NZ332476A - substituted 4-(carboxybenzylsulphinyl)-2-oxo-azetidine derivatives - Google Patents
substituted 4-(carboxybenzylsulphinyl)-2-oxo-azetidine derivativesInfo
- Publication number
- NZ332476A NZ332476A NZ332476A NZ33247697A NZ332476A NZ 332476 A NZ332476 A NZ 332476A NZ 332476 A NZ332476 A NZ 332476A NZ 33247697 A NZ33247697 A NZ 33247697A NZ 332476 A NZ332476 A NZ 332476A
- Authority
- NZ
- New Zealand
- Prior art keywords
- compound
- oxoazetidin
- fluorophenyl
- alkyl
- formula
- Prior art date
Links
- DJEMGFRHNCESMF-UHFFFAOYSA-N 2-(4-oxoazetidin-2-yl)sulfinyl-2-phenylacetic acid Chemical class C(=O)(O)C(C1=CC=CC=C1)S(=O)C1CC(N1)=O DJEMGFRHNCESMF-UHFFFAOYSA-N 0.000 title 1
- -1 2-oxo-azetidin-1-yl Chemical class 0.000 claims abstract description 68
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 51
- 150000002148 esters Chemical class 0.000 claims abstract description 26
- 150000003839 salts Chemical class 0.000 claims abstract description 26
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 8
- 206010012601 diabetes mellitus Diseases 0.000 claims abstract description 7
- 125000002947 alkylene group Chemical group 0.000 claims abstract description 6
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims abstract description 5
- 235000019256 formaldehyde Nutrition 0.000 claims abstract description 5
- 206010002383 Angina Pectoris Diseases 0.000 claims abstract description 4
- 206010020772 Hypertension Diseases 0.000 claims abstract description 4
- 201000004681 Psoriasis Diseases 0.000 claims abstract description 4
- 201000000980 schizophrenia Diseases 0.000 claims abstract description 4
- 125000003107 substituted aryl group Chemical group 0.000 claims abstract description 4
- 206010040047 Sepsis Diseases 0.000 claims abstract description 3
- 230000010410 reperfusion Effects 0.000 claims abstract description 3
- 150000001875 compounds Chemical class 0.000 claims description 149
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 52
- 235000011468 Albizia julibrissin Nutrition 0.000 claims description 51
- 241001070944 Mimosa Species 0.000 claims description 51
- 239000002253 acid Substances 0.000 claims description 47
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 44
- 238000006243 chemical reaction Methods 0.000 claims description 36
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 24
- 229910052739 hydrogen Inorganic materials 0.000 claims description 24
- 239000001257 hydrogen Substances 0.000 claims description 21
- 238000000034 method Methods 0.000 claims description 19
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 18
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 18
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 17
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 15
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 13
- 230000008569 process Effects 0.000 claims description 12
- 125000003707 hexyloxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 claims description 11
- 208000035475 disorder Diseases 0.000 claims description 10
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 9
- 238000001727 in vivo Methods 0.000 claims description 9
- 238000004519 manufacturing process Methods 0.000 claims description 9
- 239000002904 solvent Substances 0.000 claims description 9
- 230000015572 biosynthetic process Effects 0.000 claims description 7
- 125000003545 alkoxy group Chemical group 0.000 claims description 6
- 229910052717 sulfur Inorganic materials 0.000 claims description 6
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 5
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 5
- 238000001640 fractional crystallisation Methods 0.000 claims description 5
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 5
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 4
- 208000038016 acute inflammation Diseases 0.000 claims description 4
- 230000006022 acute inflammation Effects 0.000 claims description 4
- 125000003342 alkenyl group Chemical group 0.000 claims description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 4
- 239000000872 buffer Substances 0.000 claims description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 4
- 208000037976 chronic inflammation Diseases 0.000 claims description 4
- 230000006020 chronic inflammation Effects 0.000 claims description 4
- KMPWYEUPVWOPIM-KODHJQJWSA-N cinchonidine Chemical compound C1=CC=C2C([C@H]([C@H]3[N@]4CC[C@H]([C@H](C4)C=C)C3)O)=CC=NC2=C1 KMPWYEUPVWOPIM-KODHJQJWSA-N 0.000 claims description 4
- KMPWYEUPVWOPIM-UHFFFAOYSA-N cinchonidine Natural products C1=CC=C2C(C(C3N4CCC(C(C4)C=C)C3)O)=CC=NC2=C1 KMPWYEUPVWOPIM-UHFFFAOYSA-N 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 4
- 208000010125 myocardial infarction Diseases 0.000 claims description 4
- 229910052760 oxygen Inorganic materials 0.000 claims description 4
- 239000001301 oxygen Substances 0.000 claims description 4
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 4
- 238000002560 therapeutic procedure Methods 0.000 claims description 4
- PMXFDIYZZWEBRW-UHFFFAOYSA-N 4-[[1-[1-[2-(2-fluorophenyl)hexoxy]ethyl]-4-oxoazetidin-2-yl]sulfinylmethyl]benzoic acid Chemical compound C=1C=CC=C(F)C=1C(CCCC)COC(C)N(C(C1)=O)C1S(=O)CC1=CC=C(C(O)=O)C=C1 PMXFDIYZZWEBRW-UHFFFAOYSA-N 0.000 claims description 3
- 208000006011 Stroke Diseases 0.000 claims description 3
- 150000001408 amides Chemical class 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 3
- 125000004185 ester group Chemical group 0.000 claims description 3
- 125000001475 halogen functional group Chemical group 0.000 claims description 3
- 208000028867 ischemia Diseases 0.000 claims description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 3
- 159000000000 sodium salts Chemical class 0.000 claims description 3
- 125000001424 substituent group Chemical group 0.000 claims description 3
- 208000024827 Alzheimer disease Diseases 0.000 claims description 2
- 206010063837 Reperfusion injury Diseases 0.000 claims description 2
- MZVQCMJNVPIDEA-UHFFFAOYSA-N [CH2]CN(CC)CC Chemical group [CH2]CN(CC)CC MZVQCMJNVPIDEA-UHFFFAOYSA-N 0.000 claims description 2
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 claims description 2
- 230000003213 activating effect Effects 0.000 claims description 2
- 125000005041 acyloxyalkyl group Chemical group 0.000 claims description 2
- 150000001412 amines Chemical class 0.000 claims description 2
- 210000004556 brain Anatomy 0.000 claims description 2
- 125000004985 dialkyl amino alkyl group Chemical group 0.000 claims description 2
- 125000006264 diethylaminomethyl group Chemical group [H]C([H])([H])C([H])([H])N(C([H])([H])*)C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 125000006222 dimethylaminomethyl group Chemical group [H]C([H])([H])N(C([H])([H])[H])C([H])([H])* 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 230000004968 inflammatory condition Effects 0.000 claims description 2
- 125000000686 lactone group Chemical group 0.000 claims description 2
- 230000020477 pH reduction Effects 0.000 claims description 2
- 125000005633 phthalidyl group Chemical group 0.000 claims description 2
- 229910052700 potassium Inorganic materials 0.000 claims description 2
- 239000011780 sodium chloride Substances 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 3
- 239000003814 drug Substances 0.000 claims 2
- 101150026303 HEX1 gene Proteins 0.000 claims 1
- 229910019142 PO4 Inorganic materials 0.000 claims 1
- 102000057297 Pepsin A Human genes 0.000 claims 1
- 108090000284 Pepsin A Proteins 0.000 claims 1
- 238000000354 decomposition reaction Methods 0.000 claims 1
- 230000001747 exhibiting effect Effects 0.000 claims 1
- 239000012530 fluid Substances 0.000 claims 1
- 230000002496 gastric effect Effects 0.000 claims 1
- 229940111202 pepsin Drugs 0.000 claims 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims 1
- 239000010452 phosphate Substances 0.000 claims 1
- 201000001320 Atherosclerosis Diseases 0.000 abstract description 13
- 125000000547 substituted alkyl group Chemical group 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 162
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 152
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 112
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 88
- 239000000243 solution Substances 0.000 description 83
- 239000000203 mixture Substances 0.000 description 75
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 66
- 239000003921 oil Substances 0.000 description 63
- 235000019198 oils Nutrition 0.000 description 63
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 56
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 50
- 239000007787 solid Substances 0.000 description 46
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 38
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 37
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 36
- 239000012267 brine Substances 0.000 description 34
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 34
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 33
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 31
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 30
- 239000000284 extract Substances 0.000 description 29
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 28
- 238000003818 flash chromatography Methods 0.000 description 27
- 239000010410 layer Substances 0.000 description 27
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 26
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 25
- 239000000047 product Substances 0.000 description 25
- 238000000746 purification Methods 0.000 description 23
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 21
- 239000000741 silica gel Substances 0.000 description 21
- 229910002027 silica gel Inorganic materials 0.000 description 21
- 102000016752 1-Alkyl-2-acetylglycerophosphocholine Esterase Human genes 0.000 description 20
- 108010024976 Asparaginase Proteins 0.000 description 20
- 238000001816 cooling Methods 0.000 description 20
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 20
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 19
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- 238000001665 trituration Methods 0.000 description 17
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 16
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 16
- 101100073357 Streptomyces halstedii sch2 gene Proteins 0.000 description 15
- 229910052757 nitrogen Inorganic materials 0.000 description 15
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 14
- 239000000377 silicon dioxide Substances 0.000 description 14
- 101150041968 CDC13 gene Proteins 0.000 description 12
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 12
- 239000013078 crystal Substances 0.000 description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 12
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 12
- 229960000583 acetic acid Drugs 0.000 description 11
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 10
- 238000004587 chromatography analysis Methods 0.000 description 10
- 239000000706 filtrate Substances 0.000 description 10
- 239000002808 molecular sieve Substances 0.000 description 10
- 229910000027 potassium carbonate Inorganic materials 0.000 description 10
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 10
- 239000000725 suspension Substances 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- 235000019502 Orange oil Nutrition 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 239000000463 material Substances 0.000 description 9
- 239000010502 orange oil Substances 0.000 description 9
- 239000012044 organic layer Substances 0.000 description 9
- 235000017557 sodium bicarbonate Nutrition 0.000 description 9
- RYCNUMLMNKHWPZ-SNVBAGLBSA-N 1-acetyl-sn-glycero-3-phosphocholine Chemical compound CC(=O)OC[C@@H](O)COP([O-])(=O)OCC[N+](C)(C)C RYCNUMLMNKHWPZ-SNVBAGLBSA-N 0.000 description 8
- 102000004190 Enzymes Human genes 0.000 description 8
- 108090000790 Enzymes Proteins 0.000 description 8
- 239000004133 Sodium thiosulphate Substances 0.000 description 8
- 238000010828 elution Methods 0.000 description 8
- 235000010265 sodium sulphite Nutrition 0.000 description 8
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 8
- 235000019345 sodium thiosulphate Nutrition 0.000 description 8
- MNFORVFSTILPAW-UHFFFAOYSA-N azetidin-2-one Chemical class O=C1CCN1 MNFORVFSTILPAW-UHFFFAOYSA-N 0.000 description 7
- 239000002585 base Substances 0.000 description 7
- 239000003112 inhibitor Substances 0.000 description 7
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- 239000006071 cream Substances 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 6
- 201000010099 disease Diseases 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
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- 150000003462 sulfoxides Chemical class 0.000 description 5
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 5
- 125000004149 thio group Chemical group *S* 0.000 description 5
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 4
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- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 description 4
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 3
- GVNVAWHJIKLAGL-UHFFFAOYSA-N 2-(cyclohexen-1-yl)cyclohexan-1-one Chemical compound O=C1CCCCC1C1=CCCCC1 GVNVAWHJIKLAGL-UHFFFAOYSA-N 0.000 description 3
- CQQSQBRPAJSTFB-UHFFFAOYSA-N 4-(bromomethyl)benzoic acid Chemical compound OC(=O)C1=CC=C(CBr)C=C1 CQQSQBRPAJSTFB-UHFFFAOYSA-N 0.000 description 3
- 241000282472 Canis lupus familiaris Species 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
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- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
- CBENFWSGALASAD-UHFFFAOYSA-N Ozone Chemical compound [O-][O+]=O CBENFWSGALASAD-UHFFFAOYSA-N 0.000 description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 3
- 102100038239 Protein Churchill Human genes 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 230000002152 alkylating effect Effects 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 230000008694 endothelial dysfunction Effects 0.000 description 3
- JTTXRFNOFFGPFI-UHFFFAOYSA-N ethyl 4-(chloromethyl)benzoate Chemical compound CCOC(=O)C1=CC=C(CCl)C=C1 JTTXRFNOFFGPFI-UHFFFAOYSA-N 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 3
- 230000003859 lipid peroxidation Effects 0.000 description 3
- 239000003358 phospholipase A2 inhibitor Substances 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
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- 230000001575 pathological effect Effects 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 230000010412 perfusion Effects 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- 229960005235 piperonyl butoxide Drugs 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- FYPMFJGVHOHGLL-UHFFFAOYSA-N probucol Chemical compound C=1C(C(C)(C)C)=C(O)C(C(C)(C)C)=CC=1SC(C)(C)SC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 FYPMFJGVHOHGLL-UHFFFAOYSA-N 0.000 description 1
- 229960003912 probucol Drugs 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- ZZTZFWQBSIBRSW-UHFFFAOYSA-N prop-2-enyl 4-(bromomethyl)benzoate Chemical compound BrCC1=CC=C(C(=O)OCC=C)C=C1 ZZTZFWQBSIBRSW-UHFFFAOYSA-N 0.000 description 1
- QLNJFJADRCOGBJ-UHFFFAOYSA-N propionamide Chemical compound CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 0.000 description 1
- 229940080818 propionamide Drugs 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 229910052702 rhenium Inorganic materials 0.000 description 1
- 231100000489 sensitizer Toxicity 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 150000004760 silicates Chemical class 0.000 description 1
- 229910001961 silver nitrate Inorganic materials 0.000 description 1
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical class [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- HJHVQCXHVMGZNC-JCJNLNMISA-M sodium;(2z)-2-[(3r,4s,5s,8s,9s,10s,11r,13r,14s,16s)-16-acetyloxy-3,11-dihydroxy-4,8,10,14-tetramethyl-2,3,4,5,6,7,9,11,12,13,15,16-dodecahydro-1h-cyclopenta[a]phenanthren-17-ylidene]-6-methylhept-5-enoate Chemical class [Na+].O[C@@H]([C@@H]12)C[C@H]3\C(=C(/CCC=C(C)C)C([O-])=O)[C@@H](OC(C)=O)C[C@]3(C)[C@@]2(C)CC[C@@H]2[C@]1(C)CC[C@@H](O)[C@H]2C HJHVQCXHVMGZNC-JCJNLNMISA-M 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 125000001273 sulfonato group Chemical class [O-]S(*)(=O)=O 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- IWSMEGWDSKFNAR-UHFFFAOYSA-N tert-butyl iodomethyl carbonate Chemical compound CC(C)(C)OC(=O)OCI IWSMEGWDSKFNAR-UHFFFAOYSA-N 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- CYTQBVOFDCPGCX-UHFFFAOYSA-N trimethyl phosphite Chemical compound COP(OC)OC CYTQBVOFDCPGCX-UHFFFAOYSA-N 0.000 description 1
- 230000007306 turnover Effects 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
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- A—HUMAN NECESSITIES
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- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
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- A61P19/00—Drugs for skeletal disorders
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- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
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- 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]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P3/00—Drugs for disorders of the metabolism
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- 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
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- 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
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- 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
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- A—HUMAN NECESSITIES
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- 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
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Abstract
The 2-oxo-azetidin-1-yl derivative has the formula I wherein: R1 is H or the corresponding pharmaceutically acceptable ester or pharmaceutically acceptable salt thereof; R2 and R3 are independently H or optionally substituted alkyl; X is X'-(CH2)m or an alkylene chain optionally interrupted by X'; X' is CO, CONR4, COO, CONR4CO, CONHCO or CH2O; R4 is H or alkyl; m is 0 to 12; Y is an optionally substituted aryl group. The 2-oxo-azetidin-1-yl has an absolute configuration (4R, SS). A pharmaceutical composition thereof is useful for treating atherosclerosis, diabetes, hypertension, angina pectoris, reperfusion stoke, sepsis, psoriasis or schizophrenia.
