Classifications

• • 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
• • 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
  • 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
  • A61P25/04—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
  • A61P39/00—General protective or antinoxious agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P39/00—General protective or antinoxious agents
  • A61P39/06—Free radical scavengers or antioxidants
• • 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
• • 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
  • 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

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 (Lp-PLA2) - also previously known as Platelet Activating Factor Acetyl Hydrolase (PAF acetyl hydrolase) - 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- PLA? action are biologically active with lysophosphatidylcholine, a component of oxidised LDL.
• 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 ofthe formation of lysophosphatidylcholine and oxidised free fatty acids) and so be useful in the treatment of atherosclerosis.
• Lp-PLA2 The increased lysophosphatidylcholine content of oxidatively modified LDL is also thought to be responsible for the endothelial dysfunction observed in patients with atherosclerosis. Inhibitors of Lp-PLA? 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 lipid peroxidation in conjunction with Lp-PLA2 activity to produce the two injurious products, lysophosphatidylcholine and oxidatively modified fatty acids.
• Such conditions include atherosclerosis and diabetes along with other conditions such as rheumatoid arthritis, stroke, inflammatory conditions of the brain such as Alzheimer's Disease, myocardial infarction, reperfusion injury, restenosis. acute and chronic inflammation and sepsis.
• 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-PLA2- Examples of such disorders include psoriasis.
• Patent applications WO 96/13484, WO96/19451 and WO 97/02242 disclose inter alia various series of 4-thionyl/sulf ⁇ nyl/sulfonyl azetidinone compounds characterised by the general formula (A):
• R a and R D which may be the same or different, is each selected from hydrogen, halogen or optionally substituted
• R c is C ⁇ _8)alkyl, C(3_g)cycloalkyl, C(3-8)cycloalkylC ⁇ _6)alkyl, aryl, aryl(C i .4)alkyl. heteroaryl, or heteroaryl(C ⁇ _4)alkyl each of which may be optionally substituted
• R and R e which may be the same or different is each selected from hydrogen
• C(i _6)alkyl C(2-6) a lkenyl, aryl. aryl(C j.4)alkyl and heteroaryl(C ⁇ _4)alkyl each of which may be optionally substituted or R ⁇ and R e may be linked together to form the remainder of a (C3_7)cycloalkyl ⁇ ng;
• X is a linker group, in partcular a group X'(CH2) m in which X' is CO, CONR 2 , COO,
• R 2 is hydrogen or Cn .g ⁇ alkyl and m is 0 or an integer from 1 to 12; or a C(j.i2) a ⁇ ylene chain optionally interupted by X', oxygen or a carbon-carbon double or triple bond; Y is an optionally substituted aryl group; and n is 0, 1 or 2.
• Such compounds of formula (A) are inhibitors of Lp-PLA2 and as such are expected to be of use in treating atherosclerosis and the other disease conditions noted above.
• Rl and R 2 which may be the same or different, is each selected from hydrogen, halogen or C ⁇ _g ⁇ alkyl;
• R is C(i_8)alkyl.
• R 4 and R5 which may be the same or different is each selected from hydrogen, C(j_ 6)alkyl.
• Y is an optionally substituted aryl group; and n is 0, ! or 2.
• R ⁇ and R 2 include hydrogen, bromo. methyl and ethyl.
• R 1 and R 2 is each hydrogen or one of Rl and R 2 is hydrogen and the other of R ⁇ and R 2 is methyl (to give a trans-methyl).
• R and R 2 is each hydrogen.
• Representative values for R ⁇ include arylC ⁇ _3 ⁇ alkyl. Within R ⁇ , representative examples ofthe aryl group include phenyl and naphthyl.
• R ⁇ examples include benzyl, 2-pheny lethy 1 and 3-phenylpropyl in each of which the phenyl ring may be optionally substituted by up to three substituents.
• Suitable substituents for a phenyi or naphthyl ring in R include halo, hydroxy, C(i_6)alkyl, C( 1 _6)alkoxy, C( 1 _6)alkoxycarbonyl, C(2-6)aikenyloxycarbonyl. carboxy and pharmaceutically acceptable salts and in vivo hydrolysable esters thereof.
• aryl group for when R ⁇ is aryl 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, Cr ⁇ . 6)alkoxy, C( ⁇ ⁇ alkoxycarbonyl, C(2-6) a lkenyloxycarbonyl, carboxy and pharmaceutically acceptable salts and in vivo hydrolysable esters thereof.
• R ⁇ when R ⁇ is C ⁇ _g)alkyl is C ⁇ _g)alkyl.
• C ⁇ _g)cycloalkyl or C(3_g)cycloalkylC(]_6)alkyl include methyl, n-butyl, t-butyl and n-hexyl, cyclohexyl and cyclohexyi methyl, suitably n-butyl, t-butyl or n-hexyl.
• Suitable substituents for the alkyl or cycloalkyl group in R3 include halo, hydroxy, C ⁇ _g)alkoxycarbonyl,
• R 3 include heteroarylC ⁇ _3)alkyl, preferably heteroarylmethyl.
• Representative examples ofthe heteroarylaryl group for use in R ⁇ include pyridyl, pyridyl N-oxide, furanyl, thienyl and thiazolyl.
• Suitable substituents for a heteroaryl ring in R ⁇ include halo, hydroxy, C ⁇ _6)alkyl, C(i_ C(i_6)alkoxycarbonyl, C(2-6)alkenyloxycarbonyl, carboxy and pharmaceutically acceptable salts and in vivo hydrolysable esters thereof. It will be appreciated that within R ⁇ , an optional substituent may be located in the alkyl, cycloalkyl. aryl and/or heteroaryl portion.
• R ⁇ is arylC(i_3)alkyl or heteroarylC ⁇ _3)alkyl. More preferably ary'C(i_3)alkyl.
• n is 1 or 2, more preferably 1.
• S(O) n R J is optionally substitued benzylsuiphinyl, more preferably
• R 4 is hydrogen and R ⁇ is methyi or R ⁇ and R ⁇ is each hydrogen.
• A is CFbO or CONH.
• Suitable examples of X include CONH(CH 2 )5CO and CH 2 0(CH 2 )5CO.
• Y is a benzene ring, optionally substituted by up to three further substituents.
• Suitable substituents include halo, hydroxy, C ⁇ and
• 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 ⁇ and R 3 are not the same. This will give rise to the existence of extra stereoisomers.
• the present invention encompasses all such stereoisomers.
• m compounds of formula (I) in which n is 1, that is sulphoxide compounds the presence of the SO moiety will introduce an additional chiral centre into the molecule and therefore 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, «-propyl, /JO- propyl, /i-butyl, .yec-butyl, /yo-butyl, t-butyl. «-pentyl and Ai-hexyl.
