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
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
  • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
  • C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
  • C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
  • C07D205/085—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams with a nitrogen atom directly attached in position 3
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
  • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
  • C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
  • C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
  • C07D205/09—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams with a sulfur atom directly attached in position 4
  • C07D205/095—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams with a sulfur atom directly attached in position 4 and with a nitrogen atom directly attached in position 3
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
  • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
  • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
  • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
  • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

• the present invention relates to certain novel monocyclic ⁇ -lactam compounds, processes for their preparation, intermediates useful in their preparation,
• compositions containing them and their use in therapy, in particular in the treatment of atherosclerosis.
• Lipoprotein Associated Phospholipase A 2 (Lp-PLA 2 ).
• the sequence of the enzyme, the isolation and purification thereof, isolated nucleic acids encoding the enzyme, recombinant host cells transformed with DNA encoding the enzyme are described in patent application WO 95/00649 (SmithKline Beecham plc). 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.
• 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 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. A 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.
• 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 .
• 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, 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
• R 1 and R 2 which may be the same or different, is each selected from hydrogen, halogen or C (1-8) alkyl;
• R 4 and R 5 which may be the same or different is each selected from hydrogen, C (1- 6) alkyl, C (2-6) alkenyl, aryl, aryl(C 1-4 )alkyl and heteroa ⁇ yl(C 1-4 )alkyl each of which may be optionally substituted or R 4 and R 5 may be linked together to form the remainder of a (C 3-7 )cycloalkyl ring;
• X is a linker group
• Y is an optionally substituted aryl group
• Z is oxygen and R 3 is C (1-8) alkyl, C (3-8) Cycloalkyl, C (3-8) cycloalkylC (1-6) alkyl, heteroaryl, heteroaryl (C 1-4 )alkyl, aryl, or aryl(C 1 -4 )alkyl, each of which may be optionally substituted or Z is S(O) n in which n is 0, 1 or 2 and R 3 is C (1-8) alkyl, C (3- 8) cycloalkyl, C (3-8) cycloalkylC (1-6) alkyl, aryl, aryl(C 1-4 )alkyl, heteroaryl, or heteroaryl(C 1-4 )alkyl, each of which may be optionally substituted; and
• X is a direct bond; a group X 1 (CH 2 ) m in which X 1 is CO, CONR 6 , COO,
• Z is S(O) n in which n is 0, 1 or 2 and R 3 is C (1-8) alkyl, C (3-8) cycloalkyl, C (3-
• R 4 and R 5 is each hydrogen.
• X is a direct bond; a group X 1 (CH 2 ) m in which X 1 is CO, CONR 6 , COO, CONR 6 CO, or CONR 6 O in which R 6 is hydrogen or C (1-6) alkyl and m is 0 or an integer from 1 to 12; a group (X 1 ) a X 2 in which a is 0 or 1 and X 2 is a C (1- 12) alkylene chain interupted and/or terminated at the end adjacent to Y by one or more groups X 3 selected from O, S(O) x , NR 6 , alkene or alkyne, in which x is 0, 1 or 2; or a C (1-12) alkylene chain optionally interupted by X 1 .
• Suitable sub-sets of compounds within formula (I) include those in which: (a) X is a direct bond; a group X 1 (CH 2 ) m as hereinbefore defined; a group (X 1 ) a X 2 as hereinbefore defined; or a C (1-12) alkylene chain optionally interupted by X 1 ;
• Z is oxygen and R 3 is C (1-8) alkyl, C (3-8) cycloalkyl, C (3-8) cycloalkylC (1-6) alkyl, heteroaryl, heteroaryl(C 1-4 )alkyl, aryl, or aryl(C 1-4 )alkyl, each of which may be optionally substituted or Z is S(O) n in which n is 0, 1 or 2 and R 3 is heteroaryl or heteroaryl(C 1-4 )alkyl, each of which may be optionally substituted;
• R 4 and R 5 are as hereinbefore defined;
• X is a direct bond; a group X 1 (CH 2 )m as hereinbefore defined; a group (X 1 ) a X 2 as hereinbefore defined; or a C (1-12) alkylene chain optionally interupted by X 1 ;
• Z is S(O) n in which n is 0, 1 or 2 and R 3 is C (1-8) alkyl, C (3-8) cycloalkyl, C (3- 8) cycloalkylC (1-6) alkyl, aryl or aryl(C 1-4 )alkyl, each of which may be optionally substituted;
• R 4 and R 5 which may be the same or different is each selected from hydrogen, C (1- 6) alkyl, C (2-6) alkenyl, aryl, aryl(C 1-4 )alkyl and heteroaryl(C 1-4 )alkyl each of which may be optionally substituted or R 4 and R 5 may be linked together to form the remainder of a (C 3-7 )cycloalkyl ring, with the proviso that R 4 and R 5 are not both hydrogen; or
• X is a group (X 1 ) a X 2 as hereinbefore defined;
• Z is S(O) n in which n is 0, 1 or 2 and R 3 is C (1-8) alkyl, C (3-8) cycloalkyl, C (3- 8 )cycloalkylC (1-6) alkyl, aryl or aryl(C 1-4 )alkyl, each of which may be optionally substituted; and
• R 4 and R 5 is each hydrogen.
