EP0865429A1 - Composes azetidinone destines au traitement de l'atherosclerose - Google Patents

Composes azetidinone destines au traitement de l'atherosclerose

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Publication number
EP0865429A1
EP0865429A1 EP96942375A EP96942375A EP0865429A1 EP 0865429 A1 EP0865429 A1 EP 0865429A1 EP 96942375 A EP96942375 A EP 96942375A EP 96942375 A EP96942375 A EP 96942375A EP 0865429 A1 EP0865429 A1 EP 0865429A1
Authority
EP
European Patent Office
Prior art keywords
oxoazetidin
alkyl
compound
formula
pyridyl
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Withdrawn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
EP96942375A
Other languages
German (de)
English (en)
Inventor
Deirdre Mary Bernadette Hickey
Dashyant Dhanak
Robert John Ife
Colin Andrew Leach
David Graham 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 GBGB9525149.2A external-priority patent/GB9525149D0/en
Priority claimed from GBGB9525150.0A external-priority patent/GB9525150D0/en
Priority claimed from GBGB9525148.4A external-priority patent/GB9525148D0/en
Application filed by SmithKline Beecham Ltd filed Critical SmithKline Beecham Ltd
Publication of EP0865429A1 publication Critical patent/EP0865429A1/fr
Withdrawn legal-status Critical Current

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    • 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
    • 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
    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • 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
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • 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
    • 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
    • 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
    • C07D205/09—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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen 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 invenuon relates to certain novel monocyclic ⁇ -lactam compounds, processes for their preparation, intermediates useful in their preparation, pharmaceuucal compositions containing them and their use in therapy, in parucular in the treatment of atherosclerosis.
  • WO 95/00649 (SmithKline Beecham pic) describe the phospholipase A2 enzyme Lipoprotein Associated Phospholipase A2 (Lp-PLA2), the sequence, isolation and purificauon thereof, isolated nucleic acids encoding the enzyme, and recombinant host cells transformed with DNA encoding the enzyme.
  • Lp-PLA2 Lipoprotein Associated Phospholipase A2
  • Suggested therapeuuc uses for mhibitors of the enzyme mcluded atherosclerosis, diabetes, rheumatoid arthritis, stroke, myocardial infarcuon, reperfusion injury and acute and chronic inflammation.
  • a subsequent publicauon from the same group further describes this enzyme (Tew D et al, Arte ⁇ oscler Thromb Vas Biol 1996:16:591-9) wherein it is referred to as LDL-PLA2.
  • LDL-PLA2 A later patent applicauon (WO 95/09921, Icos Co orauon) and a related publicauon in Nature (Tjoelker et al, vol 374, 6 April 1995, 549) describe the enzyme PAF-AH which has essentially the same sequence as Lp-PLA2 and suggest that it may have potential as a therapuetic protein for regulating pathological inflammatory events.
  • Lp-PLA2 is responsible for the conversion of phosphaudylcholine to lysophosphatidylcholine, during the conversion of low density lipoprotein (LDL) to its oxidised form.
  • the enzyme is known to hydrolyse the sn-2 ester of the oxidised phosphaudylcholine to give lysophosphatidylcholine and an oxidauvely modified fatty acid.
  • Both products of Lp-PLA2 acuon are biologically acuve with lysophosphatidylcholine, a component of oxidised LDL, known to be a potent chemoattractant for cuculaung monocytes.
  • lysophosphaudylchohne is thought play a significant role in atherosclerosis by being responsible for the - accumulauon of cells loaded with cholesterol ester in the arteries. Inhibiuon of the Lp-PLA2 enzyme would therefore be expected to stop the build up of these macrophage enriched lesions (by inhibiuon of the formauon of lysophosphatidylcholine and oxidised free fatty acids) and so be useful in the treatment of atherosclerosis.
