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WO1998051671A1 - Substituted tetrahydroisoquinoline derivatives as modulators of dopamine d3 receptors - Google Patents

Substituted tetrahydroisoquinoline derivatives as modulators of dopamine d3 receptors Download PDF

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Publication number
WO1998051671A1
WO1998051671A1 PCT/EP1998/002584 EP9802584W WO9851671A1 WO 1998051671 A1 WO1998051671 A1 WO 1998051671A1 EP 9802584 W EP9802584 W EP 9802584W WO 9851671 A1 WO9851671 A1 WO 9851671A1
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Prior art keywords
formula
group
compound
optionally substituted
4alkyl
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PCT/EP1998/002584
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French (fr)
Inventor
Christopher Norbert Johnson
Geoffrey Stemp
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Smithkline Beecham Plc
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Application filed by Smithkline Beecham Plc filed Critical Smithkline Beecham Plc
Priority to JP54874198A priority Critical patent/JP2001525813A/en
Priority to EP98924263A priority patent/EP0983245A1/en
Priority to CA002288850A priority patent/CA2288850A1/en
Publication of WO1998051671A1 publication Critical patent/WO1998051671A1/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
    • C07D401/12—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
    • 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
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
    • C07D217/04—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom

Definitions

  • the present invention relates to novel tetrahydroisoquinoline derivatives, processes for their preparation, pharmaceutical compositions containing them and then- use in therapy, as modulators of dopamine D3 receptors, in particular as antipsychotic agents.
  • B is a carbonyl group or a sulphonyl group
  • Rl, R ⁇ , R ⁇ and R ⁇ are each hydrogen or a lower alkyl group, or R and R 2 or R 1 and R ⁇ may be combined together to make a non- aromatic hydrocarbon ring, or R* and R ⁇ may be combined together to make an aromatic ring, and n is 0 or 1;
  • A is a non-aromatic hydrocarbon ring, and p and q are each 0, 1, or 2;
  • Ar is an aromatic ring, a heteroaromatic group, a benzoyl group, a phenoxy group, or a phenylthio group and G is N, CH, or CHOH.
  • the compounds are said to be useful as antipsychotic agents.
  • WO 95/10513 describes benzothiophene derivatives and related compounds as estrogen agonists.
  • the present invention provides compounds of formula (I) : ormula (I) wherein:
  • R! represents a substituent selected from: a hydrogen or halogen atom; a hydroxy, cyano, nitro, trifluoromethyl, trifluoromethoxy, trifluoromethanesulfonyloxy, pentafluoroethyl, Chal y., C ⁇ _4alkoxy, arylC ⁇ 4alkoxy, Ci ⁇ alkylthio, C ⁇ .4alkoxyC ⁇ -.4- ⁇ lkyl, C3_6cycloalkylC ⁇ _4alkoxy, C ⁇ _4- ⁇ lkanoyl, C ⁇ _4alkoxycarbonyl, C ⁇ .4alkylsulphonyl, C ⁇ _4alkylsulphonyloxy, arylsulphonyl, arylsulphonyloxy, arylsulphonylCi ⁇ alkyl, C ⁇ _4alkylsulphonamido, C ⁇ _
  • R2 represents a hydrogen atom or a C ⁇ _4al yl group; q is 1 or 2; s represents an integer from zero to 2 and r represents an integer from 1 to 4, such that the sum of s + r is 1 to 4; t represents an integer from zero to 1 and u represents an integer from zero to 2;
  • A represents a group of the formula (a), (b) or (c):
  • Ar represents an optionally substituted phenyl ring or an optionally substituted 5- or 6- membered aromatic heterocyclic ring; or an optionally substituted bicyclic system;
  • Ar* and Ar ⁇ each independently represent an optionally substituted phenyl ring or an optionally substituted 5- or 6- membered aromatic heterocyclic ring;
  • Y represents a bond, -NHCO-, -CONH-, -CH 2 -, or -(CH 2 ) m Y 1 (CH 2 ) n -, wherein Y 1 represents O, S, SO 2 , or CO and m and n each represent zero or 1 such that the sum of m+n is zero or 1 ; providing that when A represents a group of formula (a), any substituent present in Ar ortho to the carboxamide moiety is necessarily a hydrogen or a methoxy group; and salts thereof.
  • alkyl group or moiety may be straight or branched.
  • Alkyl groups which may be employed include methyl, ethyl, n-propyl, n- butyl, n-pentyl, n-hexyl and any branched isomers thereof such as isopropyl, t-butyl, sec- pentyl, and the like.
  • Examples of compounds of formula (I) include those in which Ar is a bicyclic aromatic or heteroaromatic ring system, and t and u are both 1 and in which R is other than pentafluoroethyl.
  • R* represents an arylC ⁇ _4alkoxy, arylsulphonyl, arylsulphonyloxy, arylsulphonylC ⁇ _4alkyl, arylsulphonamido, arylcarboxamido, arylsulphonamidoC ⁇ _4aIkyl, arylcarboxamidoC ⁇ _4alkyl, aroyl, aroylC ⁇ alkyl, or arylC ⁇ _4- ⁇ lkanoyl group
  • the aryl moiety may be selected from an optionally substituted phenyl ring or an optionally substituted 5- or 6-membered heterocyclic ring.
  • an aryl moiety may be optionally substituted by one or more substituents selected from hydrogen, halogen, amino, cyano, C1.4a.kyl, C ⁇ _4alkylamino, C ⁇ di- ⁇ cylamino, C ⁇ _4alkylamido, C ⁇ _4alkanoyl, or R ⁇ R NCO where each of R ⁇ and R ⁇ independently represents a hydrogen atom or C ⁇ _4alkyl group.
  • a halogen atom present in the compounds of formula (I) may be fluorine, chlorine, bromine or iodine.
  • An optionally substituted 5- or 6-membered heterocyclic aromatic ring may contain from 1 to 4 heteroatoms selected from O, N or S. When the ring contains 2-4 heteroatoms, one is preferably selected from O, N and S and the remaining heteroatoms are preferably N.
  • 5 and 6- membered heterocyclic groups include furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyridyl, triazolyl, triazinyl, pyridazyl, pyrimidinyl and pyrazolyl.
  • bicyclic, for example, bicyclic aromatic or heteroaromatic, ring systems for Ar include naphthyl, indazolyl, indolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzisothiazolyl, quinolinyl, quinoxolinyl, quinazolinyl, cinnolinyl, isoquinolinyl, pyrazolo[l,5- a]pyrimidyl, pyrrolo[3,2-b]pyridyl, pyrrolo[3,2-c]pyridyl, thieno[3,2-b]thiophenyl , 1,2- dihydro-2-oxo-quinolinyl, 2,3-dihydro-3-oxo-4H-benzoxazinyl, 1 ,2-dihydro-2-oxo-3 ⁇ - ind
  • the rings Ar, Ar ⁇ , or Ar ⁇ may each independently be optionally substituted by one or more substituents selected from: a hydrogen or halogen atom, or a hydroxy, cyano, nitro, C _4--lkyl, C ⁇ _4--lkoxy, C _4--lky-enedioxy, C ⁇ alkanoyl, C ⁇ . alkylsulphonyl, C .
  • R 7 and R 8 independently represents a hydrogen atom or a C1.4 alkyl group, or R 7 R 8 together form a C3.6 alkylene chain.
  • Ar and Ar ⁇ may be optionally substituted by one or more 5- or 6- • membered heterocyclic rings, as defined above, optionally substituted by a C ⁇ _ alkyl or R 7 R 8 N- group; wherein R 7 and R 8 are as defined above.
  • rings Ar and Ar ⁇ substituents positioned ortho to one another may be linked to form a 5- or 6- membered ring.
  • salts of formula (I) should be physiologically acceptable.
  • suitable physiologically acceptable salts will be apparent to those skilled in the art and include for example acid addition salts formed with inorganic acids eg. hydrochloric, hydrobromic, sulphuric, nitric or phosphoric acid; and organic acids eg. succinic, maleic, acetic, fumaric, citric, tartaric, benzoic, p-toluenesulphonic, methanesulphonic or naphthalenesulphonic acid.
  • Other non-physiologically acceptable salts eg. oxalates, may be used, for example in the isolation of compounds of formula (I) and are included within the scope of this invention.
  • solvates and hydrates of compounds of formula (I) are also included within the scope of the invention. Certain of the compounds of formula (I) may form acid addition salts with one or more equivalents of the acid.
  • the present invention includes within its scope all possible stoichiometric and non-stoichiometric forms.
  • each diastereoisomer can exist as 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 invention.
  • (+) and (-) designations used herein indicate the direction of rotation of plane-polarised light by the compounds.
  • the prefix (+) indicates that the isomer is dextrorotatory (which can also be designated d) and the prefix (-) indicates the levorotatory isomer (which can also be designated 1). It will thus be appreciated that the invention extends to the individual diastereoisomers, individual enantiomers and any and all mixtures of these forms. Certain of the other compounds of formula (I) can also exist in the form of cis- and trans- isomers. The present invention includes within its scope all such isomers, including mixtures.
  • A is as hereinbefore defined and X is a halogen atom or the residue of an activated ester;
  • R a represents a group W wherein W is a halogen atom or a trifluoromethylsulphonyloxy group, or W is a group M selected from a boron derivative e.g. a boronic acid function B(OH) or a metal function such as trialkylstannyl e.g.
  • R , R Ar and W are as hereinbefore defined, with a compound Ar ⁇ -W 1 , wherein W 1 is a halogen atom or a trifluoromethylsulphonyloxy group when W is a group M, or W is a group M when W is a halogen atom or a trifluoromethylsulphonyloxy group.
  • W 1 is a halogen atom or a trifluoromethylsulphonyloxy group when W is a group M
  • W is a group M when W is a halogen atom or a trifluoromethylsulphonyloxy group.
  • R 1 , R ⁇ , ⁇ , S, t and u are as hereinbefore defined and P is a protecting group such as t-butoxycarbonyl or trifluoroacetyl , to a compound of fomula (V).
  • R 1 , q, r and s are as hereinbefore defined and v is 1 or 2, into a corresponding ketone, followed by reductive amination.
  • This may be effected by methods well known in the art for (i) conversion of a ketal to a ketone in the presence of aqueous acid; followed by (ii) reductive amination of the ketone with R ⁇ NH 2 or ammonium acetate in the presence of a reducing agent.
  • Suitable reducing agents which may be employed include sodium borohydride, cyanoborohydride or triacetoxyborohydride under acidic conditions, or catalytic hydrogenation.
  • the reaction may conveniently be effected in a solvent such as methanol, ethanol or dichloroethane..
  • Processes (h), (i) and (k) require the presence of a reducing agent.
