IE19970474A1

IE19970474A1 - Pharmacologically active CNS compounds

Info

Publication number: IE19970474A1
Application number: IE1997/0474A
Authority: IE
Inventors: Ainslie Miller Alistair; Stuart Nobbs Malcolm; Martin Hyde Richard; John Leach Michael
Original assignee: The Wellcome Foundation Limited
Filing date: 1989-12-06
Publication date: 1990-06-07

Description

PHARHACOLOGICALLY ACIIVE CHS_§QHPOUHQ§ A class of substituted phenylpyrimidine compounds are d1sc1osed which are potent inhibitors of the excitatory amino acid, g1utamate. Such compounds are usefu1 in the treatment or prevention of a range of CNS disorders inc1uding cerebral ischaemic damage and epilepsy.

Tnuec PHARIACOLOGICALLY 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., 9;, 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) §§ 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.21121 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 gt_gl Epilepsia gz, 490-497 1986, A.A.Miller gt gl 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 central are also states of the compounds of formula I the above mentioned disorders and disease nervous system. The pyrimidine inhibitors of aspartate release.

Thus in a first aspect of the present invention there is provided the 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 £3 R; R5 in Formula I, R1 and R2 are the same or different and are selected from hydrogen, halo, hydroxy, alkoxy, alkyl, alkylthio and a group NR1R11 where R1 and R 1 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; R3 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, $(0)na]ky], di(alkyloxy)a}kyl, -C(R):HOH or —COR or -COZR wherein R is hydrogen or alkyl, or a group cnzx where x is hydroxy, aryloxy, arylalkyloxy, halo, cyano, -NRIRII wherein R1 and R11 defined above, 5(0)"-alkyl where n is 1 or 2, or SOZNRIRII; each of R4 to R8 are the same or different and each is selected from hydrogen, halo, alkyl, perhaloalkyl, cyano, carbamoyl, carbony, COR, alkoxy, are as IE 970474 nitro, amino, alkylsulphonylamino, alkoxy, S(0)n-alkyl where n is 1 or 2, or soznalall; or R4 and R5 or R5 and R6 together are the group -CH=CH-CH=CH- or the group -CH2-CH2-CH2-CH2- in which case both R7 and R3 are hydrogen; and optionally one of the nitrogen atoms in the pyrimidine ring may be ﬂ alkylated or optionally may be an ﬂ oxide; the foregoing alkyl groups or mieties of alkyl-containing groups having from 1 to 6 carbon atoms, and the aryl groups or aryl of aryl-containing groups having 6 or 10 carbon atoms. moieties 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 R1, R2 and R3 are hydroxy, they may also exist in their tautomeric form.

A preferred class of Formula I of compounds which are potent inhibitors of glutamate are those wherein one of R1 and R2 is amino and the other is selected from amino, hydroxy, halo, morpholino, piperazinyl, Q-alkylpiperazinyl, ﬁ,ﬁ-dialkylamino, ﬂ-alkylamino or alkylthio; R3 is alkyl optionally substituted by one or more halo radicals, or is alkyl, alkylthio, hydrogen, hydroxy, alkoxy, halo, carboxy, carbamoyl, or a group CHZX where X is alkylthio; one of R4 and R5 is hydrogen; R6 is halo, hydrogen, nitro or amino; R7 is hydrogen, halo, cyano, alkylthio, SOZNRIRII alkyl, nitro, amino or methanesulphonamido; and R3 is hydrogen or halo. hydroxy, phenoxy, benzyloxy, alkoxy or halo and the other is selected from halo or In the present invention, R1 is preferably hydroxy, amino, ﬂ¢alkylamino, morpholino, piperazinyl, ﬂ-alkylpiperazinyl; ﬂ,ﬂ:diajkylamino, IE 970474 R2 is preferably chloro, amino, ﬂ,ﬂ-dialkylamino or piperidino; R3 is preferably hydrogen, alkyl, methoxymethyl, benzyloxymethyl, phenoxymethyl or methylthiomethyl; R4 to R8 are preferably selected from hydrogen and chloro. the alkyl moieties contain from 1 to 4 carbon atoms. trifluoromethyl, Preferably In Formula I, advantageously at least one of R1 and R2 is amino and the other is amino, piperazinyl or ﬂ-methylpiperazinyl, ﬁgalkylamino, ﬁ,ﬂ-dialkylamino; and R3 is hydrogen, methyl, trifluoromethyl or methoxymethyl.

It is a preferred feature of Formula l chloro, in particular it is that two of R4, R5 and R7 are preferred that all of R4, R5 and R7 are chloro. Such compounds are highly potent inhibitors of glutamate release. Preferred examples of the group NRIRI1 are amino, ﬂ-methylamino, ﬂ-ethylamino, ﬁ,ﬂ-dimethylamino, piperazinyl, ﬂ-methylpiperazinyl, piperidinyl, and morpholino.

An especially preferred class of compounds within Formula I are those wherein R1 is selected from amino, piperazinyl, N-morpholino, ﬂ,ﬁpdimethylamino, and ﬂ-ethylamino; Q-methylpiperazinyl, R2 is amino; R3 is selected from trifluoromethyl, hydrogen, benzyloxymethyl, methoxymethyl and methylthiomethyl; R4 is chloro; and at least one of R5, R6 and R7 is chloro, and the remainder are selected from hydrogen, chloro and nitro; and R8 is hydrogen or R4 and R8 are both hydrogen, R5 and R7 are both chloro and R6 is selected from hydrogen chloro and nitro. methyl, 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 IC50 of >20um) or insignificant inhibitory effects on the enzyme dihydrofolate reductase Accordingly, in a preferred IE 970474 embodiment of the present invention there is provided compounds of Formula I where R1 to R8 are hereinbefore defined with the proviso that when R7 is halo, then R3 is hydrogen, perhaloalkyl, methyl or methoxymethyl and/or R5 is nitro and/or R1 is ﬂ-alkylpiperazinyl, morpholino, ﬁ,ﬂ—dimethylamino, piperazinyl or ﬂ-ethylamino; or with the proviso that when R6 is chloro then R, is nzln, u a ', '2 hv"'ug%r, gcrhaloalkyl, methoxymethyl, methyl or halo and/or R] is ﬂ—m§ihylpipcrazlnyl, piperazinyl, morpholino or ﬂ,ﬂ- dimethylamino, or ﬂ-ethylamino.

Compounds of Formula I may be used in the treatment or prophylaxis of acute and chronic disorders of the mamalian 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. which may be treated include Alzeheimer's disease, Huntington's chorea, Olivopontocerebrellar 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.

Chronic neuro- degenerative disorders In a further aspect, the present invention provides a method of treatment or prevention of a CNS disorder or disease of a mamal, including man, comprising the administration to the mammal of a non-toxic effective amount of a compound of Formula I 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 IE 970474 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. Q, 185-200 (1951); JACS, 1;, 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 and accordingly the present invention provides a compound of Formula I or an acid addition salt thereof wherein R1 to R8 are as hereindefined, with the proviso that at least one of R4 to R8 is other than hydrogen, and further with the proviso that when R1 and R2 are both amino, or when R1 is hydroxy and R2 is amino, and R3 is alkyl or hydrogen, and R7 is hydrogen, then R4 and R5 are both halo.

Other novel compounds of the present invchlluﬂ are Iho.0 nhflt RI ‘ R3 and R8 are as hereinbefore define? and awe n° VJ of 9; a~ ~:L« than hydrogen, and R7 is halo, a?t;¥, pklﬂalmjlhvl, uy£Ho_ n;u»- amino, alkylthio, 5(0)"-alkyl or Sognulull.

A third class of novel compounds of the present invention are those of Formula I where R1 is morpholino, piperazinyl, 3,3-dialkylamino, ﬂ;alkylamino or alkylthio and hereinbefore defined.

Q-alkylpiperazinyl, R2 to R8 are as A fourth class of novel compounds of the present invention are those of Formula I where R1 and R2 are as hereinbefore defined; _ and R3 is alkoxy, alkylthio or alkyl substituted by one or more halo radicals, or is a group CHZX where X is alkylthio, arylalkyloxy, alkyloxy or hydroxy; aryloxy, IE 970474 R4 to R6 ‘are the same or different and are each selected from hydrogen, haio, perhaloalkyl, cyano, nitro, amino or aTky1thio; R7 is haio, alkyi, perhaioalkyl, cyano, nitro, soznurz ‘)2 wherein R1" is alkyl; and R3 is hydrogen or halo. amino, or a group A fifth class of novei compounds of the present invention are those of Formula I where R1 and R2 and R4 to R8 are as hereindefined, and R3 is aikoxy, aryioxy, arylaikyioxy or alkyithio.

IE 970474 include the hereinafter compounds of the present invention numbers referring to the Examples Preferred ‘novel following, the appearing:- Example No. 1. 4-Amino(4-methylpiperazinyl)—5-(2,3,5-trichlorophenyl) trifluoromethylpyrimidine 2. 2,4-Diamino-5—(2,3,5-trichlorophenyl)methoxymethylpyrimidine 4-Amino(4-methylpiperazinyl)(2,3,5-trichlorophenyl) pyrimidine 2,4-Diamino(2.3,5-trichlorophenyl)trifluoromethylpyrimidine 2,4-Diamino(4-nitro-2,3.5-trichlorophenyl)pyrimidine 2,4-Diamino(2.3,5-trichlorophenylJmethylpyrimidine 4-Amino-2qﬂ-orpholino(2,3,5-trichlorophenyl)-6~trifluoro- methylpyrimidine 8. 4-Aminoﬂhﬁ-dimethylamino(2,3.5-trichlorophenyl) trifluoromethylpyrimidine 9. 4-Aminomorpholino-ﬂ(2,3,5-trichlorophenyl)pyrimidine . 4-Amino3,3-dimethylamino(2,3,5-trichlorophenyl)pyrimidine 11. 4-Aminomethyl(4-methylpiperazinyl)(2,3,5-trichloro- phenyl)pyrimidine - 14. 2,4-Diamino(2,3-dichlorophenyl)trifluoromethylpyrimidine . 2,4-Diamino(2.3-dichlorophenyl)methylpyrimidine 16. 2,4-Diamino-S-(2,3-dichlorophenyl)methoxymethylpyrimidine . 2,4-Diamino(2,4-dichlorophenyl)trifluoromethylpyrimidine 26. 6-Benzyloxymethyl-2,4-diamino—5-(2,4-dichlorophenyl)pyrimidine 27. 2-N-methylpiperazinyl-4—amino(2.4-dichlorophenyl)pyrimidine 28. 2.4-Diamino—5-(2,5-dichlorophenyl)trifluoromethylpyrimidine 29. 2,4-Diamino(2.3,5-trichlorophenyl)pyrimidine 36. 4-Amino(3.5-dichlorophenyl)methyl(4-methylpiperazin yllpyrimidine 58; 4-Aminoﬂyethylamino(2,3,5-trichlorophenyl)pyrimidine ‘~lO‘IU'l4> 79. 4-Aminoﬂ-methylamina(2,3,5-trichlorophenyl)pyrimidine IE 970474 or an acidcaddition 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, fumaric, maleic, oxaloacetic, methanesulphonic, ethanesulphonic, g-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 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 IE 970474 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 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 free- flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, lubricating, 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. surface active or anti- Formulations for parenteral administration include aqueous non-aqueous sterile injection solutions which may contain oxidants, buffers, bacteriostats and solutes which render formulation isotonic with the blood of the intended recipient; 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 -kJnd previously described.

IE 970474 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 Smg to 500mg, usually around 10mg to 250mg.

The compounds disorders or of the Formula I are preferably used to treat CNS 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 IE 970474 _ 12 . 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 lLjCCLlUH at a Jase of may be administered orally or win from 0.1 to Bﬂmgfkg per day. The dose range for adult humans is generally from 8 to 2,400 mg/day and preferably 3i to 1,050 mg/day. A5 acting, it may be advantageous to administer an initial dune of 70 tr 2,400 mg the first day then a loner dose of 20 subsequent days. certain compounds of the Formula I are lung to l,}.'_Oi:' mi,‘ mt Examples of such long acting compounds are: 2,4-diamino(2,3,5-trichlorophenyl)trifluoromethylpyrimidine; 4-amino(4-methylpiperazinyl)(2,3,5-trichlorophenyl) trifluoromethylpyrimidine; and 4-amino(4-methylpiperazinyl)(2,3,5-trichlorophenyl)- pyrimidine. ‘mug acting cmmpnnnds in the Lllnlf are advantageous because they are situation, they may be administered the minimum of direct. medical conditions, patient compliance is encouraged by minimising daily dosing. Conversely, short acting compounds such as: 51534" to mnrane. in the Lhrenic without infusion and there is intervention; also in acute compound with great precision, since such compounds will be cleared from the central nervous system rapidly.

IE 970474 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 preparation of a compound of Formula I or an acid addition salt thereof, which comprises the reaction of a 'ompwnnd of Formula II RS\\ « "E3 — of K+ ‘K3 II wherein R3 to R8 are as hereinbefore defined, L is a leaving group, and Y is cyano or carboxy, carbonyl, or alkoxycarbonyl with a compound or salt thereof of formula III ::*i III Ii2_r\J " C: " £2‘ wherein R1 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 addition salt thereof. compound of Formula I or an acid of Formula III for the corresponding tautomeric It will be appreciated that certain compounds example where R1 is hydroxy exists in form (eg. as urea).

