WO2000010980A1 - Pyrimidinone derivatives for the treatment of atherosclerosis - Google Patents

Pyrimidinone derivatives for the treatment of atherosclerosis Download PDF

Info

Publication number
WO2000010980A1
WO2000010980A1 PCT/EP1999/006093 EP9906093W WO0010980A1 WO 2000010980 A1 WO2000010980 A1 WO 2000010980A1 EP 9906093 W EP9906093 W EP 9906093W WO 0010980 A1 WO0010980 A1 WO 0010980A1
Authority
WO
WIPO (PCT)
Prior art keywords
pyrimidin
fluorobenzyl
ylmethyl
oxopyrimid
alkyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/EP1999/006093
Other languages
French (fr)
Inventor
Colin Andrew Leach
Stephen Allan Smith
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
SmithKline Beecham Ltd
Original Assignee
SmithKline Beecham Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GBGB9818375.9A external-priority patent/GB9818375D0/en
Priority claimed from GBGB9902009.1A external-priority patent/GB9902009D0/en
Application filed by SmithKline Beecham Ltd filed Critical SmithKline Beecham Ltd
Priority to JP2000566254A priority Critical patent/JP2002523402A/en
Priority to AT99942894T priority patent/ATE251613T1/en
Priority to EP99942894A priority patent/EP1105377B1/en
Priority to US09/763,492 priority patent/US6559155B1/en
Priority to DE69911980T priority patent/DE69911980T2/en
Publication of WO2000010980A1 publication Critical patent/WO2000010980A1/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • 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

Definitions

  • the present invention relates to certain novel pyrimidinone compounds, processes for their preparation, intermediates useful in their preparation, pharmaceutical compositions containing them and their use in therapy, in particular in the treatment of atherosclerosis.
  • WO 95/00649 (SmithKline Beecham pic) describe the phospholipase A2 enzyme Lipoprotein Associated Phospholipase A2 (Lp-PLA2), the sequence, isolation and purification thereof, isolated nucleic acids encoding the enzyme, and recombinant host cells transformed with DNA encoding the enzyme. Suggested therapeutic uses for inhibitors of the enzyme included atherosclerosis, diabetes, rheumatoid arthritis, stroke, myocardial infarction, reperfusion injury and acute and chronic inflammation. A subsequent publication from the same group further describes this enzyme (Tew D et al, Arterioscler Thromb Vas Biol 1996: 16;591-9) wherein it is referred to as LDL-PLA2.
  • LDL-PLA2 Lipoprotein Associated Phospholipase A2
  • Lp-PLA2 is responsible for the conversion of phosphatidylcholine to lysophosphatidylcholine, during the conversion of low density lipoprotein (LDL) to its oxidised form.
  • the enzyme is known to hydrolyse the sn-2 ester of the oxidised phosphatidylcholine to give lysophosphatidylcholine and an oxidatively modified fatty acid.
  • Both products of Lp-PLA2 action are biologically active with lysophosphatidylcholine, a component of oxidised LDL, known to be a potent chemoattractant for circulating monocytes.
  • lysophosphatidylcholine is thought play a significant role in atherosclerosis by being responsible for the accumulation of cells loaded with cholesterol ester in the arteries. Inhibition of the Lp-PLA2 enzyme would therefore be expected to stop the build up of these macrophage enriched lesions (by inhibition of the formation of lysophosphatidylcholine and oxidised free fatty acids) and so be useful in the treatment of atherosclerosis.
  • Lp-PLA2 The increased lysophosphatidylcholine content of oxidatively modified LDL is also thought to be responsible for the endothelial dysfunction observed in patients with atherosclerosis. Inhibitors of Lp-PLA2 could therefore prove beneficial in the treatment of this phenomenon. An Lp-PLA2 inhibitor could also find utility in other disease states that exhibit endothelial dysfunction including diabetes, hypertension, angina pectoris and after ischaemia and reperfusion. In addition, Lp-PLA2 inhibitors may also have a general application in any disorder that involves activated monocytes, macrophages or lymphocytes, as all of these cell types express Lp-PLA 2 . Examples of such disorders include psoriasis.
  • Lp-PLA2 inhibitors may also have a general application in any disorder that involves lipid peroxidation in conjunction with Lp-PLA2 activity to produce the two injurious products, lysophosphatidylcholine and oxidatively modified fatty acids.
  • Such conditions include the aforementioned conditions atherosclerosis, diabetes, rheumatoid arthritis, stroke, myocardial infarction, reperfusion injury and acute and chronic inflammation. Further such conditions include various neuropsychiatric disorders such as schizophrenia (see Psychopharmacology Bulletin, 31, 159-165, 1995).
  • Patent applications WO 96/12963, WO 96/13484, WO96/19451, WO 97/02242, WO97/217675, WO97/217676, WO 96/41098, and WO97/41099 disclose ter alia various series of 4-thionyl/sulfinyl/sulfonyl azetidinone compounds which are inhibitors of the enzyme Lp-PLA2- These are irreversible, acylating inhibitors (Tew et al, Biochemistry, 37, 10087, 1998).
  • WO 99/24420 (SmithKline Beecham) describes a new class of compounds which are inhibitors of Lp-PLA2, namely a group of pyrimidone compounds.
  • pyrimidone compounds which have a 5-(2-oxopyrimid-5- ylmethyl) substituent and which are potent inhibitors of Lp-PLA2
  • the present invention provides a compound of the formula (I):
  • R 1 is COOH or a salt thereof, COOR 10 , CONR 1 l R 12 , CN or CH 2 OH;
  • R 2 is a mono- or bicyclic aromatic ring system containing up to 10 carbon atoms in the ring system, or a mono- or bicyclic heteroaromatic ring system including up to 4 heteroatoms selected from N, O and S; optionally substituted by 1, 2, 3 or 4 substituents selected from C j ⁇ alkyl, C ⁇ _ 4 aTkoxy, C ⁇ _ 4 alkylthio, aryl, aralkyl, hydroxy, oxo, halogen, CN, COOH or a salt thereof, COO-C,.
  • R 3 is C ⁇ _ 2 o alkyl, C3.6 cycloalkyl, C 3 .6cycloalkylC ⁇ .5alkyl, or C1 _ ⁇ o alkoxyCi _ ⁇ o alkyl, each optionally substituted by 1 or 2 substituents selected from hydroxy, C ⁇ io alkoxy, COOH or a salt thereof, COOC1.15 alkyl, CONR 17 R 18 , NR 17 R 18 ' NR 17 COR 18 , NR ⁇ 9 0 r an aromatic or heteroaromatic ring system as defined for R 2 , or R3 is an aromatic or heteroaromatic ring system as hereinbefore defined for R 2 ;
  • RIO is C ⁇ _ 4 alkyl or a pharmaceutically acceptable in vivo hydroly sable ester group
  • R! 1 and R ⁇ 2 which may be the same or different is each selected from hydrogen, C 2 alkyl, CH2R 13 , CHR 14 CO2H or a salt thereof, or R 1 1 and R 12 together with the nitrogen to which they are attached form a 5- to 7 membered ring optionally containing one or more further heteroatoms selected from oxygen, nitrogen and sulphur, and optionally substituted by one or two substituents selected from hydroxy, oxo, C ⁇ _4alkyl, C ⁇ _4alkylCO, aryl, e.g. phenyl, or aralkyl, e.g benzyl, for instance morpholine or piperazine;
  • R 13 is COOH or a salt thereof, COOR ⁇ , CONR 1 *R 12 , CN or CH 2 OH;
  • Rl4 i s an amino acid side chain such as CH2OH from serine
  • Rl5 and R ⁇ 6 are independently hydrogen or C 1.4 alkyl e.g. methyl or ethyl
  • Rl and Rl8 are independently hydrogen, C1. ⁇ 5 alkyl, eg methyl or ethyl, C1 _I Q alkoxyCi .10 alkyl or arylCi _io alkyl, e.g. benzyl;
  • Rl9 together with the nitrogen atom to which it is attached forms a 5- to 7 membered ring optionally containing one or more further heteroatoms selected from oxygen, nitrogen and sulphur, and optionally substituted by one or two substituents selected from hydroxy, oxo, C1.4 alkyl, aryl, e.g. phenyl, or aralkyl, e.g benzyl;
  • W is SO 2 or a bond
  • X is O or S
  • R ⁇ include carboxy (COOH) and corresponding salts, esters (COORlO) and amides (CONRl 1R ⁇ 2 ) thereof, for instance a sodium salt, an ethyl ester or an amide comprising an N-alkyl substituent, for instance, methyl, 2-methoxyethyl, octyl, dodecyl, N-benzyl, N-naphthylmethyl or a disubstitued amide comprising a combination thereof, or an amide in which the N forms part of a heterocyclic ring, for instance a piperidine ring.
  • Representative examples of the aromatic ring system represented by R 2 include phenyl and naphthyl.
  • Representative examples of the heteroaromatic ring system which may be represented by R 2 include pyridyl, pyrimidinyl, pyrazolyl, furanyl, thienyl, thiazolyl, quinolyl, benzothiazolyl, pyridazolyl and pyrazinyl.
  • Representative examples of R 2 include the phenyl group optionally substituted by 1 , 2 or 3 substituents selected from halogen (e.g. chlorine or fluorine), Cj_4 alkyl (e.g. methyl or ethyl) or Ci .4 alkoxy (e.g. methoxy), for instance 4-fluorophenyl.
  • Examples of the aryl and aralkyl substituents in the R 2 group include respectively phenyl and benzyl.
  • R 3 include C ⁇ _ 20 alkyl, for instance methyl and undecyl, and R 17 R 18 NHCOCH2 in which R ⁇ 7 and R 18 is each independently C ⁇ .
  • ⁇ alkyl for instance R1 7 is methyl and Rl8 i s methyl, octyl, or dodecyl.
  • W is a bond
  • R W is N-(l-Dodecyl)-N-methylaminocarbonylmethyl.
  • the group X is preferably S.
  • Preferred compounds of formula (I) include those in which Y is a bond, i.e. A*, A 2 and A 3 each representing a bond.
  • Other preferred examples of the groups A ⁇ and A 3 are straight chain alkylene groups.
  • a ⁇ is preferably a bond.
  • Other preferred examples of Y are (CH2)7 or CO(CH2)6-
  • compositions for R ⁇ O include those which break down readily in the human body to leave the parent acid or its salt.
  • R ® Representative examples of values of pharmaceutically acceptable in vivo hydrolysable ester groups for R ® include: -CH(Ra)O.CO.R b ; -CH(R a )O.CO.OR c ; -CH(Ra)CO.NR e R f -R d NReRf; -CH 2 ORg;
  • R a is hydrogen, (Ci -6)alkyl, in particular methyl, (C3-7)cycloalkyl, or phenyl, each of which may be optionally substituted;
  • Rb is (Ci -6)alkyl, (C ⁇ -g)alkoxy(C ⁇ -6)alkyl, phenyl, benzyl, (C3-7)cycloalkyl,
  • R a and R D together form a 1 ,2-phenylene group optionally substituted by one or two methoxy groups;
  • R c is (C ⁇ -6)alkyl, (C3-7)cycloalkyl, (C ⁇ -6)alkyl(C 3 -7)cycloalkyl;
  • R" is (Ci -6)alkylene optionally substituted with a methyl or ethyl group; R e and Rf which may be the same or different is each (C ⁇ -g)alkyl; or ary C ⁇ -4) alkyl, optionally substituted with e.g. hydroxy;
  • Rg is (C ⁇ -6)alkyl
  • R n is hydrogen, (C ⁇ -6)alkyl or phenyl
  • R 1 is hydrogen or phenyl optionally substituted by up to three groups selected from halogen, (Cj-g ⁇ alkyl, or (C ⁇ -6)alkoxy; and ⁇ l is oxygen or NH; for instance:
  • acyloxyalkyl groups such as acetoxymethyl, isobutyryloxymethyl, pivaloyloxymethyl, benzoyloxymethyl, ⁇ -acetoxyethyl, ⁇ -pivaloyloxy ethyl,
  • alkoxy/cycloalkoxycarbonyloxyalkyl groups such as ethoxycarbonyloxymethyl, t- butyloxycarbonyloxymethyl, cyclohexyloxycarbonyloxymethyl, 1- methylcyclohexyloxycarbonyloxymethyl and ⁇ -ethoxycarbonyloxyethyl;
  • dialkylaminoalkyl especially di-loweralkylamino alkyl groups such as dimethylaminomethyl, dimethylaminoethyl, diethylaminomethyl or diethylaminoethyl;
  • acetamido groups such as N,N-dimethylaminocarbonylmethyl, N,N-(2- hydroxyethyl)aminocarbonylmethyl
  • lactone groups such as phthalidyl and dimethoxyphthalidyl
  • Representative examples of pharmaceutically acceptable in vivo hydrolysable ester groups for R 10 include:
  • alkyl and similar terms such as “alkoxy” include all straight chain and branched isomers.
  • compounds of the present invention may include a carboxy group as a substituent.
  • Such carboxy groups may be used to form salts, in particular pharmaceutically acceptable salts.
  • Pharmaceutically acceptable salts include those described by Berge, Bighley, and Monkhouse, J. Pharm. Sci., 1977, 66, 1-19.
  • Preferred salts include alkali metal salts such as the sodium and potassium salts.
