PYRIMIDINE COMPOUNDS

Abstract: Compounds of the formula (I) :- (I) and their salts are histamine H₂-antagonists, wherein: R o is 2-guanidinothiazol-4-yl or a group R¹R²N(CH n -Z- wherein R¹ and R² are independently hydrogen, C 1-6 alkyl, phenyl(C 1-6 )alkyl, furanyl(C 1-6 )alkyl, thienyl(C 1-6 )alkyl, C 3-10 cycloalkyl, hydroxy( C2-6 )alkyl, or halo(C 2-6 )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) r - wherein r 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; R³ is hydrogen or C 1-6 alkyl; and R⁴ is hydrogen, optionally substituted C 1-6 alkyl, C 3-10 - cycloalkyl, C 3-10 cycloalkyl(C 1-6 )alkyl, C 2-6 alkenyl or C 2-6 alkynyl,and when q is zero R⁴ may also be -(CH₂) s B wherein s is 1 to 6 and B is optionally substituted aryl or heteroaryl. Pharmaceutical compositions containing them are described as are processes for their preparation.

Description: This invention relates to 5-oxypyrimidinone 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 H₂-antagonists. 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 H₂-antagonist. 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. A small group of compounds has now been invented, which compounds have a 5-oxy substituent on a pyrimidin-4-one ring and have a particularly favourable level of activity as H₂-antagonists. Accordingly the present invention provides a compound of the formula (I) :- or a salt thereof, wherein: R o is 2-guanidinothiazol-4-yl or a group R¹R²N(CH₂) n -Z-wherein: R¹ and R² are independently hydrogen, C 1-6 alkyl, phenyl(C 1-6 )alkyl, furanyl(C 1-6 )alkyl, thienyl(C 1-6 )alkyl, C 3-10 cycloalkyl, hydroxy(C 2-6 )alkyl, or halo (C 2-6 )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) r - wherein r 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; R³ is hydrogen or C₁₋₆alkyl; and R⁴ is hydrogen, or C₁₋₆alkyl. 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. Suitably R¹ is phenyl(C₁₋₆)alkyl for example benzyl or phenethyl, furanyl(C₁₋₆)alkyl such as furanylmethyl or thienyl(C 1-6 )alkyl such as thienyl-methyl, halo(C 2-6 )alkyl for example 2,2,2-trifluoroethyl, or C 3-10 cycloalkyl for example cyclohexyl. More suitably R¹ is C 1-6 alkyl, for example methyl, ethyl or propyl. Suitably R² is hydrogen or C 1-6 alkyl, 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 R¹R²N(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) n -Z-(CH₂) m -Y-may represent 2-dimethylaminomethylthiazol-4-ylmethylthio. In a further aspect R o is 2-guanidinothiazol-4-yl, in such compounds preferably Y is sulphur, for example R o -(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) m Y-(CH₂) p - is -O-(CH₂)₃- or -CH₂SCH₂CH₂-. For example R¹R²N(CH₂) n -Z-(CH₂) m -Y(CH₂) p - may represent: 4-dimethylaminomethylpyrid-2-ylmethylthioethyl, 4-piperidinomethylpyrid-2-ylmethylthioethyl, 4-dimethylaminomethylpyrid-2-yloxypropyl, 4-piperidinomethylpyrid-2-yloxypropyl, 3-dimethylaminomethylphenoxypropyl, 3-piperidinomethylphenoxypropyl, 3-dimethylaminomethylphenylmethylthioethyl, 3-piperidinomethylphenylmethylthioethyl or 3-pyrrolidinomethylphenoxypropyl. Preferably p is 3 when m is zero. Preferably p is 2 when m is one. Suitably q is zero. Suitably R³ is C₁₋₆alkyl for example methyl. Preferably R³ is hydrogen. Favourably R⁴ is hydrogen. Preferably R⁴ is C₁₋₆alkyl for example methyl, ethyl, n-propyl, isopropyl or n-butyl. Of these methyl is favoured. In a favoured aspect the present invention provides compounds of the formula (I) wherein R¹R²N(CR₂) n -is dimethylaminomethyl or piperidinomethyl, Z is 1,3-phenylene, m is zero, Y is oxygen, p is 3, q is zero, and R³ is 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 : 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 histamine-induced 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. 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 H₂-antagonists. 