WO1999059974A1 - Tetraisoquinololine derivatives as modulators of dopamine d3 receptors - Google Patents

Tetraisoquinololine derivatives as modulators of dopamine d3 receptors Download PDF

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Publication number
WO1999059974A1
WO1999059974A1 PCT/EP1999/003371 EP9903371W WO9959974A1 WO 1999059974 A1 WO1999059974 A1 WO 1999059974A1 EP 9903371 W EP9903371 W EP 9903371W WO 9959974 A1 WO9959974 A1 WO 9959974A1
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Prior art keywords
cyano
cyclohexyl
tetrahydroisoquinoline
ethyl
formula
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PCT/EP1999/003371
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French (fr)
Inventor
Antonio Kuok Keong Vong
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Smithkline Beecham Plc
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Priority to CA002332316A priority Critical patent/CA2332316A1/en
Priority to AU42627/99A priority patent/AU4262799A/en
Priority to US09/700,775 priority patent/US6414154B1/en
Priority to JP2000549593A priority patent/JP2002515489A/en
Priority to EP99952090A priority patent/EP1086084A1/en
Publication of WO1999059974A1 publication Critical patent/WO1999059974A1/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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to novel tetrahydroisoquinoline derivatives, processes for their preparation, pharmaceutical compositions containing them and their use in therapy, as modulators of dopamine D3 receptors, in particular as antipsychotic agents.
  • 1S an optionally substituted thienyl or optionally substituted phenyl ring
  • R ⁇ , R 2 and R 3 are each inter alia hydrogen
  • X is inter alia (CH2) m NR'CO
  • m is 2-4
  • Ar is an optionally substituted heterocyclic ring or an optionally substituted phenyl ring.
  • the compounds are said to be useful as antiarrhythmic agents.
  • EPA 431 ,580 describes compounds of formula
  • R is OR 3 , NR 4 R 5 , or N(OR 4 )R 5 , R 4 and R 5 are inter alia hydrogen, lower alkyl, aroyl or heteroaroyl; m is zero, 1 or 2; R ⁇ is hydrogen, aryl or various heteroaryl groups; n is zero or 1-4; and R 2 is:
  • the compounds are said to be dopaminergic agents useful as antipsychotics, antihypertensives and also of use in the treatment of hyperprolactinaemia-related conditions and several central nervous system disorders.
  • WO 95/10513 describes benzothiophene derivatives and related compounds as estrogen agonists.
  • R! represents a substituent selected from: a hydrogen or halogen atom; a hydroxy, cyano, nitro, trifluoromethyl, trifluoromethoxy, trifluoromethanesulfonyloxy, pentafluoroethyl, C 1.4 alkyl, C ⁇ _4alkoxy, arylC ⁇ _4alkoxy, C ⁇ alkylthio, C ⁇ _4alkoxyC ⁇ _4alkyl, C3_6cycloalkylC ⁇ _4alkoxy, C ⁇ _4alkanoyl, Ci ⁇ alkoxycarbonyl, C ⁇ _4alkylsulfonyl, C ⁇ _4alkylsulfonyloxy, C ⁇ _4alkylsulfonylC ⁇ _4alkyl, arylsulfonyl, arylsulfonyloxy, C ⁇ _4alkylamido, C 1 _4alkylsulfona
  • R 3 alkyl, or arylC ⁇ _4alkanoyl group a group R 3 OCO(CH 2 )p, R 3 CON(R 4 )(CH 2 ) p , R R 4 NCO(CH 2 ) p or R 3 R 4 NSO 2 (CH 2 ) p where each of R 3 and R 4 independently represents a hydrogen atom or a C1 _4alkyl group or R 3 R 4 forms part of a C3.
  • R 2 represents a hydrogen atom or a C ⁇ _4alkyl group; q is 1 or 2;
  • A represents a group of formula
  • r and s independently represent an integer from zero to 3 such that the sum of r and s is equal to an integer from 1 to 4;
  • V represents a bond, O or S;
  • 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; and salts thereof.
  • 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- butyl, and the like.
  • R 1 represents an arylCi ⁇ alkoxy, arylsulfonyl, arylsulfonyloxy, arylsulfonylC 1 -4alkyl, arylsulfonamido, arylcarboxamido, arylsulfonamidoC 1 _4alkyl, arylcarboxamidoC ⁇ _4alkyl, aroyl, aroylCi ⁇ alkyl, or arylC ⁇ alkanoyl 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, C ⁇ alkyl, C ⁇ alkylamino, Ci ⁇ dialkylamino, Ci ⁇ alkylamido, Ci .
  • R5 and R ⁇ independently represents a hydrogen atom or C 1.4 alkyl group.
  • a halogen atom present in the compounds of formula (I) may be fluorine, chlorine, bromine or iodine.
  • the substituents R! may be the same or different.
  • An optionally substituted 5- or 6-membered heterocyclic aromatic ring as defined for either of the groups Ar or Ar ⁇ 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, isoxazolyl, isothiazolyl, 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 ⁇ - indoly
  • the group Ar or Ar ⁇ may be independently optionally substituted by one or more substituents selected from: a hydrogen or halogen atom, or a hydroxy, oxo, cyano, nitro, C1.4a.kyl, C ⁇ _4alkoxy, C ⁇ _4alkylenedioxy, C ⁇ _4alkanoyl, Cj ⁇ alkylsulfonyl, C ⁇ alkylsulfinyl, C1_4alky.tl.io, R 7 SO 2 N(R 8 )-, R 7 R 8 NSO 2 -, R 7 R 8 N-, R 7 R 8 NCO-, or R 7 CON(R 8 )- group wherein each of 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.
  • substituents selected from: a hydrogen or halogen atom, or a hydroxy, oxo, cyano, nitro, C1.4
  • Ar may be optionally substituted by one or more 5- or 6-membered heterocyclic rings, as defined above, optionally substituted by a C1 _ 2 alkyl or R 7 R 8 N- group; wherein R 7 and R 8 are as defined above.
  • 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, sulfuric, nitric or phosphoric acid; and organic acids eg. succinic, maleic, acetic, fumaric, citric, tartaric, benzoic, p-toluenesulfonic, methanesulfonic or naphthalenesulfonic 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.
  • 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.
  • the compounds of formula (I) can exist in the form of cis- and trans- isomers with respect to the configuration at the cyclohexyl ring.
  • Preferably the compounds of the invention are in the trans configuration with respect to the cyclohexyl ring.
  • R! represents a substituent selected from: a halogen atom, methyl, cyano, trifluoromethyl, pentafluoroethyl, or trifluoromethoxy group.
  • a cyano group for example in the 6- or 7-position of the tetrahydroisoquinoline ring, is especially preferred.
  • q is 1.
  • R2 is preferably a hydrogen atom.
  • r is 1, v represents a bond and s is zero.
  • Ar is preferably a substituted phenyl group.
  • 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 :- tr ⁇ ns-6-Cyano-2-(2-(l-(4-phenylacetamido)cyclohexyl)ethyl)- 1,2,3,4- tetrahydroisoquinoline tr n -6-Cyano-2-(2-(l-(4-(2-naphthyl)acetamido)cyclohexyl)ethyl)-l,2,3,4- tetrahydroisoquinoline tr ⁇ s-6-Cyano-2-(2-( 1 -(4-(2-fluorophenyl)acetamido)cyclohexyl)ethyl)- 1 ,2,3,4- tetrahydroisoquinoline tr ⁇ ns-6-Cyano-2-(2-( 1 -(4-(3-fluorophenyl)acetamido)cyclohexyl)ethyl)
  • These compounds may be in the form of their free base or physiologically acceptable salts thereof, particularly the monohydrochloride or monomesylate salts.
  • the present invention also provides a process for preparing compounds of formula (I) which process comprises :
  • A is as hereinbefore defined and X is a halogen atom or the residue of an activated ester;
  • R and A are as hereinbefore defined and one R a represents a group W wherein W is a halogen atom or a trifluoromethylsulfonyloxy group, or W is a group M selected from a boron derivative e.g. a boronic acid function B(OH) 2 or a metal function such as trialkylstannyl e.g.