As examples of interconversion of compounds of Formula I, when in the product of the above process one of R1, R2 or R3 is hydroxy the compound may be halogenated for example using the Vilsmeier Haack reagent or phosphorus oxychloride (P0Cl3), to the corresponding halo compound. This compound may be further converted into a compound of Formula I wherein R1, R2 or R3 is alkylthio by reaction with the IE 970474 -14.. appropriate alkylthiolate or to the corresponding amino compound (R1, R2 or R3 being NRIRII) by reaction with the appropriate amino compound in a suitable solvent such as an alkanol, eg. ethanol, or converted to a compound where R1, R2 or R3 is alkoxy by reaction with appropriate alkoxide.

If it is required to make a compound of Formula I in which one of R4 to R8 is nitro, this can be made from the corresponding compound of Formula I where one of R4 to R8 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 Ptoz, Ac0H, H2.

It will be appreciated that amino or halo compounds can be further‘ standard when R3 is dikyl succinimide converted to R4 to R8 as herewithin defined by interconversion, for example, via the diazonium salts. alkyl this may be converted into perhaloalkyl, or a halogenated moiety by reaction with the appropriate halogen or N-halo (NXS) in a suitable solvent such as acetic acid.

Ci uvbﬁds lL which R3 is CHr0[t)2 may be converted into the hydrolysis with dilute acid(s) and o the corresponding alcohol with a standard reducing agent (eg. sodium borahydride NaBH4), 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 KMnO4 (potassium permanganate) to give the corresponding acid, which may in turn be reacted with an alcohol to give the corresponding ester. corresponding aldehyde by CHfTcolfvF r~3. , 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 CHZX by reaction with HX (X - halo) in, for example acetic acid, and this IE 970474 -15.. 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) or to a group CHZNRIRII by reaction with the appropriate amine. Alternatively, the group CHZOR can be dealkylated to give the corresponding alcohol, for example with He3SiI, and this further converted to fluoromethyl with diethylaminosulphur trifluoride (DAST).

Hhere R3 to R8 contains an alkylthio moiety, this can be oxidised to the corresponding sulphoxide and sulphone example MCPBA (metachloroperbenzoic acid). using for 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 NRIRII as hereindefined eg. anilino, benzylamino, or alkylthio. alkoxy, alkylthio, or a Advantageously R1 is amino, ﬁ—methylpiperazinyl.

(L) include C1_4 alkoxy, halo, morpholino, C1_4 alkylamino, Preferably in Formula III, R1 is hydroxy, group NRIRII as herein defined. alkylamino, dialkylamino, piperazinyl or 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.

IE 970474 _ 15 - wherein R3 to R8 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 I! 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 R1 is piperazinyl or alkyl piperazinyl these can be made by standard methods for example by reaction of a known compound of Formula III where R1 is alkylthio with the appropriate amine, eg. ﬂ-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 ‘i F Rue I?" wherein Y and R3 are as hereinbefore defined and R10 and R11‘are alkyl or collectively form a group (CR2)n where n is 2 to 4 and R is H or IE 970474 - 17 . alkyl, with a compound of Formula III. Most preferably R1 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 R3 to R8 are as defined and L is hydrogen with a compound of Formula III.

In the Examples other abbreviations meanings:- NaBH4 NaHC03 MgS04 Et20 Na0Et Et0H H2504 ACOH Me0H Na0H Si02 DMSO EtOAc CHZCIZ _uI=-ry the invention set forth below, the chemical used are standard 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 IE 970474 and have these MeNH2‘ ' NH40H S0Cl2 CCl4 DHFR PtO2 TFAA Me3SiI DAST MCPBA AIBN IE 970474 methylamine ammonium 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) IE 970474 §:es=_l_a_1 * 1" 3-’ a7’:...5;1 " i£:_’?..?.f3.' Elm-..a.r:.a,t..i2v;=. 0 L 4 ~ tun 1‘ n,<>_—-_;’_-_(c'!,—.vn_e thy Lu 7'95‘: ta; 1‘ re :1 - y L) - .§"J!-’. n 6 -I. r if i u 0 ran-c UJ.U..-" '1'". ='_n.!_:-"-21 .i_n.«;< Preparation of N-methvloiperazinoformamidine hgdriodige Thiourea (10.89) 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 vaguo, 29.29, 113-115°C. The methiodide salt (Sg) 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 jg xgggg. The residue was slurried with ethanol, filtered and dried ggleaggg, 4.939, m.pt.230-242°C. 2. Preparation of 2.3.5-trighlgrobenzylalcohol To a solution of 2,3,5-trichlorobenzaldehyde (Aldrich, sogms) in ethanol (1.0L) at room temperature was added NaBH4 (7.00gms) and the resulting mixture stirred for 3.5 hours. The reaction was quenched with water, and the solvent evaporated jn_xggug 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 ggggg to leave a white solid. 43.oogms, 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 PBr3 (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 washed with benzene (x3) and the combined benzene extracts washed with saturated NaHC03 solution and water, dried over MgS04, IE 970474 filtered and the solvent evaporated to leave a brownish which solidified on standing, 37.53gms, mp. 40-42°C. liquid Preparation of 2.3.S-trichloroohengjacetonitrile The bromide was suspended in our (130ml)/ water(86.67ml) at 0°C and KCN(12.99gms) added in portions. After stirring at 3o-35° for 3 hours, the suspension was diluted with water and extracted with Et20. The combined ether extracts were washed with water, dried over M9504. filtered and the solvent evaporated in ggggg.

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.

E£s'3.P§Li3_tL>_" of 2-.(_?._i_3_t5_-_t;;igLi.l,oL0i2h_en. v. D -4 i.’L_4;!._r_i_I.l_u9.r,o;.3_-_c>_:9_~ P_U.§XL0_"Lt.£i_'£ To a solution of Na0Et (from 1.04gms Na) in Et0H (60ml) at room temperature under Hz was added the nitrile (B.40gms) followed by ethyl trifluoroacetate (6.57gms) and the mixture stirred at reflux for 5 hours. After cooling, the solvent was removed in gggug and the residue dissolved in water. The aqueous phase was " ’ daidified with H2504 and extracted ii ~2?o. ins :»m:inud {:90 extracts were washed with water, ' ane solvent evaporated in xgggg to i . _ . . i as. =i;id-card with petroleum ether, and the solid filtered off and dried: The solid was azeotroped with toluene (x5), 4.89gms, mp. 160-163°C. , , , . ,, wa~ryd nrtn rt,U tntsaaraeul, ii’ ' it-I’ Ml".':»\'.".. ii iii)! v9’? ail-‘,' . _' ‘veu- IL ~=i 7*?’ -5_t‘_’lJvfl}.: 5L -'4 .i- Li‘.if_ I up v:o_-,3; P !I1'—'.l’_-‘-,"_0._'~a_'l,'»7’ .0... :21’ _2— CL Sp-‘_cv:.Lc.b..l.o.v_ me_t.h9_x : enon 1' t r 11.9.

To a solution of the trifluoromethyl ketone in Etzo (39.62ml) at room temperature was added diazomethane (from 8.55gms Diazald) in Et20 (79.62ml), and the resulting mixture left to stand at room temperature overnight. Excess diazomethane was then removed in vacuo into Ac0H, and the residue was dissolved__jn Etzo, dried IE 970474 over HgS04, filtered and the solvent evaporated jg vacug to leave a brownish oil, 5.20gms. .v?-';:_ri-<‘= I24. t 1L;:.n,_9_7' ,:1- Eu 1' 90-2 - ( 4 :F1-" t..h_'.v. 112.‘-'.r».c‘<_r;a z..i n;i - vi ) -, —‘> — f . 7 .j :. .1" 1’; h 10. ri-—':».f‘-.+:r,vl l -15» if r If lu.c:m.r{1_c:iih‘:' Us .vr,.=' W M me.

To A snlutiun sf Neﬂbt {from 0.1449 Of Na) in Et0H (12.5ml) was added N-methylpiperazinoformamidine hydriodide (1.399). After above intermediate (0.859) in Et0H (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 vaggo. Chromatography on silica gel, eluting with CHCl3 -4* Me0H/CHCl3, gave the desired product which was triturated with petroleum ether (b.p. 40-60°C) and dried jg _v_a_cgg. 0.559, m.pt 127-129°c. ﬁ;5m1go-2: 4-meth I i era in- --l - -‘ trifluorometh l imidine meth nesul he ate The phenyl pyrimidine base (9.69) was dissolved in absolute ethanol, cooled at OQC, and methanesulphonic acid (2.14g, 1.62mi) was added. .After stirring at room temperature for 2 hours, the solution was evaporated to dryness and the residue triturated with Etzo, filtered and dried jg_yaggg to leave a beige coloured solid. This was dissolved in water (soomls) and freeze-dried to leave 10.7g 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. 8.33g mp. 145-7°C. l.9.r.q2h_e.n_v_.l L.-6 .

IE 970474 £aa:e1s_z P I_c:el;.-=-13¢ ion of 3.. -1 —,f1*.:31n.i.tv_@_: S; i 3 it "_lt'§ 'LL0_'"£P_.'L~’.€‘.Y U: _f;.-._t.=.».e.t ,i:»c::ayn_IL;T_.I1>:’|. pyrimidine A. :-(2:11?-}VlQUigﬁ0pﬁCﬂ}l)~5-ﬂwlﬂﬁglf3:J5Q—hgZyﬂQﬂl§Tiif In é sttrruf re‘luxxng solution at swdium cihonide (from sodium) in ethanol (25ml) was added 2,3.5-trichlorophenylacetonitrile (119) and ethyl methoxyacetate (8.859) in dry DME (25ml). After 4 hours the mixture was cooled on ice and acidified by dropwise addition of acetic acid (ca. 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. ﬁyﬁg Homogeneous by TLC (19:1 CH2Cl2:Me0H). 1.389 over 5 minutes a mixtwre of Pf9pdL££lgQ_g:_g*3;QlgmlDO-S-(2,3,5ﬁﬁFlChlOFODh&QVll;§; !"£-‘1J_02£1llL¢ﬂ_Y_"LQYIi'"_i£1i'J.‘2 A suspension of the crude acyl acetonitrile (8.5g) in ether (looml), cooled on ice was treated with an excess of an alcohol free solution of diazomethane in ether (0.035M). After one hour TLC (19:1 CH2Cl2:MeOH) showed no starting material. The solution was concentrated to give a brwn waxy solid, which was used without further purification.

To a solution of sodium ethoxide (from 0.76g sodium) in ethanol (30ml) was added guanidine hydrochloride (2.99). 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 Na0H (150ml) and the dark solid filtered off, washed with water, dried in air and recrystallised from ethanol (150ml). 5g M.pt. 214-216°C. nc (1:9 Me0H:CHCl3) Rf"O.35. §ygthesis of IE 970474 -24. 2 . 4.-.0. I_am__ir_w.:3;l2..l.§.-. _t.r i c h_l.or.opbs_rJ1ll;§_1n_c:e*:tLv.l.t;zu1ui,d.);r1s ethanesylphate To a stirred suspension of the phenylpyrimidine (Zg) in ethanol (75ml) was added dropwise ethanesulphonic acid (0.67g) in ethanol (loml). After ca 30 minutes the solution became cloudy.

Stirring was continued for a further 1.5 hours and the solvent then concentrated to ca Zomls. Ether was added, the solid filtered off and washed with Et20 before drying jg_yggug, 2.179, m.pt. 265-268°C. 4-Amino(4~methylpiperazin-l;yl)-S-(2,3L5—trichlorg; phenvl)_gyrimidine mgsylate Preparation of 2-(2,3,$—trichlorophenyl)-3;gxo-progionjtgilgy sodium salt To a solution of Na0Et (from 0.8039 of sodium) in ethanol 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 (6.829). (55ml) EC§QiK§LiQﬂ Of Z-{§.a.Q;;richloroohenvl)-3—methoxv-acrvlonitrile The above solid was dissolved in DMF (36ml) and methyl iodide (2ml) was added. The reaction vessel was sealed before stirring 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 (M9504) and the solvent evaporated to give the crude product as a red-brown oil that solidified on standing (5.049).

IE 970474 3- Ezepesation of 4;Amino—Z-(5;meLbxl2i2eLa;in;L;xll;§;12.3.i; tgjghlgggpbenyllpyrimiqjgg To a solution of Na0Et (from 0.21g of sodium) in ethanol (20ml) was added N—methylpiperazinoformamidine hydriodide (2.069) (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 Si02, eluting with CHCl3 to 4% Me0H/CHCI3 to give the title compound as the free base. 0.899, mp. 162-164°C.

The free base (0.805g) was then dissolved in ethanol (35ml) and cooled in an ice bath. Hethanesulphonic acid (0.219) was added and the reaction was stirred at room temperature for 2 hours.

The solvent was then evaporated and the residue was triturated with diethyl ether, filtered, dissolved in cold water and freeze dried to give the title salt as a pale green solid, 0.989, mp. 143-146°C. is l,‘ 1‘ yo 1 Q l rig To a solution of Na0Et (from 0.889 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 in yacuo. Chromatography on silica gel eluting with CHCI3 to 2* Me0H:CHCl3 gave the desired product which was triturated with 5:20 and dried 13 vacuo, 1.78gms, m.p. 226-227°C.

IE 970474 Em-J21 .5_".';'I,L},r1-'_‘;3.l_'L3.*.?._."e_7: 3.1-£1<1n;1n.o,-,f:U.-!1.i.:,r;9.:.2..3.i IL L~rJ.'I,o12;2 M212 Y..U. pg; midine The compound from Example 29 was dissolved in concentrated acid (2.5ml), potassium nitrate stirred for 3 hours. basified with 10 N NaOH. sulphuric (25.8mg) added and the solution The solution was then poured onto’ ice and The product was extracted with ethyl acetate (x3), dried over HgS04, filtered and the solvent evaporated.

