WO2007093587A1 - Use of r-(-)-2,4-diamino-5-(2, 3-dichlorophenyl)-6-fluoromethyl pyrimidine for the treatment of psychotic disorders - Google Patents

Abstract

The present invention is concerned with the use of R(-)-2,4-diamino-5-(2,3-dichlorophenyl)-6-fluoromethyl pyrimidine of formula (I), or pharmaceutically acceptable salts, solvates or prodrugs thereof, either as monotherapy or in combination with another therapeutic agent, for the treatment of psychotic disorders:

Description

USE OF R- ( - ) -2 , 4-DIAMINO-S- (2 , 3-DICHLOROPHENYL) -6-FLUOROMETHYL PYRIMIDINE FOR THE TREATMENT OF PSYCHOTIC DISORDERS

This invention concerns the use of the compound R(-)-2,4-dlamino-5-(2,3-dichiorophenyi)- 6-fluoromethyl pyrirnidiπe, or pharmaceutically acceptable salts, solvates or prodrugs thereof, for the treatment of psychotic disorders, for example schizofrenia.

R(-)-2,4-diamino-5-{2,3-dicftlorophenyl)-64luoromethyl pyrirnidine, having formula (I) below, and some salts thereof, its preparation and us use in the treatment of pain, functional bowel disorders, epilepsy, bipolar disorders and unipolar depression, dependence, and neurodegenerative diseases are disclosed in published International Patent application WO 97/09317 and in the corresponding patents EP0879230B and US 6,124,308.

The above-mentioned patents and paten! application are herein incorporated by reference as if each individual publication were specifically and individually indicated to be incorporated by reference herein as though fully set forth.

There remains the need to identify further and improved medicaments for the treatment or prevention of psychotic disorders.

The present invention \$ concerned with the use of R(-)-2.4-diaminα-5-(2.3- dicbloroρheny^;)-6-ftuorornethy! pyrimidine of formula (!), or pharmaceutically acceptable salts, solvates or prodrugs thereof, either as monotherapy or in combination with another therapeutic agent, for the treatment of the above mentioned psychotic disorders. in a first aspect, the present invention provides the use of R(-)-2,4-diamino-5-(2,3- dichlorophenyi)-6-fiuorornethyl pyrimidine of formuia (I)₁ or pharmaceutically acceptable salts, solvates or prodrugs thereof, in the treatment of psychotic disorders.

In another aspect, the invention provides the use of R{-)-2,4-dtamiPo-5-(2,3- dich!orophenyl)-€-ftuoromethy! pyrimidine of formula (I)₁ or pharmaceutically acceptable salts, solvates or prodrugs thereof, in the manufacture of a medicament for the treatment of psychotic disorders.

In a further aspect, the invention provides a method of treatment of psycnot^c disorders comprising administering Io a human a therapeutically effective amount of R{-)-2,4- diam!no-5-(2,3-dichiorophenyl)-6-fiυorornethyl pyrimidine of formula (!). or pharmaceutically acceptable salts, solvates or prodrugs thereof.

Within the context of the present invention, the terms describing the indications used herein are classified in the Diagnostic and Statistical Manual of Mentai Disorders, A\h Edition, published by the American Psychiatric Association (DSM-IV) and/or the international Classification of Diseases, 10th Edition (ICD-10). The various subtypes of the disorders mentioned herein are contemplated as part of the present invention. Numbers irs brackets after the listed diseases below refer to the classffication code in DSM-IV.

Psychotic disorders of the invention include: Schizophrenia including the subtypes Paranoid Type (295.30), Disorganised Type (295.10), Catatonic Type (295.20), undifferentiated Type (295.90) and Residua* Type (295.60); Schizophreniform Disorder (295.40); Schizoaffective Disorder (295.70) including the subtypes Bipolar Type and Depressive Type; Delusional Disorder (297.1 ) including the subtypes Erotomanic Type, Grandiose Type, Jealous Type, Persecutory Type, Somatic Type, Mixed Type and Unspecified Type: Brief Psychotic Disorder (298.8); Shared Psychotic Disorder (297.3); Psychotic Disorder Due to a General Medical Condition including the subtypes With Delusions and With Hallucinations; Substance-induced Psychotic Disorder Including the subtypes With Delusions (293.81 } and With Hallucinations (293.82); and Psychotic Disorder Not Otherwise Specified (298.9).

Within the context of the present invention the term schizophrenia also includes cognitive impairment associated with schizophrenia and dementia in schizophrenia.

In one embodiment, the psychotic disorder is Schizophrenia, including the subtypes Paranoid Type (295.30), Disorganised Type (295.10), Catatonic Type (295.20), Undifferentiated Type (295,90) and Residual Type (295.80).

All of the various forms and sub-forms of the disorders mentioned herein are contemplated as part of the present invention.

R(-)-2_>4-diamino-5-(2,3-dichforophenyi}-δ-fiuoromethyi pyrirπidine and salts and solvates thereof are described in PCT publication No. WO 97/09317, published 13 March 1997, and corresponding US 6,124,3O8A and EP087923081. R(-)-2,4-diamino-5-(2,3- dich!oroρhenyi)-6-fiuorornethy! pyrimidine may be prepared by any method described in WO 97/09317. and equivalent patent applications. The disclosure of this reference is incorporated herein in Its entirety.

Conveniently, R{-)-2,4-diamino-5-(2,3-dicrrtorophenyl)-6-f!uoromethyl pyrimidine may be isolated following work-up in the form of the free base. Pharmaceutically acceptable acid addition saits of R(-)-2.4-diamino-5-(2,3-dichiorophenyl)-6-fluoromethy! pyrimidine may be prepared using conventional means,

It is intended that references herein to R{-)-2,4-diammo-5-{2,3-dichloropheny!)-6- fluorornethy! pyrimidine be interpreted to mean that the pharmaceutically acceptable saits, solvates ar>d prodrugs of R{-)-2.4-diamiπo-5-(2,3-dich!orophenyi)-6-fiuoromethy! pyrimidine may also be employed. Typically, a pharmaceutically acceptable salt may be readily prepared by using a desired acid or base as appropriate. The salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent.