  • Lp-PLA2 The increased lysophosphatidylcholine content of oxidauvely modified LDL is also thought to be responsible for the endothelial dysfuncuon observed in pauents with atherosclerosis. Inhibitors of Lp-PLA2 could therefore prove beneficial in the treatment of this phenomenon. An Lp-PLA2 inhibitor could also find utility in other disease states that exhibit endothelial dysfuncuon including diabetes, hypertension, angina pecto ⁇ s and after ischaemia and reperfusion. In addition, Lp-PLA2 inhibitors may also have a general applicauon in any disorder that involves acuvated monocytes, macrophages or lymphocytes, as all of these cell types express Lp-PLA 2 . Examples of such disorders include psoriasis.
  • Lp-PLA2 inhibitors may also have a general application in any disorder that involves lipid peroxidation in conjunction with Lp-PLA2 activity to produce the two injurious products, lysophosphatidylcholine and oxidatively modified fatty acids.
  • Such conditions include the aforementioned conditions atherosclerosis, diabetes, rheumatoid arthritis, stroke, myocardial infarction, reperfusion injury and acute and chronic inflammation. Further such conditions include various neuropsychiauic disorders such as schizophrenia (see Psychopharmacology Bulletin, 31, 159-165, 1995).
  • R ⁇ is CR ⁇ -X- i -Y 1 , CR R5- ⁇ 2- ⁇ 2 f or (CH 2 )pX 3 (CH 2 ) q Y 3 ;
  • Rl and R 2 which may be the same or different, is each selected from hydrogen, halogen or C(i_8)alkyl; R 4 and R- ⁇ which may be the same or different is each selected from hydrogen and
  • C(i_6)alkyl, or R 4 and R 5 may be linked together to form the residue of a C(3_7) cycloalkyl ring;
  • X 1 is a linker group and Y 1 is optionally substituted t. ⁇ alkyl C(2-i2)*"""kenyl.
  • X 3 is a heteroaryl group and Y 3 is an optionally substituted aryl group, p is an integer from 1 to 6, q is 0 or an an integer from 1 to 6;
  • Z is O and R 3 is C(i Vietnamese8)alkyl, arylC( ⁇ _4)alkyl or aryl each of which may be opuonally 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, arylC( i _4)alkyl or heteroarylC(i _4)alkyl each of which may be optionally substituted.
  • Compounds of formula (I) are inhibitors of Lp-PLA2 and as such are expected to be of use in treating atherosclerosis and the other disease conditions noted elsewhere.
  • R* and R 2 include hydrogen, bromo, methyl and ethyl.
  • R 1 and R 2 is each hydrogen or one of R 1 and R 2 is hydrogen and the other of R 1 and R 2 is methyl (to give a tra/w-methyl).
  • R 1 and R 2 is each hydrogen.
  • C(i_g)alkyl for R 3 include methyl, n-butyl, t- butyl and n-hexyl, cyclohexyl and cyclohexylmethyl, suitably methyl, n-butyl, t-butyl or n-hexyl.
  • Suitable substituents for the alkyl or cycloalkyl group include halo, hydroxy and carboxy and esters thereof.
  • Representative examples of arylC(j,_4)alkyl for R 3 include arylC(i _3)alkyl, preferably arylCH2-
  • Representative examples of the aryl group include phenyl and naphthyl, preferably phenyl.
  • Suitable examples include benzyl, 2-phenylethyl and 3-phenylpropyl in each of which the phenyl ring may be optionally substituted by up to two substituents.
  • Suitable substituents include halo, hydroxy, C(i_6)alkyl, C(i_6)alkoxy, arylC(i_6)alkoxy, carboxy and esters thereof, (C ⁇ alkylthio, (C ⁇ _6)alkylsulphinyl, and (Ci ⁇ alkylsulphonyl.
  • aryl for R 3 include phenyl and naphthyl.
  • the aryl group is optionally substitued phenyl.
  • Suitable substituents for a phenyl or naphthyl ring include halo, hydroxy, C(i_6)alkyl, C(i_6)alkoxy, arylC(i_6)alkoxy, carboxy and esters thereof, (C ⁇ -6)alkylthio, (C i _6)alkylsulphinyl, and (C ⁇ _6)alkylsulphonyl.