  • Suitable reducing agents which may be employed include sodium borohydride, cyanoborohydride or triacetoxyborohydride under acidic conditions, or catalytic hydrogenation.
  • the reaction may conveniently be effected in a solvent such as ethanol.
  • Process (g) may be effected by standard methods well known in the art for (i) removal of a t-butoxycarbonyl group, e.g., using acidic conditions; (ii) removal of a trifluoroacetyl group, e.g., using basic conditions.
  • Reaction of a compound of formula (VII) with Ar W*, according to process (b) or a compound of formula (IX) with Ar ⁇ -Wl according to process (d) may be effected in the presence of a transition metal eg palladium catalyst such as bis- triphenylphosphinepalladium dichloride or tetr ⁇ / w-triphenylphosphinepalladium (0).
  • a transition metal eg palladium catalyst
  • M represents a boronic acid function such as B(OH) 2
  • the reaction may be carried out under basic conditions, for example using aqueous sodium carbonate in a suitable solvent such as dioxane.
  • M is trialkylstannyl
  • the reaction may be carried out in an inert solvent, such as xylene or dioxane optionally in the presence of LiCl.
  • M is a zinc or magnesium halide
  • the reaction may be effected in an aprotic solvent such as tetrahydrofuran.
  • the substituent W is preferably a halogen atom such as bromine, or a sulphonyloxy group such as trifluoromethylsulphonyloxy; and W* is preferably a goup M, such as trialkylstannyl or B(OH) .
  • the reagent serving to introduce the group Ar 3 is preferably a compound of formula Ar 3 -Hal, wherein Hal is a halogen atom.
  • the reaction may be effected in the presence of a base, such as potassium carbonate, in a solvent such as dimethylformamide.
  • Interconversion reactions according to process (e) may be effected using methods well known in the art.
  • Compounds of formula (VII), (VIII) or (IX) may be prepared by processes analogous to (a), (g), (h) and (i) described above.
  • Compounds Ar ⁇ W , Ar 3 W and Ar 3 Hal are commercially available or may be prepared by standard methods.
  • Compounds of formula (I) have been found to exhibit affinity for dopamine receptors, in particular the D3 receptor, and are expected to be useful in the treatment of disease states which require modulation of such receptors, such as psychotic conditions. Compounds of formula (I) have also been found to have greater affinity for dopamine D3 than for D 2 receptors.
  • antipsychotic agents neuropeptides
  • eps extrapyramidal side effects
  • Preferred compounds of the present invention are therefore those which have higher affinity for dopamine D3 than dopamine D 2 receptors (such affinity can be measured using standard methodology for example using cloned dopamine receptors). Said compounds may advantageously be used as selective modulators of D3 receptors.
  • D3 antagonists are of potential use as antipsychotic agents for example in the treatment of schizophrenia, schizo-affective disorders, psychotic depression, mania, paranoid and delusional disorders.
  • Conditions which may be treated by dopamine D3 receptor agonists include dyskinetic disorders such as Parkinson's disease, neuroleptic-induced parkinsonism and tardive dyskinesias; depression; anxiety, memory disorders, sexual dysfunction and drug (eg. cocaine) dependency.
  • the present invention provides a method of treating conditions which require modulation of dopamine D3 receptors, for example psychoses such as schizophrenia, which comprises administering to a subject in need thereof an effective amount of a compound of formula (I) or a physiologically acceptable salt thereof.
  • the invention also provides the use of a compound of formula (I) or a physiologically acceptable salt thereof in the manufacture of a medicament for the treatment of conditions which require modulation of dopamine D3 receptors, for example psychoses such as schizophrenia.
  • a preferred use for D3 antagonists according to the present invention is in the treatment of psychoses such as schizophrenia.
  • a preferred use for D3 agonists according to the present invention is in the treatment of dyskinetic disorders such as Parkinson's disease.
  • the compounds of the present invention are usually administered as a standard pharmaceutical composition.
  • the present invention therefore provides in a further aspect pharmaceutical compositions comprising a novel compound of formula (I) or a physiologically acceptable salt thereof and a physiologically acceptable carrier.
  • the compounds of formula (I) may be administered by any convenient method, for example by oral, parenteral, buccal, sublingual, nasal, rectal or transdermal administration and the pharmaceutical compositions adapted accordingly.
  • the compounds of formula (I) and their physiologically acceptable salts which are active when given orally can be formulated as liquids or solids, for example syrups, suspensions or emulsions, tablets, capsules and lozenges.
  • a liquid formulation will generally consist of a suspension or solution of the compound or physiologically acceptable salt in a suitable liquid carrier(s) for example an aqueous solvent such as water, ethanol or glycerine, or a non-aqueous solvent, such as polyethylene glycol or an oil.
  • the formulation may also contain 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.
  • pellets containing the active ingredient can be prepared using standard carriers and then filled into a hard gelatin capsule; alternatively, a dispersion or suspension can be prepared using any suitable pharmaceutical carrier(s), for example aqueous gums, celluloses, silicates or oils and the dispersion or suspension then filled into a soft gelatin capsule.
  • Typical parenteral compositions consist of a solution or suspension of the compound or physiologically acceptable salt in a sterile aqueous carrier or parenterally acceptable oil, for example polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil.
  • a sterile aqueous carrier or parenterally acceptable oil for example polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil.
  • the solution can be lyophilised and then reconstituted with a suitable solvent just prior to administration.
  • compositions for nasal administration may conveniently be formulated as aerosols, drops, gels and . powders.
  • Aerosol formulations typically comprise a solution or fine suspension of the active substance in a physiologically acceptable aqueous or non- aqueous solvent and are usually presented in single or multidose quantities in sterile form in a sealed container, which can take the form of a cartridge or refill for use with an atomising device.
  • the sealed container may be a unitary dispensing device such as a single dose nasal inhaler or an aerosol dispenser fitted with a metering valve which is intended for disposal once the contents of the container have been exhausted.
  • the dosage form comprises an aerosol dispenser
  • a propellant which can be a compressed gas such as compressed air or an organic propellant such as a fluoro- chlorohydrocarbon.
  • the aerosol dosage forms can also take the form of a pump- atomiser.
  • compositions suitable for buccal or sublingual administration include tablets, lozenges and pastilles, wherein the active ingredient is formulated with a carrier such as sugar and acacia, tragacanth, or gelatin and glycerin.
  • a carrier such as sugar and acacia, tragacanth, or gelatin and glycerin.
  • compositions for rectal administration are conveniently in the form of suppositories containing a conventional suppository base such as cocoa butter.
  • compositions suitable for transdermal administration include ointments, gels and patches.
  • 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 physiologically acceptable salt thereof calculated as the free base.
  • the physiologically 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 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 and 25 mg of the compound of the formula (I) or a physiologically acceptable salt thereof calculated as the 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 ability of the compounds to bind selectively to human D3 dopamine receptors can be demonstrated by measuring their binding to cloned receptors.
  • the inhibition constants (Kj) of test compounds for displacement of [ ⁇ 5rj iodosulpride binding to human D3 dopamine receptors expressed in CHO cells were determined as follows. The cell lines were shown to be free from bacterial, fungal and mycoplasmal contaminants, and stocks of each were stored frozen in liquid nitrogen. Cultures were grown as monolayers or in suspension in standard cell culture media. Cells were recovered by scraping (from monolayers) or by centrifugation (from suspension cultures), and were washed two or three times by suspension in phosphate buffered saline followed by collection by centrifugation. Cell pellets were stored frozen at -40°C. Crude cell membranes were prepared by homogenisation followed by high-speed centrifugation, and characterisation of cloned receptors achieved by radioligand binding. Preparation of CHO cell membranes
  • the membrane pellet was resuspended in ice-cold 50 mM Tris salts (pH 7.4 @ 37°C), using an Ultra-Turrax, and recentrifuged at 18,000 r.p.m for 15 min at 4°C in a Sorvall RC5C. The membranes were washed two more times with ice-cold 50 mM Tris salts (pH 7.4 @ 37°C). The final pellet was resuspended in 50 mM Tris salts (pH 7.4 @ 37°C), and the protein content determined using bovine serum albumin as a standard (Bradford, M. M. (1976) Anal. Biochem. 72, 248-254).
  • Non-specific binding was defined as the radioligand binding remaining after incubation in the presence of 100 uM iodosulpride.
  • 14 concentrations (half-log dilutions) of competing cold drug were used. Competition curves were analysed simultaneously whenever possible using non-linear least-squares fitting procedures, capable of fitting one, two or three site models.
  • the functional activity of compounds at human D2 and human D3 receptors may be determined using a Cytosensor Microphysiometer (McConnell HM et al Science 1992 257 1906-1912)
  • McConnell HM et al Science 1992 257 1906-1912 a Cytosensor Microphysiometer
  • cells hD2_CHO or hD3_CHO
  • FCS foetal calf serum
  • cups were loaded into the sensor chambers of the Cytosensor Microphysiometer (Molecular Devices) and the chambers perfused with running medium (bicarbonate-free Dulbecco's modified Eagles medium containing 2 mM glutamine and 44 mM NaCl) at a flow rate of 100 ul/min. Each pump cycle lasted 90s. The pump was on for the first 60s and the acidification rate determined between 68 and 88s, using the Cytosoft programme. Test compounds were diluted in running medium. In experiments to determine agonist activity, cells were exposed (4.5 min for hD2, 7.5 min for hD3) to increasing concentrations of putative agonist at half hour intervals. Seven concentrations of the putative agonist were used.
  • running medium bicarbonate-free Dulbecco's modified Eagles medium containing 2 mM glutamine and 44 mM NaCl
  • Peak acidification rate to each putative agonist concentration was determined and concentration-response curves fitted using Robofit [Tilford, N.S., Bowen, W.P. & Baxter, G.S. Br. J. Pharmacol. (1995) in press].
  • cells were treated at 30 min intervals with five pulses of a submaximal concentration of quinpirole (100 nM for hD2 cells, 30 nM for hD3 cells), before exposure to the lowest concentration of putative antagonist. At the end of the next 30 min interval, cells were pulsed again with quinpirole (in the continued presence of the antagonist) before exposure to the next highest antagonist concentration. In all, five concentrations of antagonist were used in each experiment. Peak acidification rate to each agonist concentration was determined and concentration-inhibition curves fitted using Robofit.
  • Buffer Suitable buffers include citrate, phosphate, sodium hydroxide/hydrochloric acid.
  • Solven Typically water but may also include cyclodextrins (1-100 mg) and co- solvents such as propylene glycol, polyethylene glycol and alcohol.
  • cyclodextrins Diluent e.g. Microcrystalline cellulose, lactose, starch
  • Binder e.g. Polyvinylpyrrolidone, hydroxypropymethylcellulose
  • Disintegrant e.g. Sodium starch glycollate, crospovidone
  • Lubricant e.g. Magnesium stearate, sodium stearyl fumarate.
