[go: up one dir, main page]

WO2000066566A1 - Composes de pyrimidine - Google Patents

Composes de pyrimidine Download PDF

Info

Publication number
WO2000066566A1
WO2000066566A1 PCT/EP2000/003726 EP0003726W WO0066566A1 WO 2000066566 A1 WO2000066566 A1 WO 2000066566A1 EP 0003726 W EP0003726 W EP 0003726W WO 0066566 A1 WO0066566 A1 WO 0066566A1
Authority
WO
WIPO (PCT)
Prior art keywords
formula
compound
nmr
requires
apci
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/EP2000/003726
Other languages
English (en)
Inventor
Deirdre Mary Bernadette Hickey
Robert John Ife
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
Application filed by SmithKline Beecham Ltd filed Critical SmithKline Beecham Ltd
Priority to AU45567/00A priority Critical patent/AU4556700A/en
Priority to EP00927053A priority patent/EP1173424A1/fr
Priority to JP2000615597A priority patent/JP2002543189A/ja
Publication of WO2000066566A1 publication Critical patent/WO2000066566A1/fr
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
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • 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
    • 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
    • A61P9/12—Antihypertensives
    • 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
    • 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
    • C07D403/02—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 two hetero rings
    • C07D403/06—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 two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • 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 py ⁇ midinone 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 phospnohpase A2 enzyme Lipoprotein Associated Phospnohpase A .
  • Lp-PLA 7 the sequence, isolation and purification thereof, isolated nucleic acids encoding the enzyme, and recombinant host cells transformed w ith 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
  • This enzyme Tew D et al.
  • Lp-PLAi is responsible for the conversion of phosphatidylcholine to lysophosphatidylcho ne. during the conversion of low density lipoprotein (LDL) to its oxidised form
  • LDL low density lipoprotein
  • the enzyme is known to hydrolyse the sn-2 ester of the oxidised phosphatidv lcho ne to give Ivsophosphatidvlcholine and an oxidativeiv modified fatty acid
  • Both products of Lp-PLA2 action are biologically active with I ophosphatidv lcholine.
  • lysophosphatidylchohne is thought play a significant role in atherosclerosis bv being responsible for the accumulation of cells loaded with cholesterol ester in the a ⁇ e ⁇ es Inhibition of the Lp-PLAo enzyme would theretore be expected to stop the build up of these macrophage enriched lesions (by inhibition of the formation of
  • Ivsophosphatidvlcholine content of oxidativeiv modified LDL is also thought to be responsible for the endothehal dysfunction observed in patients v ⁇ ith atherosclerosis
  • Inhibitors of Lp-PLAo could therefore prove beneficial in the treatment of this phenomenon
  • An Lp-PLAi inhibitor could also find utility in other disease states that exhibit endothehal dvsfunction including diabetes, hypertension, angina pecto ⁇ s and after ischaemia and repertusion
  • Lp-PL.A.2 inhibitors may also have a general application in anv disorder that involves activated monocytes.
  • macrophages or lymphocytes as all of these cell types express Lp-PLA ⁇ Examples of such disorders include psoriasis
  • Lp-PLA2 inhibitors may also have a general application in anv disorder that involves lipid oxidation in conjunction with Lp-PLA 7 activity to produce the two injurious products, lysophosphatidylchohne and oxidativeiv 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 neuropsychiat ⁇ c disorders such as schizophrenia (see Psychopharmacology Bulletin, 31 , 159- 165, 1995)
