CA1132559A - Process for preparing pyrimidone derivatives - Google Patents

Abstract

ABSTRACT

2-Aminopyrimidones which are histamine H2- antagonists having the structure in which Het is an optionally substituted 2- or 4- imidazolyl, 2-pyridyl, 2-thiazolyl, 3-isothiazolyl, 3-(1,2,5)-thiadiazolyl or a 2-(5-amino-1,3,4-thiadiazolyl) group, Y is sulphur or methylene, Z is hydrogen or lower alkyl, A is C1-C5 alkylene and Het1 is a pyridyl group substituted by hydroxy or N-oxo and optionally substituted by lower alkyl or lower alkoxy, are prepared by a process in which an amine Het-CH2-Y-(CH2)2NH2 is reacted with a compound of Structure

Description

~13'~559 - 1 - 1173~p _ This invention relates to a process for preparing ~` ~~ pfiarmacological-ly active~pyrïmidone~~er~ivatives and pharmaceutical compositions containing them.

According to the present invention there is provided a pyrimidone of Structure (1) Z
HN ~ -Het-CH2-Y-(CH2)2NH ~ N ~ O
(1) in which Het is a 2- or 4- imidazolyl group optionally substituted by lower alkyl (preferably methyl), halogen (preferably chlorine or bromine~, trifluoromethyl or hydroxymethyl, a 2-pyridyl group optionally substituted by one or more(which can be the same or different) lower alkyl (preferably methyl), lower alkoxy (preferably methoxy), halogen (preferably chlorine or bromine), amino or hydroxy groups, a 2-thiazolyl group, a 3-isothiazolyl group optionally substituted by chlorine or bromine, a 3-(1,2,5)-thiadiazolyl group optionally substituted by chlorine orbromine, or a 2-(5-amino-1,3,4-thiadiazolyl) group: Y is sulphur or methylene; ~ is hydrogen or lower alkyl (pre~erably methyl); A is ClC5 alkylene; and Hetl is a pyridyl group substituted by hydroxy or N-oxo and optionally substituted by lower alkyl, or lower alkoxy.

Throughout this specif ication by the terms 'lower alkyl' and 'lower alkoxy' is meant alkyl and alkoxy groups containing 1 to4 carbon atoms which can be straight or branched. Particular lower alkyl groups are methyl, ethyl, l-propyl and 2-propyl. Particular lower alkoxy groups are methoxy, ethoxy, l-propoxy and 2-propoxy.

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1 Pre~erably Het is a 5-methyl-4-imidazolyl, 5-bromo-4-imidazolyl, 2-pyridyl, 3-methyl-2-pyridyl, 3-methoxy-2-pyridyl, 3-ethoxy-2-pyridyl, 3,4-dimethoxy-2-pyridyl, 3-~luoro-2-pyridyl, 3-chloro-2-pyridyl, 3-bromo-2-pyridyl,~
3-iodo-2-pyr~dyl, 3-bromo-4-methyl-2-pyridyl or 2-thiazolyl group.

Pre~erably Z is hydrogen.

Preferably A is straight ~,~-alkylene, particularly methylene.

Particular meanings of Hetl are 4-hydroxy-2-pyridyl, 6-hydroxy-3-pyridyl, 2-hydroxy-4-pyridyl, 4-hydroxy-5-methyl-2-pyridyl, 6-hydroxy-5-methyl-3-pyridyl, 2-hydroxy-6-methyl-4-pyridy~6-hydroxy-5-m~thoxy-3-pyridyi, N-oxo-3-pyridyl,N-oxo-6-methyl-3-pyridyl, and N-oxo-4-pyridyl.

Pre~erably ~etl is a pyridyl group substituted by hydroxy and optionally substituted by lower alkyl, and particularly 4-hydroxy-2-pyridyl, 6-hydroxy-3-pyridyl or

2-hydroxy-4-pyridyl .

The compounds of the inve~tion a're show~ and described as 4-~yrimidones and these exist in equil~brium with the corresponding 6-pyrimidones, and to a lesser extent in the ~ollowing tautomeric forms:

~ H
The 2-,4- and 6-hydroxypyridyl groups can exist as L~-pyridone tautomers, and certain o~ the Het groups can - exist in several tautomeric forms. All these tautomeric ~orms of the compounds o~ Structure 1 are withi~ the scope of the present in~ention.

~3~559 1 rn a process of the invention a compound of Structure (1) is prepared by reacting a compound o~ Structure (3);
z ~;N,I ~, A -Het 2 Het-CH2~Y-(c~2)2NH2 ¦ I
Q ~ N~0 (2) (~) in which Q is nitroamino (N02NH-), lower alkylthio, benzylthio, chlorine, bromine or other group which can be displaced with a primary amine, Z and A are as ~efined for Structure(l~ and Het is a pyridyl group substituted by hydroxy, a protected hydroxy group or N-oxo and optionally substituted by lower alkyl or lower alkoxy, with an amine o~ Structure(2~ in which Het and Y are as de~ined for Structure(l)and removal of any hydroxy protecting groups.

This reaction can be carried out at an elevated 15 te~perature in the absence of a solven~, for example at 80 to 170, pre~erably 120 to 140, or in a solvent at a~
elevated temperature, for example at the re~lux temperature of the reaction mixture. The choice of s-olvent is affected by solubility characteristics of the reactants and the particular meaning of Q. Preferably the solvent is pyridine, a picoline or mixture of picoli~es, a,lower alkanol, pre~erably ethanol or l-propanol, an aqueous mixture of a lGwer alkanol, 1,2-ethanediol, a ketone, for example acetone or 2-butanone, or a polar aprotic solvent for example dimethylformamide, dimethylacetamide, dimethylsulphoxide, hexamethylphosphoramide, sulpholane, acetonitrile or nitro-methane. Particularly preferably Q is nitroamino and the reactio~ i~ carried out in refluxing ethanol, re~luxing 1-propanol or refluxing pyridine, or Q is methylthio and the reaction is carried out in re~luxing pyridine.

