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EP0869943A1 - Derives de beta-lactame monocycliques utilises dans le traitement de l'atherosclerose - Google Patents

Derives de beta-lactame monocycliques utilises dans le traitement de l'atherosclerose

Info

Publication number
EP0869943A1
EP0869943A1 EP96943110A EP96943110A EP0869943A1 EP 0869943 A1 EP0869943 A1 EP 0869943A1 EP 96943110 A EP96943110 A EP 96943110A EP 96943110 A EP96943110 A EP 96943110A EP 0869943 A1 EP0869943 A1 EP 0869943A1
Authority
EP
European Patent Office
Prior art keywords
alkyl
compound
oxoazetidin
formula
hydrogen
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Withdrawn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
EP96943110A
Other languages
German (de)
English (en)
Inventor
Deirdre M.B.- SmithKline Beecham Pharm. HICKEY
Dashyant-SmithKline Beecham Pharmaceutic. DHANAK
Robert John-SmithKline Beecham Pharmaceutic IFE
Colin Andrew SmithKline Beecham Pharmac. LEACH
David Graham SmithKline Beecham Pharmac. 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 GBGB9525131.0A external-priority patent/GB9525131D0/en
Priority claimed from GBGB9623756.5A external-priority patent/GB9623756D0/en
Application filed by SmithKline Beecham Ltd filed Critical SmithKline Beecham Ltd
Publication of EP0869943A1 publication Critical patent/EP0869943A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • 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
    • 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

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.
  • WO 95/00649 (SmithKline Beecham plc) describe the phospholipase A2 enzyme Lipoprotein Associated Phospholipase A 2 (Lp-PLA 2 ), the sequence, isolation and purification thereof, isolated nucleic acids encoding the enzyme, and recombinant host cells transformed with DNA encoding the enzyme. Suggested therapeutic uses for inhibitors of the enzyme included atherosclerosis, diabetes, rheumatoid arthritis, stroke, myocardial infarction, reperfusion injury and acute and chronic inflammation.
  • Lp-PLA 2 is responsible for the conversion of
  • phosphatidylcholine to lysophosphatidylcholine, during the conversion of low density lipoprotein (LDL) to its oxidised form.
  • LDL low density lipoprotein
  • the enzyme is known to hydrolyse the sn-2 ester of the oxidised phosphatidylcholine to give lysophosphatidylcholine and an oxidatively modified fatty acid.
  • Both products of Lp-PLA 2 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-PLA 2 enzyme would therefore be expected to stop the build up of these macrophage enriched lesions (by inhibition of the formation of lysophosphatidylcholine and oxidised free fatty acids) and so be useful in the treatment of atherosclerosis.
  • Lp-PLA 2 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-PLA 2 could therefore prove beneficial in the treatment of this phenomenon. An Lp-PLA 2 inhibitor could also find utility in other disease states that exhibit endothelial dysfunction including diabetes, hypertension, angina pectoris and after ischaemia and reperfusion. In addition, Lp-PLA 2 inhibitors may also have a general application in any disorder that involves activated monocytes, macrophages or lymphocytes, as all of these cell types express Lp-PLA 2 . Examples of such disorders include psoriasis.
  • Lp-PLA 2 inhibitors may also have a general application in any disorder that involves lipid peroxidation in conjunction with Lp-PLA 2 activity to produce the two injurious products, lysophosphatidylcholine and oxidatively modified fatty acids.
  • Such conditions include the aforementioned conditions atherosclerosis, diabetes, rheumatoid arthritis, stroke, myocardial infarction, reperfusion injury and acute and chronic inflammation. Further such conditions include various neuropsychiatric disorders such as schizophrenia (see Psychopharmacology Bulletin, 31, 159-165, 1995).
  • EP96/02765 (SmithKline Beecham pic) describe a series of azetidinone derivatives which are inhibitors of Lp PLA2.
  • Compounds disclosed therein having a terminal carboxyl substituent at C4 were found to have good activity in in vitro assays of Lp-PLA2 activity. It was however found that, in in vivo animal models, the activity of these carboxyl compounds when given orally was compromised by a poor pharmacokinetic profile. This problem was not overcome by using the simple alkyl or alkenyl ester derivatives also disclosed therein. It has been found that this problem may be overcome by using more sophisticated ester derivatives as 'pro-drugs'.
