IE45082B1 - Derivatives of pyrimidone and thiopyrimidone - Google Patents
Derivatives of pyrimidone and thiopyrimidoneInfo
- Publication number
- IE45082B1 IE45082B1 IE2814/76A IE281476A IE45082B1 IE 45082 B1 IE45082 B1 IE 45082B1 IE 2814/76 A IE2814/76 A IE 2814/76A IE 281476 A IE281476 A IE 281476A IE 45082 B1 IE45082 B1 IE 45082B1
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- pyrimidone
- pyridyl
- het
- compound according
- pyridylmethyl
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/56—One oxygen atom and one sulfur atom
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Thiazole And Isothizaole Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The pyrimid-4-one derivatives of the general formula I, in which the symbols have the meaning given in Claim 1, as well as the corresponding pyrimid-4-thione derivatives, are valuable drugs which possess activity both as histamine H1 antagonists and as histamine H2 antagonists. They are prepared by reacting an isocytosine derivative of the formula II, in which Q represents a reactive radical which is displaced by an amine during the reaction, with an amine of the formula III. The compounds thus obtained are converted into the corresponding pyrimid-4-thione derivatives by reaction with phosphorus pentasulphide.
Description
This Invention relates to pyrimidone derivatives, to processes for preparing these compounds and to pharmaceutical compositions containing them.
Many physiologically active substances elicit their biological actions 5 - by interaction with specific sites known as receptors. Histamine is J such a substance and has a number of biological actions. Those biological ; actions of histamine which are Inhibited by drugs commonly called anti-histamines of which m'epyramine, diphenydramine and chloropheniramine are examples, are mediated through histamine Hj-receptors (Ash and Schild, Brit. J. Phamsc. Chemother, 27.427, (1966)), . and drugs With this activity are hereinafter referred to as histamine antagonists. However, other of the biological actions of histamine are not inhibited by histamine H^-antagonists and actions of this type which are inhibited by a compound described by Black et al. (Nature, 238, jl5 385, (1972) and called burimamidears mediated through receptors which are defined by Black et al. as histamine H,-receptors. Thus histamine Hg-receptors may be defined as those histamine receptors which are not blocked by mppyramine but are blocked by burimamide. Compounds which block histamine Hg-receptors are referred ttf as histamine Hg-antagonists.
' - Blockage of:histamine Hg-receptors is of utility in inhibiting ‘ - the biological actions of histamine which are not inhibited by histamine. H|-antagonists. Histamine Hg-antagonists are therefore useful, ; for example, as inhibitors of gastric acid secretion, as anti-inflammatory i .....’ ' 2 ¢3082 agents and as agents which act on the cardiovascular system, for example, as inhibitors of the effects of histamine on blood pressure.
In the treatment of certain conditions, for example, inflammation and in inhibiting the actions of histamine on blood pressure, a combination of histamine and (^-antagonists is useful.
The compounds of this invention have both histamine H-j-antagonist and histamine (^-antagonist activity, and are useful in the treatment of conditions wherein histamine (^-antagonists are useful and conditions wherein a combination of histamine H^- and (^-antagonists are useful.
According to the present invention there is provided a compound of formula (1):- Z (I) and salts thereof where Het is a Z- or 4-imidazolyl group optionally substituted with lower alkyl, halogen, trifluoromethyl or 45083 hydroxymethyl; a 2-pyridyl group optionally substituted with lower alkyl, lower alkoxy, halogen, amino or hydroxy; a 2-thiazolyl group, a 3-isothiazolyl group optionally substituted with chlorine or bromine; a 3-(l,2,5)-thiadiazolyl group optionally substituted with chlorine or bromine; or 2-(5-amino -1,3,4thiadiazolyl) group; Y is sulphur or methylene; Z is hydrogen or lower alkyl; X is oxygen or sulphur; W is methylene, oxygen or sulphur; p and q are such that their sum is from 1 to 4 when W is oxygen or sulphur, or from. 0 to 4 when U.is methylene; Het' is a 5 or 6 membered Ιθ heteroaryl group optionally substituted with lower alkyl, lower alkoxy, or may have a phenyl group or substituted phenyl group fused to it.
When used herein lower alkyl and lower alko:^ mean such groups containing up to four carbon atoms.
When Het is a 2- or 4-imidazolyT or 2-pyridyl group substituted with lower alkyl, preferably the substituent is methyl.
When Het is a 2- or 4-imidazolyl or 2-pyridyl group substituted with halogen preferably the substituent is chlorine or bromine.
When Het is a 2-pyridyl group substituted with lower alkoxy preferably the substituent is methoxy.
Preferably Het is a 2-thiazolyl, 5 - methyl - 4 - imidazolyl, - bromo - 4 - imidazolyl, 3 - bromo -^- pyridyl, 3 - chloro 2 - pyridyl „ 3 - methoxy - 2 - pyridyl or 3 - hydroxy - 2 - pyridyl group.
Preferably Y is sulphur, Preferably X is oxygen Preferably Z is hydrogen, Preferably W is methylene and p and q are both 0. αΰ083 By way of example Het' represents a pyridyl, furyl, thienyl, thiazolyl, oxazolyl, isothiazolyl, imidazolyl, pyrazinyl, pyridazinyl, or pyrimidyl group optionally substituted with lower alkyl, lower alkoxy or may have a benzene ring or substituted benzene ring fused to it.
Preferably Het' is a 2-furyl, 2-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-thiazolyl, 2-imidazolyl, 2-pyrimidyl, 2-pyrazinyl or 4-pyridazinyl group, each of which are optionally substituted with lower alkyl or lower alkoxy.
More preferably Het1 is a 2-thienyl, 2-pyridyl, 3-pyridyl, 4- pyridyl or 2-thiazolyl group. ' s : Most preferably Het' is a 3-pyridyl group.
Some specific compounds which fall within the scope of the present invention are:15 2 - [2 - (5 - methyl - 4 - imidazolylmethylthio)ethylaminoj| 5- (4- pyr idyl methyl) - 4 - pyrimidone - [2-(2- thiazolylmethylthio)ethylaminoj -5-(4- pyridylmethyl) 4 - pyrimidone - [2-(3- bromo - 2 - pyridylmethylthiojethylamino] - 5 20 (4 - pyridylmethyl) - 4 - pyrimidone 2-(2-(5- methyl - 4 - imidazolylmethylthiojethylaminoj - 5 (2 - thienylmethyl) - 4 - pyrimidone - [2 - (5 - methyl - 4 - imidazolylmethylthio)ethylamino] - 5 (2 - pyridylmethyl) - 4 - pyrimidone yj.30 8" - £2-(5- methy] - 4 - imidazolylmethylthiojethylamino] - 5 (3 - pyridyl methyl) - 4 - pyrimidone - 02-(3- bromo - 2 - pyridyl methy lthio) ethyl ami no] - 5 (2 - pyridylmethyl )-4- pyrimidone 2-02-(5- methyl - 4 - imidazolyl methyl thio) ethyl ami no] -5-(2- thiazolylmethyl) - 4 - pyrimidone - 02 - (2 - thiazolylmethylthiojethylamino] -5-(3pyridylmethyl) - 4 - pyrimidone - 02 - (3 - bromo-2-pyridy1methylthio)ethylaniino£j - 5 10 (3 - pyridylmethyl) - 4 - pyrimidone - [j - (3 - methoxy - 2 - pyridyl)butylaminoj - 5 (3 - pyridylmethyl) - 4 - pyrimidone and 2-04-(3 - amino - 2 - pyridyl)butylamino] -5-(3- pyridylmethyl) 15 - 4 - pyrimidone Examples of salts of compounds of formula (I) include in particular those with acids such that the addition salt is pharmaceutically acceptable, in particular, those with hydrochloric, hydrobromic, hydroiodic, sulphuric and maleic acids.
