CA2288308A1 - Substituted tetrahydroisoquinoline derivatives as modulators of dopamine d3 receptors - Google Patents

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, C1-4alkyl, C14alkoxy, arylC1-4alkoxy, C1-4alkylthio, C1-4alkoxyC1-4alkyl, C3-6cycloalkylC1-4alkoxy, C1-4alkanoyl, C1-4alkoxycarbonyl, C1-4alkylsulphonyl, C14alkylsulphonyloxy, C1-4alkylsulphonylC1-4alkyl, arylsulphonyl, arylsulphonyloxy, arylsulphonylC1-4alkyl, C1-4alkylsulphonamido, C14alkylamido, C1-4alkylsulphonamidoC1-4alkyl, C1-4alkylamidoC1-4alkyl, arylsulphonamido, arylcarboxamido, arylsulphonamidoC1-4alkyl, arylcarboxamidoC1-4alkyl, aroyl, aroylC1-4alkyl, or arylC1-4alkanoyl 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 C1-4alkyl group or R3R4 forms part of a C3-6 azacycloalkane or C3-6(2-oxo)azacycloalkane ring and p represents zero or an integer from 1 to 4; or a group Ar1Z, 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 CH2; R2 represents a hydrogen atom or a C1-4alkyl group; q is 1 or 2; 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. 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

RECEPTORS
COMPOUNDS
The present invention relates to novel tetrahydroisoquinoline derivatives, processes for their preparation, pharmaceutical compositions containing them and their S 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:
R' N~
X ~Ar' R
wherein is an optionally substituted thienyl or optionally substituted phenyl ring; R1, R2 and R3 are each inter alia hydrogen; X is inter alia (CH2)mNR~CO; m is 2-4; and Arl is an optionally substituted heterocyclic ring or an optionally substituted phenyl ring. The compounds are said to be useful as antiarrhythmic agents.
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) Rz i N~Ar (R~)a N
O
Formula (I) wherein:
R 1 represents a substituent selected from: a hydrogen or halogen atom; a hydroxy, cyano, nitro, trifluoromethyl, trifluoromethoxy, trifluoromethanesulfonyloxy, pentafluoroethyl, C 1 _4alkyl, C 1 _4alkoxy, arylC 1 _4alkoxy, C 1 ~alkylthio, C 1 ~alkoxyC 1 alkyl, C3_6cyc1oalkylC 1 _4alkoxy, C 1 ~alkanoyl, C 1 _4alkoxycarbonyl, C 1 ~alkylsulphonyl, C 1 _4alkylsulphonyioxy, C 1 ~alkylsulphonylC 1 _4alkyl, arylsulphonyl, arylsulphonyloxy, arylsulphonyIC 1 ~alkyI, C 1 ~alkyisulphonamido, C 1 _ SUBSTITUTE SHEET (RULE 26) 4alkylamido, C 1 _4alkylsulphonamidoC 1 _4alkyl, C 1 ~.alkylamidoC 1 alkyl, arylsulphonamido, arylcarboxamido, arylsulphonamidoC 1 _4alkyl, arylcarboxamidoC 1 _ 4alkyl, aroyl, aroylC 1 alkyl, or arylC 1 _4alkanoyl group; a group R30C0(CH2)p , R3CON(R4)(CH2)p, R3R4NC0(CH2)p or R3R4NS02(CH2)p where each of R3 and R4 independently represents a hydrogen atom or a C 1 _4alkyl group or R3R4 forms part of a C3_6azacyloalkane 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 Ar 1 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 1 _4alkyl group;
q is 1 or 2;
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-pentyl, and the like.
Examples of compounds of formula (I) include those in which Ar is a bicyclic aromatic or heteroaromatic ring system and in which R1 is other than pentafluoroethyl.
When R1 represents an arylC1-4alkoxy, arylsulphonyl, arylsulphonyloxy, arylsulphonylC 1 _4alkyl, arylsulphonamido, arylcarboxamido, arylsulphonamidoC 1 alkyl, arylcarboxamidoC 1 _4alkyl, aroyl, aroylC 1 _4alkyl, or arylC 1 _4alkanoyl 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 1 an aryl moiety may be optionally substituted by one or more substituents selected from hydrogen, halogen, amino, cyano, C 1 _4alkyl, C 1 _4alkylamino, C 1 _ 4dialkylamino, C 1 _4alkylamido, C 1 _4alkanoyl, or RSR6NC0 where each of RS
and R6 independently represents a hydrogen atom or C 1 _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 1 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 Arl 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, SUBSTITUTE SHEET (RUtE 26) WO 98!49145 PCT/EP98/OZ581 benzothiazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzisothiazolyl, quinolinyl, quinoxolinyl, quinazolinyl, cinnolinyl, isoquinolinyl, pyrazolo[1,5-a]pyrimidyl, pyrrolo[3,2-bJpyridyl, pyrrolo[3,2-cJpyridyl, thieno[3,2-b]thiophenyl, 1,2-dihydro-2-oxo-quinolinyl, 2,3-dihydro-3-oxo-4H-benzoxazinyl, 1,2-dihydro-2-oxo-indolyl.
The group Ar may be optionally substituted by one or more substituents selected from: a hydrogen or halogen atom, or a hydroxy, oxo, cyano, nitro, C 1 _4alkyl, C 1 _4alkoxy, C 1 _4alkylenedioxy, C 1 _4alkanoyl, C 1 _4alkylsulphonyl, C 1 ~alkylsulphinyl, C 1-4alkylthio, R~S02N(Rg)-, R~RgNS02-, R~R8N-, R~RgNCO-, or R~CON(Rg)- group wherein each of R~ and R8 independently represents a hydrogen atom or a C1-4 alkyl group, or R~Rg 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 R~RgN- group; wherein R~ and Rg are as defined above.
In the group Ar substituents positioned ortho to one another may be linked to form a 5- ar 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, malefic, 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.
In compounds of formula (I), it is preferred that R 1 represents a substituent selected from: a halogen atom, methyl, cyano, trifluoromethylsulfonyloxy, trifluoromethyl, pentafluoroethyl, or trifluoromethoxy group.
It is also preferred that 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.
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:
2-(4-(2-Indolylcarboxamido)butyl)- 7-trifluoromethoxy-1,2,3,4-tetrahydroisoquinoline;
7-Cyano-2-(4-(2-indolylcarboxamido)butyl)-1,2,3,4-tetrahydroisoquinoline;

