WO1997041098A1 - Azetidinone derivatives for the treatment of atherosclerosis - Google Patents
Azetidinone derivatives for the treatment of atherosclerosis Download PDFInfo
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- WO1997041098A1 WO1997041098A1 PCT/EP1997/001898 EP9701898W WO9741098A1 WO 1997041098 A1 WO1997041098 A1 WO 1997041098A1 EP 9701898 W EP9701898 W EP 9701898W WO 9741098 A1 WO9741098 A1 WO 9741098A1
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- oxoazetidin
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- compound
- fluorophenyl
- alkyl
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- 0 *C(C1)NC1=C Chemical compound *C(C1)NC1=C 0.000 description 3
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- 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
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- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
- C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
- 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 pic) describe the phospholipase A2 enzyme Lipoprotein Associated Phospholipase A2 (Lp-PLA2). 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. A subsequent publication from the same group further describes this enzyme (Tew D et al, Arterioscler Thromb Vas Biol 1996:16;591- 9) wherein it is referred to as LDL-PLA2.
- LDL-PLA2 Lipoprotein Associated Phospholipase A2
- Lp-PLA2 is responsible for the conversion of phosphatidylcholine to lysophosphatidylcholine, during the conversion of low density lipoprotein (LDL) to its oxidised form.
- the enzyme is known to hydrolyse the sn-2 ester of the oxidised phosphatidylcholine to give lysophosphatidylcholine and an oxidatively modified fatty acid.
- Both products of Lp-PLA2 action are biologically active with lysophosphatidylcholine, a component of oxidised LDL, known to be a potent chemoattractant for circulating monocytes.
- lysophosphatidylcholine is thought play a significant role in atherosclerosis by being responsible for the accumulation of cells loaded with cholesterol ester in the arteries. Inhibition of the Lp-PLA2 enzyme would therefore be expected to stop the build up of these macrophage enriched lesions (by inhibition of the formation of lysophosphatidylcholine and oxidised free fatty acids) and so be useful in the treatment of atherosclerosis.
- 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-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 dysfunction including diabetes, hypertension, angina pectoris and after ischaemia and reperfusion.
- Lp-PLA2 inhibitors may also have a general application in any disorder that involves activated monocytes, macrophages or lymphocytes, as all of these cell types express Lp-PLA 2 .
- disorders include psoriasis.
- Lp-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 neuropsychiatric disorders such as schizophrenia (see Psychopharmacology Bulletin, 31, 159-165, 1995).
- R.1 and R.2, which may be the same or different, is each selected from hydrogen, halogen or optionally substituted C(i_g ) alkyl;
- R3 is aryl or arylC(i_4)alkyl which may be optionally substituted
- X is a linker group
- 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.
- WO 97/02242 (SmithKline Beecham pic) describes further compounds having a substiuent such a methyl on the carbon attached to N-1.
- PCT/EP96/05587 (SmithKline Beecham pic) discloses pro-drugs of compounds of formula (A) in which R ⁇ is a 4-carboxybenzyl group.
- Rl is hydrogen or a corresponding pharmaceutically acceptable ester or a pharmaceutically acceptable salt thereof
- R2 and R3 which may be the same or different is each selected from hydrogen or optionally substituted C(i_6)alkyl;
- X is a group X , (CH 2 ) m in which X' is CO, CONR 4 , COO, CONR 4 CO, CONHO or CH2O in which R 4 is hydrogen or C(i_6 ) alkyl and m is 0 or an integer from 1 to 12, or a C(j. ⁇ 2 ) alkylene chain optionally interupted by X'; and
- Y is an optionally substituted aryl group; having the absolute configuration (4R,SS).
- X include CO(CH2) m , CONH(CH2) m , COO(CH 2 ) m , CONHCO(CH 2 ) m , CONHO(CH 2 )rn CH2 ⁇ (CH 2 )m and C ( ⁇ j2 ) alkylene.
- X' is CO, CONR 2 or CH2O, more preferably CONH.
- m is 1, 2, 5, 6, 7 or 9, preferably 6.
- X is CONH ( CH 2 )6 or CH 2 O(CH 2 )6. preferably CONH(CH 2 )6.
- R 2 and R ⁇ is each hydrogen or R 2 is hydrogen and R-* is methyl.
- R 2 and R ⁇ is each hydrogen.
- the carbon to which they are attached will be chiral.
- the absolute configuration at this carbon is S.
- the absolute configuration of the preferred enantiomer is ( ⁇ -5, 4-R, S-S).