  • R 1 and R 2 which may be the same or different, is each selected from hydrogen, halogen or C( 1 -8 )alkyl;
  • R 3 is a pharmaceutically acceptable in vivo hydrolysable ester
  • R 4 and R 5 which may be the same or different is each selected from hydrogen
  • X is a linker group
  • Y is an optionally substituted aryl group
  • Z 1 is O and Z 2 is C ( 1-8) alkyl, aryl C ( 1-4) alkyl or aryl each of which may be optionally substituted, or Z 1 is S(O) n in which n is 0, 1 or 2 and Z 2 is C ( 1 -8) alkyl, C (3-8) cycloalkyl,
  • R 4 and R 5 is each hydrogen, Z 1 is S(O) n in which n is 0, 1 or 2 and Z 2 is
  • R 3 is C (1-6 )alkyl or C (2-6) alkenyl.
  • Compounds of formula (I) are inhibitors of Lp-PLA 2 and as such are expected to be of use in treating atherosclerosis and the other disease conditions noted elsewhere. Such compounds are found to act as inhibitors of Lp-PLA 2 in in vitro assays and have an improved pharmacokinetic profile in in vivo assays.
  • R 1 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 trans-methyl).
  • R 1 and R 2 is each hydrogen.
  • Suitable pharmaceutically acceptable in vivo hydrolysable ester groups for incorporation in R 3 include those which break down readily in the human body to leave the parent acid or its salt.
  • R 3 examples of suitable values for R 3 include:
  • R a is hydrogen, (C 1 -6 )alkyl, in particular methyl, (C 3-7 )cycloalkyl, or phenyl, each of which may be optionally substituted;
  • R b is (C 1-6 )alkyl, (C 1 -6 )alkoxy(C 1 -6 )alkyl, phenyl, benzyl, (C 3-7 )cycloalkyl,
  • R a and R b together form a 1,2-phenylene group optionally substituted by one or two methoxy groups;
  • R c is (C 1 -6 )alkyl, (C 3-7 )cycloalkyl, (C 1 -6 )alkyl(C 3-7 )cycloalkyl;
  • R d is (C 1 -6 )alkylene optionally substituted with a methyl or ethyl group
  • R e and R f which may be the same or different is each (C 1 -6 )alkyl; or aryl(C 1 -4 ) alkyl, optionally substituted with e.g. hydroxy;
  • R g is (C 1-6 )alkyl
  • R h is hydrogen, (C 1 -6 )alkyl or phenyl
  • R i is hydrogen or phenyl optionally substituted by up to three groups selected from halogen, (C 1 -6 )-alkyl, or (C 1 -6 )alkoxy;
  • Y 1 is oxygen or NH
  • pivaloyloxymethyl benzoyloxymethyl, ⁇ -acetoxyethyl, ⁇ -pivaloyloxyethyl,
  • alkoxy/cycloalkoxycarbonyloxyalkyl groups such as ethoxycarbonyloxymethyl, t-butyloxycarbonyloxymethyl, cyclohexyloxycarbonyloxymethyl, 1-methylcyclohexyloxycarbonyloxymethyl and ⁇ -ethoxycarbonyloxyethyl;
  • dialkylaminoalkyl especially di-loweralkylamino alkyl groups such as
  • dimethylaminomethyl dimethylaminoethyl, diethylaminomethyl or diethylaminoethyl;
  • lactone groups such as phthalidyl and dimethoxyphthalidyl
  • R 3 Representative examples of R 3 include:
  • Representative examples of a (C 3-7 )cycloalkyl ring include cyclopropyl.
  • R 4 and R 5 are both hydrogen or R 4 is hydrogen and R 5 methyl.
  • X is:
  • A-B in which A is a direct bond or X' and B is a C ( 1 -12) alkylene chain interupted and/or terminated at the end remote from A by one or more groups M selected from O, S(O) n , NR 6 , alkene or alkyne in which R 6 is hydrogen or C (1-6) alkyl and n is 0,
  • X include CO(CH 2 ) m , CONH(CH 2 ) m , COO(CH 2 ) m ,
  • CONHCO(CH 2 ) m CONHO(CH 2 ) m and C ( 1 _12) alkylene.
  • X' is CO or CONR 6 , more preferably CONH.
  • m is 1 , 2, 5, 6, 7 or 9, preferably 6.
  • X is CONH(CH 2 ) 6 .
  • A'(CH 2 ) a CH CH(CH 2 ) b , A'(CH 2 ) a C ⁇ C(CH 2 ) b or A'(CH 2 ) a (O) c (CH 2 ) b (O) d in which
  • A' is a direct bond or CONR 6 , a is an integer from 1 to 12, b is 0 or an integer from 1 to 12 such that a+b ⁇ 12, suitably ⁇ 6, c is 0 or 1 and d is 1 or c is 1 and d is 0, with the proviso that if c and d are both 1, then b ⁇ 1.