Suitable addition salts are formed from acids which form non-toxic salts and examples are hydrochloride, hydrobroroide, hydro! odide, sulphate, disuiphate, nitrate, phosphate, hydrogen phosphate, acetate, maieafe, malate, fumarale, lactate, tartrate, citrate, formate, gluconate, succinate, psruvate, oxalate, oxaloacetate, trifiuoroaceiate. saccharate, beπzoate, methansulphcnate, ethanesuiphonale, benzenesulphonate, p- toiuensulphonate, rnethanesuiphomc, ethanesuiphorsiC, p-toluenesulphonic, and isethionafe.

Those skilled in the art of organic chemistry will appreciate that many organic compounds can form complexes with solvents in which they are reacted or from which they are precipitated or crystal Ii zed, These complexes are known as "solvates". For example, a complex with water is known as a "hydrate".

As used herein, the term "prodrug" means a compound which is converted within the body, e.g. by hydrolysis in the blood, into its active form that has medical effects. Pharmaceutically acceptable proαrugs are described in T. Higuchi and V. Stella, Prodrugs as Novel Deliver/ Systems, Vol. 14 of the A. C. S. Symposium Series, Edward 3. Roche, ed., BioreversiDie Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987. and in D. Fleisher, S. Ramon and H. Barbra ^''improved oral drug delivery: solubility limitations overcome by the use of prodrugs", Advanced Drug Delivery Reviews (1996) 13(2) 115-130, each of which are incorporated herein by reference.

Prodrugs are any covalently bonded carriers thai release R(-)-2,4-diamιno-5-f'2_s3- dichloropheny!)-6-fiuoromethyl pynmsdine in vivo when such prodrug is administered to a patient. Prodrugs are generally prepared by modifying functional groups in a way such that the modification is cleaved, either by routine rnampuiation or in vivo, yielding the parent compound. Prodrugs include, for example, R(-)-2.4-dtam;no-5-{2,3-dιchioropheny!)- 8-tluoromethyl pyrimidine wherein amine groups are bonded to any group that, when administered to a patient, cleaves Io form the amine group. Thus, representative examples of prodrugs include (but are not limited to) acetate, formate and benzoate derivatives of amine functional groups of R(-)-2,4-diaminc~5-(2,3-dich!orophenyl)-6- fiuoromethyi pyrimidine.

R(-)-2,4-diamino-5-(2₁3-dichiorophenyi)-6-flυoromethyl pyrimidine, or pharmaceutically acceptable salts, solvates or prodrug thereof, are coπvenientiy administered in the form of pharmaceutical compositions. Such compositions may conveniently be presented for use in conventional manner in admixture with one or more physiologically acceptable earners or e*

R(-)-2,4-diamino-5-(2,3-dichloropheny!)-6-fluoromefhyl pyάmidine, or pharmaceutically acceptable salts, solvates or prodrug thereof, may be formulated for administration in any suitable manner. They may, for example, be formulated for topical administration or administration by inhalation or. for example, for oral, transdermal or parenteral administration. The pharmaceutical composition may be in a form such that it can effect controlled release of R(-)-2,4-dtaffiino-5-(2,3-dichlorophenyi}-6-fluoromethyl pyrimidine, or pharmaceutically acceptable salts, solvates or prodrug thereof.

The compositions may contain from 0.1% by weight, for example from 10-60% by weight, of the active material, depending on the method of administration. Where the compositions comprise dosage units, each unit will for example contain from 0.5-1000 mg of the active ingredient. The dosage as employed for aduit human treatment may range from 0.5 to 3000 mg per day depending on the route and frequency of administration. For oral administration a typical dose may be in the range of 0.5 to 1500 mg per day. for example 0.5 to 1000 mg per day.

The dosages of the drugs used in She present invention may, in the final analysis, be set by the physician in charge of the case, using knowledge of the drugs, the properties of the drugs in combination as determined in clinical trials, and the characteristics of the patient, including diseases other than that for which the physician is treating iϊ)e patient. General outlines of the dosages, and some examples of dosages, can and will be provided here. For oral administration, the pharmaceutical composition may take the form of, for example, tablets (including sυb-ϋnguai tablets), capsules, powders, solutions, syrups or suspensions prepared by conventional means with acceptable excipients.

For transdermal administration, the pharmaceutical composition may be given in the form of a transdermal patch, such as a transdermal iontophoretic patch.

For parenteral administration, the pharmaceutical composition may be given as an injection or a continuous infusion (e.g. intravenously, intravascular^ or subcutaneousiy).

The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles and may contain forrnuiatory agents such as suspending, stabilising and/or dispersing agents. For administration by injection these may take the form of a unit dose presentation or as a muitidose presentation preferably with an added preservative.

Alternatively for parenteral administration the active ingredient may be in powder form for reconstitution with a suitable vehicle.

R(-)-2,4-diamιno-5-(2.3-dichiorcphenyl)-6-fiucromethyl pyrirnidine, or pharmaceutically acceptable salts, solvates or prodrug thereof, may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example subcutaneousiy or intramuscularly) or by intramuscular injection. Thus, for example, R(-)-2,4~diam!no~5-(2,3-dich!orophenyi)-6-Huoromethyi pyrimidine, or pharmaceutically acceptable salts, solvates or prodrug thereof, may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soiubie derivatives, for example, as a sparingly soluble salt.

A proposed daily dosage of R(-)-2,4-diaminα-5-{2,3-dich!oropherιyi)-8-fluorornethyl pyrimidine for the treatment of man is O.OImg/kg to 500mg/kg, such as Q.05mg/kg to 100mg/kg, e.g. 0.8-3.0mg/kg, which may be conveniently administered in 1 to 4 doses. The precise dose employed wili depend on the age and condition of the patient and on the route of administration. Thus, for example, a daily dose of 0.25mg/kg to 10mg/kg may be suitable for systemic administration.

In a particular embodiment of the present invention, R(-)-2,4-diamιno-5-(2,3- dichiorophenyl)-6-f!uoromethyi pynmidiπe, or pharmaceutically acceptable salts, solvates or prodrug thereof, are υsed in the form of tablets for oral administration.

Furthermore, the invention concerns the use of R{-)-2,4-diam!nα-5-(2.3-dichiorophenyl)-6- fluoromethyi pyrimidine, or pharmaceutically acceptable salts, solvates or prodrug thereof, as monotherapy or in combination with another therapeutic agent for the treatment of psychotic disorders as above defined.