- Y is phenyl, optionally substituted by up to three further substituents. Suitable substituents include halo, hydroxy, C ( i_g ) alkyl and C(j_g)alkoxy.
- Y is phenyl optionally substituted by halo, more preferably 4-chloro or 4-fluoro-phenyl, most preferably, 4-fIuoro-phenyl.
- X-Y is CONH(CH 2 )6Ph(4-F)/(4-CI).
- Suitable pharmaceutically acceptable esters include C ( i_6 ) alkyl or C ( 2-6 ) alk en yl esters, as well as pharmaceutically acceptable in vivo hydrolysable esters.
- C ( i_6 ) alkyl or C ( 2-6 ) alk en yl esters as well as pharmaceutically acceptable in vivo hydrolysable esters.
- simple C(i_6 ) alkyl or C(2-6 ) alke n y! benzoate esters show little if any tendency to break down in the human body, to leave the parent acid or its salt, even though they may be susceptible to in vivo hydrolysis in animals such as rabbits and dogs.
- the term "in vivo hydrolysable ester” is not therefore conventionally considered to include such esters.
- Suitable C(i_6 ) alkyl or C(2-6 ) alkenyl esters include ethyl and allyl esters.
- Suitable pharmaceutically acceptable in vivo hydrolysable ester groups for incorporation in R include those which break down readily in the human body to leave the parent acid or its salt.
- Suitable values of R* for use in vivo hydrolysable esters include: -CH(R a )O.CO.R b ; -CH(R a )O.CO.OR c ; -CH(R a )CO.NReR f -R d NReRf; -CH 2 ORg;
- R a is hydrogen, (C ⁇ -6)alkyl, in particular methyl, (C ⁇ - ⁇ teycloalkyl, or phenyl, each of which may be optionally substituted;
- R b is (C ⁇ -6)alkyl, (C ⁇ -6)alkoxy(C ⁇ -6)alkyl, phenyl, benzyl, (C3-7)cycloalkyl,
- R a and R D together form a 1,2-phenylene group optionally substituted by one or two methoxy groups
- R c is (C ⁇ -6)alkyl, (C ⁇ cycloalkyl, (C ⁇ alkyKC ⁇ - ⁇ Jcycloalkyl;
- R d is (C ⁇ -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 ⁇ -6)alkyl; or ary!(C 1 -4) alkyl, optionally substituted with e.g. hydroxy;
- Rg is (C ⁇ -6)alkyl
- R n is hydrogen, (C ⁇ -6)alkyl or phenyl
- R* is hydrogen or phenyl optionally substituted by up to three groups selected from halogen, (C ⁇ -6)-alkyI, or (Cj-6)alkoxy; and ⁇ l is oxygen or NH.
- Suitable values of R* include:
- acyloxyalkyl groups such as acetoxymethyl, isobutyryloxymethyl, pivaloyloxymethyl, benzoyloxymethyl, ⁇ -acetoxyethyl, ⁇ -pivaloyloxyethyl, l-(cyclohexylcarbonyloxy)ethyl, (l-aminoethyl)carbonyloxymethyl, 2- methoxyprop-2-ylcarbonyloxymethyl, phenylcarbonyloxymethyl and 4- methoxyphenyl-carbonyloxymethyl;
- 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;
- acetamido groups such as N,N-dimethylaminocarbonylmethyl, N,N-(2- hydroxyethyl)aminocarbonylmethyl ;
- lactone groups such as phthalidyl and dimethoxyphthalidyl
- R 1 include: (2-methoxycarbonyI-E-but-2-en-yl)methyl, isobutyryloxymethyl, 2- methoxyprop-2-ylcarbonyloxymethyl, phenylcarbonyloxymethyl, 4-methoxyphenyl-carbonyloxymethyl, t-butyloxycarbonyloxymethyl, cyclohexyloxy-carbonyloxymethyl, 1-methylcyclohexyloxycarbonyloxymethyl, N,N-dimethylaminocarbonylmethyl, N-N-di-(2- hydroxyethyl)aminocarbonylmethyloxy and (5-methyl-2-oxo- 1 ,3-dioxolen-4- yl)methyl.
- Especially preferred compounds of Formula (I) include: (4R, S5)-N-[6-(4-Fluorophenyl)hex-l-yl]-4-(4-carboxybenzylsulphinyl)-2- oxoazetidin-l-yl)acetamide and pharmaceuticaly acceptable salts thereof, in particular the sodium salt.