  • Compounds of formula (I) are inhibitors of Lp-PLA2 and as such are expected to be of use in treating atherosclerosis and the other disease conditions noted elsewhere. Such compounds are found to act as inhibitors of Lp-PLA2 in in vitro assays .
  • Particularly preferred compounds of formula (I) include:
  • the compounds of the present invention are intended for use in pharmaceutical compositions, it will be understood that they are each provided in substantially pure form, for example at least 50% pure, more suitably at least 75% pure and preferably at least 95% pure (% are on a wt/wt basis). Impure preparations of the compounds of formula (I) may be used for preparing the more pure forms used in the pharmaceutical compositions.
  • the purity of intermediate compounds of the present invention is less critical, it will be readily understood that the substantially pure form is preferred as for the compounds of formula (I).
  • the compounds of the present invention are obtained in crystalline form.
  • solvent of crystallisation may be present in the crystalline product.
  • This invention includes within its scope such solvates.
  • some of the compounds of this invention may be crystallised or recrystallised from solvents containing water. In such cases water of hydration may be formed.
  • This invention includes within its scope stoichiometric hydrates as well as compounds containing variable amounts of water that may be produced by processes such as lyophilisation.
  • different crystallisation conditions may lead to the formation of different polymorphic forms of crystalline products.
  • This invention includes within its scope all polymorphic forms of the compounds of formula (I).
  • Compounds of the present invention are inhibitors of the enzyme lipoprotein associated phospholipase A2 (Lp-PLA2) and as such are expected to be of use in therapy, in particular in the treatment of atherosclerosis.
  • Lp-PLA2 lipoprotein associated phospholipase A2
  • the present invention provides a compound of formula (I) for use in therapy.
  • the compounds of formula (I) are inhibitors of lysophosphatidylcholine production by Lp-PLA2 and may therefore also have a general application in any disorder that involves endothelial dysfunction, for example atherosclerosis, diabetes, hypertension, angina pectoris and after ischaemia and reperfusion.
  • compounds of formula (I) may have a general application in any disorder that involves lipid peroxidation in conjunction with enzyme activity, for example in addition to conditions such as atherosclerosis and diabetes, other conditions such as rheumatoid arthritis, stroke, inflammatory conditions of the brain such as Alzheimer's Disease, myocardial infarction, reperfusion injury, sepsis, and acute and chronic inflammation. Further such conditions include various neuropsychiatric disorders such as schizophrenia (see Psychopharmacology Bulletin, 31, 159-165, 1995).
  • Further applications include any disorder that involves activated monocytes, macrophages or lymphocytes, as all of these cell types express Lp-PLA 2 .
  • disorders include psoriasis.
  • the present invention provides for a method of treating a disease state associated with activity of the enzyme Lp-PLA 2 which method involves treating a patient in need thereof with a therapeutically effective amount of an inhibitor of the enzyme.
  • the disease state may be associated with the increased involvement of monocytes, macrophages or lymphocytes; with the formation of lysophosphatidylcholine and oxidised free fatty acids; with lipid peroxidation in conjunction with Lp PLA2 activity; or with endothelial dysfunction.
  • Compounds of the present invention may also be of use in treating the above mentioned disease states in combination with anti-hyperlipidaemic or anti-atherosclerotic or anti- diabetic or anti-anginal or anti-inflammatory or anti-hypertension agents.
  • examples of the above include cholesterol synthesis inhibitors such as statins, anti-oxidants such as probucol, insulin sensitisers, calcium channel antagonists, and anti-inflammatory drugs such as NSAIDs.
  • the compounds of the present invention are usually administered in a standard pharmaceutical composition.
  • the present invention therefore provides, in a further aspect, a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable carrier.
  • Suitable pharmaceutical compositions include those which are adapted for oral or parenteral administration or as a suppository.
  • Compounds of formula (I) which are active when given orally can be formulated as liquids, for example syrups, suspensions or emulsions, tablets, capsules and lozenges.
  • a liquid formulation will generally consist of a suspension or solution of the compound or pharmaceutically acceptable salt in a suitable liquid carrier(s) for example, ethanol, glycerine, non-aqueous solvent, for example polyethylene glycol, oils, or water with a suspending agent, preservative, flavouring or colouring agent.
  • a composition in the form of a tablet can be prepared using any suitable pharmaceutical carrier(s) routinely used for preparing solid formulations.
  • a composition in the form of a capsule can be prepared using routine encapsulation procedures.
  • pellets containing the active ingredient can be prepared using standard carriers and then filled into a hard gelatin capsule; alternatively, a dispersion or suspension can be prepared using any suitable pharmaceutical carrier(s), for example aqueous gums, celluloses, silicates or oils and the dispersion or suspension then filled into a soft gelatin capsule.
  • Typical parenteral compositions consist of a solution or suspension of the compound of formula (I) in a sterile aqueous carrier or parenterally acceptable oil, for example polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil.
  • a sterile aqueous carrier or parenterally acceptable oil for example polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil.
  • the solution can be lyophilised and then reconstituted with a suitable solvent just prior to administration.
  • a typical suppository formulation comprises a compound of formula (I) which is active when administered in this way, with a binding and/or lubricating agent such as polymeric glycols, gelatins or cocoa butter or other low melting vegetable or synthetic waxes or fats.
  • the composition is in unit dose form such as a tablet or capsule.
  • Each dosage unit for oral administration contains preferably from 1 to 500 mg (and for parenteral administration contains preferably from 0.1 to 25 mg) of a compound of the formula (I).
  • the daily dosage regimen for an adult patient may be, for example, an oral dose of between 1 mg and 1000 mg, preferably between 1 mg and 500 mg, or an intravenous, subcutaneous, or intramuscular dose of between 0.1 mg and 100 mg, preferably between 0.1 mg and 25 mg, of the compound of the formula (I), the compound being administered 1 to 4 times per day.
  • the compounds will be administered for a period of continuous therapy, for example for a week or more.
  • R 2 , R 3 , W, X and Y are as hereinbefore defined; with an alkylating agent of formula R!-CH 2 -L1 in which R ⁇ is as hereinbefore defined and L* is a leaving group such as chloride, bromide, iodide or mesylate, in the presence of a base such as potassium carbonate; and thereafter, and if necessary, intercon verting groups in R , for example COOR ⁇ to COOH by standard conditions (alkaline hydrolysis, hydrogenation of benzyl ester, etc), or COOH to CONRl 1R ⁇ 2 by amide coupling.
  • a compound of formula (II) can conveniently by prepared by O-dealkylation of the corresponding compound of formula (III):
  • R ⁇ is C 1 4 alkyl, arylmethyl or diarylmethyl and R 2 , R 3 , W, X and Y are as hereinbefore defined.
  • Typical conditions include treatment with boron tribromide or B- bromocatecholborane in dichloromethane at temperatures between -20° and ambient; hydrogenolysis of benzyloxy groups; acid cleavage of O-tBu.
  • a compound of formula (III) may be readily prepared in a series of steps from a compound of formula (IV):
  • R 2 is hydrogen or C ⁇ _4 alkyl, for instance methyl or ethyl
  • R 22 is hydrogen or methyl
  • R 2 ⁇ is as hereinbefore defined; using procedures well known in the art for thiouracil formation, N-alkylation and thioetherification .
  • a compound of formula (IV) in which R 2 * is hydrogen and R 22 is methyl may be treated with oxalyl chloride in a dry solvent such as dichloroethane, to form an intermediate acyl chloride, followed by treatment with potassium thiocyanate in the presence of a solvent such as acetonitrile, and then treatment with a compound of the formula (V):
  • a compound of formula (IV) in which R ⁇ is Ci .4 alkyl, for instance methyl, and R 22 is methyl may be treated with thiourea, to form a thiouracil of the formula (VIII):
  • Compounds of formula (IV) may be readily obtained from a convenient, readily available pyrimdine starting material such as a 2-alkoxy 5-bromopyrimidine, using processes well known in the art.
  • This pyrimidine may be coupled with an acrylate ester such as ethyl or methyl acrylate, using a Heck reaction, and the intermediate then subjected to catalytic hydrogenation to give a propionic acid ester derivative.
  • This in turn may be treated with methyl formate in the presence of a strong base such as potassium t-butoxide or sodium hydride, to give a compound of formula (IV) in which R 22 is hydrogen.
  • a compound of formula (IV) in which R 22 is alkyl may be obtained from the corresponding ester by hydrolysis under basic conditions, for instance aqueous sodium hydroxide.
  • the crude material was purified by flash chromatography (fine silica, methanol-ethyl acetate) to give 0.9 g of material that was dissolved in dry dimethylformamide (15ml) and heated with ethyl bromoacetate (0.17ml) and anhydrous potassium carbonate (0.43g) (oil bath 70°C) with stirring for 2h. The solvent was evaporated and the residue treated with water and extracted with ethyl acetate. The combined extracts were washed with water, dried (MgSO 4 ), evaporated and purified by flash chromatography (fine silica, methanol-ethyl acetate) to give the title compound as an oil, yield 0.52 g.
  • Example 16 The acid of Example 16 (4.9 lg) was added to a solution/suspension of sodium bicarbonate (0.64g) in water (60ml). The mixture was stirred at room temperature for 5 min and at 50°C for 5 min. After sonication for 8 min at room temperature, further water (100ml) was added and the undissolved material broken up. The mixture was heated and stirred for a further 5 min at 50°C and sonicated for a further 8 min at room temperature. Any remaining solid was filtered off and washed with water. The clear filtrate was freeze-dried for 16h to give the sodium salt.
  • Enzyme activity was determined by measuring the rate of turnover of the artificial substrate (A) at 37 C in 50mM HEPES (N-2-hydroxyethylpiperazine-N -2- ethanesulphonic acid) buffer containing 150mM NaCl, pH 7.4.
  • HEPES N-2-hydroxyethylpiperazine-N -2- ethanesulphonic acid
  • Recombinant LpPLA2 was purified to homogeneity from baculovirus infected Sf9 cells, using a zinc chelating column, blue sepharose affinity chromatography and an anion exchange column. Following purification and ultrafiltration, the enzyme was stored at 6mg/ml at 4°C. Assay plates of compound or vehicle plus buffer were set up using automated robotics to a volume of 170 ⁇ l. The reaction was initiated by the addition of 20 ⁇ l of lOx substrate (A) to give a final substrate concentration of 20 ⁇ M and 10 ⁇ l of diluted enzyme to a final 0.2nM LpPLA2.
  • the reaction was followed at 405 nm and 37 °C for 20 minutes using a plate reader with automatic mixing.
  • the rate of reaction was measured as the rate of change of absorbance.