R(-)-2,4-diamino-5-(2,3-dichioropheny!}-6-f1uoromethyl pyrimidine, or pharmaceutically acceptable salts, solvates or prodrug thereof, may be used in combination with the following agents to treat or prevent psychotic disorders: i) neuroleptic drugs; ii) drugs for extrapyramidal side effects, for example anticholinergics (such as benztropine, biperiden. procyciidine and trihexyphenidyl), antihistamines (such as diphenhydramine) and dopaminergics (such as amantadine); iit) antidepressants; iv) anxiolytics; and v) cognitive enhancers for example choirπesterase inhibitors (such as tacrine, donepezii, rivastigmme and galantamiπe).

Neuroleptic drugs include both classical and atypical neuroleptics.

Within the context of the present invention, neuroleptic drugs are also intended to include antipsychotic agents.

Antidepressant drugs include serotonin reuptake inhibitors (such as citaiopram. escitaiopram, fluoxetine, paroxetine and sertraline); dual serotonin/noradrenaiine reuptake inhibitors (such as venlafaxine, duioxetine snά milπaαpran); Noradrenaline reuptake inhibitors (such as reboxetine); tricyclic antidepressants (such as amitriptyline, clomipramine, irniprarnine, maprotiline, nortriptyline and trimipramine); monoamine oxidase inhibitors (such as isocarboxazide, moclobemide. phenelzine and tranylcypromine); and others (such as bupropion, mianserin, mirtazapine, nefazodone and trazodone).

Mood stabiliser drugs include lithium, sodium valproate/valproic acid/divaiproex, carbamazepine, lamotrigiπe, gabapenttn, topiramate and iiagabine.

Anxiolytics include benzodiazepines such as alprazolam and lorazeparn,

As stated above, R{-)-2₎4-diamino-5-{2.3-cichioropheπy!)-6-fluoromethyi pyrimidine, or pharmaceutically acceptable salts, solvates or prodrug thereof, may also be used in combination with other therapeutic agents.

The invention thus provides, -n a further aspect, a combination comprising R(-)-2,4- diamino-5-(2,3-dichlorophenyl)-6-fiuoromethyl pyrimidine, or a pharmaceutically accectable salt, solvate or prodrug thereof, together with a further therapeutic aαent.

The invention thus provides, in a further aspect, a combination comprising R(-)-2,4- diamino-5-(2,3-diChiorophenyi)-6-fluoromethyl pyrimidine, or a pharmaceutically acceptable salt, solvate or prodrug thereof, together with a neuroleptic drug.

The invention thus provides, m another embodiment, a combination comprising R(-)-2.4- diamino-5-(2,3-dichloropheny1)-6-fluoromethy! pyrimidine, or a pharmaceutically acceptable salt, solvate or prodrug thereof, together with 3-{2-[4-(6-fluoro- 1 ,2- ben2isoxazol-3-y!)-1 -ρiperidinyl]ethyi}-2~methyl-6,7,8,9-tetrahydro-4H-pyπdo(1 ,2- a}pyrimidin-4-one. or a pharmaceutically acceptable salt, solvate or prodrug thereof.

The invention thus provides, in one embodiment, a combination comprising R(-)-2,4- diamtno-5-{2,3-dichlorophenyi)-6-fiuoromethyl pyrimidine, or a pharmaceutically acceptable salt, solvate or prodrug thereof, together with 3-hydroxy-2-pheπyi-/V-f(1 S)-I- pheny!propy!]-4-quinoiinecarboxamide, or a pharmaceutically acceptable salt, solvate or prodrug thereof.

The invention thus provides, in a further embodiment, a combination comprising R(-)-2,4- diamino-5-(2₎3-dichioropheπyi)-6-f!υoronnethyl pyrimidine. or a pharmaceutically acceptable salt, solvate or prodrug thereof, together with 7-[4-(4-chloro-benzy!oxy)- benzenesuifonyl]-8-methoκy-3-methyi-2,3,4.5-tetrahydrα-1 W-3-benzazepine. or a pharmace'jticaliy acceptable sal, solvate or prodrug thereof.

The invention thus provides, in a further aspect, a combination comprising R(-)-2,4- diamino-5-(2,3-dichiαrophenyi)-6-fruorornethyl pyrimidine, or a pharmaceutically acceptable salt, solvate or prodrug thereof, together with a further therapeutic agent for use in therapy,

The invention thus provides, in one embodiment, a combination comprising R(-)-2,4- diamino-5-(2,3-dich!orophenyi)-6-fluoromethyl pyrimidine, or a pharmaceutically acceptable salt, solvate or prodrug thereof, together with a neuroleptic drug for use in therapy.

The invention thus provides, in one embodiment, a combination comprising R(-;-2,4- diamino-5-(2,3-dichlαrGphenyi)-6-f!uoromethyl pyrimidine. or a pharmaceutically acceptable salt, solvate or prodrug thereof, together with 3-{2-[4-{6-fIuoro-1 ,2- benzisoxazol-3-yl)-1-piperidiπyi}ethyi}-2-methyl-6,7.8,9-tefrahydro-4W-pyrido[1 ,2- a]pyrim!din-4-one. or a pharmaceutically acceptable salt, solvate or prodrug thereof, for use in

The invention thus provides, in one embodiment, a combination comprising R(-}-2,4- diamιno-5-(2,3-dichlorophanyi)-6-f!uoromefhyl pyrimidine, or a pharmaceutically acceptable salt, solvate or prodrug thereof, together with 3-hydroxy-2-pheny<-Λ/-[(1 S)-1- ρhenyipropyO-4-quinoiineoarboxarnide, or a pharmaceutically acceptable salt, solvate or prodrug thereof, for use in therapy. The invention thus provides, in another embodiment, 3 combination comprising R{-}-2,4- dtamino-5-(2,3-dichiorophenyl)-6-fiuoromethyl pyrimidine, or a pharmaceuiicaliy acceptable salt, solvate or prodrug thereof, together with 7-[4-(4-chlorα-benzyloxy)- benzenesulfonyi]-8-methoxy-3-meihyi-2,3,4,5-te!rahydro-1H-3-benzazep!ne, or a pharmaceutically acceptable salt, solvate or prodrug thereof, for use in therapy.