- the compounds of Formula (I) 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. Although 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). Preferably, whenever possible, the compounds of the present invention are obtained in crystalline form.
- solvent of crystallisation may be present in the crystalline product.
- This invention includes within its scope such solvates.
- some of the compounds of this invention may be crystallised or recrystallised from solvents containing water. In such cases water of hydration may be formed.
- This invention includes within its scope stoichiometric hydrates as well as compounds containing variable amounts of water that may be produced by processes such as lyophilisation.
- different crystallisation conditions may lead to the formation of different polymorphic forms of crystalline products.
- This invention includes within its scope all polymorphic forms of the compounds of Formula (I).
- Compounds of the present invention are inhibitors of the enzyme lipoprotein associated phospholipase A2 (Lp-PLA2) and as such are expected to be of use in therapy, in particular in the treatment of atherosclerosis.
- Lp-PLA2 lipoprotein associated phospholipase A2
- the present invention provides a compound of Formula (I) for use in therapy.
- the compounds of Formula (I) are inhibitors of lysophosphatidylcholine production by Lp-PLA2 and may therefore also have a general application in any disorder that involves endothelial dysfunction, for example atherosclerosis, diabetes, hypertension, angina pectoris and after ischaemia and reperfusion.
- compounds of Formula (I) may have a general application in any disorder that involves lipid peroxidation in conjunction with enzyme activity, for example in addition to conditions such as atherosclerosis and diabetes, other conditions such as rheumatoid arthritis, stroke, inflammatory conditions of the brain such as Alzheimer's Disease, myocardial infarction, reperfusion injury, sepsis, and acute and chronic inflammation. Further such conditions include various neuropsychiatric disorders such as schizophrenia (see Psychopharmacology Bulletin, 31, 159-165, 1995).
- the present invention provides for a method of treating a disease state associated with activity of the enzyme Lp-PLA2 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 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 gelaun capsule; alternatively, a dispersion or suspension can be prepared using any suitable pharmaceutical carrier(s), for example aqueous gums, celluloses, sihcates or oils and the dispersion or suspension then filled into a soft gelatin capsule.
- Typical parenteral compositions consist of a solution or suspension of the compound of Formula (I) in a sterile aqueous carrier or parenterally acceptable oil, for example polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil.
- a sterile aqueous carrier or parenterally acceptable oil for example polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil.
- the solution can be lyophilised and then reconstituted with a suitable solvent just prior to administration.
- a typical suppository formulation comprises a compound of Formula (I) which is active when administered in this way, with a binding and/or lubricating agent such as polymeric glycols, gelatins or cocoa butter or other low melting vegetable or synthetic waxes or fats.
- a binding and/or lubricating agent such as polymeric glycols, gelatins or cocoa butter or other low melting vegetable or synthetic waxes or fats.
- the composition is in unit dose form such as a tablet or capsule.
- Each dosage unit for oral administration contains preferably from 1 to 500 mg (and for parenteral administration contains preferably from 0.1 to 25 mg) of a compound of the Formula (I).
- the daily dosage regimen for an adult patient may be, for example, an oral dose of between 1 rag 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.
- Preferred compounds of formula (I) in which X is an amide CONH may be prepared by a process which comprises treating a compound of formula (LI):
- R 4 is a reactive esterifying leaving group; and Rl is as hereinbefore defined; under ester forming conditions.
- the free acid may be regenerated from a corresponding compound in which the carboxy group is protected as a C ⁇ . ⁇ alkyl or C(2-6) a U £en y 1 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 dichloromethane).
- step (b) above salts by prepared by treating the corresponding acid with an appropriate base.
- Suitable ester forming conditions for use in step (c) above 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:
- Preferred conditions include the use of the sodium salt of the acid in combination with a halide or sulphonate derivative of the compound of formula (TV).
- Compounds of formula (I) may also be obtained by an alternative process in which the two steps hereinbefore described are reversed, that is a compound of formula (V) is first treated with a compound of formula (LTI), to form the amide bond, and the resultant thio intermediate then oxidised to the corresponding sulfoxide of formula (II), preferably using a chiral oxidising system which yields the required isomer as the predominant product.
- a compound of formula (V) is first treated with a compound of formula (LTI), to form the amide bond, and the resultant thio intermediate then oxidised to the corresponding sulfoxide of formula (II), preferably using a chiral oxidising system which yields the required isomer as the predominant product.
- Diastereoisomeric salts formed from a compound of formula (VI) and a chiral base are of use in preparing compounds of formula (I). Therefore, in a further aspect, the present invention provides for such salts.