Description
New Zealand Paient Spedficaiion for Paient Number 332476
%
Intellectual Property Office of New Zealand IP Summary Report
Page: 1 of 1 Date: 02 June 2000 Time: 16:49:35 (Iprip02 2.00.23)
(51) Classification: A61K31/395, C07D205/09, C07D405/12
IPC Edition: IPC
Status: 70 Accepted
332476
Client Ref: P398456 THS/gg
Version number 5 IP type: Patent PCT Inward
Date actions completed: Application Accepted Next renewal date:
(86) International Application number: EP97/01898
(87) WO Publication number: 97/41098
Elected: Y
(22) NZ Filing date: 15 April 1337 Date entered National phase: 23 October 1998 (30) Priority Data: (31)96 9608646 (32) 26 Apr»1996 (33) EP (30) Priority Data: (31)93 9623756 (32) 15 November 1996 (33) EP
(30) Priority Data: (31) 96 9625121 (32) 03 December 1996 (33) EP
(71) Applicant: SMITHKLINE BEECHAM PLC, New Horizons
Court, Brentford, Middlesex TW8 9EP, United Kingdom
(72) Inventors: Leach, Colin Andrew
Hlckey, Deirdre Mary Bemadetto Ife, Robert John Theobald, Colin Dhanak, Dashyant Contact- A J PARK, 6th Floor, Huddart Parker Building, 1 Post
Office Square, Wellington, New Zealand Primary Examiner: JENNY JEBSON Journal: 1452
Office title: substituted 4-fcarboxybenzylsulphinyl)-2-oxo-azetidine derivatives (54) Applicant title: Azetldlnone derivatives for the treatment of atherosclerosis Drawing:
02 June 2000 15 April 2001
'C3~co'b'
0 crV —XY
Ct)
" End of report "
AZETIDINONE DERIVATIVES FOR THE TREATMENT OF ATHEROSCLEROSIS
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-PLAj). 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-PLAj. A later patent application (WO 95/09921, Icos Corporation) and a related publication in Nature (Tjoelker etal, vol 374,6 April 1995,549) describe the enzyme PAF-AH which has essentially the same sequence as Lp-PLA2 and suggest that it may have potenti<il as a therapuetic protein for regulating pathological inflammatory events.
It has been shown that 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. As such, 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.
The increased lysophosphatidylcholine content of oxidatively modified LDL is also thought to be responsible for the endothelial dysfunction observed in
Printed from Mimosa
PCT/EP97/D1I98
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 re perfusion.
In addition, 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.
Furthermore, 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).
An earlier patent application (WO 96/19451, SmithKline Beecham pic) discloses compounds of the formula (A):
in which:
Rl and r2. which may be the same or different, is each selected from hydrogen, halogen or optionally substituted C^.gjalkyl;
r3 is aryl or arylCfi^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-l. In addtion.
R'
ch2—x-Y
(A)
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PCIYEP97/0I898
PCT/EP96/05587 (SmithKline Beecham pic) discloses pro-drags of compounds of formula (A) in which R^ is a 4-carboxybenzyl group.
Compounds of formula (A) exist in a number of stereoisomeric forms. The C-4 carbon of the ^-lactam ring is a chiral centre which will give rise to the presence of stereoisomers. Furthermore, in compounds of formula (A) in which n is 1, that is suiphoxide 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. Preferred compounds of formula (A) are said to be those in which the relative configurations at C-4 and the SO moiety are R,S (4R,SS) and SJt (4S,SR) with the most preferred compounds having the absolute configuration (4A.S5).
Accordingly, the present invention provides for a compound of the formula (I):
wSOCH,^ y— CO,R'
jX
0 CRW —XY
a)
in which:
Rl is hydrogen or a corresponding pharmaceutically acceptable ester or t pharmaceutical^ acceptable salt thereof;
R? and R^ which may be the same or different is each selected from hydrogen or optionally substituted C( i.^aDcyl;
X is a group X (CH2)m in which X is CO. CONR4, COO, CONR^O, CONHO or CH2O in which R* is hydrogen or C(i_g)alkyl and m is 0 or an integer from i to 12. or a C(i_i2)*lkylene chain optionally intempted by X'; and Y is an optionally substituted aryl group;
having the absolute configuration (4A.S5).
Representative examples of X include CCKCF^W CONH(CH2)m. COO(CH2)m. CONHCO(CH2)in. CONHO(CH2)n, CH20(CH2)m and C(i.i2)alkylene. Preferably, X' is CO, CONR2 or CH2O, more preferably CONH. Preferably, m is 1,2, 5, 6,7 or 9, preferably 6. Suitably, X is CONH(CH2)6 or CH20(CH2)6. preferably CONH(CH2)6.
Suitably. R2 and R* is each hydrogen or R^ is hydrogen and R^ is methyl. Preferably, R? and R^ is each hydrogen. It will be readily appreciated that when
Printed from Mimosa
PCT/EP97/OI898
and R-* have different values, the carbon to which they are attached will be chiral. Preferably, the absolute configuration a£ this carbon is S. In such compounds of formuh (I), the absolute configuration of the preferred cnantiomer is (a-S, 4-R, S-S).
Suitably, Y is phenyl, optionally substituted by up to three further substituents. Suitiible substituents include halo, hydroxy, C(i_8)alkyl and C(i_g)alkoxy. Preferably, Y is phenyl optionally substituted by halo, more preferably 4-chloio or 4-fIuoro-phenyl, most preferably, 4-fluoro-phenyl.
Suitably X-Y is CONH(CH2>6Ph{4-F)/(4-CI).
Suitable p^iarmacentically acceptable esters include C(i_6)alkyl or C(2-6)aikenyl esters, as well as pharmaceutically acceptable in vivo hydrolysable esters. The skilled person will appreciate that simple C(i_6)alkyl or C(2-6>alkenyl ben;:oate 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 vh o 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)&lkenyl 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 R1 for use in vivo hydrolysable esters include: -CH(R«)O.CO.Rb;
-CH(R*)O.CO.ORc;
-CH(R»)CO.NReRf -RdNRCRf;
-CH2OR8;
h
X
R
O
-CK(Ra)O.CO.C6H4YlCOC,H(R')NH2: and
Printed from Mimosa
V 0 97/41098
O
in which:
Ra is hydrogen, (C j -6)alkyl, in particular methyl. (C3-7)cycloalkyI, or phenyl, each of which may be optionally substituted;
Rb is (Ci-6)alkyl, (C j -g)alkoxy(C i -gjalkyl, phenyl, benzyl, (C3*7)cycIoalkyl, (Ci-6)aikyl(C3-7)cycloalkyl, l-amino(Ci-g)alkyl, or
1-(C i -galkyUamino^C i*6)alkyl, each of which may be optionally substituted; or Ra and together form a 1,2-phenylene group optionally substituted by one or two methoxy groups;
Rc is (Cj-gJaikyl, (C3*7)cycIoalkyl, (Ci-6)alkyl(C3-7)cycloaIkyl;
Rd is (C]-5)alkylene optionally substituted with a methyl or ethyl group;
Re and Rf which may be the same or different is each (Cpgjalkyl; or aryl(Cj-4) alkyl, optionally substituted with e.g. hydroxy;
R8 is (Ci-6)alkyl;
Rh is hydrogen, {C]-g)alkyl or phenyl;
R* is hydrogen or phenyl optionally substituted by up to three groups selected from halogen. (Ci-g)-alkyl, or (Ci-6)alkoxy;
and
Yl is oxygen or NH.
Suitable values of R1 include:
(a) acyloxyalkyl groups such as acetoxymethyl, isobutyry' jsymethyl, pivaloyloxymethyl, benzoyloxymethyl, a-acetoxyethyl, a-pivaloyloxyethyl, l-(cyclohexylcaibooyloxy)ethyl. (l-aminoethyl)carbonyloxymethyl. 2-methoxyprop-2-ylcarbonyloxymethyl, phcnylcarbonyloxymethyl and 4-methoxypheny 1-carbony loxymethy I;
(b) alkoxy/cycloalkoxycarbonyloxyalkyl groups, such as ethoxycarbonyloxymethyl, t-butyloxycarbanyloxymethyl. cyclohexyloxycarbonyloxymethyt. 1 -methylcyclohexyloxycarbonyloxymethyl and o-ethoxycarbonyloxyethyl;
(c) dialkylaminoalkyl, especially di-loweralkylamino alkyl groups such as dimethylaminomethyl, dimethylaminoethyl, diethylaminomethyl or diethylaminoethyl;
Printed from Mimosa
(d) acetamido groups such as N»N-diraethylaminocarbonylrnethyl, N,N-(2-hydroxyethyl )aminocarbonylmethyl;
(e) lactone groups such as phthalidyl and dimethoxyphthalidyl;
(f) (5-methyl-2-oxo-13-dioxolen-4-yI)methyl; and
(g) (2-methoxycarbonyl-£-but-2-en-yl)methyl
Representative examples of R1 include: (2-raeihoxycarbonyl-£-but-2-en-yl)methyl, isobutyryloxymethyl, 2-methoxyprop-2-ylcarbonyloxymethyl, phenylcarbonyloxymethyl. 4-methoxyphenyl-carbonyloxymethyl, t-butyloxycarbonyloxymethyl. cyclobexyloxy-carbonyloxymethyl. 1 -methylcyclohexyloxycarbony ioxymethyl, N.N-dimethylarainocarbonylmethyl, N-N-di-(2-
hydroxyethyl)aminocarbonylmethyloxy and (5-methyI-2-oxo-l,3-dioxolen-4-yl)methyl.
Especially preferred compounds of Formula (1) include: (4R, S5)-N-(6-(4-Fluorophenyl)hex- l-yl]-4-(4-carboxybenzylsulphinyi)-2-oxoazetidin-l-yllacetamide and pharmaceutical acceptable salts thereof, in particular the sodium salt
Since 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 0) 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.
When some of the compounds of this invention arc allowed to crystallise or are recrystallised from organic solvents, solvent of crystallisation may be present in the crystalline product. This invention includes within its scope such solvates. Similarly, 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. In addition, different crystallisation
Printed from Mimosa
53 2 4 7
conditions may lead to the formation of different polymorphic forms of crystalline products. Thi^ invention includes within its scope all polymorphic forms of the compounds c f Formula (I).
Compounds of the present invention are inhibitors of the enzyme lipoprotein associated phospholipase A2 (Lp-PLA2> and «?s such are expected to be of use in therapy, in particular in the treatment of atherosclerosis. In a further aspect therefore the present invention provides a compound of Formula (I) for use in therapy.
The compounds of Formula (I; we inhibitors of lysophosphatidy lcholine production by Lp-PLA2 and m.\y therefore also have a general application in any disorder that involves endothell-U dysfunction, for example atherosclerosis, diabetes, hypertension, angina pectoris and after ischaemia and reperfusion. In addition, compounds of Formula (I) may have a general application in any disorder that involves lipid peroxidation in conjunction with en;:yme activity, for example in addition to conditions iuch 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 neuropsychiarric disorders such as schizophrenia (see Psychopharmacology Bulletin, 31, 15 )-165, 1995).
Further applications include any disorder that involves .activated monocytes, macrophages or lymphocyies, as all of these cell types express Lp-PLAj. Examples of such disorders include psoriasis.
Accordingly, the present invetv ion provides for a method of treating a disease state assoc iated 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 ::nzyme. The disease state may be associated with the increased involvement of monocytes, macrophages or lymphocytes; with the formation of lyjophosphatidylcholine 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 ar.ti-anginal or anti-inflammatory or anti-hypertension agents. Examples of the above include cholesterol synthesis
INTELLECTUAL PROPERIY OFFICE OF N.Z.
16 MAY 2000
PCT/EP97/01B98
inhibitors such as statins, anti-oxidants such as probucol. insulin sensitisers. calcium channel antagonists., and anti-inflammatory drugs such as NSAIDs.
In therapeutic use, 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 pharmaceutical^ 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 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 pharmaceutical^ 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 composition in the form of a tablet can be prepared using any suitable pharmaceutical carrier(s) routinely used for preparing solid formulations. Examples of such carriers include magnesium stearate. starch, lactose, sucrose and cellulose.
A composition in the form of a capsule can be prepared using routine encapsulation procedures. For example, 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 cairier(s), for example aqueous gums, celluloses, silicates or oils and the dispersion or suspension then Tilled 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. Alternatively, 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.
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Preferably 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 foi 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. Suitably the compounds will be administered for a period of continuous therapy, for example for a week or more.
Compounds of forrrula (1) may be prepared from convenient starting materials by adapting synthetic procedures well known in (he art, with reference to earlier applications WO 96/19451 and WO 97/02242 (SmithKline Beecham pic).
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 (II):
o
(II)
in which Rl is C().5)alkyl or C(2^)alkenyl and and R^ are as hereinbefore defined, and having the absolute configuration (4R.SS);
with an amine of the formula (III):
H2N(CH2)nY
(in)
under suitable amide forming conditions, for instance in the presence of an activating agent such as N,N-dicyclohexy)carbodiimide and 1-hydroxybenzotriazole in a suitable solvent such as dry dimethylformamide; and thereafter, and if necessary.
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PCT/EP97/D1898
(a) removing the ester group under suitable de-esterifying conditions to form the acid;
(b) converting the acid to a pharmaceutically acceptable salt; and/or
(c) converting the acid, a suitable salt, the ester or an activated derivative of the acid, to an in vivo hydrolysable ester by reaction with a compound of formula (TV):
r!R4
(IV)
in which:
R4 is a reactive esterifying leaving group; and Rl is as hereinbefore defined;
under ester forming conditions.
In step (a) above, the free acid may be regenerated from a corresponding compound in which the carboxy group is protected as a C(i.g)alkyl or C(2-fi)alkenyl ester; using methods well known in the art for the particular protecting group, for instance, when an allyl group, using palladium catalysed de-allylation (triphenylphosphine/ pyrrolidine/ tetrakis triphenyl-phosphinepalladium(O) in dichloromethane).
In 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 ait and are described in, for instance. Comprehensive Organic Synthesis, Pergamon Press. 1991,6, 323-380. Suitable ester forming conditions include:
(a) reacting a salt of the acid, for instance, a sodium or a tertiary amine salt such as triethylaroioe. with a compound of formula (TV), in a polar aprotic solvent such as dimethyl formamide, dimethyl suiphoxide or acetonitrile, at moderate temperature, for instance in the range 0 to 100°C;
(b) reacting the acid with a compound of formula (IV) in the presence of a base such as an alkali metal carbonate or a tertiary amine, in a polar aprotic solvent and temperature as for (a);
(c) reacting the acid with a compound of formula (IV) in which R? is a hydroxy! group, under dehydrating conditions, for instance the Mitsunobu reaction employing an azodicarboxylate and a trivalent phosphorus reagent (Mitsunobu, Synthesis, 1981, 1); or
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(d) reacting an activated derivative of the acid, for instance a mixed anhydride, for instance an uo-butylcarbonic or a methane sulphonic anhydride or a carbodiimide (DCC) adduct, with a compound of formula (TV) in which R7 is a hydroxy! group, in the presence of a suitable base such as a tertiary amine, for instance, uiethylamine, in an aprotic solvent such as tetrahydrofuran, at a moderate temperature, preferably in the range -20 to +20°C, or alternatively, in the absence of a base but using a preformed salt of the alcohol, for instance the magnesium or lithium alkoxide.
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 (IV).
Compounds of formula (II) are useful intermediates in the preparation of a compound of formula (I). Accordingly, in a further aspect, the present invention provides for a compound of formula (II) as hereinbefore defined.
Compounds of formula (II) are sulfoxides and may be readily prepared by oxidising a corresponding thio compound of formula (V):
in which R*. and R^ art as hereinbefore defined, and having the absolute configuration (4J?);
with a conventional oxidising agent such as rn-chloroperbenzoic acid (mcpba) or ozone and thereafter and, if necessary, isolating the required diastereoisomer having the desired absolute configuration (4R, S5), for instance by fractional crystallisation and/or chromatography.
Compounds of formula (V) are of use in preparing compounds of formula (I). Accordingly, in a further aspect, the present invention provides for compounds of formula (V) as hereinbefore defined.
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 (III), to form the amide
(V)
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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
Compounds of formula (V) having the absolute configuration (47?) may be obtained from the com spending racemic compound of formula (VI):
in which R* is a carboxy protecting group, for instance C(]^)alkyl or C(2-6)*lkenyl and R2 and R3 are as hereinbefore defined;
via the formation of a diastereoisomeric salt with a chiral base such as (-)-cinchonidine; and thereafter:
(a) isolating the preferred diastereoisomeric salt may be obtained by fractional crystallisation; and then
(b) generating the enantiomeric free acid therefrom by acidification.
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.
Compounds of formula (VI) may be obtained according to the procedures described in earlier applications WO 96/19451 and WO 97/02242 (SmithKline Beecham pic).