  • R and A are as hereinbefore defined and one Rl° represents a group ZH and when q is 2 the other R ⁇ 5 represents Rl ; with a reagent serving to introduce the group Ar 1 ;
  • Process (a) may be effected using conventional methods for the formation of an amide bond.
  • X is the residue of an activated ester this may be formed with e.g. a carbodiimide such as l-ethyl-3-(3-dimethylaminopropyl)carbodiimide.
  • the reaction may be carried out in a solvent such as dichloromethane.
  • Reaction of a compound of formula (IV) with Ar w may be effected in the presence of a transition metal eg palladium catalyst such as bis- triphenylphosphinepalladium dichloride or tetrafcis-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 sulfonyloxy group such as trifluoromethylsulfonyloxy; and Wl is preferably a goup M, such as trialkylstannyl or B(OH) 2 .
  • the reagent serving to introduce the group Arl is preferably a compound of formula Arl-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.
  • a compound of formula (VI) may itself be prepared by reacting a compound of formula (VII):
  • 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 or dichloroethane.
  • the individual cis- and trans- isomers of a compound of formula (II) may be prepared starting from cis- or trans- 4-amino-cyclohexaneacetic acid (T.P. Johnson, et al, J. Med. Chem., 1997, (20), 279-290) followed by functional group interchange and/or protection using methods well known in the art, to give the individual cis- or trans- isomers of a compound of formula (DC):
  • R2 is as hereinbefore defined, and P is a protecting group, for example trifluoroacetyl or tert-butoxycarbonyl.
  • P is a protecting group, for example trifluoroacetyl or tert-butoxycarbonyl.
  • Compounds of formula (TV) or (V) may be prepared by processes analogous to (a), (b) and (c) described above.
  • Compounds Ar ⁇ Wl and Ar Hal are commercially available or may be prepared by standard methods.
  • Compounds of formula (VII) are known in the literature or may be prepared by known methods.
  • the compound of formula (VIE) is likewise known in the literature.
  • 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. Furthermore, they could have utility as adjunct therapy in Parkinsons Disease, particularly with compounds such as L-DOPA and possibly dopaminergic agonists, to reduce the side effects experienced with these treatments on long term use (eg see Schwartz et al., Brain Res.
  • D3 antagonists could also have utility for the treatment of substance abuse where it has been suggested that D3 receptors are involved (eg see Levant, 1997, Pharmacol. Rev., 49, 231-252)
  • 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.
  • 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.
  • 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.
  • 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 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 (Ki) of test compounds for displacement of [ ⁇ 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.
  • 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).
  • the functional activity of compounds at human D 2 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 hD ⁇ CHO or hE>3_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 hD 2 , 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 hD 2 cells, 30 nM for I1D3 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.
  • compositions represent typical pharmaceutical formulations according to the present invention, which may be prepared using standard methods.
  • Buffer Suitable buffers include citrate, phosphate, sodium hydroxide/hydrochloric acid.
  • Solvent Typically water but may also include cyclodextrins (1-100 mg) and co- solvents such as propylene glycol, polyethylene glycol and alcohol.
  • Diluent e.g. Microcrystalline cellulose, lactose, starch Binder : e.g. Poly vinylpyrrolidone, 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
  • Preservative e.g. sodium benzoate
  • Buffer e.g. citrate
  • Co-solvent e.g. alcohol, propylene glycol, polyethylene glycol, cyclodextrin
  • 6-Cyano-l,2,3,4-tetrahydroisoquinoline Prepared in a similar manner to that described in H.G. Selnick et al., Synthetic Communications 25 (20) 3255 (1995).

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, C1-4alkoxyC1-4alkyl, C3-6cycloalkylC1-4alkoxy, C1-4alkanoyl, C1-4alkoxycarbonyl, C1-4alkylsulfonyl, C1-4alkylsulfonyloxy, C1-4alkylsulfonylC1-4alkyl, arylsulfonyl, arylsulfonyloxy, arylsulfonylC1-4alkyl, C1-4alkylsulfonamido, C1-4alkylamido, C1-4alkylsulfonamidoC1-4alkyl, C1-4alkylamidoC1-4alkyl, arylsulfonamido, arylcarboxamido, arylsulfonamidoC1-4alkyl, 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?3R4NSO¿2(CH2)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?azacyloalkane or C3-6(2-oxo)azacycloalkane ring and p represents zero or an integer from 1 to 4; or a group Ar?1¿-Z, wherein Ar1 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; R?2 represents a hydrogen atom or a C¿1-4?alkyl group; q is 1 or 2; A represents a group of formula -(CH2)r-V-(CH2)s-Ar wherein r and s independently represent an integer from zero to 3 such that the sum of r and s is equal to an integer from 1 to 4; V represents a bond, O or S; 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; and salts thereof. The compounds are useful for the treatment of conditions which require modulation of a dopamine receptor such as schizophrenia.

Description

TETRAISOQUINOLOLINE DERIVATIVES AS MODULATORS OF DOPAMINE D3 RECEPTORS
The present invention relates to novel tetrahydroisoquinoline derivatives, processes for their preparation, pharmaceutical compositions containing them and their 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:
Figure imgf000003_0001
wherein 1S an optionally substituted thienyl or optionally substituted phenyl ring; R^, R2 and R3 are each inter alia hydrogen; X is inter alia (CH2)mNR'CO; 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. EPA 431 ,580 describes compounds of formula
Figure imgf000003_0002
wherein R is OR3, NR4R5, or N(OR4)R5, R4 and R5 are inter alia hydrogen, lower alkyl, aroyl or heteroaroyl; m is zero, 1 or 2; R^ is hydrogen, aryl or various heteroaryl groups; n is zero or 1-4; and R2 is:
Figure imgf000003_0003
The compounds are said to be dopaminergic agents useful as antipsychotics, antihypertensives and also of use in the treatment of hyperprolactinaemia-related conditions and several central nervous system disorders. WO 95/10513 describes benzothiophene derivatives and related compounds as estrogen agonists.
We have now found a class of tetrahydroisoquinoline 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
Formula (I) wherein:
R! represents a substituent selected from: a hydrogen or halogen atom; a hydroxy, cyano, nitro, trifluoromethyl, trifluoromethoxy, trifluoromethanesulfonyloxy, pentafluoroethyl, C 1.4 alkyl, Cι_4alkoxy, arylCι_4alkoxy, C^alkylthio, Cι _4alkoxyCι _4alkyl, C3_6cycloalkylCι _4alkoxy, Cι _4alkanoyl, Ci^alkoxycarbonyl, Cι_4alkylsulfonyl, Cι_4alkylsulfonyloxy, Cι_4alkylsulfonylCι_4alkyl, arylsulfonyl, arylsulfonyloxy,
Figure imgf000004_0002
Cι _4alkylamido, C 1 _4alkylsulfonamidoC 1 _4alkyl, C \ _4alkylamidoC \ _4alkyl, arylsulfonamido, arylcarboxamido, arylsulfonamidoCι _4alkyl, arylcarboxamidoCi^alkyl, aroyl, aroylCi . 4alkyl, or arylCι _4alkanoyl group; a group R3OCO(CH2)p, R3CON(R4)(CH2)p, R R4NCO(CH2)p or R3R4NSO2(CH2)p where each of R3 and R4 independently represents a hydrogen atom or a C1 _4alkyl group or R3R4 forms part of a C3. gazacyloalkane or C3_6(2-oxo)azacycloalkane ring and p represents zero or an integer from 1 to 4; or a group Ar^-Z, wherein Ar 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 C\ _4alkyl group; q is 1 or 2;
A represents a group of formula
-(CH2)r-V-(CH2)s-Ar
wherein
r and s independently represent an integer from zero to 3 such that the sum of r and s is equal to an integer from 1 to 4; V represents a bond, O or S; 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; 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- butyl, and the like.
