IE20060006A1 - Pharmacologically active CNS compounds - Google Patents

Abstract

A class of substituted phenylpyrimidine compounds are disclosed which are potent inhibitors of the excitatory amino acid, glutamate. Such compounds are useful in the treatment or prevention of a range of CNS disorders including cerebral ischaemic damage and epilepsy.

Description

PHARMACOLOGICALLY ACTIVE CNS COMPOUNDS The present invention relates to a class of pyrimidine compounds which are useful in the treatment of central nervous system (CNS) diseases and disorders such as the prevention of cerebral ischaemic damage . to pharmaceutical compositions containing them, to their use in the treatment of such disorders, and to methods of preparing them.

Glutamate is an excitatory amino acid which functions as a neurotransmitter. However, when its extracellular concentration is sufficiently high, glutamate acts as a powerful neurotoxin, capable of killing neurones in the central nervous system, (Rothman & Olney (1986) Prog.Brain.Res., 63, 69). The neurotoxic effect of glutamate has been implicated in a number of central nervous system disorders and disease states including cerebral ischaemic damage, epilepsy and chronic neurodegenerative disorders, such as Alzheimer's* disease, motor system disorders, and Huntington's chorea, (Meldrum Clinical Science (1985) 68 113-122). In addition, glutamate has been implicated in other neurological disorders such as manic depression, depression, schizophrenia, high pressure neurological syndrome, chronic pain, trigeminal neuralgia and migraine.

In European Patent application No.21121 there is disclosed a group of 3.5- diamino-6-(substituted phenyl )-1,2,4-triazines which are active in the treatment of CNS disorders, for example in the treatment of epilepsy. One compound described in that application, 3.5- diamino-6-(2,3-dichlorophenyl)-l,2,4-triazine (lamotrigine), has been shown to inhibit the release of the excitatory amino acids, glutamate and aspartate, (Leach et a.1 Epilepsia 27, 490-497 1986, A.A.Miller et al New anticonvulsant drugs. Ed. Meldrum and Porter 165-177, 1987).

The present inventors have now found that a series of substituted pyrimidine compounds, as defined in Formula I, are potent inhibitors ^of glutamate release; these compounds are useful in the treatment of INT CL^A6/K Wte Co /0 zy-i/oe, Ca70 - 2 IE 0 600 06 the above mentioned disorders and disease states of the central nervous system. The pyrimidine compounds of formula I are also inhibitors of aspartate release.

Thus in a first aspect of the present invention there is provided the 5 use of a compound of Formula I or an acid addition salt thereof in the manufacture of a medicament for treating or preventing CNS disorders or diseases of a mammal, wherein in Formula I, R, and R9 are the same or different and are selected from hydrogen, 1 1111 halo, hydroxy, alkoxy, alkyl, alkylthio and a group NR R where R and rH are the same or different and are selected from hydrogen, alkyl, aryl and arylalkyl or together with the nitrogen atom to which they are attached form a cyclic ring optionally substituted with one or more alkyl groups and optionally containing a further heteroatom; R-j is hydrogen, alkyl optionally substituted by one or more halo radicals, or is amino, alkylamino, dialkylamino, cyano, nitro, halo, carbamoyl, hydroxy, carboxy, alkoxy, alkylthio, alkylthioalkyl, S(O)nalkyl, di(alkyloxy)alkyl, -C(R):NOH or -COR or -COgR wherein R is hydrogen or alkyl, or a group CH^X where X is hydroxy, alkoxy, 9n aryloxy, arylalkyloxy, halo, cyano, -NR^R^ wherein R1 and R1* are as du 111 defined above, S(0)n-a1kyl where n is 1 or 2, or S02NR R ; each of R^ to Rq are the same or different and each is selected from hydrogen, halo, alkyl, perhaloalkyl, cyano, carbamoyl, carboxy, COR, ΙΕ ο 6 Ο Ο Ο 6 nitro, amino, alkylsulphonylamino, alkoxy, S(O)n-alkyl where n is 1 or 2, or S02NR1R11; or R4 and Rg or Rg and Rg together are the group -CH=CH-CH=CH- or the group -CH2-CH2-CH2-CH2- in which case both R? and Rg are hydrogen; and optionally one of the nitrogen atoms in the pyrimidine ring may be N alkylated or optionally may be an N. oxide; the foregoing alkyl groups or moieties of alkyl-containing groups having from 1 to 6 carbon atoms, and the aryl groups or aryl moieties of aryl-containing groups having 6 or 10 carbon atoms.

Certain compounds of Formula I are chiral, and it will be appreciated that in these instances, Formula I encompasses both the racemic mixture and the individual enantiomers of such compounds. It will also be appreciated that when one or more of Rp R2 and Rg are hydroxy, they may also exist in their tautomeric form.

A preferred class of compounds of Formula I which are potent inhibitors of glutamate are those wherein one of Rj and R2 is amino and the other is selected from amino, hydroxy, halo, morpholino, piperazinyl, N-alkylpiperazinyl, Ν,Ν-dialkylamino, Ν,-alkyl amino or alky1thio; 2o Rg is alkyl optionally substituted by one or more halo radicals, or is alkyl, alkylthio, hydrogen, hydroxy, alkoxy, halo, carboxy, carbamoyl, or a group CH2X where X is hydroxy, phenoxy, benzyloxy, alkoxy or alkylthio; one of R^ and Rg is halo and the other is selected from halo or hydrogen; R, is halo, hydrogen, nitro or amino; 0 1 11 R? is hydrogen, halo, cyano, alkylthio, S02NR R alkyl, nitro, amino or methanesulphonamido; and Rg is hydrogen or halo. . 30 In the present invention, Rji is^ preferably hydroxy, amino, N-alkylamino, N,N-diaJkylamino, morpholino, piperazinyl, N-alkylpiperazinyl; - 4 IE 0 600 0 6 R2 is preferably chloro, amino, Ν,Ν-dialkylamino or piperidino; R-j is preferably hydrogen, alkyl, methoxymethyl, trifluoromethyl, benzyloxymethyl, phenoxymethyl or methylthiomethyl; t0 are PreferablY selected from hydrogen and chloro. Preferably the alkyl moieties contain from 1 to 4 carbon atoms.

In Formula I, advantageously at least one of Rj and Rg is amino and the other is amino, piperazinyl or N-methylpiperazinyl, Ν,-alkylamino, N.,fL-dialkylamino; and Rj is hydrogen, methyl, trifluoromethyl or methoxymethyl.

It is a preferred feature of Formula I that two of R4, Rg and R? are chloro, in particular it is preferred that all of R4, Rg and R? are chloro. Such compounds are highly potent inhibitors of glutamate release. Preferred examples of the group NR^11 are amino, N-methylamino, N-ethylamino, Ν,Ν-dimethylamino, piperazinyl, f(-methylpiperazinyl, piperidinyl, and morpholino.

An especially preferred class of compounds within Formula I are those wherein R^ is selected from amino, piperazinyl, Ν,-methylpiperazinyl, N-morpholino, Ν,,Ν,-dimethylamino, and N-ethylamino; Rg is amino; Rg is selected from trifluoromethyl, hydrogen, methyl, benzyloxymethyl, methoxymethyl and methylthiomethyl; R4 is chloro; and at least one of Rg, Rg and R? is chloro, and the remainder are selected from hydrogen, chloro and nitro; and Rg is hydrogen or R4 and Rg are both hydrogen, Rg and R? are both chloro and Rg is selected from hydrogen chloro and nitro.

The present invention also provides a subclass of compounds of Formula I, which whilst being potent inhibitors of glutamate release show only weak (ie. having an ICgQ of >20pm) or insignificant inhibitory effects on the enzyme dihydrofolate reductase . Accordingly, in a preferred IE 0 6 00 06 embodiment of the present invention there is provided compounds of Formula I where Rj to Rg are hereinbefore defined with the proviso that when R? is halo, then Rg is hydrogen, perhaloalkyl, methyl or methoxymethyl and/or Rg is nitro and/or Rj is ii-alkylpiperazinyl, morpholino, Ν,Ν-dimethylamino, p-iperazinyl or .N-ethylamino; or with the proviso that when Rg is chloro then R4 is halo, and Rg is hydrogen, perhaloalkyl, methoxymethyl, methyl or halo and/or Rj is N-methylpiperazinyl, piperazinyl, morpholino or Ν,Νdimethylamino, or N-ethylamino.

Compounds of Formula I may be used in the treatment or prophylaxis of acute and chronic disorders of the mammalian central nervous system. The acute condition comprises cerebral ischaemia which may arise from a variety of causes including stroke, cardiac arrest, bypass surgery, neonatal anoxia and hypoglycaemia; and also physical injury or trauma of the spinal cord or brain. Chronic neuro- degenerative disorders which may be treated include Alzeheimer’s disease, Huntington's chorea, 01ivopontocerebrellar atrophy, motor system disorders. Other neurological conditions which may be treated with a compound of Formula I include depression, manic depression, schizophrenia, chronic pain, epilepsy, trigeminal neuralgia and migraine.

In a further aspect, the present invention provides a method of treatment or prevention of a CNS disorder or disease of a mammal, including man, comprising the administration to the mammal of a non-toxic effective amount of a compound of Formula 1 or an acid addition salt thereof.

In particular, the present invention provides a method of treating a mammal predisposed to or having neurotoxic extracellular glutamate - 6 ΙΕ ο 6 Ο Ο Ο 6 levels of the central nervous system comprising the administration to the mammal of a non-toxic effective amount of a compound of Formula I or an acid addition salt thereof.

Certain substituted phenylpyrimidines of the present invention are known in the art as having antimalarial activity. See for example Brit.J.Pharmacol. £, 185-200 (1951); JACS. 73, 3763-70, (1951). Other phenylpyrimidines are known from Chem.Biol. Pteridines, 463-468, (1982) and Pharmacotherap.Budesinsky, p.129-141, (1963), ed. Oldrich Hanc.

Nonetheless, certain compounds of the present invention are novel end accordingly the present invention provides a compound of Formula I or an acid addition salt thereof wherein Rj to Rg are as hereindefined, with the proviso that at least one of R^ to Rg is other than hydrogen, and further with the proviso that when Rj and Rg are both amino, or when Rj is hydroxy and Rg is amino, and Rg is alkyl or hydrogen, and Ry is hydrogen, then R^ and Rg are both halo.

Other novel compounds of the present invention are those where R^ to Rg and Rg are as hereinbefore defined and one of R^ or Rg is other than hydrogen, and R? is halo, alkyl, perhaloalkyl, cyano, nitro, amino, alkylthio, S(O)n-alkyl or SOgNR^11.

A third class of novel compounds of the present invention are those of Formula I where R^ is morpholino, piperazinyl, N-alkylpiperazinyl, Ν,Ν-dialkylamino, N-alkylamino or alkylthio and Rg to Rg are as hereinbefore defined.

A fourth class of novel compounds of the present invention are those of Formula I where Rj and Rg are as hereinbefore defined; and Rg is alkoxy, alkylthio or alkyl substituted by one or more halo radicals, or is a group CHgX where X is alkylthio, aryloxy, arylalkyloxy, alkyloxy or hydroxy; - 7 ΙΕ ο 6 Ο Ο Ο 6 R4 to Rg *are the same or different and are each selected from hydrogen, halo, perhaloalkyl, cyano, nitro, amino or alkylthio; Ry is halo, alkyl, perhaloalkyl, cyano, nitro, amino, or a group SOgNiR^bg wherein R^11 is alkyl; and R8 is hydrogen or halo.

A fifth class of novel compounds of the present invention are those of Formula I where R^ and R2 and R^ to Rg are as hereindefined, and Rg is alkoxy, aryloxy, arylalkyloxy or alkylthio. ΙΕ θ 6 ο Ο Ο 6 Preferred novel compounds of the present invention include the following, the numbers referring to the Examples hereinafter appearing:Example No. 1. 4-Amino-2-(4-methylpiperazin-l-yl )-5-(2,3,5-trichlorophenyl )-6trifluoromethylpyrimidine 2. 2,4-Diamino-5-(2,3,5-trich1orophenyl)-6-methoxymethylpyrimidine 3. 4-Ami no-2-(4-methylpiperazin-l-yl )-5-(2,3,5-tri chlorophenyl) pyrimidine 4. 2,4-Diamino-5-(2,3,5-trichloropheny1)-6-trifluoromethylpyrimidine . 2,4-Diamino-5-(4-nitro-2,3,5-trichlorophenyl)pyrimidine 6. 2,4-0iamino-5-(2,3,5-trichlorophenyl)-6-methylpyrimidine 7. 4-Amino-2-N-morpholino-5-(2,3,5-trich1orophenyl)-6-trif luoromethylpyrimidine 8. 4-Amino-2-fj.,Ji-diinethylamino-5-(2,3,5-trichlorophenyl)-6tr ifluoromethylpyrimidine 9. 4-Amino-2-morpholino-N-5-(2,3,5-trichlorophenyl)pyrimidine . 4-Amino-2-N,N-dimethylamino-5-(2,3,5-trichlorophenyl)pyrimidirse 11. 4-Amino-6-methyl-2-(4-methylpiperazin-l-yl )-5-(2,3,5-trichloro2o phenyl)pyrimidine 14. 2,4-Diamino-5-(2,3-dichlorophenyl)-6-trif luoromethylpyrimidine . 2,4-0iamino-5-(2,3-dichloropheny1)-6«methylpyrimidine 16. 2,4-Diamino-5-(2,3-dichlorophenyl)-6-methoxymethylpyrimi dine . 2,4-Diamino-5-(2,4-dichlorophenyl)-6-tr if luoromethylpyrimidine 26. 6-Benzyloxymethyl-2,4-diamino-5-(2,4-dichlorophenyl)pyrimidine 27. 2-N-methy1piperaziny1-4-amino-5-(2,4-dichlorophenyl)pyrimidine 28. 2,4-Diamino-5-(2,5-dichlorophenyl)-6-trif luoromethylpyrimidine 29. 2,4-0iamino-5-(2,3,5-trichlorophenyl)pyrimidine 36. 4-Amino-5-(3,5-dichlorophenyl)-6-methyl-2-(4-methylpiperazin-l30 yl)pyrimidine 58. 4-Amino-2-N-ethylamino-5-(2,3,5-trichlorophenyl)pyrimidine 79. 4-Amino-2-N-methylamino-5-(2,3,5-trichlorophenyl)pyrimidine ,Ί /-a - 9 IE 0 600 0 6 or an acid'addition salt thereof.

Suitable acid addition salts of the compounds of Formula 1 include those formed with both organic or inorganic acids. Such acid addition salts will normally be pharmaceutically acceptable. Thus, preferred salts include those formed from hydrochloric, hydrobromic, sulphuric, citric, tartaric, phosphoric, lactic, pyruvic; acetic, succinic, oxalic, fumaric, maleic, oxaloacetic, methanesulphonic, ethanesulphonic, toluenesulphonic, benzenesulphonic and isethionic acids. These salts can be made by reacting the compound as the free base with the appropriate acid.

While it is possible for the compounds of Formula I to be administered as the raw chemical, it is preferable to present them as a pharmaceutical formulation. The formulations of the present invention comprise a novel compound of Formula I, as above defined, or a pharmaceutically acceptable salt thereof together with one or mere acceptable carriers therefor and optionally other therapeutic ingredients. The carrier(s) must be 'acceptable1 in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

The formulations include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular and intravenous), rectal and topical (including dermal, buccal and sublingual) administration although the most suitable route may depend upon for example the condition and disorder of the recipient. The formulations may conveniently be presented in unit dosage form and may be’ prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing into association a compound of Formula I or a pharmaceutically acceptable acid addition salt thereof ("active ingredient) with the carrier which constitutes one or more accessory Hngredjents. In general the formulations are prepared by uniformly and intimately bringing into association the active, ingredient with - 10 ΙΕ ο 6 Ο Ο Ο 6 liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.

Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary or paste.

A tablet may be made by compression or moulding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a freeflowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, lubricating, surface active or 15 dispersing agent. Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein.

Formulations for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilised) condition requiring only the addition of the sterile liquid carrier, for example, water-for-injection, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the .kind previously described/l IE 060006 - 11 10 Λ Formulations' for rectal administration may be presented as a suppository with the usual carriers such as cocoa butter or polyethylene glycol.

Formulations for topical administration in the mouth, for example buccally or sublingually, include lozenges comprising the active ingredient in a flavoured basis such as sucrose and acacia or tragacanth, and pastilles comprising the active ingredient in a basis such as gelatin and glycerin or sucrose and acacia.