  • Suspending agent e.g. Xanthan gum, microcrystalline cellulose
  • Diluent e.g. sorbitol solution, typically water
  • Preservative e.g. sodium benzoate
  • Buffer e.g. citrate
  • Co-solvent e.g. alcohol, propylene glycol, polyethylene glycol, cyclodextrin
  • Aqueous phase was further extracted with diethyl ether (25ml x 2) and the combined organic extracts were washed with brine (40ml), dried (Na 2 SO ) then evaporated in vacuo to give an oil.
  • oxalyl chloride (0.08g, 0.6 mmol) in dry dichloromethane (3ml) at -80°C under argon, was added dropwise a solution of dimethyl sulfoxide (0.09g, 1.2 mmol) in dichloromethane (0.5ml). The resulting mixture was stirred at -78°C for 0.75h, then a solution of the above oil in dry dichloromethane (3ml) was added.

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Abstract

Compounds of formula (I) wherein: R1 represents a substituent selected from: a hydrogen or halogen atom; a hydroxy, cyano, nitro, trifluoromethyl, trifluoromethoxy, trifluoromethanesulfonyloxy, pentafluoroethyl, C¿1-4?alkyl, C1-4alkoxy, arylC1-4alkoxy, C1-4alkylthio, C1-4alkoxy C1-4alkyl, C3-6cycloalkylC1-4alkoxy, C1-4alkanoyl, C1-4alkoxycarbonyl, C1-4alkylsulphonyl, C1-4alkylsulphonyloxy, C1-4alkylsulphonylC1-4alkyl, arylsulphonyl arlysulphonyloxy, arylsulphonylC1-4alkyl, C1-4alkylsulphonamido, C1-4alkylamido, C1-4alkylsulphonamidoC1-4alkyl, C1-4alkylamidoC1-4alkyl, arylsulphomanido, arylcarboxamido, arylsulphonamidoC1-4alkyl, arylcarboxamidoC1-4alkyl, aroyl, aroylC1-4alkyl, or arylC1-4alkanoyl group; a group R?3¿OCO(CH¿2?)p, R?3CON(R4)(CH¿2)p, R3R4NCO(CH¿2?)p, or R?3R4¿NSO(CH¿2?)p where each of R?3 and R4¿ independently represents a hydrogen atom or a C¿1-4?alkyl group or R?3R4¿ forms part of a C¿3-6?azacycloalkane or C3-6(2-oxo)azacycloalkane ring and p represents zero or an integer from 1 to 4; or a group Ar?3¿-Z, wherein Ar3 represents an optionally substituted phenyl ring or an optionally substituted 5- or 6- membered aromatic heterocyclic ring and Z represents a bond O, S, or CH¿2?; s represents an integer from zero to 2 and r represents an integer from 1 to 4, such that the sum of s + r is 1 to 4; t represents an integer from zero to 1 and u represents an integer from zero to 2; R?2¿ represents a hydrogen atom or a C¿1-4?alkyl group; q is 1 or 2; A represents a group of the formula (a), (b) or (c): wherein Ar represents an optionally substituted phenyl ring or an optionally substituted 5- or 6-membered aromatic heterocyclic ring; or an optionally substituted bicyclic ring system; Ar?1 and Ar2¿ each independently represent an optionally substituted phenyl ring or an optionally substituted 5- or 6-membered aromatic heterocyclic ring; and Y represents a bond, -NHCO-, -CONH-, -CH¿2?-, or -(CH2)nY'(CH2)n-, wherein Y' represents O, S, SO2, or CO and m and n each represents zero or 1 such that the sum of m+n is zero or 1; providing that when A represents a group of formula (a), any substituent present in Ar ortho to the carboxamide moiety is necessarily a hydrogen or methoxy group; and salts thereof. Compounds of formula (I) and their salts have affinity for dopamine receptors, in particular the D3 receptor, and thus potential in the treatment of conditions wherein modulation of the D3 receptor is beneficial, e.g. as antipsychotic agents.

Description

SUBSTITUTED TETRAHYDROISOQUINOLINE DERIVAΗVES AS MODULATORS OF DOPAMINE D3 RECEPTORS
The present invention relates to novel tetrahydroisoquinoline derivatives, processes for their preparation, pharmaceutical compositions containing them and then- use in therapy, as modulators of dopamine D3 receptors, in particular as antipsychotic agents.
US Patent No. 5,294,621 describes tetrahydropyridine derivatives of the formula:
wherein
Figure imgf000003_0001
is an optionally substituted thienyl or optionally substituted phenyl ring; R.1, R.2 and R.3 are each inter alia hydrogen; X is inter alia (CH2)mNR7co; m is 2-4; and Ar is an optionally substituted heterocyclic ring or an optionally substituted phenyl ring. The compounds are said to be useful as antiarrhythmic agents. European Patent Application 0 464846 Al describes imide derivatives of the formula:
Figure imgf000003_0002
wherein B is a carbonyl group or a sulphonyl group, Rl, R^, R^ and R^ are each hydrogen or a lower alkyl group, or R and R2 or R1 and R^ may be combined together to make a non- aromatic hydrocarbon ring, or R* and R^ may be combined together to make an aromatic ring, and n is 0 or 1; A is a non-aromatic hydrocarbon ring, and p and q are each 0, 1, or 2; Ar is an aromatic ring, a heteroaromatic group, a benzoyl group, a phenoxy group, or a phenylthio group and G is N, CH, or CHOH. The compounds are said to be useful as antipsychotic agents.
WO 95/10513 describes benzothiophene derivatives and related compounds as estrogen agonists.
We have now found a class of tetrahydroisquinoline derivatives which have affinity for dopamine receptors, in particular the D3 receptor, and thus potential in the treatment of conditions wherein modulation of the D3 receptor is beneficial, eg as antipsychotic agents. In a first aspect the present invention provides compounds of formula (I) :
Figure imgf000004_0001
ormula (I) wherein:
R! represents a substituent selected from: a hydrogen or halogen atom; a hydroxy, cyano, nitro, trifluoromethyl, trifluoromethoxy, trifluoromethanesulfonyloxy, pentafluoroethyl, Chal y., Cι _4alkoxy, arylCμ4alkoxy, Ci^alkylthio, Cι.4alkoxyCι-.4-ιlkyl, C3_6cycloalkylCι_4alkoxy, Cι_4-ιlkanoyl, Cι _4alkoxycarbonyl, Cι .4alkylsulphonyl, Cι_4alkylsulphonyloxy,
Figure imgf000004_0002
arylsulphonyl, arylsulphonyloxy, arylsulphonylCi^alkyl, Cι _4alkylsulphonamido, Cι_
Figure imgf000004_0003
C3.6azacyloa.kane or C3_6(2-oxo)azacycloalkane ring and p represents zero or an integer from 1 to 4; or a group Ar3-Z, wherein Ar3 represents an optionally substituted phenyl ring or an optionally substituted 5- or 6- membered aromatic heterocyclic ring and Z represents a bond, O, S , or CH2;
R2 represents a hydrogen atom or a Cι_4al yl group; q is 1 or 2; s represents an integer from zero to 2 and r represents an integer from 1 to 4, such that the sum of s + r is 1 to 4; t represents an integer from zero to 1 and u represents an integer from zero to 2;
A represents a group of the formula (a), (b) or (c):
-Ar -Y— Ar
(a) (b) (c) wherein
Ar represents an optionally substituted phenyl ring or an optionally substituted 5- or 6- membered aromatic heterocyclic ring; or an optionally substituted bicyclic system; Ar* and Ar^ each independently represent an optionally substituted phenyl ring or an optionally substituted 5- or 6- membered aromatic heterocyclic ring; and
Y represents a bond, -NHCO-, -CONH-, -CH2-, or -(CH2)mY1(CH2)n-, wherein Y1 represents O, S, SO2, or CO and m and n each represent zero or 1 such that the sum of m+n is zero or 1 ; providing that when A represents a group of formula (a), any substituent present in Ar ortho to the carboxamide moiety is necessarily a hydrogen or a methoxy group; and salts thereof.
In the compounds of formula (I) above an alkyl group or moiety may be straight or branched. Alkyl groups which may be employed include methyl, ethyl, n-propyl, n- butyl, n-pentyl, n-hexyl and any branched isomers thereof such as isopropyl, t-butyl, sec- pentyl, and the like.
Examples of compounds of formula (I) include those in which Ar is a bicyclic aromatic or heteroaromatic ring system, and t and u are both 1 and in which R is other than pentafluoroethyl. When R* represents an arylCι _4alkoxy, arylsulphonyl, arylsulphonyloxy, arylsulphonylCι _4alkyl, arylsulphonamido, arylcarboxamido, arylsulphonamidoCι _4aIkyl, arylcarboxamidoCι _4alkyl, aroyl, aroylC^alkyl, or arylCι_4-ιlkanoyl group, the aryl moiety may be selected from an optionally substituted phenyl ring or an optionally substituted 5- or 6-membered heterocyclic ring. In the group R1 an aryl moiety may be optionally substituted by one or more substituents selected from hydrogen, halogen, amino, cyano, C1.4a.kyl, Cι_4alkylamino, C^di-ύcylamino, Cι_4alkylamido, Cι_4alkanoyl, or R^R NCO where each of R^ and R^ independently represents a hydrogen atom or Cι_4alkyl group.
A halogen atom present in the compounds of formula (I) may be fluorine, chlorine, bromine or iodine.
When q is 2, the substituents R* may be the same or different.
An optionally substituted 5- or 6-membered heterocyclic aromatic ring, as defined for any of the groups Ar, Ar , Ar^ or Ar3 may contain from 1 to 4 heteroatoms selected from O, N or S. When the ring contains 2-4 heteroatoms, one is preferably selected from O, N and S and the remaining heteroatoms are preferably N. Examples of 5 and 6- membered heterocyclic groups include furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyridyl, triazolyl, triazinyl, pyridazyl, pyrimidinyl and pyrazolyl.
Examples of bicyclic, for example, bicyclic aromatic or heteroaromatic, ring systems for Ar include naphthyl, indazolyl, indolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzisothiazolyl, quinolinyl, quinoxolinyl, quinazolinyl, cinnolinyl, isoquinolinyl, pyrazolo[l,5- a]pyrimidyl, pyrrolo[3,2-b]pyridyl, pyrrolo[3,2-c]pyridyl, thieno[3,2-b]thiophenyl , 1,2- dihydro-2-oxo-quinolinyl, 2,3-dihydro-3-oxo-4H-benzoxazinyl, 1 ,2-dihydro-2-oxo-3Η- indolyl.