SUBSTITUTE SHEET (RULE 26) i 2-(4-(5-Indolylcarboxamido)butyl)-7-trifluoromethylsulfonyloxy-1,2,3,4-tetrahydroisoquinoline;
2-(4-(2-Indolylcarboxamido)butyl}-7-trifluoromethylsulfonyloxy-1,2,3,4-tetrahydroisoquinoline;
2-(4-(2-(5-Methoxy)indolylcarboxamido)butyl)-7-trifluoromethoxy-1,2,3,4-tetrahydroisoquinoline;
2-(4-(2-Benzo[b]thienylcarboxamido)butyl}-7-trifluoromethoxy-1,2,3,4-tetrahydroisoquinoline;
2-(4-(2-{5-Chloro)indoIylcarboxamido)butyl)-7-trifluoromethoxy-1,2,3,4-tetrahydroisoquinoline;
2-(4-(2-(5-Methyl)indolylcarboxamido)butyl)-7-trifluoromethoxy-1,2,3,4-tetrahydroisoquinoline;
2-(4-(2-{S-Fluoro)indolylcarboxamido)butyl)-7-trifluoromethoxy-1,2,3,4-tetrahydroisoquinoline;
and salts thereof.
The present invention also provides a process for preparing compounds of formula (I) and salts thereof which process comprises (a) reacting a compound of formula (II):
fdH
a Formula (II) wherein R 1 and q are as hereinbefore defined;
with a compound of formula (III):

I
Ar H
O
Formula (III) wherein R2 and Ar are as hereinbefore defined;
(b) reaction of a compound of formula (IV):

SUBSTITUTE SHEET (RULE 26) NH
~N
(R,) Formula (IV) wherein R 1 and R2 are as hereinbefore defined;
with a compound of formula (V):
Ar- COX
Formula (V) wherein Ar is as hereinbefore defined and X is a halogen atom or the residue of an activated ester;
(c) to prepare a compound of formula (I) wherein R1 is Arl-Z and Z is a bond, reacting a compound of formula (VI):

i N Ar (R,a)q ~ ~ ~ N
\ O
Formula (VI) wherein one R 1 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)2 or a metal function such as trialkylstannyl e.g.
SnBu3, zinc halide or magnesium halide, and when q is 2 the other R 1 a is R
1; with a compound Ar 1-W 1, wherein W 1 is a halogen atom or a trifluoromethylsulphonyloxy group when W is a group M or W 1 is a group M when W is a halogen atom or a trifluoromethylsulphonyloxy group;
(d) to prepare a compound of formula (I) wherein R1 is Arl-Z and Z is O or S, reacting a compound of formula (VII):