in a further aspect the present invention provides the use of a combination comprising R{- )-2,4-diarnino-5-(2,3-dichloropheny!)-6-fluoromethy! pyrimidine, or a pharmaceutically acceptable salt, solvate or prodrug thereof, and a neuroleptic drug for ϊne treatment of psychotic disorders as above defined.

in another embodiment, the present invention provides the use of a combination comprising R(-}-2.4-diamino-5-(2,3-dichiorophenyl)-6-fiuorornethyl pyrimidine, or a pharmaceutically acceptable salt, solvate or prodrug thereof, and 3-{2-[4-(6-fiuoro-1 ,2- oenzisoxazo[-3-yl)-1 -piperidinyi]efhyl}-2-rr!eihyi-6.?_>8,9-tetrahydro-4H-pyrido[1 ,2- ajpyrimidin-4-one, or a pharmaceutically acceptable salt, solvate or prodrug thereof, for the treatment of psychotic disorders as above defined.

in another embodiment, the present invention provides the use of a comoination comprising R(-)-2,4-diamino-5-(2,3-dichlorophenyi)-6-f!uoromethyl pyπmidine, or a pharmaceutically acceptable salt, solvate or prodrug thereof, and 3-hydroxy-2-pheny!-Λ/- [(1 S)-1-phenylpropy!]-4-quinoϋnecarboxamide, or a pharmaceutically acceptable salt, solvate or prodrug thereof, for the treatment of psychotic disorders as above defined.

In a further embodiment, the present invention provides the use of a combination comprising R{-)-2,4-diamino-5-(2,3-dscnSorophenyl)-6-fluoromethyi pyrimidine, or a pharmaceutically acceptable salt, solvate or prodrug (hereof, and 7-[4-(4-chloro- benzyloxy)-benzenesuifonyi]-8-me{hoxy-3-methyl-2,3,4,5-tetrahydro-i H-3-benzazepine, or a pharmaceutically acceptable salt, solvate or prodrug thereof, for the treatment of psychotic disorders as above defined. in a further aspect the present invention provides the use of a combination comprising R{- )-2,4-diamino-5-(2,3-cliChlorophenyi}-6-ffuorofnethyl pyrimtdine. or a pharmaceutically acceptable salt, solvate or prodrug thereof, and a neuroleptic drug in the manufacture of a medicament for the treatment of psychotic disorders as above defined.

in another embodiment, the present invention provides the use of a combination comprising R(-)-2,4-diamino-5-(2,3-dichlorophenyl)-6-fluoromethyl pyrimidine, or a pharmaceutically acceptable salt, solvate or prodrug thereof, and 3-{2-[4-(6-fiuoro-1.2- ben2isoxazol-3-yl)-1-pipendinyl}ethyi}-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1 ,2- ajpyrimidin-4-one. or a pharmaceutically acceptable salt, solvate or prodrug thereof, in the manufacture of a medicament for the treatment of psychotic disorders as above defined.

In another embodiment, the present invention provides the use of a combination comprising R(-)-2,4-diamino-5-(2.3-dichiorophenyl)-6-fiuoromethy! pyrimidine, or a pharmaceutically acceptable salt, solvate or prodrug thereof, and 3-hydroxy-2-phenyl-Λ/- [(1 S)-1 -pheny!propy!}-4-quino!inecarboxamide, or a pharmaceutically acceptable salt, solvate or prodrug thereof, in She manufacture of a medicament for the treatment of psychotic disorders as asove defined.

in a further embodiment, the present invention provides the use of a combination comprising R(-)-2_t4-diamino-5-{2,3-dichiorophenyi)-6-fluoromethyl pyrimidine, or a pharmaceutically acceptable salt, solvate or prodrug thereof, and 7-[4-(4-chloro- benzy!oxy)-benzenesulfonyl]-8-methox7-3-methyi-2,3,4,5-teirahydro-1 H-3-ber!za2epine, or a pharmaceutically acceptable salt, solvate or prodrug thereof, in the manufacture of a medicament for the treatment of psychotic disorders as above defined.

Sn a further aspect the present invention provides a method of treatment of psychotic disorders comprising administering to a human a therapeutically effective amount of a combination comprising R(-)-2,4-diamino-5-(2.3-dichiorophenyl)-6-fluoromethyl pyrimidine of formula (I), or a pharmaceutically acceptable salt, solvate or prodrug thereof, and a neuroleptic drug. In another embodiment, the present invention provides a method of treatment of psychotic. disorders comprising administering to a human a therapeutically effective amount of a combination comprising R(-)-2,4-diamho-S-(2,3-dichiorophsnyl)-6-fluoromethyl pyrimidine of formula {!), a or pharmaceutically acceptable sail, solvate or prodrug thereof, and 3-{2- [4-(6-fluoro-1 ,2-benzisoxazo!-3-yi)~1-piρeridinyljethyl}-2-methyi-6_l7_l8,9-tetrahydro-4/-/- pyridol ,2-3jpyrimid^'m-4~one. o-^r a pharmaceutically acceptable salt, solvate or prodrug thereof.

in another embodiment, the present invention provides a method of treatment of psychotic disorders comprising administering to a human a therapeutically effective amount of a combination comprising R(-)-2,4-diamino-5-(2.3-dichlorophenyf)-δ-fluoromethyl pyrimidine of formula (I)₁ a or pharmaceutically acceptable salt, solvate or prodrug thereof, and 3- hydroxy-2-phenyl-Λ/-[{ 1 S)- 1 -phenyipropylH-quinolinecarboxarnide, or a pharmaceutically acceptable salt, solvate or prodrug thereof.

In a further embodiment, the present invention provides a method of treatment of psychotic disorders comprising administering to a human a therapeutically effective amount of a combination comprising R{-)-2,4-di3mino-5-(2,3-dichlorophenyi)-6- flυoromethyl pyrimidine of formula (I), or a pharmaceutically acceotabie salt, solvate or prodrug thereof, and 7-f4-(4-chloro-benzyioxy)-beπzenesuifonyl)-8-methoxy-3-rnethyl- 2,3,4.5-tetrahydrα-1ιH-3-benza2eptne_I or a pharmaceutically acceptable sail, solvate or prodrug thereof.