When R1 represents an arylCi ^alkoxy, arylsulfonyl, arylsulfonyloxy, arylsulfonylC 1 -4alkyl, arylsulfonamido, arylcarboxamido, arylsulfonamidoC 1 _4alkyl, arylcarboxamidoCι_4alkyl, aroyl, aroylCi^alkyl, or arylC^alkanoyl 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 R an aryl moiety may be optionally substituted by one or more substituents selected from hydrogen, halogen, amino, cyano, C^alkyl, C^alkylamino, Ci ^dialkylamino, Ci^alkylamido, Ci .
4alkanoyl, or R R6NCO where each of R5 and R^ independently represents a hydrogen atom or C 1.4 alkyl 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 either of the groups Ar or Ar^ 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, isoxazolyl, isothiazolyl, 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 group Ar or Ar^ may be independently optionally substituted by one or more substituents selected from: a hydrogen or halogen atom, or a hydroxy, oxo, cyano, nitro, C1.4a.kyl, Cι _4alkoxy, Cι_4alkylenedioxy, Cι_4alkanoyl, Cj^alkylsulfonyl, C^alkylsulfinyl, C1_4alky.tl.io, R7SO2N(R8)-, R7R8NSO2-, R7R8N-, R7R8NCO-, 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 may be optionally substituted by one or more 5- or 6-membered heterocyclic rings, as defined above, optionally substituted by a C1 _2 alkyl or R7R8N- group; wherein R7 and R8 are as defined above. In the group 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, sulfuric, nitric or phosphoric acid; and organic acids eg. succinic, maleic, acetic, fumaric, citric, tartaric, benzoic, p-toluenesulfonic, methanesulfonic or naphthalenesulfonic 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. The compounds of formula (I) can exist in the form of cis- and trans- isomers with respect to the configuration at the cyclohexyl ring. Preferably the compounds of the invention are in the trans configuration with respect to the cyclohexyl ring.
In compounds of formula (I), it is preferred that R! represents a substituent selected from: a halogen atom, methyl, cyano, trifluoromethyl, pentafluoroethyl, or trifluoromethoxy group. A cyano group, for example in the 6- or 7-position of the tetrahydroisoquinoline ring, is especially preferred. Preferably q is 1. R2 is preferably a hydrogen atom. Preferably r is 1, v represents a bond and s is zero. Ar is preferably a substituted phenyl group.
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 :- trαns-6-Cyano-2-(2-(l-(4-phenylacetamido)cyclohexyl)ethyl)- 1,2,3,4- tetrahydroisoquinoline tr n -6-Cyano-2-(2-(l-(4-(2-naphthyl)acetamido)cyclohexyl)ethyl)-l,2,3,4- tetrahydroisoquinoline tr< s-6-Cyano-2-(2-( 1 -(4-(2-fluorophenyl)acetamido)cyclohexyl)ethyl)- 1 ,2,3,4- tetrahydroisoquinoline trαns-6-Cyano-2-(2-( 1 -(4-(3-fluorophenyl)acetamido)cyclohexyl)ethyl)- 1 ,2,3,4- tetrahydroisoquinoline tr n5-6-Cyano-2-(2-(l-(4-(4-fluorophenyl)acetamido)cyclohexyl)ethyl)-l,2,3,4- tetrahydroisoquinoline trαn^-6-Cyano-2-(2-(l-(4-(3-cyanophenyl)acetamido)cyclohexyl)ethyl)-l,2,3,4- tetrahydroisoquinoline tran5-6-Cyano-2-(2-(l-(4-(4-cyanophenyl)acetamido)cyclohexyl)ethyl)-l,2,3,4- tetrahydroisoquinoline trαn -6-Cyano-2-(2-(l-(4-(3-phenyl)propionamido)cyclohexyl)ethyl)-l, 2,3,4- tetrahydroisoquinoline tran.s-6-Cyano-2-(2-( 1 -(4-(4-phenyl)phenylacetamido)cyclohexyl)-ethyl)- 1 ,2,3 ,4- tetrahydroisoquinoline trαns-6-Cyano-2-(2-( 1 -(4-(2-thienyl)acetamido)cyclohexyl)ethyl)- 1 ,2,3 ,4- tetrahydroisoquinoline trαns-6-Cyano-2-(2-( 1 -(4-(3-thienyl)acetamido)cyclohexyl)ethyl)- 1 ,2,3,4- tetrahydroisoquinoline trαn5-6-Cyano-2-(2-(l-(4-(3-indolyl)acetamido)cyclohexyl)ethyl)-l,2,3,4- tetrahydroisoquinoline tr n5 ,-6-Cyano-2-(2-(l-(4-(2,5-difluoro)phenylacetamido)cyclohexyl)-ethyl)- 1,2,3,4-tetrahydroisoquinoline tr n -6-Cyano-2-(2-(l-(4-(3,4-difluoro)phenylacetamido)cyclohexyl)-ethyl)-
1 ,2,3,4-tetrahydroisoquinoline tr n5-6-Cyano-2-(2-(l-(4-(2-pyridyl)acetamido)cyclohexyl)ethyl)-l,2,3,4- tetrahydroisoquinoline tran5-6-Cyano-2-(2-( 1 -(4-(4-bromo)phenylacetamido)cyclohexyl)-ethyl)- 1 ,2,3,4- tetrahydroisoquinoline tran5-6-Cyano-2-(2-(l-(4-(4-iodo)phenylacetamido)cyclohexyl)ethyl)- 1,2,3,4- tetrahydroisoquinoline tr «5-6-Cyano-2-(2-( 1 -(4-(3-bromo)phenylacetamido)cyclohexyl)-ethyl)- 1 ,2,3,4- tetrahydroisoquinoline trαn5-6-Cyano-2-(2-(l-(4-(2,4-difluoro)phenylacetamido)cyclohexyl)-ethyl)- 1 ,2,3 ,4-tetrahydroisoquinoline tran5-6-Cyano-2-(2-(l-(4-(3-trifluoromethyl)phenylacetamido)-cyclohexyl)ethyl)- 1 ,2,3,4-tetrahydroisoquinoline tran^-6-Cyano-2-(2-(l-(4-(4-t-butyl)phenylacetamido)cyclohexyl)-ethyl)- 1,2,3,4- tetrahydroisoquinoline trαn5-6-Cyano-2-(2-(l-(4-(3-benzo[b]thienyl)acetamido)cyclohexyl)-ethyl)- 1 ,2,3,4-tetrahydroisoquinoline tran5'-6-Cyano-2-(2-(l-(4-phenoxyacetamido)cyclohexyl)ethyl)-l,2,3,4- tetrahydroisoquinoline tran5-6-Cyano-2-(2-(l-(4-(4-phenyl)butyramido)cyclohexyl)ethyl)- 1,2,3,4- tetrahydroisoquinoline and tran5-6-Cyano-2-(2-(l-(4-(3-(4-fluoro)phenyl)propionamido)-cyclohexyl)ethyl)- 1 ,2,3,4-tetrahydroisoquinoline trøns-6-Cyano-2-(2-( 1 -(4-(4-quinolyl)acetamido)-cyclohexyl)ethyl)- 1 ,2,3 ,4- tetrahydroisoquinoline trαn5-6-Cyano-2-(2-(l-(4-(4-trifluoromethyl)phenylacetamido)-cyclohexyl)ethyl)- 1 ,2,3,4-tetrahydroisoquinoline tr n5-6-Cyano-2-(2-(l-(4-(3,5-difluoro)phenylacetamido)-cyclohexyl)ethyl)- 1,2,3,4-tetrahydroisoquinoline trαn5-6-Cyano-2-(2-(l-(4-(2-benzothiophenyl)acetamido)-cyclohexyl)ethyl)- 1 ,2,3,4-tetrahydroisoquinoline tran5-6-Cyano-2-(2-( 1 -(4-(2-furanyl)acetamido)-cyclohexyl)ethyl)- 1 ,2,3,4- tetrahydroisoquinoline t n5-6-Cyano-2-(2-(l-(4-(2-benzofuranyl)acetamido)-cyclohexyl)ethyl)-l, 2,3,4- tetrahydroisoquinoline
These compounds may be in the form of their free base or physiologically acceptable salts thereof, particularly the monohydrochloride or monomesylate salts.
