EP0840725A1 - Derives de l'azetidinone pour le traitement de l'atherosclerose - Google Patents

Derives de l'azetidinone pour le traitement de l'atherosclerose

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Publication number
EP0840725A1
EP0840725A1 EP96922030A EP96922030A EP0840725A1 EP 0840725 A1 EP0840725 A1 EP 0840725A1 EP 96922030 A EP96922030 A EP 96922030A EP 96922030 A EP96922030 A EP 96922030A EP 0840725 A1 EP0840725 A1 EP 0840725A1
Authority
EP
European Patent Office
Prior art keywords
oxoazetidin
diastereoisomer
benzylsulphinyl
acetamide
ylacetamide
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.)
Withdrawn
Application number
EP96922030A
Other languages
German (de)
English (en)
Inventor
Dashyant SmithKline Beecham Pharma. DHANAK
Deirdre M.B. SmithKline Beecham Pharma. HICKEY
Robert J. SmithKline Beecham Pharmaceuticls IFE
Colin A. SmithKline Beecham Pharma. LEACH
David G. SmithKline Beecham Pharmaceuticals TEW
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 GBGB9513442.5A external-priority patent/GB9513442D0/en
Priority claimed from GBGB9515056.1A external-priority patent/GB9515056D0/en
Priority claimed from GBGB9515206.2A external-priority patent/GB9515206D0/en
Priority claimed from GBGB9516985.0A external-priority patent/GB9516985D0/en
Priority claimed from GBGB9525132.8A external-priority patent/GB9525132D0/en
Priority claimed from GBGB9608650.9A external-priority patent/GB9608650D0/en
Priority claimed from GBGB9608651.7A external-priority patent/GB9608651D0/en
Application filed by SmithKline Beecham Ltd filed Critical SmithKline Beecham Ltd
Publication of EP0840725A1 publication Critical patent/EP0840725A1/fr
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
    • C07D205/085—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams with a nitrogen atom directly attached in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
    • C07D205/09—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams with a sulfur atom directly attached in position 4
    • C07D205/095—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams with a sulfur atom directly attached in position 4 and with a nitrogen atom directly attached in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to certain novel monocyclic ⁇ -lactam 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.
  • Lipoprotein Associated Phospholipase A2 Lipoprotein Associated Phospholipase A2
  • the sequence of the enzyme, the isolation and purification thereof, isolated nucleic acids encoding the enzyme, recombinant host cells transformed with DNA encoding the enzyme are described in patent application WO 95/00649 (SmithKline Beecham pic). Suggested therapeutic uses for inhibitors of the enzyme included atherosclerosis, diabetes, rheumatoid arthritis, stroke, myocardial infarction, reperfusion injury and acute and chronic inflammation.
  • 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 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.
  • 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.
  • a 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 .
  • disorders include psoriasis.
  • Lp-PL A2 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, 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).
  • Rl and R ⁇ which may be the same or different, is each selected from hydrogen, halogen or C ( i_g ) aJkyl;
  • R 4 and R ⁇ which may be the same or different is each selected from hydrogen, C ( j_
  • X is a linker group
  • Y is an optionally substituted aryl group
  • Z is oxygen and R 3 is C ( i_g ) alkyl, C ( 3_g ) Cycloalkyl, C ( 3_g ) cycloalkylC ( i_6 ) alkyl, heteroaryl, heteroaryl (C ⁇ _4)alkyl, aryl, or aryl(C ⁇ _4)alkyl, each of which may be optionally substituted or Z is S(O) n in which n is 0, 1 or 2 and R 3 is C ( i_g ) alkyl, C 3_ g ) cycloalkyl, C ( 3_g)cycloalkylC ( i_6 ) alkyl, aryl, aryl(C ⁇ _4)alkyl, heteroaryl, or heteroaryl(C ⁇ _4)alkyl, each of which may be optionally substituted; and excluding compounds in which:
  • X is a direct bond; a group X 1 (CH2) m in which X 1 is CO, CONR 6 , COO, CONR 6 CO, or CONR 6 O in which R 6 and m are as hereinbefore defined; or a C ( i_
  • Z is S(O) n in which n is 0, 1 or 2 and R 3 is C ( i_g ) alkyl, C ( 3_g ) cycloalkyl, C ( 3_ g ) cycloaJkylC ( i_6 ) alkyl, aryl, or aryl(C ⁇ _4)alkyl, each of which may be optionally substituted; and R 4 and R ⁇ is each hydrogen.
  • X is a direct bond; a group X 1 (CH2) m in which X 1 is CO, CONR 6 , COO, CONR 6 CO, or CONR 6 O in which R 6 is hydrogen or C ( i_6 ) alkyl and m is 0 or an integer from 1 to 12; a group (X*) a ⁇ 2 in which a is 0 or 1 and X ⁇ is a Cn - 12)alkylene chain interupted and or terminated at the end adjacent to Y by one or more groups X 3 selected from O, S(O) x , NRG, alkene or alkyne, in which x is 0, 1 or 2; or a C(i_i2)alkylene chain optionally interupted by X 1 .
  • Suitable sub-sets of compounds within formula (I) include those in which: (a) X is a direct bond; a group X 1 (CH2) as hereinbefore defined; a group (X ) a ⁇ 2 as hereinbefore defined; or a C ( i_i2 ) alkylene chain optionally interupted by ⁇ l; Z is oxygen and R 3 is C ( ⁇ _g ) alkyl, C ( 3_g ) cycloalkyl, C ( 3_g ) cycloalkylC ( ⁇ _6 ) alkyl, heteroaryl, heteroaryl(Ci_4)alkyl, aryl, or aryl(C ⁇ _4)alkyl, each of which may be optionally substituted or Z is S(O) n in which n is 0, 1 or 2 and R 3 is heteroaryl or heteroaryl(C ⁇ _4)alkyl, each of which may be optionally substituted; R 4 and R ⁇ are as hereinbefore defined; or (b)
  • Z is S(O) n in which n is 0, 1 or 2 and R 3 is C ( i_g ) alkyl, C ( 3_g ) cycloalkyl, C ( 3_ g)cycloalkylC ( i_6 ) alkyl, aryl or aryl(C ⁇ _4)alkyl, each of which may be optionally substituted; and R 4 and R-5 is each hydrogen.
  • 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 above.
  • Representative examples of R* and R ⁇ include hydrogen, bromo, methyl and ethyl.
  • R* and R ⁇ is each hydrogen or one of Rl and R2 is hydrogen and the other of Rl and R ⁇ is methyl (to give a tr ⁇ ns-methyl).