  • heteroaryl group for inco ⁇ oration into R 3 ⁇ include include pyridyl, pyridyl N-oxide, furanyl, thienyl and thiazolyl.
  • the heteroarylalkyi group is heteroarylC(i_3)alkyl, more suitably heteroarylmethyl.
  • Preferred values include optionally substitued pyridylmethyl, furanylmethyl, thienylmethyl or thiazolylmethyl.
  • Suitable substituents for a heteroaryl ring include halo, hydroxy, C(i_6)alkyl, C(i_6)alkoxy, arylC(i _6)alkoxy, carboxy and esters thereof, (C ⁇ -6)alkylthio, (C ⁇ _6)alkylsulphiny ⁇ and (C ⁇ _6)alkylsulphonyl.
  • Z is S(O)n
  • n is 1 or 2, more preferably 1.
  • Z is SO and R 3 is arylmethyl or heteroarylmethyl, in particular benzyl or furanylmethyl, especially benzyl.
  • Suitable esters for inco ⁇ ora ⁇ on into R 3 include pharmaceutically acceptable esters of the formula CO2 . Such esters may be active in their own right and /or be hydrolysable under in vivo conditions in the human body. Suitable pharmaceutically acceptable in vivo hydrolysable ester groups for inco ⁇ oration in R include those which break down readily in the human body to leave the parent acid or its salt.
  • suitable values for R include for instance, methyl, ethyl and propyl, (C2"6)alkenyl, for instance allyl. Further examples of suitable values for R include:
  • R a is hydrogen, (C ⁇ -6)alkyl, in particular methyl, (C3-7)cycloalkyl, or phenyl;
  • R D is (C ⁇ -6)alkyl, (C 1 - 6 )alkoxy(C ⁇ -6)alkyl, phenyl, benzyl, (C3- 7 )cycloalkyl,
  • R a and R* 5 together form a 1,2-phenylene group optionally substituted by one or two methoxy groups;
  • R c is (C ⁇ -6)alkyl, (C3-7)cycloalkyl, (C ⁇ -6)alkyl(C3- 7 )cycloalkyl;
  • R ⁇ * is (C ⁇ -6)alkylene optionally substituted with a methyl or ethyl group
  • R e and Rf which may be the same or different is each (C j -gjalkyl or aryl (C 1 -4) alkyl, optionally substituted with e.g. hydroxy;
  • RS is (C-[- 6 )alkyl
  • R n is hydrogen, (C ⁇ -g)alkyl or phenyl
  • Ri is hydrogen or phenyl optionally substituted by up to three groups selected from halogen, (Cj. -6)-alkyl, or (C ⁇ -6)alkoxy;
  • Y 4 is oxygen or NH; for instance:
  • acyloxyalkyl groups such as acetoxymethyl, isobutyryloxymethyl, pivaloyloxymethyl, benzoyloxymethyl, ⁇ -acetoxyethyl, ⁇ -pivaloyloxyethyl, l-(cyclohexylcarbonyloxy)ethyl, and (l-aminoethyl)carbonyloxymethyl;
  • alkoxy/cycloalkoxycarbonyloxyalkyl groups such as ethoxycarbonyloxymethyl, cyclohexyloxycarbonyloxymethyl and ⁇ -ethoxycarbonyloxyethyl
  • dialkylaminoalkyl especially di-loweralkylamino alkyl groups such as dimethylaminomethyl, dimethylaminoethyl, diethyiaminomethyl or diethylaminoethyl;
  • lactone groups such as phthalidyl and dimethoxyphthalidyl
  • R 4 and R- ⁇ when an alkyl group include methyl.
  • Representative examples of a (C3_7)cycloalkyl ring include cyclopropyl.
  • R 4 and R- ⁇ are both hydrogen or R 4 is hydrogen and R- ⁇ methyl.
  • X 4 is CONH.
  • x is 0.
  • X 1 is CONH.
  • Y * * the alkyl chain is unbranched.
