WO1998051671A1

WO1998051671A1 - Substituted tetrahydroisoquinoline derivatives as modulators of dopamine d3 receptors

Info

Publication number: WO1998051671A1
Application number: PCT/EP1998/002584
Authority: WO
Inventors: Christopher Norbert Johnson; Geoffrey Stemp
Original assignee: Smithkline Beecham Plc
Priority date: 1997-05-09
Filing date: 1998-04-28
Publication date: 1998-11-19
Also published as: CA2288850A1; GB9709303D0; EP0983245A1; JP2001525813A

Abstract

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

Description

SUBSTITUTED TETRAHYDROISOQUINOLINE DERIVAΗVES AS MODULATORS OF DOPAMINE D3 RECEPTORS

The present invention relates to novel tetrahydroisoquinoline derivatives, processes for their preparation, pharmaceutical compositions containing them and then- use in therapy, as modulators of dopamine D3 receptors, in particular as antipsychotic agents.

US Patent No. 5,294,621 describes tetrahydropyridine derivatives of the formula:

wherein

is an optionally substituted thienyl or optionally substituted phenyl ring; R.1, R.2 and R.3 are each inter alia hydrogen; X is inter alia (CH2)mNR7co; m is 2-4; and Ar is an optionally substituted heterocyclic ring or an optionally substituted phenyl ring. The compounds are said to be useful as antiarrhythmic agents. European Patent Application 0 464846 Al describes imide derivatives of the formula:

wherein B is a carbonyl group or a sulphonyl group, Rl, R^, R^ and R^ are each hydrogen or a lower alkyl group, or R and R² or R¹ and R^ may be combined together to make a non- aromatic hydrocarbon ring, or R* and R^ may be combined together to make an aromatic ring, and n is 0 or 1; A is a non-aromatic hydrocarbon ring, and p and q are each 0, 1, or 2; Ar is an aromatic ring, a heteroaromatic group, a benzoyl group, a phenoxy group, or a phenylthio group and G is N, CH, or CHOH. The compounds are said to be useful as antipsychotic agents.

WO 95/10513 describes benzothiophene derivatives and related compounds as estrogen agonists.

We have now found a class of tetrahydroisquinoline derivatives which have affinity for dopamine receptors, in particular the D3 receptor, and thus potential in the treatment of conditions wherein modulation of the D3 receptor is beneficial, eg as antipsychotic agents. In a first aspect the present invention provides compounds of formula (I) :

ormula (I) wherein:

R! represents a substituent selected from: a hydrogen or halogen atom; a hydroxy, cyano, nitro, trifluoromethyl, trifluoromethoxy, trifluoromethanesulfonyloxy, pentafluoroethyl, Chal y., Cι _4alkoxy, arylCμ4alkoxy, Ci^alkylthio, Cι.4alkoxyCι-.4-ιlkyl, C3_6cycloalkylCι_4alkoxy, Cι_4-ιlkanoyl, Cι _4alkoxycarbonyl, Cι .4alkylsulphonyl, Cι_4alkylsulphonyloxy,

arylsulphonyl, arylsulphonyloxy, arylsulphonylCi^alkyl, Cι _4alkylsulphonamido, Cι_

C3.6azacyloa.kane or C3_6(2-oxo)azacycloalkane ring and p represents zero or an integer from 1 to 4; or a group Ar³-Z, wherein Ar³ represents an optionally substituted phenyl ring or an optionally substituted 5- or 6- membered aromatic heterocyclic ring and Z represents a bond, O, S , or CH₂;

R2 represents a hydrogen atom or a Cι_4al yl group; q is 1 or 2; s represents an integer from zero to 2 and r represents an integer from 1 to 4, such that the sum of s + r is 1 to 4; t represents an integer from zero to 1 and u represents an integer from zero to 2;

A represents a group of the formula (a), (b) or (c):

-Ar -Y— Ar

(a) (b) (c) wherein

Ar represents an optionally substituted phenyl ring or an optionally substituted 5- or 6- membered aromatic heterocyclic ring; or an optionally substituted bicyclic system; Ar* and Ar^ each independently represent an optionally substituted phenyl ring or an optionally substituted 5- or 6- membered aromatic heterocyclic ring; and

Y represents a bond, -NHCO-, -CONH-, -CH₂-, or -(CH₂)_mY¹(CH₂)_n-, wherein Y¹ represents O, S, SO₂, or CO and m and n each represent zero or 1 such that the sum of m+n is zero or 1 ; providing that when A represents a group of formula (a), any substituent present in Ar ortho to the carboxamide moiety is necessarily a hydrogen or a methoxy group; and salts thereof.

In the compounds of formula (I) above an alkyl group or moiety may be straight or branched. Alkyl groups which may be employed include methyl, ethyl, n-propyl, n- butyl, n-pentyl, n-hexyl and any branched isomers thereof such as isopropyl, t-butyl, sec- pentyl, and the like.

Examples of compounds of formula (I) include those in which Ar is a bicyclic aromatic or heteroaromatic ring system, and t and u are both 1 and in which R is other than pentafluoroethyl. When R* represents an arylCι _4alkoxy, arylsulphonyl, arylsulphonyloxy, arylsulphonylCι _4alkyl, arylsulphonamido, arylcarboxamido, arylsulphonamidoCι _4aIkyl, arylcarboxamidoCι _4alkyl, aroyl, aroylC^alkyl, or arylCι_4-ιlkanoyl group, the aryl moiety may be selected from an optionally substituted phenyl ring or an optionally substituted 5- or 6-membered heterocyclic ring. In the group R¹ an aryl moiety may be optionally substituted by one or more substituents selected from hydrogen, halogen, amino, cyano, C1.4a.kyl, Cι_4alkylamino, C^di-ύcylamino, Cι_4alkylamido, Cι_4alkanoyl, or R^R NCO where each of R^ and R^ independently represents a hydrogen atom or Cι_4alkyl group.

A halogen atom present in the compounds of formula (I) may be fluorine, chlorine, bromine or iodine.

When q is 2, the substituents R* may be the same or different.

An optionally substituted 5- or 6-membered heterocyclic aromatic ring, as defined for any of the groups Ar, Ar , Ar^ or Ar³ may contain from 1 to 4 heteroatoms selected from O, N or S. When the ring contains 2-4 heteroatoms, one is preferably selected from O, N and S and the remaining heteroatoms are preferably N. Examples of 5 and 6- membered heterocyclic groups include furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyridyl, triazolyl, triazinyl, pyridazyl, pyrimidinyl and pyrazolyl.

Examples of bicyclic, for example, bicyclic aromatic or heteroaromatic, ring systems for Ar include naphthyl, indazolyl, indolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzisothiazolyl, quinolinyl, quinoxolinyl, quinazolinyl, cinnolinyl, isoquinolinyl, pyrazolo[l,5- a]pyrimidyl, pyrrolo[3,2-b]pyridyl, pyrrolo[3,2-c]pyridyl, thieno[3,2-b]thiophenyl , 1,2- dihydro-2-oxo-quinolinyl, 2,3-dihydro-3-oxo-4H-benzoxazinyl, 1 ,2-dihydro-2-oxo-3Η- indolyl.

The rings Ar, Ar^, or Ar^ may each independently be optionally substituted by one or more substituents selected from: a hydrogen or halogen atom, or a hydroxy, cyano, nitro, C _4--lkyl, Cι_4--lkoxy, C _4--lky-enedioxy, C ^alkanoyl, C\. alkylsulphonyl, C .₄alkylsulphinyl, C1.4aIkylt.1io, R⁷SO₂N(R⁸)-, R⁷R⁸N-, R⁷R⁸NCO-, R⁷R⁸NSO2-, or R⁷CON(R⁸)- group wherein each of R⁷ and R⁸ independently represents a hydrogen atom or a C1.4 alkyl group, or R⁷R⁸ together form a C3.6 alkylene chain. Alternatively, Ar and Ar^ may be optionally substituted by one or more 5- or 6- • membered heterocyclic rings, as defined above, optionally substituted by a Cι_ alkyl or R⁷R⁸N- group; wherein R⁷ and R⁸ are as defined above.