- the compound of formula (VII) may be a single enantiomer, having the required absolute configuration (4R).
- Suitable alkylating agents include an alkyl iodide, 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.
- suitable alkylating solvent such as tetrahydrofuran (THF)
- suitable alkylating solvent such as tetrahydrofuran (THF)
- suitable alkylating solvent such as tetrahydrofuran (THF)
- THF tetrahydrofuran
- Other suitable conditions include lithium bis(trimethylsilyl)amide in THF, optionally with l,3-dimethylimidazolidin-2-one, and at a temperature of about -70°C.
- the newly formed propionate ester may then be converted to the corresponding acid, using basic conditions such as aqueous sodium hydroxide in THF, followed by amide bond formation and then oxidation of the thio group, as previously described.
- Enantiomers may be usefully isolated by chiral chromatography, for instance hplc using a chiral stationary phase, on compounds of formula (I), at the alkyl/alkenyl ester stage.
- compounds of formula (I) in which the linker group X contains an ether function may be prepared by a suitable ether coupling reaction, for instance, when X' is CH2O, treating a compound of formula (VU ⁇ ):
- VLLI compound of formula (VLLI) is a racemic compound, this will lead to a mixture of diastereoisomers. Oxidation of the thio group will create a further chiral centre and the resultant distereoisomers may be separated by fractional crystallisation and/or chromatography. Individual enatiomers may then be obtained by chiral chromatography. Suitable compounds of formula (VLTI) may be prepared by analogy with the processes described in WO 97/02242.
- (+/-)-4-(4-(Allyloxycarbonyl)benzylthio)-2-oxoazetidin-l-ylacetic acid To a solution of methyl 4-(4-(aIlyIoxycarbonyl)benzylthio)-2-oxoazetidin-l- ylacetate (2.17 g, 6.21mmol) in tetrahydrofuran (20 ml) was added dropwise with cooling (ice bath) over 10 min a 1 molar aqueous solution of potassium hydroxide. After a further 30 min, the solution was diluted with water and extracted twice with ether. The aqueous layer was then acidified (dil.
- Example 8 (+)-4R, S5-N-(6-(4-Fluorophenyl)hexyl)-4-(4- e thoxy carbonylbenzylsulphinyl)-2-oxoazetidin-l-ylaceta ⁇ nide a. p-Methoxybenzyl [(35, 4R)-4-acetylthio-3-bromo-2-oxoazetidin-l- yljacetate
- Ozonised oxygen was bubbled through a solution of p-methoxybenzyl 2-[(35, 4R)-4-acetylthio-3-bromo-2-oxoazetidin- 1 -yl]-3-methylbut-2-enoate (Osborne N. F. et al., J. Chem. Soc., Perkin Trans. 1, 1994, 179) (20.16 g, 0.0456 mol) in ethyl acetate (400 ml) at -65 to -70°C until a permanent blue solution was obtained. Excess ozone was removed by the passage of oxygen, then trimethyl phosphite (53.8 ml, 0.456 mol) was added dropwise. After 15 min.
- the cooling bath was removed and the mixture stirred at RT for 2hrs.
- the solution was shaken with a mixture of saturated aqueous sodium sulphite and saturated sodium hydrogen carbonate and the organic layer separated, washed with water, dried (MgSOJ and evaporated to an oil.
- 6-(4-Fluorophenyl)hexyloxy ethanol (4.0g), pyridine (1.43g) and DMAP (40mg) were dissolved in dry dichloromethane (30ml), cooled to -10°C and triflic anhydride (5.6g) in dry dichloromethane (10ml) was added over 5 minutes keeping temperature below 0°C. The mixture was stirred at -10°C to 0°C over 60 minutes and then washed with water (50ml), brine (50ml), dried (MgSO4) and evaporated to a brown oil (6.17g, 99%).
- (+)-l-(2-(6-Fluorophenyl)hexyloxy)ethyl-4-(4-allyloxycarbonylbenzylsulphinyl)- 2-oxoazetidine 140mg
- triphenylphosphine 7mg
- tetrakis(triphenylphosphine)palladium (0) 14 cmg
- pyrrolidine 23.5 ⁇ l
- Ethylene glycol (51.1g) and 6-(4-chlorophenyl)hexyl bromide (22.7g) were added to a solution of sodium hydroxide (3.46g) in water (3.1ml) and the mixture was heated at 110°for 24 hours.