The process hereinbefore described for compounds of formula (I), as well as an alternative process for preparing compounds of formula (II). in which R^ and R^ is each hydrogen is summarised in the following scheme, in which R corresponds to CF^C^lfyCOjR *:
ctfR* COjH
(VI)
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PCT/Ef97/01898
O O V—CO,N*«
Q*C *» am - l— ,/*" •»*«*
I
0>
o
K rf o<*~N\--C0 »•<«*,»*** 0^~N^_CO,H
<>) on ar
* M / i) lw 1) IH
^ ^— '»«» v_/ n A«wco.iaw
J—n Tnk+o& LA a u»-« J-n _
a 0^Ms-co^t o ^«vmi
Compounds of formula (I) in which is hydrogen and is alkyl, for instance methyl, may be usefully prepared by a corresponding process in which the alkyl group is introduced at an early stage, by alkylating an azetidinone acetate of formula (VII):
^SCHjC.H, —co,n*
° N— CO,»*M
(VD)
in which R** is C(i.5)alkyl. for instance, methyl, and R* is as hereinbefore defined;
with an alkylating agent under standard alkylating conditions; and thereafter, isolating the diastereoisomers thus obtained by fractional crystallisation and/or chromatography. Suitably, the compound of formula (VII) may be a single enantiomer, having the required absolute configuration (AR).
Suiuble 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. Other suiuble conditions include lithium bisUrimethylsilyDamide in THF. optionally with 1.3*dimethyli:nidazoUdin-2-one. and at a temperature of about -70°C.
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PCT/EP97/01W8
The newly formed propionate ester may then be converted to the corresponding Kid. using basic conditions such as aqueous sodium hydroxide in THF. followed by amide bond fonnation 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.
The sequences can be readily adapted for other values of X, by reference to earlier applications WO 96/19451 and WO 97/02242 (SmithKline Beecham pic).
For instance, 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 (VIII):
in which one of L2 and is a halogen or another suitable leaving group such as triflate or tosylate and the other is OH or a suitable salt therof and m and Y are as hereinbefore defined; under standard ether forming conditions. The thus formed ether compound may then be treated with an oxidising agent to convert the thio group into a sulphinyl group, to give a compound of formula (II
If lh" compound of formul* (VIII) 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.
(VHD
in which R1. R2 and R3 are as hereinbefore defined; with a compound of formula (IX):
L3(CH2)mY
(DO
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PCI7ET97/01898
Suitable compounds of formula (VHI) may be prepared by analogy with the processes described in WO 97/02242.
Compounds of formula (I) which are in vivo hydrolysable pharmaceutically acceptable estr »may be conveniently prepared from the corresponding parent acid by a process which compromises treating the corresponding parent acid or a salt, alkyl ester or activated derivative thereof;
The present invention will now be illustrated by the following examples. Chiral compounds are described as 4/? or 45. SR or SS where the 4 describes the centre at the C4 position in the azetidinone and the S describes the sulfoxide centre. Diastereoisomer 1 derived from a 4ft sulfide has the configuration 4R, SR. The corresponding diastereoisomer 2 is 4R, Sj. Such configurations are by extrapolation, based on their 'H NMR spectra, from configurations obtained initially by x-ray analysis of a limited number of compounds. The absolute configuration at the chiral a-carbon, when one of R2 and is hydrogen and the other is methyl, is described as a-R or a-5.
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Example 1 - (R)-N*l6-{4-Fluorophenyl)hex-l-yl]-4-(4-alloxycarbonyIbenzylthio)-2-oxoazetidjn-l-yl)acetaniide a. Ally! 4-(bromomethyl)benzoale
4-(Bromomethyl)benzoic acid (103 g, 0.48 moles)was suspended in thionyl chloride (200 m!) and dimethylformamide (1 ml) was added. The mixture was heated under reflux until clear, evaporated and azectroped with toluene (2 x 150 ml). The resulting oil was dissolved in dichloromethane and added dropwise to a cooled solution of pyridine (42 ml) and allyl alcohol (40 ml) in dichloromethane. The mixture was stirred at room temperature for 1 hour, then washed with water, 2M hydrochloric acid, sodium hydrogen carbonate solution and brine. The organic v^ution was dried and evaporated to give aliyl 4-(bromomethyl)benzoate as a clear oil (98g, 84% yield). 'H NMR d (CDC1,) 4.61 (2H, s, CH,), 4.82 (2H, m, CHjO). 5.34 (2H, m, C&CH-). 6.05 (1H. m, CHCH,), 7.45 (2H. d, Ph-H), 8.03 (2H, d. Ph-H).
b. Allyl 4-{acetylthiomethyl)benzoate
Allyl 4-(bromomethyl)benzoate (98 g, 0.4 moles) in dry dimethylformamide (100 ml) was added dropwise to a cooled suspension of potassium thioacetate (46 g. 0.4 moles) in dry dimethylformamide (200 ml). The cooling bath was removed and the mixture was stirred ovemighL The rection mixture was poured into water and extracted with ethyl acetate (x3). The combined extracts were washed with water and brine. The mixture was dried and evaporated to give allyl 4-(acetylthiomethyl)benzoate as an orange oil (lOOg, 100% yield). 'H NMR d (CDC1,) 2.36 (3H. s. COCH,), 4.13 (2H. s, CH2), 4.82 (2H, m, CH,0), 5.32 (2H, m, CHjCH-). 6.05 (1H, m, CHCH,), 7.35 (2H, d. Ph-H), 7.98 (2H, d, Ph-H).
c. 4-(4-(Allyloxycarbony!)benzy!thio)azetidin-2-one
Allyl alcohol (27 ml) in dry tetrahydrofuran (50 ml) was added dropwise to a solution of potassium rerr-butoxide (4.93 g. 0.044 moles) in dry tetrahydrofuran (100 ml). After stining for 5 minutes a solution of allyl 4-(acetylthiomethyl)benzoate (10.1 g, 0.04 moles) in dry tetrahydrofuran (100 ml) w&r- udded dropwise. After stining for 15 minutes a solution of 4-acetoxyazetidin-2-one (5.16 g, 0.04 moles) was added dropwise. The mixture was stirred for 1 hour and evaporated. The residue was partitioned between ethyl acetate and water and the aqueouse was extracted with ethyl acetate. The combined extracts were washed with brine, dried and evaporated. Flash chromatography (silica gel. ethyl acetate-petrol) gave 4-(4-allyloxycarbonylbenzylthio)azetidin-2-one as an oil (9.1g, 82% yield). 'H NMR d (CDCy 2.84 (!H, dd, H3a), 4.31 (1H. dd, H3b), 3.88 (2H, s, S-CH2), 4.68 (1H, dd, H4), 4.78 (2H, m, CH,0), 5.35 (2H, ra. CH,CH), 6.05 (1H. m, CHCH,), 6.07 (IH. br. singlet. N-H). 7.40 (2H, d. Ph-H), 8.03 (2H. d, Ph-H).
d. Methyl 4-(4-(Allyloxyearbonyl)benzylthio)-2-oxoazetidln-l-ylacetate
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To a stirring solution of 4-(4-(ailyloxycarbonyl)benzylthio)azetidin-2-one (2.55 g, 9.2 mmol), tetrabutylammonium bromide (0.33 g. 1.02 mmol) and methyl bromoacelate (1.06 ml. 11.2 mmol) in dry tetrahydrofuran (40 ml) was added powdered potassium hydroxide (0.63 g. 11.2 mmol) keeping the reaction temperature below 30 by means of a cold water bath. After 2 h, the mixture was diluted with water and extracted three times with ethyl acetate. The combined extracts were dried (MgS04) and evaporated and the residue chroma tographed (fine silica, ethyl acetate-petrol) to give the title compound as a clear oil. yield 2.66 g (83%).
'H NMR S (CDCI3) 2.97 (1H, dd. H3a), 3.26, 4.07 (each 1H, CH^O, d), 3.42 (1H. dd, H3b), 3.70 (3H. s, CH3O), 3.81 (2H, s. SCH2), 4-83 (2H, m, CH20), 4.93 (1H, dd. H4). 5.35 (2H, m. QfcCH). 6.03 (1H. m, CHCH2), 7.39 (2H, d. Ph-H). 8.02 (2H, d, Ph-H)
e. (+/-)-4-(4-(Allyloxycarbonyl)benzylthio)-2-oxoazetidin-l-ylacetic acid
To a solution of methyl 4-(4-(allyloxycarbonyl)benzylthio)-2-oxoazetidin-l-ylacetate (2.17 g, 6.21 mmol) 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. hydrochloric acid"* with cooling and the oil which precipited was extracted into ether. The combined extracts were dried (MgS04) and evaporated to a clear oil which eventually crystallised under petrol and was filtered, washed and dried to give the title compound as white crystals. 1.87 g, 90% yield 'H NMR 5 (CDCI3) 2.98 (1H, dd. H3a), 3.34, 4.06 (each 1H. CifeCO. d). 3.42 (1H, dd, H3b), 3.82 (2H. s. SCH2), 4.82 (2H. m, CH20), 4.92 (1H, dd, H4). 5.34 (2H, m. QfcCH), 6.03 (1H, m. CHCH2), 7.39 (2H, d. Ph-H). 8.02 (2H. d. Ph-H)
f. (-)-(R)-4-(4-(Allyloxycarbonyl)benzylthio)-2-oxoazetjdJn-l-ylacetic add 4-(4-(Allyloxycarbonyl)benzylthio)-2-oxoazetidin-l-ylacetic acid ( 3.41 g, 10.2 mmol) and cinchonidine (2.99 g, 10.2 mmol) in ethanol (40 ml) were heated to boiling when a clear solution was obtained. On standing for 90 min, the crystalline salt which had precipitated was filtered off. and recrystallised from ethanol (20 ml). The solid obtained was stirred vigorously with ether and water whilst acidifying with dil. hydrochloric acid, and when complete solution was obtained the layers were separated and the aqueous layer further extracted with ether. The combined extracts were dried (MgS04) and evaporated to an oil which crystallised on trituration with light petrol to give the title compound as white crystals, m.p. 74-6°C, 6.7 g, 50% yield a^" = -24.2 (c. 0.7 w/v CHC1,. 25°C)
'H NMR 8 (CDCI3) 2.97 (1H, dd, H3a). 3.26.4.07 (each 1H, CH2CO, d), 3.42 (1H, dd. H3b), 3.70 (3H. s. CH3O), 3.81 (2H, s, SCH2), 4.83 (2H, m, QfeO),
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4.93 (1H. dd. H4), 5.35 (2H. m. CH2CH). 6.03 (1H. ra. CHCH2). 739 (2H- d-Ph-H). 8,02 (2H. d. Ph-H)
g. (R)-N-[6-(4-Fluorophenyl)hex-l-yl]-4-(4-alloxyc£rbonylbenzylthio)-2-oxoazetidin-l-yl)acetamkle
To a cooled (ice bath) solution of (R)-4-(4-(ailyloxycarbonyl)benzylthio)-2-oxoazetidin-l-ylacetic acid (12,51 g. 0.0373 mol), 1-hydroxybenzotriazole hydrate (5.04 g, 0.0373 mol) and 6-(4-fluorophenyl)hexylamine (0.0373 mol) in dry dimethylformamide (150 ml) was added with stirring dicyclohexylcarbodiimide (7.29 g, 0.0373 mol). After 20 min the cooling bath was removed, and after a further 16 h, the solvent was evaporated under reduced pressure and the residue treated with ethyl acetate and the insoluble precipitate filtered off and discarded. The filtrate was further diluted with ethyl acetate, washed with 0.2 M hydrochloric acid, then saturated sodium hydrogen carbonate, dried and evaporated under reduced pressure. The residue was triturated with ethyl acetate/light petrol to give the title compound us white crystals, m.p. 54-7°C, 17 g. 89% yield
'H NMR 5 (CDC13) 1 JO-1.60 (8H, m. 4xCH,). 2.55 (2H. t. J=7.6 Hz, C&Ph),
2.90. 2.97 (1H. dd. J=2.4, 15.4 Hz.H,), 3.23 (2H, m. NHCH,). 3.35. 3.41 (1H. dd, J=5.1,15.4 Hz, 3.53, 3.78 (each 1H. d, J=16.6 Hz. NCfl,), 3.86 (2H. s, SCH,), 4.83 (3H, m, CO^H,. H.). 5.37 (2H, m, CH2=CH), 6.0 (2H, m. NH, CHj=CH), 6.94 (2H, m. 4-FPh-H), 7.10 (2H, m. 4-FPh-H). 7.39 (2H. d, J=8 3 Hz, 4-CO,allylPh-H), 8.02 (2H, d. J=8.3 Hz. 4-CO,allylPh-H)
Example 2 - (4/f, S5)-N-[6-<4-FluorophenyI)hex-l-y!]-4-(4-aOoxyau-bonylbcnzylsulphlnyI)-2-oxoazetidiin-l-yl)acetainlde
A solution of (R)-N-{6-(4-fluorophenyl)hex-l-yl]-4-(4-alloxycarbonylbenzylthio)-2-oxoazetidin-l-yl)acetamide (16.36 g. 0.0319 mol) in dichloromethane (150 ml) was cooled to -65 to -70 and a solution of m-chloroperbenzoic acid (6.61 g, 0.0383 mol) in dichloromethane (120 ml) added dropwise with stirring over 20 min. After 1 h, the mixture was washed with saturated sodium metabisulphite solution, then saturated sodium hydrogen carbonate, then dried (MgSC>4) and evaporated to a solid which was recrystallised from ethyl acetate to give a mixture of diastereoisomers 2 and 1 in the ratio 3:2. Chromatographic separation (HPLC) gave diastereomer 2 (4R, SS) as a white crystal' inc solid, m.p. 133-5°C, 33 g. 20% yield a/"0 = +74.0 (c. 0.6% w/v CHC1,, 25°C)
'H NMR 8 (CDCI3) 1.30-1.60 (8H. m. 4xCHj), 2.56 (2H. t, J=7.6 Hz. CH^Ph).
2.91. 2.95 (1H, dd. J=2.4, 15.2 Hz. H,). 3.27 (3H. m, NHCH,. H,). 3.94,4.22 (each 1H, d, J=17.2 Hz, NCH,), 4.04.4.18 (each 1H. d. J=12.8 Hz, SOCH,). 4.65 (1H. m. H.). 4.84 (2H, m. CO^H,), 5.37 (2H. m. CH,=CH), 6.0 (1H, m.
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PCF/EP97/01898
CH,=CH), 6.95 (3H, m, 4-FPh-H, NH).). 7.10 (2H, m, 4-FPh-H). 7.36 (2H, m. 4-CO,allylPh-H). 8.09 (2H. m. 4-CO,allylPh-H).
Example 3 - (4U, SJt)-N-[6-(4-Fluorophenyl)hex-l-yl]-4-(4-•lloxycarbonylbenzylsulphinyl )-2-oxoazetidJn-1 -yl)acetamidc
From the HPLC chromatography described in Example 2 above the other diastereoisomer (Dia 1:4R, SR) was obtained as a white crystalline solid (1.8 g. 11% yield) m.p. 175-7°C a^ =-119.7 (c. 0.5% w/v CHCl,. 25°C)
'H NMR 5 (CDCI,) 1.30-1.60 (8H, m, 4xCHj), 2.55 (2H, t, J=7.6 Hz, CH^h),
2.95.2.98 (1H. dd, J=4.8, 14.8 Hz. H3). 3.24 (2H, m. NHCH,), 3.42, 3.46 (1H, dd, J=2.4. 14.8 Hz, H3), 3.76,4.09 (each 1H. d, J=17.2 Hz. NCH,), 3.95,4.01 (each 1H. d. J=13.2 Hz, SOCH,). 4.59 (1H. m. H4). 4.84 (2H. m, COjCH,), 5.37 (2H, m. CH,=CH), 6.0 (1H. m, CH,=CH). 6.53 (1H. m, NH). 6.95 (2H, m, 4-FPh-H). 7.10 (2H. m, 4-FPh-H). 7.36 (2H. d. J=8 Hz, 4-COIallyIPh-H). 8.09 (2H, d, J=8 Hz, 4-COjallylPh-H).
Example 4 - (4R, SS)-N-{6-(4-FJuorophenyl)hex-l-yl]-4-(4-carboxy bcnzylsulphinyl)-2-oxoazetidin-1 -yl)acetamlde
A solution of (4/?, SS)-N-[6-(4-Fluorophenyl)hex-l-yI]-4-(4-alloxycarbonylbenzylsulphinyl)-2-oxoazetidin-l-yl)acetaniide (Example 2) (0.185 g, 0.35 mmol). triphenylphosphine (0.092 g, 0.35 mmol), pyrrolidine (0.033 ml, 0.4 mmol) and tetrakis triphenylphosphinepalladium(O) (0.012 g, 0.01 mmol) in dichloromethane (10 ml) was stirred under nitrogen for 16 h. A further 0.012 g (0.01 mmol) of tetrakis triphenylphosphinepalladium(O) was added and after a further 4 h the reaction was complete. The solution was diluted with water, acidified (2N HC1), the layers separated and the aqueous layer further extracted with dichloromethane. The combined extracts were dried (MgS04)and evaporated to a yellow oil, which was triturated with ether. A yellow solid was obtained which was filtered off and dissolved in sodium hydrogen carbonate solution. Shaking with ether gave an emulsion which was separated by treatment with ethyl acetate and centrifugation. The aqueous layer was then acidified (2N HQ) and extracted with dichloromethane. and the extracts dried (MgSC>4)and evaporated. The residue was triturated with ether to give a white solid which was filtered, washed and dried to give the title compound as a white solid, m.p. 105-7°C, 0.1 g. 58% yield a,,15*0 = -31.7 (c. 0.5% wN DMSO. 25°C)
'H NMR 8 (DMSO) 1.26 (4H. m. 2xCH,). 138 (2H. m, CH,). 1.50 (2H. m. CH,).