• Compounds of formula (I) are inhibitors of Lp-PLA 2 and as such are expected to be of use in treating atherosclerosis and the other disease conditions noted above.
• 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 tr ⁇ ns-methyl).
• R 1 and R 2 is each hydrogen.
• R 3 is aryl(C 1-4 )alkyl
• arylC (1-3) alkyl Representative values for when R 3 is aryl(C 1-4 )alkyl include arylC (1-3) alkyl.
• representative examples of the aryl group include phenyl and naphthyl.
• Suitable examples of R 3 include benzyl, 2-phenylethyl and 3-phenylpropyl in each of which the phenyl ring may be optionally substituted by up to three substituents.
• Suitable substituents for a phenyl or naphthyl ring in R 3 include halo, hydroxy, C (1- 6 )alkyl, C (1-6) alkoxy, C (1-6) alkoxycarbonyl, C (2-6) alkenyloxycarbonyl, carboxy, carboxyC (1-6) alkyl and C (1-6) alkoxycarbonylC (1-6) alkyl. More preferably, R 3 is 4-carboxybenzyl or a corresponding C (1-6) alkyl or C (2-6) alkenyl ester thereof.
• aryl group for when R 3 is aryl include phenyl and naphthyl.
• the aryl group is optionally subsumed phenyl.
• Suitable substituents for a phenyl or naphthyl ring include halo, hydroxy, C (1-6) alkyl, C (1- 6) alkoxy, C (1-6) alkoxycarbonyl, C (2-6) alkenyloxycarbonyl, carboxy, carboxyC (1- 6) alkyl and C (1-6) alkoxycarbonylC (1-6) alkyl.
• R 3 when R 3 is C (1-8) alkyl, C (3-8) cycloalkyl or C (3-8) cycloalkylC (1-6) alkyl include methyl, n-butyl, t-butyl and n-hexyl, cyclohexyl and cyclohexyl methyl, suitably n-butyl, t-butyl or n-hexyl.
• Suitable substituents for the alkyl or cycloalkyl group in R 3 include halo, hydroxy, C (1-6) alkyl, C (1-6) alkoxy, C (1-6) alkoxycarbonyl, C (2-6) alkenyloxycarbonyl, carboxy, carboxyC (1-6) alkyl and C (1-6) alkoxycart ⁇ )nylC (1-6) alkyl,
• R 3 include heteroarylC (1-3) alkyl, preferably heteroarylmethyl.
• Representative examples of the heteroarylaryl group for use in R 3 include pyridyl, pyridyl N-oxide, furanyl, thienyl and thiazolyl.
• Suitable substituents for a heteroaryl ring in R 3 include halo, hydroxy, C (1-6) alkyl, C (1-6) alkoxy, C (1- 6 )alkoxycarbonyl, C (2-6) alkenyloxycarbonyl, carboxy, carboxyC (1-6) alkyl and C (1- 6 )alkoxycarbonylC (1-6) alkyl.
• an optional substituent may be located in the alkyl, cycloalkyl, aryl and/or heteroaryl portion.
• the substituent is carboxy or a C (1-6) alkyl or C (2-6) alkenylester thereof.