In the rings Ar and Ar^ substituents positioned ortho to one another may be linked to form a 5- or 6- membered ring.

It will be appreciated that for use in medicine the salts of formula (I) should be physiologically acceptable. Suitable physiologically acceptable salts will be apparent to those skilled in the art and include for example acid addition salts formed with inorganic acids eg. hydrochloric, hydrobromic, sulphuric, nitric or phosphoric acid; and organic acids eg. succinic, maleic, acetic, fumaric, citric, tartaric, benzoic, p-toluenesulphonic, methanesulphonic or naphthalenesulphonic acid. Other non-physiologically acceptable salts eg. oxalates, may be used, for example in the isolation of compounds of formula (I) and are included within the scope of this invention. Also included within the scope of the invention are solvates and hydrates of compounds of formula (I). Certain of the compounds of formula (I) may form acid addition salts with one or more equivalents of the acid. The present invention includes within its scope all possible stoichiometric and non-stoichiometric forms.

It will be appreciated certain of the compounds of formula (I) contain two asymmetric centres. Such compounds can exist in diastereomeric forms, namely cis- and trans- isomers; both forms and all mixtures thereof are included within the scope of this invention. Furthermore, each diastereoisomer can exist as optical isomers (enantiomers). Both the pure enantiomers, racemic mixtures (50% of each enantiomer) and unequal mixtures of the two are included within the scope of the invention. In accordance with convention the (+) and (-) designations used herein indicate the direction of rotation of plane-polarised light by the compounds. The prefix (+) indicates that the isomer is dextrorotatory (which can also be designated d) and the prefix (-) indicates the levorotatory isomer (which can also be designated 1). It will thus be appreciated that the invention extends to the individual diastereoisomers, individual enantiomers and any and all mixtures of these forms. Certain of the other compounds of formula (I) can also exist in the form of cis- and trans- isomers. The present invention includes within its scope all such isomers, including mixtures.

In compounds of formula (I), it is preferred that either t and u are both zero or that t and u are both 1. Certain of the substituted heteroaromatic ring systems included in compounds of formula (I) may exist in one or more tautomeric forms. The present invention includes within its scope all such tautomeric forms, including mixtures.

Particular compounds according to the invention include those specifically exemplified and named hereinafter. The present invention also provides a processs for preparing compounds of formula (I) which process comprises:

(a) reacting a compound of formula (V):

Formula (V)

with a compound of formula (VI):

A-COX

Formula (VI)

wherein A is as hereinbefore defined and X is a halogen atom or the residue of an activated ester;

(b) to prepare a compound of formula (I) wherein R¹ is Ar³-Z and Z is a bond, reacting a compound of formula (VII):

Formula (VII)

wherein one R ^a represents a group W wherein W is a halogen atom or a trifluoromethylsulphonyloxy group, or W is a group M selected from a boron derivative e.g. a boronic acid function B(OH) or a metal function such as trialkylstannyl e.g. SnBu3, zinc halide or magnesium halide, and when q is 2 the other R*^a is Rl; with a compound Ar³-W^, wherein W^ is a halogen atom or a trifluoromethylsulphonyloxy group when W is a group M or W is a group M when W is a halogen atom or a trifluoromethylsulphonyloxy group;

(c) to prepare a compound of formula (I) wherein R¹ is Ar³-Z and Z is O or S, reacting a compound of formula (Vϋl):

Formula (VIII) wherein one R^{1 D} represents a group ZH and when q is 2 the other R^{1 D} represents R¹; with a reagent serving to introduce the group Ar³; (d) to prepare a compound of formula (I) where Y is a bond, reaction of a compound of formula (IX):

Formula (IX)

wherein R , R Ar and W are as hereinbefore defined, with a compound Ar^-W¹, wherein W¹ is a halogen atom or a trifluoromethylsulphonyloxy group when W is a group M, or W is a group M when W is a halogen atom or a trifluoromethylsulphonyloxy group. (e) interconversion of one compound of formula (I) to a different compound of formula (I) e.g. (i) alkylation of a compound (I) wherein R^ represents hydrogen, (ii) conversion of one R¹ from alkoxy (e.g.methoxy) to hydroxy, or (iii) conversion of R from hydroxy to sulphonyloxy, eg alkylsulphonyloxy or trifluoromethanesulphonyloxy;

(iv) conversion of a compound wherein Y represents S to a compound wherein Y is SO₂ or (v) conversion of Y from CO to CH₂;

(f) where appropriate, separation of enantiomers, diastereoisomers, or cis- and trans- isomers of compounds of formula (I), or intermediates thereto, by conventional methods, e.g. chromatography or crystallisation; and optionally thereafter forming a salt of formula (I).

Compounds of formula (V) may be prepared by :-

(g) conversion of a compound of formula (IV):

Formula (IV)

wherein R¹, R^, Γ, S, t and u are as hereinbefore defined and P is a protecting group such as t-butoxycarbonyl or trifluoroacetyl , to a compound of fomula (V).

Compounds of formula (IV) in which t is 1 may be prepared by:-

(h) by reacting a compound of formula (II):

Formula (II)

wherein R! and q are as hereinbefore defined; with a compound of formula (Ilia):

Formula (Ilia)

wherein P, R^, r, s, and u are as hereinbefore defined;

Compounds of formula (IV) where t is zero may be prepared by: -

(i) reacting a compound of formula (II), wherein R and q are hereinbefore defined, with a compound of formula (nib):

Formula (mb)

wherein P, R^, r, s, and u are as hereinbefore defined.

Compounds of formula (V), where t and u are both zero may be prepared by :-

(j) conversion of a compound of formula (X):-

ormula (X)

wherein R¹, q, r and s are as hereinbefore defined and v is 1 or 2, into a corresponding ketone, followed by reductive amination. This may be effected by methods well known in the art for (i) conversion of a ketal to a ketone in the presence of aqueous acid; followed by (ii) reductive amination of the ketone with R^NH₂ or ammonium acetate in the presence of a reducing agent. Suitable reducing agents which may be employed include sodium borohydride, cyanoborohydride or triacetoxyborohydride under acidic conditions, or catalytic hydrogenation. The reaction may conveniently be effected in a solvent such as methanol, ethanol or dichloroethane..

Compounds of formula (X) wherein R and q are as hereinbefore defined, may be prepared by:-

(k) reacting a compound of formula (XI):-

Formula (XI)

wherein v, r and s are as hereinbefore defined, with a compound of formula (II), wherein R! and q are as hereinbefore defined .

Processes (h), (i) and (k) require the presence of a reducing agent. Suitable reducing agents which may be employed include sodium borohydride, cyanoborohydride or triacetoxyborohydride under acidic conditions, or catalytic hydrogenation. The reaction may conveniently be effected in a solvent such as ethanol. Process (g) may be effected by standard methods well known in the art for (i) removal of a t-butoxycarbonyl group, e.g., using acidic conditions; (ii) removal of a trifluoroacetyl group, e.g., using basic conditions.