Chromatography on silica gel eluting with ethyl acetate gave the desired product, 40.7mg, mp. 293-295°C. T £X_IQ.LLQ ﬁgggaration of 2,4-Diamjgg;§;jgL},5ytrichlorophenyl)methyl pyrimidine 1. ﬂggggrat;gQ_gj_§;§§*§L§;§:jchj95ophenvl);§¢oxobutyronitrile To a solution of NaOEt (from 0.689 of sodium) in ethanol was added 2,3,5-trichlorophenylacetonitriie 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 H2504 and extracted with ether. The extracts were bulked, dried (MgS04) and evaporated, 2.599, mp. 134-135°c. (20ml) 2. Ez:r;p_«3.r.a.t.i9o,..o.f_2—.f_2.l..5-_trm:J2_r91zbe,n_yLl;3;@Le05y_l2eL£; en 9.r.U'_t_tj.ls To a solution of the ketone in ether (looml) at room temperature was added diazomethane (from 5.439 Diazald) 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. 2.459.

IE 970474 . 27 - 3. Preparation of 2,4-Diamino(2.3.5-trichloroohenvllmethyl; pyrimidine Guanidine hydrochloride (3.879) was added to a solution of sodium ethoxide (from 1.01g 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) (5.609) 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 jg_ ggggg.

Chromatography on silica gel eluting with CHCl3 to 2% HeOH-CHCl3 gave the desired product which was triturated with "ether and dried _1_ggg_¢_gg. Yield 1.709, mp. 236-238°C. trifluoromethvlpvrimidine.

To a solution of Na0Et (from 0.1449 of Na) in Et0H (12.5ml) was added morpholinoformamidine hydrobromide (1.089) (Lancaster Synthesis). The resulting white stirred at room temperature for 10 minutes. A solution of the enol ether (0.859) (Example 1.6) in EtOH (2.5ml) was added end the resulting mixture was stirred at reflux for After filtered, and the filtrate was evaporated to dryness in gggug. Chromatography on silica gel, eluting with CHCl3, gave the desired product which was triturated (b.p. 40-50%) and dried _i_Q _»;a_<_:y_9, 0.479, mp. suspension was 4.5 hours. cooling, the suspension was with petroleum ether 177-181°C.

IE 970474 §Lan.19_§ .5_‘.?is1=_i1é*‘9§_i_9."...9i.£:/‘-"I 1' Q9.‘ Zl';‘1.l(:a:1iu»:: §.Pw.l_<'=r!!_i,t‘Io.);f2-1.2. 3 . 5.2‘ if h..";~? #9:-_ _z, j'i_»;->.'_‘. y_l_l -_Q_:V§ r_ i_’_f_ l___g rqmr:- t h 3 l _ pyr im_i_d_i_r1_r_{._ To a solution of Na0Et (from 0.1449 of Na) in Et0H (12.5ml) was added 1.1-dimethylguanidine sulphate (1.49), (Aldrich). The resulting white suspension was stirred at room temperature for 10 minutes. A solution of 2-(2.3,5-trichlorophenyl)-4,4,4-trifluoromethoxybuteno- nitrile (see Example 1.6) (0.859) in Et0H (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 jg xgggg. Chromatography on silica gel, eluting with CHCI3, gave the desired product, 0.61g, mp. 124-126°C.

Egggle Q §ynthesis of 4-AminoN-morpholino1g,3,5-trichlgrogheng])- pyrimidine To a solution of Ha0Et (from 0.219 of sodium) in ethanol (20ml) was added morpholinoformamidine hydrobromide (1.6g). After stirring for 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 CHCl3 to give the desired product. 0.739, mp. 168-170°C.

E’ .) IE 970474 2 - §;ﬂMU9ﬁ%j1J;dwctm1ymu0k512iL£:UﬂghhmQmm§N): pvr 'Ir.Lc: To a solution of Na0Et (from 0.219 of sodium) in ethanol (goml) was added 1,1-dimethylguanidine sulphate (2.07g). 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, eluting with CHCT3 to give the desired product, 0.699, mp. 145-147°C. £.u!i¢_1l ﬁygthesis of 4;Aminomethyl—2-(4-methylpiperazinyl)(Z4§J§; grichlorgphenyl)pyrimidine To a solution of NaOEt (from 0.16g of sodium) in ethanol (lsml) was added ﬂ-methylpiperazinoformamidine hydriodide (l.6g). After stirring for 10 minutes the enol ether of Example 6.2 (O.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 CHCI3 to 4% Me0H/CHCl3 to give the desired product, o.31g, mp. 156-159°C.

Ln.-yd.-.12 §ynthg;i§__of 2,4-diaminomethvl(2,3.5-trichloronitrophenyl) pvrimidine 2,4-Diaminomethyl(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 sat room IE 970474 temperature overnight, then poured onto ice and basified with 0.880 ammonia. The product was extracted into ethyl acetate, bulked, dried (MgS04) and evaporated. The residue was purified by chromatography on Si02 gel, eluting with Et0Ac to 8% MeOH/Et0Ac to give the desired product, o.13g, mp. 313-315°C. £n1Le_1_1 SyeAh£2i§__ def- _ :1 ~: mine: ~ 51,- {ti ..-'_‘_:eQ.‘.'_'?!'?_l-,") .v.I no 3 .r:v;.f~.ay..l-.5 ..,3 . - l. l‘ l luv.‘ NaOEt (from 0.169 of sodium) added 1,1-dimethylguanidine sulphate (1.69). After stirring for 10 ether of Example 6.2 (0.829) in ethanol (Sml) was added and the mixture was stirred at reflux for 5 hours.

To a solution of in ethanol (l5ml) was minutes the enol 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 give the deszred product, 54mg, mp. 151-153°C; 55912.15. -_2.:z~ v i am w c — - L2,.3:11-::_{Ll.o,r‘orm r._.v1 lr 7".l_U.<*_'_'.::1m_n‘: um 1. ",$'l,L’~£»,'é'£l£ .0‘ Qjgjmidigg 1. Preparation of 2,3-djchlorobenzvl alcohol To a solution of 2,3-dichlorobenzaldehyde (Aldrich, Sogms) in alcohol (B00mL) at room temperature was added NaBH4 (8.54gms) and the resulting mixture stirred for 1.5 hours. The reaction was quenched with water and the solvent evaporated jg_gggug 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 gaggg to leave a white solid, 48.38gms, mp. 37-s7.5°c.

IE 970474 Preparation of 2.3-dichlorobenzyl bromide To a solution of the alcohol in benzene (500ml) under N was added PBr3 (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 HaHCO} solution and water, dried over MQSUJ, _ ‘V iilterej and the solvent evaporated to leave a brownish liquid . .. ... . , , 0, whl(h solidiiiod on standing. 3/.53gms, mp. 31-32 L. :":r‘ r..i,»«‘a I W‘ 01; 2 ..3_- s1_~'.<:,h .!.0_r.9;.-r,-9!.u_l.ag tm1.i_tv_*ils lhe bromide was suspended in DMSO (l55ml)/ 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 5:20. The combined ether extracts were washed with water, dried over MgSO4, filtered and the solvent evaporated in gaggg to leave a white solid. 27.52gms, mp. 64-67°C.

Pregqrgtjgn of 2-(2,3-gichlgggghgnyll-4 4,A;jrj_luoro;}—oxo- butyronitrjle To a solution of Na0Et (from 1.48gms Na) in Et0H (25ml) at room temperature under H? was added the nitrile (10.0gms) followed by ethyl tiiilucrcacetatc (9.3gms) and the mixture stirred'at reflux ‘or 2 hours. After cooling, the solvent was removed in vacuo and the residue dissolved in wazer. The aqueous phase was washed with Et20 (discarded), acidified with H2504 and extracted with Et20. The combined Et2O extracts were washed with water, dried over MgS04, filtered and the solvent evaporated in ggggg to leave an oil. This was triturated with petroleum ether, and the solid filtered off and dried. 9.56gms, mp. 74-75°C.

IE 970474 gggparation of 2-(2,3-dichlorophggyl)~4,4,4-trifluoro~3- m2_t.h9>s1l2u_t_-.2;e_@_n_.i.t.r_i..!_*: To a solution of the trifluoromethyl ketone in Et20 (90ml) at room temperature was added diazomethane (from 19.35gms Diazald) in 5:20 (180ml), and the resulting mixture left to stand at room temperature overnight. Excess diazomethane was then removed in ygggg into Ac0H, and the residue was dissolved in 5:20. dried over MgSO4, filtered and the solvent evaporated in xgggg to leave a brownish solid, 6.44gms.

LS - !‘.>.‘i.e-.!:":..‘i I10. ri.-J 2 ,_ 3; J M 1_<1-";C*££'.';'.'.'! vl l:.-'ia:- $3. ‘id-‘_‘.ux:—:.<;0. from rqliQn_9_ methylgygimigine To a solution of the above enol ether in ethanol (37ml) was added guanidine hydrochloride (1.92gms) followed by a solution of Na0Et (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 ygggg.

Chromatography on silica gel eluting with CHCl3 to 2% Me0H-CHCl3 gave the desired product which was triturated with Et20 and dried in ygggg, 673mg, m.pt.218-9°C. 1-i;D¥@ﬂNdé-§:f&.3;¢’*HlJr9p£:nyll:6-ifliluaradeihvlrvvlmidluu methanesulghonate To a suspension of the free base (loomg) in ethanol was added methanesulphonic acid (3Dmg) 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 _1_r;v_acy_q, 107mg, m.pt. 253-256°C. 2J4-U[gmino~5-(2J3;dichlorophenylltrijluoromethylpyrimidine hydrochloride To a solution of the free base (150mg) in methanol was added ethereal hydrogen chloride. After stirring, the solvent was evaporated to dryness and the resulting solid triturated with ether, filtered, and dried _1_n_ _v_a_t_:_u_g, 160mg, In.pt. 233-236°C.

IE 970474 Lsg1s_:L'E' ' :3 53. of Z D. i .ar;i.n.s2 -.13.: I 2 . 3 - d 1' 9:)‘ 19 I‘ o9.h~:o.v_l_.l,- E:-_-M: Pu‘ 7..0.l‘;'_".l..'!'id.l£t: This compound was made in an analogous manner to the compound of Example 6 from 2,3-dichlorophenylaceonitrile, m.pt. 245-247°C.

£!Q1_I_l.§ Svuthesis of 2 4~Diamlno~5~ 2 3~dichloro0henvll—6«uwthaxvmelh l a_m,"_____. _.. "._a . h_. ,_ ;,_- _.H . _. ."a__ "m_u...-_m_h"Y" .v1_ri_rm'L'u.c. 1. Ereparation of 2-(z,3-dichlgrophenvl)methoxvoxg;§utyro- nitrilg To a stirred refluxing solution of Na0Et (from 1.38gms Na) in Et0H (25ml) was added a mixture of ethyl methoxyacetate (8.85gms) and 2,3-dichlorophenylacetonitrile (Example 14.3) (9.39) dissolved in DME (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 in ygggg and the residue partitioned between ether and water (the ether phase was discarded). The aqueous residue was acidified with ZN H2504 and extracted with eaher (35). {he wwtiuuc F1qP extracts were washed with water, Grind over Mgsn. filtered crd evaporated in ygggg to give a yellow solid (5). inc sodium salt (above) was dissolved in water and the solution extracted with ether and discarded. The aqueous solution was acidified with 2M H2504 and extracted with ether. The ether extract was washed with water, dried over M9504, filtered and evaporated in yggug to give a white solid (b).

The above products (a) and (b) were combined to give a yield of .4gms which was used without further purification. Single spot by TLC (l9:1 CHZCTZ: Me0H) Rf 0.35.

IE 970474 2 - E.Lc;o2:3t_i0n_ gf__2.-1.2. .3.-_<.i.i..c..h..1. -29 _he.ru'D_-131 - d iziltegh;-u.v_bu_t —.-Z :(-’_D_0:. m’ .9‘ iii: 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 innwdiate reaction was produced. The mixture was left stirring at room temperature for 3 hours and evaporated jg_yg§gg, into Ac0H to give the enol ether. 3. Pre aration of 2 4-Diami o- dichl ro hen l - - methoxvmethvlpvrimidine To a solution of Na0Et (from 0.92gms Na) in Et0H (40ml) was added guanidine hydrochloride (3.44gms). A solution of the enol ether (above) in Et0H (30ml) was added and the mixture refluxed for 5;; 3 hours. After cooling, the solvent was evaporated off in ygrgg and the residue treated with SN Na0H (gag 50ml). The red solid was filtered off, dissolved in ACOH (gag 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 Et0H, 4.39gms, mp. 237-24o°c.

.E_xg_l1_LZ l‘. :'-:‘:.-_a.r.=3_‘»_‘Lcu2. .s;:f 2 . 1' a,nj.ng.5 —-u .- u;~:.n_'c-.L.'t!.i:.l_).L:.i:r_m1d of NaOEt (from ethanol (60ml) at room temperature under N2 was added 1-naphthylacetonitrile (Aldrich, .02gms). After stirring for 10 minutes, ethyl formate (8.B8gm5) 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 ggggg (6.86gms).

To A solution 1.45gms Na) in IE 970474 added, and the reaction vessel sealed before stirring the contents at 40°C for 4 hours. __ _ggggg, and the residue partitioned between Et0Ac and water. The organic phase was washed with water, dried over H9504, filtered, and the solvent evaporated in ygggg to leave the crude product as a viscous reddish oil (5.4gms).

