AMINOPYRIMIDINONE DERIVATIVES AS HISTAMINE H2-ANTAGONISTS

Abstract: Compounds of the formula (I): and their salts are histamine H₂-antagonists, wherein: R⁰ is 2-­ guanidinothiazol-4-yl or a group R¹R²N(CH₂) n Z- wherein R¹ and R² are hydrogen or various substituted alkyl groups or are joined together to form a ring; n ist 1 to 6; Z is 2,5-furanyl, 2,5-thienyl, 2,4-­ pyridyl (wherein R¹R²N(CH₂) n - is at position 4), 2,4-thiazolyl (wherein R¹R²N(CH₂) n is at position 2) or 1,3-or 1,4-phenylene; m is zero or one; Y is a bond, oxygen, sulphur or methylene; p is 2 to 4; q is zero or one; R³ is hydrogen or C₁₋₆ alkyl; and R⁴ is hydrogen or C₁₋₆alkanoyl. Pharmaceutical compositions containing them are de­ scribed as are processes for their preparation and intermediates therefor.

Description: CHEMICAL COMPOUNDS This invention relates to aminopyrimidinone derivatives, pharmaceutical compositions containing them, their use as histamine H2-antagonists, processes for their preparation and intermediates therefor. Histamine, a physiologically active compound endogenous in'mammals, exerts its action by interacting with certain sites called receptors. One type of receptor is known as a histamine H1-receptor (Ash and Schild, Brit. J. Pharmac. Chemother. 27 427 (1966)) and the actions of histamine mediated through these receptors are blocked by drugs commonly called "antihistamines" (histamine H1-antagonists) a common example of which is mepyramine. A second type of histamine receptor is known as the H2-receptor (Black et al. Nature 1972, 236, 385). These receptors are not blocked by mepyramine but are blocked by burimamide. Compounds which block these histamine H2-receptors are called histamine H2antagonists. Histamine H2 -antagonists are useful in treating disease conditions caused by the biological effects of histamine mediated through H2-receptors, for example, as inhibitors of gastric acid secretion, in the treatment of inflammation mediated through histamine H2-receptors and as agents which act on the cardiovascular system, for example, as inhibitors of effects of histamine on blood pressure mediated through histamine H2-receptors. Cimetidine is an example of a histamine H2antagonist. Cimetidine has been shown to be useful in the treatment of duodenal, gastric, recurrent and stomal ulceration, and reflux oesophagitis and in the management of patients who are at high risk from haemorrhage of the upper gastrointestinal tract. In some physiological conditions the biological actions of histamine are mediated through both histamine H1- and H2-receptors and blockade of both types of receptors is useful. These conditions include inflammation mediated by histamine, for example skin inflammation, and those hypersensitivity responses due to the action of histamine at H1- and H2-receptors, for example allergies. In the histamine H2 -antagonist art there have been a large number. of applications directed to compounds comprising a pyrimidinone ring substituted in the 5position. Such applications include British Specifications 1582527, 1595291 and 2030979, and EP-A-3677, 10894, 13071, 15138 and 49173. Despite the interest shown in such compounds there has never been any suggestion of the 5-substituent being an amino or alkanoylamino group. Japanese Patent Application Nos 55-115877 and 55-115860 disclose compounds of the formulae EMI2.1 wherein A7 is nitrogen or methine (=CH-); A5 and A6 are the same or different and are oxygen or sulphur; A1 is hydrogen, lower alkyl, substituted or unsubstituted amino(lower)alkyl or cycloalkylamino(lower)alkyl optionally interrupted with oxygen; A2 is hydrogen or lower alkyl; a and b are each 1 to 3; c is 0 to 2; d is 1 to 4; A8 is substituted or unsubstituted amidino, substituted or unsubstituted guanidino, biguanidino, hydrazino or a group of the formula : RaRbN-Alk- wherein Alk is straight or branched chain lower alkylene and Ra and Rb are the same or different and are hydrogen or lower alkyl or Ra and Rb together with the nitrogen atom may form a heterocyclic group optionally containing an oxygen atom; A3 and A4 represent a wide variety of substituents and inter alia can together with the carbon atom and the nitrogen atoms bonded thereto form an optionally substituted 5- or 6-membered heterocyclic group. However there is no suggestion in either application of amino or alkanoylamino being a substituent for any such heterocyclic ring, and no suggestion that pyrimidinone is a favoured ring system. A small group of compounds has now been invented, which have a 5-amino or 5-alkanoylamino substituent on a pyrimidin-4-one ring and have a particularly favourable level of activity and duration as H2-antagonists. Accordingly the present invention provides a compound of the formula (I) EMI3.1 or a salt thereof, wherein: RO is 2-guanidinothiazol-4-yl or a group R1R2N (CH2) -Z- 2n wherein: R1 and R2 are independently hydrogen, C1 6alkyl, aryl(Cl 6)alkyl, heteroaryl (C16)alkyl, C3-10 cycloalkyl, hydroxy(C2¯6)alkyl, or halo (C26)- alkyl (wherein said hydroxy and halo groups are not substituted on the carbon atom adjacent to the nitrogen atom); or R1 and R2 together represent - (CH2) q - wherein q is 4 to 7, to form together with the nitrogen atom to which they are attached a 5-8 membered saturated ring; n is an integer from 1 to 6; Z is 2,5-furanyl, 2,5-thienyl, 2,4-pyridyl wherein the R1R2N(CH2)n group is in the 4-position, 2,4 R12 thiazolyl wherein the R N(CH2) n group is in the 2-position, or 1,3- or 1,4-phenylene; m is one; or if Z is pyridyl or phenylene m may also be zero; Y is oxygen, sulphur or methylene; or if Z is furanyl, thienyl or thiazolyl Y may also be a bond; p is two, three or four; q is zero or one; R3 is hydrogen or C1 6alkyl; and R4 is hydrogen or Cl¯6alkanoyl. The compounds of this invention are preferably provided in a form suitable for pharmaceutical use as a compound of the formula (I) or a pharmaceutically acceptable salt thereof. When used herein 'alkyl' means groups that are either straight-chained or branched. In general preferred alkyl groups are methyl and ethyl. In one aspect of this invention R0 is a group R1R2N(CH2)n -Z- as herein defined. Suitably R1 is aryl(C16)alkyl for example benzyl or phenethyl, heteroaryl(C1¯6)alky1 for example furanyl (C16)alkyl such as furanylmethyl or thienyl(Cl 6)alkyl such as thienylmethyl, halo(C2¯6)alkyl for example 2,2,2-trifluoroethyl, or C31 cycloalkyl for example cyclohexyl. More suitably R is C1 6alkyl, for example methyl, ethyl or propyl. Suitably R2 is hydrogen or Ci 6alkyl, for example methyl, ethyl or propyl. Suitably R1 and R2 have the same value, for example they both are methyl or they are both ethyl. In another suitable aspect R1 and R2 together with the nitrogen atom to which they are attached form a pyrrolidino, piperidino or hexahydroazepino ring, preferably a piperidino ring. Preferably n is one. Suitably Z is 2,5-furanyl or 2,5-thienyl. In such compounds preferably Y is sulphur. For example R1RêN(CH2)n-Z-(CH2)m-Y may represent 5-dimethylaminomethylfuran-2-ylmethylthio, 5-piperidinomethylfuran-2-ylmethylthio or 5-pyrrolidinomethylfuran-2-ylmethylthio. In another aspect Z is 2,4-thiazolyl. In such compounds preferably Y is sulphur, for example R1R2N(CH2)nZ(CH2)m -Y- may represent 2-dimethylaminomethylthiazol-4-ylmethylthio. In a further aspect R0 is 2-guanidinothiazol-4-yl, in such compounds preferably Y is sulphur, for example R0-(CH2)m-Y- may represent 2-guanidinothiazol-4-ylmethylthio. In a preferred aspect Z is 2,4-pyridyl. In an alternative preferred aspect Z is 1,3-phenylene. In each type of compound preferably -(CH2) Y-(CH2)P- is -O-(CH2)3- or -CH2SCH2CH2-. For example R1ff2N:2) -Z- (CH;) -Y-(CHZ) may represent: 4-dimethylaminomethylpyrid-2-ylmethylthioethyl, 4-piperidinomethylpyrid-2-ylmethylthioethyl, 4-dimethylaminomethylpyr id-2-yloxypropyl, 4-piperidinomethylpyrid-2-yloxypropyl, 3-dimethylaminomethylphenoxypropyl, 3-piperidinomethylphenoxypropyl, 3-dimethylaminomethylphenylmethylthioethyl or 3-piperidinomethylphenylmethylthioethyl. Preferably p is 3 when m is zero. Preferably p is 2 when m is one. Suitably q is zero. Suitably q is one. Suitably R3 is C16 alkyl for example methyl. Preferably R3 is hydrogen. Suitably R4 is C16 alkanoyl for example formyl, acetyl or propionyl. Preferably R is hydrogen. In a favoured aspect the present invention provides compounds of the formula (I) wherein R1R2N(CH2)n is dimethylaminomethyl or piperidinomethyl, Z is 1,3-phenylene, m is zero, Y is oxygen, p is 3, q is zero or one, and R3 and R4 are both hydrogen. The compounds of the formula (I), are shown and described as 4-pyrimidinone derivatives and these derivatives exist in equilibrium with the corresponding 6-pyrimidinone tautomers. These compounds also exist to a lesser extent as the hydroxy tautomers and the pyrimidinone ring, when q is one, may also exist in the following tautomeric forms EMI7.1 The activity of the compounds of formula (I) as histamine H2-antagonists can be demonstrated by their ability to inhibit histamine-stimulated secretion of gastric acid from the lumen-perfused stomachs of rats anaesthetised with urethane, and to reverse histamineinduced inhibition of contractions of the isolated rat uterus. These are actions of histamine which, according to Ash and Schild, Brit. J. Pharmac. Chemother. 