The present invention also provides a process for preparing compounds of formula (I) which process comprises :
(a) reacting a compound of formula (II):
Figure imgf000008_0001
Formula (II)
wherein Rl, R2 and q are as hereinbefore defined, with a compound of formula (III):
A-COX
Formula (III)
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 Rl is Arl-Z and Z is a bond, reacting a compound of formula (IV):
Figure imgf000008_0002
Formula (IV)
wherein R and A are as hereinbefore defined and one R a represents a group W wherein W is a halogen atom or a trifluoromethylsulfonyloxy group, or W is a group M selected from a boron derivative e.g. a boronic acid function B(OH)2 or a metal function such as trialkylstannyl e.g. S11BU3, zinc halide or magnesium halide, and when q is 2 the other Rla is Rl ; with a compound Ar -Wl , wherein W is a halogen atom or a trifluoromethylsulfonyloxy group when W is a group M or Wl is a group M when W is a halogen atom or a trifluoromethylsulfonyloxy group;
(c) to prepare a compound of formula (I) wherein R is Ar -Z and Z is O or S, reacting a compound of formula (V):
Figure imgf000009_0001
Formula (V)
wherein R and A are as hereinbefore defined and one Rl° represents a group ZH and when q is 2 the other R^5 represents Rl ; with a reagent serving to introduce the group Ar1;
(d) 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 Rl from alkoxy (e.g.methoxy) to hydroxy, or (iii) conversion of Rl from hydroxy to sulfonyloxy, eg alkylsulfonyloxy or trifluoromethanesulfonyloxy;
(e) separation of cis- and trans- isomers of compounds of formula (I) by conventional methods, e.g. chromatography or crystallisation; and optionally thereafter forming a salt of formula (I).
Process (a) may be effected using conventional methods for the formation of an amide bond. When X is the residue of an activated ester this may be formed with e.g. a carbodiimide such as l-ethyl-3-(3-dimethylaminopropyl)carbodiimide. The reaction may be carried out in a solvent such as dichloromethane.
Reaction of a compound of formula (IV) with Ar w , according to process (b) may be effected in the presence of a transition metal eg palladium catalyst such as bis- triphenylphosphinepalladium dichloride or tetrafcis-triphenylphosphinepalladium (0). When 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. 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 sulfonyloxy group such as trifluoromethylsulfonyloxy; and Wl is preferably a goup M, such as trialkylstannyl or B(OH)2.
In process (c) the reagent serving to introduce the group Arl is preferably a compound of formula Arl-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 (d) may be effected using methods well known in the art. Compounds of formula (II) may be prepared by conversion of a compound of formula (VI), wherein R and q are as hereinbefore defined,
Figure imgf000010_0001
Formula (VI)
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 R2NH2 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. A compound of formula (VI) may itself be prepared by reacting a compound of formula (VII):
Figure imgf000010_0002
Formula (VII)
wherein Rl and q are as hereinbefore defined; with a compound of formula (VIII):
Figure imgf000010_0003
Formula (VIII)
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 ethanol or dichloroethane.
The individual cis- and trans- isomers of a compound of formula (II) may be prepared starting from cis- or trans- 4-amino-cyclohexaneacetic acid (T.P. Johnson, et al, J. Med. Chem., 1997, (20), 279-290) followed by functional group interchange and/or protection using methods well known in the art, to give the individual cis- or trans- isomers of a compound of formula (DC):
Figure imgf000011_0001
Formula (IX)
wherein R2 is as hereinbefore defined, and P is a protecting group, for example trifluoroacetyl or tert-butoxycarbonyl. Subsequent reaction of a compound of formula (IX) with a compound of formula (VII) in the presence of a reducing agent as described above followed by deprotection using standard methodology gives the individual isomers of a compound of formula (II) wherein R is as hereinbefore defined.
Compounds of formula (IXI) are known or may be prepared using standard procedures.
Compounds of formula (TV) or (V) may be prepared by processes analogous to (a), (b) and (c) described above. Compounds Ar^Wl and Ar Hal are commercially available or may be prepared by standard methods. Compounds of formula (VII) are known in the literature or may be prepared by known methods. The compound of formula (VIE) is likewise known in the literature.
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. Furthermore, they could have utility as adjunct therapy in Parkinsons Disease, particularly with compounds such as L-DOPA and possibly dopaminergic agonists, to reduce the side effects experienced with these treatments on long term use (eg see Schwartz et al., Brain Res. Reviews, 1998, 26, 236-242). From the localisation of D3 receptors, it could also be envisaged that D3 antagonists could also have utility for the treatment of substance abuse where it has been suggested that D3 receptors are involved (eg see Levant, 1997, Pharmacol. Rev., 49, 231-252) 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 (Ki) of test compounds for displacement of [ η 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 [125j] 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 μM 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 1 - 33 had pKi values of between 7.9 and 8.5 at the 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 (hD^CHO or hE>3_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%CO , 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 I1D3 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. Solvent : 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 - lOO mg
* may also include cyclodextrins
Diluent : e.g. Microcrystalline cellulose, lactose, starch Binder : e.g. Poly vinylpyrrolidone, 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
6-Cyano-l,2,3,4-tetrahydroisoquinoline Prepared in a similar manner to that described in H.G. Selnick et al., Synthetic Communications 25 (20) 3255 (1995).
Mass spectrum (APr): Found 159 (MH+). C10H10N2 requires 158.
'H NMR (CDCL) δ: 2.47 (1H, br s), 2.82 (2H, m), 3.15 (2H, m), 4.05 (2H, s), 7.10 (1H, d, J = 8 Hz), 7.40 (2H, m).
Description 2
trans-2-(l-(4-(N- tørt-Butyloxycarbonyl)amino)cyclohexyl)acetic acid, methyl ester
A mixture of tran5-(4-amino)cyclohexylactic acid hydrogen sulfate (T.P. Johnston et al; J. Med Chem., 1977, 20 (2), 279-290), (27.0g, 106mmol), cone. H2SO4 (3ml), and methanol (300ml) was stirred at reflux for 5h. Resulting solution was filtered and the filtrate evaporated in vacuo to give a brown oil (36g). A mixture of this material, triethylamine (36ml; 26. lg, 259 mmol), dichloromethane (600ml) and di-t-butyl dicarbonate (25.5g, 117mmol) was stirred at 20°C for 18h. Resulting solution was partitioned between saturated aqueous NaHCO3 (500ml) and dichloromethane (3x200ml), and the combined extracts were dried (NajSO and evaporated in vacuo to give the title compound (24.6g, 86%) as a colourless solid.
'H NMR (CDCl,) δ: 1.08 (4H, m), 1.43 (9H, s), 1.76 (3H, m), 2.00 (2H, m), 2.20 (2H, d, J = 7 Hz), 3.37 (1H, m), 3.66 (3H, s), 4.39 (1H, br s).
Description 3
trαns-2-(l-(4-(N-tert-Butyloxycarbonyl)amino)cyclohexyl)acetaldehyde
To a stirred solution of tran5-2-(l-(4-(N-tert-butyloxycarbonyl)amino)cyclohexyl)acetic acid, methyl ester (46.0g, 170 mmol) in dry toluene (920ml) at -78°C under argon was added a solution of di-isobutylaluminium hydride (1M; 285 ml; 285 mmol), dropwise over 0.5h. Resulting solution was stirred for a further 0.3h and quenched with a mixture of methanol (28ml) in toluene (50ml) and then poured into saturated aqueous potassium sodium tartrate (1.2L). The resultant mixture was extracted with ether (4xlL). The combined organic extracts were dried (Na.SO4) and evaporated in vacuo to give a waxy solid which was purified using silica gel, eluting with 10-50% ethyl acetate/hexane to give the title compound (21.77g, 53%) as a colourless solid.