To a solution of Na0Et (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 in yggug and the residue partitioned between CHCl3 and water. The organic phase was washed with water, dried over H9504, filtered and the solvent evaporated to leave a pale yellow solid.

Chromatography on SiO2 eluting with CHCI3 to 48 CHCl3:MeOH, followed by recrystallisation from ethanol gave the desired product as a white solid. 2.82gms mp.171-3°C. £:_a_s;1:_La I _)r ,l_i_ .1: ’ IL-A‘ f.‘1n:A:r l"»f! (":1 1 1 I ; ya x l ;C-_ v" _, '.'7~ci1’._‘..‘2 lznf.-_L-ij§r‘._Llj_4-6_—['_1j_*;;_1!1_:;g,g-ga.‘.f/[flyI). 1.389 sodium) in ethanol (25ml) was added over 5 minutes a mixture of ethyl diethoxyacetate (l3.21g; 75nnnl) and (Example 14.3) 2,3- dichlorophenylacetonitrile (9.39; Sommol) in dry dimethoxyethane (20ml). After 4 hours cooled and evaporated jg yaggg.

IE 970474 1N H250‘. Extraction with CH2Cl2 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 (£§& 39) in ether. After 2 hours the solution was evaporated jg gaggg to give the desired enol ether as an oil, which was used without further purification.

To a solution of NaOEt (from 1.49 sodium) in ethanol (50ml) was added guanidine hydrochloride (4.8g;'50mmol). A solution of the above enol ether in ethanol (20ml) was added and the mixture refluxed for 4 hours cooled, and concentrated jg ggggg to gg; 30ml and diluted with water to give a dark purple solid which was filtered, dissolved in CH2Cl , washed with water, dried over MgS04 and evaporated jg ggggg. The residue was triturated with ethanol (50ml) and filtered to give the desired product (8.49) which was used without further purification. (mp. 214-217°C). 2,§-Diamino-5;(2,3:6ighjnrophenyljgyrimidjne—g-carbogaidehyde A mixture of the above acetal (7g) and 0.4M HCl (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 (6.29), which was used without further purification. 3 4~Diamin~="—’" 7-‘ichior h i'- -h drox th 1 To a stirred solution of the above aldehyde (2.89: lommol) in a mixture of dimethoxyethane (lsml) and ethanol (lsml) was added in portions sodium borohydride (llomg: Bnmnl). 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 MgSO4. Evaporation of the solvent_jg_1aggg_ gave a pink solid, which was triturated with ether, filtered and dried IE 970474 (1.6g); Recrystallisation from methanol (50ml) gave the desired product as fine colourless crystals. 0.65g, m.p. 173-6°C. 4. 3,4-Diamino—§-(2,3-djchlorophenvl)fjgoromethvlpvrimidine To a stirred suspension of 2,4-diamino(2,3-dichlorophenyl) hydroxymethylpyrimidine (185mg; lnnnl) in dry dichloromethane (2Sml), under nitrogen at -70°C, was added dropwise diethylaminosulphur trifluoride (263pl; Zmmol). The mixture was allowed to warm to 0°C and kept at this temperature for 4 hours.

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 (M9504). Concentration gave a colourless gum (0.29). Chromatography on silica gel, eluting with 0.01:1:19 Et3N:Me0H:CH2Cl2 gave the desired product which was triturated with CCl4 and dried in vacug. 111mg, mp. 224-6°C. ' x 10 2 4-Diamino- ~ 2 th 1 To a stirred solution of Na0Et (from 1.389 sodium), in ethanol (70ml) at reflux, was added over 10 minutes a mixture of 2,3-dichlorophenyl- acetonitrile (9.39) 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 ygggg.

The residue was dissolved in water, washed with ether (discarded), acidified with ZN hydrochloric acid and extracted with dichloromethane. The combined extracts were washed with brine, dried (MgS04) and evaporated in ggggg to leave a tan coloured solid (39), 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 _djazomethane in ether. After stirring for 1 hour at room temperature the solution was vacuo to leave a dark oil vacuo. The residue was shaken with 5M Na0H to give a dark oil, IE 970474 concentrated jg vacuo to give the enol ether, which was used without further purification.

To a solution of sodium ethoxide (from 0.639 sodium) in ethanol (25ml) at room temperature was added guanidine hydrochloride (2.399). 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 in yaggg. The residue was suspended in 2H Na0H (75ml), filtered, washed with water, dried in air and recrystallised from ethanol to give the desired product as a colourless solid. 3.329. mp. 211-213°C.

Exglg 2Q 2,4-Diamino(2.3;gjchlorophenvllmethvlthiomethvlovrimigjgg To a stirred solution of NaOEt (from 1.339 sodium), in ethanol (25nl) at reflux, was added over 5 minutes a mixture of 2,3-dichlorophenylacetonitrile (9.39) and ethyl methylthioacetate (10.07g) in dry dimethoxyethane (20ml). After stirring at reflux for hours the mixture was cooled on ice, acidified with acetic acid (Sml), poured into cold water and extracted with dichloromethane. The combined extracts were washed with water, dried (MgS04) and concentrated to give a yellow oil which was used without further purification.

The crude acyl acetonitrile was heated under Hz with triethyl orthoformate (40ml) at 140-150°C for 4 hours, distilling off low boiling material. After cooling, the mixture was concentrated 15 (15.29). The oil was dissolved in ethanol (20ml) and added to a mixture of guanidine hydrochloride (4.89) and sodium ethoxide (from 1.389 sodium) in ethanol (50ml). After stirring at reflux for 4 hours the mixture was cooled and concentrated in which was extracted with dichloromethane, washed with water and dried IE 970474 (MgS04). Concentration jg vgcuo left a dark gum. The desired product crystallised from ethanol (20ml) as a light tan solid, 0.579, mp. 205-7°C. " 1. "1'! Q’gf«-~l-:.-.i_i!:".-f--5’ ii i ‘~:,r}>; ! I _';»lr rfTll:l7_{}li: 2-(2.3-dichloronhenvl)oxo-progiggitrile To a solution of Na0Et (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 jg ygggg.

The solid was dissolved in water , filtered, acidified with concentrated hydrochloric acid and the precipitate filtered off and dried in ygggg, l4.35gms, 45% yield. b. A solution of the above product, ethylene glycol (9.19gms) and p-toluene-sulphonic acid (8.9gms) in toluene (looml) was stirred at reflux, with the water being collected in a Dean and Stark trap. After cooling, the solution was washed with water, IN HaOH and water before drying over MgSO4. Evaporation of the solvent left an oil (20.17gms) which was dissolved in Et0H (70ml). After standing for 1 hour the cream precipitate was filtered off and dried jg xgggg (10.44gms). c. To a solution of Na0Me (5.1gms) in ethanol (75ml) was added guanidine hydrochloride (8.2gms). After stirring for 30 minutes the Natl 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 gave the product, as a whit 212.5I214°c.

The diamino-pyrimidine (6.1 (250ml), concentrated hydroch suspension chilled for 2 filtered off and dried to giv lo I Concentrated hydrochloric aci ice (150ml), the solution add (30.6gms), and the mixture re over H9504. 31.3gms.

Evaporation of £b.vL2_._3.-. Qi ,C_h.?.-::r'='Lt>.h.§nLl the ac concentrated H2504 (1ml) and hours. After cooling, the so treated with concentrated N organic phase was extracted the solvent evaporated to lea To a FUSp9HSluP of Eﬂvhiiﬁiﬂkhmﬁmwuﬂk To a mixture of the ester orthoformate (69.24gms) was the resulting pale yellow sol After cooling, the mixture w precipitate started to form, us 970474 e solid. 7.67gms, 70% yield, mp.

Zgms) was dissolved in ethanol loric acid (2.07ml) added, and the hours. The precipitate was then e the hydrochloride salt, 5.52gms.

J:u1u9UY]ﬁ£9§i§ 355g d (100ml) was poured onto crushed ed to 2,3-dichlorophenylacetonitrile fluxed for 3 hours. After cooling, water (500ml), extracted with Et0Ac the solvent left a white solid, id in ethanol (200ml) was added thv mixture stirred at reflux for 3 TTPV1 wﬂs ?m£p*lﬂfvi éﬂd Tit V "u; Hqnu (Em!) in nato' (iﬂml). Ihu inzu Tu,Ll?, d.ied ever M9504, and vs a clear liquid, 19.88gms. 3.-,rl;r_u.».«:1>i1oJ_i 'l0_- <3; r‘y.7«‘;te: (40.7gms) and ethyl added acetic anhydride (0.5ml) and ution stirred at reflux for 3 hours. as concentrated in ygggg. A white and this was filtered off before , morpholine IE 970474 further concentrating the filtrate to give a brownish clear oil.

Standing overnight in vacug gave a yellow solid, 34.34gms. ?. .3.-_ﬁ._i.c_'n_,! <2 1‘ 0;» Iv any ms-;*J_c;'.t.t.1.<—._‘?I_1é'.

To the above ester was added guanidine hydrochloride (26.6gms) 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 gggug, diluted with water (100ml) and then washed with 5:20 (200ml).

The aqueous phase was acidified with Ac0H, and the precipitate filtered off and washed with Eton and then Etzo before drying in xgggg, 13.48gms.

U1-J. .4_~.c_I1.l.o_v‘2: §»~.( 2a_3_~.d 3'.c.h.l9:9n tv1o.y..l..L-..rT.’_-_r?_v1‘_1'mc1m.v.l dimethylfgrmamidine To a mixture of the above isocytosine (14.4gms) in CHZCIZ (200ml) was added dropwise during 30 minutes fresh Vilsmeier-Haack reagent (from 2.75 equivalents of SOCl2 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 CH2Cl2 and the combined organic extracts washed with brine before drying over M9504. Evaporation of the solvent and chromatography on Si02 gel, eluting with Et0Ac gave 13.6gms, mp. 113-115°C. 2-Aminochloro(2,3-dichloroghgnyl[pyrimidine To the formamidine in Et0H (50ml) was added ethanolic-MeNH2 (8 equiv.) in Et0H (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 ggggg, the residue mixed with IN Na0H (75ml), filtered, washed with water and dried in ggggg, l1.2gms, mp. 228-30°C. 3L9-Diamino-S-(2L§;"ichlorophenyl)pyrimidine To 2-aminochloro(2,3-dichlorophenyl)pyrimidine (6.73gms) was added ethanolic ammonia (30 equiv. in 50m1"Et0H) and the IE 970474 mixture sealed in a Parr reaction vessel and heated to 125°C for 38 hours. After cooling, the mixture was concentrated lg ggggg and the residue mixed with 1N Na0H (75ml), filtered, washed with water and dried in xgggg, 6.l4gms, mp. 208-211°C. £z£!1£_ZZ §:.nt!:c.s’='s .4-,0j->:m=>;S::.(I.i~ ii‘!-'»'~1~:«.r~i'~»:-vwxv 3.)'f;7f'.€‘ﬂ‘.‘:'C1*§ ‘/..r...‘lﬁ_‘-L‘m:: This compound was prepared according to JACS, (1951), 11, 3763-70. mp. 225°C. 1 la gxnthesis of 2,4-Diamino(2—chlorgphenyljpyrimidine This compound was prepared according to JACS, (1951, 1}, 3763-70, mp. 12s—3°c.

Exggglo 24 :I§‘[V‘ '-L114‘ :5:-' 2 4* 4/‘ . -‘A — '1)’ 521-31 :2: 1» - {.5 -.«i.~’U ‘>v;<‘~.r'_=_=.:~a-M.) - 6 — e t?1;v 1:1-.'zr‘,i_'Iv >';J.f_m'-: Prepared as for Example 22, except that eth;lk propionate replaced ethyl acetate. mp. 197-a°c.

Exggglo Z5 §1nthesis of pyrimidine This compound was prepared in a manner analogous to the compound of Example 14 from 2,4-dichlorophenylacetonitrile (Aldrich): mp. 220.5- 221°C. 244-Diamino—5—(ZJ4-dichlorophenyl)—6-trifluoromcthyl IE 970474 £zeaJ;_2i izcrxthwri-sits. 2?’ _ 6_~£i_e.n_‘: 2' !.<;',-=_s/«pet-.‘!uvl-.2451,‘-d.i,a1nino-5:f;»1_4:n1 L‘.-'.Uf7‘,7'?£ZlF.?1T‘DiH. pyrimidine .

This l:()1i‘.;‘a,r.-Lrwi WJS p1':f:{‘:€:."v;~;! in o nI.1m1:'-2‘ m'I.‘1l-\«)«'»11*f- in :n-- compound Of iaample Eh Tvnm 3,4 di«hlcruphcnylgucionltrilu and ethyl hunzyloxvnrutate, \.I?gm3, mp. JXIVEYEOL x lo 2 3rL£:E&LhilRiQ§Fi£i":L:Xll'F;ﬁmiﬂ9-§:(Z,3;dichiorouhenvlluvrimiéiné A) A solution of 55.7g (0.4equiv) of §ymethylisothiourea sulphate in 280ml of water was prepared and gently heated on a steam bath with stirring. Then 40g (0.4mol) of 3-methyl~piperazine was slowly dripped into the solution while sweeping the flask out 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 ggggg and chilled which caused the N-methyl-N‘-amidinopiperazine sulphate to crystallise; 50.799 was collected.

B) A mixture of 76.3g (0.356 mol) of a-formyl-2,4-dichlorophenyl- acetonitrile, 63.79 of isoamyl alcohol, 0.369 of Q-toluenesulphonic 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 IE 970474 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 ﬂ-methyl-ﬂ‘-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 ygggg. 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; N, 20.71; Found: C, 53.58; H, 5.14; N, 20.40.