  • Useful such values of Y** include C(6-io) alkyl. preferably C(g_ ⁇ o) alkyl or C(3_7)cycloalkylC(5_7) alkyl, preferably cyclohexylC(5_7)alkyl.
  • Representative examples of ⁇ l include nonyl and cyclohexylhexyl.
  • X 2 is:
  • X 2 include CO(CH2) y , CONH(CH2) y , COO(CH 2 ) y , CONHCO(CH 2 ) y , CONHO(CH 2 ) y and C ( 1 . 12 )alkylene.
  • X 3 is CO or CONR 6 , more preferably CONH.
  • y is 1, 2, 5, 6, 7 or 9, preferably 6.
  • X 2 is CONH(CH 2 )6-
  • heteroaryl rings for inco ⁇ oration into Y 2 include pyridyl and pyridyl N-oxide.
  • Suitable substituents for a heteroaryl ring include halo, hydroxy, CQ _g)alkyl and C(i_g)alkoxy.
  • Y 2 is 2-pyridyl or 4- pyridyl, preferably in combination with ⁇ l being CONH(CH2)6-
  • X 3 include thiazolyl and oxazolyl, in particular
  • p is 1.
  • Representative examples of aryl rings for inco ⁇ oration into Y 3 include phenyl and naphthyl. Suitable substituents for the aryl ring include halo, hydroxy, C(i_g ) alkyl and C ( i_g ) alkoxy.
  • Y 3 is phenyl.
  • Representative examples of X 3 - Y 3 include:
  • R° is CH 2 CONH ⁇ l in which Y 1 is C(g_ ⁇ o) alkyl or cyclohexylC(5_7)alkyl, in particular nonyl or cyclohexylhexyl.
  • 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 in compounds of formula (I) in which z is SO.
  • the present invention encompasses all such stereoisomers.
  • a further 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, w ⁇ -propyl, n-butyl, sec-butyl, iso-butyl, t-butyl, n-pentyl and n-hexyl.
  • Suitable substituents for an alkyl group include, for example, and unless otherwise defined, halogen, cyano, azido, nitro, carboxy, (C ⁇ _6)alkoxycarbonyl, carbamoyl, mono- or di-(C ⁇ _6)alkylcarbamoyl, sulpho, sulphamoyl, mono- or di-(C ⁇ .
  • 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, and unless otherwise defined, halogen, cyano, (Ci ⁇ alkyl, (C3-7)cycloalkyI, (C ⁇ -6)alkoxy, halo(C ⁇ -6)alkyl, hydroxy, amino, mono- or di-(C ⁇ -6)alkylamino, acylamino, nitro, carboxy, (C ⁇ -6)alkoxycarbonyl, (Ci -gjalkenyloxycarbonyl, (C ⁇ -6)alkoxycarbonyl(C ⁇ -6)alkyl, carboxy(C ⁇ -6)alkyl, (Ci- ⁇ alkylcarbonyloxy, carboxy(C ⁇ -6)alkyloxy, (Ci- ⁇ t ⁇ lJcoxycarbonyKC i - ⁇
  • 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.
  • 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-(Nonyl)-(4-benzylsulphinyl-2-oxoazetidin-l-yl)acetamide (Diastereoisomer 2); and N-(Nonyl)-(4-benzylsulphonyl-2-oxoazetidin- l-yl)acetamide.
  • Preferred compounds of formula (I) in which, in R ⁇ , Y 2 is heteroaryl include:
  • Preferred compounds of formula (I) in which R° is (CH2)pX 3 (CH2)nY 3 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 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 polymo ⁇ hic forms of crystalline products.
  • This invention includes within its scope all polymo ⁇ hic forms of the compounds of formula (I).
  • Compounds of the present invention are inhibitors of the enzyme lipoprotein associated phospholipase A (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 A
  • 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 neuropsychiauic 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 j . Examples of such disorders include psoriasis.
  • the present invention provides for a method of treating a disease state associated with activity of the enzyme Lp-PLA 2 which method involves treating a patient in need thereof with a therapeutically effective amount of an inhibitor of the enzyme.