The compounds of formula (I) are shown and described as 4-pyrimidone and 4-thione derivatives and these derivatives exist in equilibrium with the corresponding 6-one and 6-thiOne tautomers. <2 50 8 3 These compounds also exist to a lesser extent as the mercapto and hydroxy tautomers, and the pyrimidine ring may also exist in the following tautomeric forms: H Certain Het and Het' may also exist in several tuatomeric forms, and it will be understood that all these tautomeric forms are within the scope of the present invention.
Compounds of formula (I) and their salts may also exist in and hydrate forms,Ait will be understood that these are also within the scope of this invention. 8¾ The compounds of formula (I) can be prepared by a process which comprises reacting ah isocytosine of formula (2):- (CH2)p-ii-(CH2)q-Het' (2) wherein Ζ, U, p, q, and Het1 are as defined with reference to 5 formula (I) and Q is a grouping which is displaced by an amine, with an amine of formula (3):, Het-CH2-Y-(CH2)2-NH2 (3) where Het and Y are as defined in formula (I), In formula (2) Q is for example lower alkyl, benzylthio or halogen. Preferably Q is methylthio.
Preferably the reaction is carried out in the absence of a solvent at an elevated temperature, e.g., 150°C, or in the presence of a solvent, for example in refluxing pyridine.
Compounds of formula (I) wherein W is sulphur may alternatively 15 be prepared by a process which comprises treating an isocytosine of formula (4):8 (4) where Het, Y, Z and p are as defined in formula (I), and V is a mercapto, chloro or bromo group, with a compound of formula (5):U-(CH2)q~ Het‘ (5) where Het' is as defined in formula (I) U is SH when V is chloro or bromo and U is chloro or bromo when V is mercapto, provided that when I) is chloro or brcmo q may only be 0 if U is an ‘active1 halogen (i.e. ortho or para to a heterocyclic nitrogen atom).
Acid addition salts of compounds of formula (I) can be prepared by standard procedures for example by reacting the free base with an acid in a lower alkanol or by use of an ion exchange resin. Acid addition salts of compounds of formula (I) can also be interconverted using ion exchange resins.
The intermediates of formula (2) where W is methylene, Z is hydrogen and Q is loweralkylthio (shown as formula (7)) can be prepared according to Scheme 1:9 SCHEME 1 Het’(CH2)aCH2CH3C02Et (5) 1) Ha, HCO^Et 2) . thiourea (6) alkyl halide or sulphate ,^Λ«νί« AIRS (7) In this scheme Het1 is as defined in formula (I), a is 0 to 4 and Alk is lower alkyl.
The esters of Formula {5; can be prepared by general methods knorm to the art, for example compounds where a is 0 Gan fee prepared by condensing an aldehyde*3et’-CEO with malonic acid in the presence -o£ pyridine and piperidine and hydrogenating and esterifying the product.
The intermediates of Formula 2 where w is methylene, Z is lower alkyl, and Q’ is loweralkyl thio (shown .as Formula 8) can fee prepared according to Scheme 2 wherein Het1 is as defined in formula (I), a is 0 to 4, Hal is chlorine or bromine, and Alk is lower alley!. 3 0 8 3 SCHEME 2 CH2(CH2)aHet> ZCOCHgCOgEt NaOEt,HalGHg(CH2)&Het' Z-COCHCOgEt thiourea 2)aHet’ .alk?] alkyl halide or sulphate CH2(CH2)aHet’ .The intermediates of Formula 2 methylene (shown ;as Formula 10) where Q is halogen and ff is can be prepared according to Scheme 3f 1 where Het' and Z are as defined in formula (1), a is 0 to 4 and Hal is chlorine or bromine.
SCHEME 3 CHgCCHg)aHet' ZCOCHCOgEt sodium salt (9) . 1) HCl, NaN02 2) Cu2Hal2 Ψ Z hn η Hal^N -Ad (10) ,CH2(CH2)aHet’ ie' intermediates of Formula2 where. W is oxygen or sulphur can he prepared by the following methods :(a) p is 0 Het' (CHg^WCHgCOgEt 1) HCO„Et, Na --£-2) thiourea 3) alkyl halide sulphate AlkS A-π o · or WIs oxygen or sulphur (b) p is 1 These compounds can be prepared from ethyl 3-benayloxypropionate, or a similar protected derivative of ethyl 3-hydroxypropionate, by a process analogous to that outlined in Scheme 1, followed successively by deprotection, treatment with thionyl chloride, and treatment with the sodium derivative of Het'(CH2)qOH or Het' (CHgJ^SH.
IQ (c) p is 2 to 4 ethyl formate, sodium^ 45083 1) thiourea 2) alkyl halide or sulphate f is oxygen or sulphur p is 2 to 4 Compounds of Formula 1 wherein X is sulphur can be prepared by treating the compounds of Formula 1 wherein X is oxygen with phosphorus pentasulphide in a solvent such as pyridine.
The amines of formula (3) can be prepared by processes or by analogy with processes described in our Patent Specifications Nos. 35577, 3&Q5Q and 1708/75and in British Patent Specification No. 1,565,647. •j The compounds of Formula 1 block histamine Hg-receptors, - that is they inhibit the biological actions of histamine which are not inhibited by histamine H^-antagonists such as mepyramine but are inhibited by burimamide. For example, the compounds of this invention have been found to inhibit histamine-stimulated secretion of gastric acid from the lumen-perfused stomachs of rats anaesthetised with urethane9 at doses of from 0.5 to 16 micromoles per kilogram intravenously. This procedure is referred to in the'abovementioned paper of Ash and Schild. The activity of these compounds as histamine Hg-antagonists is also demonstrated by their ability to inhibit other actions of histamine which, according to the above mentioned paper of Ash and Schild, are not mediated by histamine H^-receptors, For example, they inhibit the actions of histamine on the isolated guinea pig atrium and isolated rat uterus.
The compounds of this invention inhibit the basal secretion of gastric acid and also that stimulated by peatagastrin or by food.
In addition, the compounds of this invention show antiinflammatory activity in conventional tests such as the rat paw oedema test, where the oedema is induced by an irritant, the rat paw volume is reduced by subcutaneous injection of doses of a compound of Formula 1. In a conventional test, for example· the measurement of blood pressure in the anaesthetised cat, th© action of the compounds of this invention in inhibiting the vasodilator action of histamine can also be demonstrated. The level of activity of the compounds of this invention is illustrated by the effective dose producing 50% inhibition of gastric acid secretion in the anaesthetised rat (which for many of the compounds of Formula 1 is from 1 to 10 micromoles per kilogram) and the dose producing 50% inhibition of 35 histamine-induced tachycardia in the isolated guinea pig atrium. 43083 The compound of formula (I) also block histamine Ιή-receptors, that is they inhibit the biological actions of histamine which are inhibited by mepyramine, di-phenydramine and chlorpheniramine. For example the compounds of this invention have been found to inhibit the action of histamine in the isolated guinea-pig ileum. For many of -5 the compounds of formula (I) a dose of from 10 Mole inhibits the histamine-stimulated contractions of the guinea pig ileum.
For therapeutic use, the compounds of formula (I) and their pharmaceutically acceptable acid addition salts will normally be administered as a pharmaceutical composition.
Accordingly the invention also provides a pharmaceutical composition comprising a compound of formula (I) as defined above or a pharmaceutically acceptable acid addition salt thereof and a pharmaceutically acceptable carrier.
The compositions of this invention can be prepared in a form suitable for oral, parenteral or topical application by selection of an appropriate carrier.
The carrier employed can be a solid, for example lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate or stearic acid; or a liquid, for example, syrup, peanut oil, olive oil or water.
If a solid carrier is used, the composition can be tableted or encapsulated in powder or pellet form, in a hard gelatin shell or formed into a troche or lozenge. The amount of solid carrier can be varied widely but preferably will be from 25 mg to 1 g.
If a liquid carrier is used, the composition may be a syrup, emulsion, soft gelatin capsule, sterile injectable liquid dispensed in an ampoule, or an aqueous or non-aqueous liquid suspension. ‘ .