Preferred unit dosage formulations are those containing an effective dose, an hereinbelow recited, or an appropriate fraction thereof, of the active ingredient.

It should be understood that in addition to the ingredients particularly mentioned above, the formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavouring agents.

Tablets or other forms of presentation provided in discrete units may conveniently contain an amount of compound of the Formula I which is effective at such dosage or as a multiple of the same, for instance, units containing 5mg to 500mg, usually around lOmg to 250mg.

The compounds of the Formula I are preferably used to treat CNS disorders or diseases by oral administration or injection ♦ (intraparenteral or subcutaneous). The precise amount of compound administered to a patient will be the responsibility of the attendant physician. However the dose employed will depend on a number of factors, including the age and sex of the patient, the precise disorder being treated, and its severity. Thus for example when treating a patient with epilepsy the dose range is likely to be significantly lower than when treating a patient after stroke to - 12 .

IE 0600 06 alleviate Cerebral ischaemic damage. Also the route of administration is likely to vary depending on the condition and its severity.

The compounds of the Formula I may be administered orally or via injection at a dose of from 0.1 to 30mg/kg per day. The dose range for adult humans is generally from 8 to 2,400 mg/day and preferably 35 to 1,050 mg/day. As certain compounds of the Formula I are long acting, it may be advantageous to administer an initial dose of 70 to 2,400 mg the first day then a lower dose of 20 to 1,200 mg on subsequent days.

Examples of such long acting compounds are: 2.4- diamino-5-(2,3,5-trichlorophenyl)-6-trifluoromethylpyrimidine; 4-amino-2-(4-methylpiperazin-l-yl)-5-(2,3,5-trichlorophenyl)-6trifluoromethylpyrimidine; and 4-amino-2-(4-methylpiperazin-l-yl)-5-(2,3,5-trichlorophenyl)15 pyrimidine.

Long acting compounds in the clinic are advantageous because they are easier to manage. In the chronic situation, they may be administered without infusion and there is the minimum of direct, medical intervention; also in acute conditions, patient compliance is encouraged by minimising daily dosing. Conversely, short acting compounds such as: 2.4- diamino-5-(2,3,5-trichlorophenyl)-6-methoxymethylpyrimidine permit the clinician to control the pharmacological effect of the compound with great precision, since such compounds will be cleared from the central nervous system rapidly.

IE 0 6 00 0 6 - 13 Compounds of the present invention may be made in any manner known to make analogous compounds known in the art (eg. JACS vol 73 (1951) 3763-70).

The present invention also provides a process for the compound of Formula I or an acid addition salt preparation of a thereof, which and V is cyano or carboxy, carbonyl, or alkoxycarbonyl with a compound or salt thereof of formula III II leaving group, n _ 1,1 HiKi-C- R, wherein Rj is as hereindefined, and isolating the compound of Formula I as the free base or an acid addition salt thereof, and optionally converting the base into an acid addition salt thereof or into another acid addition salt, or into another compound of Formula I or an acid addition salt thereof.

It will be appreciated that certain compounds of Formula III for example where Rj is hydroxy exists in the corresponding tautomeric form (eg. as urea).

As examples of interconversion of compounds of Formula I, when in the product of the above process one of Rp R2 or R^ is hydroxy the compound may be halogenated for example using the Vilsmeier Haack reagent or phosphorus oxychloride (POCK), to the corresponding halo compound. This compound may be further converted into a compound of Formula I wherein Rp R2 or R^ is alkylthio by reaction with the IE 0 6 00 06 - 14 appropriate alkylthiolate or to the corresponding amino compound (R., 11 * R2 or Rg being NR R ) by reaction with the appropriate amino compound in a suitable solvent such as an alkanol, eg. ethanol, or converted to a compound where Rj, or ^3 1S alkoxy by reaction with appropriate alkoxide.

If it is required to make a compound of Formula I in which one of R^ to Rg is nitro, this can be made from the corresponding compound of Formula I where one of R^ to Rg is hydrogen by utilising standard nitration conditions, eg. sulphuric acid and potassium nitrate, and then further converted by standard reduction means to the corresponding amino compound, eg. utilising PtOg, AcOH, Hg.

It will be appreciated that amino or halo compounds can be further converted to R^ to Rg as herewithin defined by standard interconversion, for example, via the diazonium salts. When Rg is alkyl this may be converted into perhaloalkyl, or a halogenated alkyl moiety by reaction with the appropriate halogen or N-halo succinimide (NXS) in a suitable solvent such as acetic acid.

Compounds in which Rg is CHfOEtJg may be converted into the corresponding aldehyde by hydrolysis with dilute acid(s) and thereafter reduced to the corresponding alcohol with a standard reducing agent (eg. sodium borahydride NaBH^), or converted to the corresponding oxime (hydroxylamine hydrochloride in ethanol), which in turn can be converted to the corresponding cyano compound utilising, for example trifluoroacetic anhydride (TFAA), and then to the corresponding amido compound utilising concentrated sulphuric acid. Alternatively, the aldehyde may be oxidised with KMnO^ (potassium permanganate) to give the corresponding acid, which may in turn be reacted with an alcohol to give the corresponding ester. φ Where in the product of the above process Rg is a group CH^OR where R ( 30 is alkyl or arylalkyl this product may be converted to CHgX by reaction with HX (X » halo) in, for example acetic acid, and this IE 0 6 00 0 6 - 15 further converted to the corresponding cyano compound, for example by treatment with sodium cyanide and OMF, or to fluoromethyl by treatment with for example cesium fluoride (CsF) or to a group CHgNR^11 by reaction with the appropriate amine. Alternatively, the group CHgOR can be dealkylated to give the corresponding alcohol, for example with MegSil, and this further converted to fluoromethyl with diethylaminosulphur trifluoride (DAST).

Where Rg to Rg contains an alkylthio moiety, this can be oxidised to the corresponding sulphoxide and sulphone using for example MCPBA (metachloroperbenzoic acid).

It will be appreciated that other interconversions may be effected as required by those skilled in the art using standard methodologies.

Examples of suitable leaving groups (L) include C, „ alkoxy, halo, 1 11 NR R as hereindef ined eg. anilino, morpholino, alkylamino, benzylamino, or alkylthio. Preferably in Formula III, R. is hydroxy, 111 A alkoxy, alkylthio, or a group NR R as herein defined. Advantageously Rj is amino, alkylamino, dialkylamino, piperazinyl or N-methylpiperazinyl.

Preferably the reaction of the compound of Formula I and II is carried 20 out in a non-aqueous solvent, for example an alkanol, eg. ethanol at elevated temperatures (eg. between 50 to 110°C) in a base, preferably an alkanoxide, preferably under reflux using sodium ethoxide as the base.

Alternatively a compound of Formula I or an acid addition salt thereof 25 may also be made by the reaction of a compound of Formula III with a compound of Formula IV ToT V IE 0 6 00 06 - 16 wherein Rg to Rg and Y are as herein defined. The reaction preferably takes place in a non-aqueous solvent, eg. alkanols, such as ethanol, and at elevated temperatures, preferably under reflux.

Compounds of formula IV can be made by methods known in the art (JACS, 1951, 73, 3763-3770).

Compounds of Formula II may be made by methods known in the art (JACS supra) for example by the reaction of a compound of Formula IV with diazomethane or with alkylorthoesters (JACS, 1952, 74, 1310-1313), or by condensation with an amine.

In Formula III when R^ is piperazinyl or alkyl piperazinyl these can be made by standard methods for example by reaction of a known compound of Formula III where R^ is alkylthio with the appropriate amine, eg. N-methylpiperazine. This reaction preferably takes place at room temperature in water.

Compounds of formula I may also be made by the reaction of a- compound of Formula V wherein Y and Rg are as hereinbefore defined and R1Q and R^are alkyl or collectively form a group (CRg),, where n is 2 to 4 and R is H or - 17 IE 0 6 0 0 0 6 alkyl, witfT a compound of Formula III. Most preferably Rj is amino, piperazinyl or methyl piperazinyl. Preferably the reaction is carried out in a non-aqueous solvent, eg. ethanol, under reflux using sodium ethoxide as the base.

Compounds of Formula I may also be prepared from the corresponding dihydropyrimidine by utilising standard dehydrogenation conditions, (eg. JCS, 1956, 1019).

Such dihydropyrimidine can be prepared by the reaction of a compound of Formula II where R^ to Rg are as defined and L is hydrogen with a iq compound of Formula III. - 18 ΙΕ ο 6 ο Ο Ο 6 In the Examples of the invention set forth below, other abbreviations used are standard in the art meanings:the chemical and and have these NaBH4 : sodium borohydride 5 chci3 : chloroform NaHCO3 : sodium bicarbonate MgS04 : magnesium sulphate PSr3 : phosphorus tribromide DMF : dimethylformamide 10 KCN : potassium cyanide Et20 : diethyl ether NaOEt : sodium ethoxide EtOH : ethanol h2so4 : sulphuric acid 15 AcOH : acetic acid MeOH : methanolN2 : nitrogen HC1 : hydrochloric acid NaOH : sodium hydroxide 20 Si02 : silica DMSO : dimethylsulphoxide Na : sodium DME : dimethoxyethane Mel : methyl iodide (iodomethane) 25 EtOAc : ethyl acetate ch2ci2 : dichloromethane Et3N : triethylamine - 19 IE 0 6 00 0 6 MeNH2 ' : methylamine nh4oh : ammonium hydroxide soci2 : thionyl chloride THF : tetrahydrofuran 5 NaH : sodium hydride cci4 : carbon tetrachloride DHFR : dihydrofolate reductase pto2 : platinum oxide (Adams' catalyst) NXS : N-halo succinimide io x2 : halogen TFAA : trifluoroacetic anhydride CsF ; cesium fluoride MegSil : trimethyl silyliodide DAST : diethylaminosulphur trifluoride 15 MCPBA : roetachloroperbenzoic acid AIBN : β,β'-azoisobutyronitrile (2,2'-azobis(2-methylpropionitrile) - 20 ΙΕ ο 6 Ο Ο Ο 6 £xaslfi_l Preparation of 4-Amino-2-(4-methvlpiDerazin-l-vl)-5-(2.3.5-trichlorophenv1)-6-trif1uororoethvlpvrimidine 1. Preparation of N-methvIpiperazinoformamidine hvdriodide 5 Thiourea (10.8g) was dissolved in acetone (250ml) at 50°C.

Iodomethane (10ml) was added and the reaction was stirred at 50°C for 4 hours. After cooling, the solution was diluted with ether (1 litre) and the methiodide salt was filtered, washed with ether and dried in vacuo. 29.2g, 113-115°C. The methiodide salt (5g) Iq was dissolved in water, (30ml) and N-methylpiperazine was added.

The solution was stirred, with nitrogen bubbled through, at room temperature for 24 hours. The solution was concentrated in vacuo. The residue was slurried with ethanol, filtered and dried in vacuo. 4.98g, m.pt.230-242°C. 2. Preparation of 2.3,5-trichiorobenzvlalcohol To a solution of 2,3,5-trichlorobenzaldehyde (Aldrich, 50gms) in ethanol (1.0L) at room temperature was added NaBH^ (7.00gms) and the resulting mixture stirred for 3.5 hours. The reaction was quenched with water, and the solvent evaporated in vacuo before 2Q partitioning the residue between CHCI3 and saturated NaHCOg solution. The organic phase was washed with brine, dried over MgS04, filtered and the solvent evaporated jn vacuo to leave a white solid. 43.00gms, mp. 90-93°C. 3. Preparation of 2.3.5-trichlorobenzvl bromide To a solution of the alcohol in benzene (400ml) under N2 was added PBr^ (126.58gms), and the mixture stirred at 55-60°C for 3.5 hours. After cooling, the mixture was poured onto crushed ice (2L) and the benzene layer separated. The aqueous phase was Λ washed with benzene (x3) and the combined benzene extracts washed ff i . 3q ’ i with saturated NaHCOg solution and water, dried over MgS04, - 21 10 ΙΕ ο 6 ο Ο Ο 6 filtered and the solvent evaporated to leave a brownish liquid which solidified on standing, 37.53gms, mp. 40-42°C. 4. Preparation of 2.3,5-trichlorophenvlacetonitrile The bromide was suspended in DMF (130ml)/ water(86.67ml) at 0°C and KCN(12.99gms) added in portions. After stirring at 30-35° for 3 hours, the suspension was diluted with water and extracted with EtgO. The combined ether extracts were washed with water, dried over MgS04, filtered and the solvent evaporated jn vacuo. Chromatography on silica gel eluting with hexane to 20% ether-hexane gave the desired product as a white solid, 18.52gms, mp. 60-62°C.

. Preparation of 2-(2.3.5-trichlorophenvl)-4.4.4-trifluoro-3-oxobutvronitrile To a solution of NaOEt (from 1.04gms Na) in EtOH (60ml) at room temperature under Ng was added the nitrile (8.40gms) followed by ethyl trifluoroacetate (6.57gms) and the mixture stirred at reflux for 5 hours. After cooling, the solvent was removed in vacuo and the residue dissolved in water. The aqueous phase was washed with EtgO (discarded), acidified with HgS04 and extracted with EtgO. The combined EtgO extracts were washed with water, dried over MgS04, filtered and the solvent evaporated in vacuo to leave an oil. This was triturated with petroleum ether, and the solid filtered off and dried'. The solid was azeotroped with toluene (x5), 4.89gms, mp. 160-163°C. 6. Preparation of 2-(2.3.5-trichlorophenvl)-4.4,4-trifluoro-3methoxvbut-2-enonitrile To a solution of the trifluoromethyl ketone in EtgO (39.62ml) at room temperature was added diazomethane (from 8.55gms Oiazald) in EtgO (79.62ml), and the resulting mixture left to stand at room temperature overnight. Excess diazomethane was then removed jn (vacuo into AcOH, and the residue was dissolved, jn EtgO, dried IE 0 6 0 0 0 6 - 22 over RgSO^, filtered and the solvent evaporated in vacuo to leave a brownish oil, 5.20gms. 7. Preparation of 4-Amino-2-(4-methvlpiperazin-l-vll-5-(2.3.5trichlorophenvl)-6-trifluoromethvlpyrimidine 5 To a solution of NaOEt (from 0.144g of Na) in EtOH (12.5ml) was added N-methylpiperazinoformamidine hydriodide (1.39g). After stirring for 10 minutes at room temperature a solution of the above intermediate (0.85g) in EtOH (2.5ml) was added and the resulting mixture was stirred at reflux for 4.5 hours. After cooling, the suspension was filtered, and the filtrate was evaporated to dryness in vacuo. Chromatography on silica gel, eluting with CHClg -4* MeOH/CHClg, gave the desired product which was triturated with petroleum ether (b.p. 40-60°C) and dried jn vacuo. 0.56g, m.pt 127-129°C. 8. 4-Aniino-2-(4-methylpiperazin-l-vl)-5-(2.3.5-trichlorophenvl)-6° trifluoromethvlpyrimidine methanesulohonate The phenyl pyrimidine base (9.6g) was dissolved in absolute ethanol, cooled at 0°C, and methanesulphonic acid (2.14g, 1.62ml) was added. ,After stirring at room temperature for 2 hours, the solution was evaporated to dryness and the residue triturated with EtgO, filtered and dried in vacuo to leave a beige coloured solid. This was dissolved in water (500mls) and freeze-dried to leave 10.7g as a tan coloured solid. The methanesulphonate salt could be further purified by triturating with ^uOH (30ml), filtering, dissolving in water and again freeze drying to leave the title product as a off-white solid. 8.33g mp. 145-7°C. - 23 ΙΕ ο β ο ο Ο 6 ExMylj? Preparation of 2.4-Diamino-5-(2.3.5-trichlorophenvl)-6-methoxvmethvl pyrimidine A. 2-(2.3.5-trichlorophenvl)-4-methoxv-3-oxo-butyronitri1e ’ To a stirred refluxing solution of sodium ethoxide (from 1.38g sodium) in ethanol (25ml) was added over 5 minutes a mixture of 2,3,5-trichlorophenylacetonitrile (llg) and ethyl methoxyacetate (8.85g) in dry DME (25ml). After 4 hours the mixture was cooled on ice and acidified by dropwise addition of acetic pcid (ca. 1θ 6ml), diluted with ice-water (150ml) and extracted with dichloromethane (2 x 100ml). The dichloromethane extract was washed with water, dried over MgS04 and concentrated giving a yellow solid, which was triturated with a little ether and filtered. 8.6q Homogeneous by TLC (19:1 CH2C12:MeOH).