1 Pre~erably approximately equimolar amounts of the reactants are used, although an excess for example a slight excess of from 1.1 to 1.5 molar equivalents or a larger excess of from 1.5 to 4 molar equivalents, of either reactant can be used. I~ an excess o~ a reactant is used then preferably an excess of the amine of Structure(2)is used.
An excess of either reactant can be present at~ the start ~ of the reaction or can be added during the course o~ the reaction.

Examples of hydroxy protecting groups are methoxymethyl, methylthiomethyl, tetrahydropyranyl, arylmethyl, for example benzyl, lower alkyl, for example methyl, and acyl, for example ~ormyl or acetyl. Compounds o~ Structure(l~in which Hetl is a 2-, 4- or 6-hydroxypyridyl group can be 15 con~eniently prepared from a compound of Structure(3)in which Het is a pyridyl group with a 2-,4-, or 6-lower alkoxy substituted by acid hydrolysis o~ the product o~ the reaction with an amine of Structure(~

The compounds of Structure(3)i~ which Q is nitroamino 20 can be prepared by reacting a ~-oxoester of Structure(4) 0~
CH-A-Het3' ~02R

(4) iu which Z is hydrogen or lower alkyl, R is lower alkyl, A is as defined for Structure(~, and Het3 is a pyridyl group optionally substituted by lower alkyl, or a pyridyl group substituted by hydroxy, a _protected hydroxy group, or N-oxo 30 and optionally substituted by lower alkyl or lower alkoxy wit~ nitroguanidine, and when Het3 is a pyridyl ~roup optiona-lly substltuted by lower alkyl or lower alkoxy t reacting the product with an oxidising agent to give a N-oxo-pyridyl derivative, and optionally removing any ~ydroxy 35 protecting group present.

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1 The compounds of Structure(3)in which Q is lower alkyl-thio or benzylthio can be prepared by reacting a ~-oxoester of Structure(4)in which Het3 is a pyridyl group substituted by hydroxy, a protected hydroxy group or N-oxo, and optionally substituted by lower alkyl or lower alkoxy, with thiourea, and alkylating or benzylating the 2-thiouracil formed, and optionally removing any hydroxy protecting group present.
The c~mpounds of Structure(3)in which Q is chlorine or 10 bromine can be prepared by reacting a ~-oxoester of Structure ~4)with guanidine and diazotising the product in hydrochloric acid in the presence of cuprous chloride or in hydrobromic acid in the presence o~ cuprous bromide, and when Het3 is a pyridyl group optionally substituted by lower alkyl or tower 15 alkoxy, reacting the product with an o~idising agent to give a-N-oxo-pyridyl derivative, and optionally removing any hydroxy group present.
Preferably the reactions of the ~-oxoester o~ Structure ~4 ~ith nitroguanidine, thiourea and guanidine are carried out 20 in the presence of a base, for example, an alkali metal lowe~ alkoxide, preferably sodium methoxide or sodium ethogide, an alkali metal carbonate or hydroxide, preferably potassium carbonate or sodium hydroxide, sodium hydride or a quarternary ammonium hydro~ide, ~or ex~mple benzyltrimethyl-25 ammonium hydroxide. Preferably this reaction is carried outat an elevated temperature, for example the re~lux temperature o~ the solvent mixture. Preferably the solvent is a lo~er ~lkanol, for example ethanol, an aqueous mixture of a lo~er alkanol, a ketone, for example 2-butanone, or a polar 30 aprotic solvent, ~or example dimethylformamide. When Z is hydrogen the ~-o~oester of Structure(4)can be used in the l'orm of a hemiacetal of a lower alkanol.

Preferably a peroxycarboxylic acid, for example 3-35 chloroperoxybenzoic acid, peroxybenzoic acid or peracetic acid is used as the oxidising agent to convert a pyridyl group into a N-oxo-pyridyl group. Preferably this oxidation is carried out in acetic acid.

~3;~55 1 The amines of Structure(2)in which Y is sulphur can be prepared by reacting cysteamine with a compound of formula Het-CH2L where L is a group displaceable with a thiol, for example hydroxy, acyloxy (for example acetoxy, methane-sulphonyloxy or p-toluenesulp~onyloxy), lower alkoxy (for example metho~y)" chlorine, bromine or triarylphosphonium (for example triphenylphosphoLium). Preferably L is hydroxy or methoxy and the reaction is carried out under æidic conditions, for example in hydrochloric or hydrobromic 10 acid.

The amines oi' Structure(2)in which Y is methylene and Het is a 2-pyridyl group with a lower alko~y group or halogen atom in the 3-position can be prepared by reacting a 2-halo-

3-nitropyridine with diethyl 2-(2-cyanoethyl)-malonate.
15 Hydrolysis and decarboxylation oi the product ~ollowed by reduction with palladium and charcoal glves a 3-amino-3-(3-cyanopropyl)pyridine which can be diazotised in 2~ sulphuric acid and alkylated in dimethyl sulphoxide to give a 3-alko~y-2~3-cyanopropyl)pyridi~e. The 3-amino-2-(3-cyanopropyl~ .
20 pyridines can be reduced with lithium aluminium hydride to give a 4-(3-amino-2-pyridyl)-buty-lamine which can be diazotised in strong hydrochloric acid in the presenee of cuprous chloride to give a 3-chloro amine, or diazotised 1 stro~g hydrobromic acid in the presence of cuprous bromide 25 to give a 3-bromo amine, or diazotised in dilute sulphuric acid containing sodium iodide to give a 3-iodo amine. The 3-amino-2-(3-cyanopropyl)pyridines can be diazotised in fluoroboric acid and reduced with lithium aluminium hydride to give a ~-(3-fluoro-2-pyridyl)butylamine.

