IE84435B1 - Pharmacologically active CNS compounds - Google Patents

Description

Phannacologically 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., ga, 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, lfieldrum Clinical Science (1985) gs 113-122). In addition, glutamate has been implicated in other neurological disorders such as manic depression, depression, schizophrenia, high pressure neurological chronic pain, trigeminal neuralgia and migraine. syndrome, In European Patent application No.2112l there is disclosed a group of 3,5-diamino(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(2,3-dichlorophenyl)-1,2,4-triazine (lamotrigine), has been shown to inhibit the release of the excitatory amino acids, glutamate and aspartate, (Leach g;_al Epilepsia gz, 490-497 1986, A.A.Miller et 31 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 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 according to the first aspect of the present invention there is provided a pyrimidine of formula I: R3 R4 R5 .R1—$Q R6 (I) R2 R8 R7 wherein, R1 is N—methylpiperazinyl; R2 is amino; R3 is selected from trifluoromethyl, hydrogen, methyl, benzyloxymethyl, methoxymethyl and methylthiomethyl; R4 is chloro; and and the remainder at least one of R5, R5 and R7 is chloro, of R., R6 and R, are selected from hydrogen and chloro in the case of R5 and R7, and from hydrogen, chloro and nitro in the case of R& except that R6 is not hydrogen when R1 is N—methylpiperazino, R2 is amino, each of R3 and R8 is hydrogen and each of R4, R5 and R, is chloro; RE is hydrogen; and pharmaceutically acceptable acid addition salts thereof.

(I) and it Certain pyrimidines of Formula are chiral, will be appreciated that in these instances, Formula (I) encompasses both the racemic mixture and the individual enantiomers of such compounds.

R6 and R7 are preferably selected from hydrogen and chloro.

It is a preferred feature of Formula that at least one of R5 and R7 are chloro. In particular, it is preferred that both R5 and R7 are chloro. Such compounds are highly potent inhibitors of glutamate release.

The present invention also provides a subclass of pyrimidines of Formula (I), which whilst being potent inhibitors of glutamate release show only weak (i.e. having an ICW of >20um) or insignificant inhibitory effects on the enzyme dihydrofolate reductase. Accordingly, in a preferred embodiment of the present invention there are provided pyrimidines of Formula (I) where R7 to R8 are hereinbefore defined with the proviso that when R7 is chloro, then R3 is hydrogen, methyl or methoxymethyl and/or R6 is nitro; or with the proviso that when R6 is chloro then R, is chloro, and R3 is hydrogen, methoxymethyl, methyl or halo.

Preferred compounds of the present invention are: 2-(4—methylpiperazin—1-yl)-4—amino—5-(2,3,5,- trichlorophenyl)—6—trifluoromethylpyrimidine; 2~(4-methylpiperazin—1—yl)—4-amino—5—(2,3,5- trichlorophenyl)methylpyrimidine; 2-(4—methylpiperazin—l-yl)—4—amino—5—(2,4- dichlorophenyl)pyrimidine; and pharmaceutically acceptable acid addition salts thereof.

In a preferred embodiment the present invention also provides a pharmaceutically acceptable acid addition salt of a pyrimidine as described above.

The compounds of the invention 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; also physical injury or trauma of the spinal cord or brain. Chronic neuro~ degenerative disorders which may be treated include Alzheimer's disease, Huntington's chorea, Olivoponteocerebrellar atrophy and motor system disorders.

Other neurological conditions which may be treated with a compound of the invention include depression, manic depression, chronic pain, schizophrenia, epilepsy, trigeminal neuralgia and migraine.

A compound of the invention can be used in the treatment of a disease or disorder of the central nervous system of a mammal in which extracellular glutamate is implicated.

A mammal predisposed to or having neurotoxic extracellular glutamate levels of the central nervous system can thus be treated.

Certain substituted phenylpyrimidines of the present invention are known in the art as having antimalarial 185-200 Other phenylpyrimidines 463-468, (1982) (1963), ed. Oldrich activity. See for example Brit.J.Pharmacol. 6, (1951); JACS, 13, 3763-70, (1951). are know from Chem.Biol. Ptderidines, and Pharmacotherap.Budesinsky, p.129-141, Hanc.