- the mixture was cooled and partitioned between water (300ml) and diethyl ether (300ml). The layers were separated and the aqueous layer was washed with ether (150ml). The organic layers were combined and washed with water, brine, dried (MgSO4) and evaporated to yellow oil.
- 6-(4-Chlorophenyl)hexyloxy ethanol (7.6g), pyridine (2.53g) and DMAP (79mg) were dissolved in dry dichloromethane (60ml), cooled to -10°C and triflic anhydride (lO.Og) in dry dichloromethane (20ml) was added over 7 minutes keeping T below 0°C. The mixture was stirred at 0°C for 45 minutes, washed with water (60ml), brine (60ml), dried (MgSO4) and evaporated to a dark oil (11.13g, 97%).
- (+)-l-(2-(6-Chlorophenyl)hexyloxy)ethyl-4-(4-alIyIoxycarbonylbenzylsulphinyl)- 2-oxoazetidine (65.6mg), triphenylphosphine (3.2mg), tetrakis(triphenylphosphine)palladium (O) (4.6mg) in dry CH2CI2 (2ml) under nitrogen was treated with pyrrolidine (10.3 ⁇ l) and the mixture was stirred at room temperature for 19 hours. Purification by flash column chromatography on silica gel eluted with a CH2Cl2'acetone:acetic acid gradient elution gave the product as an oil.
- 6-(4-Fluorophenyl)hexylamine (1.55g) in dry DMF (50ml) was added to a mixture of 2-[(4-allyloxycarbonyl)benzylthio]-2-oxoazetidin-l-ylpropionic acid (2.70g) (above), 1-hydroxybenzotriazole (0.95g), N.N'-dicyclohexylcarbodiimide (1.46g) and the mixture was stirred at room temperature for 4h. The suspension was diluted with diethyl ether (100ml) and filtered to remove urea. The filtrate was washed saturated aq.NaHCO3, brine, dried (MgSO4), and evaporated to an oil.
- Diastereoisomer B2 ( ⁇ -S, 4- R. 5-S)-N-[6-(4-fluorophenyl)hexyl]-2-[(4-allyloxycarbonyl)benzylsulphinyl)]-2- oxoazetidin-1-ylpropionamide as a colourless oil.
- Impure R.R.S fractions were combined and recrystallised from ethyl acetate/diethyl ether to give ( ⁇ -R, 4-R, 5-S)-N-[6-(4-fluorophenyl)hexyl]-2-[(4- allyloxycarbonyl)benzylsulphinyl)]-2-oxoazetidin- 1 -ylpropionamide as a colourless solid (0.204g,15.8%), m.p. 102°C:
- chloro compounds were prepared from racemic 4-[(4-allyloxycarbonyl)benzylthio]-2-oxoazetidin- 1-ylacetic acid.
- Example 30 (-)-( ⁇ -S, 4-R, SS)- and (+)-( ⁇ -R, 4>S, 5-R)-N-[6-(4- Chlorophenyl)hexyl]-2-[(4-al]yIoxycarbonyI)benzylsulphinyI]-2-oxoazetidin- 1 -ylpropionamide a. N-[6-(4-Chlorophenyl)hexyI]-2-[(4-allyIoxycarbonyI)benzyIthio]-2- oxoazetidin- 1 -ylpropionamide
- racemic compounds were also prepared. These may then be separated into enantiomers by hplc, using a chiral stationary phase, in a similar manner to separations hereinbefore described.
- Enzyme activity was determined by measuring the rate of turnover of the artificial substrate (A) at 37 °C in 50mM HEPES (N-2-hydroxyethyl ⁇ i ⁇ erazine- N'-2-ethanesulphonic acid) buffer containing 150mM NaCl, pH 7.4.
- Lp-PLA2 was partially purified by density gradient centrifugation of human plasma. Active fractions were pooled and used as the source of Lp-PLA2- The enzyme was pre-incubated at 37 °C with vehicle or test compound for 10 min in a total volume of 180 ⁇ l. The reaction was then initiated by the addition of 20 ⁇ l lOx substrate (A) to give a final substrate concentration of 20 ⁇ M. The reaction was followed at 405 nm for 20 minutes using a plate reader with automatic mixing. The rate of reaction was measured as the rate of change of absorbance.
- the compounds of Examples 1 and 2 the corresponding carboxylic acid (+/-)-N- [6-(4-chlorophenyl)hex-l-yl]-4-(4-carboxybenzylsulphinyl)-2-oxoazetidin-l- yl)acetamide and the carboxylic acid (4R, S5)-N-[6-(4-fluorophenyl)hex-l-yI]-4- (4-carboxybenzylsulphinyI)-2-oxoazetidin-l-yl)acetamide had IC50 values in the range 4 to 20 nM.