The compound of formula (I) or pharmaceutically acceptable salts thereof will be present in the compositions in an effective amount to block histamine Hg-receptors.
Preferably the composition will be in unit dosage form for example, a tablet or capsule and each dosage unit will contain from 50 mg to 250 mg of a compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof calculated as the free base. The pharmaceutical compositions can be prepared by conventional techniques involving procedures such as mixing, granulating and compressing or dissolving the ingredients as appropriate to the desired preparation.
Preferably administration will be once to six times daily, daily dosage regimen will preferably be from 150 mg to 1500 mg of the compound of formula (I) or pharmaceutically acceptable acid addition salt calculated as the free base.
The following Examples in which all temperatues are in degrees centigrade illustrate the invention.
The '10 EXAMPLE 1 2- [2-(5-Methyl-4-iraidazplylmethyIthio)ethylamino)-5-(4pyridylmethyl)-4-pyrimidone trihydrochloride (1) Ethyl £-(4-pyridyl)propionaie (43.45 g) and ethyl formate (13.6 g) were added over a period of 6 hours to a stirred mixture of sodium wire (5.6 g) and dry ether (150 ml) cooled by an ice-salt bath.
The mixture was stirred for 18 hours at room temperature, evaporated to dryness and the residue treated with thiourea (18.45 g) and ethanol (130 ml) and refluxed for 7 hours. The mixture was evaporated to dryness and the residue dissolved in water and the solid product precipitated by adding glacial acid to pH4. The white solid was filtered and washed with ethanol· to give 5-(4-pyridylmethyl)-2thiouracll m.p. 320-324° (decorap). (ii) A solution of 5-(4-pyridyImethyl)-2-thiouracil (11.0 g>, methyl iodide (7.2 g) and sodium hydroxide (2.1 g) in water (SO ml) and ethanol (100 ml) was stirred at 60° for 30 minutes, allowed to cool and filtered to give 5-(4-pyridylmethyl)-2-methylthio4-pyrimidone m.p. 179-182° (ethanol). (iii) An intimate mixture of 5-(4-pyridyImethyl)-2-methylthio-4-pyrimidone (5.9 g) and 2-(5-methyl-4-imidazolylmethyIthio)-ethylamine (4.3 g) was heated at 145-150° for 5 hours and allowed to cool. .The residue was triturated with water, and treated with ethanolic hydrogen chloride to give the title compound m.p. 228(Found: C, 43.6; H, 5.1; N, 17.6; S, 7.2; Cl, 21.95; C^HggClgNgOS requires.: C, 43.8; H, 5.0; N, 18.0; S, 6.9; Cl, 22.8%). 233 ;4so83 EXAMPLE 2 2- (2-Thiazolylsiethylthi6) ethylagilno~}-5- (4-pyridylmethyl)4-pyrimidone trihydrochloride hemihydrate An intimate mixture of 5-(4-pyridyImethyl)-2-methylthio4-pyrimidone (1.55 g) pad 2-(2-thiazolylmethylthio)ethylamine (1.16 g) was heated at 135-140° with frequent stirring. After cooling, the reaction mixture was triturated under water, acidified with dilute ethanolic hydrogen chloride, evaporated to dryness and. the residue recrystallised from methanol to give the title compound m.p. 190-195°.
(Pound: C, 40.3; H, 4.4; N, 14.5; S, 13.3; Cl, 21.7; C-gH^gOSg.SHCl. |H20 requires: C, 4O.*2; H, 4.4; N, 14.7; S, 13.4; Cl, 22.3%).
EXAMPLE 3 2-C2-(3-Bromo-2-pyridylmethylthiojethylaminoT-5-(4-pyridylmethyl) -4-pyrimidone dihydrochloride. -(4"PyridyImethyX)=2-methylthiO"4—pyrimidone (1.1 g) was reacted with 2-(3-bromo-2-pyridyImethylthio)ethylamine (1.15 g) according .to the procedure of Example 2. The reaction mixture was triturated under hot water, acidified with dilute ethanolic hydrogen chloride, evaporated to dryness and the residue recrystallised from ethanol to give the title compound m.p. 211-215° (decomp).
(Pound: O, 42.35; H, 3.9; N, 13.9; S, 6.3; ClgHlgBr Ng0S.2HCl requires: C, 42.S; H, 4.0;' N, 13.9; S, 6.35%) EXAMPLE 4 ' Zv(Z-(5-iietiiyl-4-imi (ii) 5-(2-ThienyImethyl)-2-thiouracil (4.5 g) was warmed at .65° with a mixture of methyl iodide (2.8 g), sodium hydroxide (0.8g), water (75 ml) and ethanol (150 ml) to give 5-(2-thienylmethyl}-2-methyIthio-4-pyriEidcae (83%) m.p. 170.5-171.5° (ethanol). (iii) An intimate mixture of 5-(2-thienyImethyl)-2-methyl- . thio-4-pyrimidone (1.43 g) and 2-(5-methy1-4-imidazolylA® methylthiojethylamine (1.03 g) was heated at 103° for 6 hours. The cooled residue was washed with water and I i treated with dilute ethanolic HCl to give the title compound in 40% yield, m.p, 172-176° (ethanol-acetonitrile).
The dihydroehloride was passed down an ion-exchange column of ISA 400 eluting with IN hydrobromic acid, and the eluate was evaporated to dryness and recrystallised from ethanolacetonitrile to give the corresponding dihydrobromide a.p. 199-203°, (Found: C, 36.7; H, 4.2; N, 13.5; S, 12.1; Br, 30.6; Gl6H19N5OS2*2HBr requires C, 36.7; H, 4.0; N, 13.4; S, 12.2; Br, 30.5%) EXAMPLE 5 2-f2-(5-methyl-4imidaa0lylmethylthio)ethylamino1 -5-(2pyridylmethyl)-4-pyriaidone trihydrochloride hemihydrate (i) Ethylp-(2-pyridyl)-propionate (19.24 g) and ethyl formate (8.5 g) were added over a period of if hours to a stirred mixture of sodium wire (2.5 g) and dry ether (80 ml) cooled by a carbon dioxide bath. The mixture was stirred for 21 hours at room temperature, evaporated to dryness and the 35 residue was treated with thiourea (8.2 g) and ethanol (70 ml) and refluxed for 7| hours. The mixture was evaporated to dryness and the residue was dissolved in water and 45,08½ * glacial acid was added to pH 5. The white ' precipitate was filtered off, washed with water and recrystallised from water-acetic acid to give 5-(2-pyridylmethyl)-2-thiouracil, m.p. 282-7° (decomp.). (ii) A solution of 5-(2-pyridylmethyl)-2-thiouraeil (S.6 g), methyl -iodide (4.3 g) and sodium hydroxide (2.5 g) in water (100 ml) and ethanol (100 ml) was stirred at 70° for 30 minutes, allowed to cool and glacial acetic acid added to pH5. The solution was partially evaporated and cooled in an ice-bath, The precipitate was filtered off and recrystallised from ethanol to give 5-(2-pyridylmethyl)-2-methyl__ thio-4-pyriaidone, m.p. 195-197.5°. lo (iii) An intimate mixture of 5-(2-pyridylmsthyl)-2methylthio-4-pyrimidone (4.7 g) and 2-(5-methyl4-imidazoiylmethylthio)-ethylamine (3.4 g) was • heated at 130-135° for 7 hours. The cooled residue was triturated with hot water and treated with dilute ethanolic HCl to give the title compound •m.p. 207-210° (aqueous ethanol) (Found: C, 42.S; H, 4.9; H, 17.8; S, 6.9; CI, 21.3; C17H2ON6OS.3HC1.