27 247 (1966), are not mediated by histamine H1-receptors. The histamine H2 -antagonist activity of the compounds can also be demonstrated by the inhibition of histamine-stimulated acid secretion in the Heidenhain Pouch Dog, the inhibition of histamine-induced tachycardia in the isolated guinea pig right atrium and the inhibition of histamine-induced vasodilatation in the anaesthetised cat. The measurement of inhibition of histamine-stimulated secretion of gastric acid from the lumen-perfused stomachs of rats anaesthetised with urethane, and the measurement of inhibition of histamine-induced tachycardia in the isolated guinea pig right atrium, are detailed in European Patent Application Publication No 0049173. To illustrate the level of activity of the compounds of the invention we have determined that the products of the Examples, where tested, have ED50 values in the lumen-perfused rat test of less than 0.1 micromol kg i.v. and pA2 values in the guinea pig atrium test of more than six. The product of Example 2 also showed a longer duration of activity than cimetidine after intravenous administration in the Heidenhain pouch dog when dose levels had been adjusted to produce similar peak resonses. In addition this compound showed a significant increase in activity compared to a related compound wherein NHR4 is replaced by H, i.e. 2-[3-(3 (piperidinomethyl)phenoxy)propyl]pyrimidin-4-one. In order to use the compounds of the formula (I) or pharmaceutically acceptable salts thereof for medical purposes, they are normally formulated in accordance with standard pharmaceutical practice as pharmaceutical compositions. The invention further provides pharmaceutical compositions comprising a compound of the formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. The compounds of the formula (I) and their pharmaceutically acceptable salts may be administered, for example, orally, parenterally, cutaneously or rectally. The compounds of the formula (I) and their pharmaceutically acceptable salts which are active when given orally can be formulated as syrups, tablets, capsules and lozenges. A syrup formulation will generally consist of a suspension or solution of the - compound or pharmaceutically acceptable salt in a suitable liquid carrier for example, ethanol, glycerine or water with a flavouring or colouring agent. Where the composition is in the form of a tablet, any suitable pharmaceutical carrier routinely used for preparing solid formulations may be used. Examples of such carriers include magnesium stearate, starch, lactose, sucrose and cellulose. Typical parenteral compositions consist of a solution or suspension of the compound or pharmaceutically acceptable salt in a sterile aqueous carrier or parenterally acceptable oil. Typical compositions for administration to the skin include lotions and creams in which the compound of the formula (I) or pharmaceutically acceptable salt thereof is contained in a liquid vehicle. A typical suppository formulation comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof which is active when administered in this way, with a binding and/or lubricating agent such as gelatin or cocoa butter or other low melting vegetable waxes or fats. Preferably the composition is in unit dose form such as a tablet or capsule. Each dosage unit for oral administration contains preferably from 15 to 250 mg (and for parenteral administration contains preferably from 0.5 to 25 mg) of a compound of the formula (I) or a pharmaceutically acceptable salt thereof calculated as the free base. The invention also provides a method of blocking histamine H2 receptors which comprises administering to an animal an effective amount to block said receptors of a compound of the formula (I) or a pharmaceutically acceptable salt thereof. The pharmaceutically acceptable compounds of the invention will normally be administered to a subject for the treatment of peptic ulcers and other conditions caused or exacerbated by gastric acidity in the same general manner as that employed for known histamine H2-antagonists, due allowance being made in terms of dose levels for the potency of the compound of the present invention relative to known histamine H2antagonists. The daily dosage regimen for example for an adult patient may be an oral dose of between 15 mg and 1000 mg, preferably between 20 mg and 250 mg, or an intravenous, subcutaneous, or intramuscular dose of between 0.5 mg and 100 mg, preferably between 1 mg and. 20 mg, of the compound of the formula (I) or a pharmaceutically acceptable salt thereof calculated as the free base, the compound being administered 1 to 4 times per day. In a further aspect of this invention the compounds of the formula (I) and salts thereof may be prepared by a process which comprises a) for compounds of'the formula (I) wherein q is one, reacting a compound of the formula (II) with a compound of the formula (III) : R6(CH2) (CH2) pNH2 (Il) EMI10.1 wherein m, Y, p and R3 are as hereinbefore defined, R6 is a group R3 as hereinbefore defined or R6 is a furan-2-yl or thien-2-yl group; R5 is protected amino; and Q is a group displaceable by amine; or b) for compounds of the formula (I) wherein m is one and Y is sulphur, reacting a compound of the formula (IV) with a compound of the formula (V) R6-CH2-L (IV) EMI11.1 wherein R6, p, q and R3 are as hereinbefore defined, R51 is optionally protected amino and L is a moiety displaceable by thiol or chemical equivalent thereof; or c) for compounds of the formula (I) wherein m is one and Y is sulphur, reacting a compound of the formula (VI) or chemical equivalent thereof with a compound of the formula (VII): R6CH2SH (VI) EMI11.2 wherein R6, p, q, R51 and R3 are as hereinbefore defined and L1 is a moiety displaceable by thiol or chemical equivalent thereof; or d) reacting a compound of the formula (VIII) with a compound of the formula (I-X) or chemical equivalent thereof: EMI11.3 EMI12.1 wherein R6, m, Y, p, q, and R3 are as hereinbefore defined, R52 is protected amino and R7 is an ester-forming group; or e) for compounds of the formula (I) wherein Z is 2,4-pyridyl, m is zero and Y is oxygen, reacting a compound of the formula (X) with a compound of the formula (XI) or derivative thereof that permits reaction to occur: EMI12.2 wherein R1, Rê, n, p, q, R3 and R51 are as hereinbefore defined and L2 is a group displaceable by hydroxy or the equivalent thereof; or f) for compounds of the formula (I) wherein Z is phenylene, m is zero and Y is oxygen, reacting a compound of the formula (XII) or chemical equivalent thereof with a compound of the formula (XIII): EMI12.3 wherein R1, Rê, n, p, q, R3 and R51 are as hereinbefore defined and L3 is a moiety displaceable by phenol or chemical equivalent thereof; or g) for compounds of the formula (I) wherein R0 is R1RêN(CH2)n-Z-, converting a compound of the formula (XIV): EMI13.1 wherein Z, m, Y, p, q, R3 and R51 are as hereinbefore defined and R8 is a precursor of a group R1RêN(CH2)n- as hereinbefore defined; or h) for compounds of the formula (I) wherein q is one, reducing a compound of the formula (XV): EMI13.2 wherein m, Y, p, R3 and R51 are as hereinefore defined, R9 is a group R0 or R8-Z-as hereinbefore defined and R10 is a group -CH=N- or -CO-NH-; and thereafter where necessary i) reacting a compound wherein R6 is furan-2-yl or thien-2-yl with a Mannich reagent to form a compound of the formula (I) wherein n is one; ii) converting a protected amino group to amino or C16alkanoylamino; iii) optionally forming a salt. Suitably Q is nitroamino, C1¯6alkylthio, benzylthio, chloro or bromo. Of these methylthio is preferred. The reaction between a compound of the formula (II) and a compound of formula (III) can be performed, at an elevated temperature, in the absence of solvent or in the presence of a substantially inert polar solvent. When Q is methylthio the reaction may be performed for example in the.absence of solvent at 140D-1700C, or the reaction may be performed in a substantially inert solvent under reflux conditions, for example in a C1¯6alkanol, pyridine or anisole. Examples of the moiety L include chloro, bromd, hydroxy, C1¯6alkoxy for example methoxy, Cl¯6alkanoyloxy for example acetoxy, arylsulphonyloxy for example 4-methylbenzenesulphonyloxy, or Cl¯alkylsulphonyloxy for example methanesulphonyloxy. Preferably L is hydroxy in which case the reaction between the compounds of the formulae (IV) and (V) is performed under acidic conditions. When L is chloro or bromo it is preferable to perform the reaction in the presence of a strong base for example sodium ethoxide in ethanol. When L is an arylsulphonyloxy or alkylsulphonyloxy group the reaction is preferably performed under mildly basic conditions for example in pyridine solution. In the reaction of compounds of the formulae (IV) and (V), when carried out under basic conditions about one equivalent of base is used in order that a thiolate anion is preferentially formed on the HS(CH2) moiety. Suitably in the reaction of compounds of the formulae (VI) and (VII) L1is chloro, bromo, arylsulphonyloxy for example 4-methylbenzenesulphonyloxy or Cl¯6alkylsulphonyloxy for example methylsulphonyloxy. Such reactions are generally performed in the presence of a base for example triethylamine, an alkoxide or a hydroxide. The compound of the formula (IX) is depicted as a ketone or aldehyde, dependent on whether R3 is alkyl or hydrogen. This invention covers the reaction of chemical equivalents of such depicted compounds, as known in the art, for example protected or 'masked' aldehydes and ketones, for example an acetal. When it is desired