• R 3 is arylC (1-3) alkyl or heteroarylC (1-3) alkyl, more preferably arylC (1-3) alkyl, most preferably benzyl, which may be optionally substituted, in particular by a carboxy group or a C (1-6) alkyl or C (2-6) alkenylester thereof.
• Z is S(O) n .
• n is 1 or 2, more preferably 1.
• S(O) n R 3 is optionally substitued benzylsulphinyl, more preferably 4-carboxybenzylsulphinyl or a C (1-6) alkyl or C (2-6) alkenylester thereof.
• R 4 and R 5 when an alkyl group include methyl, ethyl and propyl.
• Representative examples of a C (2-6) alkenyl group include allyl.
• Representative examples of a (C 3-7 )cycloalkyl ring include cyclopropyl.
• aryl(C 1-4 )alkyl and heteroaryl(C 1-4 )alkyl include benzyl and furylmethyl, respectively.
• Representative examples of R 4 and R 5 when aryl or aralkyl include phenyl and benzyl.
• R 4 and R 5 are both hydrogen or R 4 is hydrogen and R 5 methyl.
• X include CO(CH 2 ) m , CONH(CH 2 ) m ,
• X 1 is CO or CONR 6 , more preferably CONH.
• m is 1, 2, 5, 6, 7 or 9, preferably 6.
• X is CONR 6 (CH 2 ) 4 C ⁇ C or (CH 2 )O(CH 2 ) 6 .
• Preferred examples of X include CONH(CH 2 ) 6 , CONR 6 (CH 2 ) 4 C ⁇ C and
• Y is a benzene ring, optionally substituted by up to three further substituents.
• Suitable substituents include halo, hydroxy, C (1-8) alkyl 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 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 respectively.
• '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, halogen, cyano, azido, nitro, carboxy, (C 1-6 )alkoxycarbonyl, carbamoyl, mono- or
• 'aryl' includes, unless otherwise defined, phenyl or naphthyl optionally substituted with up to five, preferably up to three substituents.
• Suitable substituents for an aryl group include, for example, halogen, cyano, (C 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, (C 1-6 )alkoxycarbonyl,
• heteroaryl' includes single and fused rings, each ring suitably comprising up to four, preferably 1 or 2, heteroatoms each selected from oxygen, nitrogen and sulphur. Each ring may have from 4 to 7, preferably 5 or 6, ring atoms.
• a fused heteroaryl ring may include carbocyclic rings and need include only one heteroaryl ring. Suitable fused heteroaryl rings include bicyclic systems.
• heterocyclyl' includes aromatic and non-aromatic single or fused rings comprising up to four hetero-atoms in the ring selected from oxygen, nitrogen and sulphur and optionally substituted with up to three substituents.
• the heterocyclic ring comprises from 4 to 7, preferably 5 to 6, ring atoms.
• a fused heterocyclic ring system may include carbocyclic rings and need only include one heterocyclic ring.
• fused heterocyclic ring system may include carbocyclic rings and need only include one heterocyclic ring.
• a heteroaryl or a heterocyclyl group may have up to three substituents. Suitable such substituents include those previously mentioned for an aryl group as well as oxo.
• halogen' and 'halo' include fluorine, chlorine, bromine and iodine and fluoro, chloro, bromo and iodo, respectively.
• Preferred compounds of formula (I) include:
• More preferred compounds include:
• the compounds of the present invention are intended for use in pharmaceutical compositions, it will be understood that they are each provided in substantially pure form, for example at least 50% pure, more suitably at least 75% pure and preferably at least 95% pure (% are on a wt/wt basis). Impure preparations of the compounds of formula (I) may be used for preparing the more pure forms used in the pharmaceutical compositions.
• the purity of intermediate compounds of the present invention is less critical, it will be readily understood that the substantially pure form is preferred as for the compounds of formula (I).
• the compounds of the present invention are obtained in crystalline form.
• solvent of crystallisation may be present in the crystalline product
• This invention includes within its scope such solvates.
• some of the compounds of this invention may be crystallised or recrystallised from solvents containing water. In such cases water of hydration may be formed.
• This invention includes within its scope stoichiometric hydrates as well as compounds containing variable amounts of water that may be produced by processes such as lyophilisation.
• different crystallisation conditions may lead to the formation of different polymorphic forms of crystalline products.
