Classifications

• • 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
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
  • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
  • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
  • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

• This invention relates to pyrimidinone derivatives, to processes for their preparation, and to pharmaceutical compositions containing them.
• 2-ones which possess a metaphase arresting ability. This ability is useful for combating abnormal cell proliferation, which can be found in auto-immune diseases, and diseases such as cancers, leukaemias or cutaneous cellular proliferation, e.g. contact dermatitis or psoriasis.
• these compounds possess good water-solubility and by virtue of this are particularly easy to administer.
• R represents a group
• R 1 represents a halogen atom or a trifluoromethyl group
• R 2 represents a hydrogen atom or a C 1 -4 alkyl
• R 3 represents a hydrogen atom or, together with R 2 , represents a -CH 2 - or -CH 2 -CH 2 - chain; and represents a C 6-10 carbocyclic aromatic group or a carbon-attached heterocyclic group containing a 5- or 6- membered unsaturated heterocyclic ring which ring contains one or more heteroatoms selected from O, N and S and optionally carries a fused carbocyclic ring, which carbocyclic or heterocyclic group may carry one or more substituents selected from halogen atoms, C 1 -4 alkyl, C 1 -4 alkanoyl,
• the adducts according to the invention are salts of sulphonic acids and are thus ionic materials.
• Such salts are conveniently physiologically acceptable, water soluble salts and may advantageously be sodium, potassium, calcium, magnesium, ammonium, mono-, di- or trialkylammonium salts, or salts derived from polyamines.
• adduct is conveniently formed directly through an addition reaction, however the term "adduct" is used herein to refer to the final product irrespective of its manner of production and thus includes within its scope compounds produced other than by direct bisulphite addition to compounds of formula (I).
• adduct is used herein to refer to the final product irrespective of its manner of production and thus includes within its scope compounds produced other than by direct bisulphite addition to compounds of formula (I).
• M represents a cation; and R and R 1 are as defined above.
• the sulphonic acid grouping can be in either the 4- or 6-position as in the compounds of formula (Ila) and (lIb) below:
• M represents a cation, preferably selected from sodium, potassium, calcium, magnesium, ammonium, mono-, di-and trialkylammonium, or a cation derived from a polyamine e.g. ethylenediamine; and R and
• R 1 are as defined above) and salts thereof, separately or in admixture.
• Examples of the C 6-10 carbocyclic aromatic groups within the definition of the ring A are phenyl or naphthyl groups which may be substituted by the groups indicated above.
• Examples of the optional substituents which may be present on a phenyl or naphthyl group include one, two or more chlorine or fluorine atoms, or methyl, acetyl, methoxy, methoxycarbonyl, ethoxycarbonyl, methylthio, hydroxyl, nitro, cyano, formyl, -NH 2 , dimethylamino, acetylammino or hydroxymethyl groups. Substituents on the phenyl group may be present, for example, in the 2-, 3- and/or 4- positions.
• the ring A may conveniently be a five or six-membered unsaturated heterocyclic ring containing one, two or three hetero atoms. Such heterocyclic rings include thienyl, thiazolyl and pyrrolyl.
• heterocyclic group By referring to the heterocyclic group as being carbon-attached it is meant that it is linked by carbon-carbon bonds to the remainder of group R.
• the five- or six-membered unsaturated heterocyclic ring may have another ring, fused to it, which may be a carbocyclic ring such as phenyl.
• substituents which optionally may be present on the heterocyclic ring, or on any fused ring, are halogen atoms such as chlorine atoms or C 1-4 alkyl groups e.g. methyl groups.
• n is an integer having the value 1 or 2
• n is an integer having the value 1 or 2
• R includes J in which R 2 represents a hydrogen atom or a methyl or phenyl group.
• each alkyl group conveniently contains up to 4 carbon atoms.
• Such cations include for example dimethylammonium and triethylammonium.
• the cation M is derived from a polyamine, it may be derived, for example, from ethylenediamine,
• the cation M in formula (IIa) or (lIb) is preferably a sodium ion.
• Particularly interesting compounds include those water-soluble compounds of formulae (Ila) and (lIb) in which: M is a sodium, potassium, calcium, magnesium, ammonium, mono-, di- or trialkylammonium ion, or an ion derived from a polyamine, preferably a sodium, potassium, ammonium, dimethylammonium, triethylammonium or ethylenediamine ion, especially a sodium ion;