The amines o~ Structure(2)in which Y is methylene a~d Het is a 2-thiazolyl group can be prepared by reacting a thioamide of structure ~H2CS(CH~)4Q where Q is a protected amino group with a dialkyl acetal o~ bromoacetaldehyde and removal o~ the amino-protecting group.

2~S9 l The esters of Structure(4)can be prepared by alkylating a dialkyl malonate ~oll~wed by hydrolysis and decarboxylation, or by condensing an aldehyde with malonic acid and decarboxylating, esteri~ying and reducing the product.

The compounds of Structure(l)have histamine E2-antagonist activity and also have histamin~ Hl-antagonist activity and are particularly active as histamine H2-antagonists whe~
compared to analogous compounds in which Hetl is other than a pyridyl ring substituted by hydroxy or N-oxo. The compounds lO of Structure(l)also have a lo~ lipophilicity as measured by octanol-water distribution.

In this speci~ication by histamine H2-receptors is meant receptors defined by Black et al. (Nature, 236, 385 (1972)) as those histamine receptors which are not blocked by 15 mepyramine but are blocked by burimamide, and by histamine Hl-receptors is meant receptors in~olved in mepyramine-sensiti~e histamine responses. Compounds which block - ~
histamine H~-receptors are referred to as histamine H2-- an~agonists and compounds which block histamine ~l-receptors 20 are referred to as hi~tamine ~l-antagonists Bloc~ade OI histamine H2-receptors is of value in inhibiting the biological actions o~ ~istamine which are not inhibited by histamine Hl-antagonists. Histamine H2-antagonists are acti~e, for example, as inhibitors of gastric 25 acid secretion, as antiinfl~ ~ory agents and as agents ~hich act on the cardiovascular system, for example as inhibitors of the ef~ects of hlstamine on blood pressure.

In some physiological conditions the biological actions of histamine are mediated through both histamine ~1- and ~2-30 receptors and blockade o~ both types of receptors isuseful. These conditions include inflammation mediated by histamine, ~or example skin inflammation, and those ~13'~55~3 1 hypersensitivity responses due to the action o~ histamine at ~1- and H2-receptors, ~or example allergies.

The activity of the compounds of Structure (1) as histamine H2-antagonists can be demonstrated by the inhibition of histamine-~timulated secretion of gastric acid irom the lumen-per~used stomachs of rats anaesthetised with urethane, at doses of less than 16 ~icromoles per kilogram intravenously. This procedure is referred to in Ash and Schild, Brit. J. Pharmac. Chemother. 27, 427 (1966). Their 10 activity as histamine H2-antagonists can also be demonstrated by their ability to inhibit other actions o~ histamine which?
according to the above mentioned paper of Ash and Schild, are not mediated by histami~e Hl-receptors. For example, they inhibit the actions o~ histamine on the isolated guinea pig 15 atrium and isolated rat uterus. They inhibit the basal secretion o~ gastric acid and also that stimuIated by pentagastrin or by food. In a conventional test such as the measurement o~ blood pressure in the anaesthetised cat, at doses o~ ~rom 0.5 to 256 micromoles per kilogram intrave~ously 20 they inhibit the vasodilator action o~ histamine. The potency o~ these compounds is illustrated by the-e~ective doses producing 5070 i~hibition o~ gastric acid secretion i~
the anaesthetised rat and the dose pro,ducing 50~ inhibition o~ the histamine-induced tachycardia in the isolated guinea 25 pig atrium (less than 10 4 Molar).

~132~S9 9 _ 11730p 1 The activity of the compounds of Structure (1) as histamine H1-antagonists can be demonstrated by the inhibition of histamine-stimulated contractions of the isolated guinea-pig ileum. It is advantageous to administer a single compound having histamine Hl- and H2-antagonist activity rather than to administer individual compounds having histamine Hl-antagonist activity and histamine H2-antagonist activity as difficulties arising from differing rates of absorption 10 and pharmacokinetic characteristics are avoided A pharmaceutical composition having utility as a histamine H2- antagonist can be prepared by mixing a compound of Structure (1) in the basic form, or in the form of an acid addition salt with a pharmaceutically-acceptable acid, with a pharmaceutically-acceptable 15 diluent or carrier. Such addition salts include those with hydrochloric, hydrobromic, hydriodic, sulphuric and maleic acids and may conveniently be formed from the corresponding compounds of Structure (1) by standard procedures, for example by treating them 20 with an acid in a lower alkanol or by the use of ion exchange resins to form the required salt either directly from the compound in the base form from a different addition salt.

The pharmaceutical carried employed can be a solid 25 or liquid. Examples of solid carriers are lactose, maize starch, potato starch, or modified starches, dicalcium phosphate, terra alba, sucrose, celluloses, talc, gelatin, agar, pectin, acacia, magnesium stearate and stearic acid. Examples of liquid carriers are syrup, peanut oil, 30 olive oil, alcohol, propylene glycol, polyethylene glycols and water.

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., , If a solid carrier is used, the composition can be prepared in the form of a tablet, capsule containing powder or pellets, troche or lozenge. The amount of solid carrier in a unit dosage form is generally from about - 25 mg to about 300 mg. If a liquid carrier is used, the composition can be in the ~orm of a syrup, emulsion?
multiple emulsion, sterile injectable liquid or an aqueous or non-aqueous solution or liquid suspension. Other additives such as preservatives, for example antioxidants or antibacterials, and/or flavouring or colouring agents can also be included. The sterile liquids can be lS prepared in ampoules, multidose vials or unit dose disposable systems. The preparation can also be in a semi-solid form, for example a cream, paste, oi~tment or gel, or in a liquid or aerosol form for topical application. The pharmaceutical compositions are prepared by conventional techniques involving procedures such as milling, mixing, granulating and compressing, spray dryi~g,freeze drying or dissolving or dispersi~g the ingredients as appropriate to the desired preparation.
The active ingredient is present in the compositions in an effective amount to block histamine H2-receptors.
Preferably, each dosage unit contains the acti~e ingredient in an amount of from about 50 mg to about 250 mg.