|H2O 25 ! requires: C, 43.0; H, 5 ,V ET, 17.7; S, 6.8; Cl, 22.4%) ΕΣΑΜΡ1Ε 6 2-C2-(5-Methyl-4-imidazolylmQthylthio)-ethylamiao3-5 (3-pyridylmethyl)-4-pyrimidone trihydrochloride (i) Ethyl (3-pyridyl)^propionate (33.9 g) and ethyl formate (17.0 g) were added over a period of 2$ hours to a stirred mixture ’of sodium wire (5.0 g) ' and dry ether (150 ml) cooled by an ice bath. The «5082 mixture was stirred for 22 hours at room temperature, evaporated to dryness and the residue was treated with thiourea (16.5 g) and ethanol (130 ml) and refluxed for 8 hours. The mixture was evaporated to dryness and the residue was dissolved in water and acetic added to pK5 to give 5-(3-pyridylmethyl)-2-thiouracil, m.p. 271-4° (decomp.) (acetic acid-water) (ii) A solution of 5-(3-pyridylmethyl)-2-thiouracil (11.0 g), methyl' iodide (7.1 g) and sodium hydroxide (4.2 g) in water (150 al) and ethanol (150 ml) was stirred at 65° for 40 minutes, allowed to cool and acetic acid was added tc pH5. The solution was partially evaporated, cooled and filtered to give 5~(3-pyridylmethyl)-2-methylthio4-pyrimidone, m'.p. 247-9° (ex. ethanol-acetic acid). _ (iii) An intimate mixture oi 5-(3-pyridylmethyl)-2iSQ methylthio-4-pyrimidone (6.55 g) and 2-(5-methyl4-imidazolylmethylthio)-ethylamine (4.8 g) was heated at 130-135° for 7 hours. The cool mixture was triturated with hot water and treated with dilute ethanolic KC1 to give the title compound m.p, 237-241° 25 £thanol-water) (Found: C, 43.7; H, 5.2; N, 17.4;. S, 6.5; Cl~22.0. C^^HgQligOS. 3HC1 requires C, 43.8; H, 5.0; », 18.0; S, 6.9; Cl, 22.3%) EXAMPLE 7 2-C2-(3-Bromo-2-pyridylmethylthio)-ethylamino3-5-(2pyrldylmethyl)-4-pyrimidone toihydrobr.omide 'An intimate mixture of 5-(2-pyridylmethyl)-2-methylthioΦ tt 4-pyrimidone (1.5 g) and 2-(3-bromo-2-pyridylmethylthio)21 45083 ethylamine (1.6 g) was heated at 130 for 6 hours. After cooling, the residue was triturated with hot water and treated with dilute hydrobromic acid to give ths title compound, in 44.5% yield, m.p. 225-230° (decomp.) (ex g methanol-water).
(Found: C, 32.1; H, 3.1; N, 10.5; S, 4.8; Br 35.0%. C^gH^gBrNgOS.SHBr requires C, 32.0; H, 3.1; ΪΓ, 10.4; S, 4.8; Br , 35.5%), EXAMPiE 8 2- Si- (5-methyl-4-imidazoly Imethylthio)-ethylamino1-5(2-thiagolyiinet’nv1 )-4-pyrimidone trihydrochloride (i) A solution of 2-thiazoleacrylic acid (26.76 g) and concentrated sulphuric acid (10 ml) in ethanol (150 al) was refluxed for IS hours. The solution was partially evaporated and dissolved - in water. This solution was extracted with ether and the etheral extracts were evaporated to give ethyl 2-thiazoleacrylate. (ii) Ethyl 2-thiazoleacrylate (14.3 g) was dissolved in ethanol (170 ml) and hydrogenated at 40° and a pressure of 50 psi using 10% Palladium on charcoal to give ethyl 2-thiazolepropionate. (iii) Ethyl 2-thiazolepropionate (14.2 g) and ethyl formate (5.9 g) were added over a period of 2¾ hours to a stirred mixture of sodium wire (1.8 g) and dry ether (¢5 ml) cooled by an ice-bath. The mixture was stirred for 21 hours at room temperature, ’ evaporated to dryness and the residue was treated with thiourea (5.8 g) and.ethanol (60 ml) and refluxed for 9 hours. The solid product v/as obtained according to the procedure of Example 5(i) to give 5-(2-thiazoly1methyl )-2-thiouracil, ZZ '10 =4508 2 m.p. 275-280° (decomp.) (ex acetic acid). (iv) A solution of 5-(2-thiazo^.lmethyl )-2-thiouracii (4.8 g) methyl iodide (3.0 g.) and sodium hydroxide (0.9 g.) in water (75 ml) and ethanol (150 ml) was stirred at 70° for 30 minutes.
The solid product was obtained according to the procedure of Example 5(ii), giving 5-(2-thiazolylmethyl)-2-aethylthio-4-pyrimidone, m.p. 181-182.5° (ex ethanol). (v) An intimate mixture of 5-(2-thiaz.olylmethyl )-2methylthio-4-pyrimidone (1.4 g) and 2-(5-methyl4-imidazolylmethylthio)-ethylamine (1.0 g) was heated at 145-150° for 6 hours. The cooled residue was triturated with hot water and treated ' with dilute ethanolic HCl to give the title compound m.p. 208-211° (ex. ethanol-water) (Found: C, 38.9; K, 4.7; N., 17.9; S, 13.5; Cl, 21.6. C^gH^g&’gOSg-SHCl requires C, 38.2; H, 4.5; N, 17.8; 3, 13.6; Cl, 22.5%) EXAMPLE 9 2-C2-(2-Thiazolylmethylthio)-ethylamino)]-5r(3-pyridylmethyl)4- pyrimidone trihydrobromide - (3-Pyridylmethyl)-2-methylthio-4-pyrimidone (1.74 g) was reacted with 2-(2-thiazolylmethylthio)-ethylamine (1.30 g) according to the procedure in Example 2. The reaction mixture was triturated in hot water and treated with dilute hydrobromic acid to give the title compound, m.p. 229-233.5° (ex. methanol-water).
(Found: C, 32.1; H, 3.4; N, 11.7; S, 10.3; Br , 39.9; ClgH17NgOS2.3HBr requires: C, 31.9; H,· 3.4; N, 11.6; S, 10.7; Br 39.8%) EXAMPLE 10 2-C2-(3-Bromo-2-pyridylmethyIthio)-ethylamino! -5(3-pyridyImethyl)-4-pyrimidone trihydrobroaide -(3-Pyridylm.ethyl)-2-methylthio-4-pyrimidone (1.27 g) was reacted with 2-(3-broao-2-pyridyImethylthio)-ethylamine (1.35 g) according to the procedure in Example 2.
