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WO2003015786A1 - Derives de 2,5-substituee 1-(aminocarbonylalkyl) -pyrimidin-4-one a activite inhibitrice de l'enzyme lp-pla2 permettant de traiter l'atherosclerose - Google Patents

Derives de 2,5-substituee 1-(aminocarbonylalkyl) -pyrimidin-4-one a activite inhibitrice de l'enzyme lp-pla2 permettant de traiter l'atherosclerose Download PDF

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WO2003015786A1
WO2003015786A1 PCT/EP2002/009068 EP0209068W WO03015786A1 WO 2003015786 A1 WO2003015786 A1 WO 2003015786A1 EP 0209068 W EP0209068 W EP 0209068W WO 03015786 A1 WO03015786 A1 WO 03015786A1
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compound
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alkyl
alkoxy
halogen
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Richard Leonard Elliott
Colin Andrew Leach
Stephen Allan Smith
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SmithKline Beecham Ltd
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SmithKline Beecham Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings

Definitions

  • the present invention relates to certain novel pyrimidinone compounds, processes for their preparation, intermediates useful in their preparation, pharmaceutical compositions containing 5 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
  • Lp-PLA2 is responsible for the conversion of phosphatidylcholine to 20 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.
  • 25 lysophosphatidylcholine is thought to 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.
  • 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.
  • L -PLA2 inhibitors may also have a general application in any disorder that involves lipid oxidation 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.
  • Patent applications WO 96/12963, WO 96/13484, WO96/19451, WO 97/02242, WO97/217675, WO97/217676, WO 96/41098, and WO97/41099 disclose inter 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).
  • Patent applications WO 99/24420, WO 00/10980, WO 00/66567, WO 00/66566 and WO 00/68208 (SmithKline Beecham pic) describe a new class of reversible, non-acylating inhibitors of the enzyme Lp-PLA2, in particular classes of pyrimidinone compounds.
  • 2-(alkyltMo)pyrirnidin-4-one chemical lead is described in Bioorganic and Medicinal Chemistry Letters, 2000, 10, 395-8.
  • the early Nl-substituted pyrimidinone leads are described in Bioorganic and Medicinal Chemistry Letters, 2000, 10, 2557-2561.
  • R 1 is an aryl or heteroaryl group, optionally substituted by 1, 2, 3 or 4 substituents which may be the same or different selected from Cn. ⁇ 8) a H ⁇ > C(l-1 g- alkoxy, Cn -l 8)alkylthio,
  • C(i _4)alkoxy or, as a single substituent, optionally in combination with a further substituent as hereinbefore defined, CH COOH or a salt thereof, CH 2 COOR 8 , CH2CONR 9 R 10 , CH 2 CN, (CH 2 ) m NR 9 R 10 , (CH 2 ) m OH or (CH 2 ) m OR 6 where m is an integer from 1 to 3;
  • R is an aryl or heteroaryl group, optionally substituted by 1, 2, 3 or 4 substituents which may be the same or different selected from C -18) a lkyl s C _ ⁇ 8)alkoxy, Cn _j g-jalkylthio, arylC(i_ 18 )alkoxy, hydroxy, halogen, CN, COR 6 , carboxy, COOR 6 , CONR 9 R 10 , NR 6 COR 7 , SO 2 NR 9 R 10 , NR 6 SO 2 R 7 , NR 9 R 10 , mono to perfluoro-C(i_4)alkyl, mono to perfluoro- Cn _4)alkoxy, and arylCn_4)alkyl;