  • WO 97/217675, WO 97/217676, WO 96/41098, and WO 97/41099 disclose inter alia va ⁇ ous series of 4-th ⁇ onyl/sulf ⁇ nyl/sulfonyl azetidinone compounds which are inhibitors of the enzyme Lp-PLA2 T ese are irreversible, acylating inhibitors (Tew et al. Biochemistry, 37, 10087, 1998)
  • Patent applications WO 99/24420 and WO 00/10980 (SmithKline Beecham pic, published after the priority date of the present application) describe a new class of reversible, non-acylating inhibitors of the enzyme Lp-PLA . in particular a class of pyrimidone compounds
  • the early 2-(alkylth ⁇ o)py ⁇ m ⁇ d ⁇ n-4-one chemical lead is described in Bioorganic and Medicinal Chemistry Letters. 2000 10. 395-8
  • 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 Cn.igvalkyl, C(]_ ⁇ g)aikoxy, C(].j3)alkylth ⁇ o, arylC( j.jgvalkoxy, hydroxy, halogen, CN.
  • COR 4 carboxy, COOR 4 , CONR 7 R 8 .
  • NR 7 R 8 mono to perfluoro-C ( ⁇ _4)alkyl and mono to perfluoro-C ( j ⁇ valkoxy, or.
  • 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 Cn.igvalkyl.
  • SO 2 NR 7 R 8 , NR 4 SO R 5 , NR 7 R 8 mono to perfluoro-C ( 1 . ) alkyl. mono to perfluoro-C ( ⁇ _4)alkoxy, and arylO 1.
  • R3 IS selected from hydrogen, C( ⁇ _20) a 'kyl, C( ⁇ _20 ) a 'kenyl, arylC ( ⁇ _ ⁇ o) lkyl. heteroarylC/ j _ ⁇ o)alkyl, C ⁇ O ⁇ 'kylcarbamoyl, C ⁇ _20)alkylsulphamoyl.
  • R 4 and R ⁇ are independently hydrogen or O ⁇ O ⁇ 'kyl.
  • R" is C ( i_4)alkyl or a pharmaceutically acceptable in vivo hydrolysable ester group; R 7 and R 8 which may be the same or different is each selected from hydrogen,
  • R' is an ar l or a heteroaryl ring optionally substituted by 1.2. or 3 substituents which may be the same or different selected from C ( ] _ ⁇ g ) alkyl.
  • COR 4 carboxy, COOR 4 .
  • R'" is hydrogen or an aryl ring which is further optionally substituted by 1, 2, 3 or 4 substituents which may be the same or different selected from C ( j _ j g ⁇ alky 1.
  • CN COR 4 , carboxy. COOR 4 , CONR 4 R ⁇ NR COR 5 , SO NR 4 R 5 , NR 4 SO 2 R 5 .
  • NR 4 R 5 mono to perfluoro-C( ] _4)alkyl and mono to perfluoro-C( i_4)alkoxy;
  • R 1 1 is COOH or a salt thereof.
  • R ' ⁇ is an a ino acid side chain such as CJiJOH from se ⁇ ne;
  • n is an integer from 1 to 4. preferably 1 or 3;
  • X is O or S:
  • Z is CR ⁇ R 1 where R and R are each hydrogen or C ⁇ i _4)alkyl. or R ⁇ and R ' 4 together with the intervening carbon atom form a C ⁇ _ f j)cycloalkyl ⁇ n ?-
  • Compounds of formula (I) are inhibitors of Lp-PLA-> 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-PLA in in vitro assays ..
  • Z is CH 2 .
  • R ' is a 5- or 6- membered, monocyclic heteroaryl group containing 1 or 2 nitrogen heteroatoms, more preferably pyridyl, pyrimidyl or pyrazolyl: yet more preferably, pyrimidyl, optionally substituted by 1 or 2 substituents preferably selected from oxo, arylC( ] _4)alkyl (e.g. benzyl), C ⁇ . ⁇ - j alkyl (e.g. methyl or ethyl), C(3_6)cycloalkyl hydroxy,
  • C( ]_4)alkoxy (e.g. methoxy).
  • carboxy j . ⁇ alkyl, C .6) a 'kylcarboxyC( j_ )alkyl.
  • diC( t j .gvalkyl e.g. methyl or ethyl).
  • ZR ' IS py ⁇ m ⁇ d-5-ylmethyl.
  • R ' when an aryl group include phenyl and naphthyl.
  • R- when an aryl group include phenyl and naphthyl
  • R- when a heteroaryl group include pyridyl, py ⁇ midin l, pyrazolyl. furanyl, thienyl. thiazolyl. quinolyl.benzothiazolyl. py ⁇ dazolyl and pyrazinyl.
  • R- is phenyl optionally substituted by halogen.
  • X is S.
  • R-CH ⁇ X include 4-fluorobenzylthio.
  • C ] .20 ) a lkylcarbamoyl, C(i_20 ) lkvlsulphonyl. in which the alkyl moiety is preferably C ( 6_i2 ) alkyl, phenylC( ⁇ _4)alkyl. or R"