The rings Ar, Ar^, or Ar^ may each independently be optionally substituted by one or more substituents selected from: a hydrogen or halogen atom, or a hydroxy, cyano, nitro, C _4--lkyl, Cι_4--lkoxy, C _4--lky-enedioxy, C ^alkanoyl, C\. alkylsulphonyl, C .4alkylsulphinyl, C1.4aIkylt.1io, R7SO2N(R8)-, R7R8N-, R7R8NCO-, R7R8NSO2-, or R7CON(R8)- group wherein each of R7 and R8 independently represents a hydrogen atom or a C1.4 alkyl group, or R7R8 together form a C3.6 alkylene chain. Alternatively, Ar and Ar^ may be optionally substituted by one or more 5- or 6- • membered heterocyclic rings, as defined above, optionally substituted by a Cι_ alkyl or R7R8N- group; wherein R7 and R8 are as defined above.
In the rings Ar and Ar^ substituents positioned ortho to one another may be linked to form a 5- or 6- membered ring.
It will be appreciated that for use in medicine the salts of formula (I) should be physiologically acceptable. Suitable physiologically acceptable salts will be apparent to those skilled in the art and include for example acid addition salts formed with inorganic acids eg. hydrochloric, hydrobromic, sulphuric, nitric or phosphoric acid; and organic acids eg. succinic, maleic, acetic, fumaric, citric, tartaric, benzoic, p-toluenesulphonic, methanesulphonic or naphthalenesulphonic acid. Other non-physiologically acceptable salts eg. 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). Certain of the compounds of formula (I) may form acid addition salts with one or more equivalents of the acid. The present invention includes within its scope all possible stoichiometric and non-stoichiometric forms.
It will be appreciated certain of the compounds of formula (I) contain two asymmetric centres. Such compounds can exist in diastereomeric forms, namely cis- and trans- isomers; both forms and all mixtures thereof are included within the scope of this invention. Furthermore, each diastereoisomer can exist as 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 invention. In accordance with convention the (+) and (-) designations used herein indicate the direction of rotation of plane-polarised light by the compounds. The prefix (+) indicates that the isomer is dextrorotatory (which can also be designated d) and the prefix (-) indicates the levorotatory isomer (which can also be designated 1). It will thus be appreciated that the invention extends to the individual diastereoisomers, individual enantiomers and any and all mixtures of these forms. Certain of the other compounds of formula (I) can also exist in the form of cis- and trans- isomers. The present invention includes within its scope all such isomers, including mixtures.
In compounds of formula (I), it is preferred that either t and u are both zero or that t and u are both 1. Certain of the substituted heteroaromatic ring systems included in compounds of formula (I) may exist in one or more tautomeric forms. The present invention includes within its scope all such tautomeric forms, including mixtures.
Particular compounds according to the invention include those specifically exemplified and named hereinafter. The present invention also provides a processs for preparing compounds of formula (I) which process comprises:
(a) reacting a compound of formula (V):
Figure imgf000007_0001
Formula (V)
with a compound of formula (VI):
A-COX
Formula (VI)
wherein A is as hereinbefore defined and X is a halogen atom or the residue of an activated ester;
(b) to prepare a compound of formula (I) wherein R1 is Ar3-Z and Z is a bond, reacting a compound of formula (VII):
Figure imgf000007_0002
Formula (VII)
wherein one R a represents a group W wherein W is a halogen atom or a trifluoromethylsulphonyloxy group, or W is a group M selected from a boron derivative e.g. a boronic acid function B(OH) or a metal function such as trialkylstannyl e.g. SnBu3, zinc halide or magnesium halide, and when q is 2 the other R*a is Rl; with a compound Ar3-W^, wherein W^ is a halogen atom or a trifluoromethylsulphonyloxy group when W is a group M or W is a group M when W is a halogen atom or a trifluoromethylsulphonyloxy group;
(c) to prepare a compound of formula (I) wherein R1 is Ar3-Z and Z is O or S, reacting a compound of formula (Vϋl):
Figure imgf000007_0003
Formula (VIII) wherein one R1 D represents a group ZH and when q is 2 the other R1 D represents R1; with a reagent serving to introduce the group Ar3; (d) to prepare a compound of formula (I) where Y is a bond, reaction of a compound of formula (IX):
Figure imgf000008_0001
Formula (IX)
wherein R , R Ar and W are as hereinbefore defined, with a compound Ar^-W1, wherein W1 is a halogen atom or a trifluoromethylsulphonyloxy group when W is a group M, or W is a group M when W is a halogen atom or a trifluoromethylsulphonyloxy group. (e) interconversion of one compound of formula (I) to a different compound of formula (I) e.g. (i) alkylation of a compound (I) wherein R^ represents hydrogen, (ii) conversion of one R1 from alkoxy (e.g.methoxy) to hydroxy, or (iii) conversion of R from hydroxy to sulphonyloxy, eg alkylsulphonyloxy or trifluoromethanesulphonyloxy;
(iv) conversion of a compound wherein Y represents S to a compound wherein Y is SO2 or (v) conversion of Y from CO to CH2;
(f) where appropriate, separation of enantiomers, diastereoisomers, or cis- and trans- isomers of compounds of formula (I), or intermediates thereto, by conventional methods, e.g. chromatography or crystallisation; and optionally thereafter forming a salt of formula (I).
Compounds of formula (V) may be prepared by :-
(g) conversion of a compound of formula (IV):
Figure imgf000008_0002
Formula (IV)
wherein R1, R^, Γ, S, t and u are as hereinbefore defined and P is a protecting group such as t-butoxycarbonyl or trifluoroacetyl , to a compound of fomula (V).
Compounds of formula (IV) in which t is 1 may be prepared by:-
(h) by reacting a compound of formula (II):
Figure imgf000009_0001
Formula (II)
wherein R! and q are as hereinbefore defined; with a compound of formula (Ilia):
Figure imgf000009_0002
Formula (Ilia)
wherein P, R^, r, s, and u are as hereinbefore defined;
Compounds of formula (IV) where t is zero may be prepared by: -
(i) reacting a compound of formula (II), wherein R and q are hereinbefore defined, with a compound of formula (nib):
Figure imgf000009_0003
Formula (mb)
wherein P, R^, r, s, and u are as hereinbefore defined.
Compounds of formula (V), where t and u are both zero may be prepared by :-
(j) conversion of a compound of formula (X):-
Figure imgf000009_0004
ormula (X)
wherein R1, q, r and s are as hereinbefore defined and v is 1 or 2, into a corresponding ketone, followed by reductive amination. This may be effected by methods well known in the art for (i) conversion of a ketal to a ketone in the presence of aqueous acid; followed by (ii) reductive amination of the ketone with R^NH2 or ammonium acetate in the presence of a reducing agent. Suitable reducing agents which may be employed include sodium borohydride, cyanoborohydride or triacetoxyborohydride under acidic conditions, or catalytic hydrogenation. The reaction may conveniently be effected in a solvent such as methanol, ethanol or dichloroethane..
Compounds of formula (X) wherein R and q are as hereinbefore defined, may be prepared by:-
(k) reacting a compound of formula (XI):-
Figure imgf000010_0001
Formula (XI)
wherein v, r and s are as hereinbefore defined, with a compound of formula (II), wherein R! and q are as hereinbefore defined .
Processes (h), (i) and (k) require the presence of a reducing agent. Suitable reducing agents which may be employed include sodium borohydride, cyanoborohydride or triacetoxyborohydride under acidic conditions, or catalytic hydrogenation. The reaction may conveniently be effected in a solvent such as ethanol. Process (g) may be effected by standard methods well known in the art for (i) removal of a t-butoxycarbonyl group, e.g., using acidic conditions; (ii) removal of a trifluoroacetyl group, e.g., using basic conditions.
Reaction of a compound of formula (VII) with Ar W*, according to process (b) or a compound of formula (IX) with Ar^-Wl according to process (d) may be effected in the presence of a transition metal eg palladium catalyst such as bis- triphenylphosphinepalladium dichloride or tetrα/ w-triphenylphosphinepalladium (0). When M represents a boronic acid function such as B(OH)2the reaction may be carried out under basic conditions, for example using aqueous sodium carbonate in a suitable solvent such as dioxane. When M is trialkylstannyl the reaction may be carried out in an inert solvent, such as xylene or dioxane optionally in the presence of LiCl. When M is a zinc or magnesium halide the reaction may be effected in an aprotic solvent such as tetrahydrofuran. The substituent W is preferably a halogen atom such as bromine, or a sulphonyloxy group such as trifluoromethylsulphonyloxy; and W* is preferably a goup M, such as trialkylstannyl or B(OH) . In process (c) the reagent serving to introduce the group Ar3 is preferably a compound of formula Ar3-Hal, wherein Hal is a halogen atom. The reaction may be effected in the presence of a base, such as potassium carbonate, in a solvent such as dimethylformamide. Interconversion reactions according to process (e) may be effected using methods well known in the art.
Compounds of formula (II) may be prepared by methods known in the art.
Compounds of formula (Ilia) and (Illb) are known or may be prepared using standard procedures.
Compounds of formula (VII), (VIII) or (IX) may be prepared by processes analogous to (a), (g), (h) and (i) described above. Compounds Ar^W , Ar3W and Ar3Hal are commercially available or may be prepared by standard methods.
Compounds of formula (XI) are commercially available or may be prepared using standard procedures.
Compounds of formula (I) have been found to exhibit affinity for dopamine receptors, in particular the D3 receptor, and are expected to be useful in the treatment of disease states which require modulation of such receptors, such as psychotic conditions. Compounds of formula (I) have also been found to have greater affinity for dopamine D3 than for D2 receptors. The therapeutic effect of currently available antipsychotic agents (neuroleptics) is generally believed to be exerted via blockade of D2 receptors; however this mechanism is also thought to be responsible for undesirable extrapyramidal side effects (eps) associated with many neuroleptic agents. Without wishing to be bound by theory, it has been suggested that blockade of the recently characterised dopamine D3 receptor may give rise to beneficial antipsychotic activity without significant eps. (see for example Sokoloff et al, Nature, 1990; 347: 146-151; and Schwartz et al, Clinical Neuropharmacology, Vol 16, No. 4, 295-314, 1993). Preferred compounds of the present invention are therefore those which have higher affinity for dopamine D3 than dopamine D2 receptors (such affinity can be measured using standard methodology for example using cloned dopamine receptors). Said compounds may advantageously be used as selective modulators of D3 receptors.
We have found that certain compounds of formula (I) are dopamine D3 receptor antagonists, others may be agonists or partial agonists. The functional activity of compounds of the invention (i.e. whether they are antagonists, agonists or partial agonists) can be readily determined using the test method described hereinafter, which does not require undue experimentation. D3 antagonists are of potential use as antipsychotic agents for example in the treatment of schizophrenia, schizo-affective disorders, psychotic depression, mania, paranoid and delusional disorders. Conditions which may be treated by dopamine D3 receptor agonists include dyskinetic disorders such as Parkinson's disease, neuroleptic-induced parkinsonism and tardive dyskinesias; depression; anxiety, memory disorders, sexual dysfunction and drug (eg. cocaine) dependency.