  • R3 is Het-C(o_4)alkyl in which Het is a 5- to 7- membered heterocyclyl ring, bonded directly through a ring carbon atom, comprising N and optionally O or S, and in which N may be substituted by COR 7 , COOR 7 , CONR 9 R 10 , or C( 1 _ 6 )alkyl optionally substituted by 1, 2 or 3 substituents selected from hydroxy, halogen, OR 7 , COR 7 , carboxy, COOR 7 , COOR 8 , CONR 9 R10 or R RlO, for instance, piperidin-4-yl or pyrrolidin-3-yl;
  • R4 is an aryl or a heteroaryl ring optionally substituted by 1, 2, 3 or 4 substituents which may be the same or different selected from Cn_i8)alkyL Cn _ ⁇ alkoxy, Cn. ⁇ g ⁇ alkylthio, arylC( 1 . 1 8)alkoxy, hydroxy, SO2NR 9 R 10 , NR 6 S0 2 R 7 , NR 9 R 10 , mono to perfluoro-C(i_4)alkyl and mono to perfluoro- Cn_4)alkoxy;
  • R5 is an aryl ring which is further optionally substituted by 1, 2, 3 or 4 substituents which may be the same or different selected from Cn_ ⁇ g ⁇ alkyl, Cn _ ⁇ g ⁇ alkoxy, Cn_ ⁇ g)alkylthio,
  • R 6 and R 7 are independently hydrogen or Cn _20)alkyl, for instance (e.g. methyl or ethyl); R 8 is Cn _4)alkyl or a pharmaceutically acceptable in vivo hydrolysable ester group;
  • R 9 and RlO which may be the same or different is each selected from hydrogen, C(i_i2)alkyl, CH2R 1 1 , CHR 12 CO2H or a salt thereof, or R 9 and R 10 together with the nitrogen to which they are attached form a 4- to 7-, preferably 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, Cn _4)alky Cn _ 4)alkylCO, aryl, e.g. phenyl, or aralkyl, e.g benzyl, for instance morpholine or piperazine;
  • R 1 1 is COOH or a salt thereof, COOR 8 , CONR 6 R 7 , CN, CH 2 OH or CH OR 6 ;
  • R!2 is an amino acid side chain such as CH/TOH from serine; n is an integer from 1 to 4, preferably 1 or 3; X is O or S; and
  • Z is CR 13 R 14 where R 3 and R ⁇ are each hydrogen or C ⁇ _4)alkyl, or R" and R*4 together with the intervening carbon atom form a C(3_6)cycloalkyl ring.
  • Z is CH2.
  • R1 when an aryl group examples include phenyl and naphthyl.
  • R when a heteroaryl group include a 5- or 6- membered, monocyclic heteroaryl group comprising 1 or 2 nitrogen heteroatoms.
  • R* is pyrimidyl optionally substituted by 1 or 2 substituents preferably selected from oxo, arylCn 4)alkyl (e.g. benzyl), Cn_6)alkyl (e.g. methyl or ethyl), C(3_6)cycloalkyl, hydroxy, Cn_4)alkoxy (e.g. methoxy), carboxyCn 6)alkyl, Cn g ⁇ alltylcarboxyCn g ⁇ alkyl, di- Cn _6)alkylamino, and morpholino; or pyrazolyl optionally substituted by Cn g ⁇ alkyl (e.g. methyl or ethyl).
  • substituents preferably selected from oxo, arylCn 4)alkyl (e.g. benzyl), Cn_6)alkyl (e.g. methyl or ethyl), C(3_6)cycloalkyl, hydroxy, Cn
  • ZR* is pyrimid-5-ylmethyl optionally substituted by 2-methoxy, 2-trifluoromethyl, 2- (4-morpholino) or 2-dimethylamino; 2-oxo-pyrimid-5-ylmethyl or l-methyl-4-pyrazolylmethyl.
  • X is S.
  • R ⁇ when an aryl group include phenyl and naphthyl.
  • R 2 when a heteroaryl group include pyridyl, pyrimidinyl, pyrazolyl, furanyl, thienyl, thiazolyl, quinolyl, benzothiazolyl, pyridazolyl and pyrazinyl.
  • R-2 is phenyl optionally substituted by halogen.
  • R ⁇ CB ⁇ X examples include 4-fluorobenzylthio and 2,3-difluorobenzylthio.
  • R ⁇ examples include Het-C(0-4)alkyl in which Het is a 5- to 7- membered heterocyclyl ring, bonded directly through a ring carbon atom, comprising N and in which N may be substituted by C( ⁇ _g)alkyl. optionally substituted by C( ⁇ _4)alkoxy.
  • R ⁇ is l-(2- methoxyethyl)piperidin-4-yl, 1 -methylpiperidin-4-yl, 1 -ethylpiperidin-4-yl, 1 -isopropylpiperidin- 4-yl and l-ethylpyrrolidin-2-ylmethyl.
  • R ⁇ examples include phenyl optionally substituted by halogen; thiophene; pyridine; and pyrimidine.