Nonetheless, compounds of the present invention are novel and accordingly the present invention provides a (I) wherein R1 to R3 are as hereindefined. pyrimidine of Formula or an acid addition salt thereof Preferred novel compounds of the present invention include the following, the numbers referring to the Examples hereinafter appearing:— Example No. . 4—Amino—2—(4—methylpiperazin—1—yl)(2,3,5- trichlorophenyl)—6-trifluoromethylpyrimidine . 4-Amino—6-methyl(4—methylpiperazin—1—yl)(2,3,5- trichlorophenyl)pyrimidine . 2-N—methylpiperazinylamino(2,4- dichlorophenyl)pyrimidine or an acidraddition salt thereof.

Suitable acid addition salts of the compounds of Formula I 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, maleic, oxaloacetic, methanesulphonic, ethanesulphonic, p-toluenesulphonic, benzenesulphonic and isethionic acids. These salts can be made by reacting the compound as the free fumaric, 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 more acceptable carriers therefor and optionally other therapeutic ingredients. The carrier(s) must be ‘acceptable’ 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 ingredients. In general the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both and then, 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 tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension an aqueous liquid or a non-aqueous liquid; liquid emulsion or a water-in-oil in or as an oil-in-water 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 free- flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, lubricating, surface active or 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 and non-aqueous sterile solutions which may contain anti- oxidants, 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, water-for-injection, to solutions and suspensions may be prepared and tablets of the .kind previously include aqueous injection for example, US9- Extemporaneous injection from sterile described. immediately prior powders, granules for rectal administration suppository with the polyethylene glycol.

Formulations may be presented as a usual carriers such as cocoa butter or Formulations for topical administration buccally or sublingually, include ingredient in a flavoured basis in the mouth, for example lozenges comprising the active 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, as 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 Smg to 500mg, usually around 10mg 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. factors, including the However the dose employed will depend on a number of 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 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(l) 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(Q are long acting, it may be advantageous to administer an initial dose of 70 to 2,400 mg the first day than a lower dose of 20 to 1,200 mg on subsequent days.

An example of such a long acting compound is: -amino(4-methylpiperazinyl)(2.3,5-trichlorophenyl) trifluoromethylpyrimidine Long acting compounds in the clinic are advantageous because they are easier to manage. In the chronic situation, they may be administered without infiision 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 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.

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 (I) addition salt thereof, which comprises the reaction of a preparation of a compound of formula or an acid compound of formula (II): R6 R5 R7 (11) R4 R3 R 3 Y L wherein R3 to Rgare as hereinbefore defined, L is a leaving group, and Y is cyano with a compound or salt thereof of formula (III): ?P{ IhN—C—R1 mD wherein RI is as hereindefined; isolating the compound of (I) acceptable acid addition salt thereof; and optionally Formula as the free base or as a pharmaceutically converting the base into a pharmaceutically acceptable acid addition salt thereof or into another pyrimidine of Formula (I) or an acid addition salt thereof.

If it is required to make a compound of Formula (I) in this can be made from the which one of R6is nitro, corresponding compound of Formula where Rsis hydrogen by utilising standard nitration conditions, e.g. sulphuric acid and potassium nitrate, and then further converted by standard reduction means to the corresponding amino compound, e.g utilising PtO2,.AcoH, H, It will be appreciated that amino or halo compounds can be further converted to R4 to Reas herewithin defined by via the diazonium standard interconversion, for example, salts. When R3 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.

Where in the product of the above process R3 is a group CHZOR where R is alkyl or arylalkyl this product may be converted to CH2X by reaction with HX (X = halo) in, for example acetic acid, and this further converted to the corresponding cyano compound, for example by treatment with sodium cyanide and DMF, or to fluoromethyl by treatment with for example cesium fluoride (CSF).

Alternatively, the group CHgOR can be dealkylated to give the corresponding alcohol, for example with Me3SiI, and this further converted to fluoromethyl with diethylaminosulphur trifluoride (DAST).

Where R3 contains an alkylthio moiety, this can be oxidised to the corresponding sulphoxide and sulphone using for example MCPBA (metachlorperbenzoic acid).

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

Example of suitable leaving groups include CP4 alkoxy, halo, anilino, morpholino, CL4 alkylamino, benzylamino, or alkylthio.

Advantageously, R1 is fl—methylpiperazinyl. Preferably L is C1-C4 alkoxy.

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

(II) for example by the method of JACS, Compounds of Formula (JACS supra) 74, 1310-1313. may be made by methods known in the art 1952, In Formula (III) when R1 is methyl piperazinyl these can be made by standard methods, for example by reaction of a known compound of Formula (III) where R1 is E- methylpiperazine. This reaction preferably takes place at room temperature in water.