- the compounds of Example 12,13 and 14 had IC50 values in the range 2 to 4 nM.
- the pro-drug esters were evaluated in dog and human liver microsomes according to standard procedures for their ability to be hydrolysed to the parent acid. The results are given in the table below.
- Acid production - % conversion of test ester to parent acid by dog or liver microsomes after incubation of l ⁇ m test compound for 15 min, determined by measuring the concentration of parent acid produced by HPLC detection of acid (100% l ⁇ 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 9, 11, 12, 15, 16).
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Priority Applications (8)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP9538507A JP2000509049A (ja) | 1996-04-26 | 1997-04-15 | アテローム性動脈硬化症の治療用アゼチジノン誘導体 |
AU26986/97A AU2698697A (en) | 1996-04-26 | 1997-04-15 | Azetidinone derivatives for the treatment of atherosclerosis |
KR1019980708585A KR20000065040A (ko) | 1996-04-26 | 1997-04-15 | 아테롬성동맥경화증치료를위한아제티디논유도체 |
EP97920699A EP0915843A1 (en) | 1996-04-26 | 1997-04-15 | Azetidinone derivatives for the treatment of atheroscleroses |
IL12669697A IL126696A0 (en) | 1996-04-26 | 1997-04-15 | Azetidinone derivatives for the treatment of atherosclerosis |
BR9709196A BR9709196A (pt) | 1996-04-26 | 1997-04-15 | Derivados de azetidinona para o tratamento de aterosclerose |
NZ332476A NZ332476A (en) | 1996-04-26 | 1997-04-15 | substituted 4-(carboxybenzylsulphinyl)-2-oxo-azetidine derivatives |
NO984939A NO984939L (no) | 1996-04-26 | 1998-10-23 | Azetidinon-derivater for behandling av atherosklerose |
Applications Claiming Priority (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP9608646.7 | 1996-04-26 | ||
GBGB9608646.7A GB9608646D0 (en) | 1996-04-26 | 1996-04-26 | Novel compounds |
GBGB9623756.5A GB9623756D0 (en) | 1996-11-15 | 1996-11-15 | Novel compounds |
EP9623756.5 | 1996-11-15 | ||
GBGB9625121.0A GB9625121D0 (en) | 1996-12-03 | 1996-12-03 | Novel compounds |
EP9625121.0 | 1996-12-03 |
Publications (1)
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WO1997041098A1 true WO1997041098A1 (en) | 1997-11-06 |
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PCT/EP1997/001898 WO1997041098A1 (en) | 1996-04-26 | 1997-04-15 | Azetidinone derivatives for the treatment of atherosclerosis |
Country Status (17)
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---|---|
EP (1) | EP0915843A1 (ja) |
JP (1) | JP2000509049A (ja) |
AR (1) | AR006833A1 (ja) |
AU (1) | AU2698697A (ja) |
BR (1) | BR9709196A (ja) |
CA (1) | CA2252696A1 (ja) |
CZ (1) | CZ341098A3 (ja) |
HU (1) | HUP9901359A3 (ja) |
ID (1) | ID16660A (ja) |
IL (1) | IL126696A0 (ja) |
MA (1) | MA26426A1 (ja) |
NO (1) | NO984939L (ja) |
NZ (1) | NZ332476A (ja) |
PE (1) | PE64398A1 (ja) |
PL (1) | PL329530A1 (ja) |
TR (1) | TR199802160T2 (ja) |
WO (1) | WO1997041098A1 (ja) |
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WO2002096415A2 (en) * | 2001-05-25 | 2002-12-05 | Schering Corporation | Use of azetidinone substituted derivatives in the treatment of alzheimer's disease |
US6627757B2 (en) | 2001-03-28 | 2003-09-30 | Schering Corporation | Enantioselective synthesis of azetidinone intermediate compounds |
EP1686119A1 (en) | 2000-02-16 | 2006-08-02 | Smithkline Beecham Plc | Pyrimidine-4-one derivatives as ldl-pla2 inhibitors |
WO2008140449A1 (en) | 2007-05-11 | 2008-11-20 | Thomas Jefferson University | Methods of treatment and prevention of neurodegenerative diseases and disorders |