B. Preparation of 2.4-Diamino-5-(2.3.5-trichlorophenyl)-6methoxymethvlpyrimidine A suspension of the crude acyl acetonitrile (8.5g) in ether (100ml), cooled on ice was treated with an excess of an alcohol free solution of diazomethane in ether (0.035M). After one hour 2q TLC (19:1 CHzC^JMeOH) showed no starting material. The solution was concentrated to give a brown waxy solid, which was used without further purification.

To a solution of sodium ethoxide (from O.76g sodium) in ethanol (30ml) was added guanidine hydrochloride (2.9g). After 15 minutes a solution of the crude enol ether in ethanol (25ml) was added and the mixture refluxed with stirring for 4 hours, cooled and concentrated. The residue was shaken with 2M NaOH (150m!) and the dark solid filtered off, washed with water, dried in air and recrystallised from ethanol (150ml).

M.pt. 214-216°C. TLC (1:9 MeOH:CHCl3) Rf~0.35. - 24 IE 0 600 06 C. 2,4-DfarDino-5-(2,3.5-trich1orophenyl)-6-methoxvmethylpyrimidine ethanesulphate To a stirred suspension of the phenylpyrimidine (2g) in ethanol (75ml) was added dropwise ethanesulphonic acid (0.67g) in ethanol - (10ml). After ca 30 minutes the solution became cloudy.

Stirring was continued for a further 1.5 hours and the solvent then concentrated to £a 20mls. Ether was added, the solid filtered off and washed with Et20 before drying in vacuo. 2.17g, m.pt. 265-268°C.

Example 3 Synthesis of 4-Anrino-2-(4-methy1piperazin-l-vl)-5-(2.3.5-trichlorophenyl) pyrimidine mesylate 1. Preparation of 2-f2.3.5-trichlorophenvl)-3-oxo-propionitrile, sodium salt To a solution of NaOEt (from 0.803g of sodium) in ethanol (55ml) cooled in ice, under nitrogen, was added 2,3,5-trichlorophenyl acetonitrile (see Example 1.4). Ethyl formate (5.1ml) was added and the mixture was stirred at room temperature overnight. After stirring for a further 2.5 hours at 50°C, the mixture was cooled and filtered. The filtrate was evaporated, and the residue was triturated with diethyl ether, filtered and dried (6.82g). 2. Preparation of 2-f2.3.5-trichlorophenvl)-3-methoxv-acrvlonitrile The above solid was dissolved in DMF (36ml) and methyl iodide (2ml) was added. The reaction vessel was sealed before stirring 0 the contents at 40 C for 3 hours. The solvent was then evaporated. The residue was partitioned between water and ethyl acetate. The organic phase was washed with water, dried (MgSO^) and the solvent evaporated to give the crude product as a <'3Q, red-brown oil that solidified on standing (5.04g). - 25 IE 0 6 00 06 3. Preparation of 4-Amino-2-(4-methvlpiperazin-l-v1)-5-(2.3.5trichlorophenvDpvrimidine To a solution of NaOEt (from 0.21g of sodium) in ethanol (20ml) was added N-methylpiperazinoformamidine hydriodide (2.06g) (see Example 1.1). After stirring for a further 10 minutes, the compound of Example 3.2 (lg) was added and the mixture was stirred at reflux for 4 hours. The mixture was left standing at room temperature overnight and then filtered. The filtrate was concentrated and the residue was purified by chromatography on 10 Si02, eluting with CHClg to 4% MeOH/CHClg to give the title compound as the free base. 0.89g, mp. 162-164°C.

The free base (0.805g) was then dissolved in ethanol (35ml) and cooled in an ice bath. Methanesulphonic acid (0.21g) was added and the reaction was stirred at room temperature for 2 hours. The solvent was then evaporated and the residue was triturated 15 with diethyl ether, filtered, dissolved in cold water and freeze dried to give the title salt as a pale green solid, 0.98g, mp. 143-146°C.

Exawli 4 5vnthesis of 2.4-Diamino-5-(2.3.5-trichlorophenvl)-6-trifluoromethvl pyrimidine To a solution of NaOEt (from 0.88g of Na) in EtOH (82ml) was added guanidine hydrochloride (2.98g). The resulting white suspension was stirred at room-temperature for 10 minutes. A solution of the enol ether (Example 1.6) in ethanol (27ml) was added and the resulting mixture stirred at reflux for 4.25 hours. After cooling, the suspension was filtered, and the filtrate evaporated to dryness jn vacuo. Chromatography on silica gel eluting with CHClg to 2% Me0H:CHClg gave the desired product which was triturated with Et20 and dried in vacuo. 1.78gms, m.p. 226-227°C. - 26 ΙΕ ο 6 ο ο Ο 6 Ρηιΐι 5 Preparation of 2.4-Diamino-5-(4-nitro-2.3.5-trichloroohenvl) pyrimidine The compound from Example 29 was dissolved in concentrated sulphuric 5 acid (2.5ml), potassium nitrate (25.8mg) added and the solution stirred for 3 hours. The solution was then poured onto* ice and basified with 10 N NaOH. The product was extracted with ethyl acetate (x3), dried over MgSO^, filtered apd the solvent evaporated. Chromatography on silica gel eluting with ethyl acetate gave the desired product, 40.7mg, mp. 293-295°C.

Ex»ile 6 Preparation of 2.4-Diamino-5-(2.3,5-trichlorophenvl)-6-methyl pyrimidine 1. Preparatien of 2-(2.3.5-trichlorophenvl)-3-oxobutvronitrile To a solution of NaOEt (from 0.68g of sodium) in ethanol (20ml) was added 2,3,5-trichlorophenylacetonitrile (5g) and ethyl acetate (4.43ml). The mixture was heated under reflux, under nitrogen for 2.5 hours. The mixture was left standing at room temperature overnight. The mixture was then concentrated and the residue was dissolved in water. The aqueous phase was washed with ether, acidified with concentrated HgS04 and extracted with ether. The extracts were bulked, dried (MgSO^) and evaporated, 2.59g, mp. 134-135°C. 2. Preparation of 2-(2.3.5-trichlorophenvl)-3-methoxvbut-225 enonitrile To a solution of the ketone in ether (100ml) at room temperature was added diazomethane (from 5.43g Oiazald) in ether (50ml) and , the resulting mixture was left to stand at room temperature overnight. The ether was then distilled off to leave the desired product, 2.45g. - 27 IE 0 6 00 0 6 3. Preparation of 2.4-Diamino-5-(2.3,5-trichlorophenvl)-6-methv1pyrimidine Guanidine hydrochloride (3.87g) was added to a solution of sodium ethoxide (from l.Olg of sodium) in ethanol (80ml). The resulting white suspension was stirred at room temperature for 10 minutes and then added to a solution of the enol ether (Example 6.2) (5.60g) in ethanol (20ml). The resulting mixture was stirred at reflux for 8 hours under nitrogen. After cooling, the suspension was filtered, and the filtrate evaporated to dryness la vacuo. 1θ Chromatography on silica gel eluting with CHClg to 2* MeOH-CHClg gave the desired product which was triturated with ether and dried in vacuo. Yield 1.70g, mp. 236-238°C.

Exawl· 7 Preparation of 4-Amino-2-N-morpholino-5»(2.3.5-tr1chlorophenvl)-6,. trifluoromethvlpyrimidine.

To a solution of NaOEt (from 0.144g of Na) in EtOH (12.5ml) was added morpholinoformamidine hydrobromide (1.08g) (Lancaster Synthesis). The resulting white suspension was stirred at room temperature for 10 minutes. A solution of the enol ether (0.85g) (Example 1.6) in EtOH 20 (2.5ml) was added and the resulting mixture was stirred at reflux for 4.5 hours. After cooling, the suspension was filtered, and the filtrate was evaporated to dryness in vacuo. Chromatography on silica gel, eluting with CHClg, gave the desired product which was triturated with petroleum ether (b.p. 40-60°C) and dried in vacuo. 0.47g, mp. 177-181°C. - 28 ΙΕ ο 6 ο ο 0 e Ετ··ρ1> Β Preparation of 4-Amino-2(-N.N"dimethvlamino)-5-(2.3.5-trich1orophenvl)-6-trifluoromethvl pyrimidine.

To a solution of NaOEt (from 0.144g of Na) in EtOH (12.5ml) was added 5 1,1-dimethylguanidine sulphate (1.4g), (Aldrich). The resulting white suspension was stirred at room temperature for 10 minutes. A solution of 2-(2,3,5-tr i ch1oropheny1)-4,4,4-tr i f1uoro-3-methoxybut-2-enonitrile (see Example 1.6) (0.85g) in EtOH (2.5ml) was added and the resulting mixture was stirred at reflux for 4.5 hours. After cooling, the suspension was filtered, and the filtrate was evaporated to dryness in vacuo. Chromatography on silica gel, eluting with CHClg, gave the desired product, 0.61g, mp. 124-126°C.

Ex—pi· 9 Synthesis of 4-Amino-2-N-morpholino-5-(2,3.5-trichlorophenvl)15 pyrimidine To a solution of NaOEt (from 0.21g of sodium) in ethanol (20ml) was added morpholinoformamidine hydrobromide (1.6g). After stirring for 10 minutes the adduct of Example 3.2 (lg) was added and the mixture was stirred at reflux for 4 hours. The mixture was left standing at room temperature overnight and then filtered. The filtrate was concentrated and the residue was purified by chromatography on Si02 gel, eluting with CHClg to give the desired product, 0.73g, mp. 168-170°C. v IE 0 6 0 0 0 6 - 29 Exawl· 10Svnthesis of 4-Amino-2-(N.N-dimethvlaniino)-5-(2.3.5-trichlorophenvl)pyrimidine To a solution of NaOEt (from 0.21g of sodium) in ethanol (20ml) was 5 added 1,1-dimethylguanidine sulphate (2.07g). After stirring for 10 minutes the adduct of Example 3.2 (Ig) was added and the mixture was stirred at reflux for 4 hours. The mixture was left standing at room temperature overnight and then filtered. The filtrate was concentrated and the residue was purified by chromatography on Si02» eluting with CHClj to give the desired product, 0.69g, mp. 145-147°C.

Exayl· U Synthesis of 4-Amino-6-methyl-2-(4-methvlpiperazin-l-vl)-5-(2,3.5trichlorophenvDpvrimidine To a solution of NaOEt (from 0.16g of sodium) in ethanol (15ml) was 15 added N-methylpiperazinoformamidine hydriodide (1.6g). After stirring for 10 minutes the enol ether of Example 6.2 (0.82g) in ethanol (5ml) was added and the mixture was stirred at reflux for 5 hours. The mixture was left standing at room temperature overnight and then filtered. The filtrate was concentrated and the residue was purified by chromatography on Si02 gel, eluting with CHClj to 4% MeOH/CHCl^ to give the desired product, 0.31g, mp. 156-159°C.

Exawl· 12 Synthesis of 2.4-diamino-6-methvl-5-(2.3.5-trichloro-4-nitrophenvl) pyrimidine 2,4-Diamino-6-methyl-5-(2,3,5-trichlorophenyl)pyrimidine (0.152g) (Example 6) was dissolved in concentrated sulphuric acid and potassium nitrate, (50mg) was added. The solution was stirred -at room - 30 IE 0 6 00 0 6 temperature overnight, then poured onto ice and basified with 0.880 ammonia. The product was extracted into ethyl acetate, bulked, dried (MgSO^) and evaporated. The residue was purified by chromatography on SiO2 gel, eluting with EtOAc to 8% MeOH/EtOAc to give the desired product, 0.13g, mp. 313-315°C.

Example 13 Synthesis of 4-Amino-2-(N.N-dimethvlamino)-6-methvl-5-(2.3.5°tri chlorophenvllpyrimidine To a solution of NaOEt (from 0.16g of sodium) in ethanol (15ml) was 10 added 1,1-dimethylguanidine sulphate (1.6g). After stirring for 10 minutes the enol ether of Example 6.2 (0.82g) in ethanol (5ml) was added and the mixture was stirred at reflux for 5 hours. The mixture was left standing at room temperature overnight and then filtered.

The filtrate was concentrated and the residue was purified by 15 chromatography on Si02 gel, eluting with CHClg to give the desired product, 54mg, mp. 151-153°C.

Example 14 Synthesis of 2.4-Diamino-5-(2.3-dich1orophenv1)-6-trif1uoromethv1 pyrimidine 1. Preparation of 2.3-dichlorobenzvl alcohol To a solution of 2,3-dichlorobenzaldehyde (Aldrich, 50gms) in alcohol (800mL) at room temperature was added NaBH^ (8.54gms) and the resulting mixture stirred for 1.5 hours. The reaction was quenched with water and the solvent evaporated jn vacuo before partitioning the residue between CHClg and saturated NaHCOg solution. The organic phase was washed with brine, dried over MgS04, filtered and the solvent evaporated in vacuo to leave a white solid, 48.38gms, mp. 87-87.5°C. ΙΕ ο 6 Ο Ο Ο 6 -31 2. Preparation of 2,3-dichlorobenzvl bromide To a solution of the alcohol in benzene (500ml) under N2 was added PBr^ (167.8gms), and the mixture stirred at 55-60°C for 3.5 hours. After cooling, the mixture was poured onto crushed ice ) (2L) and the benzene layer separated. The aqueous phase was washed with benzene (x3) and the combined benzene extracts washed with saturated NaHCOg solution and water, dried over Mg$04, filtered and the solvent evaporated to leave a brownish liquid which solidified on standing. 37.53gms, mp. 31-32°C. 3. Preparation of 2.3-dichlorophenvlacetonitrile The bromide was suspended in DMSO (155ml)/ water(105ml) at 0°C and KCN (20.24gms) added in portions. After stirring at 30-35°C for 2 hours, the suspension was diluted with water and extracted with Et20. The combined ether extracts were washed with water, dried over MgSO^, filtered and the solvent evaporated jn vacuo to leave a white solid, 27.52gms, mp. 64-67°C. 4. Preparation of 2-(2.3-dichloroDhenvl)»4,4.4-trifluoro-3-oxo·» butvronitrile To a solution of NaOEt (from 1.48gms Na) in EtOH (25ml) at room 20 temperature under N2 was added the nitrile (lO.Ogms) followed by ethyl trifluoroacetate (9.3gms) and the mixture stirred*at reflux for 5 hours. After cooling, the solvent was removed in vacuo and the residue dissolved in water. The aqueous phase was washed with Et2O (discarded), acidified with HgSO^ and extracted with Et20. The combined Et2O extracts were washed with water, dried over MgSO^, filtered and the solvent evaporated ip vacuo to leave an oil. This was triturated with petroleum ether, and the solid filtered off and dried. 9.56gms, mp. 74-75°C. - 32 ΙΕ ο 6 Ο Ο 0 6 . Preparation of 2»(2.3-dichlorophenvl)-4.4.4-trifluoro-3roethoxvbut-2-enonitrile To a solution of the trifluoromethyl ketone in EtgO (90ml) at room temperature was added diazomethane (from 19.35gms Diazald) in EtgO (180ml), and the resulting mixture left to stand at room temperature overnight. Excess diazomethane was then removed in vacuo into AcOH, and the residue was dissolved in EtgO, dried over MgSO^, filtered and the solvent evaporated in vacuo to leave a brownish solid, 6.44gms. 6. Preparation of 2.4-Diamino-5-(2.3-dichlorophenvl)-6-trifluoro methylpyrimidine To a solution of the above enol ether in ethanol (37ml) was added guanidine hydrochloride (1.92gms) followed by a solution of NaOEt (from 540mgs of Na) in EtOH (90ml), and the resulting mixture stirred at reflux for 3 hours. After cooling, the suspension was filtered, and the filtrate evaporated to dryness in vacuo. Chromatography on silica gel eluting with CHClg to 2% MeOH-CHClg gave the desired product which was triturated with EtgO and dried jn vacuo. 673mg, m.pt.218-9°C. 7. 2.4-Diamino-5-(2.3-dichlorophenvl)-6-trifluoromethvlpyrimidine methanesulphonate To a suspension of the free base (lOOmg) in ethanol was added methanesulphonic acid (30mg) and the resulting clear solution stirred at room temperature for 2 hours. The solution was evaporated to dryness, and the resulting solid triturated with ether, filtered, and dried in vacuo. 107mg, m.pt. 253-256°C. 8. 2.4-Diamino-5-(2.3-dichlorophenvl)-6-trifluoromethvlpyrimidine hydrochloride To a solution of the free base (150mg) in methanol was added 30 ethereal hydrogen chloride. After stirring, the solvent was evaporated to dryness and the resulting solid, triturated with •ether, filtered, and dried in vacuo. 160mg, m.pt. 233-236°C. - 33 IE 0 6 00 06 PwU 15Svnthesis of 2.4-Diamino-5-(2.3-dichlorophenvl)-6-methylpyrimidine This compound was made in an analogous manner to the compound of Example 6 from 2,3-dichlorophenylaceonitrile, m.pt. 245-247°C. Ετ»·ρ1· 16 Synthesis of 2.4-Diamino-5-(2.3-dichlorophenvl)-6-roethoxvmethvl pyrimidine 1. Preparation of 2-(2.3-dichlorophenvl)-4-methoxv-3-oxo-butvronitrile 10 To a stirred refluxing solution of NaOEt (from 1.38gms Na) in EtOH (25ml) was added a mixture of ethyl methoxyacetate (8.85gms) and 2,3-dichlorophenylacetonitrile (Example 14.3) (9.3g) dissolved in OME (20ml) during 5 minutes. After 5 hours a precipitate had appeared (sodium salt of product). The mixture was cooled and filtered, the filtrate evaporated to dryness jn vacuo and the residue partitioned between ether and water (the ether phase was discarded). The aqueous residue was acidified with 2N HgSO^ and extracted with ether (2x). The combined EtgO extracts were washed with water, dried over MgSO^, filtered and evaporated in vacuo to give a yellow solid (a). The sodium salt (above) was dissolved in water and the solution extracted with ether and discarded. The aqueous solution was acidified with 2N HgSO^ and extracted with ether. The ether extract was washed with water, dried over MgSO^, filtered and evaporated in vacuo to give a white solid (b).