Reaction of a compound of formula (VII) with Ar W*, according to process (b) or a compound of formula (IX) with Ar^-Wl according to process (d) may be effected in the presence of a transition metal eg palladium catalyst such as bis- triphenylphosphinepalladium dichloride or tetrα/ w-triphenylphosphinepalladium (0). When M represents a boronic acid function such as B(OH)₂the reaction may be carried out under basic conditions, for example using aqueous sodium carbonate in a suitable solvent such as dioxane. When M is trialkylstannyl the reaction may be carried out in an inert solvent, such as xylene or dioxane optionally in the presence of LiCl. When M is a zinc or magnesium halide the reaction may be effected in an aprotic solvent such as tetrahydrofuran. The substituent W is preferably a halogen atom such as bromine, or a sulphonyloxy group such as trifluoromethylsulphonyloxy; and W* is preferably a goup M, such as trialkylstannyl or B(OH) . In process (c) the reagent serving to introduce the group Ar³ is preferably a compound of formula Ar³-Hal, wherein Hal is a halogen atom. The reaction may be effected in the presence of a base, such as potassium carbonate, in a solvent such as dimethylformamide. Interconversion reactions according to process (e) may be effected using methods well known in the art.

Compounds of formula (II) may be prepared by methods known in the art.

Compounds of formula (Ilia) and (Illb) are known or may be prepared using standard procedures.

Compounds of formula (VII), (VIII) or (IX) may be prepared by processes analogous to (a), (g), (h) and (i) described above. Compounds Ar^W , Ar³W and Ar³Hal are commercially available or may be prepared by standard methods.

Compounds of formula (XI) are commercially available or may be prepared using standard procedures.

Compounds of formula (I) have been found to exhibit affinity for dopamine receptors, in particular the D3 receptor, and are expected to be useful in the treatment of disease states which require modulation of such receptors, such as psychotic conditions. Compounds of formula (I) have also been found to have greater affinity for dopamine D3 than for D₂ receptors. The therapeutic effect of currently available antipsychotic agents (neuroleptics) is generally believed to be exerted via blockade of D₂ receptors; however this mechanism is also thought to be responsible for undesirable extrapyramidal side effects (eps) associated with many neuroleptic agents. Without wishing to be bound by theory, it has been suggested that blockade of the recently characterised dopamine D3 receptor may give rise to beneficial antipsychotic activity without significant eps. (see for example Sokoloff et al, Nature, 1990; 347: 146-151; and Schwartz et al, Clinical Neuropharmacology, Vol 16, No. 4, 295-314, 1993). Preferred compounds of the present invention are therefore those which have higher affinity for dopamine D3 than dopamine D₂ receptors (such affinity can be measured using standard methodology for example using cloned dopamine receptors). Said compounds may advantageously be used as selective modulators of D3 receptors.

We have found that certain compounds of formula (I) are dopamine D3 receptor antagonists, others may be agonists or partial agonists. The functional activity of compounds of the invention (i.e. whether they are antagonists, agonists or partial agonists) can be readily determined using the test method described hereinafter, which does not require undue experimentation. D3 antagonists are of potential use as antipsychotic agents for example in the treatment of schizophrenia, schizo-affective disorders, psychotic depression, mania, paranoid and delusional disorders. Conditions which may be treated by dopamine D3 receptor agonists include dyskinetic disorders such as Parkinson's disease, neuroleptic-induced parkinsonism and tardive dyskinesias; depression; anxiety, memory disorders, sexual dysfunction and drug (eg. cocaine) dependency.

In a further aspect therefore the present invention provides a method of treating conditions which require modulation of dopamine D3 receptors, for example psychoses such as schizophrenia, which comprises administering to a subject in need thereof an effective amount of a compound of formula (I) or a physiologically acceptable salt thereof. The invention also provides the use of a compound of formula (I) or a physiologically acceptable salt thereof in the manufacture of a medicament for the treatment of conditions which require modulation of dopamine D3 receptors, for example psychoses such as schizophrenia. A preferred use for D3 antagonists according to the present invention is in the treatment of psychoses such as schizophrenia.

A preferred use for D3 agonists according to the present invention is in the treatment of dyskinetic disorders such as Parkinson's disease.

For use in medicine, the compounds of the present invention are usually administered as a standard pharmaceutical composition. The present invention therefore provides in a further aspect pharmaceutical compositions comprising a novel compound of formula (I) or a physiologically acceptable salt thereof and a physiologically acceptable carrier.

The compounds of formula (I) may be administered by any convenient method, for example by oral, parenteral, buccal, sublingual, nasal, rectal or transdermal administration and the pharmaceutical compositions adapted accordingly.

The compounds of formula (I) and their physiologically acceptable salts which are active when given orally can be formulated as liquids or solids, for example syrups, suspensions or emulsions, tablets, capsules and lozenges. A liquid formulation will generally consist of a suspension or solution of the compound or physiologically acceptable salt in a suitable liquid carrier(s) for example an aqueous solvent such as water, ethanol or glycerine, or a non-aqueous solvent, such as polyethylene glycol or an oil. The formulation may also contain a suspending agent, preservative, flavouring or colouring agent. A composition in the form of a tablet can be prepared using any suitable pharmaceutical carrier(s) routinely used for preparing solid formulations. Examples of such carriers include magnesium stearate, starch, lactose, sucrose and cellulose.

A composition in the form of a capsule can be prepared using routine encapsulation procedures. For example, pellets containing the active ingredient can be prepared using standard carriers and then filled into a hard gelatin capsule; alternatively, a dispersion or suspension can be prepared using any suitable pharmaceutical carrier(s), for example aqueous gums, celluloses, silicates or oils and the dispersion or suspension then filled into a soft gelatin capsule.

Typical parenteral compositions consist of a solution or suspension of the compound or physiologically acceptable salt in a sterile aqueous carrier or parenterally acceptable oil, for example polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil. Alternatively, the solution can be lyophilised and then reconstituted with a suitable solvent just prior to administration.

Compositions for nasal administration may conveniently be formulated as aerosols, drops, gels and_. powders. Aerosol formulations typically comprise a solution or fine suspension of the active substance in a physiologically acceptable aqueous or non- aqueous solvent and are usually presented in single or multidose quantities in sterile form in a sealed container, which can take the form of a cartridge or refill for use with an atomising device. Alternatively the sealed container may be a unitary dispensing device such as a single dose nasal inhaler or an aerosol dispenser fitted with a metering valve which is intended for disposal once the contents of the container have been exhausted. Where the dosage form comprises an aerosol dispenser, it will contain a propellant which can be a compressed gas such as compressed air or an organic propellant such as a fluoro- chlorohydrocarbon. The aerosol dosage forms can also take the form of a pump- atomiser.

Compositions suitable for buccal or sublingual administration include tablets, lozenges and pastilles, wherein the active ingredient is formulated with a carrier such as sugar and acacia, tragacanth, or gelatin and glycerin.

Compositions for rectal administration are conveniently in the form of suppositories containing a conventional suppository base such as cocoa butter.

Compositions suitable for transdermal administration include ointments, gels and patches. Preferably the composition is in unit dose form such as a tablet, capsule or ampoule.

Each dosage unit for oral administration contains preferably from 1 to 250 mg (and for parenteral administration contains preferably from 0.1 to 25 mg) of a compound of the formula (I) or a physiologically acceptable salt thereof calculated as the free base. The physiologically acceptable compounds of the invention will normally be administered in a daily dosage regimen (for an adult patient) of, for example, an oral dose of between 1 mg and 500 mg, preferably between 10 mg and 400 mg.e.g. between 10 and 250 mg or an intravenous, subcutaneous, or intramuscular dose of between 0.1 mg and 100 mg, preferably between 0.1 mg and 50 mg, e.g. between 1 and 25 mg of the compound of the formula (I) or a physiologically acceptable salt thereof calculated as the free base, the compound being administered 1 to 4 times per day. Suitably the compounds will be administered for a period of continuous therapy, for example for a week or more.