  • R* and R ⁇ is each hydrogen.
  • R 3 is aryl(C ⁇ _4)alkyl
  • arylC ( i_3 ) alkyl Representative values for when R 3 is aryl(C ⁇ _4)alkyl include arylC ( i_3 ) alkyl.
  • representative examples of the aryl group include phenyl and naphthyl.
  • Suitable examples of R 3 include benzyl, 2-phenylethyl and 3-phenylpropyl in each of which the phenyl ring may be optionally substituted by up to three substituents.
  • Suitable substituents for a phenyl or naphthyl ring in R 3 include halo, hydroxy, C ( j.
  • R 3 is 4- carboxybenzyl or a corresponding C(i_6)alkyl or C(2-6>alkenyl ester thereof.
  • Representative examples of the aryl group for when R 3 is aryl include phenyl and naphthyl. Preferably, the aryl group is optionally subsumed phenyl.
  • Suitable substituents for a phenyl or naphthyl ring include halo, hydroxy, C ( i_6 ) alkyl, C(i_ 6 ) alkoxy, C(i_6 ) alkoxycarbonyl, C ( 2-6 ) alkenyloxycarbonyl, carboxy, carboxyC ( i_ 6 ) alkyl and C ( i_6)alkoxycarbonylC(i_6)alkyl.
  • C(3_g ) cycloalkylC ( i_6 ) a_kyjl include methyl, n-butyl, t-butyl and n-hexyl, cyclohexyl and cyclohexyl methyl, suitably n-butyl, t-butyl or n-hexyl.
  • Suitable substituents for the alkyl or cycloalkyl group in R 3 include halo, hydroxy, C ( i_6 ) alkyl, C ( i_6 ) alkoxy, C ( i_6 ) alkoxycarbonyl, C ( 2-6 ) alkenyloxycarbonyl, carboxy, carboxyC ( i_6 ) alkyl and C ( i_6 ) alkoxycart ⁇ )nylC ( i_6 ) a _kyl,
  • R 3 include heteroarylC ( i_3 ) alkyl, preferably heteroarylmethyl.
  • Representative examples of the heteroarylaryl group for use in R 3 include pyridyl, pyridyl N-oxide, furanyl, thienyl and thiazolyl.
  • Suitable substituents for a heteroaryl ring in R 3 include halo, hydroxy, C ( i_6 ) alkyl, C ( i_6 ) alkoxy, C ( j.
  • an optional substituent may be located in the alkyl, cycloalkyl, aryl and/or heteroaryl portion.
  • the substituent is carboxy or a C ( i_6 ) aJkyl or C ( 2-6 ) alkenylester thereof.
  • R 3 is arylC ( i_3 ) alkyl or heteroarylC ( i_3 ) alkyl, more preferably arylC ( i_3 ) alkyl, most preferably benzyl, which may be optionally substituted, in particular by a carboxy group or a C ( i_6 ) alkyl or C ( 2-6 ) alkenylester thereof.
  • Z is S(O) n .
  • n is 1 or 2, more preferably 1.
  • S(O) n R 3 is optionally substitued benzylsulphinyl, more preferably 4-carboxybenzylsulphinyl or a C ( ⁇ -6 ) alkyl or C ( 2-6) a U cen yl ester thereof.
  • R 4 and R ⁇ when an alkyl group include methyl, ethyl and propyl.
  • Representative examples of a C ⁇ - ⁇ ) 3 ⁇ 1 ⁇ group include allyl.
  • Representative examples of a (C3_7)cycloalkyl ring include cyclopropyl.
  • Representative examples of aryl(C ⁇ _4)alkyl and heteroaryl(C ⁇ _4)alkyl include benzyl and furylmethyl, respectively.
  • Representative examples of R 4 and R ⁇ when aryl or aralkyl include phenyl and benzyl.
  • R 4 and R ⁇ are both hydrogen or R 4 is hydrogen and R ⁇ methyl.
  • X include CO(CI-2) m , CONH(CH2) , COO(CH 2 ) m , CONHCO(CH 2 ) ra , CONHO(CH 2 ) m and C(i. 12 )alkylene.
  • X 1 is CO or CONR 6 , more preferably CONH.
  • m is 1, 2, 5, 6, 7 or 9, preferably 6.
  • X is CONR6(CH 2 )4C ⁇ C or (CH )O(CH 2 )6.
  • X examples include CONH(C__2>6, CONR 6 (CH2)4C ⁇ C and
  • Y is a benzene ring, optionally substituted by up to three further substituents. Suitable substituents include halo, hydroxy, C ( i_g ) alkyl and C ( i_g ) alkoxy. Preferably, Y is phenyl optionally substituted by halo.
  • C-4 of the ⁇ -lactam ring is a chiral centre which will give rise to the presence of stereoisomers.
  • the present invention encompasses all such stereoisomers.
  • An additional chiral centre will be introduced when R 4 and R ⁇ are not the same. This will give rise to the existence of extra stereoisomers.
  • the present invention encompasses all such stereoisomers.
  • the absolute configurations at C-4 and the SO moiety are R and S respectively.
  • 'alkyl' and similar terms such as 'alkoxy * includes all straight chain and branched isomers. Representative examples thereof include methyl, ethyl, n-propyl, iyo-propyl, n-butyl, sec-butyl, iso-butyl, t-butyl, /i-pentyl and ⁇ -hexyl.
  • Suitable substituents for an alkyl group include, for example, halogen, cyano, azido, nitro, carboxy, (C ⁇ _6)alkoxycarbonyl, carbamoyl, mono- or di-(C ⁇ _6)alkylcarbamoyl, sulpho, sulphamoyl, mono- or di-(C ⁇ _6)alky_sulphamoyl, amino, mono- or di-(C ⁇ .6)alkylamino, acylamino, ureido, (C ⁇ _6)alkoxycarbonylamino, 2,2,2-trichloroet oxycarbonylamino, aryl, heterocyclyl, hydroxy, (C ⁇ _6)alkoxy, acyloxy, oxo, acyl, 2-thienoyl, (C ⁇ _6)alkylthio, (C ⁇ _6)a_kylsulphinyl, (C ⁇ 6)alkylsulphonyl, hydroxyimino,
  • the term 'aryl' includes, unless otherwise defined, phenyl or naphthyl optionally substituted with up to five, preferably up to three substituents.
  • Suitable substituents for an aryl group include, for example, halogen, cyano, (C ⁇ -6)alkyl, (C3-7)cycloalkyl, (Cj- ⁇ alkoxy, halo(C ⁇ -6)alkyl, hydroxy, amino, mono- or di-(C ⁇ -6)alkylamino, acylamino, nitro, carboxy, (C ⁇ -6)alkoxycarbonyl, (C j -6)alkenyloxycarbonyl, (C ⁇ -6)alkoxycarbonyl(C -6)alkyl, (C -gjalkylcarbonyloxy, carboxy(C -gjalkyloxy, (C i - ⁇ alkylcarbonyloxy, (C j -6)alkylthio, (C ⁇
  • heteroaryl' includes single and fused rings, each ring suitably 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 fused heteroaryl ring may include carbocyclic rings and need include only one heteroaryl ring. Suitable fused heteroaryl rings include bicyclic systems.
  • heterocyclyl' includes aromatic and non-aromatic single or fused rings comprising up to four hetero-atoms in the ring selected from oxygen, nitrogen and sulphur and optionally substituted with up to three substituents.
  • the heterocyclic ring comprises from 4 to 7, preferably 5 to 6, ring atoms.
  • a fused heterocyclic ring system may include carbocyclic rings and need only include one heterocyclic ring.
  • fused heterocyclic ring system may include carbocyclic rings and need only include one heterocyclic ring.