  • R ⁇ examples include phenyl optionally substituted by halogen, trifluoromethyl, or trifluoromethoxy, preferably at the 4-position.
  • R ⁇ and R ⁇ together form a 4-(phenyl)phenyl substituent in which the remote phenyl ring may be optionally substituted by halogen or trifluoromethyl, preferably at the 4-position.
  • compositions for R 8 include those which break down readily in the human body to leave the parent acid or its salt.
  • R 8 examples of values of pharmaceutically acceptable in vivo hydrolysable ester groups for R 8 include:
  • R a is hydrogen, (C ⁇ -6)alkyl, in particular methyl, (C3-7)cycloalkyl, or phenyl, each of which may be optionally substituted;
  • R D is (C ⁇ -g)alkyl, (C ⁇ -6)alkoxy(C ⁇ -6)alkyl, phenyl, benzyl, (C3-7)cycloalkyl,
  • R c is (C ⁇ - 6 )alkyl, (C 3 - 7 )cycloalkyL (C 1 - 6 )alkyl(C 3 - 7 )cycloalkyl;
  • R" is (C ⁇ -6)alkylene optionally substituted with a methyl or ethyl group
  • R e and R ⁇ which may be the same or different is each (Ci -g)alkyl; or aryl(C ⁇ -4) alkyl, optionally substituted with e.g. hydroxy;
  • Rg is (C ⁇ - 6 )alkyl
  • R" is hydrogen, (Cj- ⁇ alkyl or phenyl
  • R 1 is hydrogen or phenyl optionally substituted by up to three groups selected from halogen,
  • Y* is oxygen orNH; for instance:
  • acyloxyalkyl groups such as acetoxymethyl, isobutyryloxymethyl, pivaloyloxymethyl, benzoyloxymethyl, ⁇ -acetoxyethyl, ⁇ -pivaloyloxyethyl, l-(cyclohexylcarbonyloxy)ethyl, (1 -aminoethyl)carbonyloxymethyl, 2-methoxyprop-2-ylcarbonyloxymethyl, phenylcarbonyloxymethyl and 4-methoxyphenyl-carbonyloxymethyl;
  • 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;
  • esters-E-but-2-en-yl examples 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-l,3-dioxolen-4-yl)methyl.
  • compounds of the present invention may include a basic function such as an amino group as a substituent.
  • Such basic functions may be used to form acid addition salts, in particular pharmaceutically acceptable salts.
  • Pharmaceutically acceptable salts include those described by Berge, Bighley, and Monkhouse, J. Pharm. Sci., 1977, 66, 1-19. Such salts may be formed from inorganic and organic acids.
  • Representative examples thereof include maleic, fumaric, benzoic, ascorbic, pamoic, succinic, bismethylenesalicylic, methanesulfonic, p-toluenesulfonic, ethanedisulfonic, acetic, propionic, tartaric, salicylic, citric, gluconic, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, taurocholic acid, benzenesulfonic, hydrochloric, hydrobromic, sulfuric, cyclohexylsulfamic, phosphoric and nitric acids.
  • 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.
  • alkyl and similar terms such as “alkoxy” includes all straight chain and branched isomers. Representative examples thereof include methyl, ethyl, ⁇ -propyl, iso- propyl, «-butyl, -fee-butyl, iso-butyl, t-butyl, «-pentyl and «-hexyl.
  • aryl refers to, unless otherwise defined, a mono- or bicyclic aromatic ring system containing up to 10 carbon atoms in the ring system, for instance phenyl or naphthyl.
  • heteroaryl refers to a mono- or bicyclic heteroaromatic ring system comprising up to four, preferably 1 or 2, heteroatoms each selected from oxygen, nitrogen and sulphur. Each ring may have from 4 to 7, preferably 5 or 6, ring atoms.
  • a bicyclic heteroaromatic ring system may include a carbocyclic ring.
  • 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.
  • 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 oxidation 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 oxidation 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 an anti-hyperlipidaemic, anti-atherosclerotic, anti-diabetic, anti- anginal, anti-inflammatory, or anti-hypertension agent or an agent for lowering Lp(a).