Biological Test Methods

The ability of the compounds to bind selectively to human D3 dopamine receptors can be demonstrated by measuring their binding to cloned receptors. The inhibition constants (Kj) of test compounds for displacement of [^5rj iodosulpride binding to human D3 dopamine receptors expressed in CHO cells were determined as follows. The cell lines were shown to be free from bacterial, fungal and mycoplasmal contaminants, and stocks of each were stored frozen in liquid nitrogen. Cultures were grown as monolayers or in suspension in standard cell culture media. Cells were recovered by scraping (from monolayers) or by centrifugation (from suspension cultures), and were washed two or three times by suspension in phosphate buffered saline followed by collection by centrifugation. Cell pellets were stored frozen at -40°C. Crude cell membranes were prepared by homogenisation followed by high-speed centrifugation, and characterisation of cloned receptors achieved by radioligand binding. Preparation of CHO cell membranes

Cell pellets were gently thawed at room temperature, and resuspended in about 20 volumes of ice-cold 50 mM Tris salts (pH 7.4 @ 37°C), 20mM EDTA, 0.2 M sucrose. The suspension was homogenised using an Ultra-Turrax at full speed for 15 sec. The homogenate was centrifuged at 18,000 r.p.m for 20 min at 4°C in a Sorvall RC5C centrifuge. The membrane pellet was resuspended in ice-cold 50 mM Tris salts (pH 7.4 @ 37°C), using an Ultra-Turrax, and recentrifuged at 18,000 r.p.m for 15 min at 4°C in a Sorvall RC5C. The membranes were washed two more times with ice-cold 50 mM Tris salts (pH 7.4 @ 37°C). The final pellet was resuspended in 50 mM Tris salts (pH 7.4 @ 37°C), and the protein content determined using bovine serum albumin as a standard (Bradford, M. M. (1976) Anal. Biochem. 72, 248-254).

Binding experiments on cloned dopamine receptors Crude cell membranes were incubated with 0.1 nM [^5rj iodosulpride (-2000 Ci/mmol; Amersham, U. K.), and the test compound in a buffer containing 50 mM Tris salts (pH

7.4 @ 37°C), 120 mM NaCl, 5 mM KCl, 2 mM CaCl₂, 1 mM MgCl₂, 0.1% (w/v) bovine serum albumin, in a total volume of 1 ml for 30 min at 37°C. Following incubation, samples were filtered using a Brandel Cell Harvester, and washed three times with ice- cold 50 mM Tris salts (pH 7.4 @ 37°C), 120 mM NaCl, 5 mM KCl, 2 mM CaCl₂, 1 mM MgCl₂. The radioactivity on the filters was measured using a Cobra gamma counter (Canberra Packard). Non-specific binding was defined as the radioligand binding remaining after incubation in the presence of 100 uM iodosulpride. For competition curves, 14 concentrations (half-log dilutions) of competing cold drug were used. Competition curves were analysed simultaneously whenever possible using non-linear least-squares fitting procedures, capable of fitting one, two or three site models.

Compounds of Examples tested according to this method had pKi values in the range 7.0 -

8.5 at the human cloned dopamine D3 receptor.

Functional Activity at cloned dopamine receptors

The functional activity of compounds at human D2 and human D3 receptors (ie agonism or antagonism) may be determined using a Cytosensor Microphysiometer (McConnell HM et al Science 1992 257 1906-1912) In Microphysiometer experiments, cells (hD2_CHO or hD3_CHO) were seeded into 12mm Transwell inserts (Costar) at 300000 cells/cup in foetal calf serum (FCS)-containing medium. The cells were incubated for 6h at 37°C in 5%CO₂, before changing to FCS-free medium. After a further 16-18h, cups were loaded into the sensor chambers of the Cytosensor Microphysiometer (Molecular Devices) and the chambers perfused with running medium (bicarbonate-free Dulbecco's modified Eagles medium containing 2 mM glutamine and 44 mM NaCl) at a flow rate of 100 ul/min. Each pump cycle lasted 90s. The pump was on for the first 60s and the acidification rate determined between 68 and 88s, using the Cytosoft programme. Test compounds were diluted in running medium. In experiments to determine agonist activity, cells were exposed (4.5 min for hD2, 7.5 min for hD3) to increasing concentrations of putative agonist at half hour intervals. Seven concentrations of the putative agonist were used. Peak acidification rate to each putative agonist concentration was determined and concentration-response curves fitted using Robofit [Tilford, N.S., Bowen, W.P. & Baxter, G.S. Br. J. Pharmacol. (1995) in press]. In experiments to determine antagonist potency, cells were treated at 30 min intervals with five pulses of a submaximal concentration of quinpirole (100 nM for hD2 cells, 30 nM for hD3 cells), before exposure to the lowest concentration of putative antagonist. At the end of the next 30 min interval, cells were pulsed again with quinpirole (in the continued presence of the antagonist) before exposure to the next highest antagonist concentration. In all, five concentrations of antagonist were used in each experiment. Peak acidification rate to each agonist concentration was determined and concentration-inhibition curves fitted using Robofit.

Pharmaceutical Formulations

The following represent typical pharmaceutical formulations according to the present invention, which may be prepared using standard methods.

IV Infusion

Compound of formula (I) 1-40 mg

Buffer to pH ca 7

Solvent/complexing agent to 100 ml

Bolus Injection

Compound of formula (I) 1-40 mg

Buffer to pH ca 7

Co-Solvent to 5 ml

Buffer : Suitable buffers include citrate, phosphate, sodium hydroxide/hydrochloric acid.

Solven : Typically water but may also include cyclodextrins (1-100 mg) and co- solvents such as propylene glycol, polyethylene glycol and alcohol.

Tablet

Compound 1 - 40 mg Diluent Filler * 50 - 250 mg

Binder 5 - 25 mg

Disentegrant * 5 - 50 mg

Lubricant 1 - 5 mg

Cyclodextrin 1 - 100 mg

may also include cyclodextrins Diluent : e.g. Microcrystalline cellulose, lactose, starch

Binder : e.g. Polyvinylpyrrolidone, hydroxypropymethylcellulose

Disintegrant : e.g. Sodium starch glycollate, crospovidone

Lubricant : e.g. Magnesium stearate, sodium stearyl fumarate.

Oral Suspension

Compound 1 - 40 mg

Suspending Agent 0.1 - 10 mg

Diluent 20 - 60 mg Preservative 0.01 - 1.0 mg

Buffer to pH ca 5 - 8

Co-solvent 0 - 40 mg

Flavour 0.01 - 1.0 mg

Colourant 0.001 - 0.1 mg

Suspending agent :e.g. Xanthan gum, microcrystalline cellulose

Diluent : e.g. sorbitol solution, typically water

Preservative : e.g. sodium benzoate

Buffer : e.g. citrate Co-solvent : e.g. alcohol, propylene glycol, polyethylene glycol, cyclodextrin

The invention is further illustrated by the following non-limiting examples :

Description 1

7-Bromo-l,2,3,4-tetrahydroisoquinoline

A mixture of 7-bromo-2-trifluoroacetyl-l,2,3,4-tetrahydoisoquinoline (G.E. Stokker, Tetrahedron Letters 1996, 37, 5453) (43.4g, 0.14 mol), potassium carbonate (104.3g, 0.75 mol), methanol (IL) and water (150ml) was heated at reflux for lh, then cooled and evaporated in vacuo. Residue was partitioned between water (IL) and dichloromethane (4 x 200ml). Combined extracts were dried (Na.SO₄) and evaporated in vacuo to give an oil which was dissolved in hexane. The mixture was filtered and the filtrate evaporated in vacuo to give the title compound as an oil (17.7g, 60%).

Η NMR (CDC1₃) 5: 1.77 (IH, br s), 2.73 (2H, t, J = 7 Hz), 3.13 (2H, t, J = 7 Hz), 3.98 (2H, s), 6.96 (IH, d, J = 9 Hz), 7.16 (IH, d, J = 2 Hz), 7.26 (IH, dd, J = 9, 2 Hz). The following compounds were prepared in a similar manner to Description 1

(a) 7-Cyano-l,2,3,4-tetrahydroisoquinoline

Mass spectrum (APT): Found 159 (MH⁺). C₁₀H_I0N₂ requires 158.