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 m is one and Y is sulphur, reacting a compound of the formula (IV) with a compound of the formula (V) :- wherein R⁶, p, q and R³ are as hereinbefore defined, R 5' is an optionally protected group R⁴, and L is a moiety displaceable by thiol or chemical equivalent thereof; or b) 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): wherein R⁶, p, q, R 5' and R³ are as hereinbefore defined and L¹ is a moiety displaceable by thiol or chemical equivalent thereof; or c) reacting a compound of the formula (VIII) with a compound of the formula (IX) or chemical equivalent thereof: wherein R⁶, m, Y, p, q, R³ and R⁵ are as hereinbefore defined, and R⁷ is an ester-forming group; or d) 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: wherein R¹, R², n, p, q, R³ and R⁵ are as hereinbefore defined and L² is a group displaceable by hydroxy or the equivalent thereof; or e) 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): wherein R¹, R², n, p, q, R³ and R 5' are as hereinbefore defined and L³ is a moiety displaceable by phenol or chemical equivalent thereof; or f) for compounds of the formula (I) wherein R⁰ is R¹R²N(CH₂) n -Z-, converting a compound of the formula (XIV): wherein Z, m, Y, p, q, R³ and R 5' are as hereinbefore defined and R⁸ is a precursor of a group R¹R²N(CH₂) n - as hereinbefore defined; 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 hydroxy group to hydroxy; iii) optionally forming a salt. Examples of the moiety L include chloro, bromo, hydroxy, C₁₋₆alkoxy for example methoxy, C₁₋₆alkanoyloxy for example acetoxy, arylsulphonyloxy for example 4-methylbenzenesulphonyloxy, or C₁₋₆alkylsulphonyloxy 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) q - moiety. When performed under basic conditions the group R 5' represents a protected group R⁴. Suitably in the reaction of compounds of the formulae (VI) and (VII) L¹ is chloro, bromo, arylsulphonyloxy for example 4-methylbenzenesulphonyloxy or C 1-6 alkylsulphonyloxy 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: wherein R⁷ and R⁵ 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-0- (for example C 1-6 alkanoyloxy), or an ether forming residue (for example C 1-6 alkoxy such as methoxy or ethoxy). Additional examples for X include secondary and tertiary amino groups, for example di-C 1-6 -alkylamino such as dimethylamino, cyclic amines such as piperidino, pyrrolidino and morpholino, anilino and 1-imidazolyl. Preferably X is C 1-6 alkoxy and in particular ethoxy. In compounds of the formulae (IX) and (IXA) the ester-forming group R⁷ can be a C 1-4 alkyl 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 C 1-4 alkoxides, 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 C 1-4 alkanol, (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 0°C and 100°C, suitably between ambient and 70°C. In the compounds of the formula (XIV) in one suitable aspect R⁸ is a group R¹R²N(CH₂) x CO(CH₂) y -wherein x + y = n-1. 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 R¹R²N(CH₂) x CO(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 R¹R²N(CH₂) n . Such transformations may be caried out in conventional manner. Suitable protected hydroxy groups OR⁵ and OR 5' are those which may be converted to hydroxy by hydrolysis or by hydrogenolysis in conventional manner. These include optionally substituted benzyloxy groups referred to above. Suitably acid hydrolysis of a benzyloxy group to a hydroxy group may be employed. Suitably functional groups on the group R⁴ may be protected and deprotected in conventional manner. 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 R⁶ is unsubstituted furan-2-yl or thien-2-yl, in a convenient solvent such as ethanol. Alternatively where R¹ and R² are both C 1-4 alkyl, the Mannich reagent may be a di-(C 1-4 alkyl)methylene ammonium salt for example dimethylmethylene ammonium chloride or iodide, or may be a bis di-C 1-4 alkylaminomethane, for example bis(dimethylamino)methane. Similarily, or concurrently, a group -CH₂NR a R b may be introduced on to a furanyl- or thienyl- alkoxy group R⁴0-. 