Η NMR (CDCL) δ: 1.12 (4H, m), 1.44 (9H, s), 1.78 (3H, m), 2.00 (2H, m), 2.33 (2H, dd, J = 7, 2 Hz), 3.37 (1H, m), 4.40 (1H, m), 9.75 (1H, m). Description 4
fr ns-2-(2-(l-(4-(N-ter -Butyloxycarbonyl)amino)cyclohexyI)ethyl)-6-cyano-l,2,3,4- tetrahydroisoquinoline
A mixture of trans-2-(l-(4-(N-tert-butyloxycarbonyl)amino)cyclohexyl)acetaldehyde (6.0g, 24.9 mmol), 6-cyano- 1,2,3,4-tetrahydroisoquinoline (3.93g, 24.9 mmol), sodium triacetoxyborohydride (7.7g, 36.3 mmol) in 1,2-dichloroethane (270ml) was stirred at 20°C for 16h. Resulting solution was partitioned between aqueous K,CO3 (200ml) and dichloromethane (100ml), and the combined extracts were washed with brine (200ml), dried (ΝajSO4) and evaporated in vacuo to a minimum volume and filtered through a pad of silica (lOOg), washing with ethyl acetate. The filtrate was evaporated in vacuo to give the title compound (8.33g, 87%) as a yellow solid.
Η NMR (CDC13) δ: 1.08 (4H, m), 1.28 (IH, m), 1.44 (9H, s), 1.48 (2H, m), 1.78 (2H, m), 1.99 (2H, m), 2.52 (2H, m), 2.72 (2H, t, J = 7 Hz), 2.91 (2H, ,m), 3.37 (IH, m), 3.63 (2H, m), 4.40 (IH, m), 7.12 (IH, d, J = 8 Hz), 7.39 (2H, m).
Description 5
/r ns-2-(2-(l-(4-Amino)cyclohexyl)ethyl)-6-cyano-l,2,3,4-tetrahydroisoquinoline
A mixture of trans-2-(2-(\-(4-(N- tert-butyloxycarbonyl)amino)cyclohexyl)ethyl)-6- cyano- 1,2,3,4-tetrahydroisoquinoline (8.3g, 21.7 mmol), trifluoroacetic acid (15ml) and dichloromethane (180ml) was stirred at 20°C for 2h. Resulting solution was evaporated in vacuo and the residue partitioned between saturated aqueous KJCOJ (200ml) and dichloromethane (2x100ml). The combined organic extracts were washed with brine (100ml), dried (Na,SO4) and evaporated in vacuo to give the title compound (4.99g, 81%) as a brown oil.
Mass spectrum (APT): Found 284 (MH+). C18H25N3 requires 283.
Η NMR (CDCI3) δ: 0.91 - 1.16 (4H, m), 1.22 - 1.40 (3H, m), 1.47 (2H, m), 1.72 - 1.91 (4H, m), 2.52 (2H, m), 2.59 (IH, m), 2.72 (2H, t, J = 7 Hz), 2.92 (2H, m), 3.64 (2H, s), 7.11 (IH, d, J = 8 Hz), 7.39 (2H, m).
Description 6
6-Cyano-l,2,3,4-tetrahydroisoquinoIine hydrochloride
As an alternative procedure to that contained within Description 1, a solution of 6-bromo- 1,2,3,4-tetrahydroisoquinoline hydrochloride (6.0g, 24 mmol) and triethylamine (7.4ml, 5.36g, 53 mmol) in dichloromethane (100ml) was treated with trifluoroacetic anhydride (3.7ml, 5.54g, 26.4 mmol) with ice cooling. Mixture was stirred at 20°C for ι.5n. t en partitioned between saturated aqueous NaHCO3 (250ml) and dichloromethane (3x50ml). Combined organic extracts were dried (Na2SO4) and evaporated in vacuo to give a solid (8.3g). A mixture of the latter with copper (I) cyanide (5. lg, 56.6 mmol) in l-methyl-2- pyrrolidinone (100ml) was heated at reflux under argon for 4h, then cooled and partitioned between water (300ml), .880 aqueous ammonia (100ml) and dichloromethane (5x200ml). Combined organic extracts were dried (Na.SO4) and evaporated in vacuo to give an oil. The latter was dissolved in ether and treated with ethereal HC1 to give the title compound (4.47g, 85%) as a colourless solid.
Mass spectrum (APT): Found 159 (MIT). C10H10N2 requires 158.
Example 1
trαns-6-Cyano-2-(2-(l-(4-phenylacetamido)cyclohexyl)ethyl)-l,2,3,4- tetrahydroisoquinoline
A mixture of trani,-2-(2-(l-(4-amino)cyclohexyl)ethyl)-6-cyano-l,2,3,4- tetrahydroisoquinoline (0.10 g, 0.35 mmol), phenylacetic acid (0.053 g, 0.39 mmol), 1- ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.075 g, 0.39 mmol), 1- hydroxybenzotriazole (catalytic amount) and dichloromethane (8 ml) was shaken for 16 h. Saturated sodium bicarbonate (4ml) was then added and the mixture shaken for 0.25 h. Chromatography of the organic layer on silica with 50 - 100% ethyl acetate in hexane and 0 - 10% methanol in ethyl acetate gradient elution gave the title compound (0.090 g, 64%) as a colourless solid.
Mass spectrum (APr): Found 402 (MH+). C28H29N5O requires 401.
Η NMR (CDC13) δ: 0.90 - 1.30 (5 H, m), 1.40 - 1.52 (2 H, m), 1.60 - 1.80 (2 H, m), 1.85 - 1.95 (2 H, m), 2.40 - 2.60 (2 H, m), 2 65 - 2.80 (2 H, m), 2.85 - 2.95 (2 H, m), 3.50 (2 H, s), 3.60 (2 H, s), 3.65 - 3.80 (1 H, m), 5.13 (1 H, d, J = 8 Hz), 7.09 (1 H, d, J 8 Hz), 7.20 - 7.40 (7 H, m).
The following compounds were prepared according to the procedure of Example 1
Figure imgf000019_0001
Figure imgf000020_0001
Figure imgf000021_0001
2.45 - 2.55 (2H, m), 2.65 - 2.80 (2H, m), 2.90 - 3.00 (2H, m), 3.60 (2H, s), 3.60 - 3.80 (IH, m), 3.68 (2H, s), 7.03 (IH, d, J = 8 Hz), 7.10 (IH, d, J = 8 Hz), 7.16 - 7.45 (4H, m), 7.60 - 7.70 (IH, m), 8.53
(!H, d, J = 5 Hz). W -CH2C6H4(4-Br) MHT 480. C26H30 79BrN3O requires 479.
0.91 - 1.16 (4H, m), 1.26 (IH, m), 1.47 (2H, m),
1.76 (2H, m), 1.91 (2H, m), 2.51 (2H, m), 2.70 (2H, t, J = 6 Hz), 2.90 (2H, m), 3.48 (2H, s), 3.62 (2H, s), 3.70 (IH, m), 5.15 (IH, m), 7.12 (3H, m), 7.38 (2H, m), 7.47 (2H, m).
17 -CH2C6H4(4-I) MW 528. C26H30IN3O requires 527.
0.91 - 1.16 (4H, m), 1.25 (IH, m), 1.47 (2H, m),
1.77 (2H, m), 1.90 (2H, m), 2.50 (2H, m), 2.70 (2H, t, J = 6 Hz), 2.90 (2H, m), 3.46 (2H, s), 3.69 (2H, s), 3.68 (IH, m), 5.13 (IH, m), 7.00 (2H, d, J = 8 Hz), 7.10 (IH, d, J = 8 Hz), 7.38 (2H, m), 7.66 (2H, d, J = 8 Hz).
18 -CH2C6H4(3-Br) MW 480. C26H30"BrN3O requires 479.
0.91 - 1.16 (4H, m), 1.26 (IH, m), 1.48 (2H, m),
1.76 (2H, m), 1.93 (2H, m), 2.51 (2H, m), 2.71 (2H, m), 2.90 (2H, m), 3.49 (2H, s), 3.62(2H, s), 3.71 (IH, m), 5.19 (IH, m), 7.10 (IH, d, J = 8 Hz), 7.21 (2H, m), 7.40 (4H, m).
19 -CH2C6H3(2,4-diF) MHT 438. C26H29F2N3O requires 437.