to form a compound of the formula (I) wherein R3 is hydrogen, then for example a compound of the formula (VIII) may be reacted with a compound of the formula (IXA) and thereafter deprotecting if necessary: EMI15.1 wherein R7 and R51 are as hereinbefore defined and X is a displaceable group. For example X may be hydroxy (in which case the form depicted is tautomeric with formula (IX)) or a derivative thereof, so that for example X is protected hydroxy such as silyloxy, an acid residue RCO-O- (for example Cl¯6alkanoyloxy), or an ether forming residue (for example C16alkoxy such as methoxy or ethoxy). Additional examples for X include secondary and tertiary amino groups, for example di-C16alky1amino such as dimethylamino, cyclic amines such as piperidino, pyrrolidino and morpholino, anilino and l-imidazolyl. Preferably X is Cl¯6alkoxy and in particular ethoxy. In compounds of the formulae (IX) and (IXA) the ester-forming group R7 can be a Cl¯qalkyl group and is preferably methyl or ethyl. The reaction between the compounds of formulae (VIII) and (IX) or (IXA) is carried out in the presence of base. Examples of suitable bases include alkali metal hydroxides and C1 4alkoxides, sodium hydride, and quaternary ammonium hydroxides, for example benzyltrimethylammonium hydroxide. Preferably the base is sodium ethoxide or sodium methoxide. The reaction can be carried out in the presence of a solvent the choice of which is not critical to the success of the process provided that it is substantially inert to the reagents and product. Preferably the solvent is a C14alkanol, (for example, methanol, ethanol or propanol) or dimethylformamide. The reaction can be carried out at moderate temperatures, for example from room temperature to the reflux temperature of the solvent. Suitably in the compounds of the formula (X), L2 is chloro or bromo. The reaction of a compound of the formula (X) with a compound of the formula (XI) is generally performed under basic conditions, for example the anion of the compound of the formula (XI) may be generated, for example using sodium hydride in a suitable solvent. In the reaction between the compounds of the formulae (XII) and (XIII) suitably L3 is chloro or bromo. Suitably the reaction is performed under basic conditions, for example the anion of the compound of the formula (XII) may be generated, for example using sodium hydride. The reaction is performed in a suitable aprotic solvent for example dimethylformamide at a non-extreme temperature for example between OOC and 1000C, suitably between ambient and 700C. In the compounds of the formulae (XIV) and (XV) in one suitable aspect R8 is a group R1R2N(CH2) CO(CH2)y wherein x + y = n-l. Favourably x and y are both zero so that the group R1R2NCO- is a precursor to the group R1R2NCH2-. The conversion of such a group RlR2N(CH2)xCO(CH2)y¯ may be performed by reduction for example with a hydride for example lithium aluminium hydride. In an alternative aspect R8 is a group CHO-(CH2)n-1¯ which may be converted to a group R1R2N(CH2) n on reaction with an amine R1R2NH under conditions of reductive amination. Furthermore in another suitable aspect R8 may be a group HO(CH2)n which may be converted directly to R1R2N(CH2)n or indirectly thereto for example via a moiety such as Br(CH2)n and thence to R1RêN(CH2) -. Such transformations 2n may be caried out in conventional manner. The compounds of the formula (XV) may be reduced to form compounds of the formula (I) wherein q is one, for example using lithium aluminium hydride in an ether solvent when R is - CONH-; and for example using a borohydride in an alkanol, lithium aluminium hydride in an ether solvent, or catalytically hydrogenating when R10 is -CH=N-. A suitable protected amino group is nitro (-NO2) which may be converted to amino (-NH2) by reduction. Such nitro compounds are primarily of interest as intermediates, but also have H2-antagonist activity in their own right. One suitable method of reduction of the nitro compounds comprises catalytic hydrogenation in the presence of a suitable transition metal catalyst for example palladium or platinum. In one aspect hydrogen gas may be used over a palladium catalyst, suitably palladium on carbon, for example 10% palladium on carbon, in a suitable solvent such as a Cl¯6alkanol, in particular methanol or ethanol. In another aspect catalytic transfer hydrogenation may be employed, for example using cyclohexene and palladium on carbon, conveniently in a mixed solvent system, for example with a C 6alkanol such as methanol. Such catalytic transfer hydrogenation is normally performed at elevated temperatures, conveniently under conditions of reflux. In yet another suitable aspect a transition metal catalyst for example palladium on carbon or Raney nickel may be used in the presence of hydrazine (conveniently as the hydrate), suitably at elevated temperatures for example under reflux, in a C16 alkanol for example ethanol. Suitably the nitro group may be converted to amino with a suitable anionic sulphur compound. For example a dithionite salt, conveniently the sodium salt may be used in the presence of aqueous ammonia at a basic pH. In a preferred aspect of this invention it has been found that unexpectedly good yields of a compound of the formula (I) wherein R4 is amino are obtained from a corresponding nitro compound using stannous chloride under substantially neutral conditions. Conveniently stannous chloride is in anhydrous form or in the form of the dihydrate. The reaction is preferably performed at a non-extreme temperature, for example betwen OOC and 500C, favourably at ambient temperature. The reaction is preferably performed in a'C1,6 alkanol, in particular ethanol, or in ethyl acetate. Mixtures of these solvents may also be used. Other suitable methods of reducing the nitro group to the amino group include using suitable metals in the presence of acid, for example iron and hydrochloric acid or zinc and hydrochloric acid. In addition hydride reductions may be employed, for example using lithium aluminium hydride or sodium borohydride. Accordingly in another aspect of this invention there is provided a process for preparing a compound of the formula (I) wherein R4 is hydrogen which comprises reducing a compound of the formula (XVI): EMI19.1 wherein RO, m, Y, p, q and R3 are as hereinbefore defined. Another suitable protected amino group is optionally substituted benzylidene, for example formed by reaction of an amino group (-NH2) with benzaldehyde. This protecting group is cleavable on treatment with mild acid. Other suitable protected amino groups include tertiary-butyloxycarbonylamino removable by trifluoroacetic acid, benzyloxycarbonylamino removable by hydrogenolysis or hydrobromic acid, and p-nitrobenzyloxycarbonylamino removable by hydrogenolysis. In addition the term protected amino covers those compounds wherein R5 is C16 alkanoylamino, thus leading directly to compounds within formula (I). Furthermore compounds of the formula (I) wherein R4 is C1¯6alkanoylamino may be prepared from compounds of the formula (I) wherein R4 is amino by conventional methods of acylation for example reaction with an acid halide, in particular a chloride, in an organic solvent. In an alternative a compound of the formula (I) wherein R4 is C1 6alkanoylamino may be prepared from a corresponding nitro compound by dissolving metal reduction for example with iron powder and Cl¯6alkanoic acid. For converting a compound wherein R6 is furan-2-yl or thien-2-yl to a compound of the formula (I) wherein m is 1, suitable Mannich reagents include formaldehyde and an amine R1R2NH or salt thereof. Such a reaction may be carried out by treatment of an amine salt with aqueous formaldehyde and a compound wherein R6 is unsubstituted furan-2-yl or thien-2-yl, or by heating an amine salt with paraformaldehyde and a compound wherein 6 R6 is unsubstituted furan-2-yl or thien-2-yl, in a convenient solvent such as ethanol. Alternatively where R1 and R2 are both C1 alkyl, the Mannich reagent 1-4 may be a di-(Cl¯qalkyl)methylene ammonium salt for example dimethylmethylene ammonium chloride or iodide, or may be a bis di-C14alkylaminomethane, for example bis (dimethylamino) methane. Any group in the remainder of the molecule that is capable of reacting with a Mannich reagent may be optionally protected during the reaction, and may be subsequently deprotected in conventional manner. Thus any deprotection of the 5-pyrimidinone substituent is preferably performed after the Mannich reaction. The formation of the group R1R2N(CH2)n may be performed at any convenient stage of the synthetic procedures outlined herein or in the art. Such introduction may be direct or may involve two or more steps for example converting a hydroxyalkyl substituent to bromoalkyl and subsequently to RlR2N(CH2)n¯. Pharmaceutically acceptable acid addition salts of the compounds of the formula (I) may be prepared from the corresponding base of the compounds of the formula (I) in conventional manner. For example the base may be reacted with an acid in a C 4alkanol, or an ion-exchange resin may be used. The salts of the compounds of the formula (I) may be interconverted using ion-exchange resins. Non-pharmaceutically acceptable salts are therefore of use as they can be converted to pharmaceutically acceptable salts. Suitable pharmaceutically acceptable acid addition salts of the compounds of the formula (I) include those formed with