2.96.2.99 (1H, dd, J=2,15.2 Hz. H,). 3.06 (2H, m, NHCH,), 3.84,4.09 (each lH,d, J=17.2 Hz. NCH,). 4.13.4.31 (each 1H, d. J=12.8 Hz, SOCHJ, 4.84
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PCT/EP97/0I898
(1H. m,H«). 7.05 (2H, m, 4-FPh-H). 7.19 (2H. it,. 4-FPh-H). 7.47 (2H. d. J=8 Hz, 4-CO,allyIPh-H). 7.93 (2H. d. J=8 Hz, 4-CO:allylPh-H), 8.13 (1H, m, NH). 13 (1H, bs. COJi).
Example 5 - (-M4J?, SS)-N-[6-(4-Fluorophenyl)hex-l-y!]-4-(4-carboxybenzylsulphlny!)-2-oxoaiet<din-l-yl)acetainide, sodium sail A mixture of N-[6-(4-fluorophenyl)hex-l-yl]-4-(4-carboxybenzylsulphinyl)-2-oxoazetidin-l-yl)acetaiuide (0.51 g) and sodium bicarbonate (0.088 g) in water (15 ml) was sonicated for 5 min. methanol added (20 ml) and the mixture sonicated for a further 20 min. After filtration the solution was evapotated to a low volume, diluted with water and lyophilised to give the title compound as a white powder (0.52 g). m.p. 238-40°C. i^ = -31.7° (c 0.5, DMSO)
Example 6 - 4JT, SS-N-<6-(4-Fluorophenyl)hexyl)-4-(4-ethoxycarbonylbenzylsulphinylV2-oxoazetldln-l>ylacetamide a. Ethyl 4-(bromomethyl)benzoate
4-(Bromomethyl)benzotc acid (25.75g, 0.1197moles) was suspended in thionyl chloride (50ml) ana dimethylformamide (0.25ml) was added. The mixture was heated under reflux for 25 minutes until clear, evaporated and azeotroped with toluene (x2). The resulting oil was dissolved in dichloromethane (75ml) and added dropwise over 10 minutes to a solution of absolute alcohol (8.6ml. 0.1465moles). pyridine (10.5ml, 0.1298moles) in dry dichloromethane (50ml), cooled to 10°C. The ice bath was removed and the reaction was stirred for 45 minutes. then washed with water, 2NHC1, water, sodium hydrogen carbonate solution and brine. The organic solution was dried (MgS04) and evaporated to give a mixture of 60:40 ethyl 4-(bromomethyl)benzoate: ethyl 4-(chloromethyl)benzoate as an oil (25.6g, 94%)
*H nmr 8 (CDClj) 1.40 (3H. m, CH3). 4.40 (2H. m. CH20). 4.50, 4.61 (2H. 2xs. CH2CI/BO, 7.45 (2H, m. Ar-H), 8.01 (2H. m. Ar-H)
b. Ethyl 4-(acetylthiomethyl)benzoate
60:40 Ethyl 4-(bromomethyl)beuzoate: ethyl 4-(chloromethyl)benzoate (25.0g, 0.111 moles) 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). The organic extracts were combined, washed with water, dried (MgS04). charcoaled and evaporated to give ethyl 4-(acetylthiomethyl)benzoate as a brown soild (26.0g. 99%), m.p. 36-37°C JH nmr 8 (CDCI3) 1.38 (3H. t. J=7.lHz. CH3). 2.36 (3H, s. COCH3). 4.14 (2H, s. CH2S). 436 (2H, q. CH20). 7.35 (2H, d, J = 8.2Hz, Ar-H). 7.97 (2H, d, J= 8.2Hz, Ar-H)
Printed from Mimosa
c. 4-(4-(EthoxycarbonyI)benzylthio)azetldln-Z-onc
A solution of sodium (1.87g, 0.0813moles) in absolute alcohol (300ml) was-treated with a solution of ethyl 4-(acety!thiomethyl)benzoate (19.4g,
0.0814moles) in absolute alcohol (75ml) over 3 minutes. The reaction was stirred at room temperature for 30 minutes, cooled to -5°C and treated with a solution of 4-acetoxyazetidin-2-one (lO.Og, 0.07745moJes) over 5 minutes. The cooling bath was removed and reaction was stirred for 2 hoars, evaporated to dryness and treated with brine (200ml) and extracted with ethyl acetate (200ml, 100ml). The organic extracts were combined washed with brine, dried (MgS04) and evaporated to a red oiL Purified by flash column chromatography on silica gel eluted with 3:1 to 1:2 petroleum ether 40-60°C:ethyl acetate to give 4-(4-(ethoxycarbonyl)benzylthio)azetidin-2-one as an orange oil (18.64g, 91%).
lH nmr 5 (CDClj) 1.38 (3H, t, J=7.1Hz, CH3). 2.82. 2.89 (1H. 2xm, H3). 3.29, 3.35 (1H. 2xm, H3). 3.88 (2H. s. CH2S). 4.37 (2H. q. CH20). 4.70 (1H. m, H4), 5.70 (lH.bs, NH), 7.40 (2H, d. J = 8.3Hz, Ar-H). 8.00 (2H. m. Ar-H)
d. Methyl (4-{4-ethoxycarbonyl)benzylthio)-2-oxoazetldin-l-ylacetate
A stirred solution of 4-(4-(ethoxycarbonyl)benzylthio)azetidin-2-one (217.3g, 0.819mol), methyl bromoacetate (I28.5g.0.84mol) and tetrabutylammonium bromide (25.8g.0.08mol) in dry THF (900ml) was cooled in an ice bath to 20°C and finely ground potassium hydroxide (48.3g, 0.86mol) was added in one portion. The reaction exothermed to 45°C and was allowed to cool back to 30°C when the ice bath was removed and stining continued for Ihr. More potassium hydroxide (2.4g, 0.043mol) was added and stirred 30mins when this addition was repeated. After a further 30mins, the reaction mixture was filtered through hyflo, washing with more THF. The combined organics were evaporated to a red oil. Ether (11) was added an shaken well. The ether was decanted and the process repeated. The combined ether extracts were evaporated to give the title compound as a dark red oil (199.8g, 72% yield)
*H NMR 8 (CDCI3), 1.40 (3H, t. J=7Hz. CH2CH3). 2.98 (1H, dd, J=2,15 Hz, tit). 3.26,4.03 (each 1H, d. J=18 Hz. NCH,). 3,42 (1H. dd. J=5. 15 Hz, H,). 3.70 (3H, s. OCH3). 3.81, (2H. m. SCH2). 4.38 (2H, q. J=7 Hz, OCH2). 4-93 (1H. m. H.). 739 (2H, m. Ph-H). 7.99 (2H, m, Ph-H )•
e. (4-(4-Ethoxycarbonyi)benzylthlo)-2-oxoazetidin-l-ylacetic add Methyl (4-(4-ethoxycarbonyl)benzylthio)-2-oxoazetidin-1 -ylacetate (169.8g,0.503mol) was disolved in THF (750ml), cooled to 0°C and a solution of potassium hydroxide (29.7g, 0.529mol) in water (500ml) was added over 15min at 0 • 5°C then the mixture was stirred at 0°C for45mins. Ether (11) and water (21) were added, the layers separated and the aqueous washed with ether (11), then acidified with conc hydrochloric acid (55ml) and extracted with dichloromethane
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WO 97/41098 PCT/EP97/01898
(2 x 11). The combined extracts were washed with brine, dried (MgS04> and evaporated to give the title compound as a green solid (128.4g, 79% yield).
f. (->R-<4-(4-EthoxycarbonyI)ben2ylthio)-2-oxoazetidin-l-ylacetic acid 4-(4-Ethoxycarbonyl)benzylthio)-2-oxoazeyidin-l-ylacetic acid (46.0g, 0.1422mo!es) and (-)-cinchonidine (41.88g, 0.1423moles) were dissolved in abolute alcohol (450ml). The solution was cooled for 1.5 hours, filtered, and dried to give the salt as a cream solid (33.i5g). This solid was recrystallised from absolute alcohol (300ml) to give 23.6g of sait which was mixed with water (500ml) and diethyl ether (500ml) and acidified with dilute HC1 (50ml). When all the solid had dissolved the layers were separated and the aquous layer was extracted with ether (250ml). The organic extracts were combined, ethyl acetate (100ml) was added and washed with water, dried (MgS04), filtered and evaporated to give R-(4-(4-ethoxycarbonyl)benzylthio)-2-oxoazetidin-l-yIacetic acid as a colourless solid. (10.93g, 23.8%) m.p. 135-137°C.
aj, = -23.5 (c = 0.46 w/v in chloroform at 25°C)
'H NMR S(CDC13) 1.39 (3H.uJ=7.1Hz,CH3), 2.96, 3.02 (1H, dd. J =2.2. 15.3 Hz.H3). 3.33,4.05 (each 1H. d. J=18.4 Hz. NCH2CO2H). 3.40. 3.46 (1H, dd. J= 5.1, 15.3 Hz.H3). 3.82 (2H. s. SCH2). 4-37 (2H, q, CO2CH2X 4.68 (1H, b, CO2
H), 4.92 (1H, ra, H4). 7.38 (2H. d, J=8.2Hz, Ph-H), 7.99 (2H. d. J=8.2Hz. Ph-
W
g. 4A^»/f-(4-(4-EthoxycarbonyI)benzylsu]phinyl)-2-oxoazetidln-l-ylacetlc add (diastereoisomer 1)
h. 4R,S5-<4-<4-Ethoxycarbonyl)benzylsulphinyI)-2-oxoazetidin-l-ylacetic add (diastereoisomer 2)
A solution of (-)-/?-(4-(4-ethoxycarbonyl)benzylthio)-2-oxoazetidin-1 -ylacetic acid (10.81g, 0.03343moles) in dry dichloromethane (400ml) at -70°C was treated with ozone until a blue colouration appeared. The reaction was allowed to warm to room temperature and dichloromethane (50ml) was added to aid stining. The solution was evaporated to dryness and the resulting soild was mixed with chloroform (200ml). The colourless solid was collected by filtration to give 4A,SA-(4-(4-ethoxycarbonyl)benzylsulphinyl-2-oxoazetidin-l-ylacetic acid (4.1 lg, 36%) m.p.l62-(64cC. (contains 15.8:1 dial:dia2)
'H NMR 8 (DMSO) 1.33 (3H. t, J=7Hz, CH3), 2.97, 3.04 (1H. dd, J=4.8,14.8Hz, H3). 3.12.3.16 (1H. dd. J= 1.6. 14.8Hz. H3). 3.83. 4.17 (each 1H. d. J= 18Hz. NCH2CO2H), 4.92. 4.24 (1H. d. J » 12.8Hz, SOCH2). 4.32 (2H. q. CO2CH2). 4.99 (1H. m. H4). 7.48 (2H. d. J=8.0Hz. Ph-H). 7.96 (2H. d. J=8.0Hz. Ph-H) The filtrate from the above was evaporated, mixed with diethyl ether and filtered to give 4/?,S5-(4-(4-ethoxycarbonyl)benzyIsulphinyl-2-oxoazetidin-l-ylacetic acid (6.42.56%) m.p. 152-155°C. (contains 92:8 dia2:dial)
Printed from Mimosa
PCT/EP97/0189S
lH NMR 8 (DMSO) 1.33 (3H, t, J=7 Hz. CH3). 2.97, 3.01 (1H. dd. J=2.0,!5.5Kz, H3). 3.35 (1H. tn, H3). 3.95. 4.17 (each IH. d. J= 18.2Hz. NCH2CO2H). 4.15 (1H. d. 1 of SOCH2). 4.32 (3H, m, 1 of SOCH2. CO2CH2). 4.82 (IH. m, H4), 7.51 (2H. d. J=8.2Hz, Ph-H). 7.97 (2H, d. J=8.2Hz, Ph-H) i. (+MfT, S5-N-(6-(4-FluorophenyI)hexyl)-4-(4-ethoxycarbonyibenzylsulphinyl)-2-oxoazetidln-l-ylacetaiiiide 6-(4-Fluorophenyl)hexylaidine (1.82g, 0.00932moles) in dry dimethylformamide (75ml) was added to a mixture of 4/t.SS -(4-(4-ethoxycarbonyl)benzylsulphinyl-2-cxoazetidin-l-ylacetic acid (3.15g, 0.00928moles), N.N.-dicyclohexylcarbodiimide (1.92g. 0.00931moles) and 1-hydroxybenzorriazole (1.25g, Q.00925moles). The reaction was stirred at room temperature for 3.5 hours, diluted with ethyl acetate (100ml) and cooled. The mixture was filtered to remove urea and the filtrate was evaporated to dryness. The residue was dissolved in ethyl acetate (400ral). washed with sodium hydrogen carbonate solution, brine, dried and evaporated to a colourless solid (5.8g) which was recrystallised from ethyl acetate (125 ml) to give the product (3.0g). Purification by column chromatography gave 4R.SS -(4-(4-edioxycarbonyl)benzylsulphinyl-2-oxoazetidin-l-ylacetic acid as a colourless solid, 155-156°C, 1.8 g. 38% yield
'H NMR 8 (CDCI3) 1.3-1.6 (1 IH, m. 4xCH2. CH3). 2 56 J = 7 6Hz-CZfePh). 2.89. 2.96 (IH. dd. J.=2.4,15.3Hz, H3). 3.25 (3H. m. NHCH* Ifc). 3.94,4.22 (each IH. d, J=17Hz, NCH2CO). 4.03,4.18 (each IH, d, J=12Hz, SOCH2). <39 (2H, q, C02CH2), 4.65 (IH. m, H4). 6.9-7.12 (5H. m. NH.p-QPh-H), 7.35 (2H, d, J=8.3Hz, Ph-H), 8.07 (2H. d. J=8.3Hz, Ph-H)
a„ = +85.2 (c = 0.5% w/v in chloroform at 25°C)
Found: C. 62.6; H, 6.3; N, 5.4%; CjyH^F^OsS requires: C, 62.8; H. 6.4; N, 5.4%
Example 7 - (+)-4/?, S5-N-(6-(4-Chlorophenyi)he*yi)-4-(4-ethcxycarbonylbenzylsulphJnyl)-2-oxoazetidin-1 •ylacetamide Treatment of 4/?,S5-(4-(4-ethoxycarbonyl)benzylsulphinyl-2-oxoazetidin-l-ylacetic acid with 6-(4-chlorophenyl)hexylamine, N.N-dicyclohexylcarbodiimide, and 1-hydroxybenzotriazole in dry dimethylformamide as described for Example 6 above, followed by the same work-up procedure gave the title compound as a colourless solid, 159-161°C, 45% yield
H NMR 8 (CDC13; 1.3-1.6 (11H, m. 4xCH2- CH3). 2.56 (2H, t, J = 7.6Hz. CH2Ph). 2.89, 2.95 (IH. dd. J=2.4,15.3Hz.H3). 3 25 (3H, m. NHCH2. H3). 3.94.4.24 (each IH. d. J=17Hz. NCH2CO), 4.03,4.18 (each IH. d. J=12Hz, SOCH2), 4.36 (2H, q, C02CH2), 4.65 (IH, m, H4), 7.04 (IH. m. NH), 7.06-7.26 (4H. ra. p-ClPh-H), 7.35 (2H. d. J=8.3Hx, Ph-H), 8.07 (2H. d. J=8.3Hz, Ph-H)
Printed from Mimosa
a,, = +83.9 (c = 1.0% w/v in chloroform at 25°C)
Found: C. 60.9; H. 6.1; N, 5.2%: C27H33CIN2O5S requires: C, 60.8; a 6.2; N, 5.3%
Example 8 - (+)-4R, SS-N-(6-(4-Fluorophenyl)hexyl)-4-{4-ethoxycarbouy!benzylsulphinyI)-2-oxoazetidln-l-ylacetainide a. p-Methoxy benzyl [(35,4/f)-4-acetylthio-3-bromo-2-oxoazetidin-l-yl]acetate
Ozonised oxygen was bubbled through a solution of p-methoxybenzyl 2-[(35. 4/?H-acetylthio-3-bromo-2-oxoazetidin-l-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 solution was allowed to warm to room temperature, then stood for 16 hr. The solvents were evaporated and the residue reevaporated twice from toluene.then dissolved in ethyl acetate (300 ml) and stirred vigorously for 1.5 hr. with a solution of p-toluenesulphonic acid (2 g) in water (100 ml). After dilution with water the organic layer was separated and the aqueous layer further extracted with ethyl acetate. The combined extracts were washed successively with saturated aq. sodium hydrogen carbonate and brine, then dried (MgSO^ and evaporated. Purification by flash chromatography (silica, ethyl acetate-pet. ether) gave the tide compound as a light brown oil, yield 10.6 g (58%).