SUBSTITUTE SHEET {RULE 26) SUBSTITUT

Rz i N~A~
~R~b) I NN
Formula (VII) wherein one R 1 b represent a group ZH and when q is 2 the other R 1 b represents R 1;
with a reagent serving to introduce the group Arl;
(e) 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 R1 from alkoxy (e.g.methoxy) to hydroxy, or (iii) conversion of R1 from hydroxy to sulphonyloxy, eg alkylsulphonyloxy or trifluoromethanesulphonyloxy;
and optionally thereafter forming a salt of formula (I).
Process (a) requires 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.
Process (b) may be effected by methods well known in the art for formation of an amide bond.
Reaction of a compound of formula (VI) with ArlWl, according to process (c) may be effected in the presence of a transition metal eg palladium catalyst such as bis-triphenyiphosphinepalladium dichloride or tetrakis-triphenylphosphinepalladium (0).
When M represents a boronic acid function such as B(OH)Zthe 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 LiCI. 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 1 is preferably a goup M, such as trialkylstannyl or B(OH)2.
In process (d) 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 (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 (III) are known or may be prepared using standard procedures.
A compound of formula (IV) may be prepared by alkylation of a compound (II) by standard methods. Thus, for example a compound of formula (II) may be reacted SUBSTITUTE SHEET (RULE 26) with N-(4-bromobutylphthalimide) followed by removal of the phthalimide group to give a compound of formula (IV) where R2 is hydrogen. Compounds where R2 is alkyl may be prepared by subsequent reaction with the appropriate aldehyde using conditions analogous to process (a) above.
Compounds of formula (VI), and (VII) may be prepared by processes analogous to (a) or (b) described above. Compounds ArlWl and Arllial 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 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.
***e) 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 _7_ SUBSTITUTE SHEET (RULE 26) WO 98/49!45 PCT/EP98/02581 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 carriers) 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 carriers) 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 carner(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 _g_ SU8ST1TUTE SHEET (RULE 26) 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 fluorochlorohydrocarbon. The aerosol dosage forms can also take the form of a pump-atomiser.
Compositions suitable for buccal or sublingual administration include tablets, lozenges and pastilles, wherein the active ingredient is formulated with a carrier such as sugar and acacia, tragacanth, or gelatin and glycerin.
Compositions for rectal administration are conveniently in the form of suppositories containing a conventional suppository base such as cocoa butter.
Compositions suitable for transdermal administration include ointments, gels and patches.
Preferably the composition is in unit dose form such as a tablet, capsule or ampoule.
Each dosage unit for oral administration contains preferably from I 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 [ 125I] iodosuipride 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 SUBSTITUTE SHEET (RULE 26) 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 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 RCSC
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 RCSC. 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 [ 125I] 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 NaCI, 5 mM KCI, 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 NaCI, 5 mM
KCI, 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 E1M
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 Example 1 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 l2mm Transwell inserts (Costar) at 300000 cells/cup in foetal calf serum (FCS)-containing medium. The cells were incubated for 6h at 37oC in 5%C02, 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 SUBSTITUTE SHEET (RULE 26) medium (bicarbonate-free Dulbecco's modified Eagles medium containing 2 mM
glutamine and 44 mM NaCI) at a flow rate of 100 ul/min. Each pump cycle lasted 90s.
The pump was on for the first bOs and the acidification rate determined between 68 and 88s, using the Cytosoft programme. Agonists and antagonists 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 agonist were used. Peak acidification rate to each 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 Solventlcomplexing agent to 100 mi Bolus Injection Compound of formula (I) 1-4.0 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.
SUBSTITUTE SHEET (RULE 26) WO 98!49145 PCT/EP98/02581 Tablet Compound t - 40 mg Diluent/Filler * 50 - 250 mg Binder 5 - 25 mg Disentegrant * 5 - 50 mg Lubricant 1 - S 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 glycoilate, 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-1,2,3,4-tetrahydroisoquinoline A mixture of 7-bromo-2-triouoroacetyl-1,2,3,4-tetrahydoisoquinoline (G.E.
Stokker, Tetrahedron Letters 1996, 37, 5453) (43.4g, 0.14 mol), potassium carbonate ( 104.3g, 0.75 mol), methanol ( 1 L) and water ( 1 SOmI) was heated at reflux for 1 h, then cooled and evaporated in vacuo. Residue was partitioned w SUBSTITUTE SHEET (RULE 26) between water (IL) and dichloromethane (4 x 200m1). Combined extracts were dried (Na~S04) 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%).