  • 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.
  • agents for lowering Lp(a) include the aminophosphonates described in WO 97/02037, WO 98/28310, WO 98/28311 and WO 98/28312 (Symphar SA and SmithKline Beecham).
  • a preferred combination therapy will be the use of a compound of the present invention and a statin.
  • the statins are a well known class of cholesterol lowering agents and include atorvastatin, simvarstatin, pravastatin, cerivastatin, fluvastatin, lovastatin and ZD 4522 (also referred to as S- 4522, rosuvastatin, Astra Zeneca).
  • the two agents may be administered at substantially the same time or at different times, according to the discretion of the physician.
  • a further preferred combination therapy will be the use of a compound of the present invention and an anti-diabetic agent or an insulin sensitiser, as coronary heart disease is a major cause of death for diabetics.
  • preferred compounds for use with a compound of the present invention include the PPARgamma activators, for instance GI262570 (GlaxoSmithKline) and also the glitazone class of compounds such as rosiglitazone (Avandia, GlaxoSmithKline), troglitazone and pioglitazone.
  • 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.
  • a compound of formula (I) may be prepared by a number of processes which include:
  • Preferred coupling agents include those developed for use in peptide chemistry, such as l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride ("EDC”), preferably in the presence of an additive such as 1-hydroxybenzotriazole, or 0-(7-azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (“HATU”), preferably in the presence of di-isopropylethylamine.
  • EDC l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
  • HATU 0-(7-azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate
  • n, R 3 , 4 and R ⁇ are as hereinbefore defined, and L* is a leaving group such as halogen, for instance bromo or iodo, in the presence of a base such as a secondary or tertiary amine, for instance di-isopropylethylamine, in an inert solvent such as dichloromethane;
  • n, Z, R*, R 3 , R 4 and R ⁇ are as hereinbefore defined, and !?
  • ⁇ is a leaving group such as halogen or alkylthio, for instance methylthio, with a compound of formula (LX):
  • L 3 is a C(l-6)alkyl group, for instance methyl
  • R!5 is a Cn _6)alkyl group, for instance methyl, ethyl, or t-butyl, and
  • L 1 , L 2 , R 1 , R2, R 3 , R 4 , R 5 , n, X and Z are as hereinbefore defined.
  • Amide forming conditions for step (a) are well known in the art.
  • the acid of formula (II) is reacted with the amine of formula (HI) in an inert solvent, such as dichloromethane, at ambient temperature and in the presence of a coupling agent such as 0-(7-azabenzotriazol-l-yl)- N,N,N',N'-tetramethyluronium hexafluorophosphate and di-isopropylethylamine or l-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride in the presence of 1- hydroxybenzotriazole.
  • a coupling agent such as 0-(7-azabenzotriazol-l-yl)- N,N,N',N'-tetramethyluronium hexafluorophosphate and di-isopropylethylamine or l-(3- dimethylaminopropyl)-3-e
  • Alkylation conditions for step (b) include reaction in the presence of a base such as a secondary or tertiary amine, for instance di-wo-propylethylamine, in an inert solvent such as dichloromethane, forming an intermediate ester which is converted to the acid of formula (13) by hydrolysis, for instance using aqueous sodium hydroxide in a solvent such as dioxan or by alternative deprotection, for instance using trifluoracetic acid in a solvent such as dichloromethane.