Further provided by the present invention is a process for the preparation of a pyrimidine of Formula (I) which process comprises reacting a compound of Formula (V): R6 R5 R7 (V) R4 R3 R3 9 9 Y Ru) Rn wherein R3 to R8 and Y are as hereinbefore defined and RN and RH are both alkyl or together form a group —(CRgn- where R is hydrogen or alkyl, and n is an integer of from 2 to 4, with a compound of Formula (III) as defined above.

Preferably the reaction is carried out in a non-aqueous solvent, ethanol, under reflux using sodium ethoxide e.g. as the base.

Still further provided by the present invention is a pharmaceutical formulation comprising a pyrimidine of Formula (I) as defined above or a pharmaceutically acceptable acid addition salt thereof and one or more acceptable carriers therefor.

Preferably said a pharmaceutical formulation is suitable for oral administration and comprises a pyrimidine of Formula (I)as defined above or a pharmaceutically acceptable acid addition salt thereof and one or more carriers therefor.

More preferably the present invention provides capsules or tablets suitable for oral administration, each containing a predetermined amount of a pyrimidine of (I) acceptable acid addition salt thereof and one or more Formula as defined above or a pharmaceutically acceptable carriers therefor.

The present invention further provides a pharmaceutical formulation suitable for parenteral (I) as defined above or a pharmaceutically acceptable acid administration comprising a pyrimidine of Formula addition salt thereof and one or more acceptable carriers therefor.

Preferably said pharmaceutical formulation suitable for parenteral administration is presented in unit-dose containers and comprises a pyrimidine of Formula (I) as defined above or a pharmaceutically acceptable acid addition salt thereof and one or more acceptable carriers therefor.

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

Such dihydropyrimidines can be prepared by the (II) dehydrogenation conditions, reaction of a compound of Formula where R3 to R8 are as defined and L is hydrogen with a compound of Formula (III).

In the Examples meanings:- NaBH4 CHCl3 NaHC03 H9504 PBr3 DMF KCN Et20 NaOEt EtOH H2504 Ac0H HeOH "2 HCl Na0H SiO2 DMSO Na DME Mel EtOAc CH2Cl2 Et3N of the invention other abbreviations used are standard set forth below, in the art sodium borohydride chloroform sodium bicarbonate magnesium sulphate phosphorus tribromide dimethylformamide potassium cyanide diethyl ether sodium ethoxide ethanol sulphuric acid acetic acid methanol nitrogen hydrochloric acid sodium hydroxide silica dimethylsulphoxide sodium dimethoxyethane methyl iodide (iodomethane) ethyl acetate dichloromethane triethylamine the chemical and and have these HeNH2 NH40H SOCl2 THF NaH CCl4 DHFR PtO2 NXS TFAA CsF Me3SiI DAST MCPBA AIBN methylamine amonium hydroxide thionyl chloride tetrahydrofuran sodium hydride carbon tetrachloride dihydrofolate reductase platinum oxide (Adams‘ catalyst) N-halo succinimide halogen trifluoroacetic anhydride cesium fluoride trimethylsilyliodide diethylaminosulphur trifluoride metachloroperbenzoic acid a,a'-azoisobutyronitrile (2,2’-azobis(2-methylpropionitrile) Example 1 Preparation of 4—Amino(4-methyloioerazinvll(2,3,5-trichloro— ohenvlltrifluoromethvlovrimidine . Preparation of N-methvloioerazinoformamidine hvdriodide Thiourea (10.8g) was dissolved in acetone (250ml) at 50°C.

Iodomethane (loml) 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, 29.29, 113-115°C. The methiodide salt (59) 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 ggggg. The residue was slurried with ethanol, filtered and dried in vacuo, 4.989, m.pt.230-242°C.

. Preparation of 2,3.5-trichlorobenzylalcohol To a solution of 2,3,5-trichlorobenzaldehyde (Aldrich, Sogms) in ethanol (1.0L) at room temperature was added NaBH4 (7.D0gms) and the resulting mixture stirred for 3.5 hours. The reaction was quenched with water, and the solvent evaporated in ggggg before partitioning the residue between CHCl3 and saturated NaHC03 solution. The organic phase was washed with brine, dried over MgS04, filtered and the solvent evaporated in xgggg to leave a white solid. 43.00gms, mp. 90-93°C.