The reaction mixture was triturated with hot water and treated with dilute hydrobromic acid to give the title 3-0 compound, m.p. 217-220.5° (ex-methanol) (Found: C, 32.1; H, 3.2; N, 10.2; S, 4.5; Br 47.5; CjgH^gBrNgOS.SHBr requires: C, 32.0; H, 3.1; E, 10.4; S, 4.S; Br, 47.4%) EXAMPLE 11 Substitution of (a) ethyl P-(2-methoxy-3-pyridyl)pr0pionate (b) ethyl j'3-(3-methoxy-2-pyridyl)propionate (c) ethyl i3-(3,4-dimethoxy~2-pyridyl)propionate (<3) ©thyl ^-( 4»isoquinolyl)propionate for ethyl £-(4-pyridyl)prcpionata in the procedure of Example 1 leads to the production of (a) 2-1? -(S-mQthyl-4"imidaaolyimethyIthio)ethylaminoJ-S(2-methoxy"3-pyridyXmethyX)-4-pyrimidone (b) 2-l2"(5-methyl-4"imida2olylniethylthio)ethylamino3-5(3-methoxy-2-pyridylmetfcyl)-4-pyrimidone (c) 2-{2-(5-methyl-4"iEidazolylmethylihio)ethyXaainq3-5~ (3,4-d imethoxy-2-pyridyjLmetfcyl)-4-pyrimidone (d) ? -[2-(5-methyl"4-iaidazolylmethyIthio)ethylaaincQ "5" (4>-isoquinolylmethyl)-4-pyrimidone The starting materials may be made from the corresponding 0 8 2 heterocyclic carboxaldehyde by condensation with malonic acid and subsequent, hydi’ogenat ion and estei'if ication, EXAMPLE 12 ® Substitution of: (a) 2-(2-imidazolylmethyIthic)ethylamine ' ' (b) 2-(4-ImxdazolylmethyXthio)ethylamine (c) 2-(5-brom©-4-imidazolylmethylthio)ethylamine (d) 2-(5-trifluoromethyl~4-Imidazolyl10 inethylthio)ethylamine (e) 2-(5-hydroxymethyI-4-imidazolylmethylthio)ethylamina (i) 2-(2-pyridylmethylfhio)ethylamine (g) 2-(3-mcthyl-2-pyridylmethylthio)15 ethylamine (h) 2-(3-methoxy-2-pyridylmethylthio)ethylamine (i) 2-(3-chloro-2-pyridylmethylthio)efchylamine 2q (j) 2™(3amino-2-pyridylmethylthio)~ ethylamine (k) 2-(3-hydroxy-2-pyridylmethylthio)ethylamine (l) 2-(3-isothiazolylmethylthio)ethylamine (a) 2-(4"bromo-3-isothlazolyl»ethylthio)" ethylamine (n) 2-(3- (1,2,5)-thiadiaz0lylmethylthio)ethylamine (o) 2-(4-chlcro"3-(l,2,S)-thiadiazolylaethylthio)ethylamine (p) 2- (5-amino-2-'(l, 3,4) -thiadiazolylmethylthio)ethylamine for 2-(5~methyl-4~imidazolylmethylthio}ethylamine in the procedure of Example 6 leads to the production of:(a) 2-(2-(2iimidazolylmethylthio)ethylaminoJ-5-(3-pyridylmethyl)-4-pyrimidone ίο (b) 2-(2-(4-imidazolylmethylthio)ethylamino]-5(3-pyridylmethyl)-4-pyrimidone (c) 2-[2-(5-bromo-4-imidazolylmethylthio)ethyXaminoi5-(3-pyridyImethyl)-4-pyrimidone (d) 2- (2-(5-trifluoromethyl-4-imidazolyImethyIthio)ethylamino]-5-(3-pyridylmethyl)-4-pyrimidone (e) 2-^-(S-hydroxymethyl-d-imidazolylmethylthio)ethylamino.] -5-(3-pyridy lmethyl) -4-pyr imidone (£} 2~j2-(2-pyrldy!methylthio5ethylamino]-5-(3-pyridyXsethyl)-4-pyrimidone (g) 2-(2-(3-methyl-2-pyridylmethyIthio)ethylamino] -5(3-pyridylmethyl)-4-pyrlmidone (h) 2-(2-(3-methoxy-2-pyridylmethylthio.)ethy lamino]-5(3-pyridyImethy1)-4-pyrimidone (i) 2-(g-(3-chloro-2-pyridyImethyIthio)ethylamino] -5(3-pyridylmethyl)-4-pyrimidone (j) 2-(2-(3-amino-2-pyr'idylmethylthio)etfrylaminq]-5(3-pyridylmethyl)-4-pyrimidone (k) 2-(2-(3~hydroxy-2-pyridylmethylthio)ethylamino]-5(3-pyridylmethyl)-4-pyri.midoae (l) 2-(g-(3-isothiazolylaethylthio)ethylamino]-5(3-pyridylHethyl)=4-pyri2aidone (m) 2-(2-(4-broBO-3-isothlazolylmethylthio}ethyXamine] -5(3-pyridylmethyl)-4-pyrimidone (n) 2-|2-(3-(l,2,5)-thiadiazolylmethylthio)ethylamino]-5(3-pyridylmethyl)-4-pyrimidone (0) 2-(2-(4-chloro-3~(1,2,5)-thiadiazoly Imethylthio)ethyl amino] -S-(3-pyridylmethyl)-4-pyrimidone (p) 2-(2-{5-a3aino-2-(l,3,4)-thiadiazolylmethylthio)ethylaminq)-5={3"pyridylmethyl)-4-pyrimidone EXAMPLE 13 (i) Seaction Of 2-chloro-3-nitropyriaine with 2-(2»cyanoethyl)malonic acid diethyl ester and sodium hydride in tetrahydrofuran gives S-(3-nitro-2-pyridyl)-1,1-bis-(carbethozy)26 •isosa butyronitrile, m.p, 93.5-94.5°, which after alkaline hydrolysis and acidification gives 2-(3-cyanepropyl)-3-nitropyridine hydrochloride 142-145.5°. Reduction with hydrogen and palladium os charcoal gives 3-affiino~2-<3cyanopropyl/oyridine, and treatment of this with sodium nitrite and sulphuric acid and subsequent warming gives 2-(3-cyanopropyl)-3~hydroxypyridine. Methylation with methyl iodide and sodium ethoxide in dimethylsulphoxide and subsequent reduction with lithium.aluminium hydride gives 4-(3-methoxy2-pyridyl)butylamine. Reduction of 3-amino-2(S-cy&nopropyl)-/, · ^y-u'ditie with lithium aluminium hydride gives 4-(3~amino-2-pyridyl)butylamine. Diazotisation of 4-(3-amino-2-pyridyl) butylamine at pH 1 and treatment with cuprous chloride or cuprous bromide gives 4-(3-chloro2-pyridyl)butylamine and 4-(3-bromo-2-pyridyl)butylamine, respectively. (ii) Substitution of (a) 4-(4-imidazolyl)butylamine (b) 4-(3-methoxy-2-pyridyl)butylamlne (c) 4-(3-chloro-2-pyridyl)butylamine (d) 4-(3-bromo-2-pyridyl)butylamine ‘ (e) 4-(3-amino~2-pyridyl)butylamine for 2-(5-methyl-4-imidazolyImethylthio)ethylamine in the procedure of Example 6 leads to the production of: (a) 2-£l-(4-imidazolyl)butylamino3-5-(335 pyridylmethyl)-4-pyrimidone (b) 2-fe-(3-methoxy-2-pyridyl)butylamino3-5(3-pyridylmethyl)-4-pyrimidone (c) .2-lj4-(3-chloro-2-pyridyl)butylamino2"5(3-pyridylmethyl)-4-pyrimidone (d) 2-£4-(3-bromo-2-pyridyl)butylamino]-5(3-pyridylmethyl)-4-pyrimidone (e) 2-]4-(3-amino-2-pyridyl)butylamino]-5(3-pyridylmethyl)-4-pyrimidone EXAMPLE 14 Reaction of ethyl acetoacetate with sodium ethoxide' and 3-(chloromethyl)pyridine gives ethyl ct-(3-pyridylmethyl)aceto acetate which gives 5-(3-pyridylmethyl)-S-methyl-2-thiouracil when treated with thiourea and sodium ethoxide. Substitution of 5-(3-pyridylmethyl)-6-methyl-2-thiouracil for 5-(4-pyricJy Imethyl)-2-thiouracil in the general procedure of Example 1 gives 2-£2-(5-methyl-4-imidas01ylmethylthio)ethylamino]-5-(3-pyridylmethyl)-6-methyl-4-pyrimidone. 2-^-(5-Methyl-4-imidaaolylmethylthio)ethylamino]-5-(3pyridylmethyl)"S"propyl-4-pyrimidone may be prepared in a similar manner starting with ethyl butyroacetate.