  • a heteroaryl or a heterocyclyl group may have up to three substituents. Suitable such substituents include those previously mentioned for an aryl group as well as oxo.
  • halogen' and 'halo' include fluorine, chlorine, bromine and iodine and fluoro, chloro, bromo and iodo, respectively.
  • Preferred compounds of formula (I) include:
  • (+/-)-N-(6-[4-Chlorophenyl]hex-l-yl)-4-(3-furylmethylsulphinyl)-2-oxoazetidin-l- ylacetamide (+/-)-N-[6-(4-Chlorophenylhexyl)]-4-(5-memoxycarbonyl-2-furylmemylsulphinyl)-2- oxoazetidin-1-ylacetamide (diastereomer 2);
  • Diastereoisomer 2 More preferred compounds 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 NSAJDs.
  • 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.
  • the 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 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.
  • suitable pharmaceutical carrier(s) routinely used for preparing solid formulations.
  • suitable pharmaceutical carrier(s) 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; 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.
  • a binding and/or lubricating agent such as polymeric glycols, gelatins or cocoa butter or other low melting vegetable or synthetic waxes or fats.
  • 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.
  • Compounds of formula (I) may be prepared from convenient starting materials by adapting synthetic procedures well known in the art.
  • a suitable process comprises treating an azetidone of formula (Tl):
  • a suitable base such as sodium hydride or potassium hydroxide optionally with a quaternary ammonium salt such tetrabutyl ammonium bromide
  • THF tetrahydrofuran
  • a second alkyl group for R 4 /R ⁇ may be introduced by treating a first obtained compound of formula (I) in which one of R 4 and R ⁇ is hydrogen, with an alkylating agent in the presence of a suitable base such as sodium hydride, potassium hydroxide or lithium hexamethyldisilazide, in a suitable alkylating solvent such as tetrahydrofuran (THF), and at a temperature in the range -80 to 10°C.
  • a suitable base such as sodium hydride, potassium hydroxide or lithium hexamethyldisilazide
  • THF tetrahydrofuran
  • Compounds of formula (II) in which Z is O may be obtained by treating 4-acetoxyazetidinone, 4-benzoyloxyazetidinone or 4-phenylsulfonyl-azetidinone with a phenol/alcohol R 3 OH in the presence of a base such as potassium t-butoxide, in a suitable solvent such as THF at a temperature in the range 0 to 5°C
  • An acid of formula (IV) in which one of R 4 and is hydrogen may be obtained by treating a compound of formula (II) with a corresponding 2-bromo ester, for instance a (C 1.7) alkanoate ester, under alkylating conditions as hereinbefore described; followed by the hydrolysis of the thus formed intermediate ester using standard conditions.
  • a second group, for instqance an alkyl group, may then be introduced by alkylating of the first formed monoalkyl ester.
  • Z, R , R 2 , R 3 , R 4 and R 5 are as hereinbefore defined; using conditions well known in the art for such reactions, for instance heating in toluene in the presence of a catalytic amount of sodium methoxide and an alcohol.
  • a compound of formula (VII) in which one of R 4 and R ⁇ is hydrogen may be obtained by treating a compound of formula (II) with a methyl 2-bromo(C ⁇ _7) alkanoate, under alkylating conditions as hereinbefore described.
  • a compound of formula (I) in which X denotes a group COO(CH2) m or COOX 2 may be prepared by treating a compound of formula (IV) with an alcohol YX- ⁇ OH or an activated derivative thereof, for instance a tosylate.
  • Compounds of formula (X) may be obtained from the corresponding 4- acetylthioazetidinone by treatment with silver nitrate and a base in a suitable solvent such as methanol.
  • Suitable chiral intermediates may be obtained by resolution or chiral induction or by using chiral reagents, in particular natural chiral molecules, according to methods well known to those skilled in the art
  • a convenient chiral starting material is a penicillin derivative which has the preferred configuration at C-4 of the ⁇ -lactam ring. This is illustrated in the following scheme for the preparation of suitable intermediates
  • the present invention will now be illustrated by the following examples.
  • the relative configurations of the centre at the C4 position in the azetidinone and the centre alpha to the N of the azetidinone are unknown in the two diastereoisomers (a and b) described below but are thought to be R,R/S,S (diastereoisomer a) and R,S/S,R (diastereoisomer b).
  • the relative configurations of the C4 and sulfoxide centres are also unknown, but are thought to be R,R/S,S (diastereoisomer 1) or R,S/S,R (diastereoisomer 2).
  • Methyl 5-(acetylthiomethyI)-2-furoate Methyl (5-chloromethyl)-2-furoate (50 g, 0.286 mol) was dissolved in dry dimethylformamide (300 ml) and potassium thioacetate ( 32.68 g, 0,286 mol) added with stirring. The initial exotherm was controlled by cooling ( ice bath), then the reaction was stood at room temperature for 2 hr. The solvent was evaporated and the residue treated with water and thoroughly extracted with ether. The combined extracts were dried (MgSO 4 ), evaporated and purified by flash chromatography (silica- ethyl acetate/petroleum ether) to give the product as an oil (40.9g, 67% yield).
  • Ethanolamine (1.53 g) was added to NaH (1.0 g) in dimethyl sulfoxide (DMSO) (10 ml) at room temperature, followed by l-bromo-3-phenylpropane (5 g) and the mixture stirred at room temperature for 0.5 h. After aqueous work-up the title compound was obtained as a yellow oil (1.6 g, 36%).
  • DMSO dimethyl sulfoxide
  • 6-Phenylhexyloxy triflate a. 2-(6-PhenyIhexyloxy)ethanol
  • 6-Phenylhexyl bromide (6.10 g) and ethylene glycol (15.5g) were added to a solution of sodium hydroxide (1.08 g) in water (1.1 ml) and the mixture heated at 100°C for 30hrs.
  • Ether 75 ml
  • water 75 ml