Description 2 7-Cyano-2-trifluoroacetyl-l,2,3,4-tetrahydroisoquinoIine

A mixture of 7-bromo-2- trifluoroacetyl -1,2,3,4-tetrahydroisoquinoline (51.7 g, 0.168 mol), copper (I) cyanide (31.8 g, 0.35 mol) and N-methyl-2-pyrrolidinone (620 ml) was heated at reflux for 4h, cooled, then partitioned between dilute aqueous ammonia (1.5 L) and dichloromethane (5 x 300ml). The combined organic extracts were dried (Na.SO₄) and evaporated in vacuo to give the title compound (42.6 g, 100 %) as an oil.

Mass spectrum (API): Found 253 (M-H)\ C₁₂H₉F₃N₂O requires 254.

Description 3

(±)--Sr«Λ5-2-((N-(te/ϊ-Butyloxycarbonyl)amino)methyl)cyclopropane-l- carboxaldehyde

To a solution of (±)-trans- 1 -((N-(tert-butyloxycarbonyl)amino)methyl)-2-((tert- butyldiphenylsilyloxy)methyl)cyclopropane [T. Morikawa et al, J. Org. Chem., 1994. 59, 97] (0.33g, 0.75 mmol) in dry THF (10ml) at 0°C, was added a 1M solution of tetra-H- butylammonium fluoride in THF (2.3ml, 2.3 mmol). The mixture was stirred at room temperature for 3 hours, then partitioned between diethyl ether (25ml) and water (25ml). Aqueous phase was further extracted with diethyl ether (25ml x 2) and the combined organic extracts were washed with brine (40ml), dried (Na₂SO ) then evaporated in vacuo to give an oil. To a solution of oxalyl chloride (0.08g, 0.6 mmol) in dry dichloromethane (3ml) at -80°C under argon, was added dropwise a solution of dimethyl sulfoxide (0.09g, 1.2 mmol) in dichloromethane (0.5ml). The resulting mixture was stirred at -78°C for 0.75h, then a solution of the above oil in dry dichloromethane (3ml) was added. The mixture was stirred for lh then triethylamine (1ml) was added and the mixture warmed to room temperature. The mixture was partitioned between dichloromethane (100ml) and water (50ml). The organic layer was washed with water (30ml) and brine (30ml), then dried (Na₂SO₄) and evaporated in vacuo to give the title compound as an oil (0.12g, 98%) 1H NMR (CDCI3) δ: 1.07 (IH, m), 1.30 (IH, m), 1.45 (9H, s), 1.69 - 1.90 (2H, m), 2.95 - 3.30 (2H, m), 4.75 (IH, br s), 9.09 (IH, d, J = 5 Hz).

Description 4 (±)-irα w-l-(N-(-fe -ButyloxycarbonyI)amino)methyl-2-(2-(7-cyano-l,2,3,4- tetrahydro)isoquinolyI)methylcyclopropane

A mixture of (±)-trαn-.-2-((N-(tert-butyloxycarbonyl)amino)cyclopropane-l- carboxaldehyde (0.12g, 0.6 mmol), 7-cyano-l,2,3,4-tetrahydroisoquinoline (0.1 lg, 0.66 mmol) and sodium triacetoxyborohydride (0.19g, 0.9 mmol) in 1,2-dichloromethane (15ml) was allowed to stir at room temperature for 20h, then partitioned between dichloromethane (120ml) and saturated aqueous NaHCO₃ (40ml). Organic phase was washed with saturated NaHCO₃ (40ml), brine (40ml), dried (Na₂SO ) and evaporated in vacuo to an oil. Chromatography on silica with ethylacetate-hexane 20 - 40% gradient elution gave the title compound as an amber oil (0.16g, 78%).

Mass spectrum (API⁺): Found 342 (MH⁺). C₂₀H₂₇N₃O₂ requires 341.

1H NMR (CDCI3) δ: 0.40 - 0.55 (2H, m), 0.85 - 0.91 (2H, m), 1.47 (9H, s), 2.34 - 2.60 (2H, m), 2.75 - 2.85 (2H, m), 2.90 - 3.00 (2H, m), 3.02 - 3.10 (2H, m), 3.55 - 3.80 (2H, m), 4.68 (IH, br s), 7.20 (IH, d, J = 8 Hz), 7.35 (IH, s), 7.40 (IH, d, J = 8 Hz).

The following compound was prepared in a similar manner to Description 4.

(a) i -α«5-2-(l-(4-(f-Butyloxycarbonyl)aminomethyl)cyclohexylmethyl)-7-cyano- 1 ,2,3,4- tetrahydroisoquinoline

Mass spectrum (APf): Found 384 (MH⁺). C₂₃H₃₃N₃O₂ requires 383.

Description 5

(±)-trα/w-l-Aminomethyl-2-(2-(7-cyano-l,2,3,4-tetrahydro)isoquinolyl)- methylcyclopropane

To a solution of (±)-trαrt-.-l-(N-(tert-butyloxycarbonyl)methyl-2-(2-(7-cyano- 1,2,3,4- tetrahydro)isoquinolyl)methylcyclopropane (0.16g, 0.47 mmol) in dry dichloromethane (10ml) at 0°C, was added trifluoroacetic acid (0.36ml). The mixture was stirred at 0°C for lh, then more trifluoroacetic acid (0.4ml) was added. The mixture was stirred at room temperature for 5h, then partitioned between dichloromethane (100ml) and saturated aqueous NaHCO₃ (50ml). Organic phase was washed with brine (50ml), dried(Na₂SO ) and evaporated in vacuo to give the title compound as an amber oil (O.lg, 89%).

Mass spectrum (API⁺): Found 242 (MH⁺). C₁₅Hι₉N₃ requires 241.

1H NMR (CDC1₃) δ: 0.30 - 0.50 (2H, m), 0.70 - 0.90 (2H, m), 1.45 (2H, br s), 2.40 - 3.00 (8H, m), 3.68 (2H, s), 7.17 (IH, d, J = 8 Hz), 7.32 (IH, s), 7.37 (IH, d, J = 8 Hz).

The following compound was prepared in a similar manner to Description 5.

(a) ι ιw-2-(l-(4-Aminomethyl)cyclohexyImethyl)-7-cyano-l,2,3,4- tetrahydroisoquinoline

Mass spectrum (API⁺): Found 284 (MH⁺). Cι₈H₂₅N₃ requires 283.

Description 6

6-Cyano-l,2,3,4-tetrahydroisoquinoIine

Prepared in a similar manner to that described in H.G. Selnick et al., Synthetic Communications 25 (20) 3255 (1995).

Mass spectrum (API⁺): Found 159 (MH⁺). Cι₀Hι₀N₂ requires 158.

Description 7

4-(2-(7-Cyano-l,2,3,4-tetrahydro)isoquinolinyI)cyclohexanone

A mixture of 7-cyano-l,2,3,4-tetrahydroisoquinoline (2.37g, 15 mmol), 1,4-dioxaspiro- [4.5]decan-8-one (2.34g, 15 mmol) and sodium triacetoxyborohydride (4.73g, 22.5 mmol) in dichloroethane (50ml) was stirred at 20°C for 18h. Mixture was partitioned between saturated aqueous NaHCO₃ (250ml) and dichloromethane (3 x 50ml) and the combined organic extracts dried (Na₂SO₄) and evaporated in vacuo to give an oil. Chromatography on silica with 25 - 100% ethyl acetate - hexane gradient elution gave a solid (3.53g). The latter was dissolved in water containing concentrated H₂SO₄ (1.35g, 13.5 mmol) and heated at 65°C for 18h. Mixture was cooled, then partitioned between saturated aqueous NaHCO₃ (300ml) and dichloromethane (3 x 100ml). Combined organic extracts were dried (Na₂SO₄) and evaporated in vacuo to give the title compound (3.14g, 82%) as an oil.