• This invention includes within its scope all polymorphic forms of the compounds of formula (I).
• Compounds of the present invention are inhibitors of the enzyme lipoprotein associated phospholipase A2 (Lp-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
• Further applications include any disorder that involves activated monocytes, macrophages or lymphocytes, as all of these cell types express Lp-PLA 2 .
• disorders include psoriasis.
• the present invention provides for a method of treating a disease state associated with activity of the enzyme Lp-PLA 2 which method involves treating a patient in need thereof with a therapeutically effective amount of an inhibitor of the enzyme.
• the disease state may be associated with the increased involvement of monocytes, macrophages or lymphocytes; with the formation of lysophosphatidylcholine and oxidised free fatty acids; with lipid peroxidation in conjunction with Lp PLA2 activity; or with endothelial dysfunction.
• Compounds of the present invention may also be of use in treating the above mentioned disease states in combination with anti-hyperlipidaemic or anti-atherosclerotic or anti-diabetic or anti-anginal or anti-inflammatory or anti-hypertension agents.
• examples of the above include cholesterol synthesis inhibitors such as statins, anti-oxidants such as probucol, insulin sensitisers, calcium channel antagonists, and anti-inflammatory drugs such as 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. For example, pellets containing the active ingredient can be prepared using standard carriers and then filled into a hard gelatin capsule;
• a dispersion or suspension can be prepared using any suitable
• compositions for example aqueous gums, celluloses, silicates or oils and the dispersion or suspension then filled into a soft gelatin capsule.
• Typical parenteral compositions consist of a solution or suspension of the compound of formula (I) in a sterile aqueous carrier or parenterally acceptable oil, for example polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil.
• a sterile aqueous carrier or parenterally acceptable oil for example polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil.
• the solution can be lyophilised and then reconstituted with a suitable solvent just prior to administration.
• a typical suppository formulation comprises a compound of formula (I) which is active when administered in this way, with a binding and/or lubricating agent such as polymeric glycols, gelatins or cocoa butter or other low melting vegetable or synthetic waxes or fats.
• a binding and/or lubricating agent such as polymeric glycols, gelatins or cocoa butter or other low melting vegetable or synthetic waxes or fats.
• composition is in unit dose form such as a tablet or capsule.
• Each dosage unit for oral administration contains preferably from 1 to 500 mg (and for parenteral administration contains preferably from 0.1 to 25 mg) of a compound of the formula (I).
• the daily dosage regimen for an adult patient may be, for example, an oral dose of between 1 mg and 1000 mg, preferably between 1 mg and 500 mg, or an intravenous, subcutaneous, or intramuscular dose of between 0.1 mg and 100 mg, preferably between 0.1 mg and 25 mg, of the compound of the formula (I), the compound being administered 1 to 4 times per day.
• the compounds will be administered for a period of continuous therapy, for example for a week or more.
• R 1 , R 2 and R 3 are as hereinbefore defined;
• L 1 is a suitable leaving group such as halogen or triflate
• R 4 , R 5 , X and Y are as hereinbefore defined;
• a suitable base such as sodium hydride or potassium hydroxide optionally with a quaternary ammonium salt such tetrabutyl ammonium bromide
• a suitable alkylating solvent such as tetrahydrofuran (THF)
• 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 5 is hydrogen, with an alkylating agent in the presence of a suitable base such as sodium hydride, potassium hydroxide or lithium hexamethyldisilazide, in a suitable alkylating solvent such as tetrahydrofuran (THF), and at a temperature in the range -80 to 10°C.
• a suitable base such as sodium hydride, potassium hydroxide or lithium hexamethyldisilazide
• THF tetrahydrofuran
• Compounds of formula (II) in which Z is O may be obtained by treating 4-acetoxyazetidinone, 4-benzoyloxyazetidinone or 4-phenylsulfonyl-azetidinone with a phenol/alcohol R 3 OH in the presence of a base such as potassium t-butoxide, in a suitable solvent such as THF at a temperature in the range 0 to 5°C
• R 1 , R 2 , R 3 , R 4 and R 5 are as hereinbefore defined;
• DCC dicyclohexylcarbodiimide
• a suitable solvent such as chloroform or dimethyl formamide
• 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 ester, for instance a (C 1-7 ) alkanoate ester, under alkylating conditions as hereinbefore described; followed by the hydrolysis of the thus formed intermediate ester using standard conditions.