The above products (a) and (b) were combined to give a yield of * - 10.4gms which was used without further purification. Single spot by TLC (19:1 CHgClg: MeOH) Rf 0.35.

IE 0 6 0 0 6 6 - 34 2. Preparation of 2-(2,3-dichlorophenvl)-3.4-dimethoxvbut-2-enonitrile To a stirred solution of the above nitrile (9.4gms) in ether was added in portions diazomethane (0.4 - 0.45M) in ether. Initially vigorous frothing occurred and after further addition no immediate reaction was produced. The mixture was left stirring at room temperature for 3 hours and evaporated in vacuo, into AcOH to give the enol ether. 3. Preparation of 2.4-Diamino-5-(2.3-dichloroohenv1)-610 methoxvmethvlovrimidine To a solution of NaOEt (from 0.92gms Na) in EtOH (40ml) was added guanidine hydrochloride (3.44gms). A solution of the enol ether (above) in EtOH (30ml) was added and the mixture refluxed for ca. 3 hours. After cooling, the solvent was evaporated off jn vacuo and the residue treated with 5N NaOH (ca, 50ml). The red solid was filtered off, dissolved in AcOH (ca. 20ml). diluted with water (40ml), treated with charcoal, and filtered. The filtrate (yellow solution) was made alkaline with 2N NaOH, and the white precipitate filtered off, dried and recrystallised from EtOH, 4.39gms, mp. 237-240°C.

Example 17 Preparation of 2.4-Diamino-5-(l-naphthvl)pyrimidine To a solution of NaOEt (from 1.45gms Na) in ethanol (60ml) at room temperature under N2 was added 1-naphthylacetonitrile (Aldrich, .02gms). After stirring for 10 minutes, ethyl formate (8.88gms) was added and the mixture stirred at reflux for 5 hours. The mixture was cooled, the solvent evaporated, and the residue triturated with Et20 before filtering and drying the solid in vacuo (6.86gms). *5 Λ ·«. - 35 IE 0 600 0 6 The above scrl id was dissolved in DMF (45ml), methyl iodide (5.4gms) added, and the reaction vessel sealed before stirring the contents at 40°C for 4 hours. The solvent was then removed in vacuo, and the residue partitioned between EtOAc and water. The organic phase was washed with water, dried over MgSO^, filtered, and the solvent evaporated in vacuo to leave the crude product as a viscous reddish oil (5.4gms).

To a solution of NaOEt (from 1.19gms of Na) in ethanol (80ml) was added guanidine hydrochloride (4.94gms). After stirring for a further minutes, the above intermediate in ethanol was added and the resulting mixture stirred at reflux for 3.5 hours. After cooling, the solvent was removed jn vacuo and the residue partitioned between CHClg and water. The organic phase was washed with water, dried over Mg$04, filtered and the solvent evaporated to leave a pale yellow solid. Chromatography on SiO2 eluting with CHClg to 4% CHClgtMeOH, followed by recrystallisation from ethanol gave the desired product as a white solid. 2.82gms, mp.l71-3°C.

Example 18 Preparation of 2.4-Diamino-5-(2.3-dichlorophenvl)-6-fluoromethvl 20 pyrimidine 1. 2.4-Diamino-5-(2.3-dichloropheny1)-6-(diethoxyroethyl) pyrimidine To a stirred refluxing solution of NaOEt (from 1.38g sodium) in ethanol (25ml) was added over 5 minutes a mixture of ethyl diethoxyacetate (13.21g; 75mmol) and (Example 14.3) 2,3dichlorophenylacetonitrile (9.3g; 50mmol) in dry dimethoxyethane (20ml). After 4 hours cooled and evaporated jrj, vacuo. The * residue was partitioned between water (100ml) another (100ml), the ether phase discarded and the aqueous residue acidified with - 36 IE 0 600 0 6 IN Extraction with Cf^Clg gave the acyl acetonitrile (13.47g), which was used without further purification.

To a stirred solution of the above acyl acetonitrile in ether (100ml), cooled on ice was added in portions a solution of diazomethane (ca, 3g) in ether. After 2 hours the solution was evaporated in vacuo to give the desired enol ether as an oil, which was used without further purification.

To a solution of NaOEt (from 1.4g sodium) in ethanol (50ml) was added guanidine hydrochloride (4.8g; 50mmol). A solution of the Iq above enol ether in ethanol (20ml) was added and the mixture refluxed for 4 hours cooled, and concentrated in vacuo to ca. 30ml and diluted with water to give a dark purple solid which was filtered, dissolved in CHgClg, washed with water, dried over MgSO^ and evaporated jn vacuo. The residue was triturated with ethanol (50ml) and filtered to give the desired product (8.4g) which was used without further purification, (mp. 214-217°C). 2. 2,4-Diamino-5-(2.3-dichlorophenvl)Dvrimidine-6-carboxaldehvde A mixture of the above acetal (7g) and 0.4M HCI (150ml) was refluxed with stirring for 1 hour, cooled on ice and neutralised with 2M NaOH. The mixture was filtered, washed with water and dried in air to give the desired product (6.2g), which was used without further purification. 3. 2.4-0iamino-5-(2.3-dichlorophenvl)-6-hvdroxvmethvlpvrimidine To a stirred solution of the above aldehyde (2.8g; lOmmol) in a mixture of dimethoxyethane (15ml) and ethanol (15ml) was added in portions sodium borohydride (llOmg; 3mmol). After 30 minutes the solution was treated with water (50ml) and a few drops of acetic acid added to destroy excess borohydride. Extracted with dichloromethane (2 x 50ml), washed with water and the extract was ?. ..then dried over MgSO^. Evaporation of the solvent-in vacuo gave a pink solid, which was triturated with ether, filtered and dried - 37 ΙΕ ο β ο ο σ 6 (1.6gj/ Recrystallisation from methanol (50ml) gave the desired product as fine colourless crystals. 0.55g, m.p. 173-6°C. 4. 2.4-Diamino-5-(2.3-dichlorophenvl)-6-fluoromethvlpyrimidine To a stirred suspension of 2,4-diamino-5-(2,3-dichlorophenyl)-65 hydroxymethylpyrimidine (185mg; lmmol) in dry di chloromethane (25ml), under nitrogen at -70°C, was added dropwise diethylaminosulphur trifluoride (263/xl; 2mnol). The mixture was allowed to warm to 0°C and kept at this temperature for 4 hours. Λ * After cooling to -70 C the mixture was quenched with aqueous sodium bicarbonate, extracted with dichloromethane (2 x 50ml), washed with saturated brine and dried (MgS04). Concentration gave a colourless gum (0.2g). Chromatography on silica gel, eluting with 0.01:1:19 EtgN'.MeOHzCHgClg gave the desired product which was triturated with CC14 and dried in vacuo, lllmg, mp. 224-5°C.

Example 19 2.4-Diamino-5-(2.3-dichlorophenvl)-6-phenoxvmethvlpvrimidine To a stirred solution of NaOEt (from 1.38g sodium), in ethanol (70ml) at reflux, was added over 10 minutes a mixture of 2,3-dichlorophenyl20 acetonitrile (9.3g) and ethyl phenoxyacetate (13.5g) . in dry dimethoxyethane (50ml). After stirring at reflux for 3 hours the mixture was cooled, filtered and the solvents evaporated in vacuo. The residue was dissolved in water, washed with ether (discarded), acidified with 2N hydrochloric acid and extracted with dichloromethane. The combined extracts were washed with brine, dried (MgS04) and evaporated jn vacuo to leave a tan coloured solid (8g), which was used without further purification.

To a suspension of the crude acyl acetonitrile (8g) in ether (150ml) • / was added in portions an excess of a solution of diazomethane in 30 ether. After stirring for 1 hour at room temperature the solution was IE 0 6 00 06 - 38 concentrated in vacuo to give the enol ether, which was used without further purification.

To a solution of sodium ethoxide (from 0.63g sodium) in ethanol (25ml) at room temperature was added guanidine hydrochloride (2.39g). After minutes a solution of the above enol ether in ethanol (25ml) was added and the mixture stirred at reflux for 4 hours. After cooling the solvent was evaporated bj. vacuo. The residue was suspended in 2N NaOH (75ml), filtered, washed with water, dried in air and recrystallised from ethanol to give the desired product as a colourless solid. 3.82g, mp. 211-213°C. 2.4-Diamino-5-(2.3-dichlorophenyl)-6-methvlthioinethvlpyrimidine To a stirred solution of NaOEt (from 1.38g sodium), in ethanol (25η1) at reflux, was added over 5 minutes a mixture of 2,3-dichlorophenylacetonitrile (9.3g) and ethyl methylthioacetate (10.07g) in dry dimethoxyethane (20ml). After stirring at reflux for 5 hours the mixture was cooled on ice, acidified with acetic acid (5ml),. poured into cold water and extracted with dichloromethane. The combined extracts were washed with water, dried (MgS04) and 20 concentrated to give a yellow oil which was used without further purification.

The crude acyl acetonitrile was heated under N2 with triethyl orthoformate (40ml) at 140-150°C for 4 hours, distilling off low boiling material. After cooling, the mixture was concentrated rn vacuo to leave a dark oil (15.2g). The oil was dissolved in ethanol (20ml) and added to a mixture of guanidine hydrochloride (4.8g) and sodium ethoxide (from 1.38g sodium) in ethanol (50ml). After stirring at reflux for 4 hours the mixture was cooled and concentrated jn.

R' $ ί ' The residue was shaken with 5M NaOH to give a dark oil, which ~ jo ί was exacted with dichloromethane, washed with water and dried - 39 (MgSO^). Concentration in vacuo left a dark gum. The desired product crystallised from ethanol (20ml) as a light tan solid, 0.57g, mp. 205-7°C.

Exawle 21A ’ Preparation of 2.4»Diamino-5-(2.3-dichlorophenvl)pyrimidine a. 2-(2.3-dichlorophenvl)-3-oxo-propionitrile To a solution of NaOEt (from 3.63gms Na) in ethanol (500ml) was added 2,3-dichlorophenylacetonitrile (Example 14.3) in ethanol (150ml). Ethyl formate (16.67gms) was then added and the mixture stirred at 80°C for 45 minutes, before adding a further quantity of ethyl formate (2.78gms). After stirring at 80°C for a further 1.5 hours, the precipitate was filtered off and dried in vacuo. The solid was dissolved in water , filtered, acidified with concentrated hydrochloric acid and the precipitate filtered off and dried in vacuo. 14.35gms, 45% yield. b. A solution of the above product, ethylene glycol (9.19gms) and £-toluene-sulphonic acid (8.9gms) in toluene (100ml) was stirred at reflux, with the water being collected in a Dean and Stark trap. After cooling, the solution was washed with water, IN NaOH and water before drying over MgSO^. Evaporation of the solvent left an oil (20.17gms) which was dissolved in EtOH (70ml). After standing for 1 hour the cream precipitate was filtered off and dried in vacuo (10.44gms). c. To a solution of NaOMe (5.1gms) in ethanol (75ml) was added guanidine hydrochloride (8.2gms). After stirring for 30 minutes the NaCl was filtered off, the above acetal added and the mixture stirred at reflux for 1 hour. The solvent was then concentrated and the product filtered off. Recrystallisation from ethanol ΙΕ ο 6 0 0 0 6 - 40 gave the product . as a white solid, 7.67gms, 70% yield, mp. 212.5-214°C.

The diamino-pyrimidine (6.12gms) was dissolved in ethanol (250ml), concentrated hydrochloric acid (2.07ml) added,, and the suspension chilled for 2 hours. The precipitate was then filtered off and dried to give the hydrochloride salt, 5.52gms,.

Example 21B a. 2.3-Dichlorophenvlacetic acid Concentrated hydrochloric acid (100ml) was poured onto crushed 10 ice (150ml), the solution added to 2,3-dichlorophenylacetonitrile (30.5gms), and the mixture refluxed for 3 hours. After cooling, the mixture was diluted with water (500ml), extracted with EtOAc (600ml) and the organic phase washed with brine before drying over MgSO^. Evaporation of the solvent left a white solid, 31.3gms. b. Ethyl 2,3-dichlorophenvlacetate To a suspension of the acid in ethanol (200ml) was added concentrated HgSO^ (1ml) and the mixture stirred at reflux for 3 hours. After cooling, the solvent was evaporated and the residue treated with concentrated NH40H (3ml) in water (50ml). The organic phase was extracted into CHgClg, dried over MgSO^, and the solvent evaporated to leave a clear liquid, 19.88gms. c. Ethv1-2-(2.3-dichlorophenvl)-3-N-morpholino-acrvlate To a mixture of the ester, morpholine (40.7gms) and ethyl orthoformate (69.24gms) was added acetic anhydride (0.5ml) and the resulting pale yellow solution stirred at reflux for 3 hours. After cooling, the mixture was concentrated ,in vacuo. A white precipitate started to form, and this was filtered off before IE 0 6 00 06 - 41 further concentrating the filtrate to give a brownish clear oil. Standing overnight in vacuo gave a yellow solid, 34.34gms. d. 5-(2,3-dichlorophenyl)isocvtosine To the above ester was added guanidine hydrochloride (26.6gms) 5 slurried in sodium 2-methoxyethoxide (from 6.6gms of Na) in 2-methoxyethanol (150ml), and the mixture stirred at reflux overnight. After cooling, the mixture was concentrated in vacuo, diluted with water (100ml) and then washed with Et20 (200ml). The aqueous phase was acidified with AcOH, and the precipitate filtered off and washed with EtOH and then Et20 before drying in vacuo. I3.48gms. e. Nk[4-chloro-5-(2.3-dichlorophenvl )-2-pyrimidinvn-N^,N^dimethyl formamidine To a mixture of the above isocytosine (14.4gms) in CH2C12 (200ml) 15 was added dropwise during 30 minutes fresh Vilsmeier-Haack reagent (from 2.75 equivalents of SOC12 and 2.58 equivalents of DMF), and the mixture refluxed for 6 hours. After cooling, IN NaOH (250ml) was added slowly. The aqueous phase was washed with CH2C12 and the combined organic extracts washed with brine before drying over MgSO^. Evaporation of the solvent and chromatography on Si02 gel, eluting with EtOAc gave 13.6gms, mp. 113-115°C. f. 2-An)ino-4-chloro-5-(2.3-dichlorophenvl)pvriroidine To the formamidine in EtOH (50ml) was added ethanolic-MeNH2 (8 equiv.) in EtOH (50ml), and the mixture sealed in a Parr reaction vessel before stirring at room temperature for 5 hours. The reaction mixture was then concentrated in vacuo, the residue mixed with IN NaOH (75ml), filtered, washed with water and dried in vacuo. 11.2gms, mp. 228-30°C. 2.4-Diamino-5-(2.3-dichlorophenvl)pyrimidine VTo 2-amino-4-chloro-5-(2,3-dichlorophenyl)pyrimidine (6.73gms) was added ethanolic ammonia (30 equiv. in 50ml~Et0H) and the IE Ο 6 Ο Ο Ο β - 42 mixture sealed in a Parr reaction vessel and heated to 125°C for 38 hours. After cooling, the mixture was concentrated jn vacuo and the residue mixed with IN NaOH (75ml), filtered, washed with water and dried in vacuo. 6.14gms, mp. 208-211°C.