Mass spectrum (APf ): Found 255 (MH⁺). Ci6Hι₈N₂O requires 254.

The following compound was prepared in a similar manner to Description 7

(a) 4-(2-(6-Cyano-l,2,3,4-tetrahydro)isoquinolyl)cyclohexanone

Mass spectrum (API⁺): Found 255 (MH⁺). eHisN_∑O requires 254.

Description 8

cis- and trα»s-7-Cyano-2-(l-(4-trifluoroacetamido)cyclohexyl)-l,2,3,4- tetrahydroisoquinoline

A mixture of 4-(2-(6-cyano- 1,2,3,4- tetrahydro)isoquinolyl)cyclohexanone 2.90g, 11.4 mmol), ammonium acetate (8.7g, 0.11 mol) and sodium triacetoxyborohydride (16.6g, 79.4 mmol) in ethanol (250ml) was heated at reflux for 3h, cooled then evaporated in vacuo. Residue was partitioned between saturated aqueous NaHCO₃ (300ml) and dichloromethane (3 x 100ml). Combined organic extracts were dried (Na₂SO₄) and evaporated in vacuo to give an oil (2.78g). A mixture of the latter with triethylamine (2ml; 14.3 mmol) in dichloromethane (100ml) at 0°C was treated dropwise with trifluoroacetic anhydride (1.9ml, 13.5 mmol). Resulting solution was stirred at 20°C for 4h, then partitioned between saturated aqueous NaHCO₃ (300ml) and dichloromethane (3 x 100 ml). Combined organic extracts were dried (Na₂SO ) and evaporated in vacuo to give an oil. Chromatography on silica with 10 - 100% ethyl acetate - hexane gradient elution gave, as the first-eluting component, the cw-isomer (1.58g, 38%),

1H NMR (CDC1₃) δ: 1.50 - 2.00 (8H, m), 2.48 (IH, m), 2.87 (2H, m), 2.98 (2H, m), 3.78 (2H, s), 4.09 (IH, m), 6.29 (IH, m), 7.22 (IH, ), 7.29 - 7.49 (2H, m),

and, as the second-eluting component, the tran-.-isomer (0.63g, 15%)

Η NMR (CDC1₃) δ: 1.22 - 1.44 (2H, m), 1.45 - 1.64 (2H, m), 2.05 (2H, m), 2.17 (2H, m), 2.55 (IH, «, J = 9, 2 Hz), 2.84 (2H, m), 2.95 (2H, m), 3.78 (2H, s), 3.80 (IH, m), 6.15 (IH, m), 7.19 (IH, d, J = 8 Hz), 7.32 (IH, d, J = 1 Hz), 7.40 (IH, dd, J = 8, 1 Hz). The following compounds were prepared in a similar manner to Description 8.

(a) cis -6-Cyano-2-( l-(4-trifluoroacetamido)cyclohexyl)- 1 ,2,3,4- tetrahydroisoquinoline

1H NMR (CDC1₃) δ: 1.65 - 1.95 (8H, m), 2.47 (IH, m), 2.83 (2H, m), 1.92 (2H, m), 3.77 (2H, s), 4.05 (IH, m), 6.28 (IH, br s), 7.13 (IH, d, J = 8 Hz), 7.39 (2H, m).

(b) ira/w -6-Cyano-2-(l-(4-trifIuoroacetamido)cyclohexyl)- 1,2,3,4- tetrahydroisoquinoline

1H NMR (CDCI3) δ: 1.24 - 1.62 (4H, m), 2.03 (2H, m), 2.15 (2H, m), 2.53 (IH, tt, J = 9, 2 Hz), 2.82 (2H, m), 1.86 (2H, m), 3.76 (IH, m), 3.80 (2H, s), 6.12 (IH, m), 7.09 (IH, d, J = 8 Hz), 7.35 (2H, m).

Description 9

j-- ι-f-2-(l-(4-Amino)cyclohexyl)-7-cyano-1^2,3,4- tetrahydroisoquinoline

A mixture of trαn-.-7-cyano-2-(l-(4-trifluoroacetamido)cyclohexyl)- 1 ,2,3,4- tetrahydroisoquinoline (0.68g, 1.9 mmol), methanol (30ml), water (3.5ml) and anhydrous potassium carbonate (1.3g, 9.6 mmol) was heated at reflux for 3h, cooled then evaporated in vacuo. Residue was partitioned between saturated aqueous K₂CO₃ (50ml) and dichloromethane (3 x 50 ml), and the combined extracts were dried (Na₂SO₄) and evaporated in vacuo to give the title compound (0.48g, 96%) as an oil.

Mass spectrum (API⁺): Found 256 (MH⁺). Cι₆H₂₁N₃ requires 255.

The following compounds were prepared in a similar manner to Description 9.

(a) /r «-.-2-(l-(4-Amino)cyclohexyl)-6-cyano-1^2,3,4- tetrahydroisoquinoline

Mass spectrum (APf ): Found 256 (MH⁺). Ci₆H₂ιN₃ requires 255.

(b) /rα«5-2-(l-(4-(2-Amino)ethyl)cyclohexyl)-7-cyano-l,2,3,4-tetrahydroisoquinoline

Mass spectrum (API⁺): Found 284 (MH⁺). C,₈H₂₅N₃ requires 283. Description 10

4-(2-Trifluoroacetamidoethyl)cyclohexanone

To a mixture of 8-(2-hydroxyethyl)- 1 ,4-dioxaspiro[4.5]decane (15.5g, 83 mmol) and triethylamine (15.2ml; 0.108 mol) in dichloromethane (300ml) under argon at 0°C was added dropwise a solution of methylsulfonyl chloride (7.4ml; 96 mmol) in dichloromethane (10ml). Resulting solution was stirred at 20°C for 2h, then partitioned between saturated aqueous NaHCO₃ (500ml) and dichloromethane (3 x 50ml). Combined organic extracts were dried (Na₂SO₄) and evaporated in vacuo to give an oil (21.8g). The latter was dissolved in toluene (50ml) and added to a solution of trifluoroacetarnide anion prepared by portionwise addition of trifluoroacetarnide (7.9 lg, 70 mmol) to a stirred suspension of sodium hydride (60%; 2.6g, 65 mmol) in dimethylformamide (50ml). The resulting mixture was stirred at 20°C for 18h, then evaporated in vacuo. Residue was partitioned between ether (500ml) and water (350ml). Organic phase was washed with water(2 x

200ml), dried (Na₂SO₄) and evaporated in vacuo to give an oil (15g). Chromatography on silica with 10 - 100% ethyl acetate - hexane gradient elution gave an oil (4.96g). A solution of the latter in tetrahydrofuran (200ml) was treated with water (400ml) and concentrated H₂SO (50 drops), then heated at reflux for 3h. The mixture was cooled, concentrated in vacuo to 200ml, then extracted with dichloromethane (3 x 200ml). Combined extracts were dried (Na₂SO₄) and evaporated in vacuo to give the title compound (3.72g, 19%) as a colourless solid.

Mass spectrum (APT): Found 236 (M-H)^". Cι₀Hι₄F₃NO₂ requires 237.

Description 11

cis- and trα»-f-7-Cyano-2-(l-(4-(2-trifluoroacetamido)ethyl)cyclohexyl)-l^,3,4- tetrahydroisoquinoline

A mixture of 7-cyano-l,2,3,4-tetrahydroisoquinoline (1.5g, 9.5 mmol), 4-(2- trifluoroacetamidoethyl)cyclohexane (2.25g, 9.5 mmol) and sodium triacetoxyborohydride (3.0g, 14.3 mmol) in dichloromethane (100ml) was treated with glacial acetic acid (10 drops) and stirred at 20°C for 18h. Mixture was partitioned between saturated aqueous NaHCO₃ (300ml) and dichloromethane (4 x 50ml), and the combined extracts were dried (Na₂SO₄) and evaporated in vacuo to give an oil (4.0g). Chromatography on silica with 10 - 100% ethyl acetate - hexane gradient elution gave, as the first-eluting component, the cw-isomer (1.98g, 55%)

Η NMR (CDC1₃) δ: 1.44 - 1.85 (11H, m), 2.45 (IH, m), 2.81 (2H, m), 2.92 (2H, m), 3.40 (2H, m), 3.72 (2H, s), 6.31 (IH, br s), 7.20 (IH, d, J = 8 Hz), 7.35 (IH, d, J = 1 Hz), 7.40 (IH, dd, J = 8, 1 Hz), and, as the second-eluting component, the trα w-isomer (0.92g, 26%).