b. Silver (3S,4J?)-3-bronK>-l-(p-methoxybenzyloxycarbonyImethyl>-2-oxoazetidine-4-thiolate
A solution of /Mnethoxybenzyl [(35, 4/?)-4-acetylthio-3-bromo-2-oxoazetidin-l-yl]acetate (4.13 g, 0.01 mol) in methanol (90 ml) was added with stirring in subdued light to a solution of silver nitrate (2.27 g, 0.0133 mol) in methanol (90 ml). Triethylamine (1.87 ml, 0.0133 mol) was then added with ice cooling, and stirring continued for 1 hr. at 5-10°C followed by 30 min. at room temperature. The m are was re-cooled (ice bath) and the precipitated solid filtered and washeJ . re with >ce cold methanol then hexane to give the title compound, yield 4.6 g (96%).
c 4-Car be thoxy benzyl iodide
Treatment of 4-carboxybenzylbromide with thionyl chloride followed by ethanol in pyridine have a mixture of 4-carbethoxybenzyl chloride and bromide which was treated (14.6 g) with sodium iodide (39.8g) in acetone (150ml) at reflux temperature for 20hrs. The mixture was cooled, filtered and the solvent evaporated off. The residue was taken up in ether (150ml) and washed with
Printed from Mimosa
water, aqueous sodium thiosulphate, water, brine, dried and evaporated to give the title compound as a pale yellow solid, m.p. 61-3°C. 17.5 g (91% yield). "H NMR 6 (CDC13) 1.39(3H, t, J*7.1 Hz, CH3). 3.37(2H, q, J=7.1 Hz,
CH2CH3), 4.46(2H, s. Cfl20. 7.43 (2H, m, 3,5-Ph-H). 7.96(2H, m. 2.6-Ph-H)
d. p-Methoxybenzyl [(35,4/?M-(4-carbethoxy)benzylthio-3-bromo-2-oxoazetidin-l-yl]acetate
A solution of silver (35,4#)-3-bromo-l-(p-methoxybenzyloxycarbonylmethyl)-2-oxoazetidine-4-thiolate (2.34g, 0.005mol) in acetonitrile (20 ml) was treated with a solution of 4-carbethoxybsnzyl iodide (1.74g, 0.006mol) in acetonitrile (iOml) and the mixture stirred in subdued light for 2.5hrs. The mixture was filtered through hyflo, the filtrate evaporated and the residue purified by flash chromatography (silica, ethyl acetate-pet. ether) to give the tide compound as a white solid, m.p. 97-9°C, 1.60g (61% yield).
'H NMR 8(CDC13), 1.39(3H, t, J=7.1Hz. CH2CH3), 3.48, 4.07 (each IH, d, J=18 Hz. NCH2). 3.80 (5H, s, SCH2 + OCH3), 4.37 (2H, q, J=7.1Hz, CH2CH3), 4.61,4.91 (each IH. d, J=1.6 Hz,H3+.H4), 5.03. 5.12 (2H, 2xd,J=l 1.8Hz, XXfe). 6-89 (2H. m. 3.5-(4-CH3OPh)-H), 7.26-7.41 (4H, m. 2,6-(4-C02Et)Ph-H + 2.6-(4-CH3OPh)-H), 8.00 (2H, m. 3^-(4-C02Et)Ph-H).
e. p-Methoxybenzyl 1(35,4J?)-4-(4-carbethoxy)beniylsulphinyl-3-bromo-2-oxoazetidin-l-yl]acetate Diast2:l 75:25
p-Methoxybenzyl [(35,4/?)-4-(4-carbethoxy)benzylthio-3-bromo-2-oxoazetidin-l-yl]acetate (15.2g, 0.029mol) was dissolved in dichloromethane (400ml), cooled to -65°C and a solution of m-chloroperbenzoL- acid (8.9g,0.029mol) in dichloromethane (450 ml) added dropwise with stirring over 20 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 (MgfV -""^evaporated to an oil.
Hot mr ite (60ml) was added and after cooling in freezer overnight, p-methoxy wr? • [(35, 4j?)-4-(4-carbethoxy)benzylsulphinyl-3-bromo-2-oxoazeuuin-l-yl]acetate crystallised out as a white solid as a 75:25 mixture of diastereomers (2:1), 9.94g, (63% yield)
lH NMR of major component: 8 (CDC13), 1.39(3H, t. J=7.1Hz, CH2CH3), 3.80 (3H, OCH3). 4.0 - 4.2 (3H, m, SOCH2 + NQfc). 4.3 - 4.4 (3H. m. CH2CH3 + NCH2). 4-50.4-8* IH, d. J=1.7 Hz. H3 +H4), 5.1 (2H. m, OCH2). 6.88 (2H, m, 3,5-(4-CH3OPh)-lD, 7.26 (2H. m. 2,6-(4-CH3OPh)-H), 7.41 (2H, m. 2,6-(4-C02Et)Ph-H ). 8.00 (2H. m, 3.5-(4-C02Et)Ph-H).
f. [(4R)-4-(4-carbethoxy)benzyl5Ulphinyl-2-oxoazetidin-l-yl]acetic add Oiast 2
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WO 9^/41098
p-Methoxybenzyl {(35,4Ry v(4-carbethaxy)benzylsulphinyl-3-bromo-2-oxoazetidin-l-yl]acetate (8.75g, 16.25mmol) was dissolved by wanning in ethanol (400ml) and a solution of sodium bicarbonate (4.0g, 48mmol) in water (40mi) was added. To the cloudy mixture was added 10% Pd on carbon (0.5g) and the warm mixture (initial temp 40°C) was hydrogenated at 50psi. room temp for 2 'its. More catalyst (l.Og) was added, the mixture wanned to 35°C and hydrogenated as above for 2 hrs. The mixture was filtered through hyflo and evaporated to give a mixture of p-methcxybenzyl and ethyl esters of the des-bromo derivative as brown oil. This was dissolved in ethanol (50ml), cooled to 10"C and IN sodium hydroxide (17ml) was added dropwise over lOmin. The mixture was stirred at 10°C for 45mins then most of the ethanol was evaporated off and the residue dissolved in dichloromethane and water. The layers were separated and the aqueous washed with dichloromethane then acidified with conc hydrochloric acid (2ml) and extracted with dichloromethane. The extracts were dried (MgSC>4) with the addition of charcoal, filtered through hyflo and evaporated to a black foam. This v/as dissolved in chloroform and refrigerated ovemighL A small amount of solid was filtered off and the filtrate evaporated to a black oil which solidified under ether to give the title compound as an off-white solid, 3.77g, (68% yield) (ratio of dia 2:dia 1 94:6). The chromatographic end spectral characteristics of this material identified it as the same compound prepared in Example 6h.
'H NMR 8 (DMSO) 1.32 (3H, L J=7Hz, CH3). 2.99 (IH. m. H3). 3.33 (IH, m, H3). 3.95 (IH. d, J= 18.2Hz, NCH2). 4.15 (2H, m, NCH2 + SOCH2). 4.34 (3H, m. SOCH2 + C02CH2). 4.82 (IH, m. H4). 7.51 (2H. d, J=8.3Hz, Ph-H), 7.97 (2H, d, J=8.3Hz, Ph-H)
g. l(4JI)-4-(4-carbethoxy)benzylsulphinyl-2-oxoazeti<lin-l-yI]acetic add Diast 2
[(4/?, S5)-4-(4-carbethoxy)benzylsuIphinyl-2-oxoazetidin-l-yl]acetic acid (Diast 2) was also prepared by the following procedure: p-Methoxybenzyl [(35, 4/?)-4-(4-carbethoxy)benzylsulphinyl-3-bromo-2-oxoazetidin-l-yl]acetate (Diast 2:1 75:25) (4.59g, 8.52mmol) was dissolved in dichloromethane (50ml), cooled in an ice bath and activated zinc powder (1.1 lg, 17.05mmol) was added followed by glacial acetic acid (8ml). After 1 hr, the mixture was diluted with dichloromethane-water, and the organic layer washed with saturated aq.
NaHCOj, brine, dried (MgSO^ and evaporated to an oil which was purified by flash chromatography (silica, ethyl acetate-peL ether) to give the title compound as an oil which solidified on standing.
h. (+H*, S5»N-(6-(4-Fluorophenyl)hexyl)-4-(4-ethoxycarbonylbenzyIsulphinyD-2-oxoazetidin-l-ylacetamide
Printed from Mimosa
Treatment of [(4/?>-4-(4-carbethoxy)benzylsulphinyI-2-oxoazetidin-l-yl]acetic acid with 6-(p-fluoropheny)Ihexy lamine under the conditions described for Example 6i gave, after chromatography, the title compound with identical spectral and chromatographic characteristics to that prepared in Example 6L a^ =+71.9 (c. 1.0% w/v CHC1,, 25°C)
Example 9 - (4R, SS )-N-(6-[4-FIaoro phenyl ]hex-l-y l)-4-(4-(cydohery lory carbonyloxymethylory car bonyl)benzylsulphinyI)-2-oxoazetidin-1 -yt)acetamide
A solution of (4/?, S5>N-(6-[4-fluorophenyl]hex-l-yl)-4-(4-carboxyben~ylsulphinyl)-2-oxoazetidin-l-yl)acetannde (see above, 4 g, 0.00819 mol) and iodomethyl cyclohexyi carbonate (3.49 g. 0.0123 mol) in N-methylpyrrolidinone (40 ml, dried over 4A molecular sieves) was treated with anhydrous pr'assium carbonate (1.7 g, 0.0123 mol) and stirred for 16 h at ambient temperature. The mixture was diluted with water and extracted thoroughly with ethyl acetate, and the combined extracts washed with 5% aq. sodium thiosulphate, dried (MgSC>4) and evaporated. The residue was purified by chromatography (fine silica, ethyl acetate) and the title compound obtained as white crystals m.p.l05-7°C after trituration with ether/light petrol, 4.16 g. 79% yield
NMR 6 (DMSO) 1.23-1.51 (14H, m), 1.64 (2H, m). 1.84 (2H,m), 2.51 (2H. m), 3.04 (3H, m). 3.35 (IH, m), 3.83 and 4.09 (each IH. d), 4.15 and 4.35 (each IH, d), 4.58 (IH. ra), 4.85 (IH, m). 5.95 (2H. s), 7.05 (2H, m). 7.18 (2H. m). 7.53 (2H, d), 7.98 (2H, d). 8.11 (IH. bt).
Found: C. 61.6; H. 6.4; N,4.6%; C33H41FN208S requires: C, 61.5; H, 6.4; N, 4.3%
Example 10 - (4Ry SS)-N-(6-(4-F!uorophenyl]hex-l-yl)-4-(4-(tert-
butyloxycarbonyloxymethyloxycarbonyl)benzylsu)phinyl)-2-oxoazetidin'l-
yl)acetamide
A solution of (4R, S5)-N-(6-[4-fluorophenyI]hex-1 -yl)-4-(4-carboxybenzylsulphinyl)-2-oxoazetidin-l-yl)acetamide (0.2g. 0.00041 mol) and iodomethyl tert-butyl carbonate (0.49 g. 0.001 mol) in N-meihylpyrrolidinone (2 ml. dried over 4A molecular sieves) was treated with anhydrous potassium carbonate (0.14 g, 0.001 mol) and stirred for 16 h at ambient temperature. The mixture was diluted with water and extracted thoroughly with ethyl 2cetate. and the combined extracts washed with aq. sodium sulphite, dried (MgS04) and evaporated. The residue was crystallised by trituration with light petrol to give the title compound as white crystals m.p.l02-4°C, 0.23 g. 92%yield
Printed from Mimosa
'H NMR 6 (DMSO) 1.25-1.52 (17H. m). 2.50 (2H, m). 3.06(3H. m), 3.35 (IH, ra). 3.84 and 4.09 (each IH. d), 4.15 and 4.35 (each IH, d). 4.86 (IH, in). 5.90 (2H, s). 7.06 (2H, in), 7.18 (2H. m). 7.53 (2H. d), 7.97 (2H. d). 7.99 (IH. bt) Found: C, 60.1; H, 6.3; N, 4.7%; CjjHjgF^OgS requires: C, 60-2; H, 6.4; N. 4.5%
Example 11 - (4ft, S5)-N-(6-{4-Fluorophenyl]hex-l-yl)-4-(4-{l-melhylcyclohexyloxycarbonyloxymethyloxycarbonyl)benzylsulphinyI)-2-oxoazetldin-1 -yl)aceUunide
A solution of (4ft, S5)-N-(6-[4-fluorophenyl]hex-1 -yl)-4-(4-carboxybenzylsulphinyl)-2-oxoazetidin-I-yl)acetainide (0.2g, 0.00041 mol) and chloromethyl I-methylcyclohexyl carbonate (0.21 g. 0.001 mol) in N-methylpyrrolidinone (2 ml, dried over 4A molecular sieves) was treated with anhydrous potassium carbonate (0.14 g, 0.001 mol) and potassium iodide (0.166 g. 0.001 mol) and stirred for 16 h at ambient temperature. The mixture was diluted with water and extracted thoroughly with ethyl acetate, and the combined extracts washed with aq. sodium thiosulphate, dried (MgS04) and evaporated. The residue was purified by flash chromatography (fine silica, ethyl acetate) and the material thus obtained crystallised by trituration with ether, to give the title compound as yield white crystals, m.p. 92-3°C, 0.11 g, 41% yield !h NMR 8 (DMSO) 1.25-1.48 (16H. ra). 2.00 (2H, m), 2.5 (5H, m), 3.07 (3H. m), 3.36 (IH. ra). 3.83 and 4.09 (each IH. d). 4.15 and 4.35 (each IH, d). 4.86 (IH. m). 5.91 (2H. s). 7.06 (2H. m). 7.18 (2H. m). 7.54 (2H. d). 7,98 (2H. d). 8.11 (1H. bt)
Example 12 - (4ft, SS)-N-(6-[4-FIuorophenyl]hex-l-yl)-4-{4-
(phenylcarbonyloxymethyIoxycarbonyl)benzylsulphinyl)-2-oxoazetidin-l-
yl)acetamide
A solution of (4ft, S5)-N-(6-[4-fluorophenyl]hex-l-yl)-4-(4-carboxybenzylsulphinyl)-2-oxoazetidin-l-yl)acetamide (5 g, 0.0102 mol) and benzoyloxychlororaethane (2.62 g. 0.0154 mol) in N-methylpyrrolidinone (50 ml, dried over 4A molecular sieves) was treated with anhydrous potassium carbonate (2.12 g. 0.0154 mol) and potassium iodide (2.55 g, 0.0154 mol) and stirred for 16 h at ambient temperature. The mixture was diluted with wster and extracted thoroughly with ethyl acetate, and the combined extracts washed with aq. sodium thiosulphate, dried (MgS04) and evaporated. The residue was purified by flash chromatography (fine silica, ethyl acetate) and the material thus obtained crystallised by trituration with ether to give the title compound as white crystals, m.p.ll7-9°C, 4 g. 52% yield
Piinted from Mimosa
*H NMR 8(CDC13) 1.33 (4H, m). I J-1.62 (4H. m). 2.56 (2H. t). 2.95. (IH. dd). 3.22 (3 H, ra), 3.94 and 4.20 (each IH. d). 4.04 and 4.16 (each IH. d). 4.65 (IH. m), 6.25 (2H, s), 6.94 (3H. ra), 7,11 (2H, m), 7.37 (2H. d). 7.46 (2H. m), 7.59 (lH,m). 8.1 (4H, m)
Found: C. 63.7; H.5.5; N. 4.5%; C33H35FN2O7S requires.C. 63.7; H, 5.7; N. 4.5%
Example 13 - (4fl, SS)-N-(6-[4-FIuorophenyl]hex-l-yl)-4-(4-(4-melhoxyphenyicarbonyloxymethyloxycarbonyl)benzylsu)phinyI)-2-oxoazetldin- l-yl)acetamlde
A solution of (4R, S5)-N-(6-[4-fluorophenyl]hex-l-yl)-4-(4-carboxybenzyIsulphinyl)-2-oxoazetidin-l-yl)acetamide (2 g, 0.0041 mol) and 4-methoxybenzoyloxymethyl chloride (2 g. 0.01 mol) in N-mcthylpyrrolidinone (20 ml. dried over 4A molecular sieves) was treated with anhydrous potassium carbonate (1.38 g. 0.01 mol) and potassium iodide (1.66 g. 0.01 mol) and stirred for 16 h at ambient temperature. The mixture was diluted with water and extracted thoroughly with ethyl acetate, and the combined extracts washed with aq. sodium thiosulphate, dried (MgSC>4) and evaporated. The residue was purified by flash chromatography (fine silica, ethyl acetate) and the material thus obtained crystallised by trituration with ether, then recrystallised from dichloromethane/light petrol, to give the title compound as white crystals, m.p. 115-8°C, 1.34 g, 50% yield
*H NMR 5 (DMSO) 1.23-1.6 (8H, m). 2.50 (2H. m). 3.02-3.1(3H. m). 3.34 ( IH. m ), 3.8 and 4.09 (each IH. d). 3.84 (3H. s). 4.14 and 4.33 (each IH, d). 4.85 (IH- m), 6.17 (2H, s). 7.05 (4H. m). 7.16 (2H. m), 7.52 (2H. d). 7.97 (4H, m). 8.1 (IH, bt)
Example 14 - (4ft, SS)-N-(6-[4-Fluorophenyl]hex-l-yl)-4-(4-
(isobutyryloxyinethyk>xycarbonyl)beiizylsulphinyI)-2-oxaazetidin-l-
yDacetamide
A solution of (4R, SS)-N-(6-[4-fluorophenyl]hex-l-yl)-4-(4-carboxybenzylsulphinyl)-2-oxoazetidin-l-yl)acetamide (0.2g, 0.00041 mol) and isobutyTyloxymethyl iodide (0.23 g. 0.001 mol) in N-methylpyrrolidinone (2 ml, dried over 4A molecular sieves) was treated with anhydrous potassium carbonate (0.14 g. 0.001 mol) and stirred for 16 h at ambient temperature. The mixture was diluted with water and extracted thoroughly with ethyl acetate, and the combined extracts washed with aq. sodium thiosulphate, dried (MgS04) and evaporated. The residue was purified by chromatography (fine silica, ethyl acetate) and the material thus obtained crystallised by trituration with ether, to give the title compound as white crystals, m.p. 104-6°C, 0.14 g, 58% yield
Printed from Mimosa
lH NMR 8 (DMSO) 1.09 (6H. d), 1.25-1.52 (8H. m). 2.50 (2H. m). 2.61 (IH, m), 2.97-3.06 (3H, m), 3.34 (IH. m). 3.83 and 4.09 (each IH. d). 4.15 and 4.34 (each IH. d). 4.84 (IH. m), 5.95 (2H. s), 7.06 (2H, m). 7.16 (2H, m), 7.53 (2H. d). 7.97 (2H, d), 7.99 (IH, bt)
Example 15 - (4R, S5)-N-(6-[4-Fluorophenyl]hex-l-yi)-4-(4-(2-methoxyprop-
2-ylcarbonylorymetbyioxycarbonyI)benzylsu]pb'oyl)-2-oxoazetidIn-l-
yl)acetainide
A solution of (4R, S5)-N-(6-[4-Fluorophenyl]hex-l-yl)-4-(4-carboxybenzylsulphinyl)-2-oxoazeiiclin-l-yl)acetamide (3 g, 0.00614 mol) and 2-methoxyprop-2-ylcarbonyloxymethyl chloride (1.53 g. 0.00921 mol) in N-methylpyrrolidinone (30 ml, dried over 4A molecular sieves) was treated with anhydrous potassium carbonate 1.27 g, 0.00921 mol) and potassium iodide (1.53 g, 0.00921 mol) and stirred for 16 h at ambient temperature. The mixture was diluted with water and extracted thoroughly with ethyl acetate, and the combined extracts washed with aq. sodium thiosulphate. dried (MgS04) and evaporated. The residue was purified by chromatography (fine silica, ethyl acetate) and the material thus obtained as a solution in ethyl acetate further washed with aq.