WO2012076435A1 (en) | 2010-12-06 | 2012-06-14 | Glaxo Group Limited | Pyrimidinone compounds for use in the treatment of diseases or conditions mediated by lp - pla2 |
WO2012080497A2 (en) | 2010-12-17 | 2012-06-21 | Glaxo Group Limited | Methods of treatment and prevention of eye diseases |
WO2013000267A1 (zh) | 2011-06-27 | 2013-01-03 | 中国科学院上海药物研究所 | 唑类杂环化合物、其制备方法、药物组合物和用途 |
WO2013014185A1 (en) | 2011-07-27 | 2013-01-31 | Glaxo Group Limited | Bicyclic pyrimidone compounds |
WO2013013503A1 (en) | 2011-07-27 | 2013-01-31 | Glaxo Group Limited | 2,3-dihydroimidazo[1,2-c] pyrimidin-5(1h)-one compounds use as lp-pla2 inhibitors |
WO2014114694A1 (en) | 2013-01-25 | 2014-07-31 | Glaxosmithkline Intellectual Property Development Limited | 2,3-dihydroimidazol[1,2-c]pyrimidin-5(1h)-one based lipoprotein-associated phospholipase a2 (lp-pla2) inhibitors |
WO2014114249A1 (en) | 2013-01-25 | 2014-07-31 | Glaxosmithkline Intellectual Property Development Limited | Bicyclic pyrimidone compounds as inhibitors of lp-pla2 |
WO2014114248A1 (en) | 2013-01-25 | 2014-07-31 | Glaxosmithkline Intellectual Property Development Limited | Compounds |
US8962633B2 (en) | 2007-05-11 | 2015-02-24 | Thomas Jefferson University | Methods of treatment and prevention of metabolic bone diseases and disorders |
US9029383B2 (en) | 2007-05-11 | 2015-05-12 | The Trustees Of The University Of Pennsylvania | Methods of treatment of skin ulcers |
WO2016012917A1 (en) | 2014-07-22 | 2016-01-28 | Glaxosmithkline Intellectual Property Development Limited | 1,2,3,5-tetrahydroimidazo[1,2-c]pyrimidine derivatives useful in the treatment of diseases and disorders mediated by lp-pla2 |
WO2016012916A1 (en) | 2014-07-22 | 2016-01-28 | Glaxosmithkline Intellectual Property Development Limited | 1,2,3,5-tetrahydroimidazo[1,2-c]pyrimidine derivatives useful in the treatment of diseases and disorders mediated by lp-pla2 |
WO2021089032A1 (zh) | 2019-11-09 | 2021-05-14 | 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 |
WO2022233302A1 (zh) | 2021-05-07 | 2022-11-10 | 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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1997
- 1997-04-15 JP JP9538507A patent/JP2000509049A/ja active Pending
- 1997-04-15 CA CA002252696A patent/CA2252696A1/en not_active Abandoned
- 1997-04-15 AU AU26986/97A patent/AU2698697A/en not_active Abandoned
- 1997-04-15 NZ NZ332476A patent/NZ332476A/en unknown
- 1997-04-15 BR BR9709196A patent/BR9709196A/pt not_active Application Discontinuation
- 1997-04-15 WO PCT/EP1997/001898 patent/WO1997041098A1/en not_active Application Discontinuation
- 1997-04-15 CZ CZ983410A patent/CZ341098A3/cs unknown
- 1997-04-15 TR TR1998/02160T patent/TR199802160T2/xx unknown
- 1997-04-15 EP EP97920699A patent/EP0915843A1/en not_active Withdrawn
- 1997-04-15 HU HU9901359A patent/HUP9901359A3/hu unknown
- 1997-04-15 IL IL12669697A patent/IL126696A0/xx unknown
- 1997-04-15 PL PL97329530A patent/PL329530A1/xx unknown
- 1997-04-24 AR ARP970101682A patent/AR006833A1/es unknown
- 1997-04-24 PE PE1997000311A patent/PE64398A1/es not_active Application Discontinuation
- 1997-04-24 MA MA24565A patent/MA26426A1/fr unknown
- 1997-04-25 ID IDP971394A patent/ID16660A/id unknown
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1998
- 1998-10-23 NO NO984939A patent/NO984939L/no not_active Application Discontinuation
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Cited By (23)
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US8871775B2 (en) | 2000-02-16 | 2014-10-28 | Glaxo Group Limited | Compounds |
EP1686119A1 (en) | 2000-02-16 | 2006-08-02 | Smithkline Beecham Plc | Pyrimidine-4-one derivatives as ldl-pla2 inhibitors |