  • a base such as a secondary or tertiary amine, for instance di-wo-propylethylamine
  • an inert solvent such as dichloromethane
  • Conditions for step (c) include under thioether forming conditions.
  • the reaction is carried out in the presence of a base such as sodium ethoxide or potassium carbonate, preferably in a solvent such as ethanol or dimethyl formamide, or a secondary or tertiary amine base such as di-isopropylethyl amine, in solvent such as dichloromethane.
  • a base such as sodium ethoxide or potassium carbonate
  • solvent such as ethanol or dimethyl formamide
  • a secondary or tertiary amine base such as di-isopropylethyl amine
  • step (d) a compound of formula (XV13) is reacted with thiourea, in the presence of sodium ethoxide (preferably generated in situ from sodium and ethanol).
  • step (e) a compound of formula (XVIII) is reacted with ethyl formate in the presence of a base such as sodium hydride or potassium isopropoxide.
  • a base such as sodium hydride or potassium isopropoxide.
  • step (f) a compound of formula (IN) is reacted with a compound of formula (V) in the presence of a base such as a secondary or tertiary amine, for instance di-isopropylethylamine, in an inert solvent such as dichloromethane
  • step (g) a compound of formula (XH3) is reacted with a compound of formula (X1N) in a solvent such as dimethylformamide to form an intermediate thiourea, which is then treated with a base such as sodium methoxide.
  • step (h) a compound of formula (XVI) is reacted with a metal thiocyanate, for example potassium thiocyanate, in a solvent such as acetonitrile.
  • a metal thiocyanate for example potassium thiocyanate
  • step (i) a compound of formula (XVII) is reacted with a methylating agent such as dimethyl sulphate in the presence of a base such as potassium carbonate, followed by hydrolysis of the intermediate ester in conventional manner e.g. by basic hydrolysis using sodium hydroxide to give the corresponding carboxylic acid which may then be converted into the acyl chloride, for instance by treatment with oxalyl chloride.
  • a methylating agent such as dimethyl sulphate
  • a base such as potassium carbonate
  • step (j) a catalyst such as 4-dimethylaminopyridine, and in a solvent such as pyridine are used.
  • step (k) a compound of formula (XH3) is reacted with a compound of formula (XV) in a solvent such as dimethylformamide to form an intermediate thiourea, which is then treated with a base such as sodium methoxide.
  • a solvent such as dimethylformamide
  • Example 1 l-(N-(l-(2-Methoxyethyl)piperidin-4-yl)-N-(4-(4- trifluoromethylphenyl)benzyl)aminocarbonylmethyl)-2-(2,3-difluorobenzyl)thio-5-(l- methyl-4-pyrazoIylmethyl)pyrimidin-4-one bitartrate
  • Enzyme activity was determined by measuring the rate of turnover of the artificial substrate 1- decanoyl-2-(p-nitrophenyl glutaryl)phosphatidylcholine (A) at 37 °C in 50 mM HEPES (N-2- hydroxyethylpiperazine-N'-2-ethanesulphonic acid) buffer containing 150 mM NaCl, pH 7.4.
  • HEPES N-2- hydroxyethylpiperazine-N'-2-ethanesulphonic acid
  • Assays were performed in 96 well titre plates. Recombinant Lp PLA2 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 6 mg/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 0.2 nM LpPLA2.
  • A lOx substrate
  • 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.