~ The active ingredient is preferably administered one to six times per day. The daily dosage regimen is preferably from about 150 mg to about lSOO mg. The route of administration can be oral or parenteral. --55~
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1 The invention is illustrated by the following Examples in which temperatures axe in C.
Example 1(a) A mixture of 2 methoxy-5-cyanopyridine (61.26 g), semi-carbazide hydrochloride (76.4 g), sodium acetate (74.92 g), ethanol (1300 ml) and water (400 ml) was hydrogenated at 344 ~Pa using Ra~ey nic~el catalyst (l.0 g). The mixture was evaporated to a volume of 500 ml, water (1000 ml) was added and the mixture was allowed to stand at 0 overnight. The mixture was filtered and the solid was washed with water and 10 dissolved in 10% hydrochloric acid (1000 ml). Formaldehyde solution (36% w/v, 450 ml) was added and the mixture was warmed ~or 15 minutes, allowed to cool and was added to a solution of sodium acetate (298.5 g) in water (900 ml). This mixture was extracted with ether and the combined e~tracts 15 ~ere successively washed with aqueous potassium carbonate and water and were dried and evaporated to give 6-metho~ypyridine-3-car~ogaldehyde (31.5 g, 50%)t m.p. 48-49.

(b) A mixture of 6-methoxypyridine-3-carboxaldehyde (2.34 g)~
monoethyl malonate (4.51 g), pyridine (12 ml) and piperidine 20 (~ drops) was heated under reflu~ for 5 hours a~d was evaporated to an oil. This oil was partitioned between ether and dilute aqueous ammonia. The,'ether layer was washed with water and evaporated to an oil which crystallised on standing to give ethyl 3-(6-methoxy-3-pyridyl)acrylate 25 (2.8 g, 79~), m.p. 49-52.

(c) Ethyl 3-t6-metho~y-3-pyridyl)acrylate (32.33 g) in ethanol (160 ml) was hydrogenated at 344 kPa and 40 using palladium-on-charcoal catalyst (5%, 0.2 g). The mixture was iiltered and the ~iltrate was evaporated to give ethyl 3-(6-30 methoxy-3-pyridyl)propionate (32.7 g) as an oil~

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_ 12_ 1 (d) A mixture of ethyl 3-(6-methoxy-3-pyridyl)propionate (32.74 g) and ethyl ~ormate (17.22 g) was added dropwise over 1.5 hours to a stirred suspension of sodium hydride in oil (50~, 9.38 g) in 1,2-dimethoxyethane (50 ml) cooled to -2, and allowed to stand overnight at room temperature.
The mixture was poured on to ice and the mixture wa~
extracted with ether (discarded), and the aqueous phase was adjusted to pH 5 with 2N sulphuric acid. An oil was precipitated and crystallised on standing to give ethyl 10 2-~ormyl-3-(6-methoxy-3-pyridyl)propionate (25.9 g, 70%), m.p. 91.5-94. A sample recrystallised ~rom aqueous ethanol had m.p. 93-94.

(e) Nitroguanidine (4.7 g) was added to a solution o~ sodium methoxide (prepared i~rom 1.15 g sodium) in methanol (50 ml) 15 a~d the mixture was boiled under-reilux ~or 45 minutes.
~thyl 2-~ormyl-3-(6-methoxy-3-pyridyl)propionate (10.7 g) was added and the mixture was refluged ~or 34 hour~ and evaporated to a residue. This residue was dissolved in water and the solution was extracted with chloro~orm . 20 (subse~uently discarded). The aqueous solution was adjusted to pH 5 with acetic acid, and the solid which precipitated out was ~iltered off to give 2-nitroamino-5-(6-methoxy-3-pyridylmethyl)-4-pyrimidone,m.p. 183.5-186.

(~) An equimolar mixture o~ 2-nitroamino-5-(6-methoxy-3-25 pyridylmethyl)-4-pyrimidone and 2-(5-methyl-4-imidazolyl methylthio)-ethylamine was re~luxed in ethanol ~or i8 hours.
The solid which crystallised out on cooling was recrystal-lised from ethanol to give 2-[2-(5-methyl-4-imidazolyl methylthio)ethylamino]-5-(6-methoxy-3-pyridylmethyl)-4 30 pyrimidone~m.p. 197-198.5 in 63~ yield.

(g) 2{2-(5-Methyl-4-imidazolylmethylthio)ethylamino~-5-(6-methoxy-3-pyridylmethyl)-4-pyrimidone (0.55 g) in 2~
hydrogen chloride in ethanol was boiled under re~lu~ ior 24 1~L'32~5 l3_ 1 hours. The mixture was evaporated to dryness and the residue was recrystallised from 2-propanol~ethanol containing hydrogen chloride to give 2-[2-(5-methyl-4-imidazolylmethyl-thio)ethylamino]-5-(6-hydroxy-3-pyridylmethyl)-4-pyrimidone tr1hydrochlorideSm.p. 205-209 in 71% yield.

Example 2 (a) An equimolar mixture of 2-nitroamino-5-(6-methoxy-3-pyridylmethyl)-4-pyrimidone and 2-(2-thiazolylmethylthio) ethylamine was re~luxed in ethanol for 18 hours. The solid lOwhich crystallised out on cooling was recrystallised from ethano~ to give 2-[2-(2-thiazolylmethylthio)ethylamino]-5-(6-methoxy-3-pyridylmethyl)-4-pyrimidone~m.p. 95-97 in 60qo yield.

(b) 2-[2-(2-Thiazolylmethylthio)ethylamino]-5-(6-methoxy-153-pyridylmethyl)-4-pyrimidone in 2N hydrogen chloride in ethanol was boiled under re~lux ~or 24 hours. The mixture was evaporated to dryness and the residue wa~ recrystallised from 2-propanol/ethanol containi~g hydrogen chloride to give 2-[2-(2-thiazolylmethylthio)ethylamino]-5-(6-hydroxy-3-20pyridylmethyl)-4-pyrimidone trihydrochloride,u.p. 200-204.