• a second group, for instqance an alkyl group, may then be introduced by alkylating of the first formed monoalkyl ester.
• R 1, , R 2 , R 3 , R 4 and R 5 are as hereinbefore defined;
• a compound of formula (VII) in which one of R 4 and R 5 is hydrogen may be obtained by treating a compound of formula (II) with a methyl 2-bromo(C 1-7 ) alkanoate, under alkylating conditions as hereinbefore described.
• COO(CH 2 ) m or COOX 2 may be prepared by treating a compound of formula (IV) with an alcohol YX 5 OH or an activated derivative thereof, for instance a tosylate.
• Compounds of formula (X) may be obtained from the corresponding 4-acetylthioazetidinone by treatment with silver nitrate and a base in a suitable solvent such as methanol.
• Suitable chiral intermediates may be obtained by resolution or chiral induction or by using chiral reagents, in particular natural chiral molecules, according to methods well known to those skilled in the art
• a convenient chiral starting material is a penicillin derivative which has the preferred configuration at C-4 of the ⁇ -lactam ring. This is illustrated in the following scheme for the preparation of suitable intermediates
• a stirring mixture of paraformaldehyde (25.22 g, 0.84 mol), anhydrous zinc chloride (108.06 g), and methyl 2-furoate (100 g, 0.793 mol) were cooled to 15 °C (ice bath) and a stream of HCl gas bubbled through with stirring. The temperature was allowed to rise to 25-30 °C, and after 1 hr the mixture was poured onto ice-water. The organic layer was separated off and the aqueous layer further extracted with dichloromethane. The combined extracts were dried (MgSO 4 ) and evaporated to a dark brown oil.
• N-(6-phenylhexyl)-1-bromoacetamide was obtained as a colourless solid, 35.4 g (83%), m.p. 29-32°C.
• N-(6-phenyl-3-hexynyl)phthalimide (3.0 g) in ethanol (150 ml) was treated with hydrazine monohydrate (0.96ml) and stirred at reflux for 4h.
• the reaction was cooled, evaporated to dryness and azeotroped with water.
• the residue was treated with 1N NaOH and extracted with diethyl ether (x2).
• the organic extracts were combined and extracted with 2N HCl (x2).
• the aqueous extracts were combined and basified with NaOH(aq) and extracted with diethyl ether (x2).
• the organic extracts were combined, washed with water, dried (MgSO 4 ), evaporated to give 6-phenyl-3-hexynamine as an oil (1.52 g, 89%).
• E-N-(6-phenyl-3-hexenyl)phthalimide (4.79 g) and propylamine (5 g) in ethanol (200 ml) were stirred at reflux for 2h and then at 70°C for 18h.
• the reaction mixture was evaporated to dryness and azeotroped with ethanol.
• the residue was mixed with 1N NaOH and extracted with diethyl ether (x2).
• the organic extracts were combined, washed with 2N HCl (x2).
• the aqueous extracts were combined, washed with diethyl ether and then basified with NaOH(aq) and extracted with diethyl ether (x2).
• Ethanolamine (1.53 g) was added to NaH (1.0 g) in dimethyl sulfoxide (DMSO) (10 ml) at room temperature, followed by 1-bromo-3-phenylpropane (5 g) and the mixture stirred at room temperature for 0.5 h. After aqueous work-up the title compound was obtained as a yellow oil (1.6 g, 36%).
• DMSO dimethyl sulfoxide
• 6-Phenylhexyl bromide (6.10 g) and ethylene glycol (15.5g) were added to a solution of sodium hydroxide (1.08 g) in water (1.1 ml) and the mixture heated at 100°C for 30hrs.