  • Y is a benzene ring, optionally substituted by up to three further substituents.
  • Suitable substituents include halo, hydroxy, C (1-8) alkyl and C (1-8) alkoxy.
  • Y is phenyl optionally substituted by halo, preferably fluoro or chloro, preferably at the 4-position.
  • C (1-8) alkyl for Z 2 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 Z 2 , in addition to CO 2 R 3 , include halo and hydroxy.
  • arylC (1-4) alkyl for Z 2 include arylC (1-3) alkyl, preferably arylCH 2 .
  • Representative examples of the aryl group include phenyl and naphthyl, preferably phenyl. Suitable examples include benzyl, 2-phenylethyl and
  • Suitable extra substituents include halo, hydroxy, C (1-6) alkyl, C (1 -6) alkoxy, arylC (1-6) alkoxy, (C 1 -6 )alkylthio,
  • (C 1 -6 )alkylsulphinyl, and (C 1 -6 )alkylsulphonyl Representative examples of aryl for Z 2 include phenyl and naphthyl. Preferably, the aryl group is optionally substitued phenyl. Suitable substituents for a phenyl or naphthyl ring, in addition to CO 2 R 3 , include halo, hydroxy, C (1-6) alkyl, C (1-6) alkoxy, arylC (1 -6) alkoxy, (C 1 -6 )alkylthio, (C 1-6 )alkylsulphinyl, and (C 1 -6 )alkylsulphonyl.
  • heteroaryl group for incorporation into Z 2 include pyridyl, pyridyl N-oxide, furanyl, thienyi and thiazolyl.
  • the heteroarylalkyl group is heteroarylC ( 1 -3) alkyl, more suitably heteroarylmethyl.
  • Preferred values include optionally substitued pyridylmethyl, furanylmethyl, thienylmethyl or thiazolylmethyl.
  • Suitable substituents for a heteroaryl ring, in addition to CO 2 R 3 include halo, hydroxy, C ( 1-6) alkyl, C ( 1-6) alkoxy.
  • n is 1 or 2, more preferably 1.
  • Z 1 is SO and Z 2 is arylmethyl or heteroarylmethyl, in particular benzyl or furanylmethyl, especially furan-2-ylmethyl.
  • Z 1 Z 2 CO 2 R 3 Preferred values of Z 1 Z 2 CO 2 R 3 include:
  • 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 1 is SO.
  • the present invention encompasses all such stereoisomers.
  • a further chiral centre will be introduced when R 4 and R 5 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
  • Representative compounds of formula (I) include:
  • compounds of formula (I) are prodrugs of N-(6-[4-fluorophenyl]hex-1-yl)-4-(4-carboxybenzylsulphinyl)-2-oxoazetidin-1-yl)acetamide.
  • the preparation of this is described as Example 166 of WO 96/19451 (SmithKline Beecham plc).
  • Particularly preferred compounds of formula (I) are prodrugs of (4R,SS) N-(6-[4-fluorophenyl]hex-1-yl)-4-(4-carboxybenzylsulphinyl)-2-oxoazetidin-1-yl)acetamide; in particular a compound selected from:
  • 'alkyl' and similar terms such as 'alkoxy' includes all straight chain and branched isomers. Representative examples thereof include methyl, ethyl, n-propyl, iso-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 1 -6 )alkoxycarbonyl, carbamoyl, mono- or di-(C 1 -6 )alkylcarbamoyl, sulpho, sulphamoyl, mono- or di-(C 1 -6 )alkylsulphamoyl, amino, mono- or di-(C 1 -6 )alkylamino, acylamino, ureido, (C 1 -6 )alkoxycarbonylamino, 2,2,2-trichloroethoxycarbonylamino, aryl, heterocyclyl, hydroxy, (C 1 -6 )alkoxy, acyloxy, oxo, acyl, 2-thienoyl, (C 1 -6 )alkylthio, (C 1 -6 )alkylsulphinyl,
  • '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, (C 1 -6 )alkyl, (C 3-7 )cycloalkyl, (C 1 -6 )alkoxy, halo(C 1 -6 )alkyl, hydroxy, amino, mono- or di-(C 1 -6 )alkylamino, acylamino, nitro, carboxy,
  • 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.
  • 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 A 2 (Lp-PLA 2 ) and as such are expected to be of use in therapy, in particular in the treatment of atherosclerosis.
  • the present invention provides a compound of formula (I) for use in therapy.