Exam~le 3 (a) Sodi~m (20.8 g) was dissolved in methanol (285 ml), a ~solutio~ of 2-chloro-4-cyanopyridine (115.53 g) i~ methanol-dioxan (1:1, 850 ml) was added and the mixture was boiled 25under reflux for 2~ hours and was allowed to cool. The mixture was ~iltered and the volume of the filtrate was reduced by evaporation to 200 ml and water (400 ml) was added. The solid which precipitated out was $iltered o~
to give 2-methoxy-4-cyanopyridine (57.2 g, 51%)~ m.p.
30 93-95.5.

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1 (b) A mixture o~ 2-methoxy-4-~yanopyridine (57.2 g), semicarbazide hydrochloride (71.24 g), sodium acetate (69.86 g), ethanol (1200 ml) and water (370 ml) was hydrogenated at 344 kPa using Raney nickel catalyst (1.0 g). The mixture was evaporated to a volume of 450 ml, water (900 ml) was added and the mixture was allowed to sta~d at 0 overnight. The mixture was filtered and the solid was washed with water and was dissolved in 10~ hydrochloric acid (950 ml). Formaldehyde 10 solution (36% w/v, 420 ml) was added and the mixture was warmed for 30 minutes, allowed to cool and was added to a solution of sodium acetate (280 g) in water ~840 ml). The mixture was extracted with ether (3 z 500 ml) and th~ combined e~tracts were successively washed with 15 aqueous potassium carbonate and water and were dried and evaporated to give 2-methoxypyridine-4-carboxaldehyde (20.53 g, 35%) m.p. 33-5~. A sample recrystallised from petroleum ether had ~.p. 33-36.

(c) Substitutio~ of 2-methoxypyridine-4-carboxaldehyde 20 for 6-methoxypyridine-3-carbo~aldehyde in the general procedure of E~ample 1 (b,c,d) gave ethyl 2-formyl-3-(2 methoxy-4-pyridyl)propionate as an oil, and treatment of this with nitroguanidi~e and sodium me~hoxide according to the procedure of Example l(e) gave 2-~itroamino-5-(2-25 methoxy-4-pyridylmethyl)-4-pyrimidone in 59% yield, m.p.
194-195.5 (from aqueous acetic acid).

(d) An equimolar mixture of 2-nitroamino-5-(2-m~thoxy-4-pyridylmethyl)-4-pyrimidone and 2-(5-methyl-4-imidazolyl methylthio)ethylamine was heated under re~lux in ethanol 30 for 18 hours. The solid which crystallised out on cooling was recrystallised ~rom methanol to give 2-~2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(2-methoxy-4-pyridyl methyl)-4-pyrimidone, m.p. 177-178 in 51% yield.

_ 15_ l The latter compound was heated under reflux in 2N hydrogen chloride in ethanol for 24 hours and the mixture was evaporated to dryness. The residue was recrystallised ~rom 2-propanol/ethanol containing hydrogen chloride to give 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(2-hydroxy-4-pyridylmethyl)-4-pyrimidone trihydrochloride, m.p.
172-176, Example,4 An equimolar mixture o~ 2-nitroamino-5-(2-methoxy-4-10 pyridyl~ethyl)-4-pyrimidone and 2-(2-thiazolylmethylthio) ethylamine was heated under re~lux in ethanol for 18 hours.
The solid which crystallised out on cooling was puri~ied by column chromatography on silica gel and recrystallisation ' from 2-propanol-ethanol to give 2-[2-(2-thiazolylmethyl 15 thio)ethylamino]-5-(2-methoxy-4-pyridylmethyl)-4-pyrlmidone, m.p~ 105.5-106.5 in 41% yield. The latter compound was heated under reflu~ in 2N hydrogen chloride in ethanol ~or 24 hours to give 2-[~-(2'-thiazo~yImethylthio)ethylamino}-5-(2-hydroxy-4-pyridylmethyl)-4-pyrimidone monohydrochlorideg 20 ~.p. 169-173.
.
ExamPle 5 .
Reactio~ o~ 2-(3-bromo-2-pyridylmethylthio)ethylamine w.ith 1.15 molar equivalents of 2-nitroamino-5-(2-metho~y-

4-pyridylmethyl)-4-pyrimidone in refluxing ethanol for 18 25 hours gave 2-[2-(3-bromo-2-pyridylmethylthio)ethylamino]

- 5-(2-metho~y-4-pyridylmethyl)-4-pyrimidone m.p. 70-72 which was boiled under reflux i~ ethanol containing hydroge~
chloride to give 2-[2-(3-bromo-2-pyridylmethylthio) ethylamino]-5-(2-hydroxy-4-pyridylmethyl)-g-pyrimidone 30 trihydrochloride~m.p. 195-198.~.

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- 16_ .
1 Exam~le 6 (a) Substitution o~ 4-methoxypyridine-2-car~oxaldehyde ~or 6-methoxypyridine-3-carboxaldehyde in the procedure o~
Example l(b)(c) gave ethyl 3-(4-methoxy-2-pyridyl)propionate as an oil which was formylated with ethyl ~ormate and sodium hydride in 1,2-dimetho~yethane and reacted with ~itroguanidine and sodium ethoxide to give 2-~itroamino-5 (4-methoxy-2 pyridylmethyl)-4-pyrimidone~m.p. 196-198 (decomp)(~rom ethanol-acetic acid).

1~ (b ) Reactio~ of 2-~itroamino-5-(4-methox~-2-pyridy~
methyl)-4-pyrimidone with 1.06 molar e~uivalents o~
2-(5-methyl-4~imidàzolylmethylthio)ethylamine in reflu~ing ethanol for 24 hours gave 2-~2-(5-methyl-4-Lmida2olylmethyl thlo)ethylamino]-5-(4-methoxy-2-pyridylmethyl)-4-pyrimidone~
15 m.p. 128-130 (~rom 2-propanol).