hydrochloride, hydrobromic, sulphuric, phosphoric, acetic, citric, maleic, lactic, sorbic, fumaric, oxalic, methanesulphonic and ethanesulphonic acids. The compounds of the formula (II), (IV), (VI) and (X) may be prepared for example by the methods described in European Patent Application Publication Nos 3677, 4793, 13071, 15138, 17679, 17680, 24873 and 49173 and UK Patent Application 2030979A. The compound of the formula (III) wherein Q is Cl¯6alkylthio or benzylthio may be prepared by the reaction of a compound of the formula (XVII): EMI22.1 wherein R3, R5 and R7 are as hereinbefore defined, and R11 is hydroxy or C alkoxy; with thiourea 1-6 followed by alkylation or benzylation, and subsequently if desired converting one protected amino group, such as nitro, to another protected amino group. The compounds of the formula (III) wherein Q is chloro or bromo may be prepared by the reaction of a compound of the formula (XVII) with guanidine, followed by diazotisation in hydrochloric acid in the presence of cuprous chloride and copper, or by diazotisation in hydrobromic acid in the presence of cuprous bromide and copper. Subsequently if desired one protected amino group, such as nitro, can be converted to another protected amino group. Compounds of the formula (III) with other values of Q may be prepared in conventional manner. Preferably the reactions of the compound of the formula (XVII) with thiourea and guanidine are carried out in the presence of a base, for example, an alkali metal lower alkoxide, preferably sodium methoxide or sodium ethoxide, an alkali metal carbonate or hydroxide, preferably potassium carbonate or sodium hydroxide, sodium hydride or a quaternary ammonium hydroxide, for example benzyltrimethylammonium hydroxide. Preferably this reaction is carried out at an elevated temperature, for example the reflux temperature of the solvent mixture. Preferably the solvent is a lower alkanol, for example ethanol, an aqueous lower alkanol, a ketone, for example 2-butanone, or a polar aprotic solvent, for example dimethylformamide. The compound of the formula (XVI I) may also be used in the form of a hemiacetal, for example of a C1¯6alkanol. The compounds of the formula (XVII) may be prepared by the methods of Chem Berichte (1973), 106, p 3053. In addition this reference teaches the preparation of 5-nitro-2-thiouracil which may be converted to a compound 5 of the formula (III) wherein R is nitro and Q is Cl¯6alkylthio or benzylthio on reaction with an alkylating or benzylating agent. Compounds of formula (V) wherein q is one may be prepared by the reaction of a corresponding compound of the formula (III) with an aminoalkylthiol or protected derivative thereof. Compounds of the formulae (XI), (VII) or (XIII) wherein q is one may be prepared by the reaction of a corresponding compound of the formula (III) with an aminoalkanol and if necessary subsequently converting a hydroxy group to a group L1 or a group L3. The compounds of the formula (VIII) can be prepared by reacting a compound of formula (XVIII) EMI23.1 wherein R6, m, Y, p and q are as hereinbefore defined and R12 is a C1 4alkyl group in particular methyl, with ammonia or an ammonium salt (for example a halide and particularly the chloride) in the presence of a polar organic solvent, for example a C14alkanol, in particular methanol, at low to moderate temperatures, for example from OOC to the reflux temperature of the solvent and in particular at room temperature. The compounds of the formula (XVIII) wherein q is one are either known or can be prepared in conventional manner, for example by the methods of European Patent Application Publication Nos 49173 and 87274, Belgian Patent 867106 and UK Specification 2030979. The compounds of the formula (XVIII) wherein q is zero are either known or can be prepared in conventional manner, for example by reacting the corresponding nitrile of the formula (XIX) R6 (CH2)mY(CH2)p-CN (XIX) wherein R6, m, Y, and p are as hereinbefore defined with the corresponding C14alkanol under acidic conditions. In particular the alkanol is methanol and the acid is hydrochloric acid. By way of example, compounds of the formula (XIX) wherein m is zero and Y is oxygen may be prepared by the general method described in Description 1 hereinafter. By way of example, compounds of the formula (XIX) wherein -(CH2)mY- is -CH2S- may be prepared by the reaction of a compound of the formula (XX) : Hal-(CH2)p-CN (XX) wherein Hal is chlorine, bromine or iodine and p is as hereinbefore defined with a compound of the formula (VI). Preferably Hal is chlorine. The compound of the formula (VI) may be formed in situ from a compound of the formula (XXI) : EMI25.1 or salt thereof, in particular hydrochloride, in the presence of base for example aqueous sodium hydroxide. The compounds of the formula (XXI) may be prepared from a compound of the formula (XXII) R6CH Hal1 (XXII) 2 wherein Hall is chlorine, bromine or iodine, preferably chlorine, with thiourea. The compounds of the formula (V) wherein q is zero may be prepared by the reaction of a compound of the formula (XXIII) : EMI25.2 wherein p is as hereinbefore defined and the thiol moiety is suitably protected, with a compound of the formula (IX) or (IXA), under similar conditions to those described hereinbefore for the reaction with compounds of the formula (VIII). The compounds of the formula (XI), (VII) and (XIII) wherein q is zero may be prepared from conversion of the thiol group of compounds of the formulae (V) or may be prepared by the reaction of a formula (XXIV) : EMI26.1 wherein L4 is hydroxy or a group L1 or L3 as hereinbefore defined and p is as hereinbefore defined, and L4 is suitably protected if desired, with a compound of the formula (IX) or (IXA). The compounds of the formulae (XXIII) and (XXIV) may be prepared from the corresponding nitriles in an analogous manner to that described above. The compounds of the formula (XIV) may be prepared in a manner analogous to that described for the preparation of compounds of the formula (I), for example reacting a compound of the formula (III) with an analogue of the formula (II) wherein R6 is replaced by R8, provided that R8 is suitably protected as necessary. The compounds of the formula (XV) wherein R10 is CH=N may be prepared by the reaction of a compound of the formula (XXV) with a compound of the formula (XXVI): R9 (CH2)m-Y- (CH2) p1CHO (xxv) EMI26.2 wherein R9, m, Y, p, R3 and R51 are as hereinbefore defined, optionally in the presence of an acid catalyst. The compounds of the formula (XV) wherein R10 is -CONH may be prepared by the reaction of a compound of the formula (XXVI) with an activated derivative of a compound of the formula (XXVII): R9¯ (CH2) -Y- (CHZ) .CO,H (XXVII) wherein R9, m, Y andp are as hereinbefore defined. Suitable active derivatives are acyl halides, anhydrides and activated esters. The aldehydes of the formula (XXV) may be prepared for example by reacting a compound of the formula (XII) with a protected bromopropionaldehyde (for example protected as a cyclic acetal) and deprotecting. The acid of the formula (XXVII) and derivatives thereof may be prepared in a similar manner for example by reacting a compound of the formula (XII) with a protected bromopropionic acid and if necessary deprotecting and/or converting to the desired activiated acid derivative. The following Description and Examples serve to illustrate this invention. Description 1 2-Methylthio-5-nitropyrimidin-4-one A solution of sodium hydroxide pellets (6.84 g, 0.171 M) in distilled water 200 ml) was added to a suspension of 5-nitro-2-thiouracil (27.41 g, 0.158 M) in ethanol (400 ml). The mixture was warmed on the steam bath to effect solution and iodomethane (22,47 g, 0.158M) added. The resulting solution was heated on the steam bath for one hour and allowed to cool. The solid which crystallised out during heating was filtered off, washed with water and dried in vacuo to yield buff crystals (11.91 g), m.p. 208-100C. The mother liquor afforded further crystals after concentrating and cooling (1.22 g), m.p. 201-50C. The two solids were combined and recrystallised from water/glacial acetic acid to give the title compound as pale yellow needles (7.12 g), m.p. 214-160C. Description 2 (a) A solution of 3- (piperidinomethyl) phenol (12.05 g) in dry tetrahydrofuran (50 ml) was added dropwise to a suspensipn of sodium hydride [from 6.0 g of 50% suspension in oil washed with petroleum ether] in dry tetrahydrofuran (70 ml). The mixture was stirred under reflux for 30 minutes and allowed to cool. 4-Bromobutyronitrile (14.89 g, 10.0 ml) was added to the cool mixture and the mixture so obtained was stirred under reflux for 22 hours. Tetrahydrofuran was evaporated under reduced pressure and the residue was dissolved in water (100 ml). The solution was extracted with ether (3 x 50 ml), and the aqueous layer was adjusted to pH 9 with K2CO3. The aqueous solution was extracted with chlorofprm (3 x 100 ml), the chloroform extracts were dried (K2CO3) and chloroform was removed under reduced pressure to give a pale brown oil (16.22 g). This oil was purified by column chromatography (Kieselgel 60 70-230 mesh silica) using chloroform as eluant. The fractions containing the desired product were collected and the solvent was evaporated under reduced pressure to give 4-[3-(piperidinomethyl)phenoxy]butyronitrile as an oil (11.37 g). (b) Dry hydrogen chloride gas was introduced into a stirring solution of 