The combinations referred to above may conveniently be presented for use in the form of pharmaceutical compositions and thus pharmaceutical compositions composing a combination as defined above together with a pharmaceutically acceptable carrier or excipient comprise 8 further aspect of the invention. The individual components of such combinations may be administered either sequentially or simultaneously, in separate or combined pharmaceutical compositions.

in another aspect, the present invention provides the use of R{-)-2,4-d<arnino-5-(2,3- dichlorophenyi)-6-fluoromethy! pyπmidine, or a pharmaceutically acceptable sail, solvate or prodrug thereof, in combination with a neuroleptic drug for the manufacture of a medicament for the treatment of psychotic disorders as defined above.

In another aspect, the present invention provides the use of R(-)-2,4-diarnino-5-(2,3- dichioropheπyl}-6-fiucromethyt pyrimidine, or a pharmaceutically acceptable salt, solvate or prodrug thereof, in combination with a neuroleptic drug for the treatment of psychotic disorders as defined above.

Sn a further aspect the present invention provides a method of treatment of psychotic disorders comprising administering to a human a therapeutically effective amount of R(-)- 2₁4-diamino~5-(2,3~dichiorophenyi)-6-fiuofomethy! pyrimidine, or a pharmaceutically acceptable salt, solvate or prodrug thereof, in combination vv-th a neuroleptic drug for the treatment of psychotic disorders as above defined.

in one embodiment of the present invention, R{-)-2,4-diamino-5-{2,3-dιchlorophenyl)-6- flυorornethyl pyrimidine, or a pharmaceutically acceptable salt, solvate or prodrug thereof, either as monotherapy or in combination with a neuroleptic drug is useful for the treatment of schizophrenia.

Examples of neuroleptic drugs that are useful in the present invention include, but are not limited to; butyrophenonβs, such as haioperidof, pimozide, and droperiσoi; phenothiazines. such as chiorpromazine, thioridazine, mβsoridazine. trifluoperazine, perphenazine, fluphenazine, thiflupromazine, prochlorperazine, and acetophenazine; thiαxanthenes, such as thiothixene and chlorprothixene ; thienobenzodiazepines; dibeπzodiazepiπes; benzisoxazoles; dibenzothiazepines; irnidazolidinones ; benziso- thiazoiyl-piperazines; tiiazine such as iamotrigine; dibenzoxazepines. such as ioxapine; dihydroindolones, such as molindone; aripiprazoie; and derivatives thereof that have antipsychotic activity.

Examples of neuroleptic drugs that may be selected for use in the present invention are shown in Table 1.

Table 1

Neuroleptic drugs

^tS) Dosage ranges and medinnaan dosages are given fo^r oral dosages for an adult of a normal weight (70 kg)

Examples of tradenames and suppliers of selected neurolept c drugs are as follows clozapine ('available jnde- tne rradename CLOZARIL®, rrcm Myian, Zenith Goidime UDL Novartis) olanzapine ^avaiiabie under the tradename ZYPREX^, from Lilly ziprasidone (available under the tiadename GEODON®, from Pfizer) risperidone (available under the tradename R[SPERC⁵ALS Iron Jaπssen), qcet.aome fumarate (available under !he traderame SEROOUEL®, froτ AstraZeneca), halopeπdo! (available jnder the tradename HALDOL© trom Ortho-McNeil), chiof promazine (available under the tiadenarne THORAZINE S, from S¹TtJhK line Beβcham (GSK). fluphenazme (available under the tradename PROLIXlN E-, from Apoihecon, Copley, Scheπno, leva, and American Pharmaceutical Partners, Pasadena), thiothixene (available under the tradename NAVANE®, from Pfizer), tri^fluoperazine (10-l3-(4-m*^sιhyi-1-pιperazιnyi\prooyll-2- (tπflϋoromethyl)phenothiazne dihydrochloπde, available under the tradename STELAZINE?;, from Sn thKf πeBeecham, cerphenaz πe (available under the tradename TRLAFON'S Iron Scheπng), thioridazine (available under ihe tradename MELLARIL®, trom Novartis Roxane, HiTech, Teva, aid Aipharma) . mo irdone (avai abϊe under the tradenane MOBAN® from Endo). and ioxapine (available under ihe tradename LOXiϊANE®; from Watson). Furthermore, benperidol (Glianimon®), perazine (Taxilan®) or melperone (Eunerpan©)) may be used.

Other available neuroleptic drugs Include promazine (available under the tradename SPARINE®), triflurpromazine (available under the tradename VESPRIN®). chiorprothixene (available under the tradename TARACTAN®), droperidoi (available under (he tradename INAPSINE®), acetophenazine (available under (he tradename TINDAl®;), prochlorperazine (available under the tradename COMPAZINE©). rnethotrimeprazinβ (available under the tradename NOZI NAN®), pipotiazine (available under the tradename PiPOTRtL®). ziprasidone, and hoperidone.

Other neuroleptic drugs include the compounds disclosed in the patent application WO03/099786, filed by the same Applicant o'> the present invention. Among them the compound 7-[4-(4-ch!oro-benzyloxy)-benzenesiiifonyi|-8-rnethoxy-3-methyl-2₁3,4,5- te(rahydro-1 /-/-3-beπzazepine and Its pharmaceutically acceptable salts are examples for use in the present invention.

in one embodiment, the neuroleptic drug within the preseni invention is 7-(4-(4-chiofθ- benzyfcxy)-benzenesuifonyi]-8-rf>ethoxy-3-methyl-2,3,4,S-tetrahydro-1H-3-benzazepine maleθle; its manufacture is described in PCT Publication Number WO2005/051916. The disclosure of this reference is incorporated herein in its entirety.

in another embodiment, the neuroleptic drug is 3-hydroxy-2-pheny!-Λ/-[(1 S)-1- phenyipropyl]-4-quinoiinecarboxannide, or pharmaceutically acceptable salts, solvates or prodrugs thereof; its manufacture and pharmacological activity is described in PCT Publication Number WO9S/32948. The disclosure of this reference is incorporated herein in its entirety.