  • the ether layer was washed with water then brine, dried over MgSO4 and evaporated to an orange oil.
  • This was purified by Kugelrohr distillation (225°C/0.2mm) followed by chromatography on silica gel (40-60 petroleum ether/ethyl acetate) to give a colourless oil (3.04g; 54%) b.
  • 2-Phenoxy-l-trifluoromethanesulphonylethane was prepared in an analogous manner from the corresponding alcohol.
  • Ethyl 4-(bromomethyl)benzoate 4-(Bromomethyl)benzoic acid (25.75g, 0.1197moles) was suspended in thionyl chloride (50ml) and dimethylformamide (0.25ml) was added. The mixture was heated under reflux for 25 minutes until clear, evaporated and azeotroped with toluene (x2).
  • Ethyl 4-(bromomethyl)benzoate ethyl 4-(chloromethyl)benzoate (25.0g, 0.11 lmoles) in dry dimethylformamide (150ml), cooled to 5°C, was treated with potassium thioacetate (13.3g, 0.117moles) and the temperature rose to 20°C. The reaction was stirred at room temperature for 2 hours, poured into water (250ml) and extracted with diethyl ether (3x100ml). The organic extracts were combined, washed with water, dried (MgSO4), charcoaled and evaporated to give ethyl 4- (acetylthiomethyl)benzoate as a brown soild (26.0g, 99%), m.p. 36-37°C.
  • Example 3 N-[6-(4-chlorophenylhexyl)]-2-[4*benzylsulphinyI-2-oxoazetidin-l- yI]propionamide (diastereoisomers bl &b2)
  • a solution of N-[6-(4-chlorophenylhexyl)]-2-[4-benzylthio-2-oxoazetidin-l- yl]propionamide (diastereoisomer b) (0.96 g, 0.0021 mol) in dichoromethane (25 ml) was cooled to -65 to -70°C and a solution of m-chloroperbenzoic acid (0.43 g, 0.0025 mol) in dichloromethane (10 ml) added dropwise over 15 min.
  • N-[6-(4-fluorophenylhexyl)]-2-[4-benzylthio-2-oxoazetidin-l-yl]propionamide (diastereoisomer b)
  • 6-(4-fluorophenyl)hexylamine (3.0 g, 0.0154 mol,), 1- hydroxybenzotriazole hydrate (2.08 g, 0.0154 mol), 2-(4-benzylthio-2-oxoazetidin-l- yl)-propionic acid (4.08 g, 0.0154 mol) and dicyclohexylcarbodiimide (3.17 g, 0.0154 mol) in dimethylformamide (60 ml) was stirred for 16 h at ambient temperature.
  • Example 19 N-(Benzyl)-2-[4-be ⁇ zylthio-2-oxoazetidin-l-yl]propiona ⁇ ide (diastereoisomer a) Treatment of 2-(4-benzylthio-2-oxoazetidin-l-yl)propionic acid (Example 10b) with benzylamine under the conditions described in Example 10c gave the title compound as the higher rf product after chromatography: 1.19 g, clear oil; *H NMR d (CDCI3) (selected diagnostic peaks) 4.27 (IH, q, a-H), 4.80 (IH, m, H4);
  • Example 20 N-(Benzyl)-2-[4-be ⁇ t-ylt 'o-2 ⁇ xoazetidin-l-yl]propionamide (diastereoisomer b) From the above chromatographic separation the lower rf fractions were combined to give the title compound as a colourless
  • Dicyclohexylcarbodiimide (4.75 g, 23 mmoles) in dry dimethylformamide (50 ml) was added dropwise to a cooled solution of 4-(4-(allyloxycarbonyl)benzylthio)-2- oxoazetidin-2-ylpropionic acid (8.0 g, 23 mmoles), 1-hydroxybenzotriazole hydrate (3.11 g, 23 mmoles) and 6-(4-fluorophenyl)hexylamine (4.5 g, 23 mmoles) in dry dimethylformamide (50 ml). Cooling was removed and the mixture was stirred overnight.
  • the dimethylformamide was evaporated and the residue was purified by flash chromatography (fine silica, t -butylmethyl ether then ethyl acetate) to provide samples which were predominantiy diastereoisomer a (4.6 g), diastereoisomer b (2.7 g) and mixed fractions.
  • Diastereoisomer a yellow oil, 4.6 g, 38% yield H NMR ⁇ (CDCI3) 1.23-1.63 (11H, m), 2.55 (2H, t), 2.81 (IH, dd, H 3a ), 3.20-3.30 (3H, m, CH 2 and H 3b ), 3.90 (2H, d), 4.04 (IH, q, N-CH), 4.78-4.84 (3H, m, CH 2 and H 4 ), 5.27-5.45 (2H, m), 5.95-6.09 (IH, m), 6.50 (IH, br.
  • Example 28 (+/-)-N-[6-(4-fluorophenylhexyI)]- 2-[4-(4- (carboxy)benzylsulphJnyl)-2-oxoazetidin-l-yl]propionamide (diastereoisomers b2+bl 3:2)
  • (+/-)-N-[6-(4-fluorophenylhexyl)]- 2-[4-(4-allyloxycarbonyl)- benzylsulphinyl)-2-oxoazetidin- 1 -yljpropionamide as the mixmre of diastereoisomers produced in Example 23 (b2+bl 3:2) (0.32 g) with triphenylphosphine (0.165 g), pyrrolidine (0.045 g) and tetrakis triphenylphosphinepalladium(0) (0.02 g) in dichloromethane (40 ml)
  • 6-(4-Fluorophenyl)hexylamine (1.59g, 0.00814moles) in dry DMF (75ml) was added to a mixture of 2-(4-benzylthio-2-oxoazetidin-l-yl)-3-(3-furyl)propionic acid (2.7g, 0.00814 moles), 1-hydroxybenzotriazole (l.lg, 0.008 Mmoles), l-cyclohexyl-3-(2- mo holinoethyl)carbodiimide metho-p-toluene sulfonate (3.5g, 0.00826moles) and the resulting solution was stirred at room temperature for 19h.
  • Example 30 (+/-)-N-[6-(4-Fluorophenyl)hexyl]-2-(4-benzylsulphinyl)-2- oxoazetidin-l-yl-3-(3-furyl)propionamide
  • a solution of (+/-)-N-[6-(4-fluorophenyl)hexyl]-2-(4-benzylthio)-2-oxoazetidin-l-yl-3- (3-furyl)propionamide 80% diastereoisomer b) (0.30g, 0.00256moles) in dichloromethane (25ml), cooled to -70°C, was treated with a solution of 3- chloroperoxy benzoic acid (0.80g, 0.00255moles) in dichloromethane (25ml) over 1 hour maintaining the temperature at -70°C.
  • reaction mixture was diluted with dichloromethane (50ml) and washed with 10% aq sodium sulphite solution, sodium hydrogen carbonate solution, water, dried (MgSO4), and evaporated to a colourless oil which contained a mixture of diastereoisomers bl+b2.
  • Example 31 N-[6-(4-Fluorophenyl)hexyI]-2-(4-benzylsulphinyI)-2-oxoazetidin-l- yI-3-(3-f uryl)propionamide (diastereoisomer a2)
  • a solution of N-[6-(4-fluorophenyl)hexyl]-2-(4-benzylthio)-2-oxoazetidin- 1 -yl-3-(3- furyl)propionamide 80% diastereoisomer a) (1.13g, 0.00222moles) in dichloromethane (25ml), cooled to -70°C, was treated with a solution of 3- chloroperoxy benzoic acid (0.70g, 0.00223moles) in dichloromethane (25ml) over 1 hour maintaining the temperature at -70°C.
  • reaction mixture was diluted with dichloromethane (50ml), washed with 10% aq sodium sulphite solution, sodium hydrogen carbonate solution, water, dried (MgSO4), and evaporated to a colourless oil which contained a mixture of diastereoisomers.