4-[3-(piperidinomethyl)phenoxy3- butyronitrile (15.62 g) in dry methanol (65 ml) and dry chloroform (130 ml), cooled to -50C (ice-salt bath), under nitrogen, over 1.75 hours, at a rate such that the temperature did not exceed 10C. The solution was stirred at 0 C for a further hour, and left to stand (at about 4 C) for about 16 hours. The mixture was poured on to a solution of potassium carbonate (45 g) in ice-water (500 ml). The organic layer was separated off and the aqueous layer extracted with chloroform (4 x 150 ml). The combined organic layers were dried (K2CO3) and evaporated under reduced pressure to give methyl 4- [3- (piperidinomethyl) phenoxy] butyronimidate (14.46 g) as an oil. (c) Methyl 4-[3- (piperidinomethyl) phenoxy] - butryonimidate (14.46 g), ammonium chloride (2.66 g) and ethanol (100 ml) were stirred at room temperature for 5 hours and allowed to stand for about 16 hours. Ethanol was removed under reduced pressure and the residue purified using medium pressure chromatography, with Kieselgel 60 silica 70-230 mesh (pre-column) and 230-400 mesh (main column) and a chloroform methanol gradient elution. The fractions containing the desired product (9:1 chloroform:methanol)- were collected and the solvent was evaporated under reduced pressure to give 4-t3- (piperidinomethyl)phenoxy]butyronamidine hydrochloride (8.03 g) as a glassy solid. Example 1 2-[3-(3-(Dimethylaminomethyl)phenoxy)propylamino]-5-aminopyrimidin-4-one i) 2-[3- (3- (Dimethylaminomethyl) phenoxy) propyl amino]-5-nitropyrimidin-4-one 3- (3- (Dimethylaminomethyl) phenoxy] propylamine (2.92 g) and 5-nitro-2-methylthiopyrimidin-4-one (2.25 g) were stirred under reflux in anhydrous pyridine (40 ml) for 5 hours. The solvent was removed under reduced pressure and the semi-solid residue crystallised by trituration under hot propan-2-ol. On cooling the yellow solid was collected by filtration, washed thoroughly with propan2-ol and dried in vacuo to yield 2-[3-(3-(dimethylamino methyl) phenoxy) propylamino] -5-nitropyrimidin-4-one (3.37 g), m.p. 211-130C. ii) 2-[3-(3-(Dimethylaminomethyl)phenoxy)propyl- amino] -5-aminopyrimidin-4-one Part of the product from i) above (3.21 g) was dissolved in a solution of 2N hydrochloric acid (70 ml) and ethanol (50 ml). This solution was hydrogenated for 3 hours over 10% Palladium on carbon (0.25 g) in a 250 ml Parr hydrogenation vessel, at 344 kPa (50 p.s.i.). The reaction mixture was filtered through diatomaceous earth and the filtrate was evaporated under reduced pressure to afford a gel-like solid. Recrystallisation from ethanol, washing the crystals with ether and drying in vacuo afforded the title compound as a solid (2.55 g), m.p. 170-720C. This solid was dissolved in water and taken to pH 9.0 with 2N sodium hydroxide solution. An oil precipitated, this was extracted into dichloromethane (four times), these extracts were combined, evaporated under reduced pressure and the residue crystallised from ethanolic HC1 to afford a pale yellow solid. Recrystallisation from aqueous methanol afforded the title compound as the trihydrochloride (0.49 g), m.p. 199-2010C. Example 2 2-13-t3-(Piperidinomethyl)phenoxv)propyl]-5-amino- pyrimidin-4-one i) 2-[3- (3- (piperidinomethyl) phenoxy) propyl] -5- nitropyrimidin-4-one To a solution of sodium metal (0.37 g) in methanol (20 ml) was added 4-[3-(piperidinomethyl)phenoxy)butyronamidine hydrochloride (1.92 g) with subsequent heating under reflux for 30 minutes. The solution was cooled, ethyl ethoxymethylene nitroacetate (1.16 g) in methanol (10 ml) was added and the resultant mixture stirred under reflux for 5 hours. The mixture was cooled and evaporated under reduced pressure to afford a residue which was dissolved in water (50 ml). This solution was washed with chloroform (3 x 20 ml), and acidified to pH 9 with glacial acetic acid to afford a precipitated oily solid which was extracted into chloroform containing a small amount of methanol (4 x 30 ml). The organic extracts were combined, dried (MgSO4) and evaporated under reduced pressure to give a yellow oil which crystallised from isopropanol/methanol/diethylether to give 2-[3-(3-(piperidinomethyl)phenoxy)propyl]-5-nitro- pyrimidin-4-one as a pale yellow crystalline solid (1.17 g), m.p. 160-1620C. ii) 2-[3-(3-(Piperidinomethyl)phenoxy)propylj-5- aminopyr imidin-4 -one 2- [3- (3- (Piperidinomethyl) phenoxy) propyl] -5-nitro- pyrimidin-4-one (1.08 g), 10% Palladium on Carbon (0.1 g) and methanol (80 ml) were placed in a 250 ml Parr hydrogenation vessel. The mixture was hydrogenated at 344 kPa (50 p.s.i.) with hydrogen gas for approximately 5 hours at 400C. The mixture was filtered through diatomaceous earth, evaporated under reduced pressure and subjected to medium pressure chromatography using acetone/ methanol (9:1) as eluant. The fractions containing the major component of the reaction mixture were combined and evaporated under reduced pressure to afford the title compound. This was dissolved in ethanolic HC1 and evaporated under reduced pressure to give a residue which was recrystallised from isopropanol to give the dihydrochloride (0.19 g), m.p. 251-20C. Example 3 2-[3-(3-(Piperidinomethyl)phenoxy)propylamino]-5- acetamidopyr imidin-4-one i) 2-[3- (3- (Piperidinomethyl) phenoxy) propylamino] -5- nitropyrimidin-4-one 3-[3-(Piperidinomethyl)phenoxy]propylamine (4.71 g) and 5-nitro-2-methylthiopyrimidin-4-one (3.55 g) were stirred under reflux in pyridine (40 ml) for 4 hours. The reaction mixture was allowed to cool and the solvent evaporated under reduced pressure to afford an oily residue. This was recrystallised from 2N hydrochloric acid to give as a pale yellow crystalline solid, 2-[3-(3-(piperidinomethyl)phenoxy)propylamino]-5-nitropyrimidin-4-one as a hydrochloride salt (6.44 g), m.p. 134-60C. ii) 2-[3-(3-(Piperidinomethyl)phenoxy)propylamino] -5acetamidopyrimidin-4-one The product from Example 3 i) (added to material from another run) (8.74 g) and iron powder (9.00 g) were refluxed in glacial acetic acid (100 ml) for 4 hours. The reaction mixture was allowed to cool and evaporated under reduced pressure to afford a residue. This residue was dissolved in water, taken to pH 9.5 with aqueous sodium hydroxide, filtered through diatomaceous earth, and the filtrate was extracted with chloroform in a continuous liquid-liquid extractor for 3 hours. The combined chloroform extracts were dried (MgSO4), evaporated in vacuo and the solid residue crystallised from isopropanol/methanol. The resultant crystals were subjected to chromatography on silica gel using chloroform/methanol/0.880 ammonia (90:10:1) as eluant. The desired fractions were collected, evaporated under reduced pressure and the so-lid residue recrystallised from ethanol to afford the title compound (1.05 g), m.p. 185-60C. Example 4 2-13-(3-(Piperidinomethyl)phenoxy)propyll-5-amino- pyr imidin-4 -one 2-[3-(3-(Piperidinomethyl)phenoxy)propyl3-5-nitro- pyrimidin-4-one (5.79 g) was dissolved with warming in a mixture of methanol (350 ml) and cyclohexene (150 ml). To the stirred solution, under nitrogen, was added a slurry of 10% palladium on charcoal (approx. 2.0 g) in methanol (10 ml) and the resultant mixture was stirred under reflux for 21 hours. The mixture was allowed to cool, filtered through diatomaceous earth and the filtrate was evaporated under reduced pressure to afford a residue. The residue was dissolved in methanol, treated with charcoal, evaporated under reduced pressure and subjected to medium pressure chromatography using acetone/methanol (9:1) as eluant. The desired fractions were collected, evaporated under reduced pressure to give the title compound which was treated with dilute ethanolic HC1. The solvent was removed under reduced pressure and the residue crystallised from isopropanol to give the title compound as the dihydrochloride (1.06 g). Recrystallisation from isopropanol-methanol gave material consistent with that of Example 2. Example 5 2-[3-(3-(Piper idinomethyl) phenoxy) propylamino] -S-amino- pyrimidin-4-one i) 2- [3(3- (Piperidinomethyl) phenoxy) propylamino] -5nitropyrimidin-4-one 3- (3-(Piperidinomethyl)phenoxy)propylamine (2.48 g) and 2-methylthio-5-nitropyrimidin-4-one (1.87 g) were dissolved in pyridine (20 ml) and the solution was stirred under reflux for 4 hours. The solution was allowed to cool and evaporated under reduced pressure to give a residue that was washed with diethyl ether and crystallised from ethanol-methanol to give 2-[3-(3 (piperidinomethyl)phenoxy)propylamino]-5-nitropyrimidin4-one as a pale yellow solid (3.35 g), m.p. 149.50-1530C. ii) 2-[3-(3-(Piperidinomethyl)phenoxy)propylamino] - 5-aminopyr imidin-4-one 2-[3-(3-(Piperidinomethyl)phenoxy)propylamino]-5- nitro-pyrimidin-4-one (2.0 g) was suspended in water (40 ml) and 25% ammonia solution (approx. 