In a furtner embodiment of the present invention neuroleptic drugs include risperidone and aripiprazole (from Bristoi Myers Squibb Company, see e. g. Stahl SM; Dopamine-system stabilizers, aripiprazole and the r\e"xi generation of antipsychotics, part i ,"goldi!ocks"- aclions at dopamine receptors; J, Clin. Psychiatry 2001 ,62,1 1 : 841 -842). in another embodiment of the present invention, the neuroleptic drug within the present invention is 3-{2-[4-(6-fiuoro-1 _!2-benzisoxazoi-3-yi)-1-pipeπdinyl)ethyl}-2-me(hy!-6, 7,8,9- tetrahydro-4H-pyr!do[i ,2-ajpyrimidin-4-one (risperidone or Risperdal®), its manufacture and pharmacological activity is described in EP 0 196 132. Risperidone acts as an antagonist to neurotransmitters, in particular dopamine, and is used for the treatment of psychoses.

Within the present invention, the neuroieptic risperidone can be administered at a dose of 2-6 mg/day, preferably 4-5 mg. The dose for R(-}-2,4-diamino-5~(2,3-dichiorophenyi)-6- fluoromethyl pyrimidine may range from 0,25 mg/kg to 5 mg/kg, preferably 0.8 mg/kg to 3.0 mg/kg. For example, ine administration occurs once daily.

The invention is also directed to a novel kit-of-parts that is suitable for use in the treatment of psychotic disorders as above defined comprising a first dosage form comprising a neuroleptic drug and a second dosage form comprising R(-)-2_i4-diamino-5-{2.3- dichloropheny!)-6-(!uoromethyl pyrimidine, or a pharmaceutically acceptable salt, solvate or prodrug thereof, for simultaneous, separate or sequential administration.

According to one embodiment, the dosage form comprising a neuroieptic drug and the second dosage form comprising R(-)-2,4-diamino-5-(2,3-dichlorophenyi)-δ-flυoromethyl pyrimidine, or a pharmaceutically acceptable salt, solvate or prodrug thereof, are administered simultaneously.

According to another embodiment, the dosage form comprising a neuroleptic drug and the second dosage form comprising R{-}-2,4-diamino-5-(2.3-dichioropheny!)-6-fluoromethyl pyrimidine. or a pharmaceutically acceptable salt, solvate or prodrug thereof, are administered separately.

The dosage forms of pharmaceutical kit-of-parts may be administered enteraily (orally) or parenteraliy. Parenteral administration includes subcutaneous, intramuscular, intradermal, intramammary, intravenous, and other administrative methods known in the art. Enteral administration includes solution, tablets, sustained release capsules, enteric coated capsules, and syrups.

In a further embodiment of the present inversion the administration of dosage forms of pharmaceutical kits comprising R{-)-2,4-ciiamino-5-(2,3-dichiorophenyl)-6-πuoromethyl pyπmitisne , or pharmaceutically acceptable saits, solvates or prodrug ihereof, ,and a neuroleptic occurs enteraily (orally), in form of tablets.

The treatment of psychotic disorders with R(~}-2,4-diamino-5-{2,3-dichioroρheny!}-6- fiυoromethyl pyrirnidine, or a pharmaceutically acceptable salt, solvate or prodrug thereof, alone or in combination with a neuroleptic, may occur in addition to further drug therapies.

Thus, tranquilizers may be used for the treatment of agitation, anxiety or sleep disturbances, Preferably iorazepam is used, which belongs to the class of benzodiazepines.

it will be appreciated that references herein to "treatment" extend to prophylaxis, prevention of recurrence and suppression or amelioration of symptoms (whether mild, moderate or severe) as well as the treatment of established conditions

Preparation of R|-)-2,4^Jam ino-5^2«3-djchlorophenvS)-6-fiuQrornethyl pyrimidinβ (Example 1)

1

To a suspension of 2,3-dichiorophenyiacetonitriie {45 kg, 241 .9 mole) in methanol litres) was charged 30% w/w sodium methoxide in methanol solution ( 1 13.5 kg, 630.6 mole) then ethyifluoroacetate (29.7 kg, 280.1 mole). The reaction mixture was stirred overniøhi and the product was precipitated from aqueous hydrochloric acid (63.7 kg, 648 mole) in water (350 litres). The slurry was filtered and the solid was dissolved in ethyl acetate and washed with brine solution. Ethyl acetate (100 litres) was removed by vacuum distillation. DMF (70 litres) was added and the distillation continued to remove the remaining ethyl acetate.

To the resulting enol in DMF was added potassium carbonate (20 kg. 145 mole) over a period of 10 minutes. Aikyiation of the potassium enoiale was achieved using ethyl iodide (37.7kg, 24^ .9 mole) at 70^'C for VA hours. The reaction mixture was partitioned between toluene (140 litres) and water (75 litres) and the toluene chase was washed with water (50 litres). Toluene (75 iitres) was removed by distillation to afford the crude product as a toluene solution.

intermediate 2 (+/-) 2_!4-Diamiπo-5-(2,3»diGhlQrøphersyi)»6»f]uorQ methylpyrimidine

To gυanidine hydrochloride (25.4 kg, 286 mole) in methanol (80 litres) was added 30% w/w sodium nnethoxide in methanol solution (49.2 kg, 273.3 mole). The suspension was heated to 55^'C+2^"C. The toluene solution of 2-{2,3-dichioropheny!)-3-ethoκy-4-f!uoro-2- butenenitriie was added over a period of 45 minutes and the resultant mixture was boiled under reflux for 4 hours, cooled then quenched into water (230 litres). The solid precipitate was washed with 5 portions of methanol (25 litres) to yield the racemate as an off white solid (26.3 kg, 38% yield from 2,3-dichioropnenylacetonitrile).