• Ether 75 ml and water (75 ml) were added, separated and the ether layer was washed with water then brine, dried over MgSO 4 and evaporated to an orange oil. This was purified by Kugelrohr distillation (225°C/0.2mm) followed by
• Ethyl 4-(bromomethyl)benzoate ethyl 4-(chloromethyl)benzoate (25.0g, 0.11 lmoles) in dry dimethylformamide (150ml), cooled to 5°C, was treated with potassium thioacetate (13.3g, 0.117moles) and the temperature rose to 20°C. The reaction was stirred at room temperature for 2 hours, poured into water (250ml) and extracted with diethyl ether (3 ⁇ 100ml). The organic extracts were combined, washed with water, dried (MgSO 4 ), charcoaled and evaporated to give ethyl 4-(acetylthiomethyl)benzoate as a brown soild (26.0g, 99%), m.p. 36-37°C.
• the solid was purified by chromatography (HPLC, Chiralcell OJ column,
• dichoromethane (30 ml) was cooled to -65 to -70°C and a solution of m- chloroperbenzoic acid (0.85 g, 0.0049 mol) in dichloromethane (30 ml) added dropwise over 30 min. After 2 h the mixture was washed with a mixture of saturated sodium hydrogen carbonate and saturated sodium sulphite, dried (MgSO 4 ) and evaporated to an oil. Crystallisation from ethyl acetate - light petrol gave a mixture of diastereomers (1.18 g) (b1:b2, 1:3), m.p. 75-78°C.
• Example 10b Treatment of 2-(4-benzylthio-2-oxoazetidin-1-yl)propionic acid (Example 10b) with benzylamine under the conditions described in Example 10c gave the title compound as the higher rf product after chromatography: 1.19 g, clear oil; 1 H NMR d (CDCl 3 ) (selected diagnostic peaks) 4.27 (1H, q, a-H), 4.80 (1H, m, H4);
• Methyl 4-(4-(allyloxycarbonyl)benzylthio)-2-oxoazetidin-2-ylpropionate Methyl 4-(4-(allyloxycarbonyl)benzylthio)-2-oxoazetidin-1-ylacetate (23.8 g, 68 mmoles) was stirred at -65°C in dry tretahydrofuran under nitrogen and treated with lithium bis(trimethylsilyl)amide (81.6 ml of a 1.0 molar solution in hexane), keeping the temperature to -65°C.
• Dicyclohexylcarbodiimide (4.75 g, 23 mmoles) in dry dimethylformamide (50 ml) was added dropwise to a cooled solution of 4-(4-(allyloxycarbonyl)benzylthio)-2-oxoazetidin-2-ylpropionic acid (8.0 g, 23 mmoles), 1-hydroxybenzotriazole hydrate (3.11 g, 23 mmoles) and 6-(4-fluorophenyl)hexylamine (4.5 g, 23 mmoles) in dry dimethylformamide (50 ml). Cooling was removed and the mixture was stirred overnight.
• the dimethylformamide was evaporated and the residue was purified by flash chromatography (fine silica, tert-butylmethyl ether then ethyl acetate) to provide samples which were predominantiy diastereoisomer a (4.6 g), diastereoisomer b (2.7 g) and mixed fractions.
• Diastereoisomer a yellow oil, 4.6 g, 38% yield
• dichloromethane 50 ml was stirred at -65°C and treated with a solution of m-chloroperbenzoic acid (1.0 g, 5.7 mmoles) in dichloromethane (30 ml). The mixture was stirred for 1 hour, poured into a solution of sodium hydrogen carbonate and sodium sulphite, separated and the aqueous extracted with dichloromethane. The combined extracts were washed with brine, dried and evaporated to an oil which was purified by flash chromatography (fine silica, ethyl acetate) to give the title compound as a yellow oil, 1.3 g, 50% yield as a 3:2 mixture of sulfoxide diastereoisomers 2 and 1.
• 1,3-Dimethylimidazolidin-2-one (7.5ml, 0.0687moles) was added keeping the temperature below -74°C.
• the resulting suspension was stirred at -78°C for 30 minutes and then treated with a solution of 3-bromomethylfuran (3.0g, 0.0186moles) in dry THF (10ml) over 10 minutes keeping the temperature below -73°C.
• the reaction was stirred at -78°C for 1 hour and then allowed to warm to -20°C over 30 minutes.
• the reaction was cooled to -75°C and quenched with glacial acetic acid (1.5ml), partititioned between brine (150ml) and ethyl acetate (150ml).