1 ml) was added to take the pH to about 11. To the stirred suspension was slowly added sodium dithionite (4.0 g) whereupon the pH fell to about 9. The mixture was stirred for 4 hours maintaining the pH at 8.5 - 9 with ammonia solution and then was allowed to stand overnight. Thin layer chromatography indicated some starting material was still present so further sodium dithionite (4 g and another 4 g a few hours later) was added whilst maintaining the pH at 8.5-9. The mixture was extracted into chloroform (4 x 50 ml). The combined chloroform extracts were washed with water, dried (MgSO4) and evaporated under reduced pressure to afford a residue. This residue was dissolved in dilute ethanolic HC1, the resultant solution was evaporated under reduced pressure and the residue was dissolved in water (30 ml). On standing starting-material as the hydrochloride came out of solution as a yellow solid (0.69), m.p. 80-830C. The mother liquor was evaporated to a third of its volume whereupon further startingmaterial came out of solution. The filtrate was evaporated under reduced pressure and the residue recrystallised from ethanol to give the hydrochloride of the title compound as a yellow solid (0.77 g), m.p. 179.50-181.50C. Example 6 2-[3-(4-(Piperidinomethyl)pYrid-2-oxy)proPylaminol-5-amino- pyr imidin-4 -one i) 2-[3- (4-(piperidinomethyl) pyrid-2-oxy) propyl- amino] -5-nitropyrimidin-4-one 3- (4- (Piperidinomethyl) pyrid-2-oxy) propylamine (6.84 g) and 2-methylthio-5-nitropyrimidin-4-one (2.57 g) were dissolved in pyridine (40 ml) and stirred under reflux for 4 hours.- The solution was allowed to cool and evaporated under reduced pressure to give a residue that was washed with diethyl ether and crystallised from ethanol-methanol to give 2-[3-(4-(piperidinomethyl) pyrid-2-oxy)propylamino]-5-nitropyrimidin-4-one (3.16 g) as a pale yellow solid, m.p. 86.5a-900C. ii) 2- [3- (4- (Piperidinomethyl) pyrid-2-oxv) propyl- amino] -5-aminopyrimidin-4-one 2-[3-(4-(Piperidinomethyl)pyrid-2-oxy)propylamino]- 5-nitropyrimidin-4-one (0.97 g) and stannous chloride dihydrate (2.82 g) were stirred'in ethanol (25 ml), under nitrogen, at room temperature, for 20 hours. The majority of the ethanol was evaporated under reduced pressure and ice-water was added. Aqueous sodium bicarbonate was added to pH 8 and the solution was filtered through diatomaceous earth. The filtrate was extracted into chloroform (4 x 50 ml). The combined extracts were dried (MgSO4) and evaporated under reduced pressure to give an oily residue. This was subjected to medium pressure chromatography on silica using chloroform-methanol gradient elution. The title compound was precipitated with ether to give the free base, m.p. 164-80C (decomp). Example 7 2-[3-(4-(Piperidinomethyl)pyrid-2-oxy)propyl]-5-aminopyrimidin-4-one i) 2-[3-(4-(Piperidinomethyl)pyrid-2-oxy)propyl]-5- nitropyrimidin-4-one To a solution of sodium (0.60 g) in methanol (10 ml) was added a solution of 4-[4-(piperidinomethyl)pyrid-2oxy]butyronamidine hydrochloride (EP-A-87,274). The mixture was stirred under reflux for 30 minutes, ethyl ethoxymethylenenitroacetate (1.93 g) in methanol (10 ml) was added, and the mixture was stirred under reflux for a further 4 hours. The solvent was evaporated under reduced pressure and water (40 ml) was added to the residue. The mixture was washed with diethyl ether (3 x 20 ml), taken to pH 9 with glacial acetic acid and extracted into chloroform (4 x 25 ml). The combined chloroform extracts were dried (MgSO4) and evaporated under reduced pressure to give an oily residue. This was crystallised from ethanol-ether to give 2-[3-(4 (piperidinomethyl)pyrid-2-oxy)propyl]-5-nitropyrimidin4-one as a pale yellow solid (1.7 g), m.p. 129"-1320C. ii) 2-[3-(4- (Piperidinomethyl)pyrid-2-oxy)propyl] -5 aminopyrimidin-4-one To a suspension of 2-[3-(4-(piperidinomethyl)pyrid-2 oxy)propyl]-5-nitropyrimidin-4-one (1.43 g) in ethyl acetate (40 ml) was added, in portions, stannous chloride dihydrate (4.32 g). The mixture was stirred at room temperature for 90 minutes, taken to pH 9 with saturated aqueous sodium bicarbonate and stirred for a further 2 hours. The solid was filtered off and washed with chloroform. The ethyl acetate layer of the filtrate was collected. The aqueous layer of the filtrate was extracted with chloroform (4 x 25 ml). The ethyl acetate and chloroform washings and extracts were combined, dried (MgSO4), and evaporated under reduced pressure to give a residue. This was washed with ether and crystallised from isopropanol-ether to yield 2-[3-(4- (piperidino- methyl) pyrid-2-oxy) propyl] -5-aminopyrimidin-4-one (0.31 g), m.p. 1560-90C. Example 8 2-[3-[3-(HexahydroazePinomethyl)Phenoxy]proPYlamino]-5- aminopyrimidin-4-one i) 2-[3-[3-(Hexahydroazepinomethyl) phenoxyi propyl- amino] -5-nitropyrimidin-4-one 3-[3-(HexahydroazepinomethylYphenoxylpropylamine (7.20 g) and 2-methylthio-5-nitropyrimidin-4-one (2.57 g) were stirred under reflux in pyridine (40 ml) for 4 hours. The solvent was evaporated under reduced pressure to give a residue that was washed with diethyl ether to afford a yellow solid. Crystallisation from methanol gave 2-[3-[3-(hexahydroazepinomethyl)phenoxy]propylamino]-5- nitropyrimidin-4-one (4.28 g), m.p. 1l60-118.50C. ii) 2-[3-[3-(Hexahydroazepinomethyl)phenoxy]propyl- amino]-5-aminopyrimidin-4-one 2-[3-[3-(Hexahydroazepinomethyl)phenoxy]propylamino]- 5-nitropyrimidin-4-one (1.00 g) and stannous chloride dihydrate (2.82 g) were stirred in ethanol (25 ml), at room temperature, under nitrogen, for 18 hours. Ethanol was evaporated under reduced pressure, water was added and the mixture taken to pH 8 with aqueous sodium bicarbonate. The mixture was filtered through diatomaceous earth and the insoluble solid washed with chloroform (4 x 50 ml). The combined chloroform extracts were dried (MgSO4) and evaporated under reduced pressure to give the title compound as an oily residue. This was treated with dilute ethanolic HC1 and excess solvent evaporated. The residue was crystallised from isopropanol-ethanol to give the title compound as the di-hydrochloride salt (0.29 g) m.p. 169.50-173.50C (on recrystallisation from methanol-ethanol). Example 9 2-13-(3-PiperidinomethylOphenoxy)propyl]-5-aminopYrimidin- 4-one To a stirred suspension of 2-[3-(3-piperidinomethyl)phenoxy)propyl]-5-nitropyrimidin-4-one (3.0 g) in ethyl acetate (200 ml) was added anhydrous stannous chloride (7.8 g). A fawn coloured precipitate resulted. The reaction mixture was stirred at room temperature for one hour after which time a clear solution was observed with an oily precipitate. Saturated aqueous potassium bicarbonate (100 ml) was added and the mixture stirred vigorously for a further 40 minutes giving an emulsion. This was filtered to give two clear layers (aqueous and organic). The aqueous layer was extracted with ethyl acetate. The organic layer and ethyl acetate extractions were combined, washed with brine, dried (MgSO4) and evaporated under reduced pressure to give the title compound as a pale yellow solid (1.75 g). This was dissolved in ethanol and ethanolic HCl was added. Excess solvent was evaporated and the residue crystallised from methanol to give 2-[3-(3-piperidino methyl)phenoxy)propyl]-5-aminopyrimidin-4-one dihydrochloride (1.32 g) consistent with the material of Example 2. In a similar manner the above reaction was conducted in ethanol, on a smaller scale, to give the title product in good yield. Example 10 2- [3- (3-Piperidinomethyl) phenoxy) propyl] -5-aminopyrimidin- 4-one 2-[3-(3-Piperidinomethyl)phenoxy)propyl]-5-nitro- pyrimidin-4-one (0.5 g) was dissolved in a mixture of water/ammonia (0.88 g) (10.5 ml : 4.5 ml) to give a yellow solution having pH 11. To this stirred solution was added sodium dithionite (1.0 g) and the reaction was stirred for 2 hours at room temperature, further sodium dithionite (0.5 g) was added, the reaction stirred for a further 2 hours and then allowed to stand overnight. The reaction mixture was filtered and the mother liquor left to stand. This afforded a second precipitate which was collected, dried (0.06 g) and was the title compound, identical by t.l.c. with an authentic sample. Example 11 2-[3-(3-Piperidinomethyl)phenoxy)Propyll-5-aminopyrimidin- 4-one 2-[3-(3-Piperidinomethyl3phenoxy)propyl]-5-nitro- pyrimidin-4-one (0.1 g) and hydrazine hydrate (0.052 g) were reacted in ethanol (5 ml) in the presence of a small amount of 10% Palladium on carbon, after stirring overnight and heating under reflux for 2 hours, chromatography indicated the presence of the title compound together with impurities and starting-material. In a similar manner the 5-nitro compound (0.1 g) and hydrazine hydrate (0.06 g) were reacted in ethanol (5 ml) in the presence of a small amount of Raney nickel with similar results. Example 12 A pharmaceutical composition for oral administration is prepared containing: EMI42.1 <tb> <SEP> % <SEP> by <SEP> weight <tb> <SEP> P <SEP> -t3-(3-(piperidinomethyl)phenoxy)- <SEP> - <SEP> 55 <tb> <SEP> propyl] <SEP> -5-aminopyrimidin-4-one <tb> <SEP> A <SEP> i <SEP> dihydrochloride <tb> <SEP> Dibasic <SEP> calcium <SEP> phosphate <SEP> dihydrate <SEP> 20 <tb> <SEP> Approved <SEP> colouring <SEP> agent <SEP> 0.5 <tb> <SEP> Polyvinylpyrrolidone <SEP> 4.0 <tb> <SEP> Microcrystalline <SEP> Cellulose <SEP> 8.0 <tb> <SEP> Maize <SEP> Starch <SEP> 8.0. <SEP> <tb> B <SEP> ) <SEP> <SEP> Sodium <SEP> glycollate <SEP> 4.0 <tb> <SEP> Magnesium <SEP> Stearate <SEP> 0.5 <tb> by mixing together the ingredients A (substituting lactose or microcrystalline cellose for dibasic calcium phosphate dihydrate if desired), adding a concentrated solution of polyvinylpyrrolidone and granulating, drying and screening the dried granules; adding the ingredients B to the dried granules and compressing the mixture into tablets containing 100 mg, 150 mg or. 200 mg of the free base. Other compounds of the invention, for example those specifically described in Examples 1, 3, 4, 6, 7 and 8 can be formulated into pharmaceutical compositions by a similar procedure. The compounds of this invention, where tested, show no overt signs of toxicity at doses which are a pertinent multiple of the therapeutic dose.