  • the disease state may be associated with the increased involvement of monocytes, macrophages or lymphocytes; with the formation of lysophosphatidylcholine and oxidised free fatty acids; with lipid peroxidation in conjunction with Lp PLA2 activity; or with endothelial dysfunction.
  • Compounds of the present invention may also be of use in treating the above mentioned disease states in combination with anti-hyperlipidaemic or anti- atherosclerotic or anti-diabetic or anti-anginal or anti-inflammatory or anti- hypertension agents.
  • examples of the above include cholesterol synthesis inhibitors such as statins, anti-oxidants such as probucol, insulin sensitisers, calcium channel antagonists, and anti-inflammatory drugs such as NSAIDs.
  • the compounds of the present invention are usually administered in a standard pharmaceutical composition.
  • the present invention therefore provides, in a further aspect, a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable carrier.
  • Suitable pharmaceutical compositions include those which are adapted for oral or parenteral administration or as a suppository.
  • 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 car ⁇ ier(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 car ⁇ ier(s) for example, ethanol, glycerine, non-aqueous solvent, for example polyethylene glycol, oils, or water with a suspending agent, preservative, flavouring or colouring agent.
  • suitable pharmaceutical carrier(s) routinely used for preparing solid formulations. Examples of such carriers include magnesium stearate, starch, lactose, sucrose and cellulose.
  • a composition in the form of a capsule can be prepared using routine encapsulation procedures.
  • 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.
  • tiie 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.
  • 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 (1).
  • 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 rag and 500 mg, or an intravenous, subcutaneous, or intramuscular dose of between 0.1 mg and 100 mg, preferably between 0.1 mg and 25 mg, of the compound of the formula (I). the compound being administered 1 to 4 times per day. Suitably the compounds will be administered for a period of continuous therapy, for example for a week or more.
  • Compounds of formula (I) may be prepared by adapting processes previously described for ananlogous compounds in International patent applications WO 96/13484, WO 96/19451 and PCT EP96/02765 (SmithKline Beecham pic). Such processes include treating an azeti (II):
  • Rl, R 2 , R 3 , and Z are as hereinbefore defined; with an alkylating agent of the formula (HI):
  • R ⁇ is as hereinbefore defined; under alkylating conditions.
  • Suitable alkylating conditions are well known in the art and include carrying out the reaction in the presence of a suitable base such as sodium hydride or potassium hydroxide optionally with a quaternary ammonium salt such tetrabutyl ammonium bromide, in a suitable alkylating solvent such as tetrahydrofuran (THF), and at a temperature in the range - 10 to 0°C.
  • a suitable base such as sodium hydride or potassium hydroxide optionally with a quaternary ammonium salt such tetrabutyl ammonium bromide
  • THF tetrahydrofuran
  • the preceding alkyiation reaction is conveniently effected on compounds in which n is 0.
  • Compounds of formula (I) in which one of R 4 and R ⁇ is alkyl may also be prepared from corresponding compounds of formula (I) where both R 4 and R-> are hydrogen by treatment thereof with an alkylating agent under the conditions described above. Such compounds may be obtained by treating a compound of formula (LT) with an alkylating agent of formula (HI) in which both of R 4 and R 5 is hydrogen, under alkylating conditions as hereinbefore described.
  • a second alkyl group for R 4 /R*5 may be introduced by treating a first obtained compound of formula (I) in which one of R 4 and R 5 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-phenylsulfonylazetidinone with a phenol alcohol HOR 3 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.
  • Compounds of formula (IV) in which Z is S may be obtained by treating 4-acetoxyazetidinone with a thiol HSR 3 in the presence of a base such as sodium ethoxide, in a suitable solvent such as ethanol at a temperature in the range 0 to 5°C.
  • CONR O may be of the formula (IV):
  • a similar process may be used for preparing a compound of formula (I) in which X 2 denotes a group CONR 6 (CH 2 ) y or CONR 6 O(CH 2 ) y , but using an amine NHR 6 (CH 2 ) y Y 1 or a hydroxylamine NH 2 O(CH2) y ⁇ !.