(~3 A mixture o~ 2-[2-(5-methyl-4-imidazolylmethylthio) ethylamino~-5-(4-metho~y-2-pyridylmethyl)-4-pyrimidone (0.97 g) and aqueous hydr~bromic acid (48%, 2~ ml) was boiled under re~luY ~or 2~ hours and evaporated to dryness. The 20 r~sidue wa re~rystallised ~rom a mixture o~ ethanol and 2-propanol to give 2 E2-(5~methyl-4-imidazoiylmethylthio) ethylamino]-5-(4-hydroxy-2-pyridylmethyl)-4-pyrimidone trihydrobromide~m.p. 167-169~. On recrystallisation ~r~m a mixture o~ ethanol and 2-propanol the melting point o~ the ~5 sample was lower owing to loss of hydrogen bromide.
. _. _ . .. ....... - - I
E~am~les 7 and 8 _ . , . _ . _ _ _ .. _ _ _ _ _ . _ _ _ . _ . _ _ _ . . .. .. . _, . _ . _ . . _ _ . ., . . .. , .. ... . _ ... _ _ . I

(a) Sodiu~ (1.15 g) was dissolved in methanol (50 ml) and nitroguanidine (4.7 g) was added to the cooled solution. The miæture was heated under re~lu~ ~or 45 minutes, ethyl 2-formyl-3-(3-p~ridyl)propionate (9.3 ~) was added portionwise and the mi~ture was heated under reflug ~or 45 hours and evaporated to dryness~ Water was added to the ~3~5S9 1 residue and the mixture was extracted with chloro~orm. The residual aqueous phase was adjusted to pH 5 with acetic acid, and the solid which was precipitated was filtered off, washed and dried to give 2-nitroamino-5-(3-pyridylmethyl)-4-pyrimidone, m.p.214.5-216 in 38% yield.

(b) 3-Chloroperoxybenzoic acid (10.35 g) was added to 2-nitroamino-5-(3-pyridylmethyl)-4-pyrimidone (12.35 g) in acetic acid (300 ml) and the mixture was stirred at room temperature for 18 hours and at 60 for 5 hours and allowed to cool to room temperature. The solid was filtered off and purified by precipitation from solution in dilute sodium hydroxide by the addltion of hydrochloric acid to give 2-nitroamino-5-(N-oxo-3-pyridylmethyl)-4-pyrimidone, m.p.
271(decomp).

(c) Reaction of 2-nitroamino-5-(N-oxo-3-pyridylmethyl)-4-pyrimidone with one equivalent o~
(i) 2-(5-meth~1-4-imidazolylmethylthio)ethylamine an~
(ii) 4-(3-chloro-2-pyridyl)butylamine, in refluxing ethanol gave 20 7, 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(N-o~o-3-pyridylmethyl ?- 4-pyrimidone, m.p. 95-97, and 8. 2-[4-(3-chloro-2-pyridyl)butylami~o] 5-(N-oxo-3-pyridylmethyl)-4-pyrimidone, m.p. 84-86.

E~ample_9 5a) A mixture of 6-methylpyridine-3-carboxaldehyde (51.57 g), malQnic acid (44.30 g), piperidine (6 ml) and pyridine (300 ml) was stirred at 100 for 3 hours and was allowed to cool. The mixture was evaporated to dryness, water was added to the residue and the solid was filtered off and recrystallised from ethanol-acetic acid to give 3-(6-methyl-4-pyridyl)acrylic acid (41.Z5 g), m.p. 213.5-215.5.

1:~L3~59 1 (b) A stirred mixture of 3-(6-methyl-3-pyridyl)acrylic acid (50.~0 g) dry ethanol (350 ml) and concentrated sulphuric acid (25 ml) was heated under reflux for 18 hours and ethanol (~ 2$0 ml) ~as removed by evaporation. The residue was S poured into ice-aqueous ammonia and the mixture was extracted with ether. The ether extracts were washed with water and evaporated to an oil which crystallised on standing to give ethyl 3-(6-methyl-3-pyridyl)acrylate, m.p. 36-37.

(c) Ethyl 3-(6-methyl-3-pyridyl)acrylate (60.36 g) was 10 hydrogenat~d in ethanol at 35 and 355 kPa using palladium-pn charcoal catalyst (10%, 1.0 g). The mixture was ~iltered and the filtrate was evaporated to give ethyl 3-(6-methyl-3-pyridyl)propionate as an oil.

(d) A mixture of ethyl 3-(6-methyl-3-pyridyl~propionate 15 (1.31 g) and ethyl formate (7.43 g) was added dropwise to a stirred suspension o~ sodium hydride (50% dispersion in oil, 4.07 g) in dry 1,2-dimetho~yethane (24 ml) maintained at 0. The mixture was allo~ed to warm to room temperature, stirred overnight and poured into ice-water (300 g). The 20 mi~ture was extracted with ether, the aqueous phase was adjusted to pH 5.4 ~ith hydrochloric acid, and the solid which separated was collected to give ethyl 2-formyl-3-~6-methyl-3-pyridyl)propionate (10.5 g, 70%), mOp. 142-4.

(e) A solution of ethyl 2-formyl-3-(6-methyl-3-pyridyl)-25 propioDate (1.5~ g) in methanol (20 ml) was added to astirred solution of sodium methoxide (~rom 0.161 g sodium) in methanol (20 ml). Dried nitroguanidine (0.73 g) was added and the mi~ture was heated under re~lux overnight and evaporated to dryness. The residue was dissolved in water 30 (50 ml) and the solution was extracted with chloroform and the aqueous phase was adjusted to pE 5 with acetic acid.
The solid which precipitated was filtered off and recrystal-lised ~r~m methanol-acetic acid to give 2-nitroamino-5-(6-methyl-3-pyridylmethyl)-~-pyrimidone (0,5 g, 27%), 35 m.p. 215-6 (decomp).