'H NMR (CDC13) b: 1.77 (1H, br s), 2.73 (2H, t, J = 7Hz), 3.13 (2H, t, J =
7Hz), 3.98 (2H, s), 6.96 ( 1 H, d, J = 9Hz), 7.16 ( 1 H, d, J = 2Hz), 7.26 ( 1 H, dd, J
= 9, 2Hz).
The following compounds were prepared in a similar manner to Description 1 (a) 7-Cyano-1,2,3,4-tetrahydroisoquinoline Mass spectrum (API'): Found 159 (MH~). C,oH,oNz requires 158.
(b) 7-Trifluoromethoxy-1,2,3,4-tetrahydroisoquinoline Mass spectrum (API'): Found 218 (MH'). C,oH,oF3N0 requires 217.
Description 2 7-Cyano-2-trifluoroacetyl-1,2,3,4-tetrahydroisoquinoline 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 300m1). The combined organic extracts were dried (NazSOa) and evaporated in vacuo to give the title compound (42.6 g, 100 %) as an oil.
Mass spectrum (APT): Found 253 (M-H)~. C,ZH9F,N20 requires 254.
Description 3 2-Trifluoroacetyl-7-trifluoromethoxy-1,2,3,4-tetrahydroisoquinoline Prepared in two steps from 4-trifluoromethoxyphenethylamine using a method similar to that described in G.E. Stolcker, Tetrahedron Letters 1996 37 5453, in 69%
yield.
Mass spectrum (APT'): Found 314 (MH'). CI,HgF6NOz requires 313.
Description 4 SUBSTITUTE SHEET (RULE 26) (4-Trifluoroacetamido)butyraldehyde To a solution of 4-aminobutyraldehyde diethyl acetal ( 16. l Og, 0. l Ommol) and triethylamine ( 18.06m1, 0. l2mol) in dichloromethane ( 150m1) at 0°C
was added a solution of trifluoroacetic anhydride (16.9m1, 0.1 lmol) in dichloromethane (60m1). The reaction mixture was warmed to room temperature and stirred for 3h, then partitioned between 5% aq NaHCO, (400m1) and dichloromethane (400m1). The aqueous layer was extracted further with dichloromethane (3x1~m1), the combined extracts were dried (NazSO,) and evaporated in vacuo to afford a pale yellow oil which was added to a stirred mixture of THF
(300m1) and water (500m1). 5N Sulfuric acid (2.27m1) was added and the reaction mixture left to stir at room temperature for 18h. Saturated aqueous sodium bicarbonate (500m1) was added and the product was extracted into dichloromethane (4x100m1). The combined organic extracts were dried (Na..SO,) and evaporated in vacuo to afford the title compound as a yellow oil (15.428, 65%}.
'H NMR (CDCI,) 8: 1.95 (2H, m), 2.62 (2H, t, J = 8Hz), 3.38 (2H, m), 7.54 -7.80 ( 1 H, br s ), 9.77 ( 1 H, s).
Description 5 7-Cyano-2-(4-trifluoroacetamidobutyl)-1,2,3,4-tetrahydroisoquinoline A mixture of (4-trifluoroacetamido)butyraldehyde (22 g, 120 mmol), 7-cyano-1,2,3,4-tetrahydroisoquinoline (19 g, 120 mmol) and sodium triacetoxyborohydride (38.3 g, 180 mmol) in dichloroethane (500 ml) was stirred at room temperature for 18 h, then patitioned between saturated aqueous NaHC03 (500 ml) and dichloromethane (2 x 200 ml). Combined organic extracts were dried (Na2S04) then evaporated in vacuo to give an oil.
Chromatography on silica with 10 - 100% ethyl acetate - hexane gradient elution gave the title compound (20.5 g, 53%) as an oil.
Mass spectrum (APT'): Found 326 (MH'). C,6H,8F,N,0 requires 325.
'H NMR (CDCl3} 8:1.70 (4H, m}, 2.55 (2H, t, J = 6 Hz), 2.80 (2H, t, J = 6 Hz), 2.95 (2H, t, J = 6 Hz), 3.40 (2H, m), 3.65 (2H, s), 7.20 ( 1 H, d, J = 8 Hz), 7.30 ( 1 H, s), 7.40 (1H, m), 8.0 (1H, br s).
The following compound was prepared in a similar manner to Description 5 2-(4-Tritluoroacetamidobutyl)-7-tritluoromethoxy -1,2,3,4-tetrahydroisoquinoline SUBSTITUTE SHEET (RULE 26) Mass spectrum (API~): Found 384 (MH'). C,6H,gF6N20z requires 384.
Description 6 2-(4-Aminobutyl)-7-cyano-1,2,3,4-tetrahydroisoquinoline S
A solution of 7-cyano-2-(4-trifiuoroacetamidobutyl)-1,2,3,4-tetrahydroisoquinoline (20 g, 61 mmol) was added to a stirred mixture of methanol {450 ml), water (45 ml) and potassium carbonate {56 g, 400 mmol) and heated at reflux for lh. The mixture was cooled then evaporated in vacuo and the residue partitioned between water (500 ml) and dichloromethane (500 ml). The aqueous phase was washed with dichloromethane (2 x 200 ml). The combined organic extracts were dried (NazSO,) and evaporated in vacuo to afford the title compound as a yellow oil (8.6 g, 82%).
Mass spectrum (API'): Found 230 (MH'). C"H,glV3 requires 229.
'H NMR (CDCI,) 8: 1.55 (4H, m), 1.85 (2H, br s), 2.50 (2H, t, J = 7 Hz), 2.75 (4H, m), 2.95 (2H, t, J = 6 Hz), 3.65 (2H, s), 7.20 ( 1 H, d, J = 8 Hz), 7.30 ( 1 H, s), 7.40 ( 1 H, m}.
The following compound was prepared in a similar manner to Description 6 2-(4-Aminobutyl)-7-trifluoromethoxy-1,2,3,4-tetrahydroisoquinoline Mass spectrum (API'): Found 289 (MH'). C,aH,9F,N20 requires 288.
Description 7 4-Phthalimidobutyraldehyde diethyl acetal A solution of 4-aminobutyraldehyde diethyl acetal (48.Sg, 0.3mo1) in tetrahydrofuran (60m1) was added dropwise to a stirred slurry of N (ethoxycarbonyl) phthalimide (65.93g, 0.3mo1) in tetrahydrofuran (250m1) at 0°C. After stirring at 0°C for 0.16h and at room temperature for 18h the solvent was removed in vacuo and the residue distilled at lmmHg to remove the ethyl carbamate by-product. The residual brown oil was allowed to cool to afford the title compound (91g, 93%).
Mass spectrum (API'): 218 (MH' for aldehyde).
'H NMR (CDCl3) 8: 1.20 (6H, t, J = 7 Hz), 1.70 (4H, m), 3.35 - 3.85 (6H, m), 4.55 { 1 H, t, J = 5 Hz), 7.70 (2H, m), 7.85 (2H, m).
Description 8 4-Phthalimidobutyraldehyde SUBSTITUTE SHEET (RULE 26) A solution of 4-phthalimidobutyraldehyde diethyl acetal (125g, 0.43 mol) in a I:1 mixture of tetrahydrofuran and 2N hydrochloric acid (800m1) was heated at reflux for 0.75h. The mixture was cooled, concentrated to 400m1 and extracted into dichloromethane (3x200m1). Combined organics were dried (NazS04) and evaporated in vacuo to afford the title compound as a brown oil that solidified on standing (95g, 100%).
Mass spectrum (API'): 218 (MH'), C,2H"NO, requires 217.
'H NMR (CDC13) 8: 2.00 (2H, m), 2.55 (2H, t, J = 5 Hz), 3.75 (2H, t, J = 5 Hz), 7.70 (2H, m), 7.85 (2H, m), 9.30 ( 1 H, s).
Description 9 7-Methoxy-2-(4-phthalimidobutyl)-1,2,3,4-tetrahydroisoquinoline To a stirred solution of 4-phthalimidobutyraldehyde (15.96g, 0.074 mol} and 7-methoxy-1,2,3,4-tetrahydroisoquinoline (lOg, 0.061 mol) in 1,2-dichloroethane (100 ml) was added sodium triacetoxyborohydride ( 19.3g, 0.091 mol) in three equal portions over 10 mins, followed by glacial acetic acid (3.72 ml, 0.061 mol). The resultant mixture was stirred at room temperature for 3h, then at 45 oC for I h, and poured into saturated aqueous potassium carbonate (600 ml). The mixture was extracted into dichloromethane (2x400 ml) and the combined extracts dried (Na2S04) and evaporated in vacuo. Trituration of the residue with hexane afforded the title compound as a pale brown gum (13.5g, 60%).
Mass spectrum (API): 365 (MH') Cz2H2,N,03 requires 364.
'H NMR (CDCl3) 8: 1.70 (4H, m), 2.50 (2H, m), 2.70 (2H, m), 2.80 (2H, m), 3.55 (2H, s), 3.55 - 3.80 (5H, m), 6.55 (1H, d, J = 2 Hz), 6.70 (1H, dd, J = 2 Hz, 8 Hz), 7.00 ( 1 H, d, J = 8 Hz), 7.70 (2H, m), 7.85 (2H, m).
Description 10 7-Hydroxy-2-(4-phthalimidobutyl)-1,2,3,4~tetrahydroisoquinoline A mixture of 7-methoxy-2-(4-phthalimidobutyl)-1,2,3,4-tetrahydroisoquinoline (58.75g, 0.161 mmol) and dichloromethane (200m1) was treated with ethereal HCl ( 1M;
185 ml) and resulting solution evaporated in vacuo. Residue was dissolved in dichloromethane (500m1), cooled to 0°C, then treated dropwise with a solution of boron tribromide in dichloromethane (IM; 520 mI). Mixture was stirred at 20°C for lh, then poured into a mixture of ice (lkg) and .880 ammonia (1L} with vigorous stirring. Resulting solid was SUBSTITUTE SHEET (RULE 26) filtered off, washed thoroughly with water and dried in vacuo to give the title compound (51.3g, 91 %).
Mass spectrum (APIr): 351 (MH') CZ~H2zN20, requires 350.
'H NMR (CDCl3) 8: I .70 (4H, m), 2.25 - 2.85 ( 1 H, br s), 2.50 (2H, t, J = 7 Hz), 2.70 (2H, d, J = 4 Hz), 2.85 (2H, d, J = 4 Hz), 3.50 (2H, s), 3.75 (2H, t, J = 7 Hz), 6.45 (1H, d, J = 2 Hz), 6.60 ( 1 H,dd, J = 2 Hz, 8 Hz), 6.90 ( I H, d, J = 8 Hz), 7.70 (2H, m), 7.85 (2H, m).
Description 11 2-(4-Phthalimidobutyl)-7-trifluoromethylsulfonyloxy.1,2,3,4.
tetrahydroisoquinoline Trifluoromethylsulfonic anhydride (33m1, 0.194 mmol) was added dropwise with stirring to an ice-cooled solution of 7-hydroxy-2-(4-phthalimidobutyl)-1,2,3,4-tetrahydroisoquinoline (5I .3g, 0.146 mmol} in anhydrous pyridine ( 150m1).
After stirring at room temperature for 18h the reaction mixture was added to 10%
aqueous Copper (II) sulfate (1L) and extracted into ethyl acetate (1L). The organic layer was separated, washed with 10% aqueous copper (II) sulfate (2x500m1), dried (NazSO,) and evaporated in vacuo. Chromatography on silica gel using 10-100% ethyl acetate-hexane gradient elution gave the title compound as a green oil (49.4g, 40%).
Mass spectrum (APIs): 483 (MH'). C22HZ,F,NZOSS requires 482.
'H NMR (CDCI,) S: 1.75 (4H, m), 2.55 (2H, t, J = 7 Hz), 2.75 (2H, t, J = 6Hz), 2.90 (2H, t, J = 6 Hz), 3.60 (2H, s), 3.75 (2H, t, J = 7 Hz), 6.90 ( 1 H, d, J = 2 Hz), 7.05 ( 1 H, dd, J = 2 Hz, 9 Hz), 7.15 ( 1 H, d, J = 9 Hz), 7.70 (2H, m), 7.85 (2H, m).
Description 12 2-(4-Aminobutyl)-7-tritluoromethylsulfonyloxy.1,2,3,4-tetrahydroisoquinoline A mixture of 2-(4-phthalimidobutyl)-7-trifluoromethylsulfonyloxy-I,2,3,4-tetrahydroisoquinoline (49.4g, 0.102 mol), hydrazine hydrate (2lml; 0.42 mol) and ethanol (1L) was stirred at 20°C for 18h then at reflux for lh. Mixture was cooled, filtered, and the filtrate evaporated in vacuo. Residue was partitioned between O.SM
hydrochloric acid (SOOmI) and dichloromethane (3x200m1). Aqueous phase was basified with .880 ammonia then extracted with dichloromethane (4x300mi).
Combined latter extracts were dried (Na2S04) and evaporated in vacuo to give the title compound (30.2g, 84%) as an oil.
Mass spectrum (APT'): 353 (MH'). C"H,9F,N20,S requires 352.