US9266841B2 (en) | 2000-02-16 | 2016-02-23 | Glaxo Group Limited | Compounds |
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WO2002096415A3 (en) * | 2001-05-25 | 2003-01-16 | Schering Corp | Use of azetidinone substituted derivatives in the treatment of alzheimer's disease |
WO2002096415A2 (en) * | 2001-05-25 | 2002-12-05 | Schering Corporation | Use of azetidinone substituted derivatives in the treatment of alzheimer's disease |
US8962633B2 (en) | 2007-05-11 | 2015-02-24 | Thomas Jefferson University | Methods of treatment and prevention of metabolic bone diseases and disorders |
WO2008140449A1 (en) | 2007-05-11 | 2008-11-20 | Thomas Jefferson University | Methods of treatment and prevention of neurodegenerative diseases and disorders |
EP2977452A2 (en) | 2007-05-11 | 2016-01-27 | Thomas Jefferson University | Methods of treatment and prevention of neurodegenerative diseases and disorders |
US9029383B2 (en) | 2007-05-11 | 2015-05-12 | The Trustees Of The University Of Pennsylvania | Methods of treatment of skin ulcers |
WO2012076435A1 (en) | 2010-12-06 | 2012-06-14 | Glaxo Group Limited | Pyrimidinone compounds for use in the treatment of diseases or conditions mediated by lp - pla2 |
WO2012080497A2 (en) | 2010-12-17 | 2012-06-21 | Glaxo Group Limited | Methods of treatment and prevention of eye diseases |
WO2013000267A1 (zh) | 2011-06-27 | 2013-01-03 | 中国科学院上海药物研究所 | 唑类杂环化合物、其制备方法、药物组合物和用途 |
WO2013013503A1 (en) | 2011-07-27 | 2013-01-31 | Glaxo Group Limited | 2,3-dihydroimidazo[1,2-c] pyrimidin-5(1h)-one compounds use as lp-pla2 inhibitors |
WO2013014185A1 (en) | 2011-07-27 | 2013-01-31 | Glaxo Group Limited | Bicyclic pyrimidone compounds |
WO2014114248A1 (en) | 2013-01-25 | 2014-07-31 | Glaxosmithkline Intellectual Property Development Limited | Compounds |
WO2014114249A1 (en) | 2013-01-25 | 2014-07-31 | Glaxosmithkline Intellectual Property Development Limited | Bicyclic pyrimidone compounds as inhibitors of lp-pla2 |
WO2014114694A1 (en) | 2013-01-25 | 2014-07-31 | Glaxosmithkline Intellectual Property Development Limited | 2,3-dihydroimidazol[1,2-c]pyrimidin-5(1h)-one based lipoprotein-associated phospholipase a2 (lp-pla2) inhibitors |
WO2016012917A1 (en) | 2014-07-22 | 2016-01-28 | Glaxosmithkline Intellectual Property Development Limited | 1,2,3,5-tetrahydroimidazo[1,2-c]pyrimidine derivatives useful in the treatment of diseases and disorders mediated by lp-pla2 |
WO2016012916A1 (en) | 2014-07-22 | 2016-01-28 | Glaxosmithkline Intellectual Property Development Limited | 1,2,3,5-tetrahydroimidazo[1,2-c]pyrimidine derivatives useful in the treatment of diseases and disorders mediated by lp-pla2 |
WO2021089032A1 (zh) | 2019-11-09 | 2021-05-14 | 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 |
WO2022233302A1 (zh) | 2021-05-07 | 2022-11-10 | 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 |
Also Published As
Publication number | Publication date |
---|---|
MA26426A1 (fr) | 2004-12-20 |
HUP9901359A2 (hu) | 1999-08-30 |
CZ341098A3 (cs) | 1999-03-17 |
PE64398A1 (es) | 1999-01-06 |
NZ332476A (en) | 2000-06-23 |
CA2252696A1 (en) | 1997-11-06 |
JP2000509049A (ja) | 2000-07-18 |
NO984939D0 (no) | 1998-10-23 |
IL126696A0 (en) | 1999-08-17 |
HUP9901359A3 (en) | 2000-03-28 |
PL329530A1 (en) | 1999-03-29 |
AU2698697A (en) | 1997-11-19 |
BR9709196A (pt) | 1999-05-25 |
ID16660A (id) | 1997-10-30 |
NO984939L (no) | 1998-12-23 |
AR006833A1 (es) | 1999-09-29 |
EP0915843A1 (en) | 1999-05-19 |
TR199802160T2 (xx) | 1999-04-21 |
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