EP0832650A2 (en) * 1996-09-18 1998-04-01 Eli Lilly And Company Use of serotonin 5-HT1F agonists for the prevention of migraine
EP0875513A1 (en) * 1997-04-14 1998-11-04 Eli Lilly And Company Substituted heteroaromatic 5-HT 1F agonists
US5942536A (en) * 1995-10-10 1999-08-24 Eli Lilly And Company N- 2-substituted-3-(2-aminoethyl)-1H-indol-5-YL!-Amides: new 5-HT1F agonists
WO2000000490A2 (en) * 1998-06-26 2000-01-06 Eli Lilly And Company 5-ht1f agonists
US6133287A (en) * 1998-03-24 2000-10-17 Allelix Biopharmaceuticals Inc. Piperidine-indole compounds having 5-HT6 affinity
WO2001047885A1 (en) * 1999-12-27 2001-07-05 Grünenthal GmbH Substituted indole mannich bases
WO2002016348A1 (en) * 2000-08-09 2002-02-28 Astrazeneca Ab Antiangiogenic bicyclic derivatives
FR2814166A1 (en) * 2000-09-21 2002-03-22 Innothera Lab Sa New 5-phenoxy indole derivatives used for treating inflammation, venous insufficiency, hemorrhoids, urological disorders, pain, migraine, and cutaneous disorders
US6565829B2 (en) 2001-08-03 2003-05-20 Pharmacia & Upjohn Company 5-arylsulfonyl indoles useful for treating disease
US6794406B2 (en) 2000-12-27 2004-09-21 Bayer Aktiengesellschaft Indole derivatives
US7125906B2 (en) 2002-04-03 2006-10-24 Astrazeneca Ab Indole derivatives having anti-angiogenetic activity
US7534791B2 (en) 2005-06-17 2009-05-19 H. Lundbeck A/S Benzo[b]furane and benzo[b]thiophene derivatives
US7563908B2 (en) 2003-12-23 2009-07-21 Jan Kehler 2-(1H-indolylsulfanyl)-benzyl amine derivatives as SSRI
US7629473B2 (en) 2005-06-17 2009-12-08 H. Lundbeck A/S 2-(1H-indolylsulfanyl)-aryl amine derivatives
US7678800B2 (en) 2004-07-16 2010-03-16 H. Lundbeck A/S 2-(1H-indolylsulfanyl)-aryl amine derivatives for use in the treatment of affective disorders, pain, ADHD and stress urinary incontinence
AU2021397252B2 (en) * 2020-12-09 2024-03-14 Caamtech, Inc. Dialkyl tryptamines and their therapeutic uses

Families Citing this family (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0716649B1 (en) * 1993-08-31 1998-09-09 Pfizer Inc. 5-arylindole derivatives
TW300214B (en) * 1996-06-06 1997-03-11 Sanfu Chemical Co Ltd Method for preparing cyclohexylamine
GB9615658D0 (en) * 1996-07-25 1996-09-04 Merck Sharp & Dohme Therapeutic agents
US6821978B2 (en) 2000-09-19 2004-11-23 Schering Corporation Xanthine phosphodiesterase V inhibitors
WO2002062780A2 (en) * 2001-02-08 2002-08-15 Karo Bio Ab Phenoxy substituted benzocondensed heteroaryl derivatives as thyroid receptor ligands
US20030096379A1 (en) * 2001-03-28 2003-05-22 Kilgore James L. Method for producing tryptamine derivatives
MXPA04001891A (en) * 2001-08-28 2004-06-15 Schering Corp Polycyclic guanine phosphodiesterase v inhibitors.
DE602005019098D1 (en) * 2004-12-21 2010-03-11 Hoffmann La Roche TETRALINE AND INDANDERIVATES AND ITS APPLICATIONS
BRPI0515835A (en) * 2004-12-21 2008-08-12 Hoffmann La Roche tetraline and indane derivatives and their uses
KR20240019152A (en) 2021-06-09 2024-02-14 아타이 테라퓨틱스, 인크. Novel prodrugs and conjugates of dimethyltryptamine