SUBSTITUTE SHEET (RULE 2fi) 'H NMR (CDCl3) S: 1.50 (6H, m), 2.50 (2H, t, J = 7 Hz),2.75 (4H, m), 2.90 (2H, t, J = 6 Hz), 3.60 {2H, s), 6.90 ( 1 H, d, J = 2 Hz), 7.0 ( 1 H, dd, J =
2 Hz, 9 Hz), 7.15 ( 1 H, d, J = 9 Hz).
Example 1 7-Cyano-2-(4-(2-indolylcarboxamido)butyl)-1,2,3,4-tetrahydroisoquinoline A mixture of 2-(4-aminobutyl)-7-cyano-1,2,3,4-tetrahydroisoquinoline (0.35g, 1.53 mmol), indole-2-carboxylic acid (0.25g, 1.53 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.293g, 1.53 mmol) and 1-hydroxybenzotriazole (O.OSg) in dichloromethane ( l Oml) was shaken at 20°C for 24h.
Saturated aqueous NaHC03 (Sml) was added and shaking was continued for lh.
Chromatography of the resulting organic phase on silica with 0 - 10% methanol -ethyl acetate gradient elution gave the title compound (0.305g, 54%) as an oil.
Mass spectrum (API'): Found 373. C23HZ,N,O requires 372.
'H NMR (DMSO-db) b: 1.65 (4H, m), 2.55 (2H, m), 2.73 (2H, t, J = 7 Hz), 2.94 (2H, t, J = 7Hz), 3.36 (2H, m), 3.63 (2H, s), 7.08 ( 1 H, t, J = 9 Hz), 7.14 ( 1 H, d, J = 3 Hz), 7.22 ( 1 H, t, J = 9 Hz), 7.35 ( 1 H, d, J = 9 Hz), 7.47 ( 1 H, d, J = 9 Hz), 7.57 -7.67 (3H, m), 8.54 ( 1 H, t, J = 5 Hz), 11.59 ( 1 H, br s).
The following compounds were prepared in a similar manner to Example 1 (a) 2-(4-(2-Indolylcarboxamido)butyl)- 7-trifluoromethoxy-1,2,3,4-tetrahydroisoquinoline 'H NMR (CDCI,) b: 1.70 (4H, m), 2.55 (2H, t, J = 7Hz), 2.70 (2H, t, J = 6Hz), 2.90 (2H, t, J = 6Hz), 3.55 (2H, m), 3.65 (2H, s), 6.55 ( 1 H, d, J = 2Hz), 6.85 ( 1 H, br s), 6.90-7.10 (3H, m), 7.15-7.30 (2H, m), 7.35-7.50 (2H, m), 10.25 (1H, br s).
Mass spectrum (API'): Found 432 (MH'). CZ,HZQF,N,OZ requires 431.
(b) 2-(4-(5-Indolylcarboxamido)butyl)-7-tritluoromethylsulfonyloxy-1,2,3,4-tetrahydroisoquinoline Mass spectrum (API'): Found 496 (MH+). C23H24F3N,O,S requires 495.