. Preparation offlg,3,5-trichlorobenzyl bromide To a solution of the alcohol in benzene (400ml) under N2 was added PBr3 (126.58gms), and the mixture stirred at 55-5o°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 NaHCO3 solution and water, dried over MgSO4, filtered and the solvent evaporated to leave a brownish liquid which solidified on standing, 37.53gms, mp. 40-42°C.

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 30-350 for 3 hours, the suspension was diluted with water and extracted with Et2O. The combined ether extracts were washed with water, dried over MgS04, filtered and the solvent evaporated jg, gaggg.

Chromatography on silica gel eluting with hexane to 20% ether-hexane gave the desired product as a white solid; l8.52gms, mp. so-52°C.

Preparation of 2-(2.3,5-trichlorophenvl)-4,4,4-trifluorooxo— butvronitrile To a solution of Na0Et (from 1.04gms Na) in EtOH (60ml) at room temperature under N2 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 vgggg and the residue dissolved in water. The aqueous phase was washed with Et20 (discarded), acidified with H2504 and extracted with 5:20. The combined Et20 extracts were washed with water, dried over MgS04, filtered and the solvent evaporated in vgggg to leave an oil. This was triturated with petroleum ether, and the solid filtered off and driedl The solid was azeotroped with toluene (x5), 4.89gms, mp. 160-163°C.

Preparation of 2-(2.3.5-trichlorophenvl)-4.4,4-trifluoro methoxvbutenonitrile To a solution of the trifluoromethyl ketone in Etzo (39.62ml) at room temperature was added diazomethane (from 8.55gms Diazald) in Etzo (79.62ml), and the resulting mixture left to stand at room temperature overnight. Excess diazomethane was then removed in vggug into ACOH, and the residue was dissolved _jn Etzo, dried over M9504, filtered and the solvent evaporated in vacuo to leave a brownish oil, 5.20gms.

Preparation of 4-Amino(4-methvlpiperazinvl)(2.3.S- trichloroohenvl)trifluoromethvlpvrimidine To a solution of Na0Et (from 0.1449 of Na) in Et0H (12.5ml) was added N-methylpiperazinoformamidine hydriodide (1.399). After stirring for 10 minutes at room temperature a solution of the above intermediate (0.859) in EtDH (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 CHCl3 -4% MeOH/CHCl3, gave the desired product which ‘was triturated with petroleum ether (b.p. 40-60°C) and dried jg vacuo. 0.559, m.pt 127~129°C.

-Amino(4-methvlpioggaginvl)(2.3.5-trichloroohenvl)-6o trifluoromethvlpvrimidine methanesulghonate The phenyl pyrimidine base (9.69) was dissolved in absolute ethanol, cooled at 0°C, and methanesulphonic acid (2.149, 1.62ml) was added. ,After stirring at room temperature for 2 hours, the solution was evaporated to dryness and the residue triturated with Et2O, filtered and dried jg_1ag9Q to leave a beige coloured solid. This was dissolved in water (500mls) and freeze~dried to leave 10.79 as a tan coloured solid. The methanesulphonate salt could be further purified by triturating with tBuOH (30ml), filtering, dissolving in water and again freeze drying to leave the title product as a off-white solid. 8.339 mp. 145-7°C.

Example 2 Synthesis of trichlorophenvllpvrimjgjne To a solution of NaOEt (from 0.16g of sodium) in ethanol (lsml) was added fi—methylpiperazinoformamidine hydriodide (1.6g). After stirring for 10 minutes the enol ether of Example 6.2 (0.829) in ethanol (Sml) 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 CHCl3 to 4% Me0H/CHCl3 to give the desired product, 0.319, mp. 156-159°C. l\) L/\ Exmnme3 -(4-methylpiperazinyl)amino(2.4~dichlorophenyl)pvrimidine the N-methyl-N'-amidinopiperazine sulphate to crystallise; 50.799 was collected.

A mixture of 76.39 (0.356 mol) of a-formyl-2,4-dichlorophenyl- acetonitrile, 63.79 of isoamyl alcohol, 0.369 of 395 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 Q-toluenesulphonic acid, the theoretical amount of The solution was cooled. heated for another 20 hours, until water had been collected.

An 8.2g portion of sodium was dissolved in 500ml of absolute ethanol, and 50g of fl-methyl-fl‘-amidinopiperazine sulphate was added. The mixture was allowed to stir for 10 minutes. then added to solution B. for 6 hours, allowed to in 11222» This was The mixture was refluxed with stirring stand overnight and the solvent removed 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 309. 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. Calcd for C15H17Cl2N5; C, 53.27; H, 5.07; C, 53.58; H, 5.14; N, 20.71; Found: N, 20.40.