  • Methyl 2-(4-benzylthio-2-oxoazetidin-l-yl)-3-phenylpropionate A solution of methyl-(4-benzylthio-2-oxoazetidin-l-yl) acetate (2.03g, 0.00765moles) in dry tetrahydrofuran (40ml) at -75°C under nitrogen was treated with a 1M solution of lithium bis(trimethylsilyl)amide in hexanes (9.2ml, 0.0092moles) over 5 minutes keeping the temperature below -68°C.
  • l,3-Dimethylimidazolidin-2-one (5.0ml, 0.0457moles) was added keeping the temperature below -70°C.
  • the resulting suspension was stirred at -75°C for 30 minutes and then treated with a solution of benzyl bromide (2.36g, 0.0138moles ) over 5 minutes keeping the temperature below - 70°C.
  • the reaction was stirred for 1.5 hours during which time it reached -20°C.
  • the reaction was cooled to -75°C and quenched with glacial acetic acid (1.0ml), partititioned between brine (100ml) and ethyl acetate (100ml).
  • 6-(4-Fluorophenyl)hexylamine (0.76g, 0.00389moles) in dry DMF (40ml) was added to a mixture of 2-(4-benzylthio-2-oxoazetidin-l-yl)-3-phenylpropionic acid (1.33g, 0.00389moles), 1-hydroxybenzotriazole (0.52g, 0.00385moles), N,N'- dicyclohexylcarbodiimide (0.8g, 0.00388moles) and was stirred at room temperature for 4h. The suspension was diluted with ethyl acetate (100ml) and filtered to remove urea.
  • Example 39 (-)-N-[6-(4-Fluorophenyl)hexyl]-2-(4-benzylsulphinyl)-2- oxoazetidin-l-yl-3-phenylpropionamide (diastereoisomer (-)-b2)
  • the resulting suspension was stirred at -75°C for 30 minutes and then treated with allyl iodide (3.1ml, 0.0339moles) over 5 minutes .
  • the temperature rose to -65°C.
  • the reaction was stirred at -78°C for 30 minutes and then allowed to warm to -20°C over 30 minutes.
  • the reaction was cooled to -75°C and quenched with glacial acetic acid (5ml), partititioned between brine (150ml) and ethyl acetate (175ml).
  • the organic layer was washed with brine, dried (M SO4), and evaporated to a coloured oil.
  • 6-(4-Huorophenyl)hexylamine (2.5g, 0.0128moles) in dry DMF (75ml) was added to a mixture of 2-(4-benzylthio-2-oxoazetidin-l-yl 2-allylacetic acid (3.73g, 0.0128moles), 1-hydroxybenzotriazole (1.75g, 0.0129moles), l-cyclohexyl-3-(2- morpholinoethyl)carbodiimide metho-p-toluene sulfonate (5.42g, 0.0128moles) and was stirred at room temperature for 19h.
  • the suspension was partitioned between sodium hydogen carbonate solution (300ml) and diethyl ether (150ml). The layers were separated and the aqueous was washed with diethyl ether (100ml). The organic extracts were combined washed with water, dried (MgSO4), and evaporated to an oil (5.92g).
  • Example 42 (+/-)-N-[6-(4-Fluorophenyl)hexyl]-2-(4-benzylsulphinyl)-2- oxoazetidin-l-yl-2-allylacetamide (diastereoisomers a2+al)
  • Example 45 N-[6-(4-Fluorophenyl)hexyI]-2-[4-benzylsulphinyl-2-oxoazetidin-l- yljbutanamide.
  • Example 48 N-[6-(4-Fluorophenyl)hexyl]-2-[4-benzylsulphinyl-2-oxoazetidin-l- yl]butanamide (isomer a2)
  • the above procedure yielded 0.05g of the title compound as an oil
  • Example 53 N-(Be ⁇ _ ⁇ l)-2-[4-benzylsulp nyl-2 ⁇ xoazetidin-l-yl]propionanude (82% diastereoisomer a2) The mother liquors from the above recryatallisation were evaporated and recrystallised to give the title compound as predominantly the diastereoisomer a2, 0.67 g, m.p. 134- 5°C.
  • Example 54 R-Methyl-4-[(4-allyloxycarbonyI)benzylthio]-2-oxoazetidin-l- ylacetate a. (-)-(R)-4-(4-(Allyloxycarbonyl)benzylthio)-2-oxoazetidin-l-ylacetic acid 4-(4-(Allyloxycarbonyl)benzylthio)-2-oxoazetidin-l-ylacetic acid ( 3.41 g, 10.2 mmol) and cinchonidine (2.99 g, 10.2 mmol) in ethanol (40 ml) were heated to boiling when a clear solution was obtained.
  • reaction mixture was stirred for 30 minutes and a further 1.0ml of IN sodium hydroxide solution was added.
  • the reaction was stirred for 30 minutes, brine (75ml) was added and the reaction mixture was extracted with diethyl ether (75ml).
  • the aqueous was acidified with 2NHC1 and extracted with diethyl ether (2x75ml).
  • reaction mixture was treated with dichloromethane (50ml) and water (25ml) and acidified with 2NHC1.
  • Brine 75ml was added to the emulsion, the layers were separated and the aqueous was washed with dichloromethane (2x50ml).
  • Example 102 (+/-)-4-(P ⁇ rid-2-ylmethylsulphinyl)-l-(4-phenyl-2- oxobutyl)azetidin-2-one (diastereomer 1)
  • a solution of (+/-)-4-(pyrid-2-ylmethylthio)-l-(4-phenyl-2-oxobutyl)azetidin-2-one (2.4 g, 7 mmol) in dichlorometiiane (50 ml) was cooled to -60°C and a solution of m- chloroperoxybenzoic acid (1.46 g, 8.4 mmol) in dichloromethane (50 ml) was added dropwise.
  • Example 109 (+/-)-N-(6-Phenylhex-l-yl)-4-(2-furylmethylsulphinyI)-2- oxoazetidin-1-ylacetamide (diastereomer 1)
  • the synthesis was carried out as in example 102, using (+ -)-N-(6-phenylhex-l-yl)-4- (2-furylmethylthio)-2-oxoazetidin-l -ylacetamide (2.9 g, 7.2 mmol). Recrystallisation of the crude product from ethyl acetate gave a sample containing about 99% of diastereomer 1 (0.2 g), m.p. 160-161°C.
  • the mother liquors from example 109 were purified by chromatography (silica, 0-2% MeOH in CH 2 C1 2 ) and recrystallisation from ether/ethyl acetate to give a sample of diastereomer 2 containing 5% of diastereomer 1 (1.08 g), m.p. 61-62°C.
  • Example 120 (+/-)-N-(6-[4-Chlorophenyl]hex-l-yl)-4-(3-furylmethylthio)-2- oxoazetidin-1 -ylacetamide a) (+/-)-4-(3-Furylmethylthio)azetidin-2-one The synthesis was carried out as in example 101a, using 3-(acetylthiomethyl)furan (64 mmol) and 4-acetoxyazetidin-2-one (64 mmol). Cystallisation from ether/pet ether gave the tide compound (10 g), m.p. 60-61°C.
  • Example 122 (+/-)-N-(6-[4-Chlorophenyl]hex-l-yl)-4-(3-furylmethylsulphinyI)- 2-oxoazetidin-l -ylacetamide (diastereomer 2)
  • the mother liquors from example 121 were evaporated, triturated with ether, and recrystallised from ethyl acetate to give a sample containing 98% of diastereomer 2 (0.7 g), m.p. 95-96°C.
  • 1H NMR ⁇ (CDC1 3 ) 1.32-1.34 (4H, m), 1.50-1.60 (4H, m),
  • Example 123 (+/-)-N-(6-[4-Chlorophenyl]hex-l-yl)-4-(3-furylmethylsulphonyl)- 2-oxoazetidin- 1 -ylacetamide