  • An acid of formula (IV) in which one of R 4 and R 5 is hydrogen may be obtained by treating a compound of formula (II) with a corresponding 2-bromo (C1.7) alkanoate ester, under alkylating conditions as hereinbefore described; followed by the hydrolysis of the thus formed intermediate ester using standard conditions.
  • a second alkyl group may be inu-oduced by alkylating of the first formed monoalkyl ester.
  • R 7 is methyl; and x, R 1 , R ⁇ R ⁇ R", R 5 and Z 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-bromoalkanoate, under alkylating conditions as hereinbefore described.
  • (CH2) x COO in which x is an integer from 1 to 6 may be prepared by treating a compound of formula (IV) in which R 7 is hydrogen with an alcohol ⁇ ⁇ H or an activated derivative thereof, for instance a tosylate.
  • R** is a halogen or other suitable leaving group such as triflate or tosylate and R 1 , R 2 , R 3 , R 4 , R 5 , x and Z are as hereinbefore defined; with an alcohol ⁇ ⁇ H or a suitable salt therof.
  • compounds of formula (I) in which Z is S(O)n and n is 0 may be prepared by a process which comprises treating a compound of formula (DC):
  • Chirally pure compounds may be prepared by chiral chromatography, from chirally pure intermediates or by chiral synthesis using chiral reagents or catalysis.
  • 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:
  • Sodamide (6.63g) was suspended in Uquid ammonia (100ml) and cooled in a cardice/acetone bath. 4-Picoline (7.3ml) was added, the cooling bath removed and the mixture stirred at reflux for 2hrs. The mixture was cooled again and 5- bromopentylamine hydrobromide (18.53g) added and the mixture allowed to reflux for 5 hrs. The mixture was again cooled, quenched with ammonium chloride (lOg) and the solvent allowed to evaporate overnight. The residue was dissolved in water (100ml), made strongly alkaline with NaOH and extracted with CH,C1 2 (2x100ml).
  • N-(6-Cyclohexylhexyl)-4-benzylthio-2-oxoazetidin- 1 -ylacetamide (2.76g) was dissolved in dichloromethane (60ml), cooled to -60°C and a solution of 55-60% m- chloroperbenzoic acid (mCPBA) (1.84g;ca 6.62mM) in dichloromethane (80ml) was added dropwise over 15 mins, then the mixture was stirred at 20°C for 3 hours. The solution was washed with aq. NaHCO/Na.SO 3 , water, dried over MgSO, and evaporated to a colourless solid. This was recrystallised three times from EtOAc (cooling to 20°C only) to give the title compound as a colourless solid m.p. 150- PC, (735mg. 26%).
  • mCPBA m- chloroperbenzoic acid
  • Example 3 N-(6-Cyclohexylhexyl)-(4-benzyIsulphinyI-2-oxoazetidin-l- yl)acetamide (Diastereoisomer 2)
  • the mother liquors from the first two recrystallisations in Example 2 above were combined and evaporated to a solid which was recrystallised from EtOAc, cooling to RT and filtering to remove the first formed solid, then refrigerating to obtain a solid which was recrystallised again from EtOAc to give the title compound as a colourless solid, m.p.
  • N-(6-Cyclohexylhexyl)-(4-benzylsulphinyl-2-oxoazetidin- 1 -yl)acetamide (0.95g) was dissolved in dichloromethane (40ml), a solution of 55-60% mCPBA (0.83g) in dichloromethane (40ml) was added and stirred at 20°C for 1.5 hours. The solution was washed with aq NaHCOJNa j SO 3 and brine, dried over MgSO 4 and evaporated to a solid.