EXAMPLE 15 Treatment of 2-{j2-(5-methyl-4"iaida3oXylmethylthio)ethylamincQ-o-(3-pyr idylmethyl)-4-pyrimidone with phosphorus peatasulphide in hot pyridine leads to the production of 2-12-(5-methyl-4-imidazolylmethylthio)ethylamino] -5-(3pyridylmethyl)pyriraid-4-thione 2-S , EXAMPLE 16 (i) Butyrolactone is treated with sodium and ethyl formate, and the product is successively treated with thiourea and methyl iodide to give 5-(2hydroxyethyl)-2-methylthio-4-pyriaidone. (ii) 5-(2-Hydroxyethyl)-2-methylthio-4-pyrimidone is treated with thionyl chloride and the product is reacted'with the sodium derivative of (a) 3-(hydroxy35 methyDpyridine and (b) 3-(mereaptomethyl)pyridine to give: (a) 5-(2-(3-pyridylmethoxy)ethyl)-2methylthio-4-pyrimidone (b) 5-(2-(3~pyridylmethylthio)ethyl)-2methylthio-4-pyrimidone (iii) substitution of: (a) 5-(2- (3-pyridylmethoxy) ethyl) -2-iaethy Ithio4-pyrimidone· (b) 5-(2-(3-pyrIdylmethylthio)ethyl)-2-methyIthio4-pyrimidone for 5-(3-pyridylmethyl)-2-methylthio-4-pyrimidone is the general procedure of Example S leads to the production of: (a) 2-03-(5-:aethyl-4-imida2olylmethylthio)ethylaainoj-5-(2-(3-pyridylmethoxy)ethyl)-4-pyrimidone (b) 2-^2-(5-methyl-4-imidazolylmethylthio)ethylawincQ -5-(2-(3-pyridylmethylthio)ethyl)-4pyrimidone (iv) substitution of: (a) S-hydroxypyridine and (b) 3-mercaptopyridine for 3-(hydroxymethyl)pyridine in procedure (ii) and (iii) above leads to the production of: (a) 2-L2-(S-methyl-4-imidazolylmethylthio)ethy1amino3-5-(2-(3-pyridyloxy)ethyl)-4-pyrimidone (b) 2-{2-(5-methyl-4-imidazolylmethylthio)ethylamino3-5-(2-(3-pyridylthio)ethyl)-4-pyrimidone (v) substitution of: (a) 3-(2~hydroxyethyl)pyridine and • (b) 3-(2-mercaptoethyl)pyndine for 3-(hydroxymethyl)pyridine in procedure (ii) and (ill) above leads to the preparation of (a) 2-[2-(5-methyl-4-imidazolylmethylthio)ethylaminql-5-(2-(2-(3-pyridyl)ethoxy)ethyl)-4pyrimidone (b) 2-(2-(5-methyl-4-imidazolybnethylthio)ethylamin&S-5-(2-(2-(S-pyridyl)ethylthio)ethyl)4-pyrimidone g (vi) substitution of Salerqlactone for butyrolactone in procedure (i) (ii) and (iii) above leads to the production of (a) 2-[2-(5-methyl-4-imidazolylmefhylthio)ethylaminq]-5-(3-(3-pyridylmethoxy)propyl)-4θ pyr imid one (b) 2-^2-(5-methyl-4-imidazolyImethy 1thio) ethylamino3-5-(3-(3-pyr idyImethylthio)propyl)-4pyrimidone' EXAMPLE 17 Ethyl 3-pyridyImethoxyacetate is converted into 5-(3pyridylmetboxy)-2-thiouracil by the general procedure of Example 1 (i). Substitution of 5-(3-pyridylmethoxy)-2thiouracil for 5-(4-pyridylmethyl)-2-thiouracil in the general procedure of Example 1 gives 2-{j2-(5-methyl-4imidazolylmethylthio)ethylaminq3-5-(3-pyridyliaethoxy)-4pyrimidone, 2-j2-(5-2iethyl-4-iEidazoXy2methyltfeio)ethylamincQ-5(3-(3-pyridylpropoxy)-4-pyrimidone and 2-{2-(5-methyl-4imidazolylmethylthio)ethylamino^-5-(3-(3-p'yridy^propylthio) -4-pyrimidone.may be prepared in a similar manner starting with ethyl 3-(3-pyridyl)propoxyacetate and ethyl 3-(3pyridyl)propylthioglycolate, respectively. 0 32 EXAMPLE 18 Substitution of (a) ethyl ]J-(2-furyl )propionate (b) ethyl ^-(5-oxazolyl)propionate (c) ethyl /5-(3-isothiazolyl)propionate (d) ethyl /3-{2~pyrimidyl)propionate (e) ethyl £-(5-pyrimidyl)propionate (f) ethyl £-(2-pyrazinylj propi onate (g) ethyl /3-(4-pyri dazi nyl) propionate for ethyl J3-(4-pyridyl)propionate in the procedure of Example 1 leads to the production of (a) 2- £2-(5-me*.hyl-4-imidazoly Imethy lthio)ethy lamino] -5(2-furylmethyl)-4-pyriraidone (b) 2-£2-(5-methyI-4-imidazolylmethylthio)ethylaminaj-5(2-oxazolylmethyl)-4-pyrimidone (c) 2- £2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5(3-isothiazolylmethyl)-4-pyrimidone (d) 2~£2~(S-methyl-4~i»iidazolyimethylthio)ethylamino] -5(2-pyrimidylmethyl)-4-pyrimidone (e) 2-|2-(5-methyl-4-imidazolyImethylthio)ethylamino] -5-* (5-pyrimidylmethyl)-4-pyrimidone (f) 2-£2-(5-methyl-4-iffiida3olylmethylthi3)ethylaminoj-5~ (2-pyrazinylmetfi/l) -;-pyriinidons (g) 2-£2-(5-methyl-4"lmidazolyImethylthio)ethylamino] -5(4-pyridai-inyl methyl) -4-pyrimidcne The starting materials (b) to (g) above may be prepared by condensing the corresponding heterocyclic carboxaldehyde with malonic acid, and hydrogenating and esterifying the product.
EXAMPLE 19 Treatment of l-(4-methoxyhenzyl)-2-imidazole carboxaldehyde with malonic acid in the presence of pyridine and piperidine gives 2-jl-(4-methoxybenzyl)imidazolyl] acrylic acid. Substitution of 2-£l-(4-methoxybenzyl)imidazolyl] acrylic acid for 2-thiazoleacrylic acid in the procedure of Example 8, and removal of the benzyl protecting group from the product with anisole and hydrogen bromide in acetic acid gives 2-£2-(5-mathyl-4-imidazolylmethylthio)ethylaminqj-5-(2-imidazo1ylmethyl)-4-pyrimidone.
EXAMPLE 20 Pharmaceutical composition:- Ingredients Amounts 2-[2-(5~methyl-4-imidazolylmethylthio)ethylamino)-5-(3-pyridyImethyl)-4-pyrimidone trihydrochloride 75 mg Sucrose 75 ag Starch 25 mg Talc 5 mg Stearic Acid 2 mg The ingredients are screened, mixed and filled into a hard gelatin capsule.
EXAMPLE 21 Pharmaceutical composition:Ingredients Amounts 2-{2"(5-methyl-4-imida3olylmethylthio)ethylaminoJ-S-O-pyridy Imethyl)-4-pyrimidone trihydrochloride 100 mg Lactose 100 mg The ingredients are screened, mixed and filled into a hard gelatin capsule. 3q Similarly, the· other compounds of Formula 1 may he formulated into pharmaceutical compositions by the procedures of Examples 20 and 21.
The pharmaceutical compositions prepared as in the foregoing gg examples are administered to a subject within the dose ranges given hereabove to block histamine Hg-receptors.