Landscapes

  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

Pyrimidones of formula (I) are inhibitors of the enzyme LpPLA2 and thereof use in treating inter alia atherosclerosis. In formula (I), R1 is COOH or a salt thereof, COOR?10, CONR11R12¿, CN or CH¿2OH; R?2 is a mono- or bicyclic aromatic ring system or a mono- or bicyclic heteroaromatic ring system; R3 is C¿1-20?alkyl, C3-6cycloalkylC3-6cycloalkylC1-5alkyl, C1-10alkoxyC1-10alkyl, or an aromatic or heteroaromatic ring system; W is SO2 or a bond; X is O or S; and Y is a group of the formula A?1-A2-A3¿- in which A?1 and A3¿ each represent a bond or a straight chain or branched alkylene group, said alkylene group(s) containing a total of 1 to 10 carbon atoms and A2 represents a bond or O, S, SO, SO¿2?, CO, C=CH2, CONH, NHCO, CR?15R16¿, CH=CH or C C, providing that when A2 is O, S, SO, SO¿2? or CONH, A?3¿ contains at least two carbon atoms linking the A2 group and the CH¿2? group in formula (I).

Description

PYRIMIDINONE DER IVATIVES FOR THE TREATMENT OF ATHEROSCLEROS I S
The present invention relates to certain novel pyrimidinone compounds, processes for their preparation, intermediates useful in their preparation, pharmaceutical compositions containing them and their use in therapy, in particular in the treatment of atherosclerosis.
WO 95/00649 (SmithKline Beecham pic) describe the phospholipase A2 enzyme Lipoprotein Associated Phospholipase A2 (Lp-PLA2), the sequence, isolation and purification thereof, isolated nucleic acids encoding the enzyme, and recombinant host cells transformed with DNA encoding the enzyme. Suggested therapeutic uses for inhibitors of the enzyme included atherosclerosis, diabetes, rheumatoid arthritis, stroke, myocardial infarction, reperfusion injury and acute and chronic inflammation. A subsequent publication from the same group further describes this enzyme (Tew D et al, Arterioscler Thromb Vas Biol 1996: 16;591-9) wherein it is referred to as LDL-PLA2. A later patent application (WO 95/09921, Icos Corporation) and a related publication in Nature (Tjoelker et al, vol 374, 6 April 1995, 549) describe the enzyme PAF-AH which has essentially the same sequence as Lp-PLA2 and suggest that it may have potential as a therapeutic protein for regulating pathological inflammatory events.
It has been shown that Lp-PLA2 is responsible for the conversion of phosphatidylcholine to lysophosphatidylcholine, during the conversion of low density lipoprotein (LDL) to its oxidised form. The enzyme is known to hydrolyse the sn-2 ester of the oxidised phosphatidylcholine to give lysophosphatidylcholine and an oxidatively modified fatty acid. Both products of Lp-PLA2 action are biologically active with lysophosphatidylcholine, a component of oxidised LDL, known to be a potent chemoattractant for circulating monocytes. As such, lysophosphatidylcholine is thought play a significant role in atherosclerosis by being responsible for the accumulation of cells loaded with cholesterol ester in the arteries. Inhibition of the Lp-PLA2 enzyme would therefore be expected to stop the build up of these macrophage enriched lesions (by inhibition of the formation of lysophosphatidylcholine and oxidised free fatty acids) and so be useful in the treatment of atherosclerosis.
The increased lysophosphatidylcholine content of oxidatively modified LDL is also thought to be responsible for the endothelial dysfunction observed in patients with atherosclerosis. Inhibitors of Lp-PLA2 could therefore prove beneficial in the treatment of this phenomenon. An Lp-PLA2 inhibitor could also find utility in other disease states that exhibit endothelial dysfunction including diabetes, hypertension, angina pectoris and after ischaemia and reperfusion. In addition, Lp-PLA2 inhibitors may also have a general application in any disorder that involves activated monocytes, macrophages or lymphocytes, as all of these cell types express Lp-PLA2. Examples of such disorders include psoriasis.
Furthermore, Lp-PLA2 inhibitors may also have a general application in any disorder that involves lipid peroxidation in conjunction with Lp-PLA2 activity to produce the two injurious products, lysophosphatidylcholine and oxidatively modified fatty acids. Such conditions include the aforementioned conditions atherosclerosis, diabetes, rheumatoid arthritis, stroke, myocardial infarction, reperfusion injury and acute and chronic inflammation. Further such conditions include various neuropsychiatric disorders such as schizophrenia (see Psychopharmacology Bulletin, 31, 159-165, 1995).
Patent applications WO 96/12963, WO 96/13484, WO96/19451, WO 97/02242, WO97/217675, WO97/217676, WO 96/41098, and WO97/41099 (SmithKline Beecham pic) disclose ter alia various series of 4-thionyl/sulfinyl/sulfonyl azetidinone compounds which are inhibitors of the enzyme Lp-PLA2- These are irreversible, acylating inhibitors (Tew et al, Biochemistry, 37, 10087, 1998).
WO 99/24420 (SmithKline Beecham) describes a new class of compounds which are inhibitors of Lp-PLA2, namely a group of pyrimidone compounds. We have now identified a particular subset of pyrimidone compounds which have a 5-(2-oxopyrimid-5- ylmethyl) substituent and which are potent inhibitors of Lp-PLA2
Accordingly, the present invention provides a compound of the formula (I):
Figure imgf000004_0001
(I) in which: R1 is COOH or a salt thereof, COOR10, CONR1 lR12, CN or CH2OH;
R2 is a mono- or bicyclic aromatic ring system containing up to 10 carbon atoms in the ring system, or a mono- or bicyclic heteroaromatic ring system including up to 4 heteroatoms selected from N, O and S; optionally substituted by 1, 2, 3 or 4 substituents selected from Cj^alkyl, Cι_4aTkoxy, Cι_4alkylthio, aryl, aralkyl, hydroxy, oxo, halogen, CN, COOH or a salt thereof, COO-C,.6alkyl, CONR15R16, NR15COR16, SO2NR15R16, NR15SO2R16, NR15R16, mono to perfluoro C^alkyl and mono to perfluoro Cι.4alkoxy;
R3 is Cι_2o alkyl, C3.6 cycloalkyl, C3.6cycloalkylCι.5alkyl, or C1 _ιo alkoxyCi _ιo alkyl, each optionally substituted by 1 or 2 substituents selected from hydroxy, Cμio alkoxy, COOH or a salt thereof, COOC1.15 alkyl, CONR17R18, NR17R18 ' NR17COR18, NR^9 0r an aromatic or heteroaromatic ring system as defined for R2, or R3 is an aromatic or heteroaromatic ring system as hereinbefore defined for R2;
RIO is Cι_4alkyl or a pharmaceutically acceptable in vivo hydroly sable ester group;
R! 1 and R^2 which may be the same or different is each selected from hydrogen, C 2alkyl, CH2R13, CHR14CO2H or a salt thereof, or R1 1 and R12 together with the nitrogen to which they are attached form a 5- to 7 membered ring optionally containing one or more further heteroatoms selected from oxygen, nitrogen and sulphur, and optionally substituted by one or two substituents selected from hydroxy, oxo, Cι_4alkyl, Cι _4alkylCO, aryl, e.g. phenyl, or aralkyl, e.g benzyl, for instance morpholine or piperazine;
R13 is COOH or a salt thereof, COOR^, CONR1 *R12, CN or CH2OH;
Rl4 is an amino acid side chain such as CH2OH from serine; Rl5 and R^6 are independently hydrogen or C 1.4 alkyl e.g. methyl or ethyl;
Rl and Rl8 are independently hydrogen, C1.^5 alkyl, eg methyl or ethyl, C1 _I Q alkoxyCi .10 alkyl or arylCi _io alkyl, e.g. benzyl;
Rl9 together with the nitrogen atom to which it is attached forms a 5- to 7 membered ring optionally containing one or more further heteroatoms selected from oxygen, nitrogen and sulphur, and optionally substituted by one or two substituents selected from hydroxy, oxo, C1.4 alkyl, aryl, e.g. phenyl, or aralkyl, e.g benzyl;
W is SO2 or a bond;
X is O or S; and
Y is a group of the formula -A1-A2~A3- in which A^ and A3 each represent a bond or a straight chain or branched alkylene group, said alkylene group(s) containing a total of 1 to 10 carbon atoms and A2 represents a bond or O, S, SO, SO2, CO, C=CH2, CONH, NHCO, CR15R16, CH=CH or C≡C, providing that when A2 is O, S, SO, SO2or CONH, A3 contains at least two carbon atoms linking the A2 group and the CH2 group in formula (I).
Representative examples of R^ include carboxy (COOH) and corresponding salts, esters (COORlO) and amides (CONRl 1R^2) thereof, for instance a sodium salt, an ethyl ester or an amide comprising an N-alkyl substituent, for instance, methyl, 2-methoxyethyl, octyl, dodecyl, N-benzyl, N-naphthylmethyl or a disubstitued amide comprising a combination thereof, or an amide in which the N forms part of a heterocyclic ring, for instance a piperidine ring.
Representative examples of the aromatic ring system represented by R2 include phenyl and naphthyl. Representative examples of the heteroaromatic ring system which may be represented by R2 include pyridyl, pyrimidinyl, pyrazolyl, furanyl, thienyl, thiazolyl, quinolyl, benzothiazolyl, pyridazolyl and pyrazinyl. Representative examples of R2 include the phenyl group optionally substituted by 1 , 2 or 3 substituents selected from halogen (e.g. chlorine or fluorine), Cj_4 alkyl (e.g. methyl or ethyl) or Ci .4 alkoxy (e.g. methoxy), for instance 4-fluorophenyl. Examples of the aryl and aralkyl substituents in the R2 group include respectively phenyl and benzyl.
Representative examples of R3 include Cι_20 alkyl, for instance methyl and undecyl, and R17R18NHCOCH2 in which R^7 and R18 is each independently C\. ζ alkyl, for instance R17 is methyl and Rl8 is methyl, octyl, or dodecyl.
Preferably, W is a bond.
Preferably, R W is N-(l-Dodecyl)-N-methylaminocarbonylmethyl.
The group X is preferably S.
Preferred compounds of formula (I) include those in which Y is a bond, i.e. A*, A2 and A3 each representing a bond. Other preferred examples of the groups A^ and A3 are straight chain alkylene groups. When A2 is other than a bond, A^ is preferably a bond. Preferred examples of A2 above include CO, C=CH2 and O, the CO group being especially preferred. Other preferred examples of Y are (CH2)7 or CO(CH2)6-
Pharmaceutically acceptable in vivo hydrolysable ester groups for R^O include those which break down readily in the human body to leave the parent acid or its salt.
Representative examples of values of pharmaceutically acceptable in vivo hydrolysable ester groups for R ® include: -CH(Ra)O.CO.Rb; -CH(Ra)O.CO.ORc; -CH(Ra)CO.NReRf -RdNReRf; -CH2ORg;
CH2 .Rn
and
Figure imgf000007_0001
in which:
Ra is hydrogen, (Ci -6)alkyl, in particular methyl, (C3-7)cycloalkyl, or phenyl, each of which may be optionally substituted;
Rb is (Ci -6)alkyl, (Cι-g)alkoxy(Cι-6)alkyl, phenyl, benzyl, (C3-7)cycloalkyl,
(Cι-6)aikyl(C3-7)cycloaTkyl, l-amino(Cι -6)alkyl, or l-(Cι-6alkyl)amino(Cι-6)alkyl, each of which may be optionally substituted; or
Ra and RD together form a 1 ,2-phenylene group optionally substituted by one or two methoxy groups;
Rc is (Cι-6)alkyl, (C3-7)cycloalkyl, (Cι-6)alkyl(C3-7)cycloalkyl;
R" is (Ci -6)alkylene optionally substituted with a methyl or ethyl group; Re and Rf which may be the same or different is each (Cι -g)alkyl; or ary Cι -4) alkyl, optionally substituted with e.g. hydroxy;
Rg is (Cι -6)alkyl;
Rn is hydrogen, (Cι-6)alkyl or phenyl;
R1 is hydrogen or phenyl optionally substituted by up to three groups selected from halogen, (Cj-g^alkyl, or (Cι -6)alkoxy; and γl is oxygen or NH; for instance:
(a) acyloxyalkyl groups such as acetoxymethyl, isobutyryloxymethyl, pivaloyloxymethyl, benzoyloxymethyl, α-acetoxyethyl, α-pivaloyloxy ethyl,
1 -(cyclohexylcarbonyloxy)ethyl, ( 1 -aminoethyl)carbonyloxymethyl, 2-methoxyprop-2- ylcarbonyloxymethyl, phenylcarbonyloxymethyl and 4-methoxyphenyl- carbonyloxymethyl;
(b) alkoxy/cycloalkoxycarbonyloxyalkyl groups, such as ethoxycarbonyloxymethyl, t- butyloxycarbonyloxymethyl, cyclohexyloxycarbonyloxymethyl, 1- methylcyclohexyloxycarbonyloxymethyl and α-ethoxycarbonyloxyethyl; (c) dialkylaminoalkyl, especially di-loweralkylamino alkyl groups such as dimethylaminomethyl, dimethylaminoethyl, diethylaminomethyl or diethylaminoethyl;
(d) acetamido groups such as N,N-dimethylaminocarbonylmethyl, N,N-(2- hydroxyethyl)aminocarbonylmethyl; (e) lactone groups such as phthalidyl and dimethoxyphthalidyl;
(f) (5-methyl-2-oxo-l,3-dioxolen-4-yl)methyl; and
(g) (2-methoxycarbonyl-E-but-2-en-yl)methyl.
Representative examples of pharmaceutically acceptable in vivo hydrolysable ester groups for R10 include:
(2-methoxycarbonyl-E-but-2-en-yl)methyl, isobutyryloxymethyl, 2-methoxyprop-2- ylcarbonyloxymethyl, phenylcarbonyloxymethyl, 4-methoxyphenyl-carbonyloxymethyl, t-butyloxycarbonyloxymethyl, cyclohexyloxy-carbonyloxymethyl, 1- methylcyclohexyloxycarbonyloxymethyl, N,N-dimethylaminocarbonylmethyl, and (5- methyl-2-oxo- 1 ,3-dioxolen-4-yl)methyl.
When used herein, the term "alkyl" and similar terms such as "alkoxy" include all straight chain and branched isomers.
It will be appreciated that in some instances, compounds of the present invention may include a carboxy group as a substituent. Such carboxy groups may be used to form salts, in particular pharmaceutically acceptable salts. Pharmaceutically acceptable salts include those described by Berge, Bighley, and Monkhouse, J. Pharm. Sci., 1977, 66, 1-19. Preferred salts include alkali metal salts such as the sodium and potassium salts.