Example 22 Synthesis of 2.4-Diamino-5-(2-chlorophenvl)-6-methvl-ovrimidine This compound was prepared according to JACS, (1951), 21. 3763-70, mp. 225°C.

E«wle 23 Synthesis of 2.4-Diamino-5-(2-chloroDhenvl)ovrimidine This compound was prepared according to JACS, (1951, 22. 3763-70, mp. 125-8°C.

Exawle 24 Synthesis of 2.4-Diamino-5-(2-chlorophenvl)-6-ethvlpvrimidine Prepared as for Example 22, except that ethyl propionate replaced ethyl acetate, mp. 197-8°C.

Example 25 Synthesis of 2.4-Diamino-5-(2,4-dichlorophenvl)-6-trifluoromethvl pyrimidine 2o This compound was prepared in a manner analogous to the compound of Example 14 from 2,4-dichlorophenylacetonitrile (Aldrich): mp. 220.5221°C.

IE 0 600 06 - 43 ilMCl» 26 Synthesis of 6-Benzvloxvmethvl-2.4-diamino-5-(2.4-dichlorophenyl) pyrimidine This compound was prepared in a manner analogous to the compound of 5 Example 16 from 2,4-dichlorophenylacetonitrile and ethyl benzyloxyacetate, 3.77gms, mp. 171-172°C.

Exawle 27 2-(4-roethylpiperazin-l-vl)-4-amino-5-(2.4-dichlorophenvlIpyrimidine A) A solution of 55.7g (0.4equiv) of ^-methylisothiourea sulphate in 280ml of water was prepared and gently heated on a steam bath with stirring. Then 40g (G.4mo1) of N-methyl-piperazine was slowly dripped into the solution while sweeping the flask cut with nitrogen. The evolved gases were collected in several portions of a solution of 132g of mercuric chloride in 400ml of ethanol, which caused evolved methylmercaptan to be precipitated as methylmercuric chloride. After the addition of the N-methylpiperazine was complete, the reaction was continued until no more methylmercuric chloride precipitated. The reaction mixture was then concentrated in vacuo and chilled which caused the N-methyl-N'-amidinopiperazine sulphate to crystallise; 50.79g was collected.

B) A mixture of 76.3g (0.356 mol) of e-formy1-2,4-dichlorophenylacetonitrile, 63.7g of isoamyl alcohol, 0.36g of £-to1uenesulphonic acid, 895 ml of toluene, and 10 drops of concentrated sulphuric acid were heated under reflux for 20 hours in the presence of a Dean and Stark trap to remove water formed in the reaction. Then an equal portion of i-amyl alcohol and a few drops of sulphuric acid were added, and the reaction was - 44 IE 0 6 00 0 6 heated for another 20 hours, until the theoretical amount of water had been collected. The solution was cooled.

C) An 8.2g portion of sodium was dissolved in 500ml of absolute ethanol, and 50g of N-methyl-N'-amidinopiperazine sulphate was added. The mixture was allowed to stir for 10 minutes. This was then added to solution B. The mixture was refluxed with stirring for 6 hours, allowed to stand overnight and the solvent removed in vacuo. The residue was then extracted with dilute hydrochloric acid, which dissolved most of it. The solution was extracted three times with ether, followed by neutralization of the aqueous fraction, which precipitated a gum which solidified upon standing overnight; weight 30g. This was crystallised repeatedly from 50% ethanol with the aid of decolourising charcoal. Very slow cooling was required in order for crystals to be formed; mp. 137°C.

Anal. Cal cd for C15H17C12N5; C, 53.27; H, 5.07; N, 20.71; Found: C, 53.58; H, 5.14; N, 20.40.

Exawole 2fl Synthesis of 2,4-Diamino-5-(2.5-dichlorophenvl)-6-trifluoromethvl pyrimidine This compound was prepared in a manner analogous to the compound in Example 14 from 2,5-dichlorobenzyl alcohol (Lancaster Synthesis, 4S.26g) to give the title compound in a yield of 3.85gms, mp. 215-217°C.

’•X - 45 ff Ο 6 Ο Ο Ο 6 Exawl· 29 Preparation of 2.4-Diamino-5-(2.3.5-trich1orophenvl) pyrimidine Guanidine hydrochloride (3.20g) was added to a solution of sodium ethoxide (from 848mg sodium) in ethanol (52ml). The resulting white suspension was stirred at room temperature for 10 minutes. The enol ether from Example 3.2 (4.40g) was added and the resulting mixture stirred at reflux for 3.5 hours. After cooling, the suspension was filtered, and the filtrate evaporated to dryness in vacuo. Chromatography on silica gel eluting with CHClg to 3% MeOH-CHClg gave the desired product which was triturated with ether and dried jn vacuo. Yield = 2.01g, mp. 246-249°C.

Synthesis of 4-Amino-5-(3-bromophenvl)-5-methvl-2-(4-methvlpiperazin -1-yl) pyrimidine To a solution of NaOEt (from 0.92g of sodium) in ethanol (75ml) was added 3-bromophenylacetonitrile (Aldrich, 7.85g) and ethyl acetate (3.52g). The mixture was heated under reflux for 6 hours. After cooling, the mixture was concentrated and the residue was dissolved in water. The aqueous phase was washed with ether, acidified with 2N HC1 and extracted with ether. The extracts were bulked, dried (MgSO^) and evaporated, 3.8g, mp. 97-103°C.

The resulting ketone (3.7g), ethylene glycol (5ml) and j>-toluenesulphonic acid (lOOmg) were heated under reflux in toluene (100ml) in a Dean & Stark apparatus for 3.5 hours. The mixture was cooled, concentrated and water was added to the residue. The product was extracted with ether and the extracts were bulked, dried (MgSO^) and -λ - evaporated, 4.03g, mp. 68-71°C.

IE 0 6 00 06 To a solution of NaOEt (from 0.28g of sodium) in ethanol (30ml) was added N-methylpiperazinoformamidine hydriodide (2.7g). After stirring for 10 minutes, the ketal (1.41g) was added and the mixture was stirred at reflux for 4 hours. After cooling the suspension was filtered, and the filtrate was concentrated. The residue was purified by chromatography on SiO2 gel, eluting with 10* MeOH/CHClg to give the desired product, 0.48g, mp. 120-122°C.

Fnilg 31 Synthesis of 24-Diaroino-5-(1-naphthyl)-6-trifluoromethvlpyrimidine This compound was prepared in a manner analogous to the compound in Example 14 from 1-naphthylacetonitrile (Aldrich, lOgms), to give the title compound in a yield of 0.69gms, mp. 224-226°C.

Exaapl·.# Preparation of 2-Amino-5-(2.4-dich1orophenvl)-4.6-dichloropyrimidine 1. Ethyl 2.4-dichlorophenvlacetate 2,4-Dichlorophenylacetonitrile (27.9g, 150m.mol) was suspended in 2N NaOH (400ml) and the mixture refluxed for 4 hours. The cooled reaction mixture was extracted with ether (2x200ml) acidified to pH3 and the solid filtered and dried (22g, 70%).

The product (20g) was dissolved in EtOH (300ml) and concentrated H2S04 (5ml) added carefully. The mixture was refluxed for 7 hours. The cooled reaction mixture was evaporated under reduced pressure and the residue partitioned between CH2C12 and water (30ml each). The organic layer was extracted with saturated NaHCO, solution (200ml), washed with water (100ml), dried and ' .,25 ΙΕ ο 6 0 0 0 6 - 47 evaporated in vacuo to give ethyl 2,4-dichlorophenylacetate as an oil (22.2g, 89.5%). 2. Diethyl 2.4-Dichlorophenvl malonate Sodium (1.86g, 0.081M) was added in portions to absolute ethanol (150ml) with stirring. After all the sodium had dissolved a solution of ethyl 2,4-dichlorophenylacetate (20g) in diethyl carbonate (50ml) was added dropwise. The reaction mixture was heated until EtOH distilled over. The rate of addition was controlled such that it equalled the rate of distillation. After the completion of addition the reaction mixture was heated and distilled for further 4 hours. The cooled reaction mixture was partitioned between water (300ml) and EtOAc (300ml) and the organic layer dried and evaporated in vacuo to give a yellow oil (21g, 85%). 3. 2-Amino-5-(2,4-dichlorophenvl)-4,6-dihvdroxvpyrimidine Sodium (4.52g, 0.196M) was added in portions to ethanol (150ml). After all the sodium had dissolved guanidine hydrochloride (12.44g, 0.13M) was added followed by diethyl 2,4-dichlorophenyl malonate(20g, 0.0655M). The mixture was refluxed for 6 hours, EtOH was removed under reduced pressure and the residue partitioned between 2N NaOH (400ml) and EtOAc (400ml). The aqueous layer was acidified with concentrated hydrochloric acid with cooling and the precipitated solid was filtered and dried (llg, 62%). 4. 2-Amino-5-(2.4-dichlorophenvl)-4,6-dich1oropvrimidine A mixture of 2-amino-5-(2,4-dichlorophenyl)-4,6-dihydroxypyrimidine (lOg), phosphoryl chloride (100ml) and dimethyl aniline (1.5ml) was refluxed for 6 hours. The cooled reaction mixture was carefully added to crushed ice and the insoluble solid was 1 filtered and washed with 2N HC1, followed by water. The solid • was resuspended in water, neutralised (0.88 NH^OH^with cooling, and the mixture stood overnight at room temperature. The - 48 ΙΕ ο 6 0 ο 0 6 insolub-le solid was filtered, dried and purified by flash column chromatography to give the title compound (2.5g, 22%), mp. 211-213°C. Microanalysis: Calcd: C, 38.83; H, 1.6; N, 13.59; Found: C, 38.59; H, 1.53; N, 13.40.

Erawla 33 Synthesis of 2.4-Diamino-6-chloro-5-(2.4-dich1oroDhenvl)-pyrimidine A mixture of 2-amino-5-(2,4-dichlorophenyl)-4,6-dichloropyrimidine (0.5g) (Example 32) EtOH saturated with ammonia (20ml) and copper powder (0.05g) was heated in an autoclave at 180°C for 18 hours. The cooled reaction mixture was filtered, evaporated and the residue purified by flash column chromatography to give the title compound (0.12, 25%), mp. 219°C. Microanalysis: Calcd: C, 40.82; H, 2.55; N, 19.05; Found: C, 41.27; H, 2.46; N, 18.74.

Exa»1e 34 Synthesis of 2-Amino-4-chloro-5-(2.4-dichlorophenvl)-6-methvlthio pyrimidine A mixture of 2-amino-5-(2,4-dichlorophenyl)-4,6-dichloropyrimidine (0.5g) (Example 32) THF (15ml), methanethiol sodium salt (0.113g), copper powder (0.05g) and tris[2-(2-methoxyethoxy)ethyl]amine (O.lg) was heated in an autoclave at 180°C for 18 hours. The cooled reaction mixture was filtered, evaporated and the residue purified by flash column chromatography to give the title compound (0.262g, 52%), mp. 2Q1-2O2°C (softens at 196°C). Microanalysis: Calcd: C, 41.19; H, 2.50; N, 13.10; Found: C, 41.10; H, 2.52; N, 12.77. - 49 ΙΕ ο 6 Ο ο Ο 6 ExmpU 35- .

Synthesis of 2.4-Diamino-5-(2.4-dichlorophenvl)-6-methvlthiopyrimidine A mixture of 2-amino-4-chloro-5-(2,4-dichlorophenyl)-5-methylthio pyrimidine (O.5g) (Example 32) EtOH saturated with ammonia (20ml), copper powder (0.05g) and tris[2-(2-methoxyethoxy)ethyl]amipe (.Olg) was heated in an autoclave at 180°C for 18 hours. The cooled reaction mixture was filtered, evaporated and the residue purified by flash column chromatography to give the title compound (O.llg, 23.5%), mp. 191-192°C. Microanalysis: Calcd: for 0.2 hydrate: C, 43.33; H, 3.41; N, 18.38; Found: C, 43.37; H, 3.23; N, 18.33.

Exaaele 36 4-Amino-5-(3.5-dichlorophenv1)-6-methvl-2-(4-methvlpiperazin-l-vl) pyrimidine a. 3.5-Dichlorophenvlacetonitrile A mixture of 3,5-dichlorobenzyl alcohol (Aldrich, 25g), thionyl chloride (100ml) and DMF (0.5ml) was stirred and refluxed for 4 hours. After cooling the mixture was concentrated in vacuo, the residue was taken up in ether, washed with saturated aqueous NaHCOj and brine, dried (MgS04) and concentrated in vacuo to give 3,5-dichlorobenzyl chloride as a light yellow solid, which was used without further purification, 28g, mp. 32-36°C.

To a vigorously stirred solution of 3,5-dichlorobenzylchloride (28g) in dichlororoethane (150ml) was added a mixture of KCN (27.5g) and tetrabutylammonium hydrogen sulphate (2.38g) in water (110ml). After stirring at room temperature for 22 hours, the mixture was diluted with dichloromethane, the organic phase washed with water and concentrated jn vacuo to leave an oil. - 50 ΙΕ ο 6 Ο Ο Ο 6 Filtration through silica with toluene followed by concentration then trituration with hexane gave the desired product as a colourless solid. 15.8g, mp. 31-32°C. b. 4-Amino-5-(3.5-dichloropheny1)-6-methvl-2-(4-methv1piperazin-lvi)pvrimidine To a stirred solution of NaOEt (from 0.69g sodium), in ethanol (25ml) at reflux, was added over 5 minutes a mixture of 3,5-dichlorophenylacetonitrile (9.3g) and ethyl acetate (3.3g) in dry dimethoxyethane (10ml). After stirring at reflux for 4 ,0 hours, the mixture was cooled on ice, acidified with acetic acid, poured into cold water and extracted with dichloromethane. The combined extracts were washed with water and concentrated to give an oil. Trituration with hexane gave 2-(3,5-dichlorophenyl)-3-oxobutyronitrile as a colourless solid (4.15g).

To a solution of the acyl acetonitrile (4.1g) in ether (100ml) was added in portions an excess of a solution of diazomethane in ether. After stirring for 2 hours at room temperature the solution was concentrated in vacuo to give the enol ether.

To a stirred solution of NaOEt (from 0.72g sodium) in ethanol (25m1) was added N-methylpiperazinoformamidine hydriodide (7.29g). After 10 minutes a solution of the above enol ether in ethanol (25ml) was added and then stirred and refluxed for 4.5 hours. After cooling the solvent was evaporated in vacuo and the residue shaken with 2N NaOH (50ml). The solid was filtered off, washed with water, dried in air and chromatographed (sijica; 1:9 MeOH:CHClg) to give the desired product as a colourless solid, 1.6g, mp. 164-166°C. - 51 IE 0 6 00 06 h»»1e 37Preparation of 2,4-0iamino-5-(2.5-dichlorophenv1)-6-methvlpyrimidine This compound was made in an analogous manner to the compound of Example 6 from 2,5-dichlorobenzylalcohol (Lancaster Synthesis). Mp. 226-228°C: TLC (Si02: CHClg/MeOH, 9:1) Rf = 0.24.

Example 38 Preparation of 2.4-Diamino-5-f3.4-dichlorophenvl)-6-trifluoromethvlpyrimidine This compound was made in an analogous manner to the compound of 10 Example 4, from 3,4-dichlorophenylacetonitrile (Aldrich) mp. 252-254.5°C: TLC (Si02; methanol/chloroform, 1:9) Rf 0.38.

Example 39 Preparation of 2.4-Diamino-5-(2.3-dich1orophenvl-4-nitrophenvl)pyrimidine This compound was made in an analogous manner to the compound of Example 5 from 2,4-diamino-5-(2,3-dichlorophenyl)pyrimidine (Example 21). The reaction gave a mixture of the 4-nitro and 5-nitro derivatives from which the title compound was separated by column chromatography (Si02, EtOAc), mp. 237-9°C. Also separated in this manner was 2,4-diamino-5-(2,3-dichloro-5-nitrophenyl)pyrimidine, mp. 264-6°C. ΙΕ Η 00 Ο 6 - 52 Exawole AftPreparation of 2,4-Diamino-5-(2.4-dich1orophenvl)-6-(diethoxymethvl) pyrimidine This compound was prepared in a manner analogous to 2,4-diamino-5-(2, 5 3-dichlorophenyl)-6-(diethoxymethyl)pyrimidine (Example 18.1) from 2,4-dichlorophenylacetonitrile, mp. 225°C.