• R 1 is a chlorine atom: and R is a group
• R 2 represents a hydrogen atom or a methyl or phenyl group
• Particularly interesting compounds according to the invention include the following: 5-chloro-1,2,3,4-tetrahydro-2-oxo-1-[2-oxo-2-(2thienyl)ethyl]-4-pyrimidinesulphonic acid, sodium salt;
• the compounds according to the invention may be formulated for use in the conventional manner, and in a further aspect of the invention we provide pharmaceutical compositions comprising at least one adduct according to the invention together with one or more pharmaceutical carriers or excipients.
• compositions may be incorporated into pharmaceutical compositions of either solid or liquid forms.
• the compositions may, for example, be presented in forms suitable for administration by the rectal, parenteral or topical routes.
• Preferred forms include, for example suspensions, suppositories, creams, ointments, lotions and solutions, e.g. for injection or infusion.
• the active ingredient may be incorporated in excipients customarily employed in pharmaceutical compositions such as, for example, talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous vehicles, fatty substances of animal or vegetable origin, paraffin derivatives, glycols, various wetting, dispersing or emulsifying agents and/or preservatives.
• excipients customarily employed in pharmaceutical compositions such as, for example, talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous vehicles, fatty substances of animal or vegetable origin, paraffin derivatives, glycols, various wetting, dispersing or emulsifying agents and/or preservatives.
• compositions may be formulated as dosage units, each unit being adapted to supply a fixed dose of active ingredient.
• Suitable dosage units for adult humans contain from 50 mg to 1.0 g of active ingredient.
• the dosage which may be varied according to the compound used, the subject treated and the complaint concerned, may, for example, be from 0.25 to 7.0 g in a day in adult humans.
• compositions of the invention may take the form of compositions comprising a compound of formula (I) formulated with an aqueous solution of a physiologically acceptable bisulphite whereby the adduct is formed in situ in the composition.
• a physiologically acceptable bisulphite it is convenient to use an excess of the physiologically acceptable bisulphite and the formulation of the compound of formula (I) with the bisulphite solution is preferably carried out immediately or shortly before administration of the composition.
• the invention provides the use of adducts or compounds of formula II according to the invention (wherein the or any countercation is physiologically acceptable) for the manufacture of a therapeutic agent for use in the treatment of the human or non-human animal body to effect metaphase arrest of cell growth.
• the invention provides the use of adducts or compounds of formula II according to the invention (wherein the or any countercation is physiologically acceptable) for the treatment of the human or non-human animal body to effect metaphase arrest of cell growth.
• the invent ion provides a method of treatment of the human or non-human animal body to effect metaphase arrest of cell growth which method comprises administering to said body an effective amount of an adduct or compound of formula II according to the invention (wherein the or any countercation is physiologically acceptable).
• the invention provides a process for the preparation of a pharmaceutical composition comprising admixing an adduct or compound of formula II according to the invention (wherein the or any countercation is physiologically acceptable) with one or more pharmaceutical carriers or diluents.
• the adducts of the invention may be prepared by bisulphite addition to compounds of formula (I).
• a bisulphite adduct of the invention may be prepared by addition of bisulphite to a pyrimidinone of formula (I), where R and R 1 are as previously defined.
• the reaction may be effected using a substance providing bisulphite ions, e.g. an appropriate metabisulphite, or sulphite in an aqueous medium such as water or water with a miscible or immiscible co-solvent such as chloroform, dimethylformamide or dioxan optionally in the presence of a phase transfer catalyst such as benzyltrimethylammonium chloride.
• the reaction may be performed at for example 20° - 100°C, conveniently at 20° - 60°C.