Compounds of formula (I) are inhibitors of Lp-PLA2 and as such are expected to be of use in treating atherosclerosis and the other disease conditions noted elsewhere. Such compounds are found to act as inhibitors of Lp-PLA2 in in vitro assays .
Particularly preferred compounds of formula (I) include:
1 -(N-( 1 -Octyl)-N-methylaminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-( 1 - carboxymethyl-2-oxopyrimid-5-ylmethyl)pyrimidin-4-one;
1 -(N-( 1 -Octyl)-N-methylaminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-( 1 -
(methylaminocarbonylmethyl)-2-oxopyrimid-5-ylmethyl)pyrimidin-4-one; 1 -(N-( 1 -Dodecyl)-N-methylaminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-( 1 - (methylaminocarbonylmethyl)-2-oxopyrimid-5-ylmethyl)pyrimidin-4-one; 1 -(N-( 1 -Dodecyl)-N-methylaminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-( 1 -( 1 - morpholinocarbonylmethyl)-2-oxopyrimid-5-ylmethyl)pyrimidin-4-one; and 1 -(N-( 1 -Dodecyl)-N-methylaminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-( 1 - carboxymethyl-2-oxopyrimid-5-ylmethyl)pyrimidin-4-one and the sodium salt thereof.
Since the compounds of the present invention, in particular compounds of formula (I), are intended for use in pharmaceutical compositions, it will be understood that they are each provided in substantially pure form, for example at least 50% pure, more suitably at least 75% pure and preferably at least 95% pure (% are on a wt/wt basis). Impure preparations of the compounds of formula (I) may be used for preparing the more pure forms used in the pharmaceutical compositions. Although the purity of intermediate compounds of the present invention is less critical, it will be readily understood that the substantially pure form is preferred as for the compounds of formula (I). Preferably, whenever possible, the compounds of the present invention are obtained in crystalline form.
When some of the compounds of this invention are allowed to crystallise or are recrystallised from organic solvents, solvent of crystallisation may be present in the crystalline product. This invention includes within its scope such solvates. Similarly, some of the compounds of this invention may be crystallised or recrystallised from solvents containing water. In such cases water of hydration may be formed. This invention includes within its scope stoichiometric hydrates as well as compounds containing variable amounts of water that may be produced by processes such as lyophilisation. In addition, different crystallisation conditions may lead to the formation of different polymorphic forms of crystalline products. This invention includes within its scope all polymorphic forms of the compounds of formula (I).
Compounds of the present invention are inhibitors of the enzyme lipoprotein associated phospholipase A2 (Lp-PLA2) and as such are expected to be of use in therapy, in particular in the treatment of atherosclerosis. In a further aspect therefore the present invention provides a compound of formula (I) for use in therapy.
The compounds of formula (I) are inhibitors of lysophosphatidylcholine production by Lp-PLA2 and may therefore also have a general application in any disorder that involves endothelial dysfunction, for example atherosclerosis, diabetes, hypertension, angina pectoris and after ischaemia and reperfusion. In addition, compounds of formula (I) may have a general application in any disorder that involves lipid peroxidation in conjunction with enzyme activity, for example in addition to conditions such as atherosclerosis and diabetes, other conditions such as rheumatoid arthritis, stroke, inflammatory conditions of the brain such as Alzheimer's Disease, myocardial infarction, reperfusion injury, sepsis, and acute and chronic inflammation. Further such conditions include various neuropsychiatric disorders such as schizophrenia (see Psychopharmacology Bulletin, 31, 159-165, 1995).
Further applications include any disorder that involves activated monocytes, macrophages or lymphocytes, as all of these cell types express Lp-PLA2. Examples of such disorders include psoriasis.
Accordingly, in a further aspect, the present invention provides for a method of treating a disease state associated with activity of the enzyme Lp-PLA2 which method involves treating a patient in need thereof with a therapeutically effective amount of an inhibitor of the enzyme. The disease state may be associated with the increased involvement of monocytes, macrophages or lymphocytes; with the formation of lysophosphatidylcholine and oxidised free fatty acids; with lipid peroxidation in conjunction with Lp PLA2 activity; or with endothelial dysfunction.
Compounds of the present invention may also be of use in treating the above mentioned disease states in combination with anti-hyperlipidaemic or anti-atherosclerotic or anti- diabetic or anti-anginal or anti-inflammatory or anti-hypertension agents. Examples of the above include cholesterol synthesis inhibitors such as statins, anti-oxidants such as probucol, insulin sensitisers, calcium channel antagonists, and anti-inflammatory drugs such as NSAIDs.
In therapeutic use, the compounds of the present invention are usually administered in a standard pharmaceutical composition. The present invention therefore provides, in a further aspect, a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable carrier.
Suitable pharmaceutical compositions include those which are adapted for oral or parenteral administration or as a suppository. Compounds of formula (I) which are active when given orally can be formulated as liquids, for example syrups, suspensions or emulsions, tablets, capsules and lozenges. A liquid formulation will generally consist of a suspension or solution of the compound or pharmaceutically acceptable salt in a suitable liquid carrier(s) for example, ethanol, glycerine, non-aqueous solvent, for example polyethylene glycol, oils, or water with a suspending agent, preservative, flavouring or colouring agent. A composition in the form of a tablet can be prepared using any suitable pharmaceutical carrier(s) routinely used for preparing solid formulations. Examples of such carriers include magnesium stearate, starch, lactose, sucrose and cellulose. A composition in the form of a capsule can be prepared using routine encapsulation procedures. For example, pellets containing the active ingredient can be prepared using standard carriers and then filled into a hard gelatin capsule; alternatively, a dispersion or suspension can be prepared using any suitable pharmaceutical carrier(s), for example aqueous gums, celluloses, silicates or oils and the dispersion or suspension then filled into a soft gelatin capsule. Typical parenteral compositions consist of a solution or suspension of the compound of formula (I) in a sterile aqueous carrier or parenterally acceptable oil, for example polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil. Alternatively, the solution can be lyophilised and then reconstituted with a suitable solvent just prior to administration. A typical suppository formulation comprises a compound of formula (I) which is active when administered in this way, with a binding and/or lubricating agent such as polymeric glycols, gelatins or cocoa butter or other low melting vegetable or synthetic waxes or fats.
Preferably the composition is in unit dose form such as a tablet or capsule. Each dosage unit for oral administration contains preferably from 1 to 500 mg (and for parenteral administration contains preferably from 0.1 to 25 mg) of a compound of the formula (I). The daily dosage regimen for an adult patient may be, for example, an oral dose of between 1 mg and 1000 mg, preferably between 1 mg and 500 mg, or an intravenous, subcutaneous, or intramuscular dose of between 0.1 mg and 100 mg, preferably between 0.1 mg and 25 mg, of the compound of the formula (I), the compound being administered 1 to 4 times per day. Suitably the compounds will be administered for a period of continuous therapy, for example for a week or more.
Compounds of formula (I) may be conveniently prepared by a process which comprises reacting a compound of formula (II):
Figure imgf000011_0001
(II) in which R2, R3, W, X and Y are as hereinbefore defined; with an alkylating agent of formula R!-CH2-L1 in which R^ is as hereinbefore defined and L* is a leaving group such as chloride, bromide, iodide or mesylate, in the presence of a base such as potassium carbonate; and thereafter, and if necessary, intercon verting groups in R , for example COOR^ to COOH by standard conditions (alkaline hydrolysis, hydrogenation of benzyl ester, etc), or COOH to CONRl 1R^2 by amide coupling.
A compound of formula (II) can conveniently by prepared by O-dealkylation of the corresponding compound of formula (III):
Figure imgf000012_0001
(HI) in which R ^ is C1 4 alkyl, arylmethyl or diarylmethyl and R2, R3, W, X and Y are as hereinbefore defined. Typical conditions include treatment with boron tribromide or B- bromocatecholborane in dichloromethane at temperatures between -20° and ambient; hydrogenolysis of benzyloxy groups; acid cleavage of O-tBu.
A compound of formula (III) may be readily prepared in a series of steps from a compound of formula (IV):
Figure imgf000012_0002
(IV) in which R2 is hydrogen or Cι _4 alkyl, for instance methyl or ethyl, R22 is hydrogen or methyl and R2^ is as hereinbefore defined; using procedures well known in the art for thiouracil formation, N-alkylation and thioetherification . Thus, for instance, for a compound of formula (III) in which W is a bond, a compound of formula (IV) in which R2* is hydrogen and R22 is methyl may be treated with oxalyl chloride in a dry solvent such as dichloroethane, to form an intermediate acyl chloride, followed by treatment with potassium thiocyanate in the presence of a solvent such as acetonitrile, and then treatment with a compound of the formula (V):
R3WNH2
(V) in which W is a bond and R3 is as hereinbefore defined; followed by the addition of a base such as sodium ethoxide, to give a thiouracil compound of the formula (VI):
Figure imgf000013_0001
(VI) in which R3, R2^ and W are as hereinbefore defined. The compound of formula (VI) may then be treated with a compound of the formula (VII):
R2YCH2L 1
(VII) in which L* and R2 are as hereinbefore defined; to give a compound of formula (III) in which X is S.
In an alternative approach, a compound of formula (IV) in which R ^ is Ci .4 alkyl, for instance methyl, and R22 is methyl, may be treated with thiourea, to form a thiouracil of the formula (VIII):
Figure imgf000013_0002
(VIII) in which R ^ is a hereinbefore defined. This thiouracil may then be treated with a compound of the formula (VII) as hereinbefore described, to give a compound of formula (IX):
Figure imgf000014_0001
(IX) in which R2, R ^ and Y are as hereinbefore defined and X is S. Subsequent reaction of a compound of formula (IX) with a compound of the formula (X):
R WL!
(X) in which A, R3 and W are as hereinbefore defined; leads to a compound of formula (III) in which X is S.
Compounds of formula (IV) may be readily obtained from a convenient, readily available pyrimdine starting material such as a 2-alkoxy 5-bromopyrimidine, using processes well known in the art. This pyrimidine may be coupled with an acrylate ester such as ethyl or methyl acrylate, using a Heck reaction, and the intermediate then subjected to catalytic hydrogenation to give a propionic acid ester derivative. This in turn may be treated with methyl formate in the presence of a strong base such as potassium t-butoxide or sodium hydride, to give a compound of formula (IV) in which R22 is hydrogen. Alkylation, for instance methylation, using dimethyl sulphate, then gives a compound of formula (IV) in which R22 is alkyl. A compound of formula (IV) in which R ^ is hydrogen (ie the carboxylic acid) may be obtained from the corresponding ester by hydrolysis under basic conditions, for instance aqueous sodium hydroxide.
Compounds of formula (I) in which X is O may be conveniently be prepared from corresponding compounds of formula (I) in which X is S by treatment thereof with a compound of the formula (XI): R YCH2OH
(XI) in which R2 is as hereinbefore defined.
The present invention will now be illustrated by the following examples: cyl)-N-methylbromoacetamide
Figure imgf000015_0001
To a solution of N-methyl-N-dodecylamine (2.5 ml) and triethylamine (1.4 ml) in dichloromethane (10 ml) was added with stirring and ice cooling a solution of bromoacetyl bromide (0.87 ml) in dichloromethane (10 ml). The cooling bath was removed after 30 min and the reaction stood for 16 h at ambient temperature. The mixture was washed with water and saturated sodium hydrogen carbonate, dried (KjCOj) and the solution purified by flash chromatography (silica, methanol-dichloromethane). Appropriate fractions were combined and evaporated to a pale yellow oil, yield 1.53 g (48%).
Η-NMR (CDC13) δ 0.8 (3H,t), 1.2 (18H,m), 1.5 (2H,m,), 2.88 and 2.99 (3H,2xs), 3.27 (2H,m), 3.77 and 3.79 (2H,s)); MS (APCI+) found (M+l) = 320, 322, C15H30BrNO requires 319,321.
Intermediate 2 - N-(l-Octyl)-N-methylbromoacetamide
Figure imgf000015_0002