Example 41 Preparation of 2.4-0iamino-5-(3.5-dichlorophenvl)-6-methvlpvrimidine This compound was prepared in a manner analogous to the compound of 10 Example 6 from 3,5-dichlorophenylacetonitrile (Aldrich). mp. 242-244°C.

FiimIi <2 Preparation of 2.4-Diami no-5-(2,3-dichlorophenyl)-6-trifluoromethyl pyrimidine N-oxide This compound was made from the compound of Example 14 by reaction with MCPBA in CHCl^ at room temperature. Mp. 275-278°C.

Er»»1i 43 Preparation of 2.4-Diamino-5-(2.3-dichlorophenyl)-6-tribromomethvl pyrimidine This compound was prepared from the compound of Example 15 by reaction with excess bromine and sodium acetate in acetic acid at reflux. The title compound was separated from a mixture with the compound of Example 75 by coloumn chromatography, mp. 210°C (dec)._ IE 0 6 0 0 0 6 - 53 Exawole 44 Preparation of 2.4-Diamino-5-(2.4-dichlorophenyl)-6-methoxvmethyl pyrimidine This compound was prepared in a manner analogous to Example 2, from ’ 2,4-dichlorophenylacetonitrile, mp. 183-185°C. Single spot on TLC.

Pxawle 45 Preparation of 2.4-0iamino-5-(2.6-dichlorophenvl)-6-methvlpyrimidine This compound was prepared in a manner analogous to Example 6 from 2,6-dichlorophenylacetonitrile (Aldrich), mp. 250°C.

Exawl» <6 Preparation_of_2,4-Diamino-5-(2.4-dichlorophenvl)pvrimidine -6-carboxaldehvde This compound was made from the compound of Example 40 in an analogous manner to the compound of Example 18.2, mp. >350°C. ΕΧΜφΙ» .47 Preparation of 2.4-Diamino-5-(2.3-dichloro-4-nitrophenvl)-6-methv1 pyrimidine This compound was made from the compound of Example 15 in an analogous manner to the compound of Example 39, mp. 265°C. Also obtained from this reaction was 2,4-diamino-5(2,3-dichloro-5-nitrophenyl)-6-methyl pyrimidine. - 54 ΙΕ ο 6 Ο Ο Ο β Exawle 48 Preparation of 2,4-Diamino-5-(2.4-dichlorophenvl)-6-hvdroxvimino methylpyrimidine This compound was made from the compound of Example 46 by reaction 5 with hydroxyl amine hydrochloride in ethanol, mp. 260-5°C.

Ewpla 49 Preparation of 2.4-Diamino-5-(2.4-dichlorophenvl)-6-hvdroxvmethyl pyrimidine This compound was made from the compound of Example 46 in an analogous '0 manner to the compound in Example 18.3, mp. 169-171°C. ΕχμβΗ 50 Preparation of_2.4-Diamino-5-(2.3.4-trichlorophenvl)-6-methy1 pyrimidine This compound was made from the compound of Example 47 by reduction to 15 the amine (PtOg, Hg, AcOH), formation of the diazonium salt (NaNOg, HgSO^), and reaction of this with CuCl (as for Example 57). Sublimes at 275°C. Homogenous on TLC (methanol/chloroform, 1:9) Rf=0.36.

Exawl· 51 2,4-Diamino-5-(2,6-dichloroDhenvl)-6-methoxymethv1-pyrimidine 20 This compound was prepared in an analogous manner to the compound of Example 2 from 2,6-dichlorophenylacetonitrile (Aldrich), mp. ’ '~204-2Q7°C. - 55 ΙΕ ο 6 Ο Ο Ο 6 ΕιμρΊ» 52Preparation of 2.4-Diamino-5-(2.3.5-trichlorophenvl)-6-trichloro methyl pyrimidine This compound was made from the compound of Example 5 by reacting with 5 NCS in AcOH at 100°C (AIBN as catalyst), mp. 226-227°C.

Prawila 53 2.4-Diamino-5-(2.4-dichlorophenyl)-6-fluoromethvlovrimidine 1. 2.4-Diamino-6-bromomethyl-5-(2,4-dichlorophenvl)pyrimidine 2,4-0iamino-6-benzyloxymethyl-5-(2,4-dichlorophenyl)pyrimidine (Example 25) (6.5g) was dissolved in a 47% solution of hydrobromic acid in acetic acid (75ml) and the mixture stirred and heated at 100°C for 6 hours. After standing at room temperature overnight the di hydrobromide salt was filtered off, washed with ether and dried in vacuo, 6g.

To a stirred solution of the dihydrobromide salt (0.43g) in dimethylsulphoxide (4ml) was added dropwise a solution of sodium bicarbonate (0.84g) in water (10ml). After 30 minutes the precipitate was filtered off, washed with water then ether and dried in vacuo. 0.26g, mp.>270°C (decomposes). 2. 2.4-Diamino-5-(2.4-dichlorophenvl)-6-fluoromethvlpyrimidine To a solution of 2,4-diamino-6-bromoroethyl-5-(2,4-dichlorophenyl) pyrimidine (1.04g) in tetramethylene sulphone (4.5ml) Was added cesium fluoride (lg). The mixture was stirred and heated at 100°C for 4 hours, cooled, diluted with water and extracted with chloroform. The combined extracts were washed with water, dried (MgSO^) and concentrated jn vacuo. The residue was chromatographed (silica; 19:1:0.1 dichloromethane/methanol/ triethylamine) to give the title compound, which was • * * Λ i , > 'recrystallised from ethanol. 0.19g, mp. 210-211 C. - 56 IE 0 600 0 6 Εχ»·η1· 56 Preparation of 2.4-0iamino-5-r2-chloro-5-(N, N-dimethvlsulphamovl) phenvU-6-methvlpyrimidine 1. 2,4-Diamino-5-(2-chloro-5-nitrophenvl)-6-methvlpyrimidine To a solution of 2,4-diamino-5-(2-chlorophenyl)-6-methyl pyrimidine (11.84g) (Example 22) in concentrated Hg504 (100ml), was added potassium nitrate (5.1g). After stirring at room temperature for 90 minutes, the solution was poured onto ice and basified with ION NaOH. The product was extracted with ethyl 10 acetate, bulked, dried (MgSO4) and evaporated, 13.9g, 236-240°C. 2,4-Diamino-5-(5»amino-2-chlorophenv1)-6-methvlpyrimidine A solution of 2,4-diamino-5-(2-chloro-5-nitrophenyl)-6-methyl pyrimidine (13.9g) in acetic acid (500ml) was reduced under an atmosphere of hydrogen in the presence of PtOg (0.28g). The filtered through hyflo and the filtrate was The residue was neutralised with saturated NaHCO, mixture was concentrated solution and the product was extracted with ethyl* acetate, bulked, dried (MgS04) and evaporated. Chromatography on SiO gel, eluting with CHC1, to product, 6g, mp. 117-121°C. 40* MeOH/CHClg, gave the desired 2.4- Diami no-5-(2-chloro-5-N, N-dimethvlsulphamovl phenyl )-6-methvl pyrimidine 2.4- Diamino-5-(5-amino-2-chloropheny1)-6-methy1pyriroidine (0.25g) was dissolved in water (0.8ml) and concentrated HC1 (0.5ml). To the cooled solution (below 10°C) was added a solution of sodium nitrite (0.07g) in water (0.5ml). After stirring at room temperature for 2 hours, the solution was cooled to 5°C. Cupric chloride (0.05g) and 5.14M SOg in acetic acid (0.97ml) were added and the reaction was stirred at 5°C overnight. The mixture was - 57 IE 0 600 0 6 filtered and washed with water to give the sulphonyl chloride, 0.23g.

The sulphonyl chloride (0.16g) was dissolved in THF (2ml) aqueous dimethylamine (2ml) was added. After stirring overnight, the solution was diluted with water, extracted with ethyl acetate, bulked, dried (MgS04) and evaporated. Chromatography on Si02 gel, eluting with 2* MeOH/CHClg, gave the desired product, 0.047g, mp. 283-285°C.

Preparation of 2.4-Diamino-(3.5-dichlorophenyl)-6-methoxvmethvl pyrimidine This compound was prepared in an analogous manner to the compound in Example 2 from 3,5-dichlorophenylacetonitrile, mp. 228-230°C.

Fxwplt 58 Preparation of 2.4-Dianrino-5-(2.3-dichlorophenvl)-6-hvdroxvpvrimidine 1. Ethyl-2-cvano-2-(2.3-dichlorophenvl)acetate Sodium (1.2g) was added portionwise to ethanol (50ml) with stirring. After the sodium had dissolved a solution of 2,4-dichlorophenylacetonitrile (9.4g) in diethylcarbonate (25ml) 20 was added dropwise. The reaction mixture was heated until EtOH distilled over. The rate of addition was controlled such that it equalled the rate of distillation. After the completion of the addition, the reaction mixture was heated and distilled for a further 4 hours. The cooled reaction mixture was partitioned between water and EtOAc (300ml each). The organic layer was ·> λ dcied and evaporated in vacuo and the residue .«as purified by flash column chromatography to give the title product. (5g, 39%). - 58 IE 0 6 00 0 6 2. 2.4-01 amino-5-(2.3-dichlorophenvl)-6-hvdroxypyrimidine Sodium (1.2g, 0.052mol) was added in portions to absolute ethanol (50ml) with stirring. After the sodium had dissolved guanidine hydrochloride (3.69g, 0.039mol) was added followed by ethyl-2-cyano-2-(2,3-dichlorophenyl)acetate (5g, D.0195mol). The mixture was refluxed for 8 hours, EtOH was removed under reduced pressure and the residue was partitioned between EtOAc and water. The EtOAc layer was extracted with 2N NaOH and the extract was neutralised with 2N HC1 with cooling. The precipitated solid was filtered and dried to give the title compound. (0.22g), mp. 275°C (decomp). Microanalysis: Calcd: for 0.25 hydrate: C, 43.56; H, 3.09; N, 20.33; C, 43.76; H, 3.09; N, 20.03.

Eyawple 57 Synthesis of 2,4-Diamino-5-(2,4,5-trichlorophenvl)-6-methvlpyrimidine a. Preparation of 2-(2,4-dichlorophenvl)-3-oxo-butvronitrile A solution of 2,4-dichlorophenylacetonitrile (30.00gms, 161mmol) (Aldrich) in dry ethyl acetate (36ml) was added dropwise to an ethanolic solution of sodium ethoxide, prepared in situ from sodium metal (4.90g, 213mmo1) and dry ethanol (60ml). This reaction mixture was refluxed for two hours, allowed·to stand overnight at room temperature and the ethanol was evaporated. The yellow solid obtained was dissolved in water and the resulting solution was extracted twice with ether. The aqueous layer was chilled and acidified with hydrochloric acid. The crude product was extracted with ether to give 23.31g of white solid.

IE 0 6 00 0 8 - 59 b. Preparation of 2,4-diamino-5-(2.4-dichlorophenvl)-6-fflethvl pyrimidine A solution of crude 2-(2,4-dichlorophenyl)-3-oxo-butyronitrile (23.24gs) in dry toluene (400ml) was refluxed with· ethylene glycol (280ml) and ^-toluenesulphonic acid (8.00g, 42mmol) for four hours using a Dean and Stark trap. After cooling, the organic phase was washed with saturated NaHCOj, dried over MgS04, and the solvent evaporated to leave a solid (24.0gm).

Finely ground guanidine hydrochloride (19.lg, 200mmol) was added 1θ to an ethanolic solution of sodium ethoxide, prepared in situ from sodium metal (5.0g, 218mmol) in dry ethanol (500ml). A solution of the ketal (25.Og, 92mmol) in dry ethanol (10ml) was added to the guanidine solution. This mixture was refluxed for two hours and allowed to stand overnight at room temperature.

The ethanol was evaporated and the crude product recrystallised from hot acetone to give 17.23g of product, mp. 222-222.5°C. c. Preparation of 2.4-Diamino-5-(2.4-dichloro-5-nitropheny1)-6methvlpyrimidine Finely ground potassium nitrate (6.5g 64mmol) was added to a solution of 2,4-diamino-5-(2,4-dichlorophenyl)-6-methyl pyrimidine (17.23g, 64mmol) in concentrated sulphuric acid (150ml). This mixture was stirred at room temperature for 90 minutes. The reaction mixture was then added to sodium bicarbonate and ice. The product was extracted with ethyl acetate. After the ethyl acetate was removed, a yellow solid was obtained (30.86g). A portion of this crude product (7.0g) was passed through a silica flash chromatography column and eluted with ethyl acetate to give the pure product (4.81g). - 60 ΙΕ ο 6 Ο Ο Ο 6 d. Preparation of 2.4-Diamino-5-(5-amino-2,4-dichlorophenyl)-6methylpyrimidine 2.4- d i ami no-5-(2,4-d i ch1oro-5-n i tropheny1)-6-methy1pyr i mi d i ne (4.80g, 15mmo1) was dissolved in glacial acetic acid (18ml).

This solution and lOmg of Adam's catalyst was stirred under an atmosphere of hydrogen at room temperature for 4 hours. The catalyst was filtered off and the acetic acid was evaporated. The colourless liquid obtained was dissolved in ethyl acetate and washed 3 times with water. After evaporating the ethyl acetate, a white solid was obtained (2.64g, 9mmol). e. Preparation of 2.4-Diamino-5-(2.4.5-trichlorophenvl)-6-methvl pyrimidine 2.4- diamino-5-(5-amino-2,4-dichloropheny!)-6-methy1pyrimi dine (1.95g, 7mmol) was dissolved in a mixture of concentrated hydrochloric acid (3.6ml) and water (6ml). The temperature was lowered to 10°C. A chilled aqueous solution (3.6ml) of sodium nitrite (0.50g, 7mmol) was added dropwise, keeping the temperature at 10°C. This mixture was stirred at room temperature for 2 hours, then chilled before adding it dropwise 20 to a cold solution of cuprous chloride (1.7g, 17mmol) in concentrated hydrochloric acid (50ml). A grey solid precipitated which was filtered off and dried. This crude product (2.30g) was dissolved in ethyl acetate and washed twice with ammonium hydroxide solution and once with brine. After evaporating the ethyl acetate an off-white solid was obtained (2.04g). After recrystallisation from 10% methanol in chloroform the pure product was obtained (0.55g, 2mrool)’, mp. 262°C (dec).

IE 0 8 00 0 6 - 61 Example 58 Synthesis of 4-aroino-2-(ethylamino)-5-f2.3.5-trichloroohenvl) pyrimidine To a solution of NaOEt (from O.lg of sodium) in ethanol (10ml) was > added ethylguanidine sulphate (lg) (Aldrich). After stirring for 10 minutes, the enol ether (Example 3.2) (0.486g) was added and the mixture was stirred at reflux for 4 hours. The reaction was left standing at room temperature overnight and then filtered. The filtrate was concentrated and the residue was purified by io chromatography on Si02 gel, eluting with CHClg to give the desired product, O.llg, mp. 149-152°C.

Fnile 59 2.4- Diatnino-5-(2.4-dichlorophenvl)-6-cvanomethvl-pyrimidine This compound was prepared from 2,4-diamino-5-(2,4-dichlorophenyl)-815 bromomethyl-pyrimidine (Example 53) by reaction with sodium cyanide in DMF at room temperature, mp. 249-251°C.

Example 60 2.4- Diamino-5-(2.4-dichlorophenvl)-6-dimethvlaminomethvl pyrimidine This compound was prepared from 2,4-diamino-5-(2,4-dichlorophenyl)-620 bromomethyl-pyrimidine (Example 53) by reaction with dimethylamine in ethanol at room temperature, mp. 170-172°C.

Ex aw la 61 2.4- Diamirio-5-(2.4-dichlorophenv1)-6-cvanopyrimidine This compound was prepared from the compound of Example.48 by reaction 25 with trifluoroacetic anhydride in pyridine, mp. 249°C. - 62 IE 0 6 00 0 6 Example 62 2.4- DiaiM'no-5-(2-chloro»4-fluorophenvl)-6-methvlpvrimidine This compound was prepared in an analogous manner to the compound of Example 15 from 2-chloro-4-fluorophenylacetonitrile, which was itself prepared from 2-chloro-4-fluorotoluene (Aldrich, mp. 238°C.