  • the compounds of formula (I) are inhibitors of lysophosphatidylcholine production by Lp-PLA 2 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.
  • 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 to the compounds of the present invention.
  • the compounds of the present invention are usually provided.
  • 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) include magnesium stearate, starch, lactose, sucrose and cellulose.
  • a composition in the form of a capsule can be prepared using routine
  • 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.
  • suitable pharmaceutical carrier(s) for example aqueous gums, celluloses, silicates or oils
  • Typical parenteral compositions consist of a solution or suspension of the compound of formula (I) in a sterile aqueous carrier or parenterally acceptable oil, for example polyethylene glycol, 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.
  • dosage unit for oral administration contains preferably from 1 to 500 mg (and for parenteral administration contains preferably from 0.1 to 25 mg) of a compound of the formula (I).
  • the daily dosage regimen for an adult patient may be, for example, an oral dose of between 1 mg and 1000 mg, preferably between 1 mg and 500 mg, or an intravenous, subcutaneous, or intramuscular dose of between 0.1 mg and 100 mg, preferably between 0.1 mg and 25 mg, of the compound of the formula (I), the compound being administered 1 to 4 times per day.
  • the compounds will be administered for a period of continuous therapy, for example for a week or more.
  • R 7 is a reactive esterifying leaving group
  • R 3 is as hereinbefore defined
  • Suitable ester forming conditions are well known in the art and are described in, for instance, Comprehensive Organic Synthesis, Pergamon Press, 1991, 6, 323-380. Suitable ester forming conditions include:
  • triethylamine in an aprotic solvent such as tetrahydrofuran, at a moderate temperature, preferably in the range -20 to +20°C, or alternatively, in the absence of a base but using a preformed salt of the alcohol, for instance the magnesium or lithium alkoxide.
  • aprotic solvent such as tetrahydrofuran
  • Preferred conditions include the use of the sodium salt of the acid of formula (II) in combination with a halide or sulphonate derivative of the compound of formula (III).
  • This may be prepared by analogy with processes previously described in WO 96/19451 02765 (SmithKline Beecham plc).
  • a key step is the resolution of the early stage intermediate of formula (IV):
  • R* is carboxy protecting group, for instance a C (1-6) alkyl or C (2-6) alkenyl; via the formation of a diastereoisomeric salt with a chiral base such as (-)-cinchonidine.
  • the preferred diastereoisomeric salt may be obtained by fractional crystallisation and the enantiomeric free acid regenerated therefrom by acidification. This may be then converted through to a compound of formula (II) by analogy with processes hereinbefore described.
  • the free acid may be regenerated from a corresponding compound in which the carboxy group is protected as a C (1-6) alkyl or C (2-6) alkenyl ester; using methods well known in the art for the particular protecting group, for instance, when an allyl group, using palladium catalysed de-allylation (triphenylphosphine/ pyrrolidine/ tetrakis triphenyl-phosphinepalladium(O) in
  • Chloromethyl chloroformate is treated with cyclohexanol in dichloromethane/pyridine as generally described in the reference: Y. Yoshimura et al., J. Antibiot., 1987, 40(1), 81-90. Subsequent conversion of the chlorides to the iodides is a simple "Finkelstein reaction" well known to those skilled in the art.
  • triphenylphosphinepalladium(0) was added and after a further 4 h the reaction was complete.
  • the solution was diluted with water, acidified (2N HCl), the layers separated and the aqueous layer further extracted with dichloromethane.
  • the combined extracts were dried (MgSO 4 )and evaporated to a yellow oil, which was triturated with ether. A yellow solid was obtained which was filtered off and dissolved in sodium hydrogen carbonate solution. Shaking with ether gave an emulsion which was separated by treatment with ethyl acetate and centrifugation.
  • the aqueous layer was then acidified (2N HCl) and extracted with dichloromethane, and the extracts dried (MgSO 4 )and evaporated.
  • 6-(4-Fluorophenyl)hexylamine (1.82g, 0.00932moles) in dry dimethylformamide (75ml) was added to a mixture of 4R,SS -(4-(4-ethoxycarbonyl)benzylsulphinyl-2-oxoazetidin-1- ylacetic acid (3.15g, 0.00928moles), N,N,-dicyclohexylcarbodiimide (1.92g,
  • 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-PLA 2 was partially purified by density gradient centrifugation of human plasma. Active fractions were pooled and used as the source of Lp-PLA 2 .
  • the enzyme was preincubated 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 10x 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.