  • R" include phenyl optionally substituted by chloro, dichloro, trifluoromethyl or R' ⁇
  • R' ⁇ include phenyl optionally substituted by halogen, or trifluoromethyl, preferablv at the 4-pos ⁇ t ⁇ on Preferably.
  • R" and R.O together form a 4-(phenvl)-phenvl substituent in which the remote phenyl ring may be optionally substituted bv halogen or trifluoromethyl, preferably at the 4-pos ⁇ t ⁇ on
  • R a is hydrogen, (C j - fj lkvl in particular methyl or phenvl. each of which may be optionally substituted,
  • Rb is (C ⁇ -6)alkyl. (C ⁇ -6)alkox (C ] - )al vl, phenyl. benzyl, (C ⁇ Jcycloalkyl l-am ⁇ no(C
  • R a and R D together form a 1.2-phenvlene group optionally substituted bv one or two methoxy groups
  • R c is (C j - 6 )alkyl, (C 3 - 7 )cycloalkyl, (C ⁇ -6)alkvl(C3-7cycloalkyl,
  • R" is (C ⁇ - )alkylene optionally substituted with a methvl or ethyl group R e and R ⁇ which may be the same or different is each (C ] - 0 )alkvl or aryl( C ⁇ -4 alk l. optionally substituted with e.g hydroxy, R ⁇ ⁇ s (C 1 - 6 )alkyl.
  • R n is hydrogen, (C
  • R 1 is hydrogen or phenyl optionally substituted by up to three groups selected from halogen,
  • acyloxyalkyl groups such as acetoxymethv l. isobutyryloxymethyl, pivaloyloxymethyl, benzoyloxymethyl. ⁇ -acetoxyethyl.
  • alkoxy/cycloalkoxycarbonyloxyalkyl groups such as ethox carbonyloxymethyl, t- butyloxycarbonyloxymethyl, cyclohexyloxycarbonyioxymethyl. 1 - methylcyclohexyloxycarbony loxymethy 1 and ⁇ -ethoxycarbonyloxyethyl,
  • dialkylaminoalkyl especially di-loweralkylamino alkyl groups such as dimethylaminomethyl, dimethylaminoethyl. diethylaminomethyl or diethylaminoethyl.
  • lactone groups such as phthahdyl and dimethoxyphtha dyl.
  • compounds of the present invention may include a carboxy group as a substituent Such carboxy groups may be used to form 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 the present invention may include a basic group, such as an ammo group, as a substituent Such basic groups may be used to form acid adddition salts, in particular pharmaceutically acceptable salts.
  • Pharmaceutically acceptable salts include those described by Berge. Bighley. and Monkhouse, J Pharm Set.. 1977, 66. 1J 9
  • alkvl and similar terms such as 'alkoxv” includes all straight chain and branched isomers Representative examples thereof include methyl, ethyl, n- propyl. .so-propyl. /i-butyl, sec-buty ⁇ . / 0-butyl, f-butyl, /.-pentyl and /i-hexyl
  • aryl refers to, unless otherwise defined, a mono- or bicychc aromatic ring system containing up to 10 carbon atoms in the ring system, for instance phenyl or naphthyl
  • heteroaryl refers to a mono- or bicychc 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 bicychc heteroaromatic ring system may include a carbocyclic ring
  • halogen ' and halo include fluorine, chlorine, bromine and iodine and fluoro, chloro, bromo and lodo, respectively.
  • Particularly preferred compounds of formula (I) include
  • 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 readilv 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 recrystalhsed from solvents containing water In such cases water of hydration may be formed
  • This invention includes within its scope stoichiomet ⁇ c hydrates as well as compounds containing v ariable amounts of water that may be produced by processes such as lyophi sation
  • 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)
  • Lp-PLA2 lipoprotein associated phospnohpase A2
  • the present invention provides a compound of formula (I) for use in therapy
  • the compounds of formula (I) are inhibitors of lysophosphatidylchohne production by Lp- PLA2 and may therefore also have a general application in any disorder that involves endothehal dysfunction, for example atherosclerosis, diabetes, hypertension, angina pectoris and after ischaemia and reperfusion