0.94 - 1.17 (4H, m), 1.26 (IH, m), 1.47 (2H, m),
1.77 (2H, m), 1.93 (2H, m), 2.51 (2H, m), 2.71 (2H, t, J = 6 Hz), 2.90 (2H, m), 3.49 (2H, s), 3.62 (2H, s), 3.71 (IH, m), 5.25 (IH, m), 6.84 (2H, m), 7.10 (IH, d, J = 8 Hz), 7.27 (IH, m), 7.38 (2H, m).
20 -CH2C6H4(3-CF3) MW 470. C27H30F3N3O requires 469.
0.93 - 1.15 (4H, m), 1.26 (IH, m), 1.48 (2H, m), 1.78 (2H, m), 1.95 (2H, m), 2.51 (2H, m), 2.70 (2H, m), 2.90 (2H, m), 3.57 (2H, s), 3.62 (2H, s), 3.72 (IH, m), 5.18 (IH, m), 7.10 (IH, d, J = 8 Hz), 7.38
(2H, m), 7.46 (2H, m), 7.52 (2H, m).
21 -CH,CH4(4-'Bu) MW 458. C30H39N3O requires 457.
0.92 - 1.16 (4H, m), 1.26 (IH, m), 1.31 (9H, s), 1.47 (2H, m), 1.76 (2H, m), 1.92 (2H, m), 2.50 (2H, m), 2.70 (2H, m), 2.89 (2H, m), 3.50 (2H, s), 3.61 (2H, s), 3.71 (IH, m), 5.30 (IH, m), 7.10 (IH, d, J = 8 Hz), 7.17 (2H, d, J = 8 Hz), 7.36 (4H, m).
22 -CH2-(3-benzolbj- MHT 458. C28H31N3OS requires 457.
0.79 - 1.28 (5H, m), 1.43 (2H, m), 1.71 (2H, m), 1.86 (2H, m), 2.47 (2H, m), 2.68 (2H, t, J = 6 Hz), O 99/59974 thienyl) 2.88 (2H, m), 3.60 (2H, s), 3.72 (IH, m), 3.79 (2H, s), 5.23 (IH, m), 7.08 (IH, d, J = 8 Hz), 7.37 (5H, m), 7.72 (IH, m), 7.88 (IH, m).
23 -CROPh MNaT 440. C26H3]N3O2 requires 417.
1.02 - 1.40 (5H, m), 1.53 (2H, m), 1.84 (2H, m), 2.02 (2H, m), 2.55 (2H, m), 2.73 (2H, t, J = 7 Hz), 2.92 (2H, t, J = 7 Hz), 3.65 (2H, s), 3.84 (IH, m), 4.46 (2H, s), 6.40 (IH, d, J = 9 Hz), 6.93 (2H, d, J = 9 Hz), 7.05 (IH, t, J = 9 Hz), 7.12 (IH, d, J = 9 Hz), 7.26 - 7.44 (4H, m).
24 -CH2CH2CH2Ph MW 430. C28H35N3O requires 429.
1.02 - 1.21 (4H, m), 1.27 (IH, m), 1.50 (2H, m), 1.80 (2H, m), 1.99 (4H, m), 2.15 (2H, t, J = 9 Hz), 2.56 (2H, m), 2.60 - 2.79 (4H, m), 3.03 (2H, m),
3.64 (2H, s), 3.73 (IH, m), 5.21 (IH, d, J = 9 Hz), 7.11 (IH, d, J = 9), 7.15 - 7.24 (3H, m), 7.28 (2H, m), 7.38 (2H, m).
25 CH2CH2C6H4(4-F) MHT 434. C27H32FN3O requires 433.
0.90 - 1.19 (4H, m), 1.26 (IH, m), 1.48 (2H, m),
1.65 - 1.95 (4H, m), 2.39 (2H, t, J = 9 Hz), 2.53 (2H, m), 2.73 (2H, t, J = 7 Hz), 2.91 (4H, m), 3.65 (2H, s), 3.71 (IH, m), 5.13 (IH, d, J = 9 Hz), 6.96
(2H, m), 7.14 (3H, m), 7.40 (2H, m).
~W -CH2(4-quinolinyl) Found: 453 (MHX); C29H32N4O requires 452. δ: 0.80 - 1.30 (5H, m), 1.35 - 1.50 (2H, m), 1.70 - 1.90 (4H, m), 2.40 - 2.55 (2H, m), 2.60 - 2.75 (2H, m), 2.80 - 2.90 (2H, m), 3.59 (2H, s), 3.72 (IH, m), 3.98 (2H, s), 5.21 (IH, d, J = 8 Hz), 7.08 (IH, d, J = 8 Hz), 7.32 (IH, d, J = 4 Hz), 7.33 - 7.40 (2H, m), 7.59 (IH, m), 7.74 (IH, m), 8.00 (IH, d, J = 8 Hz), 8.14 (IH, d, J = 8 Hz), 8.85 (IH, d, J = 4 Hz).
27 -CH2Ph(4-CFT Found: 470 (MHT); C27H30F3N3O requires 469.
δ: 0.95 - 1.15 (4H, m), 1.25 (IH, m), 1.40 - 1.50 (2H, m), 1.70 - 1.85 (2H, m), 1.85 - 2.00 (2H, m), 2.51 (2H, t, J = 4.5 Hz), 2.70 (2H, t, J = 4.5 Hz), 2.85 - 2.95 (2H, m), 3.57 (2H, s), 3.62 (2H, s), 3.71 (IH, m), 5.19 (IH, d, J = 8 Hz), 7.10 (IH, d, J = 8 Hz), 7.35 - 7.40 (4H, m), 7.59 (2H, d, J = 8 Hz).
28 -CH2Ph (3,5-diF) Found: 438 (MHT); C26H29F2N3O requires 437
δ: 1.00 - 1.15 (4H, m), 1.25 (IH, m), 1.40 - 1.55 (2H, m), 1.75 - 1.85 (2H, m), 1.90 - 2.00 (2H, m), 2.45 - 2.55 (2H, m), 2.65 - 2.75 (2H, m), 2.80 - 2.95 (2H, m), 3.48 (2H, s), 3.62 (2H, s), 3.72 (IH, m), 5.18 (IH, d, J = 8 Hz), 6.65 - 6.90 (3H, m), 7.10 (IH, d, J = 8 Hz), 7.35 - 7.40 (2H, m).
29 Icτr2? Found: 458 (MH'); C28H31N3OS requires 457. benzothiophenyl) δ: 1.00 - 1.15 (4H, m), 1.22 (IH, m), 1.40 - 1.50 (2H, m), 1.70 - 1.80 (2H, m), 1.90 - 2.00 (2H, m), 2.40 - 2.50 (2H, m), 2.60 - 2.70 (2H, m), 2.80 - 2.90 (2H, m), 3.61 (2H, s), 3.72 (IH, m), 3.82 (2H, s), 5.45 (IH, d, J = 8 Hz), 7.08 (IH, d, J = 8 Hz), 7.15 (IH, s), 7.30 - 7.40 (4H, m), 7.70 - 7.85 (2H, m).
ID" -CH2(2-furanyl) Found: 392 (MHT); C24H29N3O2 requires 391.
δ: 0.90 - 1.10 (4H, m), 1.25 (IH, m), 1.40 - 1.50 (2H, m), 1.70 - 1.80 (2H, m), 1.90 - 2.00 (2H, m), 2.45 - 2.55 (2H, m), 2.65 - 2.75 (2H, m), 2.85 - 2.95 (2H, m), 3.58 (2H, s), 3.62 (2H, s), 3.70 (IH, m), 5.39 (IH, d, J = 8 Hz), 6.20 - 6.23 (IH, m), 6.32 - 6.38 (IH, m), 7.10 (IH, d, J = 8 Hz), 7.35 - 7.40 (3H, m).
31 -CH2(2-benzofuranyl) Found: 442 (MW); C28H31N3O2 requires 441.
δ: 1.00 - 1.15 (4H, m), 1.22 (IH, m), 1.40 - 1.50 (2H, m), 1.70 - 1.80 (2H, m), 1.90 - 2.00 (2H, m), 2.45 - 2.55 (2H, m), 2.65 - 2.75 (2H, m), 2.85 - 2.95 (2H, m), 3.62 (2H, s), 3.72 (2H, s), 3.78 (IH, m), 5.54 (IH, d, J = 8 Hz), 6.61 (IH, s), 7.09 (IH, d, J = 8 Hz), 7.15 - 7.30 (3H, m), 7.35 - 7.60 (3H, m).