  • Acid production - % conversion of test ester to parent acid by dog or liver microsomes after incubation of 1 ⁇ m test compound for 15 min, determined by measuring the concentration of parent acid produced by HPLC detection of acid (100% 1 ⁇ M acid produced). Figures are rounded to nearest 5%.
  • Preferred compounds are those exhibiting good conversion of ester to acid in biological systems, while showing good stability in buffers (e.g. examples 3, 5, 6, 9, 10).

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Abstract

On décrit des composés de la formule (I), lesquels sont des promédicaments des composés correspondants où CO2R<3> représente CO2H. Ces composés sont des inhibiteurs de la phospholipase A2 associée aux lipoprotéines, ou Lp-PLA2, et sont utiles pour traiter l'athérosclérose.
EP96943110A 1995-12-08 1996-12-04 Derives de beta-lactame monocycliques utilises dans le traitement de l'atherosclerose Withdrawn EP0869943A1 (fr)

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GB9525131 1995-12-08
GBGB9525131.0A GB9525131D0 (en) 1995-12-08 1995-12-08 Novel compounds
GB9623756 1996-11-15
GBGB9623756.5A GB9623756D0 (en) 1996-11-15 1996-11-15 Novel compounds
PCT/EP1996/005587 WO1997021675A1 (fr) 1995-12-08 1996-12-04 Derives de beta-lactame monocycliques utilises dans le traitement de l'atherosclerose

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BRPI0108396B1 (pt) * 2000-02-16 2015-05-19 Smithkline Beecham Plc Derivados de pirimidina-4-ona como inibidores de ldl-pla2
JP5437996B2 (ja) 2007-05-11 2014-03-12 ザ トラスティーズ オブ ザ ユニバーシティ オブ ペンシルバニア 皮膚潰瘍の治療方法
JP5277243B2 (ja) 2007-05-11 2013-08-28 トーマス・ジェファーソン・ユニバーシティ 神経変性疾患および障害を治療および阻止する方法
CN103347864B (zh) 2010-12-06 2016-08-10 葛兰素集团有限公司 用于治疗由Lp-PLA2介导的疾病或病症的嘧啶酮化合物
ES2847883T3 (es) 2010-12-17 2021-08-04 Glaxo Group Ltd Uso de inhibidores de LP-PLA2 en el tratamiento y prevención de enfermedades oculares
US20130030012A1 (en) 2011-07-27 2013-01-31 Glaxo Group Limited Compounds
JP2014521611A (ja) 2011-07-27 2014-08-28 グラクソ グループ リミテッド Ｌｐ−ＰＬＡ２阻害剤としての２，３−ジヒドロイミダゾ［１，２−ｃ］ピリミジン−５（１Ｈ）−オン化合物の使用
AU2012311050A1 (en) * 2011-09-21 2014-03-06 Stem Cell Medicine Ltd. Beta-lactam compounds for treating diabetes
BR112014004454A2 (pt) 2011-09-21 2017-03-28 Stem Cell Medicine Ltd compostos beta-lactâmicos para aumentar respostas imunes mediadas por células t
KR20150108896A (ko) 2013-01-25 2015-09-30 글락소스미스클라인 인털렉츄얼 프로퍼티 디벨로프먼트 리미티드 Lp-pla2의 억제제로서의 비시클릭 피리미돈 화합물
US9296755B2 (en) 2013-01-25 2016-03-29 Glaxosmithkline Intellectual Property Development Limited 3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one compounds and their therapeutic applications
MX2015009633A (es) 2013-01-25 2015-11-30 Glaxosmithkline Ip Dev Ltd Inhibidores de fosfolipasa a2 asociada con lipoproteinas basados en 2,3-dihidroimidazol[1,2-c] pirimidin-5(1h)-ona.
WO2016012916A1 (fr) 2014-07-22 2016-01-28 Glaxosmithkline Intellectual Property Development Limited Dérivés 1,2,3,5-tétrahydro-imidazo [1,2-c]pyrimidine utiles pour le traitement de maladies et de troubles médiés par la lp-pla2
WO2016012917A1 (fr) 2014-07-22 2016-01-28 Glaxosmithkline Intellectual Property Development Limited Dérivés 1,2,3,5-tétrahydro-imidazo [1,2-c]pyrimidine utiles pour le traitement de maladies et de troubles médiés par la lp-pla2
HUE056433T2 (hu) * 2016-04-08 2022-02-28 Adaptimmune Ltd T-sejt receptorok
CN112778331B (zh) 2019-11-09 2022-07-05 上海赛默罗生物科技有限公司 三环二氢咪唑并嘧啶酮衍生物、其制备方法、药物组合物和用途
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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