SUBSTITUTE SHEET (RULE 26) 'H NMR (CDC13) b: 1.75 (4H, m), 2.57 {2H, t, J = 6 Hz), 2.72 (2H, t, J = 6 Hz), 2.87 (2H, t, J = 6 Hz), 3.53 (2H, m), 3.61 (2H, s), 6.54 ( 1 H, m), 6.88 (2H, m), 7.00 ( 1 H, dd, J
= 8, 2 Hz), 7.12 ( 1 H, d, J = 8 Hz), 7.18 ( 1 H, d, J = 8 Hz), 7.25 ( 1 H, m), 7.50 ( 1 H, m), 8.05 ( 1 H, s), 8.50 ( 1 H, br s).
(c) 2-(4-(2-Indolyicarboxamido)butyl)-7-trifluoromethylsulfonyloxy-1,2,3,4-tetrahydroisoquinoline Mass spectrum (API+): Found 496 (MH'). CZ3HZ,F,N,O,S requires 495.
'H NMR (CDC13) b: 1.75 (4H, m), 2.59 (2H, m), 2.75 (2H, t, J = 6 Hz), 2.92 (2H, m), 3.53 (2H, m), 3.65 (2H, s), 6.59 ( 1 H, d, J = 2 Hz), 6.86 ( 1 H, br s), 6.94 ( 1 H, d, J = 2 Hz), 7.00 - 7.30 (4H, m), 7.44 (2H, m), 9.30 (1H, br s).
(d) 2-{4-(2-(5-Methoxy)indolylcarboxamido)butyl)-7-trifluoromethoxy-1,2,3,4-tetrahydroisoquinoline Mass spectrum (API~): Found 462 (MH'). Cz4Hz6F,N3O3 requires 461.
'H NMR (CDC13) 8: 1.80 (4H, m), 2.58 (2H, t, J = 6 Hz), 2.75 (2H, t, J = 6 Hz), 2.92 (2H, t, J = 6 Hz), 3.54 (2H, m), 3.65 (2H, s), 3.83 (3H, s), 6.40 ( 1 H, m), 6.78 ( 1 H, m), 6.92 (2H, m), 7.04 { 1 H, m), 7.20 (2H, m), 7.29 ( 1 H, d, J = 8 Hz), 9.45 ( 1 H, br s).
(e) 2-(4-(2-Benzo[b]thienylcarboxamido)butyl)-7-trifluoromethoxy-1,2,3,4-tetrahydroisoquinoiine Mass spectrum (API): Found 449 (MH'). CZ3HZ3F3NzOZS requires 448.
'H NMR (CDC13) 8: 1.75 (4H, m), 2.59 (2H, t, J = 6 Hz), 2.74 (2H, t, J = 6 Hz), 2.86 (2H, t, J = 6 Hz), 3.51 (2H, m), 3.64 (2H, s), 6.84 ( 1 H, m), 6.96 ( 1 H, m), 7.08 ( 1 H, m), 7.15 (1H, m), 7.35 (2H, m), 7.56 (2H, m), 7.75 (1H, m).
(fj 2-(4-(2-(5-Chloro)indolylcarboxamido)butyl)-7-trifluoromethoxy-1,2,3,4-tetrahydroisoquinoline Mass spectrum (APT'): Found 466 (MH+). CZ3HZ335C1F3N3O2 requires 465.
'H NMR (CDC13) 8: 1.75 (4H, m), 2.58 (2H, t, J = 6 Hz), 2.74 (2H, t, J = 6 Hz), 2.90 (2H, t, J = 6 Hz), 3.54 (2H, m), 3.63 (2H, s), 6.50 ( 1 H, m), 6.95 ( 1 H, m), 7.10 (3H, m), 7.30 (3H, m), 10.30 (1H, br s).