1H NMR (CDClj) δ: 0.95 - 1.17 (2H, m), 1.20 - 1.68 (5H, m), 1.84 - 2.07 (4H, m), 2.50 (IH, tt, J = 9, 2 Hz), 2.85 (2H, m), 2.93 (2H, m), 3.42 (2H, q, J = 7 Hz), 3.78 (2H, s), 6.32 (IH, br s), 7.19 (IH, d, J = 8 Hz), 7.33 (IH, d, J = 1 Hz), 7.40 (IH, d, J = 8, 1 Hz).

Description 12

tjrfl/i-.-4-(/-Butyloxycarbonyl)aminomethylcycIohexanecarboxaldehyde

A mixture of tr n5^,-4-aminomethylcyclohexanecarboxylic acid (20g, 0.127 mol), methanol (250ml) and concentrated sulfuric acid (7.5ml; 0.14 mmol) was heated at reflux for 5h then evaporated in vacuo to give a solid. The latter was mixed with dichloromethane (250ml), triethylamine (64.5ml, 0.463 mol) and di-t-butyl dicarbonate (34g, 0.155 mol), and the resulting solution stirred at 20°C for 18h. Mixture was partitioned between saturated aqueous NaHCO₃ (IL) and dichloromethane (3 x 200ml), and the combined organic extracts were dried (Na₂SO₄) and evaporated in vacuo to give a solid (36.6g). The latter was dissolved in toluene (500ml) and cooled to -78°C under argon. A solution of diisobutylaluminium hydride in toluene (1M; 270ml) was added dropwise over 0.75h, and stirring at -78°C was continued for lh. Methanol (54.5ml) was added dropwise over 0.5h and mixture stirred at -70°C for 0.25h. The resulting solution was then poured into saturated aqueous potassium sodium tartrate (IL), and the mixture stirred vigorously for 3h. The resultant was extracted with ether (3 x 200ml) and the combined organic extracts were dried (Na₂SO₄) and evaporated in vacuo to give an oil (35.5g). Chromatography on silica with 10 - 100% ethyl acetate - hexane gradient elution gave the title compound (20.9g, 64%) as an oil.

1H NMR (CDCI3) δ: 0.92 - 1.09 (2H, m), 1.18 - 1.50 (3H, m), 1.46 (9H, s), 1.89 (2H, m), 2.04 (2H, m), 2.19 (IH, m), 3.00 (2H, t, J = 7 Hz), 4.60 (IH, br s), 9.61 (IH, s).

Example 1

(±)-tr /w-l-((E)-3-(5-Indolyl)propenamido)methyl-2-(2-(7-cyano-l,2,3,4- tetrahydro)isoquinolyl)methylcyclopropane

A mixture of (±)-tr n-;-l-aminomethyl-2-(2-(7-cyano-l,2,3,4- tetrahydro)isoquinolyl)methylcyclopropane (O.lg, 0.4 mmol), (E)-3-(5-indolyl)propenoic acid (0.09g, 0.5 mmol) l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.13g) and 1-hydroxybenzotriazole (0.06g) in dimethylformamide (1ml) and dichloromethane (7ml) was shaken for 20h, then washed with water (7ml).

Chromatography of the organic phase on silica,eluting with ethyl acetate in hexane 20% - 100%, gave the title compound as a colourless solid (0.1 lg, 66%). Mass spectrum (API⁺): Found 411 (MH⁺). C₂₆H₂₆N₄O requires 410.

1H NMR (CDC1₃) δ: 0.44 - 0.64 (2H, m), 0.90 - 1.00 (2H, m), 2.35 - 2.55 (2H, m), 2.75 - 3.00 (4H, m), 3.20 - 3.50 (2H, m), 3.69 (2H, s), 2.75 - 2.80 (IH, m), 6.35 (IH, d, J = 15 Hz), 6.57 (IH, m), 7.10 - 7.40 (6H, m), 7.70 - 7.85 (2H, m), 8.40 (IH, br s).

The following compounds were prepared in a similar manner to Example 1

(a) trα/w-(E)-6-Cyano-2-(l-(4-(3-(4-fluoro)phenylpropenoyI)amino)cycIohexyl)- 1,2,3,4-tetrahydroisoquinoline

Mass spectrum (API⁺): Found 404 (MH⁺). C₂₅H₂₆FN₃O requires 403.

NMR (CDCI3) δ: 1.25 (2H, m), 1.42 - 1.64 (2H, m), 2.00 (2H, m), 2.19 (2H, m), 2.54 (IH, m), 2.85 (4H, m), 3.81 (2H, s), 3.90 (IH, m), 4.47 (IH, d, J = 8 Hz), 6.30 (IH, d, J = 16 Hz), 7.09 (3H, m), 7.34 - 7.55 (4H, m), 7.60 (IH, d, J = 16 Hz).

(b) trαn-.-(E)-7-Cyano-2-(l-(4-(3-phenylpropenoyI)amino)cyclohexyI)-l,2,3,4- tetrahydroisoquinoline

Mass spectrum (API⁺): Found 386 (MH⁺). C₂₅H₂₇N₃O requires 385.

1H NMR (CDCI3) δ: 1.25 (2H, m), 1.44 - 1.66 (2H, m), 2.00 (2H, m), 2.16 (2H, m), 2.44 (IH, m), 2.81 (2H, m), 2.93 (2H, m), 3.76 (2H, m), 3.90 (IH, m), 5.45 (IH, d, J = 8 Hz), 6.35 (IH, d, J = 16 Hz), 7.19 (IH, d, J = 8 Hz), 7.34 (5H, m), 7.49 (2H, m), 7.62 (IH, d, J = 16 Hz).

(c) trα/w-7-Cyano-2-(l-(4-(2-(2-indolyl)carboxamido)ethyl)cyclohexyl)-l,2,3,4- tetrahydroisoquinoline

Mass spectrum (API^*): Found 427 (MH⁺). C₂₇H₃₀N₄O requires 426.

1H NMR (CDC1₃ + CD₃OD) δ: 0.95 - 1.18 (2H, m), 1.25 - 1.48 (3H, m), 1.58 (2H, q, J = 7 Hz), 1.96 (4H, m), 2.50 (IH, m), 2.85 (2H, m), 2.94 (2H, m), 3.50 (2H, m), 3.79 (2H, s), 6.59 (IH, m), 6.89 (IH, s), 7.09 - 7.24 (2H, m), 7.29 (2H, m), 7.37 - 7.50 (2H, m), 7.65 (IH, d, J = 8 Hz), 9.84 (IH, br s).

(d) trα/ι-.-(E)-7-Cyano-2-(l-(4-(3-phenylpropenoyl)aminomethyl)cyclohexylmethyl)- 1,2,3,4- tetrahydroisoquinoline

Mass spectrum (API⁺): Found 414 (MH⁺). C₂₇H_3!N₃O requires 413. 1H NMR (CDC1₃) δ: 0.78 - 1.15 (4H, m), 1.56 (2H, m), 1.86 (4H, m), 2.31 (2H, d, J = .7- Hz), 2.69 (2H, t, J = 6 Hz), 2.93 (2H, t, J = 6 Hz), 3.27 (2H, t, J = 7 Hz), 3.59 (2H, s), 5.74 (IH, m), 6.40 (IH, d, J = 16 Hz), 7.19 (IH, d, J = 8 Hz), 7.33 (IH, s), 7.38 (4H, m), 7.51 (2H, m), 7.64 (IH, d, J = 16 Hz).