Prepared analogously to intermediate 1 , from N-methyl-N-octylamine. Η-NMR (CDCI3) 50.85-1.0 (3H,m), 1.1-1.4 (10H,m), 1.4-1.75 (2H,m,), 2.95 and 3.07 (3H, 2xs), 3.25-3.45 (2H,m), 3.85 and 3.86 (2H,s)); MS (APCI+) found (M+l) = 264, 266, C15H30BrNO requires 319,321.
Intermediate 3 - Ethyl 3-(2-methoxypyrimidin-5-yl)acrylate
Figure imgf000015_0003
A mixture of 2-methoxy-5-bromopyrimidine (75.43 g, 0.399 mol), ethyl acrylate (47.5 ml, 0.439 mol), palladium (II) acetate (1.07 g, 0.0048 mol), tri-o-tolylphosphine (2.92 g, 0.0096 mol) and triethylamine (84 ml) were heated at 135°C with stirring under argon for 12 h. After allowing to cool the solid mass was dissolved in water and ethyl acetate, filtered, and the aqueous phase separated and further extracted with ethyl acetate. The combined extracts were washed with saturated aqueous ammonium chloride, dried (MgSO4) and evaporated. The solid thus obtained was triturated with ether/light petrol (1:3, 350 ml), filtered, washed and dried, yield 52.41 g (63%).
Η-NMR (CDCI3) δ 1.33 (3H, t), 4.06 (3H, s), 4.28 (2H, q), 6.45 (1H, d), 7.58 (1H, d), 8.67 (2H, s); MS (APCI+) found (M+H) = 209; C10HI2N2O3 requires 208.
Intermediate 4 - Ethyl 3-(2-methoxypyrimidin-5-yl)propionate o
N "*>T "^ OEt
MeO N
A suspension of ethyl 3-(2-methoxypyrimidin-5-yl)acrylate (52.4 g, 0.252 mol) in ethanol (400 ml) and triethylamine (50 ml) was treated with 10% palladium on carbon (3 g) and hydrogenated at 50 psi for 1.75 h. The catalyst was filtered off through hyflo and the filtrate evaporated. The residue was dissolved in dichloromethane, washed twice with saturated aqueous ammonium chloride, dried (MgSO4) and evaporated to an oil, yield 41.2 g (78%).
Η-NMR (CDC13) δ 1.23 (3H, t), 2.61 (2H, t), 2.87 (2H, t), 3.99 (3H, s), 4.13 (2H, q), 8.39 (2H, s); MS (APCI+) found (M+H) = 211; C10H14N2O3 requires 210.
Intermediate 5 - 2-(Methoxymethylene)-3-(2-methoxypyrimidin-5-yl)propionic acid, mixed methyl/ethyl esters
Figure imgf000016_0001
To a stirring suspension of sodium hydride (0.83 g of a 60% dispersion in oil) in anhydrous 1 , 2-dimethoxyethane (6 ml) was added dropwise a solution of methyl formate (1.54 ml) and ethyl 3-(2-methoxypyrimid-5-yl)propionate (3.5 g) in anhydrous 1,2- dimethoxyethane (6 ml) at such a rate as to maintain the reaction temperature at 25-30°C. After 1 h, ether was added and the precipitated oil allowed to settle. The solution was decanted off and replaced with fresh ether, and the oil slowly solidified. The solid 2- (hydroxymethylene) derivative was filtered, washed and dried, yield 3.8 g. A 1.33 g portion was suspended in dimethyl formamide (10 ml) together with anhydrous potassium carbonate (1.15 g), and a solution of dimethyl sulphate (0.48 ml) in dimethylformamide (10 ml) was added dropwise with stirring over 30 min. After 16 h the solvent was evaporated and the residue treated with water and extracted with ethyl acetate. The extracts were washed with water, dried (MgSO4) and evaporated to give the product as an oil, yield 0.91 g.
Η-NMR (CDCI3) δ 1.23 (3H, t), 3.46 (2H, s), 3.69 (3H, s, methyl ester), 3.88 (3H, s), 3.97 (3H, s), 4.16 (2H, q), 7.39 (IH, s), 8.40 (2H, s). 3:2 ratio of methyl:ethyl esters. MS (APCI+) found (M+l) = 253, 239 (ethyl and methyl esters); C]2HI6N2O4 requires 252, CπH14N2O4 requires 238.
Intermediate 6 - 2-(Methoxymethylene)-3-(2-methoxypyrimidin-5-yI)propionic acid
OH
MeO N ~ OMθ A suspension of the mixed esters of intermediate 5 (0.9 g) in 2M aqueous sodium hydroxide (3.6 ml) was stirred at ambient temperature for 16 h to give a clear solution. This was diluted with water, extracted with dichloromethane and evaporated to about half volume, then acidified to pH 3-4 (2M hydrochloric acid) when the product crystallised out. The white solid was filtered, washed with ice-cold water and dried, yield 0.46 g. Η-NMR (CDCI3) δ 3.43 (2H, s), 3.91 (3H, s), 3.99 (3H, s,), 7.49 (IH, s), 8.42 (2H, s); MS (APCI+) found (M+l) = 225, C10HI2N2O4 requires 224.
Intermediate 7 - 5-(2-Methoxypyrimidin-5-ylmethyl)-2-thiouracil
Figure imgf000016_0002
To an ice cooled solution of potassium t-butoxide (7.83 g, 0.07 mol) in anhydrous THF (60 ml) was added dropwise with stirring under argon over 1 hour to a solution of ethyl 3- (2-methoxypyrimidin-5-yl) propionate (5.87 g, 0.028 mol) and methyl formate (3.6 ml, 0.059 mol) in anhydrous ether (70 ml). After stirring for 16 h, the solvents were evaporated, thiourea (4.25 g, 0.056 mol) and propan-2-ol (80 ml) added and the mixture refluxed for 5 h. The solvent was evaporated and the residue dissolved in water, extracted twice with ether and acidified to pH 4.5 with acetic acid. The solid which precipitated was filtered, washed well with water and dried, yield 5.57 g (80%). Η-NMR (d6-DMSO) δ 3.47 (2H, s), 3.85 (3H, s), 7.43 (IH, s), 8.48 (2H, s), 12.25 (IH, br s), 12.46 (IH, br s); MS (APCI+) found (M+H) = 251; C10H10N4O2S requires 250.
Intermediate 8 - l-(l-Undecyl)-5-(2-ethoxypyrimidin-5-ylmethyI)-2-thiouracil
Figure imgf000017_0001
To a slurry of 2-(methoxymethylene)-3-(2-methoxypyrimidin-5-yl)propionic acid (3.1g) in dry dichloroethane (50ml) was added oxalyl chloride (2.5ml). The mixture was stirred at room temperature for 4h and the solvent was removed in vacuo. Further dichloroethane (50ml) was added and removed in vacuo. The residue was mixed with acetonitrile (50ml) and dry potassium thiocyanate (2.0g) added. The mixture was stirred under argon for 21h and the solvent removed in vacuo. The residue was mixed with dimethylformamide and 1-undecylamine (3.0ml) added with stirring, followed by triethylamine (5ml). The mixture was stirred at room temperature under argon for 20h and a solution of sodium ethoxide in ethanol (3M, 19ml) was added. The reaction was heated at 90°C for 2h, cooled and the solvent was removed in vacuo. The residue was dissolved in water and glacial acetic acid was added to pH4.5. The solid so formed was filtered, evaporated with ethanol (100ml) in vacuo and dried in vacuo to give the desired product (5g).
Η-NMR (d6 DMSO) δ 0.75-0.95 (3H,m), 1.1-1.8 (21H,m), 3.49 (2H,s), 4.11 (2H,t), 4.31 (2H,q), 7.87 (lH,s) 8.47 (2H,s); MS (APCI+) found (M+l) = 419; C22H34N4O2S requires 418.
Intermediate 9 - l-(l-Undecyl)- 5-(2-methoxypyrimid-5-ylmethyl)-2-thiouracil
Figure imgf000017_0002
Prepared analogously to intermediate 8, except using sodium methoxide in place of ethoxide. Η-NMR (CDC13) δ 0.8-0.95 (3H,t), 1.1-1.85 (18H,m), 3.59 (2H, s), 4.01 (3H,s), 4.11
(2H,t), 7.04 (lH,s), 8.43 (2H, s); MS (APCI+) found (M+l) = 405; C21H32N4O2S requires 404. Intermediate 10 - l-(l-UndecyI)-2-(4-fluorobenzylthio)-5-(2-ethoxypyrimid-5- ylmethyl)pyrimidin-4-one
Figure imgf000018_0001
To a mixture of l-undecyl-5-(2-ethoxypyrimidin-5-ylmethyl)-2-thiouracil (5.0g) and diisopropylethylamine (2.1ml) in dry methylene chloride (200ml) was added 4- fluorobenzyl bromide (1.5ml) and the mixture stirred under argon at room temperature for 20h. The solution was washed with 5% aqueous sodium bicarbonate and the organic layer was added directly to a silica gel column (200g). Elution with ethyl acetate to 5% methanol in ethyl acetate gave the desired product (2.7g). Η-NMR (CDC13) δ 0.8-0.95 (3H,m), 1.15-1.4 (16H,m), 1.43 (3H,t), 1.55-1.8 (2H,m), 3.68 (2H,s), 3.71 (2H,t), 4.41 (2H,q), 4.47 (2H,s), 6.86 (lH,s), 6.9-7.1 (2H,m), 7.3-7.45 (2H,m), 8.45 (2H,d); MS (APCI+) found (M+l) = 527; C29H39FN4O2S requires 526.
Intermediate 11 - 2-(4-Fluorobenzylthio)-5-(2-methoxypyrimid-5- e
Figure imgf000018_0002
Prepared analogously to intermediate 10, from 5-(2-methoxypyrimidin-5-ylmethyl)-2- thiouracil.
Η-NMR (d6 DMSO) δ 3.55 (2H,s), 3.85 (3H,s), 4.36 (2H,s), 7.0-7.2 (2H,m), 7.35-7.5 (2H,m), 7.86 (lH,bs), 8.48 (2H,s) 12.81 (lH,b); MS (APCI+) found (M+l) = 359; C17H15FN4O2S requires 358.
Intermediate 12 - l-Methyl-2-(4-fluorobenzylthio)-5-(2-methoxypyrimid-5-
Figure imgf000018_0003
To a solution of intermediate 11 (10.2g) and diisopropylethylamine (6.0ml) in dry methylene chloride (120ml) was added iodomethane (1.7ml) under argon with stirring. The mixture was left at room temperature for 48h, washed with saturated ammonium chloride and saturated sodium bicarbonate and added directly to a silica (200g) column. Elution with 2% to 10% methanol in ethyl acetate gave the desired product (2.5g).
Η-NMR (CDC13) δ 3.47 (3H,s), 3.64 (2H,t), 3.99 (3H,s), 4.47 (2H,s), 6.88 (lH,s), 6.9- 7.1 (2H,m), 7.3-7. 5 (2H,m), 8.44 (2H,s); MS (APCI+) found (M+l) = 373; C18H17FN4O2S requires 372.
Intermediate 13 - l-(N-Methyl-N-(l-octyI)aminocarbonylmethyl)-2-(4- fluorobenzyIthio)-5-(2-methoxypyrimid-5-ylmethyl)pyrimidin-4-one
Figure imgf000019_0001
Prepared analogously to intermediate 12 , using N-(l-octyl)-N-methylbromoacetamide in place of iodomethane.
Η-NMR (CDCI3) δ 0.8-0.95 (3H,m), 1.1-1.7 (12H,m), 2.95 and 2.99 (3H,2xs), 3.21 and 3.36 (2H, 2xt), 3.66 (2H,s), 3.99 (3H,s), 4.48 (2H,s), 4.51 and 4.55 (2H,d), 6.80 (lH,s), 6.9-7.1 (2H,m), 7.3-7.45 (2H,m), 8.45 (2H,s); MS (APCI+) found (M+l) = 542; C28H36FN5O3S requires 541.
Intermediate 14 - l-(N-Methyl-N-(l-dodecyI)aminocarbonylmethyl)-2-(4-
Figure imgf000019_0002
A mixture of N-dodecyl-N-methylbromoacetamide (1.53g), 2-(4-fluorobenzylthio)-5-(2- methoxypyrimidyl-5-ylmethyl)pyrimid-4-one (1.71g) and N,N-diisopropylethylamine (0.92ml) in dichloromethane (7ml) was stirred at ambient temperature for 16h. The solution was washed with saturated ammonium chloride then purified by flash chromatography (fine silica, methanol-ethyl acetate) to give the product as a solid, yield 0.82g (29%).
Η-NMR (CDCI3) δ 0.85 (3H,t), 1.2 (18H,m), 1.5 (2H,m,), 2.92 and 2.95 (3H,2xs), 3.17 and 3.33 (2H,2xm), 3.63 (2H,s), 3.96 (3H,s), 4.45 (2H,s), 4.49 and 4.52 (2H,2xs), 6.79 (lH,s), 6.95 (2H,m), 7.30 (2H,m), 8.42 (2H,s); MS (APCI+) found (M+l) = 598, CJJH^FN JS requires 597.
Intermediate 15 - l-(l-Undecyl)-2-(4-fluorobenzyl)thio-5-(2-methoxypyrimid-5-
Figure imgf000019_0003
Prepared analogously to intermediate 10, from l-undecyl-5-(2-methoxypyrimidin-5- ylmethyl)-2-thiouracil
Η-NMR (CDCI3) δ 0.88 (3H, t), 1.25 (16H, m), 1.68 (2H, m), 3.64 (2H, s), 3.71 (2H, t),
4.00 (3H, s), 4.47 (2H, s), 6.87 (IH, s), 7.00 (2H, m), 7.36(2H, m), 8.46(2H, s); MS (APCI+) found (M+H) = 513; C28H37N4O2S requires 512.
Intermediate 16 - l-(l-Undecyl)-2-(4-fluorobenzyl)thio-5-(2-oxopyrimid-5- ylmethyI)pyrimidin-4-one
Figure imgf000020_0001
To a solution of intermediate 15 (0.2g) in dry methylene chloride (4ml) at 4°C was added boron tribromide (1M in methylene chloride, 2ml). The mixture was stirred under argon for 24h and poured into a mixture of ice (50ml) and 0.880 ammonia (15ml) with stirring. Extraction with 5% methanol in methylene chloride was followed by filtration through kieselguhr and drying the organic layer over sodium sulphate. Removal of the solvent in vacuo gave the desired material as a grey solid (0.15g). The same material could be prepared from intermediate 10 by an identical method.
Η-NMR (CDC13) δ 0.8-0.95 (3H,m), 1.1-1.4 (16H,m), 1.6-1.85 (2H,m), 3.49 (2H,s), 3.79 (2H,t), 4.45 (2H,s), 6.9-7.1 (2H,m), 7.2-7.45 (3H,m), 8.32 (2H,s); MS (APCI+) found (M+l) = 499; C27H35FN4O2S requires 498.
Intermediate 17 - l-(N-Methyl-N-(l-octyI)aminocarbonylmethyl)-2-(4- yrimid-5-ylmethyl)pyrimidin-4-one
Figure imgf000020_0002
Prepared analogously to intermediate 16, from l-(N-methyl-N-(l-octyl)- aminocarbonylmethyl)-2-(4-fluorobenzylthio)-5-(2-methoxypyrimid-5-ylmethyl)- pyrimidin-4-one, except that the reaction was performed at 5°C (ice-bath) for 4-6h. Η-NMR (d6 DMSO) δ 0.8-0.95 (3H,m), 1.05-1.65 (12,m), 2.81 and 2.94(3H,2xs), 3.15- 3.4 (4H,m), 4.39 (2H,s), 4.83 and 4.85 (2H,2xd), 7.05-7.2 (2H,m), 7.35-7.55 (3H,m), 7.95-8.35 (2H,b); MS (APCI+) found (M+l) = 526; C27H35FN4O2S requires 525.
Intermediate 18 - l-Methyl-2-(4-fluorobenzyl)thio-5-(2-oxopyrimid-5-
Figure imgf000020_0003
To a solution of intermediate 12 (5g) in dry methylene chloride was added a solution of boron tribromide 1M in dichloromethane (50ml) at 5°C under argon with stirring. After 0.5h, the mixture was allowed to warm to room temperature and was allowed to stir at room temperature for 72h. The mixture was decanted into a mixture of ice (50ml) and 0.880 ammonia (50ml). The solid remaining in the flask was treated with some of the aqueous mixture and 10% methanol in methylene chloride. The entire mixture was filtered through kieselguhr and the organic layer was separated. The aqueous layer was reduced to one quarter volume in vacuo and the solid formed filtered off, washed with water and dried in vacuo to give the desired product (2.2g). Η-NMR (d6 DMSO) δ 3.30 (2H,s), 3.47 (3H,s), 4.41 (2H,s), 7.05-7.25 (2H,m), 7.4-7.55 (2H,m), 7.65 (lH,s), 7.85-8.3 (2H,b); MS (APCI+) found (M+l) = 359; C17H15FN4O2S requires 358.
Example 1 - l-(l-Undecyl)-2-(4-fluorobenzyl)thio-5-(l-(ethoxycarbonylmethyl)-2- oxopyrimid-5-ylmethyl)pyrimidin-4-one
Figure imgf000021_0001
To a solution of intermediate 16 (0.64g) in dry dimethylformamide (15ml) was added ethyl bromoacetate (0.15ml) and potassium carbonate (0.38g). The mixture was heated at 70°C for 3h under argon with stirring. The dimethylformamide was removed in vacuo and the residue was partitioned between aqueous ammonium chloride (30ml) and methylene chloride. The aqueous layer was washed with further methylene chloride and the combined organic layers were added directly to a SepPak cartridge (SiO2, lOg) and eluted with 0 - 15% methanol in ethyl acetate. This gave the desired product as a gum (0.63g).