1:1;32S59 1 (f) Reaction of 2-nitroamino-5-(6-methyl-3-pyridyl methyl)-4-pyrimidone with 3-chloroperoxybenzoic acid in acetic acid gave 2-nitroamino-5-(N-oxo-6-methyl-3-pyridyl methyl)-4-pyrLmidone, m.p. 232 (decomp).

(g) Reaction o~ 2-~itroamino-5-(~-oxo-6-methyl-3-pyridylmethyl)-4.-pyrimidone with one equi~alent o~ 4-(3-chloro-2-pyridyl)butylamine in reflu~ing ethanol gives ~ 2-[4-(3-chloro-2-pyridyl)butylamino]-5-(N-oxo-6-methyl-3-pyridylmethyl)-4-pyrimidone.

Example 10 Substitution o~ 4-(3-methoxy-3~pyridyl)butylamine ~or 2-(5-methyl-4-imidazolylmethylthio)ethylamine in the procedure of Example 3(d) gave 2-[4-(3-methoxy-2-pyridyl) butylamino]-5-(2-methoxy-4-pyridylmethyl)-4-pyrimidone, m.p. 72-7~ (from aqueous 2-propanol) which was heated under reflux in 2N hydrogen chloride in ethanol to give 2-~4-(3-methoxy-2-pyridyl)butylamino]-5-(2-hydroxy-4-pyridylmethyl)-4-pyrimidone.trihydrochloride m.p.
168-171.

. Examples 11 to 13 ~ubstitution of (i) 4-(2-pyridyl)butylamine (ii) 4-(3-chloro-2-pyridyl)butylamine (iii) 4-(3-~romo-2-pyridyl)butylamine ~or 2-(5-methyl-4-imidazolylmethylthio)ethylamine in the procedure of Eæample 3(d) gives 11. 2-[4-(2-pyridyl)butylamino~-5-(2-hydroxy-4-pyridylmethyl)-4-pyrimidone 12. 2~[4-(3-chloro-2-pyridyl)butylamino~-5-(2-. hydroæy-4-pyridylmethyl)-4-pyrimidone 13.~- 2-[4-(3-bromo-~-pyridyl)butylamino]-5-(2-hydroæy-4-pyridylmethyl)-4-pyrimidone ~L~IL3~5S9 -- 20 ~
1 Examples 14 to 17 Substitution o~ (i) 4-(2-pyridyl)butylamine (ii) 4-(3-methoxy-2-pyridyl)butylamine (iii) 4-(3-chloro-2-pyridyl)butylamine (iv) 4-(3-bromo-2-pyridyl)butylamino ~or 2-(5-methyl-4-imidazolylmethylthio)ethylamine (a) in the procedure of ~xample l(~)(g) gives (i) 2-[4-(2-pyridyl)butylamino]-5-(6-hydroxy-3-pyridylmethy`l)-4-pyrimidone (ii) 2-~4-(3-methoxy-2-pyridyl)butylamino]-5-(6-hydroxy-3-pyridylmethyl)-4-pyrimidone (iii) 2-[4-~3-chloro-2-pyridyl)butylamino]-5-(6-hydroæy-3-pyridylmethyl)-4-pyrimido~e (iv) 2-[4-(3-bromo-2-pyridyl)butylamino]-5-(6-hydroxy-3-pyridylmethyl)-4-pyrimidone , (b) in the procedure o~ ~xample 6(b)(c) gives 14~ 4-(2 pyridyl)butylami~o]-~-(4-hydroxy-2-pyridylmethyl)-4-pyrimidone : 15. 2-[4-(3-methogy-2-pyridyl)butylaminoJ-5-(4-hydro~y-~-pyridylmethyl)-4-pyrimidone 20 16. 2~4-(3-chloro-2-pyridyl)butylamino]-5 (4-hydroxy-2-pyrid~lmethyl)-4-pyrimidone 17; 2-~4 (3-~romo-2-pyridyl)butylamino]-5-(4-hydroxy-2-~ridylmethyl)-4~pyrimidone Eæamples 18 and 19 Substitution o~ 5,6-dimethoxypyridine-3-carboxaldehyde i'or 6-methoxypyridine-3-carboxaldehyde in the procedure o~ ~xample l(b)-(e) gives ~-nitroamino-5-(5,6-dimethoxy-3-pyridylmethyl)-4-pyrimidone and this is reacted with 2-(5-~ethyl-4-imidazolylmethylthio)ethylami~e or 4-(3-chloro-2-pyridyl)butylamine and the product heated under reflux in 2N hydroge~ chloride in etha~ol to give 18. 2-~2-(5-methyl-4-imidaz~lylmethylthio)ethylamino]-5-(6-hydroxy-5-methoxy-3-pyrid~lmethyl)-4-pyrimidone and 19. 2-[4-(3-chloro-2-pyridyl)butylamino]-5-(6-hydro~y-5 methoxy-3-pyridylmethyl)-4-pyrimido~e.

_ 21 -1 Preparation of pharmaceutical co~osition for oral ad~inistration A pharmaceutical composition is prepared containing % w/w r The product o~ any one o~ Example 1 to 19 5~
A 1 Dibasic calcium phosphate dihydrate 20 Approved colouring agent 0.5 Polyvinylpyrrolidone 4.0 ~icrocrystalline cellulose 8.0 1~ B ~aize starch 8.0 . Sodium starch glycollate 4.0 ~agnesium stearate 0.5 by mi2i~g together the ingredients A (substituting lactose o~ microcrystalline cellulose for dibasic calcium pho~phate dihydrate i~ de~ired), 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 mi~ture into tablets, containi~g an amount o~ product corr~sponding to 100 mg, 150 mg or 200 mg o~ the free base.

l~?,Z~53 1 Preparation of pharmaceutical composition for topical administration A pharmaceutical composition is prepared containing 70 w/w r Stearyl alcohol 15.0 A ~ Beeswax 8.0 ¦ Sorbitan monooleate 1.25 Polyo~yethylene sorbitan monooleate 3.75 rThe product o~ any one o~ Examples 1 to ~ 1.0 ¦ Sorbitol solution B.P. ~.5 --~ Citric acid 0.2 B ~ Sodium citrate 0.05 ¦~ethylparaben 0.1~
¦ Propylparaben 0.02 1~ ~Water to 100 A mixture o~ the~ingredients A is heated to 72 an~
added with stirring to a mixture o~ ~he ingredients B at 70, and the stirring is continued until a cream is ~or~ed.