Example 63 2.4- Dianiino-5-(3.4-dichlorophenyl)-6-methoxymethyl pyrimidine This compound was prepared in an analogous manner to the compound of Example 2 from 3,4-dichlorophenylacetonitrile (Aldrich), mp. 2Q4-206°C.

Fnalg 64 2.4- Diamino-5-(2.3-dichlorophenvl)-6-ethylpyrimidine This compound was prepared in an analogous manner to the compound of Example 15 from ethyl propionate, mp. 228-230°C.

Example 65 24-Diamino-5-(2.4-difluorophenvl)-6-methvlpyrimidine This compound was prepared in an analogous manner to the compound of Example 6 from 2,4-difluorophenylacetonitrile (Aldrich), mp. 291-296°C. - 63 66 ΙΕ ο 6 Ο Ο Ο 6 2,4-Di amino-5-(2-naphthvl )-6-methylpyrimidine This compound was prepared in an analogous manner to the compound of Example 6 from 2-naphthylacetonitrile (Aldrich), mp. 221-222°C.

Exawle 67 2,4-Diamino-5-(1-naphthyl)-6-methvlpyrimidine This compound was prepared in an analogous manner to the compound of Example 6 from 1-naphthylacetonitrile (Aldrich), mp. 224-225°C.

Exawle ¢8 2-Hydroxv-4-amino-5-(2.3-dich1orophenvl)pyrimidine This compound was prepared from the compound of Example 21 by reaction with sodium nitrite in IN HgSO^ at reflux to give a mixture of the title compound and the compound of Example 21B.d. The title compound was separated by column chromatography, mp. 330-334°C.

Exawle 69 2-Amino-4-ethoxv-5-(2.4-dichlorophenvl)-6-inethvlthioovrimidine This compound was made from the compound of Example 32.4 by reaction with methanethiol sodium salt in ethanol, mp. 123-124°C. ΙΕ ο 6 Ο Ο Ο 6 - 64 Exawl· 702.4-Dianrino-5-(2.3.5-trichlorophenyl)-6-hvdroxymethvlpvriinidine This compound was made from the compound of Example 2 by reaction with trimethylsilyl iodide in sulpholane at 80°C, mp. 101-105°C.

Example 71 2.4- Diaiiiino-5- (2.3.5-trichlorophenvl 1-6-f luoromethvlpyrimidine This compound was prepared in an analogous manner to the compound of Example 18 from 2,4-diamino-5-(2,3,5-trichlorophenyl)-6-hydroxymethylpyrimidine, mp. 215-217°C.

Exawl· 72 2.4- 0iamino-5-(2.4-dichlorophenyl)-6-carbaroovlpvrimidine This compound was prepared from the compound of Example 61 by reaction with concentrated sulphuric acid at room temperature, mp. 298-299°C.

Exawla 73 2.4-Diamino-5-(2,4-dichlorophenvl)pvrimidine-6-carboxylic acid This compound was prepared from the compound of Example 46 reaction with potassium permanganate, mp. 227°C.

. Example ’ · ' ί Ethyl-2.4-diamino-5-(2.4-dichlorophenvl)pyrimidine-6-carboxvlate 2o This compound was prepared from the compound of Example 73 by refluxing in ethanol in the presence of concentrated, sulphuric acid, mp. 177.5°C. ΙΕ ο 6 Ο Ο Ο 6 - 65 FK*«a1t 75 . 2,4-Diamino-5-(2.3-dichlorophenvl)-6-dibromomethvlpyrimidine This compound was prepared from the compound of Example 15 by reaction with 2 eq NBS in CCl^ and AIBN as initiator. The title compound was separated from a mixture with the compound of Example 43 by column chromatography, mp. 270°C (dec).

Example 76 2-Dimethvlamino-4-amino-5-(2.4-dichlorophenvl)pyrimidine This compound was prepared in an analogous manner to the compound of Example 10 from 2,4-dichlorophenylacetonitrile (Aldrich), mp. 151°C.

ExaiTe 77 2-Dimethvlamino-4-amino-5-(3.4-dichlorophenvl)-6"inethv1pvrimidine This compound was made in an analogous manner to the compound of Example 13 from 3,4-dichlorophenylacetonitrile.

Example 78 2-N-Piperidvl-4-amino-5(2.4-dich1orophenvl)pvrimidine This compound was prepared in an analogous manner to the compound of Example 76 from 1-piperidinecarboxamidine sulphate (Bader), mp. 169°C. ΙΕ ο 6 ο Ο Ο 6 - 66 Exaggle_7£2-Methylamino-4-anrino-5-(2,3,5-trichlorophenvllovrimidine This compound was prepared in an analogous manner to the compound of Example 58 from 1-methyl-guanidine hydrochloride (Aldrich), mp. 155-157°C. Ρχ«·ρ1· 80 2.4- Diamino-5-(2-ch1oro-5-bromophenyl)-6-methylpyrimidine This compound was prepared in a similar manner to the compound of Example 54 by reaction of the diazonium salt with cuprous bromide, mp. 212-216°C.

Example 81 2.4- Diamino-5-(2-chloro-5-iodophenvl)-6-methvlpyrimidine This compound was prepared in a similar manner to the compound of Example 54 by reaction of the diazonium salt with potassium iodide, mp. 232-234°C.

Example 82 2.4- Diamino-5-(2-chloro-5-cyanophenvl)-6-methv1pyriroidine This compound was prepared in a similar manner to the compound of Example 54 by reaction of the diazonium salt with cuprous cyanide, -nnp^239«241°C.

V/ ΙΕ ο 6 ο Ο Ο 6 Example 83 2.4- Diainino-5-(2-chloro-5-f1uorophenyl)-6-methylpvriinidine This compound was prepared in a similar manner to the compound of Example 54 by way of the diazonium tetrafluoroborate salt, mp. 195-197°C. ΕτιμρΙβ ga 2.4- Diamino-5-(2-chloro-5-methylthiophenvl1-6-methvlpyrimidine This compound was prepared in a similar manner to the compound of Example 54 by reaction of the diazonium salt with methanethiol in the presence of copper powder, mp. 194-198°C.

Exhale 8S 2-Amino-4.6-di(roethvlthio)-5-(2.4-dichlorophenvl)pyritnidine This compound was prepared from the compound of Example 32.4 by reaction with methanethiol sodium salt in methanol in the presence of tris[2-(2-methoxyethoxy)ethyl]amine and copper powder, mp. 164-165°C.

Example 88 /;*> i 2.4-piamino-5-(2Chloro-5-methanesulDhonv1aminophenyl)-6-methvl pyrimidine^ This compound was prepared from 2,4-diamino-5-(2-ch1oro-5-aminophenyl) -6-methylpyrimidine from Example 54 by reaction with methanesulphonylchloride in pyridine, mp. 234-240°C.

IE 0 6 00 0 6 - 68 grail» fl7 2.4-Diamino-5-(2.3-dichlorophenvl)-l-methvlpvrimidinium iodide This compound was prepared from the compound of Example 21 and methyl iodide, mp. 280-284°C.

Exampla 88 2-Amino-4-methv1amino-5-(2.3-dichlorophenvl)pvrimidine This compound was prepared in an analogous manner to the compound of Example 21B.g by reaction with methylamine in ethanol, mp. 233-237°C. gratia 89 2-Amino-4-dimethvlamino-5-(2.3-dichlorophenv1)pyrimidine hydrochloride This compound was prepared in an analogous manner to the compound of Example 21B.g by reaction with dimethylamine in ethanol and subsequent conversion to the hydrochloride salt, mp. 295-300°C. gratia 90 2-Amino-4-chloro-5-(2.4-dich1orophenv1)pvrimidine The compound was prepared in an analogous manner to he compound of •Λ .λ Ά Example1'21 B.f. from 5-(2,4-dichlorophenyl)isocytosine, mp. 215-216°C.

V* Ex a» la 91 2-Amino-4-methv1amino-5"(2.4-dichlorophenvl)pvrimidine 20 This compound was prepared from the compound of Example_90 by reaction with methylamine in ethanol, mp. 189-90°C. ΙΕ ο 6 Ο ο ο 6 - 69 Exawle 92~ 2-Amino-4-dimethylamino-5-(2.4-dichlorophenvl)pyrin)idine hydrochloride This compound was prepared from the compound of Example 90 by reaction with dimethylamine in ethanol and subsequent conversion to the hydrochloride salt, mp. 297-301°C. ggawle 93 2"Amino-4-piperidino-5-(2.4-dichlor0Dhenv1lovrimidine hydrochloride This compound was prepared from the compound of Example 90 by reaction with piperidine in ethanol and subsequent conversation to the 10 hydrochloride salt, mp. 303°C (dec). - 70 IE 0 6 00 0 6 Preferred among the compounds of formula (I) are the pyrimidines ♦ of the foregoing Examples 1,2,3,4,14 and 16, together with salts (in particular, pharmaceutically acceptable salts) thereof; these bases have the following respective two-dimensional structures.

Example 1 Exuple 2 Example 3 - 71 Example 4 Example 14 Example 16 IE 0 6 00 0 6 IE 0 6 0 0 0 6 - 72 TABLE OF XH MW DATA (d EXAMPLE NO. SOLVENT ASSIGNMENT CDC13 7.56(d,lH), 7.18(d,lH), 4.65-4.50 (br.s,2H), 3.88(t,4H), 2.5(t,4H), 2.36(s,3H) DMSO-dg 3.06(s,3H,-0Me), 3.8(d,lH,J12.5Hz, -CH20Me), 3.9(d,lH,J12.5Hz,-CH20Me), 5.98(br.s,2H,-NH2), 6.1(br.s,2H,-NH2), 7.32(d,lH,J2.5Hz,6'-H), 7.78(d,lH, J2.5Hz,4'-H) DMSO-dg 7.8(d,lH), 7.65(s,lH), 7.36(d,lH), 6.33-6.23(brs,2H), 3.68(t,4H), 2.32(t,4H), 2.2(s,3H) DMSO-dg 6.40(s,2H), 6.55(s,2H), 7.35(s,lH), 7.80(s,lH) DMSO-dg 8.6(s,lH), 7.49(s,lH), 6.4-6.3(br.s,2H), 6.25-6.15(br.s,2H) 7 DMSO-dg 1.70(s,3H), 5.75(s,2H), 5.90(s,2H), 7.30(s,lH), 7.75(s,lH) CDC13 7.55(d,lH), 7.18(d,lH), 4.75-4.58 (br.s,2H), 3.9-3.7(m,8H) CDC13 7.55(d,lH), 7.18(d,lH),. 4.56-4.50 (br.s,2H), 3.2(s,6H) ΙΕ ο 6 0 0 0 6 - 73 - DMSO-dg 7.79(d,lH), 7.67(s,lH), 7.36(d,lH), 6.47-6.27(br.s,2H), 3.72-3.57(m,8H) DMSO-dg 7.78(d,lH), 7.64(s,lH), 7.35(d,lH), 3.08(s,6H) cdci3 * 7.51(d,lH), 7.17(d,lH), 4.40-4.22 (br.s,2H), 3.82(t,4H), 2.48(t,4H), 2.34(s,3H), 2.0(s,3H) DMSO-dg 8.28(s,lH), 6.18-6.04(br.d,4H), 2.1(s,3H) cdci3 7.51(d,lH), 7.18(d,lH), 4.36-4.22 (br.s,2H), 3.16(s,6H), 2.0(s,3H) DMSO dg 6.10(s,2H), 6.45(s,2H), 7.15(d,lH), 7.30(t,lH), 7.55(d,lH) DMSO-dg 1.70(s,3H), 5.60(s,2H), 5.80(s,2H), 7.15(d,lH), 7.30(t,lH), 7.55(d;lH) DMSO-dg 3.04(s,3H,-0Me),3.76(d,lH,J12Hz,-CH20Me) 3.85(d,lH,J12Hz,-OCH2OMe), 5.84 (br.s,2H,-NH2), 6.05(br.s,2H,-NH2), 7.22(dd,lH,J7.5,l.5Hz,6'-H), 7.38 - 4 Λ ' J (dd,lH,J7.5Hz,5'-H), 7.6(dd,lH,J7.5, 1.5Hz,4'-H) DMSO-dg 7.3-8.0(m,8H), 6.0-6.1(br.s,2H), 5.2-5.4(br.s,2H) OMSO-dg 4.75(2xdd,2H,J47,15Hz,-CH2F), 5.95(br.s,2H,-NH2), 6.15(br.s,2H,-NH2), 7.25(dd,lH,J7.5, 1.0Hz,6'-H), 7.39 IE 0 6 0 0 0 6 - 74 19 28 DMSO-dg DMSO-dg DMSO-dg DMSO-dg DMSO-dg DMSO-dg DMSO-dg cdci3 (dd,lH,J7.5Hz), 7.64(dd,lH, J7.5, 1.0Hz) ♦ 4.43(d,lH,JllHz), 4.53(d,lH,JllHz}, 5.95(br.s,2H), 6.12(br.s,2H), 6.7(m,2H), 6.85(dd,lH,J7Hz), 7.1-7.4(m,4H), 7.55(dd,lH,J7,lHz). 4.4(d,lH,J12Hz,-CH20Ph), 4.52(d,lH, J12Hz, -CH2OPh), 5.92(br.s,2H,-NH2), 6.12(br.s,2H, -NH2), 6.69(dd,lH,J7.5, l.OHz,6'-H), 6.85(dd,lH,J7.5Hz,5'-H), 7.10-7.35 (m,5H,-0Ph), 7.55(dd,1H,J7.5, 1.0Hz,4'-H) 7.52(s,lH), 7.15-7.75(m,3H), 6.02(br.s,4H,2x-NH2) 6.07(s,2H), 6.25(s,2H), 7.25(d,lH), 7.45(d,lH), 7.63(s,lH) 3.88(d,lH,JllHz), 4.0(d,1H,JllHz), 4.3(s,2H), 5.9(br.s,2H), 6.1(br.s,2H), 7.05-7.2(m,2H), 7.2-7.35{m,4H), 7.4(dd,lH,J8,2.5Hz), 7.62(d,lH,J2.5Hz) 6.25(s,2H), 6.50(s,2H), 7.30(s,lH), 7.40(d,lH), 7.50(d,lH) .85(s,2H), 6.1(s,2H), 7.25(s,lH), 7.45(s,lH), 7.7(s,lH) 7.53-7.12(m,4H), 4.48-4.30(br.s,2H), 3.81(t,4H), 2.46(t,4H), 2.33(s,3H), 2.03(s,3H) IE 0 6 0 0 0 6 - 75 32 34 CDClg 7.38(d,lH), 7.2(dd,lH), 7.08(d-,lH), 8.2(br.s,2H) DMSO-dg 7.7(d,lH), 7.48(dd,lH), 7.29(d,lH), 6.45(br.s,2H), 6.2(br.s,2H) CDClg 7.5(d,lH), 7.35(dd,lH), 7.18(d,lH), .25(br.s,2H), 2.44(s,3H) CDClg 7.52(d,lH), 7.32(dd,lH), 7.21(d,lH), .08(br.s,2H), 4.66(br.s,2H), 2.42(s,3H) DMSO-dg 1.9(s,3H,6-CH3), 2.2(s,3H,N-Me), 2.25-2.40(m,4H,-N N-), 3.55-3.75 (m,4H,-N N-), 5.85(2H,br.s,-NH2), 7.2(d,2H,J1.5Hz,2',6'-H), 7.52 DMSO-dg 7.58(dd,lH), 7.45(dd,lH), 7.35(d,lH), 7.24(br.s,lH), 3.35(br.s,2H), 3.96(br.s,2H) DMSO-dg 1.8(s,3H), 5.8(s,2H), 5.95(s,2H), 7.53(s,lH), 7.92(s,lH) DMSO-dg 7.78(d,lH), 7.59(s,lH), 7.36(d,lH), 6.60-6.47(br.t,lH), 6.25-6.03(br.s,2H), 3.25(q,2H), l.l(t,3H) In the foregoing, the signals have been abbreviated as follows: s = singlet; d « doublet; dd e doublet of doublets; t = triplet; q » quadruplet; m « multiplet; br.s broad singlet; br.t « broad triplet. - 76 IE Ο 6 Ο Ο Ο $ Pharmacological Activity Inhibition of Glutamate release and Inhibition of Rat Liver DHFR Compounds of Formula (I) were tested for their effect on veratrineevoked release of glutamate from rat brain slices according to the protocol described in Epilepsia 27(5): 490-497, 1986. The protocol for testing for inhibition of DHFR activity was a modification of that set out in Biochemical Pharmacology Vol.20 pp 561-574, 1971.