• 6-(4-Fluorophenyl)hexylamine (1.59g, 0.00814moles) in dry DMF (75ml) was added to a mixture of 2-(4-benzylthio-2-oxoazetidin-1-yl)-3-(3-furyl)propionic acid (2.7g, 0.00814 moles), 1-hydroxybenzotriazole (1.1g, 0.008 Mmoles), 1-cyclohexyl-3-(2- morpholinoethyl)carbodiimide metho-p-toluene sulfonate (3.5g, 0.00826moles) and the resulting solution was stirred at room temperature for 19h.
• Diastereoisomer a 1.17g, 28% (contains 20% diastereoisomer b)
• dichloromethane 25ml
• dichloromethane 25ml
• a solution of 3-chloroperoxy benzoic acid (0.80g, 0.00255moles) in dichloromethane (25ml) over 1 hour maintaining the temperature at -70°C.
• the cooling bath was removed and the reaction mixture was stirred for 1 hour giving a colourless solution.
• the reaction mixture was diluted with dichloromethane (50ml) and washed with 10% aq sodium sulphite solution, sodium hydrogen carbonate solution, water, dried (MgSO 4 ), and evaporated to a colourless oil which contained a mixture of diastereoisomers b1+b2.
• dichloromethane 25ml
• dichloromethane 25ml
• a solution of 3-chloroperoxy benzoic acid (0.70g, 0.00223moles) in dichloromethane (25ml) over 1 hour maintaining the temperature at -70°C.
• the cooling bath was removed and the reaction was stirred for 1 hour giving a colourless solution.
• the reaction mixture was diluted with dichloromethane (50ml), washed with 10% aq sodium sulphite solution, sodium hydrogen carbonate solution, water, dried (MgSO 4 ), and evaporated to a colourless oil which contained a mixture of diastereoisomers.
• the resulting suspension was stirred at -75°C for 30 minutes and then treated with a solution of benzyl bromide (2.36g, 0.0138moles ) over 5 minutes keeping the temperature below -70°C.
• the reaction was stirred for 1.5 hours during which time it reached -20°C.
• the reaction was cooled to -75°C and quenched with glacial acetic acid (1.0ml), partititioned between brine (100ml) and ethyl acetate (100ml).
• the organic layer was washed with water, dried (MgSO 4 ), and evaporated to a coloured oil.
• 6-(4-Fluorophenyl)hexylamine (0.76g, 0.00389moles) in dry DMF (40ml) was added to a mixture of 2-(4-benzylthio-2-oxoazetidin-1-yl)-3-phenylpropionic acid (1.33g, 0.00389moles), 1-hydroxybenzotriazole (0.52g, 0.00385moles), N,N'- dicyclohexylcarbodiimide (0.8g, 0.00388moles) and was stirred at room temperature for 4h. The suspension was diluted with ethyl acetate (100ml) and filtered to remove urea.
• the title compound was a so obtained from the b2 diastereoisomer by chiral HPLC and was isolated a gum
• the resulting suspension was stirred at -75°C for 30 minutes and then treated with allyl iodide (3.1ml, 0.0339moles) over 5 minutes .
• the temperature rose to -65°C.
• the reaction was stirred at -78°C for 30 minutes and then allowed to warm to -20°C over 30 minutes.
• the reaction was cooled to -75°C and quenched with glacial acetic acid (5ml), partititioned between brine (150ml) and ethyl acetate (175ml).
• the organic layer was washed with brine, dried (MgSO 4 ), and evaporated to a coloured oil.
• 6-(4-Huorophenyl)hexylamine (2.5g, 0.0128moles) in dry DMF (75ml) was added to a mixture of 2-(4-benzylthio-2-oxoazetidin-1-yl)-2-allylacetic acid (3.73g, 0.0128moles), 1-hydroxybenzotriazole (1.75g, 0.0129moles), 1-cyclohexyl-3-(2-morpholinoethyl)carbodiimide metho-p-toluene sulfonate (5.42g, 0.0128moles) and was stirred at room temperature for 19h.
• Example 44b corresponding amounts of the other reagents in Example 44b gave the title compound as a mixture of diastereoisomers (colourless oil), 0.8 g, 82% yield.
• reaction mixture was stirred for 30 minutes and a further 1.0ml of 1N sodium hydroxide solution was added.
• the reaction was stirred for 30 minutes, brine (75ml) was added and the reaction mixture was extracted with diethyl ether (75ml).