Claims (34)
1. A compound of the formula:- where X is oxygen or sulphur, A is HeV-CH^YiCHgJg-NH- where 5 Het is a 2- or 4-imidazolyl group optionally substituted with lower alkyl, halogen, trifluoromethyl or hydroxymethyl; a Z-pyridyl group ootionally substituted with lower alkyl, lower alkoxy, halogen, amino or hydroxy; a 2-thiazolyl group; a 3-isothiazolyl group optionally substituted with chlorine or bromine; a 10 3 - (1,2,5)- thiadiazolyl group optionally substituted with chlorine or lu bromine, or a 2 - (5 - amino - 1,3,4 - thiadiazolyl)group; Y is sulphur or methylene ' Z is hydrogen or lower alkyl; X is oxygen or sulphur; W is methylene, oxygen or 15 sulphur; p and q are such that their sum is from 1 to 4 when W is oxygen or sulphur, or from 0 to 4 when W is methylene; - 33 Het* is a 5 or 6 membered heteroaryl group optionally substituted by lower alkyl, lower alkoxy, or may have a benzene ring or substituted benzene ring fused to it, and acid addition salts thereof.
2. A compound according to claim 1 where Het' is a 5 pyridyl, furyl, thienyl, thiazolyl, oxazolyl, isothiazolyl, imidazolyl, pyrazinyl, pyridazinyl or pyrimidyl group, optionally substituted by lower alkyi, lower alkoxy, or may have a benzene ring °F substituted benzene ring fused to it.
3. A compound according to claim 2 where Het 1 is a 10 2-furyl, 2-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-thiazolyl, 2-imidazolyl, 2-pyrimidyl, 2-pyrazinyl or 4. -pyridazinyl group,optionally substituted with lower alkyl or lower alkoxy.
4. A compound according to claim 3 where Het' is a 2-furyl, 15 2-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-thiazolyl, 2-imidazolyl, 2-pyrimidyl, 2-pyrazinyl, or 4-pyridazinyl group optionally substituted with lower alkyl.
5. A compound according to claim 4 where Het' is a 2- thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl or 20 2-thiazolyl group.
6. A compound according to claim 5 where Het' is a 3- pyridyl group. - 34 sS082
7. A compound according to any one of elate 1 to δ where Z is hydrogen.
8. A compound according to any one of claims 1 to 7 where W is methylene and p and q are both 0. 5 S. A compound according to any one of claims 1 to 8 where X is oxygen.
9. 10. A compound according to claim 1 where Het is a 2- thiazolyl, 5-methyl-4-imidazolyl, 5-bromo-4-imidazolyl, 3- bromo-2-pyridyl, 3-chloro-2-pyridyl, 3-raethoxy-2-pyri dyl or 3-hydroxy-2-pyridyl group, 20 Π. A compound according to claim 10 where Y is sulphur.
10. 12. 2 - [2 -(5 - Methyl - 4 - imidazolylmethylthio)ethylamino] -5-(4- pyridylmethyl) - 4 - pyrimidone.
11. 13. 2 - [2-(2- “hiazolylmethylthiojethylaminoj -5-(425 pyridylmethyl) - 4 - pyrimidone.
12. 14. 2 - J2 2 ( 3 Bromo - 2 - pyridylmethylthio)ethylaminoj - 5 (4 - pyridylmethyl) - 4 - pyrimidone.
13. 15. 2 - [j2 - (5 - Methyl - 4 - imidazolylmethylthiojethylamino] -5-(2- thienylmethyl) - 4 - pyrimidone. 5
14. 16. 2-^2-(5- Methyl - 4 - imidazolylmethylthio)ethylamino] -5-(2- pyridylmethyl) - 4 - pyrimidone.
15. 17. 2 - [2 - (5 - Methyl - 4 - imidazolylmathylthiojethylamino’j -5-(3- pyridylmethyl) - 4 - pyrimidone.
16. 18. 2-/2 - (3 - Bronio - 2 - pyridylmathylthio)ethylamino] 10 -5-(2- pyridylmethyl) - 4 - pyrimidone.
17. 19. 2-/2- (5 - Methyl - 4 - imidazolylmsthylthiojethylamino] -5-(2- thiazolylmethyl) - 4 - pyrimidone.
18. 20. 2 - /2-(2- Thiazelylmethylthio'iethylaminoQ -5-(3pyridylmethyl) - 4 - pyrimidone. 15
19. 21. 2 - /2 - (3 - Bromo - 2 - pyridylmethylthio)ethylaminqj -5-(3- pyridylmethyl) - 4 - Pyrimidone.
20. 22. 2-(/1-(3- Methoxy - 2 - pyridyl )butylaminoj - 5 (3 - pyridylmethyl) - 4 - pyrimidone.
21. 23. 2-(4-(3- Amino - 2 - pyridyl)butylaminoj -5-(320 pyridylmethy) - 4 - pyrimidone.
22. 24. A pharmaceutically acceptable acid addition salt of a compound according to any one of claims 10 to 23.
23. 25. A process for preparing a compound according to claim 1 where X is oxygen, which comprises 25 reacting an isocytosine of formula:- 36 as Ar - Bet ' where Z, W, p, q, and Het' are as defined in claim 1 and Q is a group which is displaceable by an amine, with an amine of formula: 5 Het-CHg- Y-{CH ? ) 2 -NH 2 where Het and Y are as defined in claim 1, and thereafter optionally converting the compound so obtained into a salt.
24. 26. A process according to claim 25 where Q is lower alkylthio, senzyithio or halogen. 10
25. 27. A process according to claim 26 where Q is methylthio.
26. 28. A process for preparing a compound as claimed in claim 1 where X is oxygen and W is sulphur which comprises either a) reacting an isocytosine of formula:4ch 2 ) -v Het-CH 2 -Y-(CH 2 ) 2 -N where Het, V, Z and p are as defined in claim 1 and V is mercapto, with a compound of formula U(CH 2 )qHet' where q and Het' are as defined in claim 1, and li is chloro or bromo, provided that q may be 0 only if U is an 'active' halogen, or 5 b) reacting an isocytosine of formula:Z (CH 2 ) p -V Het-CH 2 -Y-(CH 2 ) 2 -NH where Het, Y, Z and p are as defined in claim 1 and V is chloro or bormo with a compound of formula U(CH 2 ) 0 Het' where q and Het' are as defined in claim 1 and U is mercapto, 10 and thereafter optionally converting the compound so obtained into a salt.
27. 29. A process for preparing a compound according to claim 1 where X is sulphur which comprises reacting a corresponding compound - 38 10 where X is oxygen with phorphcrus pentasulphitie and thereafter optionally converting the compound so obtained into a salt.
28. 30. A compound according to claim y where X is oxygen whenever prepared by a process according to any one of claims 25 to 28.
29. 31. A process according to claiml where X is sulphur whenever prepared by a process according to claim 29.
30. 32.. A process for preparing a compound according to claim 1 substantially as hereinbefore illustrated in any one of Examples 1 to 5.
31. 33. A process for preparing a compound according to claim 1 substantially as hereinbefore illustrated in any one of Examples 1 to 19.
32. 34. A compound according to claim ] whenever prepared by a process according to any one of claims 25 to 30.
33. 35. A pharmaceutical composition comprising a compound according to any one of claims io to 24, 30 and 34, or a pharmaceutically acceptable acid addition salt thereof and a pharmaceutically acceptable carrier.