SUBSTITUTE SHEET (RULE 26) WO 98/49145 PCT/EP98/o2581 (g) 2-(4-{2-(5-Methyl)indolylcarboxamido)butyl)-7-trifluoromethoxy-1,2,3,4-tetrahydroisoquinoGne Mass spectrum (APT'): Found 446 (MH'). C2,HZ6F3N3OZ requires 445.
'H NMR (CDC13) 8: 1.76 (4H, m), 2.40 (3H, s), 2.59 (2H, t, J = 6 Hz), 2.75 (2H, t, J = 6 Hz), 2.92 (2H, t, J = 6 Hz), 3.52 (2H, m), 3.65 (2H, s), 6.42 ( 1 H, d, J = 2 Hz), 6.89 ( 1 H, s), 7.00 - 7.20 (5H, m), 7.28 ( 1 H, d, J = 8 Hz), 9.12 ( 1 H, br s).
(h) 2-(4-(2-(5-Fluoro)indolylcarboxamido)butyl)-7-trifluoromethoxy-1,2,3,4-tetrahydroisoquinoline Mass spectrum (API'): Found 450 (MH'). C2,Hz3F4N,Oz requires 449.
'H NMR (CDC13) b: 1.77 (4H, m), 2.59 (2H, t, J = 6 Hz), 2.76 (2H, t, J = 6 Hz), 2.92 (2H, m), 3.53 (2H, m), 3.65 (2H, s), 6.47 ( 1 H, d, J = 2 Hz), 6.89 ( 1 H, s), 7.00 - 7.15 (SH, m), 7.20 ( 1 H, br s), 7.31 (2H, m), 9.41 ( 1 H, br s).