Η-NMR (CDC13) δ 0.8-0.95 (3H,m), 1.15-1.4 (19H,m), 1.65-1.85 (2H,m), 3.47 (2H,s), 3.7 (2H,t), 4.25 (2H,q), 4.46 (2H,s), 4.61 (2H,s), 6.9-7.1 (2H,m), 7.12 (lH,s), 7.3-7.45 (2H,m), 7.87 (lH,bd), 8.5 (lH,bd); MS (APCI+) found (M+l) = 585; C31H41FN4O4S requires 584.
Example 2 - l-(l-Undecyl)-2-(4-fluorobenzyl)thio-5-(l-(carboxymethyl)-2-
Figure imgf000021_0002
A solution of sodium hydroxide (0.023g) in water (1.25ml) was added to a solution of 1- undecyl-2-(4-fluorobenzyl)thio-5-( 1 -(carbethoxymethyl)-2-oxopyrimid-5-ylmethyl)- pyrimidin-4-one (0.33g) in dioxan (5ml) under argon. After 16h, the solvent was removed, almost to dryness, in vacuo and the residue dissolved in water (30ml).
Acidification to pH 1 with 2M hydrochloric acid gave a solid that was filtered, washed with water and dried in vacuo to give the desired product (0.14g) as a white solid. Η-NMR (d6 DMSO) δ 0.8-0.95 (3H,m), 1.1-1.4 (16H,m), 1.55-1.8 (2H,m), 3.38 (2H,s),
3.81 (2H,t), 4.42 (2H,s), 4.62 (2H,s), 7.05-7.2 (2H,m), 7.4-7.55 (2H,m), 7.80 (lH,s), 8.22
(lH,bd), 8.65 (lH,bd).
Example 3 - l-(l-Undecyl)-2-(4-fluorobenzyl)thio-5-(l- (dimethylaminocarbonylmethyl)-2-oxopyrimid-5-ylmethyl)pyrimidin-4-one
Figure imgf000021_0003
A mixture of l-undecyl-2-(4-fluorobenzyl)thio-5-(l-(carboxymethyl)-2-oxopyrimid-5- ylmethyl)pyrimidin-4-one, dimethylamine hydrochloride (0.02g), diisopropylethylamine (0.045ml), hydroxybenzotriazole (0.005g) and l-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (0.045g) in dry methylene chloride were stirred together for 24h and diluted with 3% methanol in methylene chloride and 5% aqueous potassium carbonate. The organic layer was added directly to a SepPak cartridge (SiO2, lOg) and eluted with 0 - 20% methanol in ethyl acetate to give the desired product (0.085g). Η-NMR (CDC13) δ 0.8-0.95 (3H,m), 1.15-1.4 (16H,m), 1.6-1.85 (2H,m), 2.98 (3H,s), 3.13 (3H,s), 3.49 (2H,s), 3.77 (2H,t), 4.46 (2H,s), 4.74 (2H,s), 6.9-7.1 (2H,m), 7.14 (lH,s), 7.3-7.45 (2H,m), 7.78 (lH,bd), 8.49 (lH,bd); MS (APCI+) found (M+l) = 584; C31H42FN5O3S requires 583.
Example 4 - l-Methyl-2-(4-fluorobenzyl)thio-5-(l-(ethoxycarbonylmethyl)-2- oxopyrimid-5-ylmethyl)pyrimidin-4-one
Figure imgf000022_0001
Prepared analogously to example 1.
Η-NMR (CDCI3) δ 1.30 (3H,t), 3.48 (2H,s), 3.54 (3H,s), 4.22 (2H,q), 4.45 (2H,s), 4.61 (2H,s), 6.9-7.1 (2H,m), 7.3-7.5 (3H,m), 7.91 (lH,d), 8.6 (lH,d); MS (APCI+) found (M+l) = 445; C2IH21FN4O4S requires 444.
Example 5 - l-Methyl-2-(4-fluorobenzyl)thio-5-(l-(carboxymethyl)-2-oxopyrimid-5- ylmethyl)pyrimidin-4-one
Figure imgf000022_0002
Prepared analogously to example 2. Η-NMR (d6 DMSO) δ 3.34 (2H,s), 3.48 (3H,t), 4.42 (2H,s), 4.55 (2H,s), 7.05-7.2 (2H,m), 7.4-7.6 (2H,m), 7.70 (lH,s), 8.01 (lH,bd), 8.58 (lH,bd).
Example 6 - l-Methyl-2-(4-fluorobenzyl)thio-5-(l-(l-octylaminocarbonylmethyl)-2- oxopyrimid-5-ylmethyl)pyrimidin-4-one
Figure imgf000022_0003
Prepared analogously to example 3.
Η-NMR (d6 DMSO) δ 0.8-0.95 (3H,t), 1.2-1.55 (12H, m), 3.05-3.2 (2H,m), 3.39 (2H,s), 3.52 (3H,s), 4.44 (2H.s), 4.47 (2H,s), 6.95-7.15 (2H,m), 7.4-7.55 (2H,m), 7.67 (lH,s) 7.95 (lH,d), 8.56 (lH,d); MS (APCI+) found (M+l) = 528; C27H34FN5O3S requires 527. Example 7 - l-Methyl-2-(4-fluorobenzyl)thio-5-(l-(N-benzyl-N-methylamino- carbonylmethyl)-2-oxopyrimid-5-ylmethyl)pyrimidin-4-one
Figure imgf000023_0001
Prepared analogously to example 3.
Η-NMR (CDC13) δ 3.00 and 3.04 (3H,2xs), 3.5 (3H,s + 2H,s), 4.47 (2H,s), 4.55-4.9
(2H,s), 6.9-7.1 (2H,m), 7.15-7.55 (8H,m), 7.75-7.9 (lH,m), 8.45-8.6 (lH,m).
Example 8 - l-Methyl-2-(4-fluorobenzyl)thio-5-(l-(N-(l-dodecyl)-N-methylamino- mid-5-ylmethyl)pyrimidin-4-one
Figure imgf000023_0002
Prepared analogously to example 3.
Η-NMR (CDCI3) δ 0.8-0.95 (3H,m), 1.1-1.75 (20H,m), 2.97 and 3.09 (3H,2xs), 3.35 (2H,t), 3.49 (2H,s), 3.52 (3H,s), 4.47 (2H,s), 4.72 (2H,s), 6.9-7.1 (2H,m), 7.23 (lH,s), 7.3-7.5 (2H,m), 7.77 (lH,bd), 8.48 (lH,bd); MS (APCI+) found (M+l) = 598; C32H44FN5O3S requires 597.
Example 9 - l-Methyl-2-(4-fluorobenzyl)thio-5-(l-(N-(2-methoxyethyl)-N-methyl- aminocarbonylmethyl)-2-oxopyrimid-5-ylmethyl)pyrimidin-4-one
Figure imgf000023_0003
Prepared analogously to example 3.
Η-NMR (CDCI3) δ 2.98 and 3.17 (3H,2xs), 3.34 and 3.38 (3H,2xs), 3.4-3.7 (9H,s), 4.47 (2H,s), 4.75 and 4.81 (2H,2xs), 6.9-7.1 (2H,m), 7.18 and 7.20 (lH,2xs), 7.3-7. 5 (2H,m), 7.7-7.85 (lH,m), 8.49 (lH,bd); MS (APCI+) found (M+23) = 510; C23H26FN5O4S requires 487.
Example 10 - l-Methyl-2-(4-fluorobenzyl)thio-5-(l-(N-(naphth-l-ylmethyl)-N- methylaminocarbonylmethyl)-2-oxopyrimid-5-ylmethyl)pyrimidin-4-one
Figure imgf000023_0004
Prepared analogously to example 3. Η-NMR (CDCI3) δ 2.99 and 3.12 (3H,2xs), 3.35-3.6 (5H,m), 4.46 and 4.47 (2H,2xs), 4.67 and 4.79 (2H,2xs), 5.07 and 5.17 (2H, 2xs), 6.9-7.1 (2H,m), 7.1-7.7 (7H,m), 7.7-8.05 (4H,m), 8.45-8.6 (lH,m); MS (APCI+) found (M+l) = 570; C31H28FN5O3S requires 569.
Example 11 - l-Methyl-2-(4-fluorobenzyl)thio-5-(l-(4-hydroxy-4-benzylpiperidin-l- ylcarbonylmethyl)-2-oxopyrimid-5-ylmethyl)pyrimidin-4-one
Figure imgf000024_0001
Prepared analogously to example 3.
Η-NMR (d6 DMSO) δ 1.25-1.65 (4H,m), 2.71 (2H,s), 2.94, (lH,bt), 3.55-3.7 (lH,m), 3.95-4.1 (lH,m), 4.41 (3H,s), 4.65-4.85 (2H,m),7.05-7.35 (7H,m), 7.4-7.6 (2H,m), 7.71 (lH,s), 7.87 (lH,d), 8.54 (lH,d); MS (APCI+) found (M+l) = 590; C31H32FN5O4S requires 589.
Example 12 - l-Methyl-2-(4-fluorobenzyI)thio-5-(l-(N-(l-octyl)-N-methylamino- carbonylmethyl)-2-oxopyrimid-5-ylmethyl)pyrimidin-4-one o
I
Prepared analogously to example 3.
Η-NMR (CDCI3) δ 0.8-0.95 (3H,m), 1.10-1.65 (12H,m), 2.95 and 3.09 (3H,2xs), 3.35 (2H,t), 3.49 (2H,s), 3.52(3H,s), 4.47 (2H,s), 4.74 (2H,s), 6.9-7.1 (2H,m), 7.19 (lH,s), 7.3- 7.5 (2H,m), 7.75 (lH,m), 8.48(lH,m); MS (APCI+) found (M+l) = 542; C28H36FN5O3S requires 541.
Example 13 - l-(N-(l-Octyl)-N-methylaminocarbonylmethyl)-2-(4-fluorobenzyl)thio- 5-(l-ethoxycarbonylmethyl-2-oxopyrimid-5-ylmethyl)pyrimidin-4-one
N C c
Prepared analogously to example 1.
Η-NMR (CDCI3) δ 0.8-1.0 (3H,m), 1.15-1.75 (15H,m), 2.94 and 3.00 (3H,2xs), 3.23 and 3.35 (2H,2xt), 3.47 (2H,s), 4.22 (2H,q), 4.46 (2H,s), 4.57 (2H,s), 4.73 and 4.75 (2H,2xs) 6.9-7.1 (2H,m), 7.35-7.45 (3H,m), 7.87 (lH,m), 8.44 (lH,m); MS (APCI+) found (M+l) = 614; CJ^JFNJOJS requires 613.
Example 14 - l-(N-(l-Octyl)-N-methylaminocarbonylmethyl)-2-(4-fluorobenzyl)thio- 5-(l-carboxymethyl-2-oxopyrimid-5-ylmethyl)pyrimidin-4-one
Figure imgf000025_0001
Prepared analogously to example 2 except that acidification was carried out with 10% aqueous NaHSO4 to pH 3, and the crude product after filtration was recrystallised from acetonitrile. Η-NMR (d6 DMSO) δ 0.8-0.95 (3H,m), 1.1-1.65 (12H,m), 2.82 and 2.95 (3H,2xs), 4.40 (2H,s), 4.56 (2H,s), 4.84 and 4.85 (2H,2xs), 7.05-7.2 (2H,m), 7.35-7.50 (2H,m), 7.54 and 7.58 (lH,2xs), 8.04 (lH,d), 8.55 (lH,d); MS (APCI-) found (M-l) = 584; C29H36FN5O5S requires 585.
Example 15 - l-(N-(l-Dodecyl)-N-methylaminocarbonylmethyl)-2-(4- fluorobenzyl)thio-5-(l-ethoxycarbonylmethyl-2-oxopyrimid-5-ylmethyl)pyrimidin-4- one
Figure imgf000025_0002
To a stirring solution of intermediate 14 (2.17 g) in dichloromethane (30 ml) was added dropwise with ice cooling a 1M solution of boron tribromide (21.8ml) such that the temperature remained between 5-10°C. After 4h the cooling bath was removed and stirring continued for 1.5h. The mixture was poured on to ice and 0.880 ammonia with stirring, diluted with more dichloromethane, shaken, and the phases allowed to separate slowly. The aqueous phase was further extracted with dichloromethane and the combined extracts dried (MgSO4) and evaporated. The crude material was purified by flash chromatography (fine silica, methanol-ethyl acetate) to give 0.9 g of material that was dissolved in dry dimethylformamide (15ml) and heated with ethyl bromoacetate (0.17ml) and anhydrous potassium carbonate (0.43g) (oil bath 70°C) with stirring for 2h. The solvent was evaporated and the residue treated with water and extracted with ethyl acetate. The combined extracts were washed with water, dried (MgSO4), evaporated and purified by flash chromatography (fine silica, methanol-ethyl acetate) to give the title compound as an oil, yield 0.52 g.
Η-NMR (CDC13) δ 0.88 (3H, t), 1.25 (21H, m), 1.45-1.75 (2H, m,), 2.95, 3.00 (3H, 2xs), 3.20- 3.43 (2H, m), 3.48 (2H, s), 4.23 (2H, q), 4.47 (2H, s), 4.99 (2H, s), 4.66 (2H, m), 7.02 (2H, m), 7.15 and 7.18 (IH, 2xs), 7.37 (2H, m) 7.84 (IH, m), 8.47 (IH, m); MS (APCI+) found (M+l) = 670, C35H48FN5O5S requires 669.
Example 16 - l-(N-(l-Dodecyl)-N-methylaminocarbonylmethyl)-2-(4- fluorobenzyl)thio-5-(l-carboxymethyl-2-oxopyrimid-5-ylmethyl)pyrimidin-4-one
Figure imgf000026_0001
To a stirring solution of l-(N-(l-dodecyl)-N-methylaminocarbonylmethyl)-2-(4- fluorobenzyl)thio-5-(l-ethoxycarbonylmethyl-2-oxopyrimid-5-ylmethyl)pyrimidin-4-one in 1,4-dioxan (8 ml) was added 0.5M sodium hydroxide (1.56ml). After 1 h, water (3 ml) was added. After a further hour, the mixture was diluted with water, extracted with ethyl acetate and acidified to pH 3 with aq. sodium bisulphate. The solid which precipitated was filtered, washed with water and ether, heated briefly with acetone and filtered again to give the product as a white solid, yield 0.28 g.
Η-NMR (d6-DMSO) δ 0.85 (3H, t), 1.22 (18H, m), 1.35-1.61 (2H, m,), 2.78, 2.95 (3H, 2xs), 3.20- 3.35 (2H, m), 3.58 (2H, s), 4.40 (2H, s), 4.55 (2H, s), 4.83 (2H, m), 7.10 (2H, m), 7.44 (2H, m), 7.54 and 7.57 (IH, 2xs), 8.03 (IH, m), 8.54 (IH, m) 13.10 (IH, br. s); MS (APCI+) found (M+l) = 642, C33H44FN5O5S requires 641.
Example 17 - l-(N-(l-Octyl)-N-methylaminocarbonylmethyl)-2-(4-fluorobenzyl)thio- 5-(l-(methylaminocarbonylmethyl)-2-oxopyrimid-5-ylmethyl)pyrimidin-4-one
Figure imgf000026_0002
Prepared analogously to example 3.
Η-NMR (CDC13) δ 0.8-0.95 (3H,t), 1.1-1.8 (12H,m), 2.73 (3H,bs), 2.93 and 3.00 (3H,2xs), 3.15-3.7 (4H,s), 4.68 (2H,bs), 4.79 (2H, bd), 6.85-7.1 (2H, m), 7.2-7.5 (3H,m), 7.71 (lH,m), 8.63 (lH,bs), 8.82(lH,bs); MS (APCI+) found (M+l) = 599; C30H39FN6O4S requires 598.
Example 18 - l-(N-(l-Dodecyl)-N-methylaminocarbonylmethyl)-2-(4-fluorobenzyl)- thio-5-(l-(methylaminocarbonylmethyl)-2-oxopyrimid-5-ylmethyl)pyrimidin-4-one
Figure imgf000026_0003
Prepared analogously to example 3.
1H-NMR (d6-DMSO) δ 0.8-0.95 (3H,m), 1.05-1.7 (20H,m), 2.60 and 2.62 (3H,2xs), 2.81 and 2.95 (3H,2xs), 3.2-3.55 (4H,m), 4.39 (2H,s), 4.45 (2H,s), 4.84 (2H,bd), 7.05-7.2
(2H,m), 7.35-7.6 (3H,m), 7.98 (lH,d), 8.1-8.25 (lH,m), 8.51 (lH,d); MS (APCI+) found (M+l) = 655; C34H47FN6O4S requires 654.
Example 19 - l-(N-(l-Dodecyl)-N-methylaminocarbonylmethyl)-2-(4-fluorobenzyl)- thio-5-(l-(l-morpholinocarbonylmethyI)-2-oxopyrimid-5-ylmethyl)pyrimidin-4-one
Figure imgf000027_0001
Prepared analogously to example 3.
1H-NMR (CDCI3) δ 0.8-0.95 (3H,m), 1.05-1.75 (20H,m), 2.6-3.9 (15H,m), 4.45 (2H,bs), 4.55-4.9 (4H,m), 6.85-7.05 (2H,m), 7.1-7.4 (3H,m), 7.87 (lH,bs), 8.47 (lH,s); MS (APCI+) found (M+l) = 711; C37H51FN6O5S requires 710.
Example 20 - l-(N-(l-Dodecyl)-N-methylaminocarbonylmethyl)-2-(4-fluorobenzyl)- id-5-ylmethyl)pyrimidin-4-one - sodium salt
Figure imgf000027_0002
The acid of Example 16 (4.9 lg) was added to a solution/suspension of sodium bicarbonate (0.64g) in water (60ml). The mixture was stirred at room temperature for 5 min and at 50°C for 5 min. After sonication for 8 min at room temperature, further water (100ml) was added and the undissolved material broken up. The mixture was heated and stirred for a further 5 min at 50°C and sonicated for a further 8 min at room temperature. Any remaining solid was filtered off and washed with water. The clear filtrate was freeze-dried for 16h to give the sodium salt. 1H-NMR (d6-DMSO) δ 0.85 (3H,t), 1.1- 1.65 (20H,m), 2.81 and 2.94 (3H,2xs), 3.2-3.4 (4H,m), 4.09 (2H,s), 4.40 (2H,s), 4.84 and 4.85 (2H,2xs), 7.05-7.2 (2H,m), 7.4-7.55 (3H,m), 7.87(lH,m), 8.38 (2H,m); MS (ES) found (M+l) (free acid)=642; C33H44FN5O4S requires 642.
Biological Data
1. Screen for Lp-PLA2 inhibition.
Enzyme activity was determined by measuring the rate of turnover of the artificial substrate (A) at 37 C in 50mM HEPES (N-2-hydroxyethylpiperazine-N -2- ethanesulphonic acid) buffer containing 150mM NaCl, pH 7.4.
Figure imgf000028_0001
(A)
Assays were performed in 96 well titre plates.
Recombinant LpPLA2 was purified to homogeneity from baculovirus infected Sf9 cells, using a zinc chelating column, blue sepharose affinity chromatography and an anion exchange column. Following purification and ultrafiltration, the enzyme was stored at 6mg/ml at 4°C. Assay plates of compound or vehicle plus buffer were set up using automated robotics to a volume of 170μl. The reaction was initiated by the addition of 20μl of lOx substrate (A) to give a final substrate concentration of 20μM and 10 μl of diluted enzyme to a final 0.2nM LpPLA2.
The reaction was followed at 405 nm and 37 °C for 20 minutes using a plate reader with automatic mixing. The rate of reaction was measured as the rate of change of absorbance.
Results
The compounds described in Examples 1 to 19 were tested as described above and had respective IC50 values of in the range 0.0004 to 3.2 uM.