In a further aspect therefore the present invention provides a method of treating conditions which require modulation of dopamine D3 receptors, for example psychoses such as schizophrenia, which comprises administering to a subject in need thereof an effective amount of a compound of formula (I) or a physiologically acceptable salt thereof. The invention also provides the use of a compound of formula (I) or a physiologically acceptable salt thereof in the manufacture of a medicament for the treatment of conditions which require modulation of dopamine D3 receptors, for example psychoses such as schizophrenia. A preferred use for D3 antagonists according to the present invention is in the treatment of psychoses such as schizophrenia.
A preferred use for D3 agonists according to the present invention is in the treatment of dyskinetic disorders such as Parkinson's disease.
For use in medicine, the compounds of the present invention are usually administered as a standard pharmaceutical composition. The present invention therefore provides in a further aspect pharmaceutical compositions comprising a novel compound of formula (I) or a physiologically acceptable salt thereof and a physiologically acceptable carrier.
The compounds of formula (I) may be administered by any convenient method, for example by oral, parenteral, buccal, sublingual, nasal, rectal or transdermal administration and the pharmaceutical compositions adapted accordingly.
The compounds of formula (I) and their physiologically acceptable salts which are active when given orally can be formulated as liquids or solids, for example syrups, suspensions or emulsions, tablets, capsules and lozenges. A liquid formulation will generally consist of a suspension or solution of the compound or physiologically acceptable salt in a suitable liquid carrier(s) for example an aqueous solvent such as water, ethanol or glycerine, or a non-aqueous solvent, such as polyethylene glycol or an oil. The formulation may also contain a suspending agent, preservative, flavouring or colouring agent. A composition in the form of a tablet can be prepared using any suitable pharmaceutical carrier(s) routinely used for preparing solid formulations. Examples of such carriers include magnesium stearate, starch, lactose, sucrose and cellulose.
A composition in the form of a capsule can be prepared using routine encapsulation procedures. For example, pellets containing the active ingredient can be prepared using standard carriers and then filled into a hard gelatin capsule; alternatively, a dispersion or suspension can be prepared using any suitable pharmaceutical carrier(s), for example aqueous gums, celluloses, silicates or oils and the dispersion or suspension then filled into a soft gelatin capsule.
Typical parenteral compositions consist of a solution or suspension of the compound or physiologically acceptable salt in a sterile aqueous carrier or parenterally acceptable oil, for example polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil. Alternatively, the solution can be lyophilised and then reconstituted with a suitable solvent just prior to administration.
Compositions for nasal administration may conveniently be formulated as aerosols, drops, gels and. powders. Aerosol formulations typically comprise a solution or fine suspension of the active substance in a physiologically acceptable aqueous or non- aqueous solvent and are usually presented in single or multidose quantities in sterile form in a sealed container, which can take the form of a cartridge or refill for use with an atomising device. Alternatively the sealed container may be a unitary dispensing device such as a single dose nasal inhaler or an aerosol dispenser fitted with a metering valve which is intended for disposal once the contents of the container have been exhausted. Where the dosage form comprises an aerosol dispenser, it will contain a propellant which can be a compressed gas such as compressed air or an organic propellant such as a fluoro- chlorohydrocarbon. 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 physiologically acceptable salt thereof calculated as the free base. The physiologically 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 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 and 25 mg of the compound of the formula (I) or a physiologically acceptable salt thereof calculated as the 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 Test Methods
The ability of the compounds to bind selectively to human D3 dopamine receptors can be demonstrated by measuring their binding to cloned receptors. The inhibition constants (Kj) of test compounds for displacement of [^5rj iodosulpride binding to human D3 dopamine receptors expressed in CHO cells were determined as follows. The cell lines were shown to be free from bacterial, fungal and mycoplasmal contaminants, and stocks of each were stored frozen in liquid nitrogen. Cultures were grown as monolayers or in suspension in standard cell culture media. Cells were recovered by scraping (from monolayers) or by centrifugation (from suspension cultures), and were washed two or three times by suspension in phosphate buffered saline followed by collection by centrifugation. Cell pellets were stored frozen at -40°C. Crude cell membranes were prepared by homogenisation followed by high-speed centrifugation, and characterisation of cloned receptors achieved by radioligand binding. Preparation of CHO cell membranes
Cell pellets were gently thawed at room temperature, and resuspended in about 20 volumes of ice-cold 50 mM Tris salts (pH 7.4 @ 37°C), 20mM EDTA, 0.2 M sucrose. The suspension was homogenised using an Ultra-Turrax at full speed for 15 sec. The homogenate was centrifuged at 18,000 r.p.m for 20 min at 4°C in a Sorvall RC5C centrifuge. The membrane pellet was resuspended in ice-cold 50 mM Tris salts (pH 7.4 @ 37°C), using an Ultra-Turrax, and recentrifuged at 18,000 r.p.m for 15 min at 4°C in a Sorvall RC5C. The membranes were washed two more times with ice-cold 50 mM Tris salts (pH 7.4 @ 37°C). The final pellet was resuspended in 50 mM Tris salts (pH 7.4 @ 37°C), and the protein content determined using bovine serum albumin as a standard (Bradford, M. M. (1976) Anal. Biochem. 72, 248-254).
Binding experiments on cloned dopamine receptors Crude cell membranes were incubated with 0.1 nM [^5rj iodosulpride (-2000 Ci/mmol; Amersham, U. K.), and the test compound in a buffer containing 50 mM Tris salts (pH
7.4 @ 37°C), 120 mM NaCl, 5 mM KCl, 2 mM CaCl2, 1 mM MgCl2, 0.1% (w/v) bovine serum albumin, in a total volume of 1 ml for 30 min at 37°C. Following incubation, samples were filtered using a Brandel Cell Harvester, and washed three times with ice- cold 50 mM Tris salts (pH 7.4 @ 37°C), 120 mM NaCl, 5 mM KCl, 2 mM CaCl2, 1 mM MgCl2. The radioactivity on the filters was measured using a Cobra gamma counter (Canberra Packard). Non-specific binding was defined as the radioligand binding remaining after incubation in the presence of 100 uM iodosulpride. For competition curves, 14 concentrations (half-log dilutions) of competing cold drug were used. Competition curves were analysed simultaneously whenever possible using non-linear least-squares fitting procedures, capable of fitting one, two or three site models.
Compounds of Examples tested according to this method had pKi values in the range 7.0 -
8.5 at the human cloned dopamine D3 receptor.
Functional Activity at cloned dopamine receptors
The functional activity of compounds at human D2 and human D3 receptors (ie agonism or antagonism) may be determined using a Cytosensor Microphysiometer (McConnell HM et al Science 1992 257 1906-1912) In Microphysiometer experiments, cells (hD2_CHO or hD3_CHO) were seeded into 12mm Transwell inserts (Costar) at 300000 cells/cup in foetal calf serum (FCS)-containing medium. The cells were incubated for 6h at 37°C in 5%CO2, before changing to FCS-free medium. After a further 16-18h, cups were loaded into the sensor chambers of the Cytosensor Microphysiometer (Molecular Devices) and the chambers perfused with running medium (bicarbonate-free Dulbecco's modified Eagles medium containing 2 mM glutamine and 44 mM NaCl) at a flow rate of 100 ul/min. Each pump cycle lasted 90s. The pump was on for the first 60s and the acidification rate determined between 68 and 88s, using the Cytosoft programme. Test compounds were diluted in running medium. In experiments to determine agonist activity, cells were exposed (4.5 min for hD2, 7.5 min for hD3) to increasing concentrations of putative agonist at half hour intervals. Seven concentrations of the putative agonist were used. Peak acidification rate to each putative agonist concentration was determined and concentration-response curves fitted using Robofit [Tilford, N.S., Bowen, W.P. & Baxter, G.S. Br. J. Pharmacol. (1995) in press]. In experiments to determine antagonist potency, cells were treated at 30 min intervals with five pulses of a submaximal concentration of quinpirole (100 nM for hD2 cells, 30 nM for hD3 cells), before exposure to the lowest concentration of putative antagonist. At the end of the next 30 min interval, cells were pulsed again with quinpirole (in the continued presence of the antagonist) before exposure to the next highest antagonist concentration. In all, five concentrations of antagonist were used in each experiment. Peak acidification rate to each agonist concentration was determined and concentration-inhibition curves fitted using Robofit.
Pharmaceutical Formulations
The following represent typical pharmaceutical formulations according to the present invention, which may be prepared using standard methods.
IV Infusion
Compound of formula (I) 1-40 mg
Buffer to pH ca 7
Solvent/complexing agent to 100 ml
Bolus Injection
Compound of formula (I) 1-40 mg
Buffer to pH ca 7
Co-Solvent to 5 ml
Buffer : Suitable buffers include citrate, phosphate, sodium hydroxide/hydrochloric acid.
Solven : Typically water but may also include cyclodextrins (1-100 mg) and co- solvents such as propylene glycol, polyethylene glycol and alcohol.
Tablet
Compound 1 - 40 mg Diluent Filler * 50 - 250 mg
Binder 5 - 25 mg
Disentegrant * 5 - 50 mg
Lubricant 1 - 5 mg
Cyclodextrin 1 - 100 mg
may also include cyclodextrins Diluent : e.g. Microcrystalline cellulose, lactose, starch
Binder : e.g. Polyvinylpyrrolidone, hydroxypropymethylcellulose
Disintegrant : e.g. Sodium starch glycollate, crospovidone
Lubricant : e.g. Magnesium stearate, sodium stearyl fumarate.
Oral Suspension
Compound 1 - 40 mg
Suspending Agent 0.1 - 10 mg
Diluent 20 - 60 mg Preservative 0.01 - 1.0 mg
Buffer to pH ca 5 - 8
Co-solvent 0 - 40 mg
Flavour 0.01 - 1.0 mg
Colourant 0.001 - 0.1 mg
Suspending agent :e.g. Xanthan gum, microcrystalline cellulose
Diluent : e.g. sorbitol solution, typically water
Preservative : e.g. sodium benzoate
Buffer : e.g. citrate Co-solvent : e.g. alcohol, propylene glycol, polyethylene glycol, cyclodextrin
The invention is further illustrated by the following non-limiting examples :
Description 1
7-Bromo-l,2,3,4-tetrahydroisoquinoline
A mixture of 7-bromo-2-trifluoroacetyl-l,2,3,4-tetrahydoisoquinoline (G.E. Stokker, Tetrahedron Letters 1996, 37, 5453) (43.4g, 0.14 mol), potassium carbonate (104.3g, 0.75 mol), methanol (IL) and water (150ml) was heated at reflux for lh, then cooled and evaporated in vacuo. Residue was partitioned between water (IL) and dichloromethane (4 x 200ml). Combined extracts were dried (Na.SO4) and evaporated in vacuo to give an oil which was dissolved in hexane. The mixture was filtered and the filtrate evaporated in vacuo to give the title compound as an oil (17.7g, 60%).