- SUBSTITUTE SHEET (RULE 26)

Claims (10)

Claims:

1. A compound of formula (I):
wherein:
R1 represents a substituent selected from: a hydrogen or halogen atom; a hydroxy, cyano, nitro, trifluoromethyl, trifluoromethoxy, trifluoromethanesulfonyloxy, pentafluoroethyl, C1-4alkyl, C1-4alkoxy, arylC1-4alkoxy, C1-4alkylthio, C1-4alkoxyC1-4alkyl, C3-6cycloalkylC1-4alkoxy, C1-4alkanoyl, C1-4alkoxycarbonyl, C1-4alkylsulphonyl, C1-4alkylsulphonyloxy, C1-4alkylsulphonylC1-4alkyl, arylsulphonyl, arylsulphonyloxy, arylsulphonylC1-4alkyl, C1-4alkylsulphonamido, C1-4alkylamido, C1-4alkylsulphonamidoC1-4alkyl, C1-4alkylamidoC1-4alkyl, arylsulphonamido, arylcarboxamido, arylsulphonamidoC1-4alkyl, arylcarboxamidoC1-4 alkyl, aroyl, aroylC1-4alkyl, or arylC1-4alkanoyl 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 C1-4 alkyl group or R3R4 forms part of a C3-6azacyloalkane or C3-6(2-oxo)azacycloalkane ring and p represents zero or an integer from 1 to 4; or a group Ar1Z, 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 CH2;
R2 represents a hydrogen atom or a C1-4alkyl group;
q is 1 or 2;
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;
or a salt thereof.

2. A compound according to claim 1 wherein q represents 1.

3. A compound of formula (I) which is:
2-(4-(2-Indolylcarboxamido)butyl)- 7-trifluoromethoxy-1,2,3,4-tetrahydroisoquinoline;
7-Cyano-2-(4-(2-indolylcarboxamido)butyl)-1,2,3,4-tetrahydroisoquinoline;
2-(4-(5-Indolylcarboxamido)butyl)-7-trifluoromethylsulfonyloxy-1,2,3,4-tetrahydroisoquinoline;

2-(4-(2-Indolylcarboxamido)butyl)-7-trifluoromethylsulfonyloxy-1,2,3,4-tetrahydroisoquinoline;
2-(4-(2-(5-Methoxy)indolylcarboxamido)butyl)-7-trifluoromethoxy-1,2,3,4-tetrahydroisoquinoline;
2-(4-(2-Benzo[b]thienylcarboxamido)butyl)-7-trifluoromethoxy-1,2,3,4-tetrahydroisoquinoline;
2-(4-(2-(5-Chloro)indolylcarboxamido)butyl)-7-trifluoromethoxy-1,2,3,4-tetrahydroisoquinoline;
2-(4-(2-(5-Methyl)indolylcarboxamido)butyl)-7-trifluoromethoxy-1,2,3,4-tetrahydroisoquinoline;
2-(4-(2-(5-Fluoro)indolylcarboxamido)butyl)-7-trifluoromethoxy-1,2,3,4-tetrahydroisoquinoline;
or a salt thereof.

4. A process for preparing a compound of formula (I) or a salt thereof as defined in any of claims 1 to 3 which process comprises:
(a) reacting a compound of formula (II):
wherein R1 and q are as hereinbefore defined;
with a compound of formula (III):
wherein R2 and Ar are as hereinbefore defined;
(b) reaction of a compound of formula (IV):

wherein R1 and R2 are as hereinbefore defined;
with a compound of formula (V):
Ar- COX
Formula (V) wherein Ar is as hereinbefore defined and X is a halogen atom or the residue of an activated ester;
(c) to prepare a compound of formula (I) wherein R1 is Ar1-Z and Z is a bond, reacting a compound of formula (VI):
wherein one R1a 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 R1a is R1; with a compound Ar1-W1, wherein W1 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 trifluoromethyisulphonyloxy group;
(d) to prepare a compound of formula (I) wherein R1 is Ar1-Z and Z is O or S, reacting a compound of formula (VII):
wherein one R1b represent a group ZH and when q is 2 the other R1b represents R1;
with a reagent serving to introduce the group Ar1;
(e) interconversion of one compound of formula (I) to a different compound of formula (I);
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 according 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.