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 R¹R²N(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 C₁₋₄alkanol, 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 hydrochloric, hydrobromic, sulphuric, phosphoric, acetic, citric, maleic, lactic, ascorbic, fumaric, oxalic, methanesulphonic and ethanesulphonic acids. The compounds of the formula (IV), (VI), (VIII) and (X) may be prepared for example by the methods described in European Patent Application Publication Nos 3677, 4793, 13071, 15138, 17679, 17680, 24873, 49173, 87274 and 89153 and UK Patent Application 2030979A. The compounds of the formula (V) wherein q is zero may be prepared by the reaction of a compound of the formula (XVII) :- 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 (XVIII) :- 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). The compounds of the formulae (XVII) and (XVIII) may be prepared from the corresponding nitriles. 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). The following Examples serve to illustrate this invention. Example 2 2-[3-[3-(Piperidinomethyl)phenoxy]propyl]-5-hydroxypyrimidin-4-one 2-[3-[3-(Piperidinomethyl)phenoxy]propyl]-5-benzyloxypyrimidin-4-one (0.68 g) was stirred under reflux for 24 hours in 1N hydrochloric acid (20 ml). The mixture was concentrated under reduced pressure and taken to pH 8 with aqueous sodium bicarbonate. This mixture was extracted with n-butanol (3x20 ml); these extracts were combined, washed with water (2x5 ml), dried (MgSO₄) and evaporated under reduced pressure to give the title compound. This was dissolved in methanol containing ethanolic HCl, excess solvent was evaporated under reduced pressure and the residue crystallised from isopropanol-acetone to give 2-[3-[3-(piperidinomethyl)phenoxy]propyl]-5-hydroxypyrimidin-4-one dihydrochloride (0.24 g), m.p. 192-4°C Example 3 2-[3-[3-(Piperidinomethyl)phenoxy]propyl]-5-methoxypyrimidin-4-one. The sodium salt of ethyl 3-oxo-2-methoxypropionate was obtained from ethyl methoxyacetate (1.18 g) and ethyl formate (0.89 g) by a method analogous to that of Example 1. This was stirred under reflux for 30 hours with the filtrate from the reaction of 4-[3-(piperidinomethyl)phenoxy]butyronamidine hydrochloride (3.12 g) and sodium (0.28 g) (see Example 1). The reaction mixture was cooled, evaporated under reduced pressure and water (25 ml) added. The solution was extracted with diethyl ether (3x20 ml), taken to pH 9 with glacial acetic acid and extracted into chloroform (3x25 ml). The combined chloroform washings were dried (MgSO₄) and evaporated under reduced pressure. The residue was crystallised from diethyl ether to give the title compound (1.36 g), m.p. 124-126.5°C (recrystallisation from isopropanol-ether). Example 4 2-[3-[3-(Piperidinomethyl)phenoxy]propyl]-5-ethoxypyrimidin-4-one. In a method analogous to Example 3 and on the same molar scale, ethyl ethoxyacetate (1.32 g), ethyl formate (0.89 g) and 4-[3-(piperidinomethyl)phenoxy]butyronamidine hydrochloride (3.12 g) gave the title compound (0.97 g) as a white solid on crystallisation from isopropanol-ether, m.p. 104.5-105.5°C. Example 9 A pharmaceutical composition for oral administration is prepared containing: 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 2 to 4 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 for the following Contracting States : BE, CH, DE, FR, GB, IT, LI, LU, NL, SE A compound of the formula (I) :- or a salt thereof, wherein: R o is 2-guanidinothiazol-4-yl or a group R¹R²N(CH₂) n -Z-wherein: R¹ and R² are independently hydrogen, C 1-6 alkyl, phenyl(C 1-6 )alkyl, furanyl(C 1-6 )alkyl, thienyl(C 1-6 )alkyl, C 3-10 cycloalkyl, hydroxy(C 2-6 )alkyl, or halo(C 2-6 )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) r wherein r 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; R³ is hydrogen or C₁₋₆alkyl; and R⁴ is hydrogen, or C₁₋₆alkyl. A compound according to claim 1 wherein R³ is hydrogen. A compound according to claim 1 or 2 wherein R⁴ is hydrogen or methyl. A compound according to any one of claims 1 to 3 wherein R¹ and R² together represent -(CH₂) r - wherein r is 4 to 7. A compound according to any one of claims 1 to 4 wherein R¹R²N(CH₂) n -Z- is 3-piperidinomethylphenyl-. A compound according to claim 1 which is : 2-[3-(3-(piperidinomethyl)phenoxy)propyl]-5-hydroxypyrimidin-4-one or a pharmaceutically acceptable salt thereof, 2-[3-(3-(piperidinomethyl)phenoxy)propyl]-5-methoxypyrimidin-4-one or a pharmaceutically acceptable salt thereof, or 2-[3-(3-(piperidinomethyl)phenoxy)propyl]-5-ethoxypyrimidin-4-one or a pharmaceutically acceptable salt thereof. A pharmaceutical composition which comprises a compound according to any one of claims 1 to 6 and a pharmaceutically acceptable carrier. A compound according to any one of claims 1 to 6 for use as a therapeutic agent. A compound according to any one of claims 1 to 6 for use as an H₂-antagonist. 