(e) -jr /w-7-Cyano-2-(l-(4-(2-indolyI)carboxamidomethyl)cycIohexylmethyl)-l^,3,4- tetrahydroisoquinoline

Mass spectrum (API⁺): Found 427 (MH⁺). C₂₇H₃₀N₄O requires 426.

1H NMR (CDC1₃ + CD₃OD) δ: 0.85 - 1.17 (4H, m), 1.60 (2H, m), 1.90 (4H, m), 2.34 (2H, d, J = 7 Hz), 2.71 (2H, t, J = 6 Hz), 2.95 (2H, t, J = 6 Hz), 3.32 (2H, t, J = 7 Hz), 3.60 (2H, s), 6.75 (IH, m), 6.91 (IH, s), 7.07 - 7.36 (4H, m), 7.42 (2H, m), 7.64 (IH, d, J = 8 Hz), 9.95 (IH, br s).

Claims

A compound of formula (I):

Formula (I) wherein:

R! represents a substituent selected from: a hydrogen or halogen atom; a hydroxy, cyano, nitro, trifluoromethyl, trifluoromethoxy, trifluoromethanesulfonyloxy, pentafluoroethyl, C1-.4a.kyl, C ^alkoxy, arylC _4alkoxy, C _4alkylthio, C╬╣.4a]koxyC╬╣.4alkyl, C3-.6cycloalkylC .4alkoxy, Ci_4alkanoyl, C╬╣_4--lkoxycarbonyl, C 1 _4-tlkylsulphonyl, C 1 _4alkylsulphonyloxy , C 1.4-╬╣lkylsulphonylC 1 _4--lkyl, arylsulphonyl, arylsulphonyloxy, arylsulphonylC^alkyl, C╬╣_4alkylsulphonamido, C╬╣_ 4-╬╣lkylamido, Ci^alkylsulphonamidoC^alkyl, C _4--lkylamidoC _4alkyl, arylsulphonamido, arylcarboxamido, arylsulphonamidoC _4alkyl, arylcarboxamidoCi. 4alkyl, aroyl, aroylCi.4alkyl, or arylC╬╣_4--lkanoyl group; a group R³OCO(CH₂)p, R CON(R⁴)(CH₂)_p, R R⁴NCO(CH₂)_p or R³R⁴NSO₂(CH₂)_p where each of R³ and R⁴ independently represents a hydrogen atom or a C╬╣_4alkyl group or R³R⁴ forms part of a C3_.6azacyloa.kane or C3_6(2-oxo)azacycloalkane ring and p represents zero or an integer from 1 to 4; or a group Ar -Z, wherein Ar³ represents an optionally substituted phenyl ring or an optionally substituted 5- or 6- membered aromatic heterocyclic ring and Z represents a bond, O, S , or CH₂; s represents an integer from zero to 2 and r represents an integer from 1 to 4, such that the sum of s + r is 1 to 4; t represents an integer from zero to 1 and u represents an integer from zero to 2; R2 represents a hydrogen atom or a C^alkyl group; q is 1 or 2;

A represents a group of the formula (a), (b) or (c):

ΓÇö Ar -Ar¹ΓÇö YΓÇö Ar (a) (b) (c) wherein

Ar represents an optionally substituted phenyl ring or an optionally substituted 5- or 6- membered aromatic heterocyclic ring; or an optionally substituted bicyclic ring system;

Ar* and Ar^ each independently represent an optionally substituted phenyl ring or an optionally substituted 5- or 6- membered aromatic heterocyclic ring; and

Y represents a bond, -NHCO-, -CONH-, -CH₂-, or -(CH₂)_mY¹(CH )_n-, wherein ╬│l represents O, S, SO , or CO and m and n each represent zero or 1 such that the sum of m+n is zero or 1; providing that when A represents a group of formula (a), any substituent present in Ar ortho to the carboxamide moiety is necessarily a hydrogen or methoxy group; and salts thereof.

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

3. A compound of formula (I) which is: (┬▒)-tr╬▒n_?-l-((E)-3-(5-Indolyl)propenamido)methyl-2-(2-(7-cyano- 1,2,3,4- tetrahydro)isoquinolyl)methylcyclopropane tr-2n5-(E)-6-Cyano-2-(l-(4-(3-(4-fluoro)phenylpropenoyl)amino)cyclohexyl)-l,2,3,4- tetrahydroisoquinoline tr╬▒n5-(E)-7-Cyano-2-(l-(4-(3-phenylpropenoyl)amino)cyclohexyl)-l,2,3,4- tetrahydroisoquinoline tr╬▒┬½-f-7-Cyano-2-(l-(4-(2-(2-indolyl)carboxamido)ethyl)cyclohexyl)-l,2,3,4- tetrahydroisoquinoline trans -(E)-7-Cyano-2-( 1 -(4-(3-phenylpropenoyl)aminomethyl)cyclohexylmethyl)- 1 ,2,3,4- tetrahydroisoquinoline trfln5-7-Cyano-2-(l-(4-(2-indolyl)carboxamidomethyl)cyclohexylmethyl)-l,2,3,4- tetrahydroisoquinoline or a salt thereof.

4. A process for preparing compounds of formula (I) which process comprises (a) reacting a compound of formula (V):

Formula (V)

with a compound of formula (VI):

A-COX

Formula (VI)

Formula (VII)

wherein one R*^a represents a group W wherein W is a halogen atom or a trifluoromethylsulphonyloxy group, or W is a group M selected from a boron derivative or a metal function, and when q is 2 the other R ^a is R*; with a compound Ar -W , wherein W* is a halogen atom or a trifluoromethylsulphonyloxy group when W is a group M or W* is a group M when W is a halogen atom or a trifluoromethylsulphonyloxy group;

(c) to prepare a compound of formula (I) wherein R! is Ar³-Z and Z is O or S, reacting a compound of formula (VIII):

Formula (VIII) wherein one R*⁰ represents a group ZH and when q is 2 the other Rl┬░ represents R ; with a reagent serving to introduce the group Ar³;

(d) to prepare a compound of formula (I) where Y is a bond, reaction of a compound of formula (IX):

Formula (IX)

wherein Rl, R^, Ar^ and W are as hereinbefore defined, with a compound Ar^-W , wherein W is a halogen atom or a trifluoromethylsulphonyloxy group when W is a group M, or W¹ is a group M when W is a halogen atom or a trifluoromethylsulphonyloxy group.

(e) interconversion of one compound of formula (I) to a different compound of formula (I);

(f) where appropriate, separation of enantiomers, diastereoisomers, or cis- and trans- isomers of compounds of formula (I), or intermediates thereto, by conventional methods; and optionally thereafter forming a salt of formula (I).

5. A pharmaceutical composition comprising a compound of formula (I) as , claimed in any of claims 1 to 3 or a physiologically acceptable salt thereof and a physiologically acceptable carrier therefor.

6. The use of a compound of formula (I) as claimed in any of claims 1 to 3 or a physiologically acceptable salt thereof in the manufacture of a medicament for the treatment of a condition which requires modulation of a dopamine receptor.

7. Use acording to claim 6 wherein the dopamine receptor is a dopamine D3 receptor.

8. Use according to claim 6 or claim 7 wherein a dopamine antagonist is required.

9. Use according to any of claims 6 to 8 wherein the condition is a psychotic condition.

10. A method of treating a condition which requires modulation of a dopamine receptor which comprises administering to a subject in need thereof an effective amount of a compound of formula (I) as claimed in claim 1 or a physiologically acceptable salt thereof.