Claims: CLAIMS (UK, BE, CH, DE, FR, IT, LI, LU, NL and SE): 1. A compound of the formula (I) : EMI43.1 or a salt thereof, wherein: R0 is 2-guanidinothiazol-4-yl or a group R1RêN(CH2)n-Z- wherein: R1 and R2 are independently hydrogen, C1-6alkyl, aryl (C16) alkyl, heteroaryl(C1-6)alkyl, C3-10 cycloalkyl, hydroxy(C2¯6)alkyl, or halo (C26)- alkyl (wherein said hydroxy and halo groups are not substituted on the carbon atom adjacent to the nitrogen atom); or R1 and R2 together represent - (CH2)q - wherein q is 4 to 7, to form together with the nitrogen atom to which they are attached a 5-8 membered saturated ring; n is an integer from 1 to 6; Z is 2,5-furanyl, 2,5-thienyl, 2,4-pyridyl wherein the R1R2N(CH2)n group is in the 4-position, 2,4 thiazolyl wherein the R1R2N(CH 2n group is in the 2-position, or 1,3- or 1,4-phenylene; m is one; or if Z is pyridyl or phenylene m may also be zero; Y is oxygen, sulphur or methylene; or if Z is furanyl, thienyl or thiazolyl Y may also be a bond; p is two, three or four; q is zero or one; R3 is hydrogen or C1 alkyl; and 1-6 R4 is hydrogen or C16 alkanoyl. 2. A compound according to claim 1 which is a compound of the formula (I) or a pharmaceutically acceptable salt thereof. 3. A compound according to either claim 1 or 2 wherein R0 is a group R1R2N(CH2)n Z- wherein R1, R2, n and Z are as defined in formula (I). 4. A compound according to any one of claims 1 to 3 wherein R4 is hydrogen. 5. A compound according to any one of claims 1 to 4 wherein q is zero. 6. A compound according to any one of claims 1 to 4 wherein q is one. 7. A compound according to any one of claims 1 to 6 wherein R3 is hydrogen. 8. A compound according to any one of claims 1 to 7 wherein R1 and Rê together represent -(CH2) q - wherein q is 4 to 7. 9. A compound according to any one of claims 1 to 8 wherein R1R2N(CH2)nZ is 3-piperidinomethylphenyl-. 10. A compound according to claim 2 which is 2-[3-(3-(dimethylaminomethyl)phenoxy)propylamino]-5-aminopyrimidin-4-one or a pharmaceutically acceptable salt thereof, 2-[3-(3-(piperidinomethyl)phenoxy)propyl]-5-amino- pyrimidin-4-one or a pharmaceutically acceptable salt thereof, 2-[3-(3-(piperidinomethyl)phenoxy)propylamino]-5- acetamidopyrimidin-4-one or a pharmaceutically acceptable salt thereof, 2-[3-(3-(piperidinomethyl)phenoxy)propylamino]-5-aminopyrimidin-4-one or a pharmaceutically acceptable salt thereof; 2-[3-(4-(piperidinomethyl)pyrid-2-oxy)propylamino]-5-amino pyrimidin-4-one or a pharmaceutically acceptable salt thereof, 2-[3-(4-(piperidinomethyl)pyrid-2-oxy)propyl]-5-aminopyrimidin-4-one or a pharmaceutically acceptable salt thereof, 2-[3-[3-(hexahydroazepinomethyl)phenoxy]propylamino]-5- aminopyrimidin-4-one or a pharmaceutically acceptable salt thereof, or 2-[3-[3-(piperidinomethyl)phenoxy]propyl]-5-amino-6-methyl- pyrimidin-4-one or a pharmaceutically acceptable salt thereof. 11. A compound according to claim 2 which is 2-[3 (3- (pipeiidinomethyl)phenoxy)propyl] -5-aminopyrimidin-4-one or a pharmaceutically acceptable salt thereof. 12. 2-[3-(3-(Piperidinomethyl)phenoxy)propyli-5- amino-pyrimidin-4-one dihydrochloride. 13. A pharmaceutical composition which comprises a compound according to any one of claims 2 to 12 and a pharmaceutically acceptable carrier. 14. A compound according to any one of claims 2 to 12 for use as a therapeutic agent. 15. A compound according to any one of claims 2 to 12 for use as an H2-antagonist. 16. A process for preparing a compound of the formula (I) as defined in claim 1 or a salt thereof which process comprises : a) for compounds of the formula (I) wherein q is one, reacting a compound of the formula (II) with a compound of the formula (III) : R6 (CH2)mY (CH2) NH2 (Il) EMI46.1 wherein m, Y, p and R3 are as hereinbefore defined, 0 R6 is a group R as hereinbefore defined or R6 is a furan-2-yl or thien-2-yl group; R5 is protected amino; and Q is a group displaceable by amine; or b) for compounds of the formula (I) wherein m is one and Y is sulphur, reacting a compound of the formula (IV) with a compound of the formula (V) : R6-CH2-L (IV) EMI47.1 wherein R6, p, q and R3 are as hereinbefore defined, R is optionally protected amino and L is a moiety displaceable by thiol or chemical equivalent thereof; or c) for compounds of the formula (I) wherein m is one and Y is sulphur, reacting a compound of the formula (VI) Qr chemical equivalent thereof with a compound of the formula (VII): R6CH2SH (VI) EMI47.2 wherein R6, p, q, R51 and R3 are as hereinbefore defined and L1 is a moiety displaceable by thiol or chemical equivalent thereof; or d) reacting a compound of the formula (VIII) with a compound of the formula (IX) or chemical equivalent thereof: EMI47.3 wherein R6, m, Y, p, q, and R3 are as hereinbefore defined, R52 is protected amino and R7 is an ester-forming group; or e) for compounds of the formula (I) wherein Z is 2,4-pyridyl, m is zero and Y is oxygen, reacting a compound of the formula (X) with a compound of the formula (XI) or derivative thereof that permits reaction to occur: EMI48.1 wherein Rl, R2, n, p, q, R3 and R51 are as hereinbefore defined and L2 is a group displaceable by hydroxy or the equivalent thereof; or f) for compounds of the formula (I) wherein Z is phenylene, m is zero and Y is oxygen, reacting a compound of the formula (XII) or chemical equivalent thereof with a compound of the formula (XIII): EMI48.2 wherein R1, R2, n, p, q, R3 and R are as hereinbefore defined and L3 is a moiety displaceable by phenol or chemical equivalent thereof; or g) for compounds of the formula (I) wherein RO is RlR2N(CH2)n¯Z¯, converting a compound of the formula (XIV): EMI49.1 wherein Z, m, Y, p, q, R3 and R5 are as hereinbefore defined and R8 is a precursor of a group R1R2N(CH2)n as hereinbefore defined; or h) for compounds of the formula (I) wherein q is one, reducing a compound of the formula (XV): EMI49.2 wherein m, Y, p, R3 and R51 are as hereinefore defined, R9 is a group R0 or R8-Z-as hereinbefore defined and R10 is a group -CH=N- or -CO-NH-; and thereafter where necessary T 'J v i) reacting a compound wherein R6 is furan-2-yl or thien-2-yl with a Mannich reagent to form a compound of the formula (I) wherein n is one; ii) converting a protected amino group to amino or C 1-6 alkanoylamino; iii) optionally forming a salt. 17. A process for preparing a compound of the formula (I) as defined in claim 1 or a salt thereof wherein R4 is hydrogen which comprises reducing a compound of the formula (XVI) or salt thereof EMI50.1 wherein RO, m, Y, p, q and R3 are as defined in claim 1. 18. A process for preparing 2-[3-(3-(piperidino methyl)phenoxy)propyl]-5-aminopyrimidin-4-one which comprises reducing 2-[3- (3-(piperidinomethyl)phenoxy) - propyl] -5-nitropyrimidin-4-one. 19. A process according to either claim 17 or 18 wherein the reducing agent comprises stannous chloride. 20. A process according to claim 19 wherein the solvent comprises ethyl acetate and stannous chloride is in anhydrous form. 21. A compound of the formula (XVI): EMI51.1 or a salt thereof, wherein: RO is 2-guanidinothiazol-4-yl or a group R1R2N(CH2) n wherein: R1 and R2 are independently hydrogen, C16 alkyl, aryl(Cl 6)alkyl, heteroaryl(C16)alkyl, C3-10 cycloalkyl, hydroxy(C2¯6)alkyl, or halo (C2¯6)- alkyl (wherein said hydroxy and halo groups are not substituted on the carbon atom adjacent to the nitrogen atom); or R1 and R2 together represent - (CH2)q - wherein q is 4 to 7, to form together with the nitrogen atom to which they are attached a 5-8 membered saturated ring; n is an integer from 1 to 6; Z is 2,5-furanyl, 2,5-thienyl, 2,4-pyridyl wherein the R1R2N(CH2)n group is in the 4-position, 2,4 thiazolyl wherein the R1RêN(CH2)n group is in the 2-position, or 1,3- or 1,4-phenylene; m is one; or if Z is pyridyl or phenylene m may also be zero; Y is oxygen, sulphur or methylene; or if Z is furanyl, thienyl or thiazolyl Y may also be a bond; p is two, three or four; q is zero or one; R3 is hydrogen or C1 6alkyl; and R4 is hydrogen or Cl¯6alkanoyl. 22. 2-!3-(3- (Piperidinomethyl) phenoxy)propyl] -5- nitropyrimidin-4-one. Claims for Austria 1. A process for preparing a compound of the formula (I) : EMI53.1 or a salt thereof, wherein: R0 is 2-guanidinothiazol-4-yl or a group R1R2N(CH2) n wherein: R1 and R2 are independently hydrogen, C1 6alkyl, aryl(C16)alkyl, heteroaryl(C1-6)alkyl, C3-1O cycloalkyl, hydroxy(C2¯6)alkyl, or halo (C26)- alkyl (wherein said hydroxy and halo groups are not substituted on the carbon atom adjacent to the nitrogen atom); or R1 and R2 together represent - (CH2) q - wherein q is 4 to 7, to form together with the nitrogen atom to which they are attached a 5-8 membered saturated ring; n is an integer from 1 to 6; Z is 2,5-furanyl, 2,5-thienyl, 2,4-pyridyl wherein the RlR2N(CH2)n group is in the 4-position, 2,4 thiazolyl wherein the R1R2N(CH2)n group is in the 2-position, or 1,3- or 1,4-phenylene; m is one; or if Z is pyridyl or phenylene m may also be zero; Y is oxygen, sulphur or methylene; or if Z is furanyl, thienyl or thiazolyl Y may also be a bond; p is two, three or four; q is zero or one; R3 is hydrogen or C1 6alkyl; and R4 is hydrogen or C1 6alkanoyl: which process comprises a) for compounds of the formula (I) wherein q is one, reacting a compound of the formula (11) with a compound of the formula (III) : EMI54.1 wherein m, Y, p and R3 are as hereinbefore defined, is is a group RO as hereinbefore defined or R6 is a furan-2-yl or thien-2-yl group; R5 is protected amino; and Q is a group displaceable by amine; or b) for compounds of the formula (I) wherein m is one and Y is sulphur, reacting a compound of the formula (IV) with a compound of the formula (V) : R6-CH2-L (IV) EMI54.2 wherein R6, p, q and R3 are as hereinbefore defined, R51 is optionally protected amino and L is a moiety displaceable by