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991018897A1 (en) * 1990-06-07 1991-12-12 The Wellcome Foundation Limited Therapeutic heterocyclic compounds
WO1992013856A1 (en) * 1991-02-12 1992-08-20 Pfizer Inc. 5-heteroyl indole derivatives
EP0505322A1 (en) * 1991-03-22 1992-09-23 Sandoz Ltd. Aminoguanidines
WO1993000333A1 (en) * 1991-06-21 1993-01-07 Smithkline Beecham Plc Tryptamine analogues, their synthesis and their use as 5-ht1-like or 5-ht2 receptor agonists
WO1993011106A1 (en) * 1991-11-25 1993-06-10 Pfizer, Inc. Indole derivatives

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5245046A (en) * 1988-11-14 1993-09-14 The Upjohn Company α-amino-indole-3-acetic acids useful as anti-diabetic, anti-obesity and anti-atherosclerotic agents
DE4122722A1 (en) * 1991-07-06 1993-01-07 Schering Ag METHOD FOR PRODUCING INDOL DERIVATIVES

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991018897A1 (en) * 1990-06-07 1991-12-12 The Wellcome Foundation Limited Therapeutic heterocyclic compounds
WO1992013856A1 (en) * 1991-02-12 1992-08-20 Pfizer Inc. 5-heteroyl indole derivatives
EP0505322A1 (en) * 1991-03-22 1992-09-23 Sandoz Ltd. Aminoguanidines
WO1993000333A1 (en) * 1991-06-21 1993-01-07 Smithkline Beecham Plc Tryptamine analogues, their synthesis and their use as 5-ht1-like or 5-ht2 receptor agonists
WO1993011106A1 (en) * 1991-11-25 1993-06-10 Pfizer, Inc. Indole derivatives

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, vol. 106, no. 13, 30 March 1987, Columbus, Ohio, US; abstract no. 98661w, MUKHOMOROV V.K.: "Influence of electronic and steric interactions on the radioprotective properties of indolylalkylamines." *
L.J. STREET ET AL.: "Synthesis and serotonergic activity of 5-(oxadiazolyl)tryptamines: potent agonists for 5-HT1D receptors", JOURNAL OF MEDICINAL CHEMISTRY, vol. 36, no. 11, 28 May 1993 (1993-05-28), WASHINGTON US, pages 1529 - 1538 *
RADIOBIOLOGIYA, vol. 26(4), 1986, pages 557 - 559 *