• Suitable substituents for an alkyl group include, for example, halogen, cyano, azido, nitro. carboxy, (C ⁇ _6)alkoxycarbonyI, carbamoyl, mono- or di-(C i _6)alkylcarbamoyl, sulpho, sulphamoyl, mono- or di-(C ⁇ _g)alkylsulphamoyl, amino, mono- or di-(C] . ⁇ alkylamino, acylamino, ureido. (C ⁇ _6)alkoxycarbonylamino, 2,2,2-trichloroethoxycarbonylamino. aryl, heterocyclyl.
• Suitable substituents for an aryl group include, for example, halogen, cyano, (C ⁇ -6)alkyl, (C3-7)cycloalkyl, (C j -6)alkoxy, halo(Cj-6)alkyl, hydroxy, amino, mono- or di-(C ⁇ -6)alkylamino. acy lamino, nitro. carboxy, (Cj-6)alkoxycarbonyl, (C i -6)alkenyloxycarbonyl. (C ⁇ -g)alkoxycarbonyl(C ⁇ -g)alkyl,
• the term 'heteroaryl' includes single and fused rings, each ⁇ ng 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. Suitabie fused heteroaryl rings include bicyclic systems.
• the term '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.
• Suitable pharmaceutically acceptable in vivo hydrolysable ester groups for inco ⁇ oration in R J include those which break down readily in the human body to leave the parent acid or its salt.
• ester forming radical for use in vivo hydrolysable esters include:
• R a is hydrogen, (C ⁇ alkyl, in particular methyl, (C3-7)cycloalkyI, or phenyl, each of which may be optionally substituted;
• R b is (C ⁇ -6)alkyl, (C ⁇ -g)alkoxy(C ⁇ -6)alkyl, phenyl, benzyl, (C3-7)cycloalkyl,
• R a and Rh together form a 1,2-phenylene group optionally substituted by one or two methoxy groups
• R c is (C ⁇ -(5)alkyl, (C 3 -7)cycloalkyl, (C ⁇ lkyl ⁇ cycloalkyl;
• Rd is (Cj-6)alkylene optionally substituted with a methyl or ethyl group; R e and Rf which may be the same or different is each (C ⁇ -6)alkyl; or aryl(C 1-4) alkyl, optionally substituted with e.g. hydroxy;
• Rg is (C ⁇ -6)alkyl
• R n is hydrogen, (C ⁇ - ⁇ )alkyl or phenyl
• R 1 is hydrogen or phenyl optionally substituted by up to three groups selected from halogen, (C ⁇ -6)-alkyl, or (C ⁇ -6)alkoxy; and is oxygen or NH.
• ester forming radical Suitable values include:
• acyloxyalkyl groups such as acetoxymethyl, isobutyryloxymethyl, 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
• (f) (5-methyl-2-oxo-l,3-dioxolen-4-yl)methyl
• the compounds ofthe 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 ofthe compounds of formula (I) may be used for preparing the more pure forms used in the pharmaceutical compositions.
• the purity of intermediate compounds ofthe 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 ofthe 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 ofthe present invention are inhibitors ofthe enzyme lipoprotein associated phospholipase A2 (Lp-PLA2) and as such are expected to be of use in therapy, in particular in the treatment of atherosclerosis.
• the present invention provides a compound of formula (I) for use in therapy.
• the compounds of formula (I) are inhibitors of lysophosphatidylcholine production by Lp-PLA2 and may therefore also have a general application in any disorder that involves endothelial dysfunction, for example atherosclerosis, diabetes, hypertension, angina pectoris and after ischaemia and reperfusion.
• compounds of formula (I) may have a general application in any disorder that involves lipid 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 ofthe brain such as Alzheimer's
• 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-PLA2, for example psoriasis.
• 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 cf 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 ofthe 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 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.
• 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, ofthe 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
• X* con-esponds to X as hereinbefore defined, except that the ketone group is present in a protected form, preferably as a ketal;
• Y is as hereinbefore defined; 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; followed, if appropriate, by the steps of:
• 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 5 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 hexamethyldisiiazide, in a suitable alkylating solvent such as tetrahydrofuran (THF), end at a temperature in the range -80 to 10°C.
• a suitable base such as sodium hydride, potassium hydroxide or lithium hexamethyldisiiazide
• THF tetrahydrofuran
• n 1 or 2
• a suitable oxidising agent such as m-chloroperbenzoic acid.
• chiral oxidising agents such as (+)- or (-)-l,l'-bi-2-naphthol / titanium /jopropoxide (N Komatsu et al, J Org Chem, 1993, 58, 7624-7626) can give diastereoisomeric selectivity, if not chirally pure compounds.
• oxidation of sulfide is carried out as a final step, prior to deprotecting the ketone group.
• Compounds of formula (III) may be readily prepared by adapting known synthetic procedures, according to the specific value of X.
• a suitable compound of formula (III) may be prepared by treating an amine NH2(CH2)sC[O]Ph in which [O] indicates a protecting group, for instance ketal, with 2-bromoacetic acid, or a suitable activated derivative thereof, under standard amide forming conditions.
• 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 (C 1.7) alkanoate ester, under alkylating conditions as hereinbefore described; followed by the hydrolysis ofthe thus formed intermediate ester using standard conditions.
• a second alkyl group may be introduced by alkylating of the first formed monoalkyl ester.
• 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 COOB may be prepared by treating a compound of formula (IV) with an alcohol YBOH or an activated derivative thereof, for instance a tosylate.
• acetylthioazetidinone by treatment with silver nitrate and a base in a suitable solvent such as methanol.
• Ethyl 4-(bromomethyl)benzoate ethyl 4-(chloromethyl)benzoate (25. Og, 0.1 1 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).
• 1- hydroxybenzotriazole ( 1.08g) and 4-benzylthio-2-oxoazetidin-l-yl acetic acid (2.15g) (ref. WO 96/19451) in dry dimethyl formamide (30ml) was stirred at room temperature for 19 hours.
• the resulting suspension was diluted with diethyl ether and washed with dilute NaHCO3 (50ml).
• Enzyme activity was determined by measuring the rate of turnover of the artificial substrate (A) at 37 °C in 50mM HEPES (N-2-hydroxyethylpi ⁇ erazine-N'-2- ethanesulphonic acid) buffer containing 150mM NaCl, pH 7.4.
• HEPES N-2-hydroxyethylpi ⁇ erazine-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 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 nM range.