thiol or chemical equivalent thereof; or c) for compounds of the formula (I) wherein m is one and Y is sulphur, reacting a compound of the formula (VI) or chemical equivalent thereof with a compound of the formula (VII): R6CH2SH (VI) EMI55.1 wherein R6 p, q, R51 and R3 are as hereinbefore defined and L1 is a moiety displaceable by thiol or chemical equivalent thereof; or d) reacting a compound of the formula (VIII) with a compound of the formula (IX) or chemical equivalent thereof: EMI55.2 wherein R6, m, Y, p, q, and R3 are as hereinbefore defined, R52 is protected amino and R7is an ester-forming group; or e) for compounds of the formula (I) wherein Z is 2,4-pyridyl, m is zero and Y is oxygen, reacting a compound of the formula (X) with a compound of the formula (XI) or derivative thereof that permits reaction to occur: EMI56.1 wherein R1, R2, n, p, q, R3 and R51 are as hereinbefore defined and L2 is a group displaceable by hydroxy or the equivalent thereof; or f) for compounds of the formula (I) wherein Z is phenylene, m is zero and Y is oxygen, reacting a compound of the formula (XII) or chemical equivalent thereof with a compound of the formula (XIII): EMI56.2 wherein R1, R2, n, p, q, R3 and R51 are as hereinbefore defined and L3 is a moiety displaceable by phenol or chemical equivalent thereof; or g) for compounds of the formula (I) wherein RO is R1R2N(CH2), Z-, converting a compound of the formula (XIV): EMI57.1 wherein Z, m, Y, p, q, R3 and R51 are as hereinbefore defined and R8 is a precursor of a group R1R2N(CH2)n as hereinbefore defined; or h) for compounds of the formula (I) wherein q is one, reducing a compound of the formula (XV): EMI57.2 wherein m, Y, p, R3 and R51 are as hereinbefore defined, R9 is a group R0 or R8-Z-as hereinbefore defined and R10 is a group -CH=N- or -CO-NH-; and thereafter where necessary 6 i) reacting a compound wherein R is furan-2-yl or thien-2-yl with a Mannich reagent to form a compound of the formula (I) wherein n is one; ii) converting a protected amino group to amino or C1 "alkanoylamino; iii) optionally forming a salt. 2. A process according to claim 1 for preparing a compound of the formula (I) or salt thereof wherein R0 is a group R1R2N(CH2)nZ wherein R1, R2, n and Z are as defined in formula (I) when performed according to any of variants a) - d). 3. A process according to either claim 1 or 2 for preparing a compound of the formula (I) or salt thereof wherein R4 is hydrogen. 4. A process'according to any one of claims 1 to 3 for preparing a compound of the formula (I) or salt thereof wherein q is zero. 5. A process according to any one of claims 1 to 3 for preparing a compound of the formula (I) or salt thereof wherein q is one. 6. A process according to any one of claims 1 to 5 for preparing a compound of the formula (I) or salt thereof wherein R3 is hydrogen. 7. A process according to any one of claims 1 to 6 for preparing a compound of the formula (I) or salt thereof wherein R1 and R2 together represent (CH2)9 wherein q is 4 to 7. 8. A process according to any one of claims 1 to 7 for preparing a compound of the formula (I) or salt thereof wherein R1R2N(CH2)nZ is 3-piperidinomethylphenyl-. 9. A process according to claim 1 for preparing 2-[3-(3-(dimethylaminomethyl)phenoxy)propylamino]-5-aminopyrimidin-4-one or a pharmaceutically acceptable salt thereof, 2-[3-(3-tpiperidinomethyl)phenoxy)propyl]-5-amino- pyrimidin-4-one or a pharmaceutically acceptable salt thereof, 2-[3-(3-(piperidinomethyl)phenoxy)propylamino]-5- acetamidopyrimidin-4-one or a pharmaceutically acceptable salt thereof, 2-[3-(3-(piperidinomethyl)phenoxy)propylaminol-5-aminopyrimidin-4-one or a pharmaceutically acceptable salt thereof; ; 2-[3-(4-(piperidinomethyl)pyrid-2-oxy)propylamino3-5-amino pyrimidin-4-one or a pharmaceutically acceptable salt thereof, 2-[3-(4-(piperidinomethyl)pyrid-2-oxy)propyl]-5-aminopyrimidin-4-one or a pharmaceutically acceptable salt thereof, 2-[3-[3-(hexahydroazepinomethyl)phenoxy]propylamino]-5- aminopyrimidin-4-one or a pharmaceutically acceptable salt thereof, or 2-[3-[3-(piperidinomethyl)phenoxy]propyl]-5-amino-6-methyl pyrimidin-4-one or a pharmaceutically acceptable salt thereof. 10. A process according to claim 1 for preparing 2-[3-(3-(piperidinomethyl)phenoxy)propyl]-5-aminopyrimidin 4-one or a pharmaceutically acceptable salt thereof. Ilvy 11. A process for preparing a compound of the formula (I) as defined in claim 1 or a salt thereof wherein R4 is hydrogen which comprises reducing a compound of the formula (XVI) or salt thereof : EMI60.1 wher1n R0, m, Y, p, q and R3 are as defined in claim;1. 12for A process for preparing 2-[3-(3-(piperidino methyl)phenoxy)propyl]-5-aminopyrimidin-4-one which comprises reducing 2-[3- (3- (piperidinomethyl) phenoxy) - propyll-5-nitropyrimidin-4-one. 13. A process according to either claim 11 or 11 wherein the reducing agent comprises stannous chloride under substantially neutral conditions. 14. A process according to claim 13 wherein the solvent comprises ethyl acetate and stannous chloride is in anhydrous form. 15. A process for preparing a pharmaceutical composition which comprises bringing into association a compound of the formula (I) as defined in claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. 16. A process according to claim 15 wherein the compound of the formula (I) is 2-[3-(3-(piperidinomethyl)phenoxy)propyl]-5-aminopyrimidin-4-one. 17. A process for preparing a compound of the formula (XVI) : EMI61.1 or a salt thereof, wherein: R0 is 2-guanidinothiazol-4-yl or a group R1R2N(CH 2n wherein: R1 and R2 are independently hydrogen, C1 6alkyl, aryl(C1-6)alkyl, heteroaryl(C1-6)alkyl, C3-1O cycloalkyl, hydroxy(C2¯6)alkyl, or halo (C26)- alkyl (wherein said hydroxy and halo groups are not substituted on the carbon atom adjacent to the nitrogen atom); or R1 and R2 together represent - (CH2) q - wherein q is 4 to 7, to form together with the nitrogen atom to which they are attached a 5-8 membered saturated ring; n is an integer from 1 to 6; Z is 2,5-furanyl, 2,5-thienyl, 2,4-pyridyl wherein the R1R2N(CH2)n group is in the 4-position, 2,4 thiazolyl wherein the R1R2N(CH2)n group is in the 2-position, or 1,3- or 1,4-phenylene; m is one; or if Z is pyridyl or phenylene m may also be zero; Y is oxygen, sulphur or methylene; or if Z is furanyl, thienyl or thiazolyl Y may also be a bond; p is two, three or four; q is zero or one; and R3 is hydrogen or C1-6alkyl: which process comprises a) for compounds of the formula (XVI) wherein q is one, reacting a compound of the formula (II) with a compound of the formula (IIIA) : R6(CH2)m-Y-(CH2) pNH2 (II) EMI62.1 wherein m, Y, p and R3 are as defined in claim 1, R6 is a group R0 as defined in claim 1 or R6 is a furan-2-yl or thien-2-yl group; and Q is a group displaceable by amine; or b) for-compounds of the formula (XVI-) wherein m is one and Y is sulphur, reacting a compound of the formula (IV) with a compound of the formula (VA) - R6-CH2-L (IV) EMI63.1 wherein R6, p, q and R3 are as defined in claim 1, and L is a moiety displaceable by thiol or chemical equivalent thereof; or c) for compounds of the formula (XVI) wherein m is one and Y is sulphur, reacting a compound of the formula (VI) or chemical equivalent thereof with a compound of the formula (VIIA): R6CH2SH (VI) EMI63.2 wherein R6, p, q and R3 are as defined in claim 1 and L1 is amoiety displaceable by thiol or chemical equivalent thereof; or d) reacting a compound of the formula (VIII) with a compound of the formula (IXB) or chemical equivalent thereof: EMI63.3 wherein R6, m, Y, p, q, and R3 are as defined in claim 1 and R7 is an ester-forming group; or e) for compounds of the formula (XVI) wherein Z is 2,4-pyridyl, m is zero and Y is oxygen, reacting a compound of the formula (X) with a compound of the formula (XIA) or derivative thereof that permits reaction to occur: EMI64.1 1 ê 3 wherein R , R , n, p, q and R are as defined in claim 1 and L2 is a group displaceable by hydroxy or the equivalent thereof; or f) for compounds of the formula (XVI) wherein Z is phenylene, m is zero and Y is oxygen, reacting a compound of the formula (XII) or chemical equivalent thereof with a compound of the formula (XIIIA): EMI64.2 R1 R2 3 wherein R1, R2, n, p, q and R3 are as defined in claim 1 and L3 is a moiety displaceable by phenol or chemical equivalent thereof; or g) for compounds of the formula (XVI) wherein RO is R1R2N(CH2)n-Z-, converting a compound of the formula (XIVA): EMI65.1 wherein Z, m, v, p, q and R3 are as defined in claim 1 and R8 is a precursor of a group RlR2N(CH2)n- as defined in claim 1; or h) for compounds of the formula (XVI) wherein q is one, reducing a compound of the formula (XVA): EMI65.2 wherein m, Y, p and R3 are as defined in claim 1, R9 is a group RO or R8-Z-as defined in claim 1 and R10 is a group -CH=N- or -CO-NH-; and thereafter where necessary i) reacting a compound wherein R6 is furan-2-yl or thien-2-yl with a Mannich reagent to form a compound of the formula (XVI) wherein n is one; ii) optionally forming a salt. 18. A process for preparing 2-[3-(3-(piperidino methyl) phenoxy) propyl] -5-nitropyrimidin-4-one which comprises reacting 4-[3-(piperidinomethyl)phenoxy]butyron- amidine and a compound of the formula (IXB) or chemical equivalent thereof as defined in claim 17. 19. A process according to claim 18 wherein the compound of the formula (IXB) or chemical equivalent thereof is of the formula EMI66.1 wherein R7 is an ester-forming group and X is a displaceable group. 20. A process according to claim 19 wherein R is C1-6alkyl and X is Cl¯6alkoxy.

Inventors: BROWN, THOMAS HENRY, TUDDENHAM, DAVID
Applicants: SMITH KLINE & FRENCH LABORATORIES LIMITED
Application year: 1984
Main classification: C07D239
IPC codes: C07D401, A61K31, C07D239, C07D417, A61P43, C07D409, C07D405