  • compounds of formula (I) av have a general application in any disorder that involves lipid oxidation in conjunction w ith 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
  • v arious neuropsvchiat ⁇ c disorders such as schizophrenia ( see Psychopharmacology Bulletin, 31. 159- 165. 1995)
  • the present invention provides for a method of treating a disease state associated with activ itv of the enzyme Lp-PLA which method in olv es treating a patient in need thereof with a therapeuticallv effectiv e 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 lysophosphatidylchohne and oxidised free fatty acids, with lipid oxidation in conjunction with Lp PLA2 activity, or with endothehal dysfunction
  • Compounds of the present invention may also be of use in treating the above mentioned disease states in combination with anti-hyper pidaemic or anti-atherosclerotic or anti- diabetic or anti-anginal or anti-inflammatory ananti-hypertension agent or an agent for lowering Lp(a)
  • agents for lowering Lp(a) include cholesterol synthesis inhibitors such as statins, anti-oxidants such as probucol, insulin sensmsers, calcium channel antagonists, and anti-inflammatory drugs such as NSAIDs
  • agents for lowering Lp(a) include the arrunophosphonates described in WO 97/02037, WO 98/28310. WO 98/2831 1 and WO 98/28312 (Symphar S A 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, ce ⁇ vastatin, fluvastatin, lovastatin and ZD 4522 (also referred to as S-4522. 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 G1262570 (Glaxo Wellcome) and also the glitazone class of compounds such as rosig tazone ( ⁇ .vand ⁇ a. SmithKline Beecham). trog tazone and piog tazone
  • 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 w hich are adapted for oral or parenteral administration or as a suppositorv
  • 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 ill generally consist of a suspension or solution of the compound or pharmaceutically acceptable salt in a suitable liquid carner( s) for example, ethanol.
  • glycerine, non-aqueous solvent for example polyethylene glycol.
  • composition in the form of a tablet can be prepared using anv suitable pharmaceutical car ⁇ er(s) routinelv used for preparing solid formulations
  • suitable pharmaceutical car ⁇ er(s) routinelv 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
  • pellets containing the active ingredient can be prepared using standard carriers and then filled into a hard gelatin capsule
  • a dispersion or suspension can be prepared using anv suitable pharmaceutical carner(s), for example aqueous gums, celluloses, silicates or oils and the dispersion or suspension then filled into a soft gelatin capsule
  • suitable pharmaceutical carner(s) for example aqueous gums, celluloses, silicates or oils
  • 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.
  • 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 intrav enous subcutaneous or intramuscular dose of between 0 1 mg and 100 mg, preferablv 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
  • R- "1 is as hereinbefore defined, in the presence of a base such as a secondary or tertiary amine.
  • a base such as a secondary or tertiary amine.
  • di-isopropyl- ethylamine in an inert solvent such as dichloromethane.
  • L J is a C( l -6)alkyl group, for instance methyl.
  • R '° is a C ( i_ )al yl group, for instance methyl, ethyl or .-but l, and L ' , L-, R ' , R-, RJ , m. n, X and Z are as hereinbefore defined
  • step (a) Amide forming conditions for step (a) are well known in the art Preferablv.