Preferred among the compounds of formula (I) is the pyrimidine of the foregoing Example 1, together with salts (in particular, pharmaceutically acceptable salts) thereof; this base has the following two-dimensional structure.

/ Ezaale 1 C] \ N TABLE OE'1H NMR DATA (él Example Solvent Assignment CDCl3 7.56(d,lH), 7.l8(d,1H), 4.65-4.50 (br.s,2H), 3.88(t, 4H), 2.5(t,4H), 2.36(s,3H) CDCl3 7,51(d,lH), 7.17(d,lH), 4.40-4.22 (br.s,2H), 3.82(t,4H), 2.48(t,4H), .34(s,3H), 2.0(s,3H) In the foregoing, the signals have been abbreviated as follows: s=singlet; d=doublet; dd=doublet of doublets; t=trip1et; q=quadruplet; m=multiplet; br.s=broad singlet; br.t=broad triplet.

Pharmacological Activity Inhibition of Glutamate release and Inhibition of Rat Liver (DHFRQ Compounds of Formula (I) were tested for their effect on veratrine—evoked release of glutamate from rat brain slices according to the protocol described in Epilepsia 27(5): 490-497, 1986. inhibition of DHFR activity was a modification of that set The protocol for testing for out in Biochemical Pharmacology Vo1.20 pp 561-574, 1971.

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

TABLE 1 ° (IJM) Rat Liver DNFR Compound of ICM (P-M) Glutamate Release (P95 limits) Example No.

(P95 limits) .18 (0.50—2.60) >100 2 4.80 (2.30-10.20) >100.00 3 ca. 10.00 >100.

The compound of Exampie 1 has been administered intravenousiy to groups of six maTe and six femaie Histar rats once daiiy at dose Teveis of upto mg/kg/day.

Phagce-uticfl Fomflation Exgjle Tabietz INGREDIENT A: Compound of Examp1e 1 Lactose Maize Starch PoTyvinylpyrro1idone Magnesium Stearate contents per tab1et.

The drug was mixed with the lactose so1ution of the po1yviny1pyrroTidone mg ) 200 mg ) 50 mg ) 4 mg ) 4 mg ) and starch in water.

The no observsed effect dose was 2.5mg/kg/day. and'granuTated with a The resuitant granules 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 water for injection.

INTRAVENOUS INJECTION FORMULATION (II) Active ingredient 0.209 Sterile, pyrogen-free phosphate buffer (pH9.0) to 10ml The compound of Example I as a salt is dissolved in most of the phosphate buffer at 35—40°C, then made up to volume and filtered through a sterile micropore filter into sterile IDml 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. mgzcagsule (a) Active ingredient 250 (b) Lactose B.P. 143 (c) Sodium Starch Glycollate 25 (d) Magnesium Stearate __g 420 Capsules may be prepared by melting the Macrogel 4000 BP, dispersing the active ingredient in the melt, and filling two-part hard gelatin capsules therewith.

Capsule Formulation B (Controlled release capsule) mgzcapsule (a) Active ingredient 250 (b) Microcrystalline Cellulose 125 (c) Lactose BP 125 (d) Ethyl Cellulose _L; 513 The controlled-release capsule formulation may be prepared by extruding mixed ingredients (a) to (c) using an extruder, then spheronising and drying the extrudate. (d) as The dried pellets are coated with ethyl cellulose a controlled-release membrane and filled into two-part hard gelatin capsules. fiyrup formulation Active ingredient 0.2500 g Sorbitol Solution 1.5000 g Glycerol 1.0000 g Sodium Benzoate 0.0050 g Flavour 0.0125 ml 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. ggppositorv formulation mgzsugoositorv Active ingredient (63pm)* 250 Hard Fat, BP (Hitepsol H15 - Dynamit Nobel) 1770 2020 * The active ingredient is used as a powder wherein at least 90% of the particles are of 53pm diameter or less. ne—fifth of the Hitepsol H15 is melted in a steam-jacketed pan at 45°C maximum. The active ingredient is sifted through a 200pm sieve and added to the molten base with mixing, using a Silverson fitted with a cutting head, until a smooth dispersion is achieved. Maintaining the mixture at 45°C, the remaining Hitepsol H15 is added to the suspension which is stirred to ensure a homogenous mix. The entire suspension is then passed through a 250pm stainless steel screen and, with. continuous stirring, allowed to cool to 40°C. At a temperature of 38-40°C, 2.029 aliquots of the mixture are filled into suitable plastic moulds and the suppositories allowed to cool to room temperature.