Η NMR (CDC13) 5: 1.77 (IH, br s), 2.73 (2H, t, J = 7 Hz), 3.13 (2H, t, J = 7 Hz), 3.98 (2H, s), 6.96 (IH, d, J = 9 Hz), 7.16 (IH, d, J = 2 Hz), 7.26 (IH, dd, J = 9, 2 Hz). The following compounds were prepared in a similar manner to Description 1
(a) 7-Cyano-l,2,3,4-tetrahydroisoquinoline
Mass spectrum (APT): Found 159 (MH+). C10HI0N2 requires 158.
Description 2 7-Cyano-2-trifluoroacetyl-l,2,3,4-tetrahydroisoquinoIine
A mixture of 7-bromo-2- trifluoroacetyl -1,2,3,4-tetrahydroisoquinoline (51.7 g, 0.168 mol), copper (I) cyanide (31.8 g, 0.35 mol) and N-methyl-2-pyrrolidinone (620 ml) was heated at reflux for 4h, cooled, then partitioned between dilute aqueous ammonia (1.5 L) and dichloromethane (5 x 300ml). The combined organic extracts were dried (Na.SO4) and evaporated in vacuo to give the title compound (42.6 g, 100 %) as an oil.
Mass spectrum (API): Found 253 (M-H)\ C12H9F3N2O requires 254.
Description 3
(±)--Sr«Λ5-2-((N-(te/ϊ-Butyloxycarbonyl)amino)methyl)cyclopropane-l- carboxaldehyde
To a solution of (±)-trans- 1 -((N-(tert-butyloxycarbonyl)amino)methyl)-2-((tert- butyldiphenylsilyloxy)methyl)cyclopropane [T. Morikawa et al, J. Org. Chem., 1994. 59, 97] (0.33g, 0.75 mmol) in dry THF (10ml) at 0°C, was added a 1M solution of tetra-H- butylammonium fluoride in THF (2.3ml, 2.3 mmol). The mixture was stirred at room temperature for 3 hours, then partitioned between diethyl ether (25ml) and water (25ml). Aqueous phase was further extracted with diethyl ether (25ml x 2) and the combined organic extracts were washed with brine (40ml), dried (Na2SO ) then evaporated in vacuo to give an oil. To a solution of oxalyl chloride (0.08g, 0.6 mmol) in dry dichloromethane (3ml) at -80°C under argon, was added dropwise a solution of dimethyl sulfoxide (0.09g, 1.2 mmol) in dichloromethane (0.5ml). The resulting mixture was stirred at -78°C for 0.75h, then a solution of the above oil in dry dichloromethane (3ml) was added. The mixture was stirred for lh then triethylamine (1ml) was added and the mixture warmed to room temperature. The mixture was partitioned between dichloromethane (100ml) and water (50ml). The organic layer was washed with water (30ml) and brine (30ml), then dried (Na2SO4) and evaporated in vacuo to give the title compound as an oil (0.12g, 98%) 1H NMR (CDCI3) δ: 1.07 (IH, m), 1.30 (IH, m), 1.45 (9H, s), 1.69 - 1.90 (2H, m), 2.95 - 3.30 (2H, m), 4.75 (IH, br s), 9.09 (IH, d, J = 5 Hz).
Description 4 (±)-irα w-l-(N-(-fe -ButyloxycarbonyI)amino)methyl-2-(2-(7-cyano-l,2,3,4- tetrahydro)isoquinolyI)methylcyclopropane
A mixture of (±)-trαn-.-2-((N-(tert-butyloxycarbonyl)amino)cyclopropane-l- carboxaldehyde (0.12g, 0.6 mmol), 7-cyano-l,2,3,4-tetrahydroisoquinoline (0.1 lg, 0.66 mmol) and sodium triacetoxyborohydride (0.19g, 0.9 mmol) in 1,2-dichloromethane (15ml) was allowed to stir at room temperature for 20h, then partitioned between dichloromethane (120ml) and saturated aqueous NaHCO3 (40ml). Organic phase was washed with saturated NaHCO3 (40ml), brine (40ml), dried (Na2SO ) and evaporated in vacuo to an oil. Chromatography on silica with ethylacetate-hexane 20 - 40% gradient elution gave the title compound as an amber oil (0.16g, 78%).
Mass spectrum (API+): Found 342 (MH+). C20H27N3O2 requires 341.
1H NMR (CDCI3) δ: 0.40 - 0.55 (2H, m), 0.85 - 0.91 (2H, m), 1.47 (9H, s), 2.34 - 2.60 (2H, m), 2.75 - 2.85 (2H, m), 2.90 - 3.00 (2H, m), 3.02 - 3.10 (2H, m), 3.55 - 3.80 (2H, m), 4.68 (IH, br s), 7.20 (IH, d, J = 8 Hz), 7.35 (IH, s), 7.40 (IH, d, J = 8 Hz).
The following compound was prepared in a similar manner to Description 4.
(a) i -α«5-2-(l-(4-(f-Butyloxycarbonyl)aminomethyl)cyclohexylmethyl)-7-cyano- 1 ,2,3,4- tetrahydroisoquinoline
Mass spectrum (APf): Found 384 (MH+). C23H33N3O2 requires 383.
Description 5
(±)-trα/w-l-Aminomethyl-2-(2-(7-cyano-l,2,3,4-tetrahydro)isoquinolyl)- methylcyclopropane
To a solution of (±)-trαrt-.-l-(N-(tert-butyloxycarbonyl)methyl-2-(2-(7-cyano- 1,2,3,4- tetrahydro)isoquinolyl)methylcyclopropane (0.16g, 0.47 mmol) in dry dichloromethane (10ml) at 0°C, was added trifluoroacetic acid (0.36ml). The mixture was stirred at 0°C for lh, then more trifluoroacetic acid (0.4ml) was added. The mixture was stirred at room temperature for 5h, then partitioned between dichloromethane (100ml) and saturated aqueous NaHCO3 (50ml). Organic phase was washed with brine (50ml), dried(Na2SO ) and evaporated in vacuo to give the title compound as an amber oil (O.lg, 89%).
Mass spectrum (API+): Found 242 (MH+). C15Hι9N3 requires 241.
1H NMR (CDC13) δ: 0.30 - 0.50 (2H, m), 0.70 - 0.90 (2H, m), 1.45 (2H, br s), 2.40 - 3.00 (8H, m), 3.68 (2H, s), 7.17 (IH, d, J = 8 Hz), 7.32 (IH, s), 7.37 (IH, d, J = 8 Hz).
The following compound was prepared in a similar manner to Description 5.
(a) ι ιw-2-(l-(4-Aminomethyl)cyclohexyImethyl)-7-cyano-l,2,3,4- tetrahydroisoquinoline
Mass spectrum (API+): Found 284 (MH+). Cι8H25N3 requires 283.
Description 6
6-Cyano-l,2,3,4-tetrahydroisoquinoIine
Prepared in a similar manner to that described in H.G. Selnick et al., Synthetic Communications 25 (20) 3255 (1995).
Mass spectrum (API+): Found 159 (MH+). Cι0Hι0N2 requires 158.
Description 7
4-(2-(7-Cyano-l,2,3,4-tetrahydro)isoquinolinyI)cyclohexanone
A mixture of 7-cyano-l,2,3,4-tetrahydroisoquinoline (2.37g, 15 mmol), 1,4-dioxaspiro- [4.5]decan-8-one (2.34g, 15 mmol) and sodium triacetoxyborohydride (4.73g, 22.5 mmol) in dichloroethane (50ml) was stirred at 20°C for 18h. Mixture was partitioned between saturated aqueous NaHCO3 (250ml) and dichloromethane (3 x 50ml) and the combined organic extracts dried (Na2SO4) and evaporated in vacuo to give an oil. Chromatography on silica with 25 - 100% ethyl acetate - hexane gradient elution gave a solid (3.53g). The latter was dissolved in water containing concentrated H2SO4 (1.35g, 13.5 mmol) and heated at 65°C for 18h. Mixture was cooled, then partitioned between saturated aqueous NaHCO3 (300ml) and dichloromethane (3 x 100ml). Combined organic extracts were dried (Na2SO4) and evaporated in vacuo to give the title compound (3.14g, 82%) as an oil.
Mass spectrum (APf ): Found 255 (MH+). Ci6Hι8N2O requires 254.
The following compound was prepared in a similar manner to Description 7
(a) 4-(2-(6-Cyano-l,2,3,4-tetrahydro)isoquinolyl)cyclohexanone
Mass spectrum (API+): Found 255 (MH+). eHisN∑O requires 254.
Description 8
cis- and trα»s-7-Cyano-2-(l-(4-trifluoroacetamido)cyclohexyl)-l,2,3,4- tetrahydroisoquinoline
A mixture of 4-(2-(6-cyano- 1,2,3,4- tetrahydro)isoquinolyl)cyclohexanone 2.90g, 11.4 mmol), ammonium acetate (8.7g, 0.11 mol) and sodium triacetoxyborohydride (16.6g, 79.4 mmol) in ethanol (250ml) was heated at reflux for 3h, cooled then evaporated in vacuo. Residue was partitioned between saturated aqueous NaHCO3 (300ml) and dichloromethane (3 x 100ml). Combined organic extracts were dried (Na2SO4) and evaporated in vacuo to give an oil (2.78g). A mixture of the latter with triethylamine (2ml; 14.3 mmol) in dichloromethane (100ml) at 0°C was treated dropwise with trifluoroacetic anhydride (1.9ml, 13.5 mmol). Resulting solution was stirred at 20°C for 4h, then partitioned between saturated aqueous NaHCO3 (300ml) and dichloromethane (3 x 100 ml). Combined organic extracts were dried (Na2SO ) and evaporated in vacuo to give an oil. Chromatography on silica with 10 - 100% ethyl acetate - hexane gradient elution gave, as the first-eluting component, the cw-isomer (1.58g, 38%),
1H NMR (CDC13) δ: 1.50 - 2.00 (8H, m), 2.48 (IH, m), 2.87 (2H, m), 2.98 (2H, m), 3.78 (2H, s), 4.09 (IH, m), 6.29 (IH, m), 7.22 (IH, ), 7.29 - 7.49 (2H, m),
and, as the second-eluting component, the tran-.-isomer (0.63g, 15%)
Η NMR (CDC13) δ: 1.22 - 1.44 (2H, m), 1.45 - 1.64 (2H, m), 2.05 (2H, m), 2.17 (2H, m), 2.55 (IH, «, J = 9, 2 Hz), 2.84 (2H, m), 2.95 (2H, m), 3.78 (2H, s), 3.80 (IH, m), 6.15 (IH, m), 7.19 (IH, d, J = 8 Hz), 7.32 (IH, d, J = 1 Hz), 7.40 (IH, dd, J = 8, 1 Hz). The following compounds were prepared in a similar manner to Description 8.