Example 32
trαns-6-Cyano-2-(2-(l-(4-(4-fluorophenyl)acetamido)cyclohexyl)ethyl)-l,2,3,4- tetrahydroisoquinoline, hydrochloride
A mixture of trans-6-cyano-2-(2-(l-(4-amino)cyclohexyl)ethyl)- 1,2,3 ,4- tetrahydroisoquinoline (0.28g, 1 mmol), 4-fluorophenylacetic acid (0.16g, 1 mmol), EDC hydrochloride (0.19g, 1 mmol) and HOBT (0.05g) in dichloromethane (8ml) was allowed to stir at room temperature for 16h, then was washed with aqueous saturated sodium bicarbonate (4ml). The organic layer was purified by silica gel chromatography eluting with ethyl acetate in hexane to give the free base of the title compound (0.24g, 57%) as colourless solid.
Mass spectrum (APT): Found MH+ 420. C26H30FN3O requires 419. Η NMR (CDC1.) δ: 0.90 - 1.30 (5H, m), 1.40 - 1.52 (2H, m), 1.65 - 2.00 (4H, m), 2.45 - 2.55 (2H, m), 2.70 (2H, t), 2.90 (2H, t), 3.49 (2H, s), 3.62 (2H, s), 3.60 - 3.75 (IH, m), 5.21 (IH, d), 6.90 - 7.10 (3H, m), 7.15 - 7.30 (2H, m), 7.35 - 7.40 (2H, m).
A sample was converted to the hydrochloride salt by treatment of a solution of the above free base in dichloromethane with a solution of HCl in ether. Evaporation of solvents in vacuo gave the title compound as a colourless solid having m.pt. 251-253 °C (decomp.).
'H NMR δ (DMSO): 0.90 - 1.20 (4H, m), 1.20 - 1.35 (IH, m), 1.60 - 1.80 (6H, m), 3.00 - 3.10 (IH, m), 3.10 - 3.30 (3H, m), 3.35 (2H, s), 3.40 - 3.50 (IH, m), 3.60 - 3.80 (2H, m), 4.32 (IH, dd, J = 16, 8 Hz), 4.62 (IH, d, J = 15 Hz), 7.05 - 7.15 (2H, m), 7.20 - 7.30 (2H, m), 7.42 (IH, d, J = 8 Hz), 7.73 (IH, dd, J = 9, 1 Hz), 7.78 (IH, s), 7.96 (IH, d, J = 8 Hz), 10.80 (IH, br s).
Example 33
trflns-6-Cyano-2-(2-(l-(4-(2,5-difluoro)phenylacetamido)cyclohexyI)ethyl)-l,2,3,4- tetrahydroisoquinoline, hydrochloride
A mixture of 6-cyano-2-(2-(l-(4-amino)cyclohexyl)ethyl- 1,2,3,4-tetrahydroisoquinoline (0.13g, 0.44 mmol), 2,5-difluorophenylacetic acid (0.09g, 0.44 mmol), EDC hydrochloride (0.12g, 0.66 mmol) and HOBT (0.025g) in dichloromethane (8ml) was allowed to stir at ambient temperature for 16h, then was washed with saturated aqueous sodium bicarbonate (4ml). The organic phase was purified by silica gel chromatography eluting with ethyl acetate in hexane, to give the free base of the title compound (O.lg, 52%) as a colourless solid.
Mass spectrum (APT): Found MH+ 438. C26H29F2N3O requires 437.
Η NMR (CDC13) δ: 1.00 - 1.20 (4H, m), 1.20 - 1.40 (IH, m), 1.40 - 1.55 (2H, m), 1.70 - 1.85 (2H, m), 1.90 - 2.00 (2H, m), 2.45 - 2.55 (2H, m), 2.65 - 2.75 (2H, m), 2.85 - 2.95 (2H, m), 3.50 (2H, s), 3.62 (2H, s), 3.60 - 3.80 (IH, m), 5.38 (IH, d, J = 8 Hz), 6.85 - 7.15 (4H, m), 7.30 - 7.40 (2H, m).
A sample was converted to the hydrochloride salt by treatment of a solution of the above free base in dichloromethane with a solution of HCl in ether. Evaporation of solvents in vacuo gave the title compound as a colourless solid having m.pt. 254-257 °C (decomp.). Η NMR δ (DMSO): 0.90 - 1.35 (5H, m), 1.60 - 1.85 (6H, m), 3.00 - 3.10 (IH, m), 3.10 - 3.50 (7H, m), 3.70 (IH, m), 4.20 - 4.40 (IH, m), 4.55 - 4.70 (IH, m), 7.00 - 7.20 (3H, m), 7.42 (IH, d, J = 8 Hz), 7.73 (IH, d, J = 8 Hz), 7.78 (IH, s), 8.02 (IH, d, J = 8 Hz), 10.75 (lH, br s).

Claims

Claims
1. A compound of formula (I)
Figure imgf000027_0001
Formula (I) wherein:
R represents a substituent selected from: a hydrogen or halogen atom; a hydroxy, cyano, nitro, trifluoromethyl, trifluoromethoxy, trifluoromethanesulfonyloxy, pentafluoroethyl, Ci^alkyl, C _4alkoxy, arylCi^alkoxy, C ^alkylthio,
C _4alkoxyC _4alkyl, C3_6cycloalkylC _4alkoxy, Ci^alkanoyl, C ^alkoxycarbonyl,
C _4alkylsulfonyl, C _4alkylsulfonyloxy, C .4alkylsulfonylCι.4alkyl, arylsulfonyl, arylsulfonyloxy, arylsulfonylC^alkyl, Ci^alkylsulfonamido, C ^alkylamido,
C i _4alkylsulfonamidoC _4alkyl, C i _4alkylamidoC i _4alkyl, arylsulfonamido, arylcarboxamido, arylsulfonamidoCι_4alkyl, arylcarboxamidoC ^alkyl, aroyl, aroylCj.
4alkyl, or arylC^alkanoyl group; a group R3OCO(CH2)p, R3CON(R4)(CH2)p,
R3R4NCO(CH2)p or R3R4NSO2(CH2)p where each of R3 and R4 independently represents a hydrogen atom or a Cι_4alkyl group or R3R4 forms part of a C3. gazacyloalkane or C3_6(2-oxo)azacycloalkane ring and p represents zero or an integer from 1 to 4; or a group Arl-Z, wherein Arl 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 Chalky 1 group; q is 1 or 2;
A represents a group of the formula :
A represents a group of formula
-(CH2)r-V-(CH2)s-Ar
wherein
r and s independently represent an integer from zero to 3 such that the sum of r and s is equal to an integer from 1 to 4; V represents a bond, O or S;
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; and salts thereof.
2. A compound according to claim 1 wherein q represents 1.
3. A compound according to any of the preceding claims wherein the group
Ar is optionally substituted by one or more substituents selected from: a hydrogen or halogen atom, cyano, methoxy, methylenedioxy, acetyl, acetylamino, methylsulfonyl, methylsulfonyloxy, methylaminosulfonyl, methylsulfonylamino, or methylaminocarbonyl group.