Procedure 1 :

To racemic (+/-)2,4-diamino-5-(2.3-dichiorophenyl}-6-fiuoronnethyi pyrirnidine (O.δOO^βg) in a flask was added (-)-dibeπzoyl-L-tartaric acid.H?O (1.049Og). Absolute ethaπol (27.7m!) was added, the mixture was warmed and the resulting solution was IeO overnight. The mother liquor was then decanted from the white crystalline solid that had formed. The solid was dried in a vacuum oven at 50 C overnight. The yield of crystalline material obtained (0.9534-g) was about 52%. The ratio of R(-)-2.4-diamino-5-(2,3-dichioropheαyi)-6-f!υoromethyi pyrimidine ("R{- jenanfiomer³¹) to S(+)-2,4-diamino-5-{2,3-dicNorophenyl)-6-fluoromethyi pyrimidine

("Sf⁺ )enantiomer") was 81:19. Crystalline materia: (0.8796g) obtained in She initial resolution step 1 was dissolved under warming in absolute ethanoi (36 mi), The solution was left to cool overnight. The mother liquor was decanted The white crystalline solid obtained was dried in a vacuum oven at 50^°C overnight; yield (0.611 1g) 89%. The ratio of R(-)enantioroer to S(+)enantiomer was 94:6%.

Recrystailised material (0.5227g) from step 2 was dissolved under warming in absolute etnano,' (25ml). The resuming solution was left to coo! overnight. The rnoiher liquor was then decanted. The remaining white crystalline solid was washed with ethanoi (1 ml) and dried at 50^"C in a vacuum oven overnight; yield (0.397g) 76%. The ratio of R(-) enaπtiomer to S(+)enantiomer was 99.8:0.2.

The crystalline salt from step 3 was then basified with 2M NaOH solution. Thus, distilled water was added to the salt. The resulting siurry was stirred at room temperature. Then 2 M NaOH was added until pH 12 was maintained. The resulting suspension was left for 1 hour. Then the solid was filtered off and washed with water. The wet solid was dried at 50^°C in vacuo to give a white solid.

Procedure 2:

To racemic {÷/-)2,4-diamino-5-{2.3-dich!oroρhenyf)-6-fluoronethyi pyrimidine (78.83g) in a flask, (-)-diben∑oyi-L-iartaric acid, H₂O (103.27g) was added followed by absolute ethanoi (2727ml). The mixture was heated to reflux until ail solids were in solution. The solution was left over 18 hours to cool to rocm temperature The white solid formed was filtered off and dried in vacuo for 3 hours at 5O C. The dried soiid was recrystaiϋsed from absolute ethanoi twice (2 x 1500m!}. The white crystalline soiid obtained was dried at 5Q^"C in vacuo for 6 hours, The ratio of R(-)enantiomer io S(+)enanliomer in the dried crystalline material obtained (22g) was >99:1 .

The mother liquors from the recrystaiiisations were concentrated in vacuo and then \.rea\eό with 2M NaOH (aqueous solution} to basify the salt. Thus, water (100ml) was added to the salt (98g) followed by 2IvI NaOH solution (250m!) in 50m! portions while the suspension was vigorously stirred. The suspension was maintained at pH 12 for 2 hours. The white soiid was filtered off and washed with water (5 x 50 ml) until pH7 was maintained. The solid was dried in vacuo at 50^'C for 4 hours to afford the free base (39g). The ratio of R{-)eπaπtiomer to S(+)enantiomer in the dried free base was 30:70. The free base enriched with She S(+} enantiomer was then recycied to the racemate. Thus, toiuene (500m!) was added to the free base (3Sg). The mixture was healed at reflux for 24 hours and then cooled to room temperature. A brown solid was filtered off which was dried in vacuo at 50^'C for 3 hours. The ratio R(-)enantiomer: S(+)enantiomer in the dried materia! obtained (33g) was 50:50.

This racemate was then submitted to step 1 to obtain more of ihe R (-)enantiomer of >99% enantiomeric purity. The combined salts were toen basified with 2M NaOH solution. Thus, distilled water (250ml) was added to the salts (86.6g) and the slurry stirred at room temperature. Then 2M NaOH (154m!) was added in 50ml portions and then two 2ml portions until pH 12 was maintained. The resulting suspension was left for 1 hour and then the solid was filtered off and washed with water (7 x 100ml). The wet solid was dried at 50^'C in vacuo io give, for this batch, a bυ^*'f-eoioυred solid (37.9g). Other batches however gave a white solid. The ratio of the R(-)eπantiomer to the S(+)enantiomer in the dried material was 99.7:0.3. Chemical purity = 89.2%

PROPERTIES OF R{-}-2₁4-D!AM!NO-5-(2.3-D!CHLOROPHENYL)-6-FLUOROMETHYL

PYRIMIDINE Chemical/Physico-chemical properties Physical appearance: white solid

Melting point: 215-216^'C

Molecular formula: CUH₆CI₂FN₄

Molecular weight: 287.13

Optica! rotation: [α]²⁵⁵ ₀ = -56.75^' (c=0.53. EtOH) [αp_H<3s_<« = -72.07^' (c=0.53, EtOH)

Optical rotation for

S(+)enantiomer: |α)^{2ε ε} _D = + 59.20^' (c=0.52, EtOH)

(α]^{2S S} Hβwβ = + 70.00¹ (c=0.52, EtOH)

NMR data: 7.85 (dd. 1 H₁ 4¹); 7.39 (t. 1 H, 5'); 7.23 (dd, 1 H, 6'); 6.15 (s, 2H₁ 2-NH₂); 5.98 (s. 2H, 4-

NHj); 4,88 (quartet (q), 1 H, CH₂F); 4.64 (q, 1 H₁ CH₂F) Example 2: Patient study

In the following, the invention will be discussed in more detai! with reference to a patient study. Other embodiments within the scope of the claims herein will be apparent to one skilled in ^[he art from consideration of the specification or practice of the invention as disclosed herein.

The study may be performed as a muiticeπter, double-blind, placebo controlled randomised, parallel group determinatior. of efficacy of compound R(-)-2,4-diamino-5-(2,3- dichlorophenyi)-6-fluorornethyl pyrimidine in combination with an atypical antipsychotic agent approved for the treatment of schizophrenia vs an atypical antipsychotic agent approved for the treatment of schizophrenia with placebo.

For example, the study may be performed using a therapeutic dose within the prescribed guidelines of Risperidone.

The patients may receive an appropriate dose of the atypical antipsychotic agent {defined antipsychotic agent or antipsychotic) ,and, depending on which group they belonged, a therapeutically effective amount R(-}-2,4-dian-iino-5-(2,3-dich!orophenyl)-6-fluoromethyl pyrimidine once daily or placebo over 12 weeks after a brief wash-out period of earlier antipsychotic medication.