Claims (15)

11730p CLAIMS:

1. A process for preparing a pyrimidone of Structure (1) (1) in which Het is a 2- or 4- imidazolyl group optionally substituted by lower alkyl, halogen, trifluoromethyl or hydroxymethyl, a 2-pyridyl group optionally substituted by one or more lower alkyl, lower alkoxy, halogen, amino or hydroxy groups, a 2-thiazolyl group, a 3-isothiazolyl group optionally substituted by chlorine or bromine, a 3-(1,2,5)-thiadiazolyl group optionally substituted by chlorine or bromine, or a 2-(5-amino-1,3,4-thiadiazolyl) group; Y is sulphur or methylene; Z is hydrogen or lower alkyl; A is C1-C5 alkylene; and Het1 is a pyridyl group substituted by hydroxy or N-oxo and optionally substituted by lower alkyl or lower alkoxy; characterised in that a compound of Structure(3) Het CH2-Y-(CH2)2NH2 (2) (3) in which Q is nitroamino, lower alkylthio, or chlorine, Z and A are as defined for Structure(1),and Het2 is a pyridyl group substituted by 11730p hydroxy, a protected hydroxy group or N-oxo and optionally substituted by lower alkyl or lower alkoxy is reacted with an amine of Structure(2) wherein Het and Y are as defined for structure(1) and followed by removal of any hydroxy protecting groups.

2. A process according to Claim 1 in which Q is nitro-amino and the reaction between the compound of Structure 3 and the amine of Structure(2)is carried out in refluxing ethanol, refluxing 1-propanol or refluxing pyridine.

3. A process according to Claim 1 in which Q is methylthio and the reaction between the compound of Structure(3)and the amine of Structure(2)is carried out in refluxlng pyridine.

4. A process according to any one of Claims 1, 2 or 3 for preparing compounds of Structure(1)in which Het1 is a 2-,4- or 6-hydroxypyridyl group which comprises reacting a compound of Structure 3 in which Het2 is a pyridyl group with a 2-,4- or 6- lower alkoxy substituent with an amine of Structure(2)and subjecting the product to acid hydrolysis.

5. A process according to any one of Claims 1, 2 or 3 in which Het is a 5-methyl-4-imidazolyl, 5-bromo-4-imidazolyl, 2-pyridyl, 3-methyl-2-pyridyl, 3-methoxy-2-pyridyl, 3-ethoxy-2-pyridyl, 3,4-dimethoxy-2-pyridyl, 3-fluoro-2-pyridyl, 3-chloro-2-pyridyl, 3-bromo-2-pyridyl, 3-iodo-2-pyridyl, 3-bromo-4-methyl-2-pyridyl or 2-thiazolyl group.

6. A process according to any one of Claims 1, 2 or 3 in which Z is hydrogen.

7. A process according to any one of Claims 1, 2 or 3 in which A is methylene.

8. A process according to Claim 1 in which Het1 is 4-hydroxy-2-pyridyl, 6-hydroxy-3-pyridyl, 2-hydroxy-4-pyridyl, 4-hydroxy-5-methyl-2-pyridyl, 6-hydroxy-5-methyl-3-pyridyl, 2-hydroxy-6-methyl-4-pyridyl, 6-hydroxy-5-methoxy-3-pyridyl, N-oxo-3-pyridyl, N-oxo-6-methyl-3-pyridyl or N-oxo-4-pyridyl.

9. A process for the preparation of 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(2-hydroxy-4-pyridylmethyl) -4-pyrimidone which comprises reacting 2-(5-methyl-4-imidazolylmethylthio)ethylamine with 2-nitroamino-5-(2-methoxy-4-pyridylmethyl)-4-pyrimidone and removing the hydroxy protecting group.

10. A process of the preparation of 2-[2-(2-thiazolylmethyl-thio)ethylamino]-5-(2-hydroxy-4-pyridylmethyl)-4-pyrimidone which comprises reacting 2-(2-thiazolylmethylthio)ethylamine with 2-nitroamino-5-(2-methoxy-4-pyridylmethyl)-4-pyrimidone and removing the hydroxy protecting group.

11. A process for the preparation of 2-[2-(3-bromo-2-pyridylmethylthio)ethylamino]-5-(2-hydroxy-4-pyridylmethyl) -4-pyrimidone which comprises reacting 2-(3-bromo-2-pyridylmethylthio)ethylamine with 2-nitroamino-5-(2-methoxy-4-pyridylmethyl)-4-pyrimidone and removing the hydroxy pro-tecting group.

12. A pyrimidone of Structure (1) as defined in Claim 1, whenever prepared by the process of Claim 1 or by its obvious chemical equivalents.

13. 2-[2-(5-Methyl-4-imidazolylmethylthio)ethylamino]-5-(2-hydroxy-4-pyridyl-methyl)-4-pyrimidone whenever prepared by the process claimed in Claim 9 or by its obvious chemical equivalents.

14. 2-[2-(2-Thiazolyl-methylthio)ethylamino]-5-(2-hydroxy-4-pyridylmethyl)-4-pyrimidone whever prepared by the process claimed in Claim 10 or by its obvious chemical equivalents.

15. 2-[2-(3-Bromo-2-pyridylmethylthio)ethylamino]-5-(2-hydroxy-4-pyridylmethyl)-4-pyrimidone whenever prepared by the process claimed in Claim 11 or by its obvious chemical equivalents.