sodium thiosulphate then stirrred for 10 min with MgS04 and decolourising charcoal. The solids were filtered off and the filtrate evaporated, and the residue crystallised by trituration with ether/light petrol to give the title compound as white crystals m.p. 92-4°C. 2.6 g, 68% yield
!H NMR 8 (CDCI3) 1.34 (4H, m), 1.45 (6H, s), 1.58 (4H, m). 2.56 (2H. t). 2.95 (IH, dd). 3.17-3.37 (3H. m + 3H, s), 3.96 and 4.10 (each IH, d), 4.05 and 4.22 (each IH, d), 4.69 (IH, m), 6.06 (2H. s), 6.93 (3H, m), 7.09 (2H, m), 7.39 (2H. d). 8.09 (2H. d)
Example 16 - (41?, SS>-N-(6-[4-Fluorophenyl]hex-l-yl)-4-{4-((5-methyl-2-oxo-1,3-dioxolen-4-yl)methyloxycarbony I )benzy Isulphiny l)-2-oxoazetidi n-1-yl)acetamide
A solution of (4?. S5)-N-(6-[4-fluorophenyI]hex-l-yI)-4-(4-carboxybe*uylsi.l;«hinyl)-2-oxoazetidin-l-yl)acetamide (5 g, 0.0102 mol) and 4-bromomethv! 5-methyl-l,3-dioxol-2-one (2.96 g. 0.0154 mol) in N-methylpyiTolidinone (50 ml, dried over 4A molecular sieves) was treated with anhydrous potassium carbonate (2.12 g, 0.0154 mol) and stined for 16 h at ambient temperature. The mixture was diluted with water and extracted thoroughly with ethyl acetate, and the combined extracts washed with wsr' r,
brine, dried (MgS04) and evaporated. The residue was purified by chromatography (fine silica, ethyl acetate) and the material thus obtained
Printed from Mimosa
crystallised by trituration with ether/light petrol lo give the tide compound as white crystals, m.p. 84-7°C, 3.81 g. 62% yield.
'H NMR 5 (CDCl3) I^4-l_54 (8H. m), 2.22 (3H. s), 2.5 (2H, ra), 2.95 (IH, dd). 3.05 (2H, m). 3.33 (IH. m). 3.84 and 4.07 (each IH. d). 4.15 and 4.32 (each IH. d), 4.85 (IH. tn), 5.22 (2H. s). 7.06 (2H, m). 7.18 (2H. m), 7.51 (2H, d), 7.98 (2H, d), 8.1 (IH, bt)
Found: C, 59.7; H. 5.5; N. 4.7%; CjofyjFNzOgS requires:C, 60.0; H, 5.5; N, 4.7%
Example 17 - (4ft, SS>N-(6-[4-FluorophenyI]hex-l-yl)-4-(4-((2-methoxycarbonyl-£-but-2-ea-y!)methyloxycarbonyI)t>enzylsulphinyl)-2-oxoazetidln-1 -yl)acetamide
A solution of (4ft, SS)-N-(6-[4-fluoraphenyl]hex-l-yl)-4-(4-carboxybenzylsulphinyl)-2-oxoazetidin-l-yI)acetamide (0.195 g. 0.0004 mol) and methyl £-2-bromomethylbut-2-enoate (0.16 g. 0.0008 mol) in N-methylpyrrolidinone (2 ml, dried over 4A molecular sieves) was treated with anhydrous potassium carbonate (0.11 g, 0.0008 mol) and stirred for 16 h at ambient temperature. The mixture was diluted with water and extracted thoroughly with ethyl acetate, and the combined extracts dried (MgS04) and evaporated. The residue was purified by chromatography (fine silica, ethyl acetate) and the material thus obtained crystallised by trituration with ether to give the title compound as white microprisms. 0.024 g, 10% yield
NMR 8 (CDC13) 1.25-1.63 (8H. m), 1.99(3H, d), 2.56 (2H. t). 2.93 (IH. dd). 3.17-3.36 (3H. ra), 3.79 (3H, s), 3.93 and 4.17 (each IH, d). 3.43 and 4.23 (each IH. d), 4.64 (IH, m), 5.12 (2H. s), 6.91-7.26 (6H. m). 7.34 (2H, d), 8.04 (2H, d)
Example 18 - (4ft, &S)-N-(6-[4-Fliiorophenyl)hex-l-yl)-4-f4-( N-N-
dimetliylaininocarbonylinethyk>xycarbonyl)benzylsuIphinyl)-2-oxoazetidin-l-
y])scetaniide
A solution of (4ft, SS)-N-(6-[4-fluorophenyl]hex-l-yl)-4-(4-carboxybenzylsulphinyl)-2-oxoazetidin-l-yI)acetamide (0.2 g. 0.0004 mol) and a-chloro-N,N-dimethyl acetamide (0.17 g. 0.001 mol) in N-methylpyirolidinone (2 ml, dried over 4A molecular sieves) was treated with anhydrous potassium carbonate (0.14 g, 0.001 mol) and stirred for 16 h at ambient temperature. The mixture was diluted with water and extracted thoroughly with ethyl acetate, and the combined extracts dried (MgS04) and evaporated. The residue was crystallised by trituration with ether to give the title compound as white cryatals, m.p. 141-4°C, 0.01 g
Printed from Mimosa
PCT/EPf 7/01898
*H NMR 8 (CDC13) 1.25-1.75 (8H. m). 2.56 (2H. t). 2.93 (IH. dd), 2.99 (3H. s), 3.04 (3H, s), 3.17-3.36 (3H, m). 3.85-4.25 (4H. 4 x d), 4.65 (IH. m). 4.97 (2H, s). 6.93 (2H, m). 7.10 (3H. m). 7.36 (2H, d), 8.13 (2H. d).
Example 19 - (4R, SS)-N-(6-[4-Fluorophenyl]hex-l-yl)-4-(4-( N-N-dl-(2-
hydroxyethyl)aminocarbonylmethyloxycarbonyI)benzylsulphinyl)-2-
oxoazetidin-l-yI)acftamide
To a solution of N.N-(l,l-dihydroxyethyl)bromoacetaraide (1.20g, 5.3mmol) in DMF (10ml) was added (4/?, S5>N-(6-[4-fluorophenyl]hex-1 -yl)-4-(4-carboxybenzylsulphinyI)-2-oxoazetitiin-l-yl)acetamide (l.OOg, 2.05mmol) followed by caesium carbonate (1.3g, 4.0mmol). The mixture was stirred for 18 hrs then separated between ethyl acetate and 2M hydrochloric acid. Separation of the organics followed by washing with brine, drying (MgS04) and concentration provided the crude product as a white solid. The solids were washed with chloroform, filtered and dried to yield the product as a white solid (0.97g, 75%) mp 119-121°C.
'H nrar 8 (DMSOJ 1.28-1.55(m,8H), 2.5(t. J=l2Hz. 2H). 2.8(br d, J=16Hz. IH). 3. l(q, J=10Hz. 2H), 3.3-3.7(m. 9H), 3.9(d. J=27Hz, IH), 4.1(d, J=27Hz, IH), 4.15(d, J-20Hz. IH). 4.35(d. J=20Hz, IH), 4.7(br, IH), 4.85(m, IH), 4.95(br, IH), 5.2(s, 2H), 7.0(apparent t, J=14Hz. 2H), 7.15(dd, J=14,9Hz. 2H). 7.5(d. J=13Hz, 2H). 8.05(d. J=l3Hz. 2H), 8.2(t, J=8Hx, IH)
Example 20 Enanttomers of (J?,S/S,/?)-l-(2-<6-Fluorophenyl)hexyIoxy)ethyl-4-(4-aI)yloxycarbonylbeiszyl5ulphlnyl)-2-oxoazetidlne a. 6-(4-Fluoroph«nyl)hexyloxy ethanol
Ethylene glycol (4l.26g) and 6-(4-nuorophenyl)hexyl bromide (17.22g) were added to a solution of sodium hydroxide (2.79g) in water (2.5ml) and the mixture was heated at 110°for 24 hours. The mixture was cooled and partitioned between water (150ml) and diethyl ether (150ml). The layers were separated and the organic layer was washed with water, brine, dried (MgSOij) and evaporated to an orange oil. Purification by column chromatography on silica gel eluted with [5:1] to [1:1] P.E 40-60°C:ethyl acetate gave the product as an orange oil (9.91g, 62%).
b. 6-(4-Fluorophenyl)hexyloxy triflate
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 (MgSC>4) and evaporated to a brown oil (6.17g, 99~).
Printed from Mimosa
c. l-<2-(6-FluorophenyI)hexyloxy)etliyl-4-(4-allyloxycarbonyIbenzylthio)-2-oxoazeddine
A solution of 6-(4-fluorophenyl)hexyloxy triflate (7.0g), 4-(4-allyloxycarbonylbenztlthio)azetidin-2-one (5.08g) and tetrabutylammonium bromide (0.59g) in dry THF (150ml) was cooled to 15°C under nitrogen and was treated with powdered potassium hydroxide (1.08g). The cooling bath was removed and the reaction was stirred for 30 minutes. Powdered KOH (50mg) was added and the reaction was stirred at room temperature for 30 minutes. The mixture was filtered throu£ i. _ elite and washed through with ethyl acetate (100ml). The filtrate was evaporated to a dark oil and purification by flash column chromatography on silica gel eluted with [3:2] to [1:1] P.E. 40-60°C: ethyl acetate gave the product as an orange oil (4.65g. 51%).
IH NMR 6 (CDCl3) 13-1.6 (8H. m, 4xCH2>). 2-55 (2H, t, J = 7.6Hz, CH2Ph). 2.85, 2.90 (IH. dd, H3). 3.05 (IH, m, IH), 3.26,3.32(1H, dd, J=4.9, 15.1Hz, H3). 3.37-3.68 (5H, m, NCH2CH2. OCH2). 3.86 (2H. s, SCH2), 4.76 (IH, m. H4). 4.81 (2H, m CO2CH2). 5.36 (2H, m. CH=CH2). 6.03 (IH, m, CH=CH2). 6.94 (2H, m p-FPh-H), 7.07 (2H,m, p-FPh-H), 7.39 (2H, d, J=8.3Hz, Ph-H), 8.01 (2H, d. J=8.3Hz, Ph-H)
d. (R,S/S,R)- l-<2-<6-Fluorophenyl)hexyloxy)ethyl-4-(4-a*.yloxycart>ony1benzylsulphinyl)-2-oxoazetidine (diast 2)
A solution of l-(2-(6-fluorophenyl)hexyloxy)ethyl-4-(4-allyloxycarbonylbenzylthio)-2-oxoazetidine (4.58g) in dichloromethane (100ml), cooled to -70°C, was treated with a solution of mcpba (2.0g) in CH202 (125ml) dropwise over 1 hour maintaining the temperature at below -70°C The cooling bath was removed and the reaction was stirred for 1.5 hours, washed with a solution of 10% aq.sodium hydrogen carbor.".t£(l 50ml) + 10% aq. sodium sulphite (150ml). The layers were separated and the organic layer was washed with brine, dried (MgSC>4) and evaporated to an oil which solidified on standing. Repeat recyrstallisations from diethyl ether (3 times) gave diastereoisomer 2 as a colourless solid (0.7g,12-2%).m.p. 73-74°C
IH NMR 5 (CDCI3) 1.3-1.6 (8H, m, 4xCH2<). 2.56 (2H. £. J = 7.8Hz. CH2Ph). 2.66,2.69 (IH. dd. J=2,14.8Hz. H3), 3.38-3.68 (7H. m. H3, NCH2CH2> OCH2), 4.07 (2H. s, SOCH2), 4.54 (IH, m, H4). 4.83 (2H. m CC^Ofe), 5.36 (2H, m, CH=CH2) 6.03 (IH, m, CH=CH2), 6.94 (2H. m. p-FPh-H), 7.10 (2H, m. p-FPh-H), 7.38 (2H, d, J=8.4Hz, Ph-H), 8.08 (2H, ra. Ph-H)
e. (/?,/Z/5^S>(2-(6-Fluorophenyl)hexyloxy)ethyl-4-(4-aIlyloxycarhonyll>enzylsulpiiinyI)-2-oxnazetidine (diast 1)
A sample of diastereoisomer 1 (contains 21% dia2) was obtained as a colourless solid, m.p.46-50°C.