  • the acid of formula (II) is reacted with the amine of formula (III) in an inert solvent, such as dichloromethane at ambient temperature and in the presence of an activating agent such as as l-(3-d ⁇ methvlam ⁇ nopropyI)-3-ethylcarbodnm ⁇ de plus hydroxybenzot ⁇ azole
  • Alkylation conditions for step (b) include reaction in the presence of a base such as a secondary or tertiary amine, for instance di-.iO-propylethvlamine. in an inert solvent such as dichloromethane, forming an intermediate ester which is converted to the acid of formula (II) by hydrolysis, for instance using aqueous sodium hvdroxide in a solvent such as dioxan or by alternative deprotection, for instance using t ⁇ fluoroacetic acid in a 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 dimethy l formamide, or a secondary or tertiary amine base such as di-isopropylethyl amine, in solvent such as dichloromethane
  • step (d) a compound of formula (XVII) 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 ethy l formate in the presence of a base such as sodium hydride or potassium isopropoxide
  • step (f) a compound of formula (IV) is reacted with a compound of formula (V) in the presence of a base such as a secondary or tertiary amine, for instance di-isopropyl- ethylamine. in an inert solvent such as dichloromethane
  • step (g) a compound of formula (XIII) is reacted with a compound of formula (XIV) 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 thiocvanate. in a solvent such as acetonit ⁇ le
  • 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 h drolvsis using sodium hydroxide to give the corresponding carboxylic acid which may then be converted into the acv l chloride, for instance by treatment with oxalyl chloride
  • step (j) a catalyst such as 4-d ⁇ methylam ⁇ nopy ⁇ d ⁇ ne, and a solvent such as pyndine are used
  • step (k) a compound of formula (XIII) is reacted with a compound of formula (XV) in a solvent such as dimethvlformamide to form an intermediate thiourea. which is then treated with a base such as sodium methoxide
  • Example 1 ' H NMR (CDCI3) ⁇ 2.09 (2H. t); 236 (2H. t); 3.12 (4H, m): 3.51 (2H, m); 3.63 (2H. s): 3.72 (2H. m); 3.90 (2H. t); 3.99 (3H, s); 4.46 (2H, s): 6.72 ( I H. d): 6.95-6.99 (3H. m); 7.08 ( I H, s); 7.31 ( I H, d); 734-738 (2H. m); 8.46 (2H. s).
  • Example s l-(3-(4-(3,4-Dichiorophenyl)piperazin-l-yIcarbonyl)prop-l-yl)-2-(4- fluorobenzyl)thio-5-(l-methyl-2-oxopyrimid-5-ylmethyl)pyrimidin-4-one
  • a mixture of l -(3-(4-(3,4-d ⁇ chlorophenyl)p ⁇ peraz ⁇ n- l-ylcarbonyl)prop- l-yl)-2-(4- fluorobenzyl)th ⁇ o-5-(2-oxopy ⁇ m ⁇ d-5-ylmethyl)pyr ⁇ m ⁇ d ⁇ n-4-one (Example 4, 0 50g, 0 78 mmol), methyl iodide (0 049ml, 0 78 mmol), potassium carbonate (0 24g, 1 73 mmol) and dry DMF ( lOml) was stirred under argon at room temperature
  • Example 7 l-(3-(4-(3,4-Dichlorophenyl)piperazin-l-ylcarbonyl)prop-l-yl)-2-(4- fluorobenzyl)thio-5-(l-carboxymethyI-2-oxopyrimid-5-yImethyl)pyr ⁇ midin-4-one l-(3-(4-(3,4-d ⁇ chlorophenyl)p ⁇ peraz ⁇ n- l-y lcarbony l)prop- i -yl)-2-(4-fluorobenzyl)th ⁇ o-5-( l- ethoxycarbonylmethyl-2-oxopynm ⁇ d-5-ylmethyl)pynm ⁇ d ⁇ n-4-one (Example 6.
  • Example 31 l-(4-(3J-DichlorophenyI)piperazin-l-ylcarbonylmethyI)-2-(4- fluorobenzy )thio-5-(l-ethyl-2-oxopyrimid-5-ylmethyl)pyrimidin-4-one
  • Example 28 by the method of Example 4, except using ethyl iodide in place of methyl iodide.
  • ' H-NMR (CDC1 3 ) ⁇ 132- 145 (3H, t). 3.08-331 (4H. m). 3.45 (2H, s), 347-3.69 (2H. br.t).
  • Example 33 l-(4-(3J-DichlorophenyI)piperazin-l-ylcarbonylmethyl)-2-(4- fluorobenzyl)thio-5-(l-(ethoxycarbonylmethyI)-2-oxopyrimid-5-ylmethyI)pyrimidin-4- one
  • Example 36 l-(4-(3J-Dichlorophenyl)piperazin-l-yIcarbonylrnethyI)-2-(4- fluorobenzyl)thio-5-(l-methylpyrazol-4-ylmethyI)pyrimidin-4-one
  • 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