Exgggle gg §vnthesis of 2,4-Diamino(2,5-dichlorophenvl)trifluoromethvl pyrimidine This compound was prepared in a manner analogous to the compound in Example 14 from 2,5-dichlorobenzyl alcohol (Lancaster Synthesis, 48.269) to give the title compound in a yield of 3.85gms, mp. 215-217°C.

IE 970474 §1LI.!;1!_21v_ Preparation of_g*ﬁ-Diamino(2.3.5-trichlgrgphenvll pyrimidine Guanidine hydrochloride (3.209) 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 (4.409) 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 jg, yggug.

Chromatography on silica gel eluting with CHCI3 to 3% MeOH-CHCI3 gave the desired product which was triturated with ether and dried in vacuo. Yield - 2.019, mp. 246-249°C.

EALQLLIQ ivnthesis of 4;Amino(3-brgmgphenvllmethvlgg-(4-methvlpipegagig yl) pyrimidine To a solution of NaOEt (from 0.929 of sodium) in ethanol (7Sml) was added 3-bromophenylacetonitrile (Aldrich, 7.859) and ethyl acetate (3.529). 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 2M Hcl and extracted with ether. The extracts were bulked, dried (HgS04) and evaporated, 3.8g, mp. 97-103°C.

The resulting ketone (3.79), ethylene glycol (5ml) and g-toluene- sulphonic acid (100mg) were heated under reflux in toluene (100ml) in a Dean 8 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 (MgS04) and evaporated. 4.039, mp. 68-71°C.

IE 970474 -45.

To a solution of Na0Et (from 0.289 of sodium) in ethanol (30ml) was added ﬂ-methylpiperazinoformamidine hydriodide (2.7g). After stirring for 10 minutes, the ketal (1.419) 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 5102 gel, eluting with 10% He0H/CHCI3 to give the desired product, 0.439. mp. 120-122°C. £seee12_11 Svnthesis of 2,4—DiaminoI1-naphthyl1-§-trifluoromethylpyrimidine This compound was prepared in a manner analogous to the compound in Example 14 from 1-naphthylacetonitrile (Aldrich, 10gms), to give the title compound in a yield of 0.69gms, mp. 224-226°C. -~:.r‘3;n pf 2 §miQ;{";[2 ¢—diLhlercphsuvll-i,L:di blur pyrjmjdinf .73 I .f.'— Q{_"_‘_.’".'. ~_w:p;"l.-1,-raj. ‘.§;.c-r ;;"__(;_ 3,I»Fichlorophenylacetonitrile (27.99, 150m.mol) was suspended in ‘H nlih (400ml) and the mixture refluxed for 4 hours. The cooled vuoczion mixture was extracted with ether (2x200ml) acidified to mm} and the solid filtered and dried (229, 70%).

The product (209) was dissolved in Et0H (300ml) and concentrated H2504 (sml) added carefully. The mixture was refluxed for 7 hours. The cooled reaction mixture was evaporated under reduced pressure and the residue partitioned between CH2Cl2 and water (30ml each). The organic layer was extracted with saturated NaHCO3 solution (200ml), washed with water (luqml), dried and IE 970474 evaporated jg vacuo to give ethyl 2,4-dichlorophenylacetate as an oil (22.29, 89.5%).

Diethvl 2.4-Dichloroghenyl malonate Sodium (1.869, 0.08lM) 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 Et0H 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 yggug to give a yellow oil (21g, 85%). * 2-Amino(2.4;gichlorophenvl)-4.§-dihydrgxygyrimidine Sodium (4.529, O.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, Et0H was removed under reduced pressure and the residue partitioned between 2N Na0H (400ml) and Et0Ac (400ml). The aqueous layer was acidified with concentrated hydrochloric acid with cooling and the precipitated solid was filtered and dried (119, 62%). 2-Amino(2,4-dichlorophenvl)-4.6-dichlgropyrimidine A mixture of 2-amino(2.4-dichlorophenyl)-4,6-dihydroxy- pyrimidine (log), phosphoryl chloride (100ml) and dimethylaniline (1.5ml) was refluxed for 6 hours. The cooled reaction mixture was carefully added to crushed ice and the insoluble solid was filtered and washed with 2N Hcl, followed by water. The solid was resuspended in water. neutralised (0.88 NH4Qﬂ1_with cooling, and the mixture stood overnight at room temperature. The IE 970474 insoluble 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. §sa!e1e_z§ ﬁynthesis of 2.4-Diaminochloro(2.4-dighlorophenyl1-pyrimidine A mixture of 2-amino(2.4-dichlorophenyl)-4,6-dichloropyrimidine (0.5g) (Example 32) EtOH saturated with ammonia (20ml) and copper powder (0.059) 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, 252), mp. 219°C. Microanalysis: Calcd: C, 40.82: H, 2.55; N, 19.05; Found: C, 41.27; H, 2.46; N, 13.74.

L"_/'7r'.7.'»':>l_~. I.-1 .'~"luil.I "‘l' ' "".'~‘-’:"*.'1‘.-: 1‘./1.. I"(\1",,4\} l.Il.V. pxrimidine A mixture of 2-amino(2,4-dichlorophenyl)-4,6-dichloropyrimidine (0.5g) (Example 32) THF (lsml), methanethiol sodium salt (0.113g), copper powder (0.059) and tris[2-(2-methoxyethoxy)ethylJamine (0.19) 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. 201-2o2°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.

IE 970474 x lo itgthezjs Q1"?.i:QiﬁWfﬂQ:5:(3u§:ﬂiﬁUlQI29h9ﬂ¥ll:5:WC£DEi{Nl£QEFimiQﬁﬂ£ A mixture of 2-aminochloro(2,4-dichlorophenyl)methylthio pyrimidine (0.5g) (Example 32) EtOH saturated with ammonia (20ml). copper powder (0.05g) and tris[2-(2-methoxyethoxy)ethyl]amine (.01g) 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 (0.119, 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. 13.33. £aeenle_1§ ﬂ;£@iﬂQ:§:L§45*dlChlgLQHﬂ§U!l1~5~mGthYl(4:mEthylDlDerazinV1 uxrnnuuee a. 3,5-Dichloroghenylacetonitrile - 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 jg ygggg, the residue was taken up in ether, washed with saturated aqueous NaHC03 and brine, dried (MgS04) and concentrated jg ggggg to give 3,5-dichlorobenzyl chloride as a light yellow solid, which was used without further purification, 289, mp. 32-36°C.

To a vigorously stirred solution of 3,5-dichlorobenzylchloride (289) in dichloromethane (150ml) was added a mixture of KCN (27.5g) and tetrabutylammonium hydrogen sulphate (2.38g) in water (lloml). After stirring at room temperature for 22 hours, the mixture was diluted with dichloromethane, the organic phase washed with water and concentrated in ygggg to -leave an oil.

IE 970474 Filtration through silica with toluene followed by concentration then trituration with hexane gave the desired product as a colourless solid. 15.89, mp. 31-32°C.

To a stirred solution of Na0Et (from 0.699 sodium), in ethanol (25ml) at reflux, was added over 5 minutes a mixture of 3,5-dichlorophenylacetonitrile (9.39) and ethyl acetate (3.39) in dry dimethoxyethane (10ml). After stirring at reflux for 4 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. 2-(3.5-dichlorophenyl)oxobutyronitrile as a colourless solid (4.159).

Trituration with hexane _ gave 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 ggggg to give the enol ether.

To a stirred solution of Na0Et (from 0.72g sodium) in ethanol (25ml) was added N-methylpiperazinoformamidine hydriodide (7.299). 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 jg ggggg and the residue shaken with 2M Na0H (50ml). The solid was filtered off, washed with water, dried in air and chromatographed (silica; 1:9 Me0H:CHCl3) to give the desired product as a colourless solid, 1.6g, mp. 164-166°C.

IE 970474 Exggplo 37- 9:F[uFHZl*ﬂ C’ 2 J-if1W’H:—?—{?_F—ﬁic%’>"t:neHv']-5 ng" v. ‘mti.

This compound was made "in and analogous manner to the compound of Example 6 from 2,5—dichlorobenzylalcohol (Lancaster Synthesis). Hp. 226-228°C: TLC (5102: CHCl3/Me0H, 9:1) Rf = 0.24.

L.II_-;_l_!_ﬂ ‘:V;J'u1l'L .: ¢ i'V‘nW '.-7 pyrimidine This compound wan Example 4. 3,4—dichlorophenylacetcnitrile (Al 1 252-254.s°c: TLC (SiO2; methanol/chloroform, 2:9) hr = c.33. made in an analogous manner to the u~n;onnd of from Exggglo :3 Fregh'ni'nr of 243-Ci mino—ﬁ (P 3-d cnlnuohﬁcrxl 2 pvt: This compound was made in an analogous manner to the compound of Example 5 from 2,4-diamino(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, Et0Ac), mp. 237-9°C. Also separated in this manner was 2,4-diamino(2,3-dichloronitrophenyl)pyrimidine, mp. 264-5°C.

IE 970474 . - Exgggil 40’ 3' 3,7’ "‘.j.,-I, ~ 1 v | H _!j, i‘ i,_. r .r» um: This compound was prepared in a manner analogous to 2,4-diamino(2, 3—dichIoropheny1)(diethoxymethyi)pyrimidine (Examp1e' 18.1) 2,4-dichlorophenyiacetonitriIe, mp. 225°C. from Exggglo 41 ":‘:‘i U7 j‘ :1: ‘pi 1‘.-L1;;'i}z;/v‘.;.=‘..-r‘ I—{j~:.'iv'-'_"~.I:;~.- '1;-2 iirv This compound was prepared in a manner analogous to the compound of Exampie 6 from 3,5-dichiorophenylacetonitri1e (Aldrich). mp. 242-244°C.

Exgggiu 52 7'°;%';?3;h gf_ _?_5-Uigﬁiﬁﬂ-5~{2_3~i:§::O'@§"9Gyi}-5;;Yifiu;' ‘* I pgrimidine N-oxide This compound was made from the compound of Exampie 14 by reaction with MCPBA in CHC13 at room temperature. Mp. 275-278°C.

Egi-J; r" -I-. N ‘UN 1;? pyrimidine This compound was prepared from the compound of Example 15 by reaction with excess bromine and sodium acetate in acetic acid at refiux. The title compound was separated from a mixture with the compound of Exampie 75 by coioumn chromatography, mp. 210°C (dec1,_ '4 ’ ".*,-I". i ,‘-{i—‘L' '1':’_:'V_.- 'i3.'.v'.,:"‘.iiVy ».'V _ ., , ....a , »...

IE 970474 _ 53 - This compound was prepared in 2 manner analogous to Example 2, from 2,4-dichiorophenyiacetonitrile, mp. 183-185°C. Single spot on TLC.

Exgggil 45 "I HT _ «.-l,_-;y_,|__’_- _ 'A-,*_' '-v‘_'('|'.i' 'Iz'.,‘_'.‘~ ,1 K This compound was prepared in a manner anaiogous to Exampie 6 from 2,6~dichioropheny1acetonitri1e (Aldrich), mp. 250°C.

Exgggiu 4§ Preparation of 2,4-Diamino-5e12.4-dichlorophenvlJbvrimiduyg -6—carboxaidehvde This compound was made from the compound of Example 40 in an anaiogous manner to the compound of Example 18.2, mp. >350°C. ixi. I.‘.; {,1 {iv _1;3,';r_-iI‘.' ‘:"'.'u'I‘.~ar_3-'_}-(_;" ‘I .\~.’;.-«':,~~,'??‘," :".".‘1i!!‘;'.(i\.|1 vi.-" .-'.-'1.—.'- pyrimidine This compound was made from the compound of Exampie 15 in an anaiogous manner to the compound of Exampie 39. mp. 265°C. Aiso obtained from this reaction was 2,4-diamino-5(2,3-dichloronitrophenyi)methyl pyrimidine.

IE 970474 Exggplo 48 Py'gpnun:L1 methylgyrimidine This compound was made from the compound of Example 46 by reaction with hydroxylamine hydrochloride in ethanol, mp. 260-5°C. -2:-f . . ? .4: !»’.i5_T_‘=ﬂl_."'__'.l_-’»',' 1?. -''« -_d 1' «:?'= ?.a_~\f0;:’2r2_n,~.-;‘ 3 ~ -5."-_h.:«ey'.»:a:_4 ‘.~'.!l..'.i'-‘_’»..’JY_.7.

Fregavatfon pyrimidine This compound was made from the compound of Example 46 in an analogous manner to the compound in Example 18.3, mp. 169-171°C.

Ex 10 5 {‘:‘Ir_:‘v‘~.: .a'.i.lrx of Rgi~?'i=:min-:v—5-(§f_7 1‘: V — ".1" 71 |_ " l.'j.{ Iuly-I} c:-HAVVT — lll::_.{,_'{_l__"V| This compound was made from the compound of Example 47 by reduction to -- ‘w 1:, »,, :.wr%_ :.-nation of the diazonium salt (NaNO2, Emu; "wan Cucl (as for Example 57). Sublimes ;;3 on llﬁ (methanol/chloroform, 1:9) Rf=0.36.

Egngplaiﬁl 2Lg;pgamjgo;§;12.5—dichloroohenvi)methoxvmethv1;pxrjmi§iQ§ This compound was prepared in an analogous manner to the compound of Example 2 from 2,6-dichlorophenylacetonitrile (Aldrich), mp. 204-207°C. ‘ '9-;>'l.lllll’I‘:l-(1-/" ‘:-"l""‘!.‘._:"'_1*-",‘l7‘yI~’ 7 IE 970474 .55.