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Abstract

L'invention concerne des composés de pyrimidinone représentés par la formule (I) inhibiteurs de l'enzyme Lp-PLA2 et utilisés en thérapie, notamment pour traiter l'athérosclérose.
PCT/EP2002/009068 2001-08-14 2002-08-13 Derives de 2,5-substituee 1-(aminocarbonylalkyl) -pyrimidin-4-one a activite inhibitrice de l'enzyme lp-pla2 permettant de traiter l'atherosclerose Ceased WO2003015786A1 (fr)

Applications Claiming Priority (2)

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GB0119793.8 2001-08-14
GB0119793A GB0119793D0 (en) 2001-08-14 2001-08-14 Novel compounds

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Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003087088A3 (fr) * 2002-04-10 2004-01-08 Glaxo Group Ltd Nouveaux composes
JP2010526805A (ja) * 2007-05-11 2010-08-05 トーマス・ジェファーソン・ユニバーシティ 神経変性疾患および障害を治療および阻止する方法
WO2012076435A1 (fr) 2010-12-06 2012-06-14 Glaxo Group Limited Composés de pyrimidinone utiles dans le traitement de maladies ou d'états pathologiques induits par la lp-pla2
WO2012080497A2 (fr) 2010-12-17 2012-06-21 Glaxo Group Limited Procédés de traitement et de prévention de maladies oculaires
WO2013013503A1 (fr) 2011-07-27 2013-01-31 Glaxo Group Limited Composés 2,3-dihydroimidazo[1,2-c]pyrimidin-5(1h)-one et utilisation en tant qu'inhibiteurs de lp-pla2
WO2013014185A1 (fr) 2011-07-27 2013-01-31 Glaxo Group Limited Composés pyrimidones bicycliques
WO2014114248A1 (fr) 2013-01-25 2014-07-31 Glaxosmithkline Intellectual Property Development Limited Composés
WO2014114694A1 (fr) 2013-01-25 2014-07-31 Glaxosmithkline Intellectual Property Development Limited Inhibiteurs de la phospholipase associée aux lipoprotéines a2 (lp-pla2) à base de 2,3-dihydro-imidazol[1,2-c]pyrimidin-5(1 h)-one
WO2014114249A1 (fr) 2013-01-25 2014-07-31 Glaxosmithkline Intellectual Property Development Limited Composés de pyrimidone bicycliques utilisés en tant qu'inhibiteurs de lp-pla2
WO2016012917A1 (fr) 2014-07-22 2016-01-28 Glaxosmithkline Intellectual Property Development Limited Dérivés 1,2,3,5-tétrahydro-imidazo [1,2-c]pyrimidine utiles pour le traitement de maladies et de troubles médiés par la lp-pla2
WO2016012916A1 (fr) 2014-07-22 2016-01-28 Glaxosmithkline Intellectual Property Development Limited Dérivés 1,2,3,5-tétrahydro-imidazo [1,2-c]pyrimidine utiles pour le traitement de maladies et de troubles médiés par la lp-pla2
AU2014200542B2 (en) * 2007-05-11 2016-08-25 Rowan University Methods of treatment and prevention of neurodegenerative diseases and disorders
WO2021089032A1 (fr) 2019-11-09 2021-05-14 上海赛默罗生物科技有限公司 Dérivé de dihydroimidazopyrimidone tricyclique, son procédé de préparation, composition pharmaceutique et son utilisation
WO2022233302A1 (fr) 2021-05-07 2022-11-10 上海赛默罗生物科技有限公司 Dérivé de pyrimidinone et son procédé de préparation, composition pharmaceutique et utilisation

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WO1999024420A1 (fr) * 1997-11-06 1999-05-20 Smithkline Beecham Plc Composes de pyrimidinone et compositions pharmaceutiques les renfermant
WO2000010980A1 (fr) * 1998-08-21 2000-03-02 Smithkline Beecham Plc Derives de pyrimidinone destines au traitement de l'atherosclerose
WO2000066567A1 (fr) * 1999-05-01 2000-11-09 Smithkline Beecham Plc Composes pyrimidinones
WO2000066566A1 (fr) * 1999-05-01 2000-11-09 Smithkline Beecham Plc Composes de pyrimidine
WO2000068208A1 (fr) * 1999-05-05 2000-11-16 Smithkline Beecham Plc Derives pyrimidinones destines au traitement de l'atherosclerose
WO2001060805A1 (fr) * 2000-02-16 2001-08-23 Smithkline Beecham P.L.C. Derives de pyrimidine-4-one utilises comme inhibiteurs de ldl-pla¿2?
WO2002030904A1 (fr) * 2000-10-10 2002-04-18 Smithkline Beecham P.L.C. Derives pyridinone permettant de traiter l'atherosclerose
WO2002030911A1 (fr) * 2000-10-10 2002-04-18 Smithkline Beecham P.L.C. Derives de pyrimidinone et leur utilisation dans le traitement de l'atherosclerose

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999024420A1 (fr) * 1997-11-06 1999-05-20 Smithkline Beecham Plc Composes de pyrimidinone et compositions pharmaceutiques les renfermant
WO2000010980A1 (fr) * 1998-08-21 2000-03-02 Smithkline Beecham Plc Derives de pyrimidinone destines au traitement de l'atherosclerose
WO2000066567A1 (fr) * 1999-05-01 2000-11-09 Smithkline Beecham Plc Composes pyrimidinones
WO2000066566A1 (fr) * 1999-05-01 2000-11-09 Smithkline Beecham Plc Composes de pyrimidine
WO2000068208A1 (fr) * 1999-05-05 2000-11-16 Smithkline Beecham Plc Derives pyrimidinones destines au traitement de l'atherosclerose
WO2001060805A1 (fr) * 2000-02-16 2001-08-23 Smithkline Beecham P.L.C. Derives de pyrimidine-4-one utilises comme inhibiteurs de ldl-pla¿2?
WO2002030904A1 (fr) * 2000-10-10 2002-04-18 Smithkline Beecham P.L.C. Derives pyridinone permettant de traiter l'atherosclerose
WO2002030911A1 (fr) * 2000-10-10 2002-04-18 Smithkline Beecham P.L.C. Derives de pyrimidinone et leur utilisation dans le traitement de l'atherosclerose

Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003087088A3 (fr) * 2002-04-10 2004-01-08 Glaxo Group Ltd Nouveaux composes
AU2007353454C1 (en) * 2007-05-11 2014-03-27 Rowan University Methods of treatment and prevention of neurodegenerative diseases and disorders
JP2010526805A (ja) * 2007-05-11 2010-08-05 トーマス・ジェファーソン・ユニバーシティ 神経変性疾患および障害を治療および阻止する方法
EP2152865A4 (fr) * 2007-05-11 2010-11-03 Univ Jefferson Méthodes de traitement et de prévention de maladies et de troubles neurodégénératifs
AU2014200542B2 (en) * 2007-05-11 2016-08-25 Rowan University Methods of treatment and prevention of neurodegenerative diseases and disorders
AU2007353454C8 (en) * 2007-05-11 2014-04-24 Rowan University Methods of treatment and prevention of neurodegenerative diseases and disorders
AU2007353454B2 (en) * 2007-05-11 2013-10-31 Rowan University Methods of treatment and prevention of neurodegenerative diseases and disorders
WO2012076435A1 (fr) 2010-12-06 2012-06-14 Glaxo Group Limited Composés de pyrimidinone utiles dans le traitement de maladies ou d'états pathologiques induits par la lp-pla2
WO2012080497A2 (fr) 2010-12-17 2012-06-21 Glaxo Group Limited Procédés de traitement et de prévention de maladies oculaires
WO2013014185A1 (fr) 2011-07-27 2013-01-31 Glaxo Group Limited Composés pyrimidones bicycliques
WO2013013503A1 (fr) 2011-07-27 2013-01-31 Glaxo Group Limited Composés 2,3-dihydroimidazo[1,2-c]pyrimidin-5(1h)-one et utilisation en tant qu'inhibiteurs de lp-pla2
WO2014114248A1 (fr) 2013-01-25 2014-07-31 Glaxosmithkline Intellectual Property Development Limited Composés
WO2014114694A1 (fr) 2013-01-25 2014-07-31 Glaxosmithkline Intellectual Property Development Limited Inhibiteurs de la phospholipase associée aux lipoprotéines a2 (lp-pla2) à base de 2,3-dihydro-imidazol[1,2-c]pyrimidin-5(1 h)-one
WO2014114249A1 (fr) 2013-01-25 2014-07-31 Glaxosmithkline Intellectual Property Development Limited Composés de pyrimidone bicycliques utilisés en tant qu'inhibiteurs de lp-pla2
WO2016012917A1 (fr) 2014-07-22 2016-01-28 Glaxosmithkline Intellectual Property Development Limited Dérivés 1,2,3,5-tétrahydro-imidazo [1,2-c]pyrimidine utiles pour le traitement de maladies et de troubles médiés par la lp-pla2
WO2016012916A1 (fr) 2014-07-22 2016-01-28 Glaxosmithkline Intellectual Property Development Limited Dérivés 1,2,3,5-tétrahydro-imidazo [1,2-c]pyrimidine utiles pour le traitement de maladies et de troubles médiés par la lp-pla2
WO2021089032A1 (fr) 2019-11-09 2021-05-14 上海赛默罗生物科技有限公司 Dérivé de dihydroimidazopyrimidone tricyclique, son procédé de préparation, composition pharmaceutique et son utilisation
WO2022233302A1 (fr) 2021-05-07 2022-11-10 上海赛默罗生物科技有限公司 Dérivé de pyrimidinone et son procédé de préparation, composition pharmaceutique et utilisation

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