Landscapes

  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Neurology (AREA)
  • Diabetes (AREA)
  • Biomedical Technology (AREA)
  • Neurosurgery (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Psychiatry (AREA)
  • Rheumatology (AREA)
  • Vascular Medicine (AREA)
  • Obesity (AREA)
  • Pain & Pain Management (AREA)
  • Urology & Nephrology (AREA)
  • Emergency Medicine (AREA)
  • Endocrinology (AREA)
  • Hematology (AREA)
  • Hospice & Palliative Care (AREA)
  • Dermatology (AREA)
  • Immunology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

Selon cette invention, les composés de pyrimidone correspondant à la formule (I): sont des inhibiteurs de l'enzyme Lp-PLA2; l'invention concerne leur utilisation thérapeutique, notamment pour le traitement de l'athérosclérose.
PCT/EP2000/003726 1999-05-01 2000-04-25 Composes de pyrimidine Ceased WO2000066566A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
AU45567/00A AU4556700A (en) 1999-05-01 2000-04-25 Pyrimidine compounds
EP00927053A EP1173424A1 (fr) 1999-05-01 2000-04-25 Composes de pyrimidine
JP2000615597A JP2002543189A (ja) 1999-05-01 2000-04-25 ピリミジン化合物

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9910079.4 1999-05-01
GBGB9910079.4A GB9910079D0 (en) 1999-05-01 1999-05-01 Novel compounds

Publications (1)

Publication Number Publication Date
WO2000066566A1 true WO2000066566A1 (fr) 2000-11-09

Family

ID=10852633

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2000/003726 Ceased WO2000066566A1 (fr) 1999-05-01 2000-04-25 Composes de pyrimidine

Country Status (5)

Country Link
EP (1) EP1173424A1 (fr)
JP (1) JP2002543189A (fr)
AU (1) AU4556700A (fr)
GB (1) GB9910079D0 (fr)
WO (1) WO2000066566A1 (fr)