• the aqueous was acidified with 2NHCl and extracted with diethyl ether (2 ⁇ 75ml).
• dicyclohexylcarbodiimide( 1.46g) in dimethylformamide (50ml) was stirred at room temperature for 4 hours.
• the reaction mixture was treated with dietiiyl ether (100ml) and filtered to remove dicyclohexylurea.
• the filtrate was washed with saturated sodium hydrogen carbonate solution, brine, dried (MgSO 4 ) and evaporated to dryness.
• triphenylphosphine (6mg)i in dry dichloromethane (5ml) was treated with pyrollidine (0.039ml) and the reaction was stirred at room temperature for 20 hours.
• the reaction mixture was treated with dichloromethane (50ml) and water (25ml) and acidified with 2NHCl.
• Brine (75ml) was added to the emulsion, the layers were separated and the aqueous was washed with dichloromethane (2 ⁇ 50ml).
• the organic extracts were dried (MgSO 4 ) and evaporated to a yellow gum (0.22g) and purified by flash column chromatography on silica gel eluted with 50:50:1
• Example 138 (+/-)-4-( 2-furylmethylthio)-1-(9-phenylnonyl)azetidin-2-one
• a suspension of sodium hydride (3.65 mmol) in dry THF (10 ml) was cooled in ice/salt, and a solution of (+/-)-4-( 2-furylmethylthio)azetidin-2-one (0.61 g, 3.32 mmol) in THF (10 ml) was added dropwise below 5°C.
• the resulting solution was further cooled to -10°C, and a solution of 9-phenylnonyl-1-triflate (1.17 g, 3.32 mmol) in THF (10 ml) was added gradually over 1 min. After stirring for a further 5 min at 0°C, the reaction mixture was poured into brine and extracted with ether.
• Example 140 (+/-)-4-( 2-furylmethylthio)-H9-(4-fluorophenyl)nonyl)azetidin-2-one
• the synthesis was carried out as in example 138, using (+/-)-4-( 2-furylmethylthio)azetidin-2-one (1.5 g, 8.2 mmol) and 9-(4-fluorophenyl)nonyl-1-triflate (2.9 g, 7.8 mmol).
• Chromatography sica, 10-25% EtOAc in pet. ether gave the title compound as an oil (0.56 g).
• tetrahydrofuran 150 ml was cooled to -30°C and a solution of potassium t-butoxide (1.85 g, 0.0165 mol) in dry tetrahydrofuran (80 ml) added dropwise over 15 min. The temperature was allowed to rise to 10°C over 2 hr, then the mixture diluted with water and extracted with ethyl acetate, filtering off and discarding any insoluble solids, the extracts were dried (MgSO 4 ), evaporated, and die product purified by flash
• Example 148 N-(6- ⁇ 4-Chlorophenyl ⁇ hexyI)-4-(5-allyloxycarbonyIfuran-2methylsulphinyl-2-oxoazetidin-1-yl)acetamide (Diastereomer 1).
• Example 135b Treatment of 4-(5-methoxycarbonylfuran-2-methyl)thioazetidin-2-one (Example 135b) and N-(4-fluorophenylhex-1-yl)bromoacetamide in dry tetrahydrofuran with a solution of potassium t-butoxide in dry tetrahydrofuran at -30°C, followed by work-up as described for Example 143 gave the title compound as a pale yellow oil, 55% yield.
• 1H NMR ⁇ (CDCI 3 ) 1.32 (4H, m, N(CH 2 ) 2 (CH 2 ) 2 ), 1.54 (4H, m, NCH 2 CH 2 +
• Example 152 N-[6-(4-Fluorophenyl)hex-1-yI]-4-(5-methoxycarbonylfuran-2- methylsulphinyl)-2-oxoazetidin-1-ylacetamide (Diastereomer 1)
• 3-methyl-4-phenoxyazetidin-2-one was prepared from 3-methyl-4-acetoxyazetidin-2-one as described in Prep 1 above and subsequently treated with N-(6-phenylhexyl)bromoacetamide as for Example 201 to give the title compound as a pale yellow oil, 52.3% yield.
• Examples 312 - 327) were prepared in the same way as described for Examples 2 and 3.

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