Printed from Mimosa
PCIYEP97/01898
IH NMR 5 (CDC13) 1.3-1.6 (8H, m. 4xCH2.). 2.55 (2H, t, J « 7.8Hz, QfrPb). 2.66. 2.69 (IH. dd. J=4.8,14.8Hz, H3). 3.38-3.68 (7H. ra. fl3. NCH2QI2. OCH2). 3.94 (2H, ra, SOQfe), 4.55 (IH. m, H4), 4.83 (2H, m CO2CH2). 5.36 (2H, ra. CH=CH2) 6.03 (IH. m, CH=CH2), 6.94 (2H. m, p-FPh-H), 7.10 (2H, ra, p-FPh-H), 7.38 (2H, d, J=8.4Hz, Ph-H). 8.08 (2H. ra. Ph-H)
Enantioraers of f/?,S/T,/?j-l-(2-(6-fluorophenyl)hexyloxy)ethyl-4-(4-allyloxycarbonylbenzylsulphinyl)-2-oxoazetidine were separated by hplc on a Chiracel OD -20MM eluted with 60:40 ethanol hexane:
f. (+}-l-(2-(6-Fluorophenyl)hexyloxy)ethyl-4-(4-allyloxycarbonylbenzylsulphIny!)-2-oxoazetIdine (diast 2)
164mg, colouriess solid. M.p. 52-53°C Enantiomerically pure
[a]D = +57.5° (c=0.5%w/v in ethanol at 25°C)
IH NMR 5 (CDCI3) 1.3-1.6 (8H, m, 4xCH2,), 2.56 (2H. t, J = 7.8Hz. CH2PQ). 2.66. 2.69 (IH. dd, J=2.14.8Hz,H3). 3.38-3.68 (7H. m. H3. NCH2CH2, OCH2). 4.07 (2H, s. SOCH2). 4.54 (IH. m. H4). 4.83 (2H. m CC^Cfe). 5.36 (2H. m, CH=CH2) 6 03 (IH. m. CH=CH2). 5.94 (2H. m, p-FPh-H). 7.10 (2H. m, p-FPh-H). 7.38 (2H, d, I=8.4Hz, Ph-H)r8.08 (2H. m. Ph-H)
g. (-) l-(2-(6-Fluorophenyl)hexyloxy)ethyl-4-(4-•Dylrxycarbonylbenzy>suJphinyl>-2-oxoazetidine (diast 2)
170mg, colourless solid M.p. 51-53°C
99.69% desired enantiomer with 0.31% of the other enantiotner present [a]0 = -57.9°C (c=0.4%w/v in ethanol at 25°C)
IH NMR 5 (CDCI3) 1.3-1.6 (8H. m. 4xCH2«). 2 56 <2H. t, J = 7.8Hz, CH2Ph). 2.66,2.69 (IH. dd. J=2.14.8Hz. H3). 3.38-3.68 (7H. m, H3, NCH2CH2, OCH2). 4.07 (2H. s, SOCH2), 4.54 (IH, ra, H4). 4.83 (2H, ra CC>2CH2). 5.36 (2H, m. CH=CH2) 6 03 (IH. m. CH=CH2). 6.94 (2H. m, p-FPh-H), 7.10 (2H. m. p-FPh-H). 7.38 (2H, d, J=8.4Hz. Ph-H), 8.08 (2H, m. Ph-H)
Example 21 (R,S/S,R)-l-{2-(6-Fluorophenyl)hexyloxy)ethyl-4-(4-carboxybenzylsulphinyl)>2-oxoazetidine (diast 2)
(R.S/S.R)-1-(2-(6-Fluorophenyl)hexyloxy)ethyI-4-(4-
allyloxycarbonylbenzylsulphinyl)-2-oxoazetidine (220mg), triphenylphosphine (1 Img), tetrakis(triphenylphosphine)palladiuin (0) (15rag) in dry CH2C12 (5ml) under nitrogen was treated with pyrrolidine (37jil) 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. The oil was dissolved in CH2CI2 (4ml) and diluted with diethyl
Printed from Mimosa
ether (75ml), washed with water, brine, dried (MgSC>4), filtered and evaporated to An oil which solidified on cooling. Trituration with diethyl ether gave the product as a cream solid (155mg, 78%) m.p.95-96°C IH NMR 5 (CDCI3) 1.25-1.6 (8H, m. 4xCH2-). 2 56 <2H> *■ J=7-6Ht, CH2Ph). 2.69. 2.76,(IH, dd, J=2.1,15.lHz,H3), 3.10, 3.17 (IH, dd, 1=5.1, 15.1Hz), 3.37-3.74 (6H,m, NCH2CH2. OCH2). 4.11 (2H, s, SOCH2). 4.64 (IH, m, H4). 6.94 (2H, m, p-FPh-H). 7.10 (2H. m. p-FPh-H). 7.41 (2H, d. J=8Hz, Ph-H), 8.07 (2H, d, J=8Hz, Ph-H)
Example 22 (-)-l-(2-(6-Fl»!orophenyi)hexyloxy)ethyM-(4-carboxybenzylsuiphinyl)-2-oxoazetidlne (diast 2)
(-)-l-(2-(6-Fluorophenyi)hexyloxy)ethyl-4-(4-aHyloxycarbonylberizylsulphinyl)-2-oxoazetidine (145mg), triphenylphosphine (7.3mg),
tetrakis(triphenylphosphine)palladium (0) (10.5mg) in dry CH2CI2 (4ml) under nitrogen was treated with pyrrolidiue (23>5|xl) and the mixture was stirred at room temperature for 6 hours. Pyrrolidine (5|jJ) was added and the reaction 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 title compound as an oil. Trituration with diethyl ether gave the product as a cream solid (113mg. 85%) m.p.l23-I24°C, [a]D = -53.5° ( c=0.5 %w/v in ethanol at 25°C)
IH NMR 8 (DMSO) 1.25-1.6 (8H, m. 4xCH2.). 2.50 (2H, t, CH2PW. 2.91, 2.95 (IH. dd. J=2.15.2Hz,H3). 3.22-3.53 (7Hjn. H3, NCH2CH2- OCH2), 4.16.4.31 (each IH. 2xd, J=13Hz, SOCH2). 4.73 (IH. m, H4). 7.0 (2H, m, p-FPh-H). 7.19 (2H. m. p-FPh-H), 7.48 (2H, d, J=8Hz, Ph-H), 7.94 (2H. d, J»8Hz, Ph-H)
Example 23 (+)-l-(2-(6-Fluorophenyl)hexyloxy)ethyl-4-(4-carboxybenzylsulphinyl)-2-oxoazetidine (diast 2)
(+)-l-(2-(6-Fluorophenyl)hexyloxy)ethyl-4-(4-allyloxycarbonylbenzylsulphinyl)-2-oxoazetidine (140mg), triphenylphosphine (7mg), tetrakis(triphenylphosphine)paIladium (0) (lOmg) in dry CH2CI2 (4ml) under nitrogen was treated with pyrrolidine (23.5}il) and the mixture was stirred at room temperature for 19 hours. 1.5mg more catalyst and pyrrolidine (5fxl) were added and the reaction was stirred for 2 hours, diluted with water (25ml) and CH2Cl2 (25ml) and acidified to pH 2 with HC1 (2N). The layers were separated and the aquoues layer was washed with CH2Q2 (25ml) The organic extracts were combined, dried (MgS04) and evaporated to a yellow oil. Purification by flash column chromatography on silica gel eluted with a CH2Cl2'.acetone:acetic acid gradient elution gave the product as an oil. Trituration with diethyl ether gave the
Printed from Mimosa
product as a colourless solid (109mg, 84%) m.p.ll8-120°C, [a]D = +50.0° ( c=0.5%w/v in ethanol al 25°C)
IH NMR 8 (DMSO) 1.25-1.6 (8H, m, 4xCH2.). 2-50 (2H-CH2Ph>. 2-91- 2-95 (IH. dd, J=2,15.2Hz, fl3), 3.22-3.53 (7H,m, H3. NCH2CH2. OQfc). 4.16,4.31 (each IH. 2xd, J=13Hz, SOCH2). 4.73 (IH, m, H4). 7.0 (2H, m. p-FPh-H). 7.19 (2H. m, p-FPh-H). 7.48 (2H, d, J=8Hz, Ph-H). 7.94 (2H, d, J=8Hz, Ph-H)
Example 24 Enantiomers of (/?,S/S,/?)-]-<2-(6-Chlorophenyl)h^)fyloxy)ethyl-4-(4-aQyk>xy car bonylbenzylsulphinyl)-2~oxoazetj dine a. 6-(4-Chlorophenyl)hexyloxy ethanol
Ethylene glycol (51.1g) and 6-(4-chlorophenyI)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 (MgSO.4) and evaporated to yellow oil. Purification by column chromatography on silica gel eluted with [3:1] to [2:1] P.E 40-60°C:ethyl acetate gave the product as a yellow oil (14.13g, 67%).
b. 6-(4-Cti)orophenyl)hexyloxy triflate
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 (MgS04.) and evaporated to a dark oil (ll.l3g. 97%).
c. (2-(6-Chloropheny!)hexyloxy)ethyl-4-(4-allyloxycarl>onylbenzylthio)-2-oxoazctkttne
A solution of 6-(4-chlorophenyl)hexyloxy triflate (1 l.lg), 4-(4-allyloxycarbonylbenztlthiojazetidin-2-onc (7.69g) and tctrabutylaramonium bromide (0.89g) in dry THF (200ml) was cooled to 10°C under nitrogen end was treated with powdered potassium hydroxide (1.63g). The cooling bath was removed and the reaction was stirred for 40 minutes. Powdered KOH (163mg) was added and the reaction was stirred at room temperature for 1.5h. partitioned between brine (600ml) and ethyl acetate (400ml). The mixture was filtered through hy-flo and the layers were separated. The organic layer was dried (MgSO^ and evaporated to a dark oil. Purification by flash column chromatography on silica gel eluted with [2:1] to [1:1] P.E. 40-60°C: ethyl acetate gave the product as an orange oil (7.28g, 51%).
IH NMR 8 (CDCI3) 13-1.6 (8H. m. 4xCH2.)> 2.55 (2H. t, J = 7.6Hz, QfePh), 2.85,2.90 (IH, dd, H3). 3.05 (IH, m. IH). 3.26.3.32(IH. dd. 1=4.9, 15.1Hz,
Printed from Mimosa
H3), 3.37-3.68 (5H. m, NCH2CH2. OCH2). 3.86 (2H, s, SCflb). 4.76 (IH. m. H4). 4.81 (2H, m CO2CH2), 5.36 (2H. m, CH=CH2) 6.03 (IH. m. CH=CH2) 7.07 (2a d. J=8.4Hz, p-ClPh-H), 7.23 (2H^n. p-ClPh-H), 7.39 (2H, d, J=8.3Hz, Ph-H), 8.01 (2H, d. J=8.3Hz. Ph-H)
d. (R,S/S,R)-1 -(2~(6-QUorophenyl)hexyloxy)cthy]-4-(4-aDyk>xycarbonyIbenzylsulphinyl)-2-oxoazetidIne
A solution of l-(2-(6-Chlorophenyl)hexyloxy)ethyl-4-(4-allyloxycarbonylbenzylthio)-2-oxoazetidine (7J2g) in dichloromethane (175ml), cooled to -70°C, was treated with a solution of mcpba (3.0g) in CH2Q2 (175ml) dropwise over 1 hour maintaining the temperature at below -70°C. The cooling bath was removed and the reaction was stirred for 1.5 hours, washed with a solution of 10% aq.sodium hydrogen carbonate(200ml) + 10% aq. sodium sulphite (200ml). The layers were separated and the organic layer was washed with brine, dried (MgSC>4) and evaporated to an oil which solidified on standing. Repeat recyrstallisations from diethyl ether (4 times) gave diastereoisomer 2 as a colourless solid (0.9g, 12.2%).
IH NMR 6 (CDCI3) 1.3-1.6 (8H. ra. 4xCH2,), 2-56 (2H, t, J = 7.8Hz, CH2Ph), 2.66,2.69 (IH, dd. J=2.4.15.2Hz.H3), 3.07.3.11 (IH. dd, J=4.8,15.2Hz. H3). 3.37-3.68 (6a m. NCH2CH2. OCH2). 4 07 (2H, s. SOCH2). 4 54 (IH. m, H4). 4.83 (2a m C02CH2), 5.36 (2H, m, CH=CH2> <5.03 (IH, m. CH=CH2) 7.09 (2H. d. J=8.8Hz, p-ClPh-H), 7.23 (2H. d. J=8.8Hz, p-ClPh-H). 7.39 (2H, d, J=8.4Hz, Ph-H). 8.07 (2a m. Ph-H)
The above racemic compound was separated by hplc on a Chiracel OD -20mm eluted with 80:20 ethanol'.hexane to give the enantiomers:
e. (-t-)-l-{2-(6-Chlorophenyl)hexyloxy)ethyl-4-(4-aIlyloxycarbonylbenzylsulphinyl)-2-oxoazetidine 83mg, colourless solid. M.p. 57-59°C
99.95% desired enantiomer with 0.05% of the other enantiomer present [a]D = +52.2° (c=0.28%w/v in ethanol at 25°C)
IH NMR 5 (CDCI3) 1.3-1.6 (8H, m, 4xCH2.). 2.56 (2H, t, J = 7.8Hz, CH2Ph), 2.66. 2.69 (IH, dd. J=2.4,15.2Hz, H3), 3.07, 3.11 (IH. dd, J=4.8. 15.2Hz, H3). 3.37-3.68 (6H, m, NCH2CH2, OCH2). 4.07 (2H, s. SOCH2), 4-54 (IH, m. H4), 4.83 (2H. m CO2CH2). 5-36 (2H, m, CH=CH2)6 03 (IH, CH=CH2) 7 09 (2H, d, J=8.8Hz, p-ClPh-H), 7.23 (2H. d, J=8.8Hz, p-ClPh-H), 7.39 (2H, d. J=8.4Hz. Ph-H), 8.07 (2H. m, Ph-H)
f. (-)- l-(2-(6-ChloropheiiyI)hexyloxy)ethyl-4-(4-allyk>xycarbonylbenzyl5ulphiiiyl)-2*oxoazetidine 103mg colourless solid M.p. 58-59°C
Printed from Mimosa
99.62% desired enantiomer with 0.38% of the other enantiomer present [a]D = -61.9°C (c=0.06%w/v in ethanol at 25°C)
IH NMR 8 (CDC13) 1.2-1.6 (8Hr m. 4xCfl2>). 2.56 (2H, U J = 7.8Hz. CH2Ph), 2.66, 2.69 (IH. dd. J=2.4.15.2Hz.H3), 3.07, 3.11 (IH. dd, J=4.8, 15.2Hz.H3), 3.37-3.68 (6H, m. NCH2CH2. OCH2,4.07 (2H. s, SOCH2). 4-54 (IH. m, H4). 4.83 (2H, m C02CH2). 5.36 (2H, m, CH=CH2) 6.03 (IH. m, CH=CH2) 7.09 (2H. d. J=8.8Hz, p-ClPh-H), 7.23 (2H. d. J=8.8Hz, p-ClPh-H), 7.39 (2H, d. J=8.4Hz, Ph-H). 8.07 (2H, m. Ph-H)
Example 25 (-)-i-(2-(&-Chlorophenyl)hexyioxy)ethyl-4-(4-carboxybenzylsu]phinyI)-2-oxoazetidine (diast 2)
(-)-l-(2-(6-Chlorophenyl)hexyloxy)ethy!-4-(4-aiiyloxycarbonylbenzylsulphinyl)-2-oxoazetidine (86.2mg), triphenylphosphine (4.2mg), tetrakis(triphenylphosphine)palladium (0) (6mg) in dry CH2C12 (2ml) under nitrogen was treated with pyrrolidine (13,5(0.1) 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 Trituration with diethyl ether gave the title compound as a cream solid (59.8rag. 75%) m.p.l02-102°C, [a]D = -37.32° (c=0.209%w/v in ethanol at 25 °C)
IH NMR 8 (CDCI3) 1.25-1.6 (8H. m. 4xCH2.)> 2-56 (2H, t J » 7.6Hz» QfePW, 2.71.2.74 (IH, dd. J=2,l5Hz,H3). 3.12, 3.15 (IH. dd. J=5.2,15HZ.H3). 338-3.72 (6H. m. NQfeOfo OCH2), 4.09 (2H, m, SOCH2), 4.60 (IH. m. H4). 7.09 (2H, d. J=8.8Hz, p-ClPh-H), 7.22 (2H. d. J=8.8Hz. p-ClPh-H), 7.40 (2H. d. J=8Hz. Ph-H). 8.08 (2H. d. J=8Hz, Ph-H)
Example 26 (+)-l-(2-(6-Chlorophenyl)hexyloxy)ethyf-4-(4-carboxybcnzylsulphinyl)-2-oxoazeddine (diast 2)
(+>l-(2-(6-Chlorophenyl)hexyloxy)ethyl-4-(4-allyloxycarbonylbenzylsulphinyl)-2-oxoazetidine (65.6mg), triphenylphosphine (3.2mg), tetrakis(triphenylphosphine)palladium (O) (4.6mg) in dry CH2C12 (2ml) under nitrogen was treated with pyrrolidine (10.3|xl) and the mixture was stined at room temperature for 19 hours. Purification by flash column chromatography on silica gel eluted with a CH2Cl2:acetoneracetic acid gradient elution gave the product as an oil. Azeotroping with water and acetone followed by trituration with diethyl ether gave the product as a cream solid (44.7mg, 73%) m.p. 104-1058C. [a]D = +51.92° (c=0.208%w/v in ethanol at 25°C)
IH NMR 8 (CDCI3) 1.25-1.6 (8H. m. 4xCH2.). 2.56 (2H, L J ■ 7.6Hz, CH2Ph). 2.71.2.74 (IH. dd, J=2,15Hz,H3). 3.12, 3.15 (IH, dd. J=5.2.15Hz.H3). 3.38-3.72 (6H, m. NCH2CH2. OCH2). 4.09 (2H, m, SOCH2). 4-60 OH. m, H4). 7.09
Printed from Mimosa
/
WO 97/41098 PCT/EP97/01898
(2H, d. J=8.8Hz. p-ClPh-H), 7.22 (2H. d. J=8.8Hz, p-ClPh-H). 7.40 (2H. d. J=8Hz, Ph-H), 8.08 (2H, d. J=8Hz, Ph-H)
Example 27 (a-S, 4-R, S-S)-N-{6-(4-nuorophcnyl)hexyI]-2-[(4-aUyloxycarbonyl)benzylsuIphinyl)]-2-oxoazetidin-l-ylpropionainide a. R-Methyl-4-[(4-*l!yloxycart>onyI)benzylthio]-2-oxcazetidln-l-ylacetate
A suspension of R-4-[(4-aUyloxycarbooyl)benzyUhio]-2-oxoaz£tidin-l-ylacetic acid (from Example If. 21.55g) and anhydrous potassium carbonate (8.88g)in 1-methyl-2-pyiTolidinone (100ml) was treated with methyl iodide (10.94g) and the mixture was stirred for 2h. Methyl iodide (l.Og) was added and after 30 minutes the reaction was partitioned between brine (500ml) and diethyl ether (500ml). The layers were separated and the aqueous layer was washed with diethyl ether (500ml). The organic extracts were combined washed with water (x2), brine,
dried (MgS04) and evaporated to an orange oil Purification by flash column chromatography on silica gel eluted with [1:1] P.E 40-60°C:ethyl acetate gave the title compound as a yellow oil (contains 2% dimethyl ester) (20.0g, 89%).