Claims

Claims
1. A compound of formula (I):
Figure imgf000029_0001
(I)
in which:
R1 is COOH or a salt thereof, COOR10, CONR1 ΪR* , CN or CH2OH;
R2 is a mono- or bicyclic aromatic ring system containing up to 10 carbon atoms in the ring system, or a mono- or bicyclic heteroaromatic ring system including up to 4 heteroatoms selected from N, O and S; optionally substituted by 1, 2, 3 or 4 substituents selected from Cι_4alkyl,
Figure imgf000029_0002
C].4alkylthio, aryl, aralkyl, hydroxy, oxo, halogen, CN, COOH or a salt thereof, COO-Cj.galkyl, CONR^R^, NR15CORl6, SO2NR15R16, NR15SO2R16, NR15R16, mono to perfluoro Cι. alkyl and mono to perfluoro
Figure imgf000029_0003
R3 is Cj_2o alkyl, C3_6 cycloalkyl, C3.6cycloalkylCj.5alkyl, or CJ.I Q alkoxyCi .1 o alkyl, each optionally substituted by 1 or 2 substituents selected from hydroxy, CI .I Q alkoxy, COOH or a salt thereof, COOC1.15 alkyl, CONR17R18, NR17R18 ' NR17COR18, NR " or an aromatic or heteroaromatic ring system as defined for R2, or R3 is an aromatic or heteroaromatic ring system as hereinbefore defined for R2;
RIO is C j.4alkyl or a pharmaceutically acceptable in vivo hydrolysable ester group;
Rl 1 and R*2 which may be the same or different is each selected from hydrogen, C 2alkyl, CH2R13, CHR14CO2H or a salt thereof, or R1 * and R12 together with the nitrogen to which they are attached form a 5- to 7 membered ring optionally containing one or more further heteroatoms selected from oxygen, nitrogen and sulphur, and optionally substituted by one or two substituents selected from hydroxy, oxo, Cj^alkyl, Cι _4alkylCO, aryl, or aralkyl;
R13 is COOH or a salt thereof, COOR10, CONR1 !R12, CN or CH2OH;
R14 is an amino acid side chain such as CH2OH from serine;
R*5 and R1^ are independently hydrogen or Cj .4 alkyl e.g. methyl or ethyl; R17 and R1^ are independently hydrogen, Cj_i5 alkyl, eg methyl or ethyl, Cι _ιo alkoxyCι _ιo alkyl or arylCi .jQ alkyl, e.g. benzyl;
R1" together with the nitrogen atom to which it is attached forms a 5- to 7 membered ring optionally containing one or more further heteroatoms selected from oxygen, nitrogen and sulphur, and optionally substituted by one or two substituents selected from hydroxy, oxo, C1.4 alkyl, aryl, e.g. phenyl, or aralkyl, e.g benzyl;
W is SO2 or a bond;
X is O or S; and
Y is a group of the formula -A1 -A2- A3- in which A1 and A3 each represent a bond or a straight chain or branched alkylene group, said alkylene group(s) containing a total of 1 to 10 carbon atoms and A2 represents a bond or O, S, SO, SO2, CO, C=CH2, CONH, NHCO, CR15R16, CH=CH or C≡C, providing that when A2 is O, S, SO, SO2or CONH, A3 contains at least two carbon atoms linking the A2 group and the CH2 group in formula (I).
2. A compound as claimed in claim 1 in which Y is S.
3. A compound as claimed in claim 1 or 2 in which W is a bond.
4. A compound as claimed in any one of claims 1 to 3 in which R2 is a phenyl ring, optionally substituted by 4-fluoro.
5. A compound as claimed in any one of claims 1 to 4 in which R3 is Cj _20 alkyl or R17R18NHCOCH2- in which R17 and R18 is each independently C is alkyl.
6. A compound as claimed in any one of claims 1 to 5 in which R1 is instance a sodium salt, an ethyl ester, an N-alkyl or di- N-alkyl amide, or an amide in which the N forms part of a heterocyclic ring.
7. A compound of formula (I) as defined in claim 1 selected from:
1 -( 1 -Undecyl)-2-(4-fluorobenzyl)thio-5-( 1 -(ethoxycarbonylmethyl)-2-oxopyrimid-5- y lmethy l)pyrimidin-4-one ;
1 -( 1 -Undecyl)-2-(4-fluorobenzyl)thio-5-( 1 -(carboxymethyl)-2-oxopyrimid-5-ylmethyl)- pyrimidin-4-one; 1 -( 1 -Undecyl)-2-(4-fluorobenzyl)thio-5-( 1 -(dimethylaminocarbonylmethyl)-2- oxopyrimid-5-ylmethyl)pyrimidin-4-one;
1 -Methyl-2-(4-fluorobenzyl)thio-5-( 1 -(ethoxycarbonylmethyl)-2-oxopyrimid-5- ylmethyl)pyrimidin-4-one; 1 -Methyl-2-(4-fluorobenzyl)thio-5-( 1 -(carboxymethyl)-2-oxopyrimid-5-ylmethyl)- pyrimidin-4-one;
1 -Methyl-2-(4-fluorobenzyl)thio-5-( 1 -( 1 -octylaminocarbonylmefhyl)-2-oxopyrimid-5- ylmethyl)pyrimidin-4-one; 1 -Methyl-2-(4-fluorobenzyl)fhio-5-( 1 -(N-benzyl-N-methylaminocarbonylmethyl)-2- oxopyrimid-5-ylmethyl)pyrimidin-4-one;
1 -Methyl-2-(4-fluorobenzyl)thio-5-( 1 -(N-( 1 -dodecyl)-N-methylaminocarbonylmethyl)-2- oxopyrimid-5-ylmethyl)pyrimidin-4-one;
1 -Methyl-2-(4-fluorobenzyl)thio-5-( 1 -(N-(2-methoxyethyl)-N-methylaminocarbonyl- methyl)-2-oxopyrimid-5-ylmethyl)pyrimidin-4-one;
1 -Methyl-2-(4-fluorobenzyl)thio-5-( 1 -(4-hydroxy-4-benzylpiperidin- 1 -ylcarbonyl- methyl)-2-oxopyrimid-5-ylmethyl)pyrimidin-4-one;
1 -Methyl-2-(4-fluorobenzyl)thio-5-( 1 -(N-( 1 -octyl)-N-methylaminocarbonylmethyl)-2- oxopyrimid-5-ylmethyl)pyrimidin-4-one; 1 -(N-( 1 -Octyl)-N-methylaminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-( 1 - ethoxycarbonylmethyl-2-oxopyrimid-5-ylmethyl)pyrimidin-4-one;
1 -(N-( 1 -Octyl)-N-methylaminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-( 1 - carboxymethyl-2-oxopyrimid-5-ylmethyl)pyrimidin-4-one;
1 -(N-( 1 -Dodecyl)-N-methylaminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-( 1 - ethoxycarbonylmethyl-2-oxopyrimid-5-ylmethyl)pyrimidin-4-one;
1 -(N-( 1 -Dodecyl)-N-methylaminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-( 1 - carboxymethyl-2-oxopyrimid-5-ylmethyl)pyrimidin-4-one;
1 -(N-( 1 -Octyl)-N-methylaminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-( 1 -
(methylaminocarbonylmethyl)-2-oxopyrimid-5-ylmethyl)pyrimidin-4-one; 1 -(N-( 1 -Dodecyl)-N-methylaminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-( 1 -
(methylaminocarbonylmethyl)-2-oxopyrimid-5-ylmethyl)pyrimidin-4-one;
1 -(N-( 1 -Dodecyl)-N-methylaminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-( 1 -( 1 - morpholinocarbonylmethyl)-2-oxopyrimid-5-ylmethyl)pyrimidin-4-one; and
1 -(N-( 1 -Dodecyl)-N-methylaminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-( 1 - carboxymethyl-2-oxopyrimid-5-ylmethyl)pyrimidin-4-one - sodium salt.
8. A process for the preparation of compounds of formula (I) as defined in claim 1 which comprises reacting a compound of formula (II):
Figure imgf000031_0001
(II) in which R2, R3, W, X and Y are as defined in claim 1; with an alkylating agent of formula R1°-CH2-L1 in which R^° is as hereinbefore defined and L is a leaving group such as chlorine, bromine, iodine or mesylate, in the presence of a base such as potassium carbonate; and thereafter, and if necessary, interconverting Z groups, for example COORlO to COOH by standard conditions
(alkaline hydrolysis, hydrogenation of benzyl ester, etc), or COOH to CONR* 1R*2 by amide coupling.
9. A pharmaceutical composition comprising a compound of formula (I) as defined in claim and a pharmaceutically acceptable carrier.
10. A compound of formula (I) as defined in claim 1 for use in therapy.
11. A compound of formula (I) as claimed in claim 1 for use in the treatment of atherosclerosis.
PCT/EP1999/006093 1998-08-21 1999-08-18 Pyrimidinone derivatives for the treatment of atherosclerosis Ceased WO2000010980A1 (en)

Priority Applications (5)

Application Number Priority Date Filing Date Title
JP2000566254A JP2002523402A (en) 1998-08-21 1999-08-18 Pyrimidinone for the treatment of atherosclerosis
AT99942894T ATE251613T1 (en) 1998-08-21 1999-08-18 PYRIMIDINONE DERIVATIVES FOR THE TREATMENT OF ATHEROSCLEROS
EP99942894A EP1105377B1 (en) 1998-08-21 1999-08-18 Pyrimidinone derivatives for the treatment of atherosclerosis
US09/763,492 US6559155B1 (en) 1998-08-21 1999-08-18 Pyrimidinone derivatives for the treatment of atherosclerosis
DE69911980T DE69911980T2 (en) 1998-08-21 1999-08-18 PYRIMIDINE DERIVATIVES FOR TREATING ATHEROSCLEROS

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
GB9818375.9 1998-08-21
GBGB9818375.9A GB9818375D0 (en) 1998-08-21 1998-08-21 Novel compounds
GBGB9902009.1A GB9902009D0 (en) 1999-01-29 1999-01-29 Novel compounds
GB9902009.1 1999-01-29

Publications (1)

Publication Number Publication Date
WO2000010980A1 true WO2000010980A1 (en) 2000-03-02

Family

ID=26314252

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1999/006093 Ceased WO2000010980A1 (en) 1998-08-21 1999-08-18 Pyrimidinone derivatives for the treatment of atherosclerosis

Country Status (6)

Country Link
US (1) US6559155B1 (en)
EP (1) EP1105377B1 (en)
JP (1) JP2002523402A (en)
AT (1) ATE251613T1 (en)
DE (1) DE69911980T2 (en)
WO (1) WO2000010980A1 (en)