''MD mi ? J-i‘¢W'u3-v—ts 4 ‘—:i':n‘;"nh5amxIl E-%"l (">1 p.v»n jgxg This compound was made from the compound of Example 6 by reacting with ncs in ACOH at 100°C (AIBN as catalyst), mp. 226-227°C. :'.x».1-v U-'7'" LII‘; l_:§I-,2" ‘}:;:in' '.h';- \ . . V ;L§~Q2;ﬂ1hG~5«bFQmumtthyl(2.4-dlChlOTODh8ﬂYl)DVTlmld4nE 2,4-Diaminobenzyloxymethyl(2,4-dichlorophenyl)pyrimidine (Example 26) (6.59) 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 dihydrobromide salt was filtered off, washed with ether and dried in ggggg, 6g.

To a stirred solution of the dihydrobromide salt (0.43g) in dimethylsulphoxide (4ml) was added dropwise a solution of sodium bicarbonate (O.84g) in water (loml). After 30 minutes the precipitate was filtered off, washed with water then ether and dried in yaggg, 0.269, mp.>270°C (decomposes). ’ " ' - —-. ..- .'~ - ' ,,.— ,4. 7 .x:':w -=1’ - '.~. ‘-1 ' iv‘ .s1"‘..’r'- To a solution of 2,4-diaminobromomethyl-S-(2,4-dichlorophenyl) pyrimidine (1.049) 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 (MgS04) and concentrated in yaggg. The residue was chromatographed (silica; 19:1:0.1 dichloromethane/methanol/ triethylamine) to give the title compound, which was recrystallised from ethanol. 0.19g, mp. 210-211°C.

IE 970474 Exgggll 54 Pro Lrition vi 2_d~0£tminn—9~l2—ﬁNlorC—5~lh_ﬂ-dimgthylsylphgrwyll ahenvl[g6—methylp,rimidin5 1. 344-Diamino(2-chloronitrophenvl)methylpyrimidine To a solution of 2,4-diamino(2-chlorophenyl)methyl pyrimidine (ll.84g) (Example 22) in concentrated H2504 (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 ,0 acetate, bulked, dried (MgS04) and evaporated, 13.9g, 236—240°C. 2 - 2...~T-.:E_'-i.«3.r-.I.7i,«i..r.v;'3,_-. .(_5,~;a.«z: 2 'L~?;QlllC£9£L'£.9I11.l;J.;f1*:U3LMDm...l.____'3 1' -"9 A solution of 2,4-diamino(2-chloronitrophenyl)methyl pyrimidine (13.99) in acetic acid (500ml) was reduced under an atmosphere of hydrogen in the presence of Pt02 (O.28g). The mixture was filtered through hyflo and the filtrate was concentrated. The residue was neutralised with saturated NaHCO3 solution and the product was extracted with ethyl‘ acetate, bulked, dried (HgSO4) and evaporated. Chromatography on Si02 gel, eluting with CHClg to 40% Me0H/CHCI3, gave the desired product, 69, mp. 117-121 C. '~"‘=v to-f i¢- H3~in i-v 1-;="+ﬂFu‘=u':LamLu1;?env'»-6~mv:h,i Lu'imndfnc 2,4-Diamino(5—aminochlorophenyl)methylpyrimidine (0.259) was dissolved in water (0.8ml) and concentrated HCl (0.5ml). To the cooled solution (below 10°C) was added a solution of sodium nitrite (0.079) in water (0.5ml). After stirring at room temperature for 2 hours, the solution was cooled to 5°C. Cupric chloride (0.059) and 5.14M $02 in acetic acid (O.97ml) were added and the reaction was stirred at 5°C overnight. The mixture was IE 970474 -57.. filtered and washed with water to give the sulphonyl _chlorice, 0.239.

The sulphonyl chloride (O.16g) was dissolved in THF (2ml) aqueous dimethylamine (Zml) was added. After stirring overnight, the solution was diluted with water, extracted with ethyl bulked, dried (HgS04) and evaporated. gel, eluting with 2% HeOH/CHCl3, gave 0.0479, mp. 283-285°C. acetate, Chromatography on SiO2 the desired product, Exggglu 55 i'pgaq3tf;m 7 of gyrimidine This compound was prepared in an analogous manner to the compound in Example 2 from 3,5-dichlorophenylacetonitrile, mp. 228-230°C. fc‘_._4_-_C = on ‘- no -1.’ 5:.J.i.r;si_l A:-_-"01-«.f'=_n:.".'::' l };§;rz‘:.i.i ’. 2. 2""? 1): Ll Exgglc 56 ' a ' é * F an-r.-a-‘. ? ; .’ 2: .'~~v ~ 1. Ethylcyano(2,3-dichlorophenyl)acetate Sodium (1.29) was added portionwise to ethanol (50ml) with After the sodium had dissolved a solution of 2,4-dichlorophenylacetonitrile (9.49) in diethylcarbonate (25ml) was added dropwise. The reaction mixture was heated until Et0H 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 Et0Ac (300ml each). The organic layer was dried and evaporated jg ygggg and the residue ,was purified by flash column chromatography to give the title product. (5g, 39%). stirring.

IE 970474 £.£;7i&TJU€-5:L?u3:iiﬁhl£"t£h:°:’l;§:5{§i9*:2:T’7‘¢1u& Sodium (1.29, 0.052mol) was added in portions to absolute ethanol (S0ml) with stirring. After the sodium had dissolved guanidine hydrochloride (3.699, 0.039mol) was added followed by ethylcyano(2,3-dichlorophenyllacetate (Sg, 0.0195mol). The mixture was refluxed for 8 hours, EtOH was removed under reduced pressure and the residue was partitioned between Et0Ac and water.

The EtOAc layer was extracted with 2N NaOH and the extract was neutralised with 2N HCl with cooling. The precipitated solid was filtered and dried to give the title compound. (0.229), 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.

Exgggle 52 E :«:r‘: t h 9: '7 s_ .01’ -2..:?_~ 0 '-Cant ‘H9: 5‘_U_._§,._57 tgr. *1 ’v:>m.0h.-?_."¢'_'! .3 ﬁr: ’i’[72’C';:; «’".‘.:f._i.:‘ Preparation of 2-(2.4~dichlorophenvl)oxo-butyronitrile A solution of 2,4-dichlorophenylacetonitrile (30.00gms, 16lmmol) (Aldrich) in dry ethyl acetate (36ml) was added dropwise to an ethanolic solution of sodium ethoxide, prepared in gjtu from sodium metal (4.909, 213mmol) 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 23.319 of white solid.

IE 970474 . 59 - jfvgeration of 2 4-4 am my G;i?‘::gjgﬂf§r§gLguyl)gﬁ;mvfhyl pyrimidine A solution of crude 2-(2,4-dichlorophenyl)oxo-butyronitrile (23.24gs) in dry toluene (400ml) was refluxed with- ethylene glycol (280ml) and 2-toluenesulphonic acid (8.009, 42mol) for four hours using a Dean and Stark trap. After cooling, the organic phase was washed with saturated HaHCO3, dried over MgSO4, and the solvent evaporated to leave a solid (24.0gm).

Finely ground guanidine hydrochloride (19.19, 200mmol) was added to an ethanolic solution of sodium ethoxide, prepared 13 .;i§g from sodium metal (5.0g. 2l8mmol) in dry ethanol (500ml). A solution of the ketal (25.09, 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 17.239 of product, mp. 222-222.5°C.

"‘!W‘?VWi".74-Q5?"?~*("4:$E5*ﬂ$5ﬂH‘*£*N#’"5: methylgyrimidine Finely ground potassium nitrate (6.59 64mmol) was added to a solution of 2,4-diamino-S—(2,4-dichlorophenyl)methyl pyrimidine (l7.23g, 64mmol) in concentrated sulphuric acid (1S0ml}. 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 (7.09) was passed through a silica flash chromatography column and eluted with ethyl acetate to give the pure product (4.819).

IE 970474 -60..

P:Gfﬂ"3i‘10_ﬁ‘ ?t4:P at U9-:-£5-’" *"-?.¢-¢‘€F "*?95""E‘):7- nl«?_' l y’ 2 ‘ {ll-V 2,4-diamino(2.4-dichloro-S-nitrophenyl)methylpyrimidine (4.809, lsmmol) was dissolved in glacial acetic acid (18ml).

This solution and 10mg 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 (2.649, Qmmol). -‘ t:' ' :2-A} L/‘.i:"»-I f',<‘."‘,-'3:’-_‘,ill;-},'3.’;'l:‘.3.I"Tt"i"i‘1’l‘«3_ pyrimidine 2,4-diamino(5-amino-2,4-dichlorophenyl)methylpyrimidine (1.959, 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 (0.509. 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 to a cold solution of cuprous chloride (1.79, 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 (0.559, 2mmo1)', mp. 262°C (dec).

IE 970474 Ex lo Synthesis of 4-amino(ethylgmino)12,3.5-trichlorophenyl) pyrimidine To a solution of NaOEt (from 0.1g of sodium) in ethanol (10ml) was added ethylguanidine sulphate (lg) (Aldrich). After stirring for 10 enol ether (Example 3.2) (0.486g) was added and the for 4 hours. The reaction was left overnight and then filtered. The concentrated and the purified by chromatography on S102 gel, eluting with CHCl3 to give the desired product, 0.l1g, mp. 149—1s2°c. minutes, the mixture was stirred at reflux standing at room temperature filtrate was residue was Exggplo 52 2,4-Diamino(2.4—dichlorophenvl)cvanomethvl—pvrimidine This compound was prepared from 2,4-diamino(2.4-dichlorophenyl) bromomethyl-pyrimidine (Example 53) by reaction with sodium cyanide in DMF at room temperature, mp. 249-251°C.

Exggglo gg . 1."-.':m::I'.‘»:?',5‘-v§_":f A__i‘ ‘ml’ v-"-_. ~Va_‘.?'~'.V"«-. ‘|\‘)l1".l'.-llilll-"..".‘l ,'r\,.' I....I «; :7- This compound was prepared from 2,4-diamino(2,4-dichlorophenyl) bromomethyl-pyrimidine (Example 53) by reaction with dimethylamine in ethanol at room temperature, mp. 170-172°C. ' Exggll 61 g44-Diamino(2.4-dichlorophenyl)cyangpyrimidine This compound was prepared from the compound of Examplg_48 by reaction with trifluoroacetic anhydride in pyridine, mp. 249°C.

IE 970474 Ezggglc §2 ‘ £-g1amlnL~§-lZ-.nlov3»d—fV.o:iphenull~fgm:iNvl::*in*1ine This compound was prepared in an analogous manner to the compound of Example 15 from 2-chlorofluorophenylacetonitrile, which was itself prepared from 2-chlorofluorotoluene (Aldrich, mp. 238°C. . .. ~ 0 ‘I ‘i W - l l , -3 "-1 1_<;l1_l 0! <1'.i!l.'_'§'i1l' 1.) -J3 ~_i.=.';-;;*—.l1.'r:I:;:m§:;.hX.l_m:_.'?.w_?_eliu2 This compound was prepared in an analogous manner to the compound of Example 2 from 3,4-dichlorophenylacetonitrile (Aldrich), mp. 204-206°C.

Exggglc §4 '* 1 ‘I am 7 ~ 5 « I.‘ 3- ~i- J3: r= L9:;=';;w‘::-" 5‘ l 1- 2:-.; This compound was prepared in an analogous manner to the compound of Example 15 from ethyl propionate, mp. 228-230°C. 7 :-h'nWlHZ-:*{3.‘~f‘€:47'Q?huVV'\-ﬁ:M:{Hy1iVV{m’§‘UQ This compound was prepared in an analogous manner to the compound of Example 6 from 2,4-difluorophenylacetonitrile (Aldrich), mp. 291-295°c.

IE 970474 Exggglo §§ .—.- .' /’ ,--.- ,| ' .. . '-,,..'...—' . l\.l :—‘J' -:‘L. .'.’~.‘ ‘»-f.-'~_-I-’-V -_'. -z~f::‘.r: This compound was prepared in 45' analogous manner to the compound of Example 6 from 2-naphthylacetonitrile (Aldrich), mp. 221-222°C. ';.::..-s-:r«.t1:-.- - _. _ This compound was prepared in an analogous manner to the compound Example 6 from 1-naphthylacetonitrile (Aldrich), mp. 224-225°C. x lo .«°_—,?.'.‘:'-;1_r;:«az.sy:_-.s’! C *1 l.9z:<_>.wJ ecn_vJ_1.c.-_v.r 1rn_i_<.LLu—: This compound was prepared from the compound of Example 21 by reaction with sodium nitrite in 1N H2504 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. . ‘ _ y -".‘=_!:‘v n -_;,»e"n'_-_.'2-,"I_ -‘_'--::w-","’~_."»_'h='.-;.1_:"i..::i.fi:j_«.

This compound was made from the compound of Example 32.4 by reaction with methanethiol sodium salt in ethanol, mp. 123-124°C.

IE 970474 -54..

Eamxzle .19" Z’ -1 vii"! f /..'m'n._~.» F— 4' _'i_ '_'-- tr" ir'_*; ";u~;;(;.hr_»|1',r '| '1 - f - f‘.-,'..)w__ x_ ,";'.-_';‘_l'; (71; _,r air, ;:'';»= This compound was made from the compound of Example 2 by reaction w‘th trimethylsilyl iodide in sulpholane at 80°C, mp. 101-105°C. .'-.:;«;':e 7L ,,T H amine W I; J.;»;ricnE.:ophenyi)-o-1iuoromethylnvrimidine This compound was prepared in an analogous manner to the compound of Example 18 from 2,4-diamino(2.3,5-trichlorophenyl)hydroxymethyl- pyrimidine, mp. 215-217°C.