(a) cis -6-Cyano-2-( l-(4-trifluoroacetamido)cyclohexyl)- 1 ,2,3,4- tetrahydroisoquinoline
1H NMR (CDC13) δ: 1.65 - 1.95 (8H, m), 2.47 (IH, m), 2.83 (2H, m), 1.92 (2H, m), 3.77 (2H, s), 4.05 (IH, m), 6.28 (IH, br s), 7.13 (IH, d, J = 8 Hz), 7.39 (2H, m).
(b) ira/w -6-Cyano-2-(l-(4-trifIuoroacetamido)cyclohexyl)- 1,2,3,4- tetrahydroisoquinoline
1H NMR (CDCI3) δ: 1.24 - 1.62 (4H, m), 2.03 (2H, m), 2.15 (2H, m), 2.53 (IH, tt, J = 9, 2 Hz), 2.82 (2H, m), 1.86 (2H, m), 3.76 (IH, m), 3.80 (2H, s), 6.12 (IH, m), 7.09 (IH, d, J = 8 Hz), 7.35 (2H, m).
Description 9
j-- ι-f-2-(l-(4-Amino)cyclohexyl)-7-cyano-1^2,3,4- tetrahydroisoquinoline
A mixture of trαn-.-7-cyano-2-(l-(4-trifluoroacetamido)cyclohexyl)- 1 ,2,3,4- tetrahydroisoquinoline (0.68g, 1.9 mmol), methanol (30ml), water (3.5ml) and anhydrous potassium carbonate (1.3g, 9.6 mmol) was heated at reflux for 3h, cooled then evaporated in vacuo. Residue was partitioned between saturated aqueous K2CO3 (50ml) and dichloromethane (3 x 50 ml), and the combined extracts were dried (Na2SO4) and evaporated in vacuo to give the title compound (0.48g, 96%) as an oil.
Mass spectrum (API+): Found 256 (MH+). Cι6H21N3 requires 255.
The following compounds were prepared in a similar manner to Description 9.
(a) /r «-.-2-(l-(4-Amino)cyclohexyl)-6-cyano-1^2,3,4- tetrahydroisoquinoline
Mass spectrum (APf ): Found 256 (MH+). Ci6H2ιN3 requires 255.
(b) /rα«5-2-(l-(4-(2-Amino)ethyl)cyclohexyl)-7-cyano-l,2,3,4-tetrahydroisoquinoline
Mass spectrum (API+): Found 284 (MH+). C,8H25N3 requires 283. Description 10
4-(2-Trifluoroacetamidoethyl)cyclohexanone
To a mixture of 8-(2-hydroxyethyl)- 1 ,4-dioxaspiro[4.5]decane (15.5g, 83 mmol) and triethylamine (15.2ml; 0.108 mol) in dichloromethane (300ml) under argon at 0°C was added dropwise a solution of methylsulfonyl chloride (7.4ml; 96 mmol) in dichloromethane (10ml). Resulting solution was stirred at 20°C for 2h, then partitioned between saturated aqueous NaHCO3 (500ml) and dichloromethane (3 x 50ml). Combined organic extracts were dried (Na2SO4) and evaporated in vacuo to give an oil (21.8g). The latter was dissolved in toluene (50ml) and added to a solution of trifluoroacetarnide anion prepared by portionwise addition of trifluoroacetarnide (7.9 lg, 70 mmol) to a stirred suspension of sodium hydride (60%; 2.6g, 65 mmol) in dimethylformamide (50ml). The resulting mixture was stirred at 20°C for 18h, then evaporated in vacuo. Residue was partitioned between ether (500ml) and water (350ml). Organic phase was washed with water(2 x
200ml), dried (Na2SO4) and evaporated in vacuo to give an oil (15g). Chromatography on silica with 10 - 100% ethyl acetate - hexane gradient elution gave an oil (4.96g). A solution of the latter in tetrahydrofuran (200ml) was treated with water (400ml) and concentrated H2SO (50 drops), then heated at reflux for 3h. The mixture was cooled, concentrated in vacuo to 200ml, then extracted with dichloromethane (3 x 200ml). Combined extracts were dried (Na2SO4) and evaporated in vacuo to give the title compound (3.72g, 19%) as a colourless solid.
Mass spectrum (APT): Found 236 (M-H)". Cι0Hι4F3NO2 requires 237.
Description 11
cis- and trα»-f-7-Cyano-2-(l-(4-(2-trifluoroacetamido)ethyl)cyclohexyl)-l^,3,4- tetrahydroisoquinoline
A mixture of 7-cyano-l,2,3,4-tetrahydroisoquinoline (1.5g, 9.5 mmol), 4-(2- trifluoroacetamidoethyl)cyclohexane (2.25g, 9.5 mmol) and sodium triacetoxyborohydride (3.0g, 14.3 mmol) in dichloromethane (100ml) was treated with glacial acetic acid (10 drops) and stirred at 20°C for 18h. Mixture was partitioned between saturated aqueous NaHCO3 (300ml) and dichloromethane (4 x 50ml), and the combined extracts were dried (Na2SO4) and evaporated in vacuo to give an oil (4.0g). Chromatography on silica with 10 - 100% ethyl acetate - hexane gradient elution gave, as the first-eluting component, the cw-isomer (1.98g, 55%)
Η NMR (CDC13) δ: 1.44 - 1.85 (11H, m), 2.45 (IH, m), 2.81 (2H, m), 2.92 (2H, m), 3.40 (2H, m), 3.72 (2H, s), 6.31 (IH, br s), 7.20 (IH, d, J = 8 Hz), 7.35 (IH, d, J = 1 Hz), 7.40 (IH, dd, J = 8, 1 Hz), and, as the second-eluting component, the trα w-isomer (0.92g, 26%).
1H NMR (CDClj) δ: 0.95 - 1.17 (2H, m), 1.20 - 1.68 (5H, m), 1.84 - 2.07 (4H, m), 2.50 (IH, tt, J = 9, 2 Hz), 2.85 (2H, m), 2.93 (2H, m), 3.42 (2H, q, J = 7 Hz), 3.78 (2H, s), 6.32 (IH, br s), 7.19 (IH, d, J = 8 Hz), 7.33 (IH, d, J = 1 Hz), 7.40 (IH, d, J = 8, 1 Hz).
Description 12
tjrfl/i-.-4-(/-Butyloxycarbonyl)aminomethylcycIohexanecarboxaldehyde
A mixture of tr n5,-4-aminomethylcyclohexanecarboxylic acid (20g, 0.127 mol), methanol (250ml) and concentrated sulfuric acid (7.5ml; 0.14 mmol) was heated at reflux for 5h then evaporated in vacuo to give a solid. The latter was mixed with dichloromethane (250ml), triethylamine (64.5ml, 0.463 mol) and di-t-butyl dicarbonate (34g, 0.155 mol), and the resulting solution stirred at 20°C for 18h. Mixture was partitioned between saturated aqueous NaHCO3 (IL) and dichloromethane (3 x 200ml), and the combined organic extracts were dried (Na2SO4) and evaporated in vacuo to give a solid (36.6g). The latter was dissolved in toluene (500ml) and cooled to -78°C under argon. A solution of diisobutylaluminium hydride in toluene (1M; 270ml) was added dropwise over 0.75h, and stirring at -78°C was continued for lh. Methanol (54.5ml) was added dropwise over 0.5h and mixture stirred at -70°C for 0.25h. The resulting solution was then poured into saturated aqueous potassium sodium tartrate (IL), and the mixture stirred vigorously for 3h. The resultant was extracted with ether (3 x 200ml) and the combined organic extracts were dried (Na2SO4) and evaporated in vacuo to give an oil (35.5g). Chromatography on silica with 10 - 100% ethyl acetate - hexane gradient elution gave the title compound (20.9g, 64%) as an oil.
1H NMR (CDCI3) δ: 0.92 - 1.09 (2H, m), 1.18 - 1.50 (3H, m), 1.46 (9H, s), 1.89 (2H, m), 2.04 (2H, m), 2.19 (IH, m), 3.00 (2H, t, J = 7 Hz), 4.60 (IH, br s), 9.61 (IH, s).
Example 1
(±)-tr /w-l-((E)-3-(5-Indolyl)propenamido)methyl-2-(2-(7-cyano-l,2,3,4- tetrahydro)isoquinolyl)methylcyclopropane
A mixture of (±)-tr n-;-l-aminomethyl-2-(2-(7-cyano-l,2,3,4- tetrahydro)isoquinolyl)methylcyclopropane (O.lg, 0.4 mmol), (E)-3-(5-indolyl)propenoic acid (0.09g, 0.5 mmol) l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.13g) and 1-hydroxybenzotriazole (0.06g) in dimethylformamide (1ml) and dichloromethane (7ml) was shaken for 20h, then washed with water (7ml).
Chromatography of the organic phase on silica,eluting with ethyl acetate in hexane 20% - 100%, gave the title compound as a colourless solid (0.1 lg, 66%). Mass spectrum (API+): Found 411 (MH+). C26H26N4O requires 410.
1H NMR (CDC13) δ: 0.44 - 0.64 (2H, m), 0.90 - 1.00 (2H, m), 2.35 - 2.55 (2H, m), 2.75 - 3.00 (4H, m), 3.20 - 3.50 (2H, m), 3.69 (2H, s), 2.75 - 2.80 (IH, m), 6.35 (IH, d, J = 15 Hz), 6.57 (IH, m), 7.10 - 7.40 (6H, m), 7.70 - 7.85 (2H, m), 8.40 (IH, br s).
The following compounds were prepared in a similar manner to Example 1
(a) trα/w-(E)-6-Cyano-2-(l-(4-(3-(4-fluoro)phenylpropenoyI)amino)cycIohexyl)- 1,2,3,4-tetrahydroisoquinoline
Mass spectrum (API+): Found 404 (MH+). C25H26FN3O requires 403.
NMR (CDCI3) δ: 1.25 (2H, m), 1.42 - 1.64 (2H, m), 2.00 (2H, m), 2.19 (2H, m), 2.54 (IH, m), 2.85 (4H, m), 3.81 (2H, s), 3.90 (IH, m), 4.47 (IH, d, J = 8 Hz), 6.30 (IH, d, J = 16 Hz), 7.09 (3H, m), 7.34 - 7.55 (4H, m), 7.60 (IH, d, J = 16 Hz).