  • N-(6-(4-pyridyl)hexyl)-4-benzylthio-2-oxoazetidin- l-ylacetamide (3.04g) was dissolved in CH 2 Cl 2 (50ml), cooled to -60°C and a solution of 55-60% m- chloroperbenzoic acid (mCPB A) (2.11 g) in CH 2 C1 2 ( 100ml) was added dropwise over 15 mins. The solution was stirred at 20-25°C for 3 hrs then washed with aq NaHCO j /Na j SO j , brine, dried over MgSO 4 and evaporated to a sticky solid.
  • mCPB A m- chloroperbenzoic acid
  • Example 12 The mother liquor from the above recrystallisation in Example 12 was evaporated to a solid which was recrystallised twice from ethyl acatate to give the title compound as a colourless solid, m.p. 109-10°C, (1.41g, 46% yield)
  • N-(6-(4-Pyridyl)hexyl)-4-benzy lsulphinyl-2-oxoazetidin- 1 -ylacetamide (Dia 1 ) (1.15g) was dissolved in CH 2 Cl 2 (50ml) and a solution of 55-60% CPBA(1.10g;ca 3.5mM) in CH 2 Cl 2 (50ml) added and stirred at 20-25°C for 3hrs and allowed to stand at 20-25°C for 16 h. mCPBA (0.13g) was added and the solution stirred for a further 3 hrs then washed with aq NaHCO/Na-SO,, brine, dried over MgSO 4 and evaporated to an oil.
  • Example 22 l-(4-(5-Phenylpentyl)thiazoI-2-ylmethyl)-4-benzylsulphinyl-2- oxoazetidine (Dia l:Dia 2 22:78) 1 -(4-(5-phenylpentyl)thiazol-2-ylmethyl)-4-benzylthio-2-oxoazetidine (1.1 equiv) was dissolved in CH 2 Cl 2 (50ml), cooled to -60°C and a solution of 55-60% m- chloroperbenzoic acid (mCPBA) (2.1 lg) in CH 2 Cl 2 (100ml) was added dropwise over 15 mins.
  • mCPBA m- chloroperbenzoic acid
  • 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
  • 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 rain 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.
  • Example 3 The compounds of Example 3, 7, 8, 13, 18 and 22 had IC50 values in the range 5 to

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Abstract

On décrit des composés azétidinone de la formule (I) dans laquelle, entre autres, R0 représente CR?4R5-X1-Y1¿ ou (CH¿2?)pX?2(CH¿2)qY?2, R4 et R5¿ qui peuvent être semblables ou différents représentent chacun hydrogène ou alkyle C¿1-6?, ou bien R?4 et R5¿ peuvent être liés ensemble afin de former le reste d'un noyau cycloalkyle C¿3-7, X?1 représente un groupe de liaison et Y1 représente alkyle C¿1-12?-alcényle C2-12, alcynyle C2-12, cycloalkyle C3-7-alkyle C1-8, éventuellement substitués, ou un groupe hétéroaryle éventuellement substitué, X?2¿ représente un groupe hétéroaryle, Y2 représente un groupe aryle éventuellement substitué, p est un nombre entier compris entre 1 et 6, et q vaut 0 ou est un nombre entier compris entre 1 et 6. Ces composés sont des inhibiteurs de la phospholipase A2 enzyme, ou Lp-PLA2, et ils sont utiles en thérapie, par exemple pour traiter l'athérosclérose.
EP96942375A 1995-12-08 1996-12-04 Composes azetidinone destines au traitement de l'atherosclerose Withdrawn EP0865429A1 (fr)

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GBGB9525149.2A GB9525149D0 (en) 1995-12-08 1995-12-08 Novel compounds
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GBGB9525150.0A GB9525150D0 (en) 1995-12-08 1995-12-08 Novel compounds
GB9525148 1995-12-08
GBGB9525148.4A GB9525148D0 (en) 1995-12-08 1995-12-08 Novel compounds
PCT/EP1996/005588 WO1997021676A1 (fr) 1995-12-08 1996-12-04 Composes azetidinone destines au traitement de l'atherosclerose

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BR112015017768A2 (pt) 2013-01-25 2017-07-11 Glaxosmithkline Ip Dev Ltd compostos
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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
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