4. A compound of formula (I) which is: tr «5-6-Cyano-2-(2-( 1 -(4-phenylacetamido)cyclohexyl)efhyl)- 1 ,2,3,4- tetrahydroisoquinoline tran5-6-Cyano-2-(2-( 1 -(4-(2-naphthyl)acetamido)cyclohexyl)ethyl)- 1,2,3,4- tetrahydroisoquinoline trani'-6-Cyano-2-(2-( 1 -(4-(2-fluorophenyl)acetamido)cyclohexyl)ethyl)- 1 ,2,3,4- tetrahydroisoquinoline tran5-6-Cyano-2-(2-(l-(4-(3-fluorophenyl)acetamido)cyclohexyl)ethyl)-l,2,3,4- tetrahy droi soquinoline trα/z.ϊ-6-Cyano-2-(2-( 1 -(4-(4-fluorophenyl)acetamido)cyclohexyl)ethyl)- 1 ,2,3,4- tetrahydroisoquinoline tran5-6-Cyano-2-(2-(l-(4-(3-cyanophenyl)acetamido)cyclohexyl)ethyl)- 1,2,3,4- tetrahydroisoquinoline trøns-6-Cyano-2-(2-(l-(4-(4-cyanophenyl)acetamido)cyclohexyl)ethyl)-l,2,3,4- tetrahydroisoquinoline trans-6-Cyano-2-(2-(l-(4-(3-phenyl)propionamido)cyclohexyl)ethyl)- 1,2,3,4- tetrahydroisoquinoline tran5-6-Cyano-2-(2-( 1 -(4-(4-phenyl)phenylacetamido)cyclohexyl)-ethyl)- 1 ,2,3 ,4- tetrahydroisoquinoline tr n -6-Cyano-2-(2-(l-(4-(2-thienyl)acetamido)cyclohexyl)ethyl)- 1,2,3,4- tetrahydroisoquinoline tr n^-6-Cyano-2-(2-(l-(4-(3-thienyl)acetamido)cyclohexyl)ethyl)- 1,2,3,4- tetrahydroisoquinoline tran -6-Cyano-2-(2-(l-(4-(3-indolyl)acetamido)cyclohexyl)ethyl)- 1,2,3,4- tetrahydroisoquinoline trαns-6-Cyano-2-(2-(l-(4-(2,5-difluoro)phenylacetamido)cyclohexyl)-ethyl)- 1 ,2,3,4-tetrahydroisoquinoline trαn^-6-Cyano-2-(2-(l-(4-(3,4-difluoro)phenylacetamido)cyclohexyl)-ethyl)- 1 ,2,3,4-tetrahydroisoquinoline trans-6-Cyano-2-(2-( 1 -(4-(2-pyridyl)acetamido)cyclohexyl)ethyl)- 1 ,2,3,4- tetrahydroisoquinoline trøn,s-6-Cyano-2-(2-( 1 -(4-(4-bromo)phenylacetamido)cyclohexyl)-ethyl)- 1 ,2,3,4- tetrahydroisoquinoline tra/w-6-Cyano-2-(2-( 1 -(4-(4-iodo)phenylacetamido)cyclohexyl)ethyl)- 1 ,2,3,4- tetrahydroisoquinoline tran,s-6-Cyano-2-(2-( 1 -(4-(3-bromo)phenylacetamido)cyclohexyl)-ethyl)- 1 ,2,3,4- tetrahydroisoquinoline tran.y-6-Cyano-2-(2-( 1 -(4-(2,4-difluoro)phenylacetamido)cyclohexyl)-ethyl)-
1 ,2,3,4-tetrahydroisoquinoline trαn5'-6-Cyano-2-(2-(l-(4-(3-trifluoromethyl)phenylacetamido)-cyclohexyl)ethyl)- 1 ,2,3,4-tetrahydroisoquinoline tran^-6-Cyano-2-(2-( 1 -(4-(4-t-butyl)phenylacetamido)cyclohexyl)-ethyl)- 1 ,2,3,4- tetrahydroisoquinoline tra«5'-6-Cyano-2-(2-(l-(4-(3-benzo[b]thienyl)acetamido)cyclohexyl)-ethyl)- 1 ,2,3 ,4-tetrahydroisoquinoline trαn5-6-Cyano-2-(2-( 1 -(4-phenoxyacetamido)cyclohexyl)ethyl)- 1 ,2,3,4- tetrahydroisoquinoline trøn.s-6-Cyano-2-(2-( 1 -(4-(4-phenyl)butyramido)cyclohexyl)ethyl)- 1 ,2,3,4- tetrahydroisoquinoline tran5,-6-Cyano-2-(2-(l-(4-(3-(4-fluoro)phenyl)propionamido)-cyclohexyl)ethyl)- 1 ,2,3,4-tetrahydroisoquinoline tran5-6-Cyano-2-(2-(l-(4-(4-quinolyl)acetamido)-cyclohexyl)ethyl)-l, 2,3,4- tetrahydroisoquinoline trans-6-Cyano-2-(2-(l-(4-(4-trifluoromethyl)phenylacetamido)-cyclohexyl)ethyl)- 1 ,2,3,4-tetrahydroisoquinoline trαn5-6-Cyano-2-(2-(l-(4-(3,5-difluoro)phenylacetamido)-cyclohexyl)ethyl)- 1 ,2,3,4-tetrahydroisoquinoline trαns-6-Cyano-2-(2-( 1 -(4-(2-benzothiophenyl)acetamido)-cyclohexyl)ethyl)-
1 ,2,3,4-tetrahydroisoquinoline trans-6-Cy ano-2-(2-( 1 -(4-(2-furanyl)acetamido)-cyclohexyl)ethy 1)- 1 ,2,3 ,4- tetrahydroisoquinoline trans-6-Cymo-2-(2-( 1 -(4-(2-benzofuranyl)acetamido)-cyclohexyl)ethyl)- 1 ,2,3,4- tetrahydroisoquinoline
or a salt thereof.
5. A process for preparing compounds of formula (I) which process comprises :
(a) reacting a compound of formula(JJ):
Figure imgf000029_0001
Formula (II) wherein Rl, R2, and q are as hereinbefore defined, with a compound of formula (HI):
A-COX
Formula (ffl)
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 Rl is Arl-Z and Z is a bond, reacting a compound of formula (IV):
Figure imgf000030_0001
Formula (IV)
wherein A, R2, and q are as hereinbefore defined, one R a represents a group W wherein W is a halogen atom or a trifluoromethylsulfonyloxy group, or W is a group M selected from a boron derivativeor a metal function, and when q is 2 the other R a is Rl; with a compound Arl-W , wherein Wl is a halogen atom or a trifluoromethylsulfonyloxy group when W is a group M or Wl is a group M when W is a halogen atom or a trifluoromethylsulfonyloxy group;
(c) to prepare a compound of formula (I) wherein Rl is Arl-Z and Z is O or S, reacting a compound of formula (V):
Figure imgf000030_0002
Formula (V) wherein A, R , and q are as hereinbefore defined, one Rib represents a group ZH and when q is 2 the other Rl° represents R ; with a reagent serving to introduce the group Arl ;
(d) interconversion of one compound of formula (I) to a different compound of formula (I) e.g. (i) alkylation of a compound (I) wherein R2 represents hydrogen, (ii) conversion of one Rl from alkoxy (e.g.methoxy) to hydroxy, or (iii) conversion of R from hydroxy to sulfonyloxy, eg alkylsulfonyloxy or trifluoromethanesulfonyloxy;
(e) separation of cis- and trans- isomers of compounds of formula (I) by conventional methods,; and optionally thereafter forming a salt of formula (I).
6 A pharmaceutical composition comprising a compound of formula (I) as claimed in any of claims 1 to 4 or a physiologically acceptable salt thereof and a physiologically acceptable carrier therefor.
7 The use of a compound of formula (I) as claimed in any of claims 1 to 7or a physiologically acceptable salt thereof in the manufacture of a medicament for the treatment of a condition which requires modulation of a dopamine receptor.
8 Use according to claim 7 wherein the dopamine receptor is a dopamine D^ receptor.
9. Use according to claim 7or claim 8 wherein a dopamine antagonist is required.
10. Use according to any of claims 6 to 8 wherein the condition is a psychotic condition.
11. Use according to claim 10 wherein the psychotic condition is schizophrenia.
12 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.
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CN111801330B (en) * 2018-01-26 2024-04-05 盐野义制药株式会社 Fused ring compounds having dopamine D3 receptor antagonism

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CA2332316A1 (en) 1999-11-25
AR016036A1 (en) 2001-05-30
EP1086084A1 (en) 2001-03-28
CO5031252A1 (en) 2001-04-27
GB9810876D0 (en) 1998-07-22
JP2002515489A (en) 2002-05-28
AU4262799A (en) 1999-12-06
US6414154B1 (en) 2002-07-02

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