  • the synthesis was carried out as in example 107, using N-(6-(4-chlorophenyl)hex-l- yl)-4-(3-futylmethylsulphinyl)-2-oxoa_Bt_din-l-ylacetamide. Trituration of the crude product with ether gave the title compound, m.p. 95-96°C.
  • Example 134 (+/-)-N-[6-(4-ChlorophenylhexyI)]-4-(t__iazol-2-ylmethylsulphinyl)- 2-oxoazetidin-l-ylacetamide (diastereomer 2)
  • the mother liquors from example 133 were concentrated and diluted with pet ether to induce crystallisation of a sample containing 94% of diastereomer 2 (0.49 g), m.p. 103- 104°C.
  • Example 135 (+/-)-N-[6-(4-ChlorophenylhexyI)]-4-(5-methoxycarbonyl-2- furylmethylthio)-2-oxoazetidin- 1-ylacetamide a) Methyl 5-(acetylthiomethyl)furan-5-carboxyIate A solution of potassium thioacetate (45.7 g, 0.4 mol) in dry DMF (100 ml) was added to an ice-cooled solution of methyl 5-(chloromethyl)furan-2-carboxylate (68 g, 0.39 mol) in dry DMF (300 ml).
  • Example 137 (+/-)-N-[6-(4-Chlorophenylhexyl)]-4-(5-methoxycarbonyl-2- furylmethylsulphinyl)-2-oxoazetidin-l-ylacetamide (diastereomer 2)
  • the mother liquors from example 136 were evaporated and recrystallised from ethyl acetate to give a sample of diastereomer 2 (1.5 g), m.p. 113-114°C. ⁇ NMR ⁇
  • Example 138 (+/-)-4-( 2-furylmethylthio)-l-(9-phenylnonyl)azetidin-2-one
  • a suspension of sodium hydride (3.65 mmol) in dry THF (10 ml) was cooled in ice/salt, and a solution of (+/-)-4-( 2-furylmethylthio)azetidin-2-one (0.61 g, 3.32 mmol) in THF (10 ml) was added dropwise below 5°C.
  • Example 139 (+/-)-4-( 2-furylme_hyls_dphinyl)-l-(9-phenylnonyl)azetidin-2-one
  • the synthesis was carried out as in example 102, using (+/-)-4-(2-furylmethylthio)-l- (9-phenylnonyl)azetidin-2-one (0.37 g, 0.97 mmol).
  • Chromatography (silica, 50-70% EtOAc in pet. ether) gave the title compound as an oil (0.28 g), containing about 63% of diastereomer 1, 37% of diastereomer 2.
  • Example 140 (+/-)-4-( 2-furylmethylthio)-H9-(4-fluorophenyl)nonyl)azetidin-2-one
  • the synthesis was carried out as in example 138, using (+/-)-4-( 2-furylmethyl- thio)azetidin-2-one (1.5 g, 8.2 mmol) and 9-(4-fluorophenyl)nonyl-l -triflate (2.9 g, 7.8 mmol).
  • Chromatography (silica, 10-25% EtOAc in pet. ether) gave the title compound as an oil (0.56 g).
  • Example 143 N-[6-(4-Fluorophenyl)hex-l-yl]-4-(5-allyloxycarbonylfuran-2- methylthio)-2-oxoazetidin-l-ylacetamide
  • a solution of 4-(5-allyloxycarbonylfuran-2-methyl)thioazetidin-2-one (4 g, 0.015 mol) and N-(4-fluorophenylhex-l-yl)bromoacetamide (4.73 g, 0.015 mol) in dry tetrahydrofuran (150 ml) was cooled to -30°C and a solution of potassium t-butoxide (1.85 g, 0.0165 mol) in dry tetrahydrofuran (80 ml) added dropwise over 15 min.
  • Example 145 N-[6-(4-Fluorophenyl)hex-l-yl]-4-(5-allyIoxycarbonylfuran-2- methylsulphinyl)-2-oxoazetidin-l-ylacetamide (Diastereomer 2)
  • Example 135b Treatment of 4-(5-methoxycarbonylfuran-2-methyl)thioazetidin-2-one (Example 135b) and N-(4-fluorophenylhex-l-yl)bromoacetamide in dry tetrahydrofuran with a solution of potassium t-butoxide in dry tetrahydrofuran at -30°C, followed by work-up as described for Example 143 gave the title compound as a pale yellow oil, 55% yield.
  • Example 153 N-[6-(4-FluorophenyI)hex-l-yl]-4-(5-methoxycarbonylfuran-2- methylsulphinyI)-2-oxoazetidin-l-ylacetamide (Diastereomer 2) White crystals, m.p. 100-2°C, 16% yield, v -_ ⁇ , 1795 cm' 1 . Found: C, 58.53; H, 5.90;
  • Example 202 N-[6-(4-Chlorophenyl)hexyl]-[4-(2-fluorophenoxy 2-oxo azetidin-1 yl) acetamide
  • 3-methyl-4-phenoxyazetidin-2-one was prepared from 3-methyl-4-acetoxyazetidin-2- one as described in Prep 1 above and subsequently treated with N-(6- phenylhexyl)bromoacetamide as for Example 201 to give the title compound as a pale yellow oil, 52.3% yield.
  • Example 220 4-Phenoxy-l-(4-phenyl-2-oxo-butyl)-azetidin-2-one 4-phenoxyazetidin-2-one (lg ,6.2mmol), l-bromo-2-oxo-4-phenylbutane (1.55g, 6.7mmol), TBAB (0.2g, 0.7mmol) and potassium hydroxide (0.4g,6.7mmol) were reacted as described above to give the title compound (0.65g, 31% yield) as a pale yellow solid, m.p. 59-60°C, after flash chromatography and recrystallisation from ether/n-hexane. Found: C, 73.0; H, 6.2; N, 4.6%.
  • Example 312 N-[6-(3-Chlorophenyl)hexyn-5-yl]-4-benzylsulphinyl-2-oxo- azetidin-1-yl acetamide
  • Example 314 N-[6-(2-Chlorophenyl)hexyn-5-yl]-4-benzylsulphinyl-2-oxo- azetidin-1-yl acetamide
  • Examples 329-331 were prepared in an analogous way, or were isolated from the mixture formed when the corresponding sulfides were treated with mCPBA.
  • Example 333 was prepared from 4-benzylthio-azetidin-2-one and die corresponding triflate in an analogous manner to Example 332.
  • Example 337-345 The following sulfoxides (Examples 337-345) were prepared by treating the corresponding sulfides with mCPBA, as described in Examples 302 & 303.
  • Example 337 l-(2-(6-Phenylhexyloxy)ethyl-4-benzylsulphinyl-2-oxoazetidine
  • Example 349 The recrystallisations of Example 349 also gave the title compound as a 68:32 mixture of diastereoisomers as a colourless solid, m.p. 53-55°C, 12.5%yield
  • Enzyme activity was determined by measuring the rate of turnover of the artificial substrate (A) at 37 °C in 50mM HEPES 0 I-2-hydroxyethylpiperazine-N-2- ethanesulphonic acid) buffer containing 150mM NaCl, pH 7.4.
  • Lp-PLA2 was partially purified by density gradient centrifugation of human plasma. Active fractions were pooled and used as the source of Lp-PLA2- The enzyme was pre-incubated at 37 °C with vehicle or test compound for 10 min in a total volume of 180 ⁇ l. The reaction was then initiated by the addition of 20 ⁇ l lOx substrate (A) to give a final substrate concentration of 20 ⁇ M. The reaction was followed at 405 nm for 20 minutes using a plate reader with automatic mixing. The rate of reaction was measured as the rate of change of absorbance.
  • the compounds according to the present invention are found to have IC50 values in the range 0.7-100,000 nM.