Claims (17)

1. 1. CLAIMS l. A pyrimidine of formula (I): R3 RR4 R5 »RT" R6 (D N R2 R3 R7 wherein, R7 is N—methyl—piperazino; R2is amino; R3 hydrogen, methyl, trifluoromethyl, benzyloxymethyl, methoxymethyl or methyl-thiomethyl; R4 is chloro; at least one of R& R6 and R7 is chloro, and the remainder of R5, R6 and R7 are selected from hydrogen and chloro in the case of R5 and R7, and from hydrogen, chloro and nitro in the case of R6 except that R6 is not hydrogen when R7 is N—methylpiperazino, R3is hydrogen and each of R5 and R7is chloro; Rgis hydrogen; and pharmaceutically acceptable acid addition salts thereof. 34

2. A compound according to claim 1 wherein R5, R6 and R, are selected from hydrogen and chloro.

3. A compound according to any one of the preceding claims wherein one or both of R5 and R, are chloro. 5

4. 2-(4-Methylpiperazim1-y1)arnino-S-(2,3,5—trichlorophenyl) trifluoromethylpyrimidine; 2-(4-Methylpip erazin-l —yl)amino- 5-(2,3,5-trichlorophenyl)methylpyrimidine; 2-(4-Methylpiperazin~l-yl)amino-S—(2, 4- dichlorophenyl)pyrimidine; and pharmaceutically acceptable acid addition salts thereof. 10

5. A pharmaceutically acceptable acid addition salt of a pyrimidine as claimed in any one of claims 1 to 4.

6. A process for the preparation of a pyrimidine of formula (I) as defined in claim 1 or a pharmaceutically acceptable acid addition salt thereof‘, which process comprises reacting a compound of formula (II): l5 7 (1:35 . 20 wherein R3 to R8 are as defined in claim 1, L is a leaving group and Y is cyano, with a compound of formula (III): 25 "l"' " ‘>—:R, (III). ‘ 52' wherein R1 is as defined in claim I, or a salt thereof; isolating the resulting pyrimidine of formula (I) as the free base or as a pharmaceutically acceptable acid 30 addition salt thereof; and optionally converting the base into a pharmaceutically 5 acceptable acid addition salt thereof or into another pyrimidine of formula (I) or a pliarmaceutically acceptable acid addition salt thereof.

7. A process according to claim 6, wherein L is C1-C4 alkoxy.

8. A process for the preparation of a pyrimidine of formula (I) as defined in claim 1, which process comprises reacting a compound of formula (V): (V) ‘ wherein R3 to R3 are defined in claim 1, Y is as defined in claim 6 and Rm and R” are both alkyl or together form a group -(C(R)2),,- where R is hydrogen or alkyl and n is an integer from 2 to 4, with a compound of formula (III) as defined in claim 6.

9. A pharmaceutical formulation comprising a pyrimidine of formula (I) as claimed in any one of claims 1 to 4 or a pharmaceutically acceptable acid addition salt thereof and one or more acceptable carrier therefor.

10. A pharmaceutical formulation suitable for oral administration comprising a pyrimidine of formula (I) as claimed in any one of claims 1 to 4 or a pharmaceutically acceptable acid addition thereof and one or more acceptable carrier therefor.

11. Capsules or tablets suitable for oral administration, each containing a predetermined amount of a pyrimidine of formula (I) as claimed in any one of claims 1 to 4 or a pharmaceutically acceptable acid addition salt thereof and one or more acceptable carrier therefor.

12. A pharmaceutical formulation suitable for parenteral administration comprising a pyrimidine of formula (I) as claimed in any one of claims 1 to 4 or a pharmaceutically acceptable acid addition salt thereof and one or more acceptable carri er therefor.

13. A pharmaceutical formulation suitable for parenteral administration, which formulation is presented in unit—dose containers and comprises a pyrimidine of formula (I) as claimed in any one of claims 1 to 4 or a pharmaceutically acceptable acid additional salt thereof and one or more acceptable carrier therefor.

14. A compound substantially as hereinbefore described with reference to the Examples.

15. A pharmaceutically acceptable acid addition salt substantially as hereinbefore described with reference to the Examples.

16. A process substantially as hereinbefore described with reference to the Examples.

17. A pharmaceutical fonnulation substantially as hereinbefore described with reference to the Examples.