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 m is one and Y is sulphur, reacting a compound of the formula (IV) with a compound of the formula (V) :- wherein R⁶, p, q and R³ are as hereinbefore defined, R 5' is an optionally protected group R⁴, and L is a moiety displaceable by thiol or chemical equivalent thereof; or b) 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): wherein R⁶, p, q, R 5' and R³ are as hereinbefore defined and L¹ is a moiety displaceable by thiol or chemical equivalent thereof; or c) reacting a compound of the formula (VIII) with a compound of the formula (IX) or chemical equivalent thereof: wherein R⁶, m, Y, p, q, R³ and R⁵ are as hereinbefore defined, and R⁷ is an ester-forming group; or d) 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: wherein R¹, R², n, p, q, R³ and R⁵ are as hereinbefore defined and L² is a group displaceable by hydroxy or the equivalent thereof; or e) 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): wherein R¹, R², n, p, q, R³ and R 5' are as hereinbefore defined and L³ is a moiety displaceable by phenol or chemical equivalent thereof; or f) for compounds of the formula (I) wherein R⁰ is R¹R²N(CH₂) n -Z-, converting a compound of the formula (XIV): wherein Z, m, Y, p, q, R³ and R 5' are as hereinbefore defined and R⁸ is a precursor of a group R¹R²N(CH₂) n -as hereinbefore defined; 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 hydroxy group to hydroxy; iii) optionally forming a salt. Claim for the following Contracting State : AT A process for preparing a compound of the formula (I) :- or a salt thereof, wherein: R⁰ is 2-guanidinothiazol-4-yl or a group R¹R²N(CH₂) n -Z- wherein: R¹ and R² are independently hydrogen, C₁₋₆alkyl, phenyl(C₁₋₆)alkyl, furanyl(C₁₋₆)alkyl, thienyl(C₁₋₆)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) r - wherein r 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; R³ is hydrogen or C₁₋₆alkyl; and R⁴ is hydrogen, or C₁₋₆alkyl: a) 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) :- wherein R⁶, p, q and R³ are as hereinbefore defined, R 5' is an optionally protected group R⁴, and L is a moiety displaceable by thiol or chemical equivalent thereof; or b) 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): wherein R⁶, p, q, R 5' and R³ are as hereinbefore defined and L¹ is a moiety displaceable by thiol or chemical equivalent thereof; or c) reacting a compound of the formula (VIII) with a compound of the formula (IX) or chemical equivalent thereof: wherein R⁶, m, Y, p, q, R³ and R⁵ are as hereinbefore defined, and R⁷ is an ester-forming group; or d) 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: wherein R¹, R², n, p, q, R³ and R⁵ are as hereinbefore defined and L² is a group displaceable by hydroxy or the equivalent thereof; or e) 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): wherein R¹, R², n, p, q, R³ and R 5' are as hereinbefore defined and L³ is a moiety displaceable by phenol or chemical equivalent thereof; or f) for compounds of the formula (I) wherein R⁰ is R¹R²N(CH₂) n -Z-, converting a compound of the formula (XIV): wherein Z, m, Y, p, q, R³ and R 5' are as hereinbefore defined and R⁸ is a precursor of a group R¹R²N(CR₂) n -as hereinbefore defined; and thereafter as 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 hydroxy group to hydroxy; iii) optionally forming a salt.

Inventors: BROWN, THOMAS HENRY, DURANT, GRAHAM JOHN
Applicants: SMITH KLINE & FRENCH LABORATORIES LIMITED
Application year: 1985
Main classification: C07D239
IPC codes: C07D417, A61P43, C07D239, C07D405, A61K31, C07D401, C07D409