Exggglu Z2 2.<1-Dieming;§g_(g;{l;d;gﬁ_g{g_py§1{1yllcarbamovlovrimidine This compound was prepared from the compound of Example 61 by reaction with concentrated sulphuric acid at room temperature, mp. 298-299°C.

LILIIJ L11 :_.' v\‘ ,_... , ,' ,a.... _.’. " '_;_i 3‘ :1‘ I,! .v‘ :x"-- V‘ ,."..'.l.. I I’, N This compound was prepared from the compound of Example 46 reaction with potassium permanganate, mp. 227°C.

Exggglo Z4 _E_§hil;2‘$_d_:'_qm__ingij2,4-dichj3rpdph»;n_y_l lp vr imidine-6—carboxv’Iate This compound was prepared from the compound of Exampje 73 by refluxing in ethanol in the presence of concentrated_sylphuric acid, mp. 177.5°c.

IE 970474 - 55 .

Exggglt 25-. 214-Diamino(2.3-dichlorophenvl)dibromomethvlpyrimidine This compound was prepared from the compound of Example 15 by reaction with 2 eq NBS in CCl4 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).

Exggla Zﬁ 2-Dimethylaminoamino(2,4-dichlorophenvllpvrimidine This compound was prepared in an analogous manner to the compound of Example 10 from 2,4-dichlorophenylacetonitrile (Aldrich), mp. 151°C.

Exggplg ZZ .Z’-.' 1' 1' we :.P13<.l..:=_«.r>.‘?.r_i_t.i-.4- «-1 "112 : ‘3 -( 3...4_-U. i'~‘_tL1::'_r 9.011? W ).:.(i:.u1¢~.ii1.v._lLrwﬁm 1' <1 ‘in: in an analogous manner to the compound cf Example 13 from 3,4-dichlorophenylacetonitrile.

This compound was made Exgggle Z8 I .‘ '. is '_".;".

Run? in the compound of 1-piperidinecarboxamidine sulphate (Bader), mp. 'i‘.'F. 4"_"uI:EJ-'llfll wz-..~. j~l",'grr':.’v'-'3 In an .'xll,l.ln-,l'.i-l"~ zr.:.

Example 76 from 169°C.

IE 970474 Exglo Z9- 2-Hntbvlemﬁno»4-ar5rc-S-(2 ?_E-trw;h\~vophen;l\gyr€mid’n9 This compound was prepared in an analogous manner to the compound of Example 58 from l—methyl-guanidine hydrochloride (Aldrich), mp. 155-1s7°c.

Ext lo ;( ;,4-ﬁiamin0—5-_‘~fV‘ ':~‘~i' ¢~3‘:wv"v"-mat‘.‘.»rih::'u~ This compound was prepared in a similar manner to the compound of Example 54 by reaction of the diazonium salt with cuprous bromine. mp. 212-216°C.

Exggglc 81 .2 .-’~_-D.LaL"-_Ln.o - 5~ ( Z-_c.h.l_c2 -:9 - 5_~_Le§«:L>b1:_sx1.).:.6;:mLb.xLnxzj_nLi.¢ :1 .02 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.

EIESEJI 82 2,4-Diamino:E~Lhloiq~Sgggrunfygli}-E—nwttying.imgding This compound was prepared in a similar manner to the compound of Example 54 by reaction of the diazonium salt with cuprous cyanide, mp. 239-241°C.

IE 970474 Exgggic §§ V J D:jmiFC"5-[?-‘N""Q;E—;]Ju"0yTgf:j)jG'jf£h)}§UF* . . ... . ..:e:%e:7n:; This compound was prepared in a similar manner to the compound of salt, mg.

Exampie 54 by way of the diazonium tetrafluoroborate 195-197°C. 1-T1amiwc—ﬁvr,LV9:§:ﬂﬁlUE13"'"¥"*UEJ}f5‘W§TrXJf§F?WiiiQ£ This compound was prepared in a simiiar manner to the compound of Exampie 54 by reaction of the diazonium salt with methanethioi in the presence of copper powder, mp. 194-198°C.

Exggpil §§ 7»3¢’nc—44ﬁ—ﬁ‘fn¢ihy'§ﬁ;Q};§;j31ﬂicfchlgrqphgnviipyrimgdjng This compound was prepared from the compound of Exampie 32.4 by reaction with methanethioi sodium salt in methanoi in the presence of tris[2-(2—methoxyethoxy)ethy1]amine and copper 164-165°C. powder, mp.

Exggglo 35 244-Eia@igg;3;(?—chlore-i—@e}naqg§yippgggjgpgngphengl}¢5~meth1l pyrimidine This compound was prepared from 2,4-diamino(2-chIoroaminophenyi) methyipyrimidine from Example 54 by with methanesuiphonylchioride in pyridine, mp. 234-240°C. reaction IE 970474 . 53 - Exggplu Q2 1 A '. .z,. ‘ ~ ~ 4' v..

W. ‘V . VV , rneﬁ!}i-].w§j@j‘: hium iﬂﬁlﬁﬁ This compound was prepared from the compound of Example 21 and methyl iodide, mp. 280-284°C. x n 88 2-Aminomethvlamino(2.3-dichlorophenvl)Dvrimidine 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.

Exglo ﬁg 2-_Nrn’.t~9 :"«_:1iw_.t.f:_v_1.r‘s.rI1_i 0:9 r_,5.: .( 2-1;: dJ,c.ﬂ9:0_t2D'.2 nu LLv.r_i.m_€._d i 0_e.h y'_c?1:-;-.-it l:v.‘_i 1.6 This compound was prepared in an analogous manner to the compound of Example 218.9 by reaction with dimethylamine in ethanol and subsequent conversion to the hydrochloride salt, mp. 295-300°C.

Exglo gg Ii ,'. .. . .' /j', . ,,'-. ' I w a _3V- , -5.,» ' .‘_ ‘yvtM,i ;u'in.H:ry Ifw 1§%mJ5ujvNK to he compound of mp. 215-216°C.

;"’N*H»w‘ir.cn aualviwus Wwmhﬂ Example 21B.f. from 5-(2.4-dichlorophenyl)isocytosine, Exggglo 31 g:Aminomethv1amjno(3.4-dighlorophenvllpvrimidine This compound was prepared from the compound of Examplg_90 by reaction with methylamine in ethanol, mp. 189-90°C.

IE 970474 .. .

Exglo 92' 7-1‘n~*I;‘ul1%.-F—(2_5-JTCh7nIn:'='u'Tpy'imiHinw h.d 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.

Q-AminoDlDPrIﬂ1ﬂ0-f‘7. 4 )‘inl~'u£'¢Wu‘1W." m=3ih~ V»T'H-’:t'2J* This compound was prepared from the compound of Example 90 by reaction with piperidine in ethanol and subsequent conversation to the hydrochloride salt, mp. 303°C (dec). _ ,0 _ IE 970474 Prefefred among the compounds of formula (I) are the pyrimidines of the foregoing Examples 1,2,3,4.l4 and 16, together with ealts (in particular, pharmaceutically acceptable salts) thereof; these bases have the following respective two—dimensional structures.

Exalplo 1 l ‘I’ _./N ;:f‘_// K-1 ‘‘ Mi:':‘ ‘\_r? ‘I \., ‘M? [nails 2 T'-...¢-.<"‘-7..-"**=j -" I n ._ V 1" Extlpll 3 ‘7 ll‘ ."/ L ' Enmh 4 Exaqah 14 Enmh 16 IE 970474 IE 970474 mu gr 1H um: um (§) EXAMPLE no. SOLVENT ASSIEIIEIT coc13 7.56(d,1H), 7.18(d,1H), 4.55-4.50 (br.s,2H), 3.88(t,4H), 2.5(t,4H), 2.36(s,3H) DMS0-d6 3.06(s,3H,-OMe), 3.3(d,1H,J12.BHz, *uMqOHe3, 3.9’JJih,J1Z.5H7,-CH:QHe), L '".'. .98(br.S,2H.-HH2), 6.](br.S,2F,-VH3), 7.32(d,lH,JE.Fm‘z,6‘—H), '/.78(-:.‘,1H, ‘0 J2.5Hz,4'-H) 3 DMS0-d6 7.8(d,1H), 7.65(s,1H), 7.36(d,1H), 6.33-6.23(brs,2H), 3.68(t,4H), 2.32(t,4H), 2.2(s,3H) . DMSO—d6 6.40(s,2H), 6.55(s,2H), 7.35(s,1H), 7.80(s.1H) nmso-as 8.6(s,1H), 7.49(s,lH), 6.4-6.3(br.s,2H), 6.25—6.15{br.s,2H) DMS0-d6 1.70(s,3H), 5.75(s,2H), 5.90(s,2H), 7.3D(s,1H), 7.75(s,1H) 7 CDC13 7.55(d.1H), 7.l8(d,1H), 4.75-4.58 (br.s,2H), 3.9-3.7(m,8H) 3 CDCI3 7.55(d,1H), 7.18(d.1H),_§;56-4.50 (br.s,2H), 3.2(s.6H) DMSO-d6 OHSO-d6 CDC13 DMSO-d CDC13 DMSO d6 DHSO-d DMSO-d DMS0-d6 DMS0-d6 IE 970474 7.79(d,1H), 7.67(s,lH), 7.36(d,1H), 6.47-6.27(br.s,2H), 3.72-3.57(m,8H) 7.78(d,1H), 7.64(S,1H), 7.35(d,1H). 3.08(s,6H) 7.5l(d,1H), 7.l7(d,1H), 4.40-4.22 (br.s,2H), 3.32(t,4H), 2.48(t,4H), 2.34(s,3H), 2.0(s,3H) 8.28(s,1H), 6.18-6.04(br.d,4H), 2.1(s,3H) 7.51(d,1H), 7.18(d,1H), 4.36-4.22 (br.s.2H), 3.16(s,6H), 2.0(s,3H) 6.10(s,2H), 6.45(s,2H), 7.15(d,1H), 7.30(t,1H), 7.55(d,lH) 1.70(s,3H), 5.60(s,2H), 5.BO(s,2H), 7.15(d,1H), 7.30(t,1H), 7.55(d)1H) 3.04(s,3H,-OMe),3.76(d,1H,J12Hz,-Cﬁ20Me) 3.85(d,1H,JI2Hz,-OCﬂ20Me), 5.84 (br.s,2H,-NH2), 6.O5(br.s,2H,-NH2), 7.22(dd,1H,J7.5,1.5Hz,6'-H). 7.38 (dd,1H,J7.5Hz,5'~H), 7.6(dd,1H,J7.5, 1.5Hz,4'-H) 7.3-8.0(m,8H), 6.0-6.1(br.s,2H), .2-5.4(br.s,2H) 4.75(2xdd,2H.J47.15Hz,-Cﬂ2F), .95(br.s,2H,-NH2), 6.15(pr.s,2H,-NH2), 7.25(dd,1H,J7.5, 1.0Hz,6'-H), 7.39 DMSO-d6 DMSO-d6 DMSO-d DMS0-d6 DMS0-d6 DMS0-d6 DHS0-d6 CDC1 IE 970474 (dd,1H,J7.5Hz). 7.64(dd,1H, J7.5, 1.0Hz) 43(d,1H,J11Hz), 4.53(d,1H,J11Hz), 95(br.s,2H). 6.12(br.s,2H), 7(m,2H), 6.85(dd,1H,J7Hz), 1-7.4(m,4H), 7.55(dd,lH,J7,lHz). 4(d,1H,J12Hz.-Cﬂ20Ph), 4.52(d,1H, J12Hz, -Cﬂ20Ph), 5.92(br.s,2H,-NH2), 1.0Hz,6'-H), 6.85(dd,lH,J7.5Hz,5'-H), l.0Hz,4'-H) 12(br.s.2H, -NH2), 6.69(dd,1H,J7.S, -7.35 (m.5H.-0Ph), 7.55(dd,1H,J7.5, 7.52(s,1H), 7.15-7.75(m,3H), 6.O2(br.s,4H,2x-NH2) .07(s.2H), 6.25(s,2H), 7.25(d,1H), .45(d,lH), 7.63(s.1H) .88(d,lH.J11Hz), 4.0(d,1H,Jl1Hz), .3(s,2H), 5.9(br.s,2H), 6.1(br.s,2H), .05-7.2(m,2H), 7.2-7.35(m,4H), .4(dd,IH,J8,2.5Hz), 7.62(d,1H,J2.5Hz) .25(s,2H), 6.50(s,2H), 7.30(s,1H), .40(d,1H), 7.50(d,1H) .85(s,2H), 6.1(s,2H), 7.25(s,1H), 7.45(s,1H), 7.7(s,1H) 53-7.12(m,4H), 4.48-4.30(br.s,2H), B1(t.4H), 2.#6(t,4H), 2.33(s,3H), 2.03(s,3H) IE 970474 32 CDC13 .38(d,1H), 7.2(dd,1H), 7.08(d;1H), .2(br.s,2H) .7(d,1H), 7.48(dd,1H), 7.29(d,1H), .45(br.s,2H), 6.2(br.s,2H) 33 DMSO-d6 .5(d.1H), 7.35(dd,1H), 7.18(d,lH), .25(br.s,2H), 2.44(s,3H) 34 CDC13 CDC1 .52(d.1H), 7.32(dd,1H), 7.21(d,1H), .08(br.s,2H), 4.66(br.s,2H), 2.42(s,34) 36 DMS0-d6 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(dd,1H, J1.5Hz,4'-H) 56 DMS0-d6 7.58(dd,1H), 7.45(dd,1H), 7.35(d,1H). 7.24(br.s,1H), 3.35(br.s,2H), 3.96(br.s,2H) ‘;/‘ ‘ "L: C‘? 1'8(sI3H)l 5'8(Sl2H)l 7.53(s,1H), 7.92(s.1H) 58 DMSO-d6 7.78(d,1H). 7.59(s,1H), 7.36(d,1H), 6.60-6.47(br.t,1H), 6.25-6.03(br.s,2H), 3.25(q,2H), 1.l(t,3H) In the foregoing, the signals have been abbreviated as fo11ows: s - sing1et; d = doubiet; dd = doublet of doublets; t - t?ip1et; q - quadrup1et; m = mu]tip1et; br.s = broad singlet; br.t - broad trip1et.