Cited By (27)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000066567A1 (en) * 1999-05-01 2000-11-09 Smithkline Beecham Plc Pyrimidinone compounds
WO2000066566A1 (en) * 1999-05-01 2000-11-09 Smithkline Beecham Plc Pyrimidine compounds
WO2000068208A1 (en) * 1999-05-05 2000-11-16 Smithkline Beecham Plc Pyrimidinones derivatives for the treatment of atherosclerosis
WO2000061551A3 (en) * 1999-04-13 2000-12-28 Basf Ag Pyrimidine-2-one derivatives as integrin receptor ligands
EP1197485A1 (en) * 2000-10-12 2002-04-17 Les Laboratoires Servier Cyclobuten-dione derivatives for use in the treatment of artherosclerosis
WO2003015786A1 (en) * 2001-08-14 2003-02-27 Smithkline Beecham P.L.C. 2, 5-substituted 1-(aminocarbonylalkyl) -pyrimidin-4-one derivatives with lp-pla2 inhinitory activity for the treatment of atherosclerosis
WO2003087088A3 (en) * 2002-04-10 2004-01-08 Glaxo Group Ltd (condensed) pyrimidone and (condensed) pyridone compounds, processes for their preparation, and pharmaceutical compositions containing them
US6939863B2 (en) 2002-01-04 2005-09-06 Wei-Jan Chen Prevention of atherosclerosis and restenosis
EP1686119A1 (en) 2000-02-16 2006-08-02 Smithkline Beecham Plc Pyrimidine-4-one derivatives as ldl-pla2 inhibitors
WO2008140449A1 (en) 2007-05-11 2008-11-20 Thomas Jefferson University Methods of treatment and prevention of neurodegenerative diseases and disorders
EP2258688A1 (en) 2000-10-10 2010-12-08 SmithKline Beecham Limited Pyridinone derivatives for treatment of atherosclerosis
WO2012076435A1 (en) 2010-12-06 2012-06-14 Glaxo Group Limited Pyrimidinone compounds for use in the treatment of diseases or conditions mediated by lp - pla2
WO2012080497A2 (en) 2010-12-17 2012-06-21 Glaxo Group Limited Methods of treatment and prevention of eye diseases
WO2013014185A1 (en) 2011-07-27 2013-01-31 Glaxo Group Limited Bicyclic pyrimidone compounds
WO2013013503A1 (en) 2011-07-27 2013-01-31 Glaxo Group Limited 2,3-dihydroimidazo[1,2-c] pyrimidin-5(1h)-one compounds use as lp-pla2 inhibitors
EP2649050A4 (en) * 2010-12-06 2014-04-23 Glaxo Group Ltd Compounds
CN103827118A (en) * 2011-07-27 2014-05-28 葛兰素集团有限公司 Bicyclic pyrimidone compounds
WO2014114249A1 (en) 2013-01-25 2014-07-31 Glaxosmithkline Intellectual Property Development Limited Bicyclic pyrimidone compounds as inhibitors of lp-pla2
WO2014114694A1 (en) 2013-01-25 2014-07-31 Glaxosmithkline Intellectual Property Development Limited 2,3-dihydroimidazol[1,2-c]pyrimidin-5(1h)-one based lipoprotein-associated phospholipase a2 (lp-pla2) inhibitors
WO2014114248A1 (en) 2013-01-25 2014-07-31 Glaxosmithkline Intellectual Property Development Limited Compounds
CN104478812A (en) * 2010-12-06 2015-04-01 葛兰素集团有限公司 Pyrimidinone compounds for use in the treatment of diseases or conditions mediated by Lp-PLA2
US9029383B2 (en) 2007-05-11 2015-05-12 The Trustees Of The University Of Pennsylvania Methods of treatment of skin ulcers
WO2016012916A1 (en) 2014-07-22 2016-01-28 Glaxosmithkline Intellectual Property Development Limited 1,2,3,5-tetrahydroimidazo[1,2-c]pyrimidine derivatives useful in the treatment of diseases and disorders mediated by lp-pla2
WO2016012917A1 (en) 2014-07-22 2016-01-28 Glaxosmithkline Intellectual Property Development Limited 1,2,3,5-tetrahydroimidazo[1,2-c]pyrimidine derivatives useful in the treatment of diseases and disorders mediated by lp-pla2
WO2021089032A1 (en) 2019-11-09 2021-05-14 上海赛默罗生物科技有限公司 Tricyclic dihydroimidazopyrimidone derivative, preparation method therefor, pharmaceutical composition and use thereof
WO2022233302A1 (en) 2021-05-07 2022-11-10 上海赛默罗生物科技有限公司 Pyrimidinone derivative and preparation method therefor, pharmaceutical composition, and use
WO2025015951A1 (en) 2023-07-17 2025-01-23 上海枢境生物科技有限公司 Bicyclo[5,6] imidazole pyrimidone derivative and preparation method therefor and use thereof

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080090852A1 (en) * 2006-10-13 2008-04-17 Colin Andrew Leach Bicyclic Heteroaromatic Compounds
US20080090851A1 (en) * 2006-10-13 2008-04-17 Colin Andrew Leach Bicyclic Heteroaromatic Compounds
AU2010232923A1 (en) * 2009-04-03 2011-11-03 Medisyn Technologies, Inc. Compositions for treatment of Alzheimer's disease
WO2024196698A2 (en) * 2023-03-17 2024-09-26 Curadh Mtr Compounds and constructs useful for targeting fibroblast activation protein

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4145546A (en) * 1975-10-02 1979-03-20 Smith Kline & French Laboratories Limited 4-Pyrimidone compounds
US4154834A (en) * 1975-12-29 1979-05-15 Smith Kline & French Laboratories Limited Substituted isocytosines having histamine H2 -antagonist activity
WO1999024420A1 (en) * 1997-11-06 1999-05-20 Smithkline Beecham Plc Pyrimidinone compounds and pharmaceutical compositions containing them

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4145546A (en) * 1975-10-02 1979-03-20 Smith Kline & French Laboratories Limited 4-Pyrimidone compounds
US4154834A (en) * 1975-12-29 1979-05-15 Smith Kline & French Laboratories Limited Substituted isocytosines having histamine H2 -antagonist activity
WO1999024420A1 (en) * 1997-11-06 1999-05-20 Smithkline Beecham Plc Pyrimidinone compounds and pharmaceutical compositions containing them

Cited By (43)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000061551A3 (en) * 1999-04-13 2000-12-28 Basf Ag Pyrimidine-2-one derivatives as integrin receptor ligands
US7125883B1 (en) 1999-04-13 2006-10-24 Abbott Gmbh & Co. Kg Integrin receptor ligands
US7115616B2 (en) 1999-05-01 2006-10-03 Smithkline Beecham Plc Pyrimidinone compounds
WO2000066566A1 (en) * 1999-05-01 2000-11-09 Smithkline Beecham Plc Pyrimidine compounds
WO2000066567A1 (en) * 1999-05-01 2000-11-09 Smithkline Beecham Plc Pyrimidinone compounds
EP1479671A1 (en) * 1999-05-01 2004-11-24 Smithkline Beecham Plc Pyrimidinone compounds
US6953803B1 (en) 1999-05-01 2005-10-11 Smithkline Beecham P.L.C. Pyrimidine compounds
WO2000068208A1 (en) * 1999-05-05 2000-11-16 Smithkline Beecham Plc Pyrimidinones derivatives for the treatment of atherosclerosis
US8871775B2 (en) 2000-02-16 2014-10-28 Glaxo Group Limited Compounds
US9266841B2 (en) 2000-02-16 2016-02-23 Glaxo Group Limited Compounds
CZ304450B6 (en) * 2000-02-16 2014-05-14 Smithkline Beecham P. L. C. Pyrimidine derivative
EP1686119A1 (en) 2000-02-16 2006-08-02 Smithkline Beecham Plc Pyrimidine-4-one derivatives as ldl-pla2 inhibitors
EP2258688A1 (en) 2000-10-10 2010-12-08 SmithKline Beecham Limited Pyridinone derivatives for treatment of atherosclerosis
FR2815345A1 (en) * 2000-10-12 2002-04-19 Servier Lab NOVEL CYCLOBUTENE-DIONE DERIVATIVES, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
EP1197485A1 (en) * 2000-10-12 2002-04-17 Les Laboratoires Servier Cyclobuten-dione derivatives for use in the treatment of artherosclerosis
WO2003015786A1 (en) * 2001-08-14 2003-02-27 Smithkline Beecham P.L.C. 2, 5-substituted 1-(aminocarbonylalkyl) -pyrimidin-4-one derivatives with lp-pla2 inhinitory activity for the treatment of atherosclerosis
US6939863B2 (en) 2002-01-04 2005-09-06 Wei-Jan Chen Prevention of atherosclerosis and restenosis
WO2003087088A3 (en) * 2002-04-10 2004-01-08 Glaxo Group Ltd (condensed) pyrimidone and (condensed) pyridone compounds, processes for their preparation, and pharmaceutical compositions containing them
WO2008140449A1 (en) 2007-05-11 2008-11-20 Thomas Jefferson University Methods of treatment and prevention of neurodegenerative diseases and disorders
EP2977452A2 (en) 2007-05-11 2016-01-27 Thomas Jefferson University Methods of treatment and prevention of neurodegenerative diseases and disorders
US9029383B2 (en) 2007-05-11 2015-05-12 The Trustees Of The University Of Pennsylvania Methods of treatment of skin ulcers
US20130252963A1 (en) * 2010-12-06 2013-09-26 Yun Jin Pyrimidinone compounds for use in the treatment of disease or conditions mediated by lp-pla2
US9174968B2 (en) 2010-12-06 2015-11-03 Glaxo Group Limited Pyrimidinone compounds for use in the treatment of diseases or conditions mediated by LP-PLA2
CN103347864A (en) * 2010-12-06 2013-10-09 葛兰素集团有限公司 Pyrimidinone compounds for use in the treatment of diseases or conditions mediated by Lp-PLA2
CN103347864B (en) * 2010-12-06 2016-08-10 葛兰素集团有限公司 Pyrimidinone compounds for use in the treatment of diseases or conditions mediated by Lp-PLA2
EA023796B1 (en) * 2010-12-06 2016-07-29 Глэксо Груп Лимитед PYRIMIDINONE COMPOUNDS FOR USE IN THE TREATMENT OF DISEASES OR CONDITIONS MEDIATED BY Lp-PLA
EP2649050A4 (en) * 2010-12-06 2014-04-23 Glaxo Group Ltd Compounds
WO2012076435A1 (en) 2010-12-06 2012-06-14 Glaxo Group Limited Pyrimidinone compounds for use in the treatment of diseases or conditions mediated by lp - pla2
US8859573B2 (en) 2010-12-06 2014-10-14 Glaxo Group Limited Pyrimidinone and pyridinone compounds for use in the treatment of diseases or conditions mediated by Lp-PLA2
CN104478812A (en) * 2010-12-06 2015-04-01 葛兰素集团有限公司 Pyrimidinone compounds for use in the treatment of diseases or conditions mediated by Lp-PLA2
WO2012080497A2 (en) 2010-12-17 2012-06-21 Glaxo Group Limited Methods of treatment and prevention of eye diseases
CN103827118B (en) * 2011-07-27 2016-03-09 葛兰素集团有限公司 Bicyclic pyrimidin ketone compound
WO2013014185A1 (en) 2011-07-27 2013-01-31 Glaxo Group Limited Bicyclic pyrimidone compounds
WO2013013503A1 (en) 2011-07-27 2013-01-31 Glaxo Group Limited 2,3-dihydroimidazo[1,2-c] pyrimidin-5(1h)-one compounds use as lp-pla2 inhibitors
CN103827118A (en) * 2011-07-27 2014-05-28 葛兰素集团有限公司 Bicyclic pyrimidone compounds
WO2014114248A1 (en) 2013-01-25 2014-07-31 Glaxosmithkline Intellectual Property Development Limited Compounds
WO2014114694A1 (en) 2013-01-25 2014-07-31 Glaxosmithkline Intellectual Property Development Limited 2,3-dihydroimidazol[1,2-c]pyrimidin-5(1h)-one based lipoprotein-associated phospholipase a2 (lp-pla2) inhibitors
WO2014114249A1 (en) 2013-01-25 2014-07-31 Glaxosmithkline Intellectual Property Development Limited Bicyclic pyrimidone compounds as inhibitors of lp-pla2
WO2016012916A1 (en) 2014-07-22 2016-01-28 Glaxosmithkline Intellectual Property Development Limited 1,2,3,5-tetrahydroimidazo[1,2-c]pyrimidine derivatives useful in the treatment of diseases and disorders mediated by lp-pla2
WO2016012917A1 (en) 2014-07-22 2016-01-28 Glaxosmithkline Intellectual Property Development Limited 1,2,3,5-tetrahydroimidazo[1,2-c]pyrimidine derivatives useful in the treatment of diseases and disorders mediated by lp-pla2
WO2021089032A1 (en) 2019-11-09 2021-05-14 上海赛默罗生物科技有限公司 Tricyclic dihydroimidazopyrimidone derivative, preparation method therefor, pharmaceutical composition and use thereof
WO2022233302A1 (en) 2021-05-07 2022-11-10 上海赛默罗生物科技有限公司 Pyrimidinone derivative and preparation method therefor, pharmaceutical composition, and use
WO2025015951A1 (en) 2023-07-17 2025-01-23 上海枢境生物科技有限公司 Bicyclo[5,6] imidazole pyrimidone derivative and preparation method therefor and use thereof

Also Published As

Publication number Publication date
US6559155B1 (en) 2003-05-06
DE69911980D1 (en) 2003-11-13
DE69911980T2 (en) 2004-09-09
JP2002523402A (en) 2002-07-30
EP1105377A1 (en) 2001-06-13
EP1105377B1 (en) 2003-10-08
ATE251613T1 (en) 2003-10-15

Similar Documents

Publication Publication Date Title
EP1105377B1 (en) Pyrimidinone derivatives for the treatment of atherosclerosis
JP2002543190A (en) Pyrimidinone compounds
JP4095804B2 (en) Pyrimidin-4-one derivatives as LDL-PLA2 inhibitors
US20050153964A1 (en) Novel compounds
EP1175409A1 (en) Pyrimidinones derivatives for the treatment of atherosclerosis
AU2001235466A1 (en) Pyrimidine-4-one derivatives as LDL-PLA2 inhibitors
US20050020832A1 (en) Pyridone, pyridazone and triazone derivatives as lp-pla2 inhibitors
EP1492533A1 (en) N-substituted pyridinone and pyrimidinone derivatives for use as lp-pla2 inhibitors in the treatment of artherosclerosis
JP2002543189A (en) Pyrimidine compounds
US20050033052A1 (en) Novel compounds
US20050043335A1 (en) Heterocyclic derivatives of glycinamide and their medical use
WO2003015786A1 (en) 2, 5-substituted 1-(aminocarbonylalkyl) -pyrimidin-4-one derivatives with lp-pla2 inhinitory activity for the treatment of atherosclerosis
HK1071362A (en) Pyrimidinone compounds

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): CA JP US

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
WWE Wipo information: entry into national phase

Ref document number: 1999942894

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 09763492

Country of ref document: US

NENP Non-entry into the national phase

Ref country code: CA

WWP Wipo information: published in national office

Ref document number: 1999942894

Country of ref document: EP

WWG Wipo information: grant in national office

Ref document number: 1999942894

Country of ref document: EP