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  • Plural Heterocyclic Compounds (AREA)

Abstract

L'invention concerne les composés de l'azétidinone présentant la formule (I). Dans cette formule, R1 et R2 peuvent être identiques ou différents, et sont chacun sélectionnés parmi de l'hydrogène, de l'halogène ou de l'alkyle (C¿1-8?); R?4 et R5¿ peuvent être semblables ou différents et sont chacun sélectionnés parmi de l'hydrogène, de l'alkyle (C¿1-6?), de l'alcényle (C2-6), de l'aryle, de l'arylalkyle (C1-4) et de l'hétéroarylalkyle (C1-4), qui peuvent être tous éventuellement substitués, ou R?4 et R5¿ peuvent être liés ensemble pour former le reste d'un noyau de cycloalkyle (C¿3-7?); X est un groupe de liaison; Y est un groupe aryle éventuellement substitué; Z est de l'oxygène et R?3¿ est de l'alkyle (C¿1-8?), du cycloalkyle (C3-8), du cycloalkyle(C3-8)alkyle(C1-6), de l'hétéroaryle, de l'hétéroarylalkyle (C1-4), de l'aryle, ou de l'arylalkyle (C1-4) qui peuvent être tous éventuellement substitués, ou Z désigne à S(O)n où n vaut 0, 1 ou 2 et R?3¿ est de l'alkyle (C¿1-8?), du cycloalkyle (C3-8), du cycloalkyle (C3-8), de l'aryle, de l'alkyle (C1-4) d'aryle, de l'hétéroaryle, ou de l' hétéroarylalkyle (C1-4), qui peuvent tous être éventuellement substitués. Ces composés sont des inhibiteurs de l'enzyme Lp PLA2 et sont particulièrement utiles dans le traitement de l'athérosclérose.
EP96922030A 1995-07-01 1996-06-20 Derives de l'azetidinone pour le traitement de l'atherosclerose Withdrawn EP0840725A1 (fr)

Applications Claiming Priority (15)