IE 970474 Pharmacoloaical Activitv 31%"-.1-’.‘j.'»_*'~n of :3l,ut_zw:e,U: r;'.*‘&:-wt‘ .:-M 1'}’lJ.5.‘$l1~‘_0-.3l7:.-Eé.§-_L.{L-1:: Compounds of Formula (I) were tested for their effect on evoked 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. veratrine- The results are given in Table 1, the IC50 being the concentration of compound to cause 50% inhibition of (a) veratrine—evoked release of glutamate and (b) of DHFR enzyme activity. caupouna Icsobsl) Ic5o(,.n) of Glutamate Releeee let Liver DHFR Exelple lo (P95 liuits) (P95 lilits) 1 1.18 (0.50-2.60) >100 2 0.56 (0.23-1.37) 33 (27.00-40.00) 3 2.15 (0.90-5.10) >100 4 0.33 (0.196-0.566) >30<100 3.50 (1.10-10.40) §g;100 6 0.70 (0.40-1.50) 0.51 (0.36-0.73) 7 <10 00 >10.0 8 <10.00 >10.0 9 <10.00 >100.00 <10.00 >100.00 11 4.80 (2.30-10.20) >100.00 12 <10.00 >100.00 13 <10 >100.00 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) §§;3.00 gg;10.00 4.6(1.60-13.30) 1.57(0.94-2.62) IE 970474 >1oo.oo 3.7 (5.2-14.7) >100 4.9 (3.90-6.20) gg;10O >1oo.oo 17.5o(9.eo-31.40) 16.01(12.05-21.282) 23.3oo(9.oo-51.00) 2o.94o(9.ob-61.00) .1o(11.oo-20.70) >1oo.oo c10.00 >1oo.oo 4s.1o(14.3o-143.90) 0.53(O.348-0.812) IE 970474 Toxicolggiéal Exggplc The compound of Example 1 has been administered intravenously to groups of six male and six female Histar 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. _F?.tLe.sr:-.'e_c3u.t.1c_.-.1 F °"l_1B't.,LD .fz.L-p_L-.

Tablet: INGREDIENT ——j-.-_—j-— A: Compound of Example 1 150 mg i Lactose 200 mg 3 Maize Starch 50 mg 7 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 IE 970474 _ 79 _ were dried, mixed with magnesium stearate and compressed to give tablets.

E: INJECTION £1! The salt of the compound of Formula I was dissolved in sterila water for injection.

INTRAVENOUS INJECTION FORMULATION (11) 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 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.

IE 970474 _ 30 _ mgzcagsule (a) Active ingredient 250 (b) Lactose B.P. 143 (c) Sodium Starch Glycollate 25 (d) Magnesium Stearate __g mgzcagsule (a) Active ingredient 250 (b) Macrogel 4000 BP ggg 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. mg[capsule (a) Active ingredient 250 (b) Microcrystalline Cellulose 125 (c) Lactose BP 125 (d) Ethyl Cellulose _;g The controlled-release capsule formulation may be prepared by extruding mixed ingredients (a) to (C) using an extruder, then spheronising and IE 970474 drying the extrudate. The dried pellets are coated with ethyl cellulose (d) as a controlled-release membrane and filled into two-part hard gelatin capsules.

Syrup 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 mi 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.

Suppository formulation mg[sugoository Active ingredient (63pm)* 250 Hard Fat, BP (Hitepsol H15 - Dynamit Nobel) 1770 * The active ingredient is used as a powder wherein at least 90% of the particles are of 63pm diameter or less.

IE 970474 One-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 suitabie plastic moulds and the suppositories allowed to cool to room temperature.

IE 970474 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 1, R1 and R2 are the same or different and are selected from hydrogen, halo, hydroxy, alkoxy, alkyl. 1R11 1 and R11 are alkylthio and a group NR where R 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; R3 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(0)nalkyl, di(alkyloxy)alkyl, -C(R):NOH or -COR or —C02R wherein R is hydrogen or alkyl, or a group CHZX where X is _NR1R11 hydroxy, alkoxy, aryloxy, arylalkyloxy, halo, cyano, wherein R and R11 are as IE 970474 defined above, 5(0)"-alkyl where n is 1 or 2, or SO2N(Rl11) 2 where R is selected from hydrogen and alkyl; each of R4 to R8 are the same or different and each is selected from hydrogen, halo, alkyl, perhaloalkyl, cyano, carbamoyl, carboxy, COR, nitro, amino, alkylsulphonylamino, alkoxy, S(0)n-alkyl where n is 1 or 2, or SO2N{R111 )2; or R4 and R5 or R5 and R6 together are the group -CH=CH-CH=CH- or the group -CH2—CH2-CH2-CH2— in which case both R7 and R8 are hydrogen; and optionally one of the nitrogen atoms in the pyrimidine ring may be ﬂ alkylated or optionally may be an E 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.

Use of a compound as claimed in claim 1 wherein one of R1 and R2 is amino, and the other is selected from amino, hydroxy, halo, morpholino, piperazinyl, Q-alkylpiperazinyl, ﬂ,ﬂ—dialkylamino, Q-alkylamino or alkylthio; R3 is alkyl optionally substituted by one or more halo radicals, or is alkyl, alkylthio, hydrogen, hydroxy, alkoxy, halo, carboxy, carbamoyl, or a group CHZX where X is hydroxy, phenoxy, benzyloxy, alkoxy or alkylthio; one of R4 and R5 is halo and the other is seiected from halo or hydrogen; R6 is halo, hydrogen, nitro or amino; R7 is hydrogen, halo, cyano, alkylthio, SO2N(R11l)2, alkyJ, nitro, amino or methanesulphonamido; and 6.

IE 970474 R8 is hydrogen or halo.

Use of a compound as claimed in claims 1 or 2 wherein R1 is hydroxy, amino, ﬂ-alkylamino, ﬁ,ﬂ-dialkylamino, morpholino, piperazinyl, ﬂ-alkylpiperazinyl.

Use of a compound as claimed in any one of claims 1 to 3 wherein R2 is chloro, amino, ﬂhﬂ-dialkylamino, or piperidino.

Use of a compound as claimed in any one of claims I to 4 wherein R3 is hydrogen, alkyl, methoxymethyl, trifluoromethyl, benzyloxymethyl, phenoxymethyl or methylthiomethyl.

Use of a compound as claimed in claims 1 or 2 wherein one of R1 and R2 is amino and the other is amino, piperazinyl or ﬂrmethylpiperazinyl, ﬂ-alkylamino, ﬁgﬂgdialkylamino and R3 is hydrogen, methyl, trifluoromethyl or methoxymethyl.

Use of a compound as claimed in claim 1 wherein R1 is selected from amino, piperazinyl, 3-methylpiperazinyl, ﬂ¢morpholino, ﬂ,ﬂ:dimethylamino, and ﬁgethylamino; R2 is amino; R3 is selected from trifluoromethyl, hydrogen, methyl, benzyloxymethyl, methoxymethyl and methylthiomethyl: R4 is chloro; and at least one of R5, R6 and R7 is chloro, and the remainder are selected from hydrogen, chloro and nitro; and IE 970474 R8 is hydrogen or R4 and R8 are both hydrogen, R5 and R7 are both chloro and R6 is selected from hydrogen, chloro and nitro.

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 R1 to R8 are as defined in claim 1 with the proviso that when 7 is halo, then R3 is hydrogen, perhaloalkyl, methyl or methoxymethyl and/or R6 is nitro and/or 1 is ﬂgalkylpiperazinyl, morpholino, ﬂ, ﬂ-dimethylamino, piperazinyl or ﬂ¢ethylamino; or with the proviso that when R6 is chloro then R4 is halo, and R3 is hydrogen, perhaloalkyl, methoxymethyl, methyl or halo and/or R1 is ﬂymethylpiperazinyl, piperazinyl, morpholino or ﬂ,ﬂ- dimethylamino, or ﬂyethylamino.

A compound or acid addition salt thereof of Formula I as defined in claim 1 with the proviso that at least one of R4 to R8 is other than hydrogen, and further with the proviso that when R1 and R2 are both amino, or when R1 is hydroxy and R2 is amino, and R3 is alkyl or hydrogen, and R7 is hydrogen, then R4 and R5 are both halo.

IE 970474 -87, A compound or acid addition salt thereof of Formula I wherein R to R and R8 are as defined in claim 1 and R7 is halo, alkyl, perhaloalkyl, cyano, nitro, amino, alkylthio, S(O)n~alkyl or S02N(R111)2.

A compound or acid addition salt of formula I wherein R2 to R8 are as defined in claim 1 and R1 is morpholino, piperazinyl, ﬂ-alkylpiperazinyl, ﬁJﬂ-dialkylamino, ﬁgalkylamino or alkylthio.

A compound or acid addition salt of formula I wherein R1 and R2 are as defined in claim 1 and R3 is alkoxy, alkylthio or alkyl substituted by one or more halo radicals, or is a group CHZX where X is alkylthio, aryloxy, arylalkyloxy, alkyloxy or hydroxy; R4 to R6 are the same or different and are each selected from hydrogen, halo, perhaloalkyl, cyano, nitro, amino or alkylthio; R7 is halo, alkyl, 111) perhaloalkyl, cyano, nitro, amino, or a group S02N(R R8 is hydrogen or halo. 2 wherein R is alkyl; and A compound or acid addition salt of formula I wherein R1, R R 21 R4: 51 R5, R7 and R8 are as defined in claim 1 and R3 is alkoxy, aryloxy, arylalkyloxy or alkylthio. 4-Amino(4—methylpiperazin-I-yl)(2,3,5—trichlorophenyl) trifluoromethyl or acid addition salt. 2,4—Diamino—5—(2,3,5-trichlorophenyl)-6—methoxymethylpyrimidine or acid addition salt.

IE 970474 4-Amino(4-methylpipgraziny1)(2.3,5—trichIoropheny1) pyrimidine dr acid addition salt. 2,4-Diamino~5-(2,3,S—trich1oropheny1)trifluoromethylpyrimidine or acid addition salt. 2,4-Diamino(4—nitro-2,3,5-trichlorophenyi)pyrimidine 2,4—Diamino-S-(2,3,5-trichlorophenyi)—6-methy1pyrimidine 4-Aminoﬂ-morpholino-5—(2,3,5—trich1orophenyl)trif1uoro- methyipyrimidine 4—Aminoﬂ,ﬂ-dimethylamino(2,3,5-trichlorophenyl)—6- trifiuoromethylpyrimidine 4-Aminomorpho]ino-ﬂ-5—(2,3,5-trichiorophenyi)pyrimidine 4-Aminoﬂ,ﬂ-dimethyiamino-5—(2,3,5-trich1oropheny1)pyrimidine 4—Amin0methyl(4-methylpiperaziny1)—5-(2,3,5-trich1oro— phenyI)pyrimidine 2,4-Diamino(2,3-dichlorophenyl)—6-trifluoromethylpyrimidine 2,4-Diamino(2.3-dich1oropheny1)-6—methy1pyrimidine 2,4-Diamino(2,3-dichiorophenyl)methoxymethyipyrimidine 2,4—Diamino(2,4-dich1orophenyI)-6—trif1uoromethyipyrimidine 6-Benzy]oxymethy]—2,4-diamino—5—(2,4—dichIoropheny1)pyrimidine 2—N—methy1piperaziny1amino-5—(2,4-dichiorophenyi)pyrimidine 2,4-Diamino(2,5-dich1oropheny1)—6—trifluoromethylpyrimidine 2,4-Diamino—5-(2.3.5-trichiorophenyi)pyrimidine I 4-Amino-5—(3,5—dich1oropheny])methy1(4-methy1piperazin y1)pyrimidine 4-Aminoﬁyethylamino(2,3,5—trich1oropheny1)pyrimidine IE 970474 _ _ 4-Amino~2—ﬁ—methylamino—S—(2,3.5-trichlorophenyl)pyrimidine or an acid addition salt thereof.

A pharmaceutical formulation comprising a compound according to any one of claims 9 to 18 together with one or more acceptable carriers 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 QB wherein R3 to R8 are as hereinbefore defined, L is a leaving group, and Y is cyano or carboxy, carbonyl, or alkoxycarbonyl with a compound of formula III xi III wherein R1 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.

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

A method of treatment or prevention of a CNS disorder or disease of a mammal, including man, comprising administering to the mammal a non- toxic effective amount of a compound of Formula I as hereinbefore defined or an acid addition salt therof.

A method of treating a mammal predisposed to or having neurotoxic extracellular glutamate levels of the central nervous system comprising the administration to a mamnal of a non-toxic effective amount of a compound of Formula I as hereinbefore defined or an acid addition salt thereof.

A use substantially as hereinbefore described with reference to the Examples.

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

A composition substantially as hereinbefore described with reference to the Examples.

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

A method substantially as hereinbefore described with reference to the Examples.

CRUICKSHANK & C0.,