Landscapes

• Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Life Sciences & Earth Sciences (AREA)
• Veterinary Medicine (AREA)
• Chemical Kinetics & Catalysis (AREA)
• General Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Pharmacology & Pharmacy (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Engineering & Computer Science (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Diabetes (AREA)
• Pain & Pain Management (AREA)
• Hematology (AREA)
• Toxicology (AREA)
• Physical Education & Sports Medicine (AREA)
• Dermatology (AREA)
• Rheumatology (AREA)
• Obesity (AREA)
• Neurology (AREA)
• Emergency Medicine (AREA)
• Endocrinology (AREA)
• Cardiology (AREA)
• Neurosurgery (AREA)
• Biochemistry (AREA)
• Biomedical Technology (AREA)
• Immunology (AREA)
• Orthopedic Medicine & Surgery (AREA)
• Heart & Thoracic Surgery (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Applications Claiming Priority (3)

Publications (1)

Family

ID=10792682

Family Applications (1)

Country Status (4)

Families Citing this family (19)

Family Cites Families (4)

• 1996
  • 1996-04-26 GB GBGB9608649.1A patent/GB9608649D0/en active Pending
• 1997
  • 1997-04-28 JP JP9538603A patent/JP2000509063A/ja active Pending
  • 1997-04-28 WO PCT/EP1997/002286 patent/WO1997041099A1/en not_active Application Discontinuation
  • 1997-04-28 EP EP97921853A patent/EP0900199A1/de not_active Withdrawn

Non-Patent Citations (1)

Also Published As

Similar Documents

Legal Events