• a salt derived from an amine where a salt derived from an amine is desired, it may be convenient to react the amine, e.g. dimethylamine, and the appropriate pyrimidinone of formula (I) in the presence of sulphur dioxide in an aqueous medium, as just described.
• the reaction may be performed at for example ambient temperature.
• R' represents a group selected from the following:
• n is an integer having the value 1 or 2;
• A represents a C 6-10 carbocylic aromatic group or a carbon-attached heterocyclic group containing a 5- or 6-membered unsaturated heterocyclic ring which ring contains one or more, preferably from 1, 2 or 3, heteroatoms selected from O, N and S and optionally carries a fused carbocyclic ring, which carbocyclic or heterocyclic group may carry one or more substituents selected from halogen atoms, C 1-4 alkyl, C 1-4 alkanoyl, C 1-4 alkoxy,
• R 4 is a hydrogen atom or a C 1-4 alkyl group
• R 5 is a hydrogen atom or a C 1-4 alkyl, C 1-4 alkanoyl or aroyl group) and C 1 -4 alkyl groups substituted by one or more hydroxy or -NR 4 R 5 groups and halogen atoms; and salts thereof.
• the metaphase arresting ability of the compounds of formulae (III) and (IV) may be determined using the test described above and the compounds of formulae (III) and (IV) may be formulated for use as previously described for the bisulphite adducts of the invention and in another aspect, the invention accordingly provides pharmaceutical compositions containing at least one compound of formula (III) or (IV) together with one or more pharmaceutical carriers or excipients.
• This agent may, for example, be a compound of formula (VI)
• Y represents a leaving atom or group e.g. a halogen atom, a hydroxy group or a reactive ether or ester derivative).
• a compound of formula (VI) is advantageously used in which Y represents an iodine, bromine or chlor ine atom or a hydrocarbonsulphonyloxy der ivative such as a mesylate, brosylate or tosylate.
• the reaction between the compounds of formulae (V) and (VI) is conveniently effected in the presence of a polar solvent such as an alkanol e.g. ethanol or dimethylformamide or a halogenated hydrocarbon such as dichloromethane.
• a polar solvent such as an alkanol e.g. ethanol or dimethylformamide or a halogenated hydrocarbon such as dichloromethane.
• the reaction may also conveniently be effected in the presence of a base, e.g. a tertiary organic base such as triethylamine or an inorganic base e.g. an alkali metal hydroxide, such as potassium hydroxide, or an alkali metal carbonate, such as sodium carbonate, in the presence of a phase transfer catalyst such as benzyltrimethylammonium chloride.
• a salt of the compound of formula (V) an added base will not normally be required.
• Such a salt may, for example, be an alkali metal,
• the compound of formula (V) may also be introduced by a two stage reaction in which the compound of formula (V) is reacted with an O-silylating agent to form an O-silyl derivative, e.g. a trialkylsilyl ether, followed by reaction with a compound of formula (VI), preferably in the presence of a Lewis acid.
• an O-silylating agent to form an O-silyl derivative, e.g. a trialkylsilyl ether
• a compound of formula (VI) preferably in the presence of a Lewis acid.
• reaction is carried out in the presence of a condensing agent such as an acetal of a C 1 -5 dialkylformamide e.g. dimethylformamide.
• a condensing agent such as an acetal of a C 1 -5 dialkylformamide e.g. dimethylformamide.
• the alkyl groups of the acetal are preferably neopentyl groups, thus dimethylformamide dineopentylacetal is a preferred condensing agent.
• the compound of formula (VI) may be in the form of an acetal of a C 1-5 dialkylformamide carrying at least one acetal group derived from the alcohol
• the intermediate compounds of formula (VI) are either known compounds or may be prepared by methods amalogous to those used for the preparation of the known compounds.
• Example 1 The following non-limiting Examples are provided to illustrate the invention.
• Example 1 The following non-limiting Examples are provided to illustrate the invention.

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Plural Heterocyclic Compounds (AREA)

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Citations (3)

• 1984
  • 1984-08-14 GB GB848420610A patent/GB8420610D0/en active Pending
• 1985
  • 1985-08-13 EP EP19850904010 patent/EP0189472A1/en not_active Withdrawn
  • 1985-08-13 WO PCT/GB1985/000360 patent/WO1986001205A1/en not_active Application Discontinuation
  • 1985-08-13 JP JP50364385A patent/JPS62500028A/ja active Pending
• 1986
  • 1986-04-04 DK DK154086A patent/DK154086D0/da not_active IP Right Cessation
  • 1986-04-11 NO NO861421A patent/NO861421L/no unknown

Patent Citations (3)

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