34. 36. A pharmaceutical composition substantially as hereinbefore illustrated in Example 20 or 21.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB5300175 | 1975-12-29 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IE45082L IE45082L (en) | 1977-06-29 |
| IE45082B1 true IE45082B1 (en) | 1982-06-16 |
Family
ID=10466233
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE2814/76A IE45082B1 (en) | 1975-12-29 | 1976-12-22 | Derivatives of pyrimidone and thiopyrimidone |
Country Status (37)
| Country | Link |
|---|---|
| JP (1) | JPS5283388A (en) |
| AR (1) | AR222290A1 (en) |
| AT (1) | AT360024B (en) |
| AU (1) | AU508123B2 (en) |
| BE (1) | BE849810A (en) |
| BG (1) | BG29722A3 (en) |
| CA (1) | CA1073458A (en) |
| CH (1) | CH631981A5 (en) |
| CS (1) | CS203995B2 (en) |
| DD (1) | DD128588A5 (en) |
| DE (1) | DE2658267A1 (en) |
| DK (1) | DK587076A (en) |
| EG (1) | EG12439A (en) |
| ES (1) | ES454656A1 (en) |
| FI (1) | FI62668C (en) |
| FR (1) | FR2336935A1 (en) |
| GR (1) | GR62441B (en) |
| HU (1) | HU175171B (en) |
| IE (1) | IE45082B1 (en) |
| IL (1) | IL51040A (en) |
| IT (2) | IT1124740B (en) |
| LU (1) | LU76481A1 (en) |
| MW (1) | MW5076A1 (en) |
| MX (1) | MX5119E (en) |
| NL (1) | NL7614538A (en) |
| NO (1) | NO146396C (en) |
| NZ (1) | NZ182759A (en) |
| OA (1) | OA05526A (en) |
| PH (1) | PH14723A (en) |
| PL (1) | PL104376B1 (en) |
| PT (1) | PT65949B (en) |
| RO (1) | RO72475A (en) |
| SE (1) | SE431544B (en) |
| SU (1) | SU791235A3 (en) |
| YU (1) | YU311676A (en) |
| ZA (1) | ZA767198B (en) |
| ZM (1) | ZM14376A1 (en) |
Families Citing this family (20)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NZ186511A (en) | 1977-03-19 | 1980-11-14 | Smith Kline French Lab | 3-substituted alkylamino-6-substituted alkyl-1,2,4-triazin-5-ones and pharmaceutical compositions 3-substituted thio-1,2,4-triazin-5-ones |
| IL56265A (en) * | 1977-12-28 | 1982-08-31 | Om Lab Sa | Process for preparing imidazolyl methylthio guanidine derivatives and a novel intermediate therefor |
| IN151188B (en) * | 1978-02-13 | 1983-03-05 | Smith Kline French Lab | |
| US4539207A (en) * | 1978-02-13 | 1985-09-03 | Smith Kline & French Laboratories Limited | Pyrimidine compounds |
| AU527202B2 (en) * | 1978-04-11 | 1983-02-24 | Smith Kline & French Laboratories Limited | 2-aminopyrimidones |
| ZA792607B (en) * | 1978-05-30 | 1980-07-30 | Smith Kline French Lab | Nitro compounds |
| ZA793392B (en) * | 1978-07-15 | 1980-08-27 | Smith Kline French Lab | Isoureas and isothioureas |
| US4374836A (en) | 1978-10-16 | 1983-02-22 | Imperial Chemical Industries Ltd. | Antisecretory heterocyclic derivatives, process for their manufacture and pharmaceutical compositions containing them |
| US4309435A (en) | 1978-10-16 | 1982-01-05 | Imperial Chemical Industries Ltd. | Antisecretory guanidine derivatives and pharmaceutical compositions containing them |
| US4496567A (en) * | 1978-11-13 | 1985-01-29 | Smith Kline & French Laboratories Limited | Phenyl alkylaminopyrimidones |
| US4521418A (en) * | 1979-02-21 | 1985-06-04 | Smith Kline & French Laboratories Limited | Guanidinothiazolyl derivatives |
| US4255428A (en) | 1979-03-24 | 1981-03-10 | Smith Kline & French Laboratories Limited | 5-(Hydroxypyridylalkyl)-4-pyrimidones |
| JPS55133379A (en) * | 1979-04-05 | 1980-10-17 | Smith Kline French Lab | Pyrimidone compound |
| DE2962542D1 (en) * | 1979-04-11 | 1982-06-03 | Smith Kline French Lab | Pyrimidone derivatives, process for preparing them and pharmaceutical compositions containing them |
| JPS55145683A (en) * | 1979-04-26 | 1980-11-13 | Smith Kline French Lab | Pyrimidone derivative |
| CA1155842A (en) * | 1980-03-29 | 1983-10-25 | Thomas H. Brown | Compounds |
| ZW21281A1 (en) * | 1980-10-01 | 1981-11-18 | Smith Kline French Lab | Amine derivatives |
| IE53068B1 (en) * | 1981-06-15 | 1988-05-25 | Merck & Co Inc | Diamino isothiazole-1-oxides and -1,1-dioxides as gastic secretion inhibitors |
| PT75074B (en) * | 1981-06-27 | 1986-02-26 | Smith Kline French Lab | Process for preparing certain pyrimidone derivatives and compositions containing them |
| US6417366B2 (en) * | 1999-06-24 | 2002-07-09 | Abbott Laboratories | Preparation of quinoline-substituted carbonate and carbamate derivatives |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1419994A (en) * | 1973-05-03 | 1976-01-07 | Smith Kline French Lab | Heterocyclicalkylaminotheterocyclic compounds methods for their preparation and compositions comprising them |
| IN146736B (en) * | 1975-10-02 | 1979-08-25 | Smith Kline French Lab |
-
1976
- 1976-11-22 MW MW50/76A patent/MW5076A1/en unknown
- 1976-11-29 NZ NZ182759A patent/NZ182759A/en unknown
- 1976-12-02 IL IL51040A patent/IL51040A/en unknown
- 1976-12-02 ZA ZA767198A patent/ZA767198B/en unknown
- 1976-12-08 CA CA267,385A patent/CA1073458A/en not_active Expired
- 1976-12-09 IT IT30235/76A patent/IT1124740B/en active
- 1976-12-10 PT PT65949A patent/PT65949B/en unknown
- 1976-12-17 PH PH19265A patent/PH14723A/en unknown
- 1976-12-17 ZM ZM143/76A patent/ZM14376A1/en unknown
- 1976-12-21 FI FI763664A patent/FI62668C/en not_active IP Right Cessation
- 1976-12-22 YU YU03116/76A patent/YU311676A/en unknown
- 1976-12-22 GR GR52462A patent/GR62441B/en unknown
- 1976-12-22 DE DE19762658267 patent/DE2658267A1/en not_active Ceased
- 1976-12-22 IE IE2814/76A patent/IE45082B1/en unknown
- 1976-12-23 CH CH1627876A patent/CH631981A5/en not_active IP Right Cessation
- 1976-12-23 JP JP15611076A patent/JPS5283388A/en active Granted
- 1976-12-23 BE BE173597A patent/BE849810A/en not_active IP Right Cessation
- 1976-12-23 AT AT960876A patent/AT360024B/en not_active IP Right Cessation
- 1976-12-27 RO RO7688851A patent/RO72475A/en unknown
- 1976-12-28 SE SE7614620A patent/SE431544B/en not_active IP Right Cessation
- 1976-12-28 LU LU76481A patent/LU76481A1/xx unknown
- 1976-12-28 PL PL1976194772A patent/PL104376B1/en unknown
- 1976-12-28 HU HU76SI1556A patent/HU175171B/en unknown
- 1976-12-28 EG EG803/76A patent/EG12439A/en active
- 1976-12-28 BG BG035033A patent/BG29722A3/en unknown
- 1976-12-28 NO NO764370A patent/NO146396C/en unknown
- 1976-12-29 DK DK587076A patent/DK587076A/en not_active Application Discontinuation
- 1976-12-29 ES ES454656A patent/ES454656A1/en not_active Expired
- 1976-12-29 AR AR266049A patent/AR222290A1/en active
- 1976-12-29 CS CS768760A patent/CS203995B2/en unknown
- 1976-12-29 OA OA56028A patent/OA05526A/en unknown
- 1976-12-29 NL NL7614538A patent/NL7614538A/en not_active Application Discontinuation
- 1976-12-29 FR FR7639465A patent/FR2336935A1/en active Granted
- 1976-12-29 DD DD7600196703A patent/DD128588A5/en unknown
- 1976-12-29 SU SU762434655A patent/SU791235A3/en active
- 1976-12-30 AU AU20976/76A patent/AU508123B2/en not_active Expired
-
1977
- 1977-01-03 MX MX775273U patent/MX5119E/en unknown
-
1979
- 1979-01-05 IT IT7919107A patent/IT7919107A0/en unknown
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