Cited By (34)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995030655A1 (en) * 1994-05-06 1995-11-16 Allelix Biopharmaceuticals Inc. Tryptamine derivatives as 5-ht-1d receptor ligands
US5852049A (en) * 1994-09-22 1998-12-22 Pierre Fabre Medicament Aromatic ethers derived from indoles which are useful as medicaments
WO1996009288A1 (en) * 1994-09-22 1996-03-28 Pierre Fabre Medicament Aromatic ethers derived from indols such as 5ht1-like ligands
FR2724933A1 (en) * 1994-09-22 1996-03-29 Pf Medicament NOVEL AROMATIC ETHERS DERIVED FROM INDOLES USEFUL AS MEDICAMENTS
WO1996011685A2 (en) * 1994-10-12 1996-04-25 Pfizer Limited Use of indole derivatives for the treatment of various diseases
WO1996011685A3 (en) * 1994-10-12 1996-08-15 Pfizer Ltd Use of indole derivatives for the treatment of various diseases
US6455567B1 (en) 1994-10-12 2002-09-24 Pfizer Inc. Method of treatment
AU702322B2 (en) * 1995-03-20 1999-02-18 Eli Lilly And Company 5-substituted-3-(1,2,3,6-tetrahydropyridin-4-yl)- and 3-(piperidin-4-yl)-1h-indoles: new 5-ht1f agonists
US5708008A (en) * 1995-03-20 1998-01-13 Eli Lilly And Company 5-Substituted-3-(1,2,3,6-tetrahydropyridin-4-yl)-and 3-(piperidin-4-yl)-1H-indoles: new 5-HT1F agonists
WO1996029075A1 (en) * 1995-03-20 1996-09-26 Eli Lilly And Company 5-substituted-3-(1,2,3,6-tetrahydropyridin-4-yl)- and 3-(piperidin-4-yl)-1h-indoles: new 5-ht1f agonists
US5962474A (en) * 1995-03-20 1999-10-05 Eli Lilly And Company 5-substituted-3-(1,2,3,6-tetrahydropyridin-4-yl)-and 3-(piperidin-4-yl)-1h-indoles: 5-HT1F agonists
EP0733628A1 (en) * 1995-03-20 1996-09-25 Eli Lilly And Company 5-Substituted-3-(1,2,3,6-tetrahydropyridin-4-yl)- and 3-(piperidin-4-yl)-1h-indoles: new 5-ht1f agonists
US5942536A (en) * 1995-10-10 1999-08-24 Eli Lilly And Company N- 2-substituted-3-(2-aminoethyl)-1H-indol-5-YL!-Amides: new 5-HT1F agonists
EP0832650A2 (en) * 1996-09-18 1998-04-01 Eli Lilly And Company Use of serotonin 5-HT1F agonists for the prevention of migraine
EP0832650A3 (en) * 1996-09-18 1998-09-02 Eli Lilly And Company Use of serotonin 5-HT1F agonists for the prevention of migraine
EP0875513A1 (en) * 1997-04-14 1998-11-04 Eli Lilly And Company Substituted heteroaromatic 5-HT 1F agonists
US6133287A (en) * 1998-03-24 2000-10-17 Allelix Biopharmaceuticals Inc. Piperidine-indole compounds having 5-HT6 affinity
WO2000000490A2 (en) * 1998-06-26 2000-01-06 Eli Lilly And Company 5-ht1f agonists
WO2000000490A3 (en) * 1998-06-26 2003-04-17 Lilly Co Eli 5-ht1f agonists
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
WO2002016348A1 (en) * 2000-08-09 2002-02-28 Astrazeneca Ab Antiangiogenic bicyclic derivatives
FR2814166A1 (en) * 2000-09-21 2002-03-22 Innothera Lab Sa New 5-phenoxy indole derivatives used for treating inflammation, venous insufficiency, hemorrhoids, urological disorders, pain, migraine, and cutaneous disorders
US6794406B2 (en) 2000-12-27 2004-09-21 Bayer Aktiengesellschaft Indole derivatives
US6565829B2 (en) 2001-08-03 2003-05-20 Pharmacia & Upjohn Company 5-arylsulfonyl indoles useful for treating disease
US7125906B2 (en) 2002-04-03 2006-10-24 Astrazeneca Ab Indole derivatives having anti-angiogenetic activity
US7563908B2 (en) 2003-12-23 2009-07-21 Jan Kehler 2-(1H-indolylsulfanyl)-benzyl amine derivatives as SSRI
US7652150B2 (en) 2003-12-23 2010-01-26 H. Lundbeck A/S 2-(1H-indolylsulfanyl)-benzyl amine derivatives as SSRIs
US7737170B2 (en) 2003-12-23 2010-06-15 H. Lundbeck A/S Uses of 2-(1H-indolylsulfanyl)-benzyl amine derivatives as SSRIS
US7737171B2 (en) 2003-12-23 2010-06-15 H. Lundbeck A/S Uses of 2-(1H-indolylsulfanyl)-benzyl amine derivatives as SSRIS
US7678800B2 (en) 2004-07-16 2010-03-16 H. Lundbeck A/S 2-(1H-indolylsulfanyl)-aryl amine derivatives for use in the treatment of affective disorders, pain, ADHD and stress urinary incontinence
US7534791B2 (en) 2005-06-17 2009-05-19 H. Lundbeck A/S Benzo[b]furane and benzo[b]thiophene derivatives
US7629473B2 (en) 2005-06-17 2009-12-08 H. Lundbeck A/S 2-(1H-indolylsulfanyl)-aryl amine derivatives
AU2021397252B2 (en) * 2020-12-09 2024-03-14 Caamtech, Inc. Dialkyl tryptamines and their therapeutic uses

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EP0674619A1 (en) 1995-10-04

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