(b) trαn-.-(E)-7-Cyano-2-(l-(4-(3-phenylpropenoyI)amino)cyclohexyI)-l,2,3,4- tetrahydroisoquinoline
Mass spectrum (API+): Found 386 (MH+). C25H27N3O requires 385.
1H NMR (CDCI3) δ: 1.25 (2H, m), 1.44 - 1.66 (2H, m), 2.00 (2H, m), 2.16 (2H, m), 2.44 (IH, m), 2.81 (2H, m), 2.93 (2H, m), 3.76 (2H, m), 3.90 (IH, m), 5.45 (IH, d, J = 8 Hz), 6.35 (IH, d, J = 16 Hz), 7.19 (IH, d, J = 8 Hz), 7.34 (5H, m), 7.49 (2H, m), 7.62 (IH, d, J = 16 Hz).
(c) trα/w-7-Cyano-2-(l-(4-(2-(2-indolyl)carboxamido)ethyl)cyclohexyl)-l,2,3,4- tetrahydroisoquinoline
Mass spectrum (API*): Found 427 (MH+). C27H30N4O requires 426.
1H NMR (CDC13 + CD3OD) δ: 0.95 - 1.18 (2H, m), 1.25 - 1.48 (3H, m), 1.58 (2H, q, J = 7 Hz), 1.96 (4H, m), 2.50 (IH, m), 2.85 (2H, m), 2.94 (2H, m), 3.50 (2H, m), 3.79 (2H, s), 6.59 (IH, m), 6.89 (IH, s), 7.09 - 7.24 (2H, m), 7.29 (2H, m), 7.37 - 7.50 (2H, m), 7.65 (IH, d, J = 8 Hz), 9.84 (IH, br s).
(d) trα/ι-.-(E)-7-Cyano-2-(l-(4-(3-phenylpropenoyl)aminomethyl)cyclohexylmethyl)- 1,2,3,4- tetrahydroisoquinoline
Mass spectrum (API+): Found 414 (MH+). C27H3!N3O requires 413. 1H NMR (CDC13) δ: 0.78 - 1.15 (4H, m), 1.56 (2H, m), 1.86 (4H, m), 2.31 (2H, d, J = .7- Hz), 2.69 (2H, t, J = 6 Hz), 2.93 (2H, t, J = 6 Hz), 3.27 (2H, t, J = 7 Hz), 3.59 (2H, s), 5.74 (IH, m), 6.40 (IH, d, J = 16 Hz), 7.19 (IH, d, J = 8 Hz), 7.33 (IH, s), 7.38 (4H, m), 7.51 (2H, m), 7.64 (IH, d, J = 16 Hz).
(e) -jr /w-7-Cyano-2-(l-(4-(2-indolyI)carboxamidomethyl)cycIohexylmethyl)-l^,3,4- tetrahydroisoquinoline
Mass spectrum (API+): Found 427 (MH+). C27H30N4O requires 426.
1H NMR (CDC13 + CD3OD) δ: 0.85 - 1.17 (4H, m), 1.60 (2H, m), 1.90 (4H, m), 2.34 (2H, d, J = 7 Hz), 2.71 (2H, t, J = 6 Hz), 2.95 (2H, t, J = 6 Hz), 3.32 (2H, t, J = 7 Hz), 3.60 (2H, s), 6.75 (IH, m), 6.91 (IH, s), 7.07 - 7.36 (4H, m), 7.42 (2H, m), 7.64 (IH, d, J = 8 Hz), 9.95 (IH, br s).

Claims

Claims
A compound of formula (I):
Figure imgf000026_0001
Formula (I) wherein:
R! represents a substituent selected from: a hydrogen or halogen atom; a hydroxy, cyano, nitro, trifluoromethyl, trifluoromethoxy, trifluoromethanesulfonyloxy, pentafluoroethyl, C1-.4a.kyl, C ^alkoxy, arylC _4alkoxy, C _4alkylthio, C╬╣.4a]koxyC╬╣.4alkyl, C3-.6cycloalkylC .4alkoxy, Ci_4alkanoyl, C╬╣_4--lkoxycarbonyl, C 1 _4-tlkylsulphonyl, C 1 _4alkylsulphonyloxy , C 1.4-╬╣lkylsulphonylC 1 _4--lkyl, arylsulphonyl, arylsulphonyloxy, arylsulphonylC^alkyl, C╬╣_4alkylsulphonamido, C╬╣_ 4-╬╣lkylamido, Ci^alkylsulphonamidoC^alkyl, C _4--lkylamidoC _4alkyl, arylsulphonamido, arylcarboxamido, arylsulphonamidoC _4alkyl, arylcarboxamidoCi. 4alkyl, aroyl, aroylCi.4alkyl, or arylC╬╣_4--lkanoyl group; a group R3OCO(CH2)p, R CON(R4)(CH2)p, R R4NCO(CH2)p or R3R4NSO2(CH2)p where each of R3 and R4 independently represents a hydrogen atom or a C╬╣_4alkyl group or R3R4 forms part of a C3_.6azacyloa.kane or C3_6(2-oxo)azacycloalkane ring and p represents zero or an integer from 1 to 4; or a group Ar -Z, wherein Ar3 represents an optionally substituted phenyl ring or an optionally substituted 5- or 6- membered aromatic heterocyclic ring and Z represents a bond, O, S , or CH2; s represents an integer from zero to 2 and r represents an integer from 1 to 4, such that the sum of s + r is 1 to 4; t represents an integer from zero to 1 and u represents an integer from zero to 2; R2 represents a hydrogen atom or a C^alkyl group; q is 1 or 2;
A represents a group of the formula (a), (b) or (c):
ΓÇö Ar -Ar1ΓÇö YΓÇö Ar (a) (b) (c) wherein
Ar represents an optionally substituted phenyl ring or an optionally substituted 5- or 6- membered aromatic heterocyclic ring; or an optionally substituted bicyclic ring system;
Ar* and Ar^ each independently represent an optionally substituted phenyl ring or an optionally substituted 5- or 6- membered aromatic heterocyclic ring; and
Y represents a bond, -NHCO-, -CONH-, -CH2-, or -(CH2)mY1(CH )n-, wherein ╬│l represents O, S, SO , or CO and m and n each represent zero or 1 such that the sum of m+n is zero or 1; providing that when A represents a group of formula (a), any substituent present in Ar ortho to the carboxamide moiety is necessarily a hydrogen or methoxy group; and salts thereof.
2. A compound according to claim 1 wherein q represents 1.
3. A compound of formula (I) which is: (±)-trαn_?-l-((E)-3-(5-Indolyl)propenamido)methyl-2-(2-(7-cyano- 1,2,3,4- tetrahydro)isoquinolyl)methylcyclopropane tr-2n5-(E)-6-Cyano-2-(l-(4-(3-(4-fluoro)phenylpropenoyl)amino)cyclohexyl)-l,2,3,4- tetrahydroisoquinoline trαn5-(E)-7-Cyano-2-(l-(4-(3-phenylpropenoyl)amino)cyclohexyl)-l,2,3,4- tetrahydroisoquinoline trα«-f-7-Cyano-2-(l-(4-(2-(2-indolyl)carboxamido)ethyl)cyclohexyl)-l,2,3,4- tetrahydroisoquinoline trans -(E)-7-Cyano-2-( 1 -(4-(3-phenylpropenoyl)aminomethyl)cyclohexylmethyl)- 1 ,2,3,4- tetrahydroisoquinoline trfln5-7-Cyano-2-(l-(4-(2-indolyl)carboxamidomethyl)cyclohexylmethyl)-l,2,3,4- tetrahydroisoquinoline or a salt thereof.
4. A process for preparing compounds of formula (I) which process comprises (a) reacting a compound of formula (V):
Figure imgf000027_0001
Formula (V)
with a compound of formula (VI):
A-COX
Formula (VI)
wherein A is as hereinbefore defined and X is a halogen atom or the residue of an activated ester;
(b) to prepare a compound of formula (I) wherein R1 is Ar3-Z and Z is a bond, reacting a compound of formula (VII):
Figure imgf000028_0001
Formula (VII)
wherein one R*a represents a group W wherein W is a halogen atom or a trifluoromethylsulphonyloxy group, or W is a group M selected from a boron derivative or a metal function, and when q is 2 the other R a is R*; with a compound Ar -W , wherein W* is a halogen atom or a trifluoromethylsulphonyloxy group when W is a group M or W* is a group M when W is a halogen atom or a trifluoromethylsulphonyloxy group;
(c) to prepare a compound of formula (I) wherein R! is Ar3-Z and Z is O or S, reacting a compound of formula (VIII):
Figure imgf000028_0002
Formula (VIII) wherein one R*0 represents a group ZH and when q is 2 the other Rl┬░ represents R ; with a reagent serving to introduce the group Ar3;
(d) to prepare a compound of formula (I) where Y is a bond, reaction of a compound of formula (IX):
Figure imgf000028_0003
Formula (IX)
wherein Rl, R^, Ar^ and W are as hereinbefore defined, with a compound Ar^-W , wherein W is a halogen atom or a trifluoromethylsulphonyloxy group when W is a group M, or W1 is a group M when W is a halogen atom or a trifluoromethylsulphonyloxy group.
(e) interconversion of one compound of formula (I) to a different compound of formula (I);
(f) where appropriate, separation of enantiomers, diastereoisomers, or cis- and trans- isomers of compounds of formula (I), or intermediates thereto, by conventional methods; and optionally thereafter forming a salt of formula (I).
5. A pharmaceutical composition comprising a compound of formula (I) as , claimed in any of claims 1 to 3 or a physiologically acceptable salt thereof and a physiologically acceptable carrier therefor.
6. The use of a compound of formula (I) as claimed in any of claims 1 to 3 or a physiologically acceptable salt thereof in the manufacture of a medicament for the treatment of a condition which requires modulation of a dopamine receptor.
7. Use acording to claim 6 wherein the dopamine receptor is a dopamine D3 receptor.
8. Use according to claim 6 or claim 7 wherein a dopamine antagonist is required.
9. Use according to any of claims 6 to 8 wherein the condition is a psychotic condition.
10. A method of treating a condition which requires modulation of a dopamine receptor which comprises administering to a subject in need thereof an effective amount of a compound of formula (I) as claimed in claim 1 or a physiologically acceptable salt thereof.
PCT/EP1998/002584 1997-05-09 1998-04-28 Substituted tetrahydroisoquinoline derivatives as modulators of dopamine d3 receptors WO1998051671A1 (en)

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US9493432B2 (en) 2013-10-15 2016-11-15 Takeda Pharmaceuticals Company Limited Cyclopentylbenzamide derivatives and their use for the treatment of psychotic and cognitive disorders
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