During the wash-out period, a benzodiazepine preparation (mostly iorazepam) may be prescribed, if necessary. Patients with agitation, anxiety, or sleeping problems may be also medicated with Iorazepam during the study.

Efficacy and tolerabiiity of R{-)-2,4-diarnino-5-(2.3-dichlorophenyl)-6-f!uoromethyi pyrimidine /antipsychotic agent vs placebo/antipsychotic agent will be assessed using the following endpoints - positive and negative syndrome scale (PANSS), Clinical Global impression score (CGi), AIMS, Simpson and Angus. Barnes Akathisia, Calgary

Depression Scale and cognition endpoints.

The use of biperideπ may be monitored as a possible indicator for side effects of the antipsychotic medication.

In order to exclude the chance that possible differences in the therapeutic effectiveness between the two groups might be due to non-compliance during the antipsychotic therapy or to differences in the antipsychotic agent metabolism, the plasma levels of this drug may be monitored during the study. The statistics may be performed according to the criterion of "last observation carried forwarcs" (LOCF), i. e., the last PANSS scores of the patients who dropped out before the end of the study were carried forward io all subsequent observation days. For the comparison of the ma^;n efficacy parameter, the mean change in ihe PANSS between the two treatment groups, t-tests for independent samples may be employed VVHh reference to the underlying hypothesis of a better outcome of R(-)-2,4-diamino-5- (2,3-dichioropheny!)-6-fluoromethyl pyhmidirse/aniipsychotic agent group, a significance of p < 0.05 may be calculated in the one-tailed i-test and used as the basis for the estimation of the sample size (statistical power) and for the comparison of the groups. For ail other comparisons, two-tailed t-tests may be used,

The improved effectiveness of the combination therapy with R(-}-2,4-diamino-5-(2,3- dichlorophenyi)~6-fiuoromethy! pyrimidine /antipsychotic agent in comparison to antipsychotic monotherapy may be clearly shown by the significantly lower PANSS global scores after the T^ό to 12 weeks of treatment Therefore, it coυid be excluded that the observed differences in the therapeutic effectiveness between the two groups may be due to incompatibility during the antipsychotic agent therapy or differences in antipsychotic metabolism. The combination of R(-)-2,4-diamino-5-(2.3-dtchlorophenyl)-6-fiυoromethyl pyrimidine and a atypical antipsychotic agent according to the present invention thus may show improved results compered to the moπopreparation of the atypical antipsychotic agent with regard to effectiveness in the treatment of schizophrenia.

Formulations for pharmaceutical use incorporating R(-)-2,4-diamiπo-5-(2,3- dich!orophenyl)-6-fiuoromethy! pyrimidine

be prepared in various forms and with numerous excipienls. Examples of such formulations are given below. Example 3: Inhalant Formulation

R(>}-2,4-diarnino-5-(2,3-dichlorophenyl)-δ-fluoromethyi pyrimidine or a pharmaceutically acceptable derivative thereof, {1 mg to 100 mg) is aerosolized from a metered dose inhaler to deliver the desired amount of drug per use. Example 4 ; Tablet Formulation Tablets/ingredients Per Tablet

1. Active ingredient 20 mg

2. Corn Starch 20 mα 3. Alginic acid 20 mg

4. Sodium Alginate 20 mg

5. Mg stearate 1.3 mg Procedure for tablet formulation: ingredients 1 , 2, 3 and 4 are blended in a suitable mixer/biender. Sufficient water is added portion-wise to the blend with careful mixing after each addition until the mass is of a consistency to permit its conversion to wet granules. The wet mass is converted to granules by passing it ihrcugh an oscillating granuiator using a No. 8 mesh (2.38 mm) screen. The we? granules are then dried in an oven at 140^*F (60⁰C) until do/. The dry granules are lubricated with ingredient No. 5, and the lubricated granules are compressed on a suitable tablet press, 3ie 5

A pharmaceutical composition for parenteral administration is prepared by dissolving an appropriate amount of R(-)-2,4-diamino-5-(2,3-dichlorophenyi)-6-ftuoromethyl pyrimidine in polyethylene glycol with heating. This solution is then diluted with water for injections

Ph Eur, (to 100 mi). The solution is then rendered sterile by filtration through a 0.22 micron membrane filter and sealed in sterile containers.

Ail publications, including but not limited to patents and patent applications, cited in this specification are herein incorporated by reference as if each individual publication were specifically and individually indicated to be incorporated by reference herein as though fully set forth.

it is to be understood that the present invention covers ail combinations of particular and preferred groups described herein above. The application of which this description and claims forms part may be used as a basis for priority in respect of any subsequent application. The claims of such subsequent application may be directed to any feature or combination of features described herein.

They may take the form of product, composition, process, cr use claims and may include, by way of example and without limitation, the following claims:

Claims

1. Use oi the compound R(-)-2.4-dιam!no-5-(2,3-dιch!orophenyl)-6-f!uorornethy! pyrimidine of formula (!)

NH ₂

or a oharmaceuticaily acceptable salt, solvate or prodrug thereof, in the manufacture of a medicament for the treatment of psychotic disorders.

2. Method of treating psychotic disorders by administering Io a human a therapeutically effective amount of R(-)-2,4-diamino-5-(2,3-dichlorophenyl)-6-fiuoromethy! pyrimidine of formula (I), or a pharmaceutically acceptable sa>l solvate or prodrug thereof.

3. Combination comprising R(-)-2_t4-diamino-5-{2,3-dichloropheny!)-6-f!uoromethyl pyrimidine, or a pharmaceutically acceptable sait. solvate or prodrug thereof, together with a neuroleptic drug.

4. Use of a combination according to claim 3, in the manufacture of a medicament for the treatment of psychotic disorders.

5. Method of treating psychotic disorders by administering to a human a combination according to claim 3,

6. A pharmaceutical composition comprising a combination according to claim 3 and a physiologically acceptable carrier.

7. Kit-of-parts suitable for the treatment of psychotic disorders comprising 3 first dosage form comprising R(-)-2,4-d!amino5-(2,3-dfChiorophenyf)-6-f^"luoromethyl pyrimidine of formula (i), or a pharmaceutically acceptable salt, solvate or prodrug thereof, and comprising a second dosage form comprisin g neuroleptic drug, for simultaneous, separate or sequential administration.