Application Number Priority Date Filing Date Title
GB9513442 1995-07-01
GBGB9513442.5A GB9513442D0 (en) 1995-07-01 1995-07-01 Novel compounds
GB9515056 1995-07-22
GBGB9515056.1A GB9515056D0 (en) 1995-07-22 1995-07-22 Novel compounds
GBGB9515206.2A GB9515206D0 (en) 1995-07-25 1995-07-25 Novel compounds
GB9515206 1995-07-25
GB9516985 1995-08-18
GBGB9516985.0A GB9516985D0 (en) 1995-08-18 1995-08-18 Novel compounds
GB9525132 1995-12-08
GBGB9525132.8A GB9525132D0 (en) 1995-12-08 1995-12-08 Novel compounds
GB9608651 1996-04-26
GBGB9608650.9A GB9608650D0 (en) 1996-04-26 1996-04-26 Novel compounds
GB9608650 1996-04-26
GBGB9608651.7A GB9608651D0 (en) 1996-04-26 1996-04-26 Novel compounds
PCT/EP1996/002765 WO1997002242A1 (fr) 1995-07-01 1996-06-20 Derives de l'azetidinone pour le traitement de l'atherosclerose

Publications (1)

Publication Number Publication Date
EP0840725A1 true EP0840725A1 (fr) 1998-05-13

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
EP96922030A Withdrawn EP0840725A1 (fr) 1995-07-01 1996-06-20 Derives de l'azetidinone pour le traitement de l'atherosclerose

Country Status (23)

Country Link
EP (1) EP0840725A1 (fr)
JP (1) JP2002515852A (fr)
KR (1) KR19990028630A (fr)
CN (1) CN1197452A (fr)
AP (1) AP728A (fr)
AU (1) AU708032B2 (fr)
BG (1) BG102214A (fr)
BR (1) BR9609445A (fr)
CA (1) CA2225627A1 (fr)
CZ (1) CZ422197A3 (fr)
EA (1) EA199800109A1 (fr)
HU (1) HUP9901153A3 (fr)
IL (1) IL122650A0 (fr)
MA (1) MA23922A1 (fr)
MX (1) MX9800186A (fr)
NO (1) NO976158L (fr)
NZ (1) NZ311684A (fr)
OA (1) OA10648A (fr)
PE (1) PE8998A1 (fr)
PL (1) PL324240A1 (fr)
SK (1) SK178497A3 (fr)
TR (1) TR199701762T1 (fr)
WO (1) WO1997002242A1 (fr)

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JP2000502079A (ja) * 1995-12-08 2000-02-22 スミスクライン・ビーチャム・パブリック・リミテッド・カンパニー アテローム性動脈硬化症の治療のための単環β―ラクタム誘導体
GB9608649D0 (en) * 1996-04-26 1996-07-03 Smithkline Beecham Plc Novel compounds
HUP9901359A3 (en) * 1996-04-26 2000-03-28 Smithkline Beecham Plc Azetidinone derivatives for the treatment of atherosclerosis, process for their producing and pharmaceutical compositions containing them
AU3546601A (en) 2000-02-16 2001-08-27 Smithkline Beecham Plc Pyrimidine-4-one derivatives as LDL-PLA<sub>2</sub> inhibitors
GB0024808D0 (en) 2000-10-10 2000-11-22 Smithkline Beecham Plc Novel compounds
MX2009012197A (es) 2007-05-11 2010-01-15 Univ Pennsylvania Metodos para tratamiento de ulceras en la piel.
US8962633B2 (en) 2007-05-11 2015-02-24 Thomas Jefferson University Methods of treatment and prevention of metabolic bone diseases and disorders
EP2977452A3 (fr) 2007-05-11 2016-05-25 Thomas Jefferson University Procédés de traitement et de prévention de maladies et de troubles neurodégénératifs
MX2013006342A (es) 2010-12-06 2013-08-26 Glaxo Group Ltd Compuestos de pirimidinona para usarse en el tratamiento de enfermedades o afecciones mediadas por fosfolipasa asociada con lipoproteinas a2 (lp-pla2).
US20130267544A1 (en) 2010-12-17 2013-10-10 Peter Adamson Use of LP-PLA2 Inhibitors in the Treatment and Prevention of Eye Diseases
US20140171431A1 (en) 2011-06-27 2014-06-19 Jianhua Shen Azole heterocyclic compound, preparation method, pharmaceutical composition and use
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
EP2736908A1 (fr) 2011-07-27 2014-06-04 Glaxo Group Limited Composés pyrimidones bicycliques
CN105008365B (zh) 2013-01-25 2017-03-15 葛兰素史密斯克莱知识产权发展有限公司 化合物
SG11201505520WA (en) 2013-01-25 2015-08-28 Glaxosmithkline Ip Dev Ltd 2,3-DIHYDROIMIDAZOL[1,2-C]PYRIMIDIN-5(1H)-ONE BASED LIPOPROTEIN-ASSOCIATED PHOSPHOLIPASE A2 (LP-PLA<sb>2</sb>) INHIBITORS
EP2948456A4 (fr) 2013-01-25 2016-09-14 Glaxosmithkline Ip Dev Ltd 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
AU2020379796C1 (en) 2019-11-09 2024-05-02 Shanghai SIMR Biotechnology Co., Ltd Tricyclic dihydroimidazopyrimidone derivative, preparation method therefor, pharmaceutical composition and use thereof
CN115304620A (zh) 2021-05-07 2022-11-08 上海赛默罗生物科技有限公司 嘧啶酮衍生物、其制备方法、药物组合物和用途

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Also Published As

Publication number Publication date
NO976158D0 (no) 1997-12-30
MX9800186A (es) 1998-07-31
AU708032B2 (en) 1999-07-29
IL122650A0 (en) 1998-08-16
JP2002515852A (ja) 2002-05-28
NZ311684A (en) 2000-04-28
TR199701762T1 (xx) 1998-05-21
NO976158L (no) 1998-02-25
HUP9901153A3 (en) 1999-11-29
AP728A (en) 1999-01-29
BR9609445A (pt) 1999-04-06
AU6305096A (en) 1997-02-05
KR19990028630A (ko) 1999-04-15
SK178497A3 (en) 1998-07-08
BG102214A (en) 1998-08-31
WO1997002242A1 (fr) 1997-01-23
MA23922A1 (fr) 1996-12-31
PL324240A1 (en) 1998-05-11
OA10648A (en) 2002-09-25
CZ422197A3 (cs) 1998-06-17
CN1197452A (zh) 1998-10-28
CA2225627A1 (fr) 1997-01-23
PE8998A1 (es) 1998-03-20
HUP9901153A2 (hu) 1999-08-30
AP9701161A0 (en) 1998-01-31
EA199800109A1 (ru) 1998-10-29

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