Cited By (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003015786A1 (fr) * 2001-08-14 2003-02-27 Smithkline Beecham P.L.C. Derives de 2,5-substituee 1-(aminocarbonylalkyl) -pyrimidin-4-one a activite inhibitrice de l'enzyme lp-pla2 permettant de traiter l'atherosclerose
US6825172B2 (en) 2002-05-31 2004-11-30 Janssen Pharmaceutica, Nv 3-descladinosyl-6-O-carbamoyl and 6-O-carbonoyl macrolide antibacterial agents
EP1686119A1 (fr) 2000-02-16 2006-08-02 Smithkline Beecham Plc Dérivés de pyrmidine-4-one comme inhibiteurs LDL-PLA2
WO2006082975A1 (fr) * 2005-02-07 2006-08-10 Mitsubishi Pharma Corporation Derive de tetrahydronaphtalene optiquement actif
WO2007078335A3 (fr) * 2005-12-21 2007-11-29 Decode Genetics Inc Inhibiteurs de biaryl-azote-heterocycle de lta4h pour traiter l'inflammation
WO2008140449A1 (fr) 2007-05-11 2008-11-20 Thomas Jefferson University Méthodes de traitement et de prévention de maladies et de troubles neurodégénératifs
EP2258688A1 (fr) 2000-10-10 2010-12-08 SmithKline Beecham Limited Dérives pyridinone permettant de traiter l'athérosclerose
WO2011083413A1 (fr) 2010-01-05 2011-07-14 Actelion Pharmaceuticals Ltd Pipérazines en tant qu'agents antipaludiques
WO2011089132A1 (fr) 2010-01-22 2011-07-28 F. Hoffmann-La Roche Ag Dérivés hétéroaryliques contenant de l'azote
WO2011154327A1 (fr) 2010-06-09 2011-12-15 F. Hoffmann-La Roche Ag Composés hétéroaryles contenant de l'azote
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
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
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
WO2014114248A1 (fr) 2013-01-25 2014-07-31 Glaxosmithkline Intellectual Property Development Limited Composés
US8889688B2 (en) 2010-01-05 2014-11-18 Actelion Pharmaceuticals Ltd. Piperazines as antimalarial agents
US9029383B2 (en) 2007-05-11 2015-05-12 The Trustees Of The University Of Pennsylvania Methods of treatment of skin ulcers
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
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
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

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BR112017016131A2 (pt) * 2015-01-30 2018-04-17 Basf Se ?uso de fenilpiridinas, fenilpirimidinas, processos para preparação de fenilpirimidinas e para preparação de composições ativas herbicidas, pirimidinas, composição herbicida, e, método para controlar vegetação indesejada?.

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0391254A2 (fr) * 1989-04-06 1990-10-10 Richter Gedeon Vegyeszeti Gyar Rt. Dérivés de thiouracile, compositions pharmaceutiques les contenant et procédé pour les préparer
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

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0391254A2 (fr) * 1989-04-06 1990-10-10 Richter Gedeon Vegyeszeti Gyar Rt. Dérivés de thiouracile, compositions pharmaceutiques les contenant et procédé pour les préparer
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

Cited By (28)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8871775B2 (en) 2000-02-16 2014-10-28 Glaxo Group Limited Compounds
EP1686119A1 (fr) 2000-02-16 2006-08-02 Smithkline Beecham Plc Dérivés de pyrmidine-4-one comme inhibiteurs LDL-PLA2
US9266841B2 (en) 2000-02-16 2016-02-23 Glaxo Group Limited Compounds
EP2258688A1 (fr) 2000-10-10 2010-12-08 SmithKline Beecham Limited Dérives pyridinone permettant de traiter l'athérosclerose
WO2003015786A1 (fr) * 2001-08-14 2003-02-27 Smithkline Beecham P.L.C. Derives de 2,5-substituee 1-(aminocarbonylalkyl) -pyrimidin-4-one a activite inhibitrice de l'enzyme lp-pla2 permettant de traiter l'atherosclerose
US6825172B2 (en) 2002-05-31 2004-11-30 Janssen Pharmaceutica, Nv 3-descladinosyl-6-O-carbamoyl and 6-O-carbonoyl macrolide antibacterial agents
WO2006082975A1 (fr) * 2005-02-07 2006-08-10 Mitsubishi Pharma Corporation Derive de tetrahydronaphtalene optiquement actif
WO2007078335A3 (fr) * 2005-12-21 2007-11-29 Decode Genetics Inc Inhibiteurs de biaryl-azote-heterocycle de lta4h pour traiter l'inflammation
US7750012B2 (en) 2005-12-21 2010-07-06 Decode Genetics Ehf Biaryl nitrogen-heterocycle inhibitors of LTA4H for treating inflammation
US9029383B2 (en) 2007-05-11 2015-05-12 The Trustees Of The University Of Pennsylvania Methods of treatment of skin ulcers
WO2008140449A1 (fr) 2007-05-11 2008-11-20 Thomas Jefferson University Méthodes de traitement et de prévention de maladies et de troubles neurodégénératifs
EP2977452A2 (fr) 2007-05-11 2016-01-27 Thomas Jefferson University Procédés de traitement et de prévention de maladies et de troubles neurodégénératifs
WO2011083413A1 (fr) 2010-01-05 2011-07-14 Actelion Pharmaceuticals Ltd Pipérazines en tant qu'agents antipaludiques
US8889688B2 (en) 2010-01-05 2014-11-18 Actelion Pharmaceuticals Ltd. Piperazines as antimalarial agents
WO2011089132A1 (fr) 2010-01-22 2011-07-28 F. Hoffmann-La Roche Ag Dérivés hétéroaryliques contenant de l'azote
WO2011154327A1 (fr) 2010-06-09 2011-12-15 F. Hoffmann-La Roche Ag Composés hétéroaryles contenant de l'azote
US8703768B2 (en) 2010-06-09 2014-04-22 Hoffmann-La Roche Inc. Nitrogen containing heteroaryl compounds
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
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
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
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