The results are given in Table 1, the ICjq being the concentration of compound to cause 50% inhibition of (a) veratrine-evoked release of glutamate and (b) of DHFR enzyme activity.

TABLE ί Compound ^5q(uN) IC50(pN) ef Glutamate Release Rat Liver DHFR Example No. (P95 limits) (P95 Halts) 1 6 π 1.18 (0.50-2.60) 0.56 (0.23-1.37) 2.15 (0.90-5.10) 0.33 (0.195-0.566) 3.50 (1.10-10.40) 0.70 (0.40-1.50) <10.00 <10.00 <10.00 <10.00 4.80 (2.30-10.20) <10.00 <10 >100 (27.00-40.00) >100 >30<100 ca.100 0.51 (0.36-0.73) >10.0 >10.0 >100.00 >100.00 >100.00 >100.00 >100.00 ΙΕ ο 6 Ο Ο Ο 6 - 77 3.1 (2.1-4.6) 2.7 (1.0-7.2) 3.2 (1.7-6.1) 2.4 (1.00-5.80) <10.00 2.6 (0.80-8.50) 4.2 (1.20-15.30) 11.5 (4.80-27.60) 2.80 (0.80-9.80) 8.70 (2.60-29.10) 2.10 (0.90-4.80) 4.10 (1.10-15.50) ca.3.00 ca.10.00 4.6(1.60-13.30) 1.57(0.94-2.62) >100.00 8.7 (5.2-14.7) >100 4.9 (3.90-6.20) ca.100 >100.00 17.50(9.80-31.40) 16.01(12.05-21.282) 23.800(9.00-61.00) .940(9.00-61.00) .10(11.00-20.70) >100.00 dO.OO >100.00 46.10(14.30-148.90) 0.53(0.348-0.812) - 78 ΙΕ ο 6 ο ο Ο 6 Toxicological Example The compound of Example 1 has been administered intravenously to groups of six male and six female Wistar rats once daily at dose levels of upto 15mg/kg/day. The no observsed effect dose was 2.5mg/kg/day.

The compound of Example 2, has been tested in both rats and dogs. In rats the no observed effect dose was 2.5mg/kg/day and in dogs, the no observed effect dose was 14mg/kg/day.

Pharmacautical Fomilation Example Tablet: INGREDIENT A: Compound of Example 1 150 mg ) Lactose 200 mg ) Maize Starch 50 mg ) Polyvinylpyrrolidone 4 mg ) Magnesium Stearate 4 mg ) ) * contents per tablet.

The drug was mixed with the lactose and starch and'granulated with a solution of the polyvinylpyrrolidone in water. The resultant granules - 79 ΙΕ ο 6 Ο Ο Ο 6 were dried, mixed with magnesium stearate and compressed to give tablets.

B: INJECTION (I) The salt of the compound of Formula I was dissolved in sterile 5 water for injection.

INTRAVENOUS INJECTION FORMULATION (III Active ingredient 0.20g Sterile, pyrogen-free phosphate buffer (pH9.0) to 10ml The compound of Example I as a salt is dissolved in most of the 10 phosphate buffer at 35-40°C, then made up to volume and filtered through a sterile micropore filter into sterile 10ml glass vials (Type 1) which are sealed with sterile closures and overseals.

In the following Examples, the active compound maybe any compound of formula (I) or pharmaceutically acceptable salt thereof.

C: Capsule formulations Capsule Formulation A Formulation A may be prepared by admixing the ingredients and filling two-part hard gelatin capsules with the resulting mixture. - 80 ΙΕ ο 6 0 Ο ο 6 mq/capsule (a) Active ingredient 250 (b) Lactose B.P. 143 (c) Sodium Starch Glycol late 25 (d) Magnesium Stearate 2 420 Capsule Formulation Β mq/capsule (a) Active ingredient 250 (b) Macrogel 4000 BP 350 600 Capsules may be prepared by melting the Macrogel 4000 BP, dispersing the 10 active ingredient in the melt, and filling two-part hard gelatin capsules therewith.

Capsule Formulation B (Controlled release capsule) mq/capsule (a) Active ingredient 250 (b) Microcrystalline Cellulose 125 (c) Lactose BP 125 (d) Ethyl Cellulose 13 513 The controlled-release capsule formulation may be prepared by extruding mixed ingredients (a) to (c) using an extruder, then spheronising and ΙΕ θ 6 Ο Ο ο 6 drying the extrudate. The dried pellets are coated with ethyl cellulose (d) as a controlled-release membrane gelatin capsules. and filled into two-part hard SvruD formulation 5 Active ingredient 0.2500 g Sorbitol Solution 1.5000 g Glycerol 1.0000 g Sodium Benzoate 0.0050 g Flavour 0.0125 ml10 Purified Water q.s. to 5.0 ml The sodium benzoate is dissolved in a portion of the purified water and the sorbitol solution added. The active ingredient is added and dissolved. The resulting solution is mixed with the glycerol and then made up to the required volume with the purified water. ir SuoDositorv formulation ma/supDositorv Active ingredient (63μΐη)* 250 Hard Fat, BP..(Witepsol Hl5 - Dynamit Nobel) 1770 2020 * The active ingredient is used as a powder wherein at least 90% of the particles are of 63μπ» diameter or less. - 82 ΙΕ θ S Ο Ο Ο 6 One-fifth of the Witepsol H15 is melted in a steam-jacketed pan at 45°C maximum. The active ingredient is sifted through a 200^m sieve and added to the molten base with mixing, using a Si Iverson fitted with a cutting head, until a smooth dispersion is achieved. Maintaining the mixture at 45°C, the remaining Witepsol H15 is added to the suspension which is stirred to ensure a homogenous mix. The entire suspension is then passed through a 250gm stainless steel screen and, with continuous stirring, allowed to cool to 40°C. At a temperature of 38-40°C, 2.02g aliquots of the mixture are filled into suitable plastic moulds and the suppositories allowed to cool to room temperature.

Claims (21)

1. Use of a compound of Formula I or an acid addition salt thereof in the manufacture of a medicament for treating or preventing CNS disorders or diseases of a mammal, wherein 5 in Formula I, Rj and R 2 are the same or different and are selected from hydrogen, halo, hydroxy, alkoxy, alkyl, alkylthio and a group NR^R^ where R^ and R 11 are the same or different and are selected from hydrogen, alkyl, aryl and arylalkyl or together with the nitrogen atom to which TO ' they are ; attached form a cyclic ring optionally substituted with one or more alk^l groups and optionally containing a further heteroatom; Rg is hydrogen, alkyl optionally substituted by one or more halo radicals, or is amino, alkylamino, dialkylamino, cyano, nitro, halo, carbamoyl, hydroxy, carboxy, alkoxy, alkylthio, alkylthioalkyl, 15 S(O) n alkyl, di(alkyloxy)alkyl, -C(R):NOH or -COR or -C0 2 R wherein R is hydrogen or alkyl, or a group CH 2 X where X is hydroxy, alkoxy, aryloxy, arylalkyloxy, halo, cyano, -NR l R^ wherein R* and R^ are as IE 0 6 00 06 - 84 defined above, S(O) n -alkyl where n is 1 or 2, or SOgNtR 111 ^ where rIH is selected from hydrogen and alkyl; each of R^ to Rg are the same or different and each is selected from hydrogen, halo, alkyl, perhaloalkyl, cyano, carbamoyl, carboxy, COR, nitro, amino, alkylsulphonylamino, alkoxy, S(O) n ~alkyl where n is 1 or 2, or S0 2 N(R 1U ) 2 ; or R^ and Rg or Rg and Rg together are the group -CH=CH-CH=CH- or the group -CH 2 -CH 2 ~CH 2 -CH 2 - in which case both R? and Rg are hydrogen; and optionally one of the nitrogen atoms in the pyrimidine ring may be 10 N alkylated or optionally may be an N oxide; the foregoing alkyl groups or moieties of alkyl-containing groups having from 1 to 6 carbon atoms, and the aryl groups or aryl moieties of aryl-containing groups having 6 or 10 carbon atoms.

2. Use of a compound as claimed in claim 1 wherein one of Rj and R 2 is 15 amino, and the other is selected from amino, hydroxy, halo, morpholino, piperazinyl, N-alkylpiperazinyl, Ν,Ν-dialkylamino, N-alkylamino or alkylthio; Rg is alkyl optionally substituted by one or more halo radicals, or is alkyl, alkylthio, hydrogen, hydroxy, alkoxy, halo, carboxy, carbamoyl, 20 or a group CHgX where X is hydroxy, phenoxy, benzyloxy, alkoxy or alkylthio; one of and Rg is halo and the other is selected from halo or hydrogen; Rg is halo, hydrogen, nitro or amino; 2 g Ry is hydrogen, halo, cyano, alkylthio, S0 2 N(R 111 ) 2 , alky.1, nitro, amino or methanesulphonamido; and - 85 ΙΕ ο 6 ο ο ο β Rg is hydrogen or halo.

3. Use of a compound as claimed in claims 1 or 2 wherein R^ is hydroxy, amino, N-alkylamino, N,N.-dialkylamino, morpholino, piperazinyl, jN-alkylpiperazinyl. 5

4. Use of a compound as claimed in any one of claims 1 to 3 wherein Rg is chloro, amino, Ν,Ν-dialkylamino, or piperidino.

5. Use of a compound as claimed in any one of claims 1 to 4 wherein Rg is hydrogen, alkyl, methoxymethyl, trifluoromethyl, benzyloxymethyl, phenoxymethyl or methyl thiomethyl. 10

6. Use of a compound as claimed in claims 1 or 2 wherein one of R^ and Rg is amino and the other is amino, piperazinyl or ji-methylpiperazinyl, tl-alkylamino, Ν,Ν-dialkylamino and Rg is hydrogen, methyl, trifluoromethyl or methoxymethyl.

7. Use of a compound as claimed in claim 1 wherein Rj is selected from 15 Λ amino, piperazinyl, N-methylpiperazinyl, N.-morpholino, . -i jNL Rg is amino; Rg is selected from trifluoromethyl, hydrogen, methyl, benzyloxymethyl, methoxymethyl and methylthiomethyl; 20 R4 is chloro; and at least one of Rg, Rg and R? is chloro, and the remainder are selected from hydrogen, chloro and nitro; and IE 2 6 0 0 0 6 - 86 Rg is hydrogen or R 4 and R g are both hydrogen, Rg and R ? are both chloro and R g is selected from hydrogen, chloro and nitro.

8. Use of a compound of Formula I or an acid addition salt thereof as defined in claim 1 in the manufacture of a medicament for treating or preventing CNS disorders or diseases of a mammal wherein to Rg are as defined in claim 1 with the proviso that when R ? is halo, then Rg is hydrogen, perhaloalkyl, methyl or methoxymethyl and/or Rg is nitro and/or Rj is N-alkylpiperazinyl, morpholino, N,N.-dimethylamino, piperazinyl or N-ethylamino; or with the proviso that when Rg is chloro then R^ is halo, and Rg is hydrogen, perhaloalkyl, methoxymethyl, methyl or halo and/or Rj is Ν,-methyl piperazinyl, piperazinyl, morpholino or Κ,Ν.dimethylamino, or .N-ethylamino. t

9. - A compound or : acid addition salt thereof of Formula I as defined in claim 1 -with the proviso that at least one of R^ to Rg is other than hydrogen, and further with the proviso that when Rj and Rg are both amino, or when R^ is hydroxy and Rg 1S an *ino, and Rg is alkyl or hydrogen, and R? is hydrogen, then R 4 and Rg are both halo. ΙΕ ο 6 Ο Ο Ο 6 - 87

10. A compound or acid addition salt thereof of Formula I wherein R, to R c 1 b and Rg are as defined in claim 1 and R? is halo, alkyl, perhaloalkyl, cyano, nitro, amino, alkylthio, S(O) n -alkyl or SO 2 N(R 111 ) 2 ·

11. A compound or acid addition salt of formula I wherein R 2 to Rg are as 5 defined in claim 1 and Rj is morpholino, piperazinyl, N-alkylpiperazinyl, Ν,Ν-dialkylamino, fl-slkylamino or alkylthio.

12. A compound or acid addition salt of formula I wherein Rj and R 2 are as defined in claim 1 and Rg is alkoxy, alkylthio or alkyl substituted by one or more halo radicals, or is a group CH 2 X where X is alkylthio, 10 aryloxy, arylalkyloxy, alkyloxy or hydroxy; R 4 to Rg are the same or different and are each selected from hydrogen, halo, perhaloalkyl, cyano, nitro, amino or alkylthio; Ry is halo, alkyl, perhaloalkyl, cyano, nitro, amino, or a group SOgNiR 1,11 ·^ wherein R 111 is alkyl; and 15 Rg is hydrogen or halo.

13. A compound or acid addition salt of formula I wherein Rp R 2 , R 4 , Rg, Rg, Jt? 'andR^^jare as defined in claim 1 and Rg is alkoxy, aryloxy, arylalkyloxy or alkylthio.

14. 4-Amino-2-(4-methylpiperaz in-1-y1)-5-(2,3,5-trichlorophenyl)-620 trifluoromethyl or acid addition salt.

15. 2,4-0iamino-5-(2,3,5-trichlorophenyl)-6-methoxymethylpyrimidine or acid addition salt.

16. ΙΕ ο 6 Ο Ο Ο 6 - 88 V8. 4-Amino-2-(4-methylpiperazin-l-yl)-5-(2,3,5-trichlorophenyl) pyrimidine -dr acid addition salt.

17. 2,4-Diamino-5-(2,3,5-trichlorophenyl)-6-trifluoromethylpyrimidine or acid addition salt.

18. 2,4-Diamino-5-(4-nitro-2,3,5-trichlorophenyl)pyrimidine 2.4- Diamino-5-(2,3,5-trichlorophenyl)-6-methylpyrimidine 4-Amino-2-N.-morpholino-5-(2,3,5-trichlorophenyl )-6-trifluoromethylpyrimidine 4. -Ami no-2-N., N-dimethylami no-5-(2,3,5-tr ichlorophenyl)-61° trifluoromethylpyrimidine 4-Ami no-2-morpholi no-N-5-(2,3,5-tri ch1oropheny1)pyr imid i ne 4-Amino-2-N,N-dimethylamino-5-(2,3,5-trichlorophenyl)pyrimidine 4-Amino-6-methyl-2-(4-methylpiperazin-l-yl)-5-(2,3,5-trichlorophenyl )pyrimidine 15 2,4-Diamino-5-(2,3-dichlorophenyl)-6-trifluoromethylpyrimidine 2.4- Diamino-5-(2,3-dichlorophenyl)-6-methylpyrimidine 2.4- Diamino'-5-(2,4-dichlorophenyl)-6-trifluoromethylpyrimidine 6-Benzyloxymethyl-2,4-diamino-5-(2,4-dichlorophenyl)pyrimidine 2-N-methylpiperazinyl-4-amino-5-(2,4-dichlorophenyl)pyrimidine 2.4- Diamino-5-(2,5-dichloropheny!)-6-trifluoromethylpyrimidine 2.4- Diamino-5-(2,3,5-trichlorophenyl)pyrimidine 4-Amino-5-(3,5-dichlorophenyl)-6-methyl-2-(4-methylpiperazin-lyl)pyrimidine 4-Amino-2-N-ethylamino-5-(2,3,5-trichloropheny!) pyrimidine IE 0 6 00 0 6 - 89 4-Amino-2-N-methylamino-5-(2,3,5-trichlorophenyl )pyrimidine or an acid addition salt thereof.

19. A pharmaceutical formulation comprising a compound according to any one of claims 9 to 18 together with one or more acceptable carriers

20. 5. Therefor and optionally other therapeutic ingredients. A process for the production of a compound or an acid salt thereof according to any one of claims 9 to 18 which comprises the reaction of a compound of formula II 2 wherein Rg to Rg are as hereinbefore defined, L is a leaving group, 10 and Y is cyano or carboxy, carbonyl, or alkoxycarbonyl with a compound of formula III \\ III wherein Rj is as hereindefined, and isolating the compound of Formula I as the free base or an acid addition salt thereof, and optionally converting the base into an acid addition salt thereof or into another ΙΕ ο 6 ο Ο Ο 6 acid addition salt, or into another compound of Formula I or an acid addition salt thereof.

21. A compound or pharmaceutically acceptable salt thereof as claimed in claim 9 to 18 for use in therapy.