Also Published As

Publication number Publication date
JP2002543189A (ja) 2002-12-17
AU4556700A (en) 2000-11-17
GB9910079D0 (en) 1999-06-30
EP1173424A1 (fr) 2002-01-23

Similar Documents

Publication Publication Date Title
EP1173424A1 (fr) Composes de pyrimidine
JP4095804B2 (ja) Ｌｄｌ−ｐｌａ２阻害剤としてのピリミジン−４−オン誘導体
US6417192B1 (en) Pyrimidinone compounds and pharmaceutical compositions containing them
KR20020012200A (ko) 피리미디논 화합물
JP2004511473A (ja) ピリミジノン誘導体類およびアテローム性動脈硬化の治療におけるそれらの使用
AU2001235466A1 (en) Pyrimidine-4-one derivatives as LDL-PLA2 inhibitors
JP2005532292A (ja) 新規化合物
US20050020832A1 (en) Pyridone, pyridazone and triazone derivatives as lp-pla2 inhibitors
JP2005535570A (ja) 新規ピリミドン誘導体
JP2003524628A (ja) アテローム性動脈硬化症の治療のためのピリミジノン誘導体
WO2003015786A1 (fr) Derives de 2,5-substituee 1-(aminocarbonylalkyl) -pyrimidin-4-one a activite inhibitrice de l'enzyme lp-pla2 permettant de traiter l'atherosclerose
RU2235722C2 (ru) 1-(диэтиламино)этил)-(4-трифторметилфенил)-бензил)аминокарбони лметил)-2-(4-фторбензил)тио-5,6-триметиленпиримидин-4-она или его фармацевтически приемлемая соль, способ получения и фармацевтическая композиция
HK1071362A (en) Pyrimidinone compounds
HK1053466B (en) Pyrimidine-4-one derivative as ldl-pla2 inhibitor

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY CA CH CN CR CU CZ DE DK DM DZ EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT TZ UA UG US UZ VN YU ZA ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW SD SL SZ TZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG

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: 2000927053

Country of ref document: EP

ENP Entry into the national phase

Ref country code: JP

Ref document number: 2000 615597

Kind code of ref document: A

Format of ref document f/p: F

WWP Wipo information: published in national office

Ref document number: 2000927053

Country of ref document: EP

REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

WWE Wipo information: entry into national phase

Ref document number: 10009914

Country of ref document: US

WWW Wipo information: withdrawn in national office

Ref document number: 2000927053

Country of ref document: EP