IH NMR 5(CDCI3) 2.94, 3.01 (lH.ddJ= 2.1, 15.2Hz,H3). 3.25 (IH, d.
J=18Hz, 1 of NCH2). 3.39. 3.45 (IH. dd. J=5.1, 15.2Hz.H3). 3.70 (3H. s,
CH3)3.81 (2H. s. SCH2). 4.04 (IH. d. J=18Hz. 1 of NCH2). 4.83 (2H. m. CO2CH2). 4.93 (IH, m. 4H), 5.35 (2H, m. CH=CH2). 6 04 (IH, m, CH=CH2), 7.39 (2H, d, J=8Hz, Ph-H). 8.02 (2H, d. J=8Hz. Ph-H)
b. a-R^-P-Methyl 2-{4-[(4-allyloxycarbonyl)benzylth]o)-2-oxoazetidin-l-yl)propfonate and a-S^-R-Methyl 2-{4-[(4-allyloxycarbonyl)benzylthio]-2-oxoazettdln- 1-yl} propionate
A solution of R-meihyl-4-{(4-allyloxycarbonyl)benfcylthio]-2-oxoazetidin-l-ylacetate (13.2g) in dry tetrahydrofuran (250ml) at -75°C under nitrogen was treated with a 1M solution of lithium bis(trimethylsilyl)amide in THF (46.3ml)
over 10 minutes keeping the temperature below -70°C. 1,3-Dimethylimidazolidin-2-one (30.5ml) was added keeping the temperature below -70°C. The resulting suspension was stined at -75°C for 30 minutes and then treated with methyl iodide (4.3ml) over 1 minute and the temperature rose to -68°C. The reaction was stirred for 1.5 hours at -75°C and then allowed to warm to -20°C over 30 minutes. The reaction was cooled to -75°C and quenched with glacial acetic acid (3_5ml), partititioned between water (300ml) and diethyl ether (250ml). The layers were separated and the aqueous layer was washed with diethyl ether (250ml). The organic extracts were combined washed with brine (x3). dried (MgSO.4). and evaporated to a coloured oil. Ratio of 50% R.R (diaA): 15% starting material :35% S,R (dia B). Repeat purification by flash column chromatography on silica gel eluted with P.E. 40-60°C:ethyl acetate gave the products as coloured oils.
Printed from Mimosa
RJt Diastereoisomer (A), 3.91g (29%) (contains 9% dia B)
IH NMR 5 (CDC13) 29 OH. dd. H3). 3.30 (IH. H3). 3.75 (3H. s. CH3).3.88 (2a s. SCH2). 4.4 (IH. m. CH). 4.83 (2H. m. CC^Qfe). 4-90 (ia m, 4H). 535 (2H, m, CH=CH2), 6.04 (IH. m. CH=CH2).7 39 (2H> d. J=8Hz- Ph'H). 8-02 (2H. d. J«8Hz, Ph-H)
S.R Diastereoisomer (B), 5.36g (39%) (contains some sm and 43% dia A) IH NMR 5 (CDCI3) 2.86.2.92 (IH. dd, J=2.4, I5.2Hz. H3). 3.28. 3.33 (lH,dd. J=5.1.15.2Hz, H3). 3.73 (3H, s, CH3)3.85 (2H, s. SCH2). 3.95 (IH, m. CH). 4.71 (IH. m. 4H). 4.83 (2H. m. CC^dfe). 4.90 (IH, m, 4H), 5.35 (2H, m, CH=CH2). 6.04 (IH. m. CH=CH2), 7.40 (2H. d, J=8Hz, Ph-H), 8.02 (2H, d, J=8Hz, Ph-H)
c. <x-S,4-R-2-4{4-{(4-AHyloxycarbonyI)benzylthio]-2-oxoazetidin-l-yl (propionic add
A solution of methyl 2-{4-[(4-aflyloxycarbonyl)benzylthio]-2-oxoazetidin-l-yl)propionate (2.65g) (mixture of 5% dia A (R,R): 27% dia B (S.R): 65 % desaMe) in THF (50ml) at 3°C was treated with a IN sodium hydroxide solution (7.5ml) over 60 minutes. The cooling bath was removed and the reaction was stiired for 30 minutes. IN NaOH (1.0ml) was added over 30 minutes and the reaction was then slined for 30 minutes, diluted with brine (75ml) and extracted with diethyl ether (75ml). The aqueous layer was acidified with 1NHC1 and extracted with diethyl ether (2x75ml). The organic extracts were combined washed with brine, dried (MgS04), and evaporated to give the tide compound as an orange oil (2.5g, 98%).and as a mixture in 5%R,R : 27%R,S : 65% des aMe.
d. a-S«4-R-N-[6-(4-Fluorophenyl)hexyl]-2>[(4-a)lyloxycarbonyl)benzylthio]-2-oxoazetidin- 1-ylpropionamide
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.NaHC03. brine, dried (MgS04), and evaporated to an oil. Purification by flash column chromatography on silica gel eluted with [2:1] P.E.40-60°C:eihyl acetate gave the product a-S. 4-R diastereoisomer (BXcontains 10% dia A) as a yellow oil (0.497g,13.4%).
JH NMR 6 (CDCI3) 1.25-1.7 (1 IH. m. 4xCH2, CH3),2.55 (2H. U J=7.6Hz, CH2Ph), 2.83,2.89 (IH. dd. H3). 3.25 (3H. m. NCH2. H3). 3 86 (2H. s. SCH2). 4.10 (IH. m. CH). 4.69 (IH. m. 4H). 4.83 (2H. m, C02CH2). 5.4 (2H, m, CH=CH2). 6.04 (IH. m. CH=CH2), 6.45 (ia m. NH). 6.94 (2H. m, p-FPh-H). 7.09 (2H. m. p-FPh-H). 7.39 (2H. d. J=8Hz. Ph-H). 8.028 (2H, m. Ph-H)
Printed from Mimosa
Diastereoisomer A was also isolated
IH NMR 5 (CDCI3) 1.25-1.7 (1 IH. m, 4xCI -2. CH3).2.55 (2H. t, J=7.6Hz, CH2Ph), 2.78,2.85 (IH, dd. J=2.3, i5.4Hz.H3). 3.25 (3H, m. NCH2. H3). 3.89 (2Rm, SCH2)-4 05 0H,m.CH), 4.81 (3H.4.CC ,"H2>. 5.4 (2H, m.
CH=CH2). 6 O4 OH.CH^H^. 6.48 (IH, m, NH;, 6.94 (2H. m. p-FPh-H), 7.09 (2H. m. p-FPh-H), 7.39 (2H, d, J=8Hz, Ph-H). 8.02 (2H. d. Ph-H) e. a-S^-R^S-S-N-f6-(4-Fluorophenyl)hexyl]-2-[(4-«llyloxycarbonyJ)beraylsulphinyI)]-2-oxoazetidin-1 -ylpropionamide A solution of S,R-N-[6-(4-fluorophenyl)hexyl]-2-[(4-allyloxycarbonyl)benzylthio]-2-oxoa2etidin-1-ylpropionamide (1.20g)(80:20 DiaB:A) in dichloromethane (25ml). cooled to -75°C, was treated with a solution of mcpba (0.7 lg) in CH2C12 (25ml) over 1 hour keeping the temperature at -75°C. The cooling bath was removed and the reaction was stirred for 2 hours, diluted with CH2C12 (25ml), washed with 10%aq. sodium sulphite (50ml), sat,NaHC03 (50ml),dried (MgSC>4) and evaporated to a coloured oil.
Purification by flash column chromatography on silica gel eluted with ethyl acetate gave the title compound as a 60:40 mixture of dia B2 (a-S, 4-R. S-S):dia Bl(a-S,4-R.J-R)
Purification on Kromasil 5|im silica (250mmx4.6mm) eluted with 50% hexane: 40% ethanol: 10% CHCI3 gave the title compound Diastereoisomer B2 : (a-S, 4-R, S-S)-N-[6-(4-fluorophenyl)hexyI]-2-[(4-allyloxycarbonyl)benzylsulphinyl)]-2-oxoazetidin- 1-ylpropionamide as a colourless oil.
IH NMR 5 (CDCI3) 1.25-1.7 (1 IH, ra. 4xCH2. CH3).2.55 (2H, t, J=7.6Hz, CH2Ph). 2.83,2.89 (IH. ddj= 2. 15Hz. H3). 3.24 (3H. m. NCH2. H3), 4.02 (2H, m, SOCH2),4 44 OH. m. CH), 4.60 (IH. ra, 4H). 4.83 (2H. m. CC^Qfc). 5.4 (2H, m. CH=CH2). 6 04 OH, m, CH=CH2). 6.85 (IH. m, NH), 6.94 (2H. m. p-FPh-H). 7.09 (2H, m, p-FPh-H), 7.37 (2H. d, J=8Hz. Ph-H), 8.08 (2H. d, J=8Hz, Ph-H)
Example 28 (a-S, 4-R, S-S)-N-(6-(4-F]uorophenyI)hexyl]-2-f(4-carboxybenzylsulphinyl)-2-oxoazetidin-l-ylpropioiiamSde
A solution of (a-S, 4-R, 5-S>N-[6-(4-fluorophenyl)hexyl]~2-[(4-allyloxycarbonyl)benzylsulphinyl]-2-oxoazetidin- 1-ylpropionamide (dia B2) (240mg),triphenylphosphine (6mg), tetrakis(triphenylphosphine)palladium (O) (15mg) in dry CH2Q2 (5ml) under nitrogen was treated with pyrrolidine (39pJ) and the mixture was stirred at room temperature for 19 hours. The mixture was diluted with CH2C12 (50ml) and water (25ml) and acidified with 2NHC1. Tine layers were separated and the aqueous was washed with CH2C12 (2x50ml). The organic extracts were combined, dried (MgSC>4) and evaporated to a yellow gum. Purification by flash column chromatography on silica gel eluted with a
Printed from Mimosa
CH2Cl2:acetone:ace^c acid gradient elutioa gave the produce as an oil. The oil was dissolved in CH2CI2 (4ml) and diluted with diethyl ether (75ml), washed with water, brine, dried (MgSCty), Filtered and evaporated to a brown foam (123rag. 56%)
[a]= No significant optical rotation (c=l.l%w/v in CHCI3)
'H NMR 8 (CDCI3) 1J2-1.6 (13H, m, Cfl3.4xCH2>. 2.55 (2H. t. J=7.6Hz. CH2Ph). 2.84,2.88 (IH. dd. J=2.4, 15.2Hz. fl3). 3.1-3.3 (3H. m. NHCH2. ^3). 4.04.4.10 (2H, 2xd, J=13Hz, SOCH2). 4.4 (IH, q. CHCH3), 4.68 (IH, m. H4), 6.94 (3H, m. N£L p-F-Ph-H). 7.10 (2H. m. p-F-Ph-H). 7.39 (2H, m. Ar-H), 8.06 (2H, m. Ar-H)
Example 29 (a-R, 4-R, S-R)- and (a-R, 4-R, S-S)-N-[6-(4-
Fluorophenyl)hexy)]-2-[(4-allyloxycarbonyl)benzylsulphinyl)]-2-oxoazetidin-
1-ylpropionamide
A solution of (a-R, 4-R)-N-[6-(4-fluorophenyl)hexyi]-2-[(4-allyloxycarbonyl)benzylthio]-2-oxoazetidin-1 -ylpropionamide (1.25g)(diastereoisomer A) in dichloromethane (25ml), cooled to -75°C, was treated with a solution of mepba (0.7Sg) in CH2CI2 (25ml) over 1 hour keeping the temperature at -75°C. The cooling bath was removed and the reaction was stirred for 2 hours, diluted with CH2G2 (50ml), washed with 10%aq. sodium sulphite (50ml), sat.NaHC03 (50ml), water, dried (MgS04) and evaporated to a coloured oil. The oil was dissolved in ethyl acetate (7.5ml) and cooled. The resulting solid was collected, washed with diethyl ether and dried to give (a-R, 4-R. S-R)-N-[6-(4-fluorophenyl)hexyl]-2-[(4-allyloxycarbonyl)benzylsulphinyI)]-2-oxoazetidin- 1-ylpropionamide (dia Al) as a colourless solid 0.125g,9.7%. The filtrate was purified by flash column chromatography on silica gel eluted with ethyl acetate: P.E. 40-60°C. Pure R,R,R fractions were combined and recrystallised from ethyl acetate/diethyl ether to give R.R.R-N-[6-(4-fliiorophenyl)hexyl]-2-[(4-allyloxycarbouyl)benzylsulphinyl)]-2-oxoazetidin-l-ylpropionamide as a colourless solid (0.195g, 15%), m.p.l39-140°C:
IH NMR 8 (CDCI3) 1.25-1.7 (1 IH. m. 4xCH2. CH3).2.56 (2H. t, J=7.6Hz, CH2Ph). 2.79, 2.83 (IH. ddj= 5,15Hz.H3), 3.20 (2H. m. NCH2). 3 33, 3.39 (IH, ddj= 2. 15HZ.H3), 3.94 (2H, m, SOCH2).416 (1K- m- CH)'4/77 (1H-m-4H), 4.83 (2H. m. C02CH2). 5.4 (2H, m. CH=CH2). 6.04 (IH, m. CH=CH2), 6.72 (IH. m. NH). 6.94 (2H, m. p-FPh-H), 7.09 (2H, m. p-FPh-H), 7.37 (2H, d, J=8Hz, Ph-H). 8.08 (2H. d. J=8Hz. Ph-H)
Impure R.R.S fractions were combined and recrystallised from ethyl acetate/diethyl ether to give (a-R, 4-R, S-S)-N-(6-(4-fluorophenyl)hexyl]-2-[(4-
Printed from Mimosa
allyloxycarbonyl)benzylsuIphinyl)]-2-oxoazetidin-1-ylpropionamide as a colourless solid (0.204g,15.8%), m.p. 102°C:
IH NMR 6 (CDCI3) 1.25-1.7 (1 IH. m. 4xCH2. CH3).2.56 (2H, t, J»7.6Hz, CH2Ph). 2.83 (IH, dd. H3). 3.20 (3H, m. NCH2. H3). 4.10 (3H, m, SOCfl2, CH), 4.65 (IH, m. 4H). 4.83 (2H, m. CO2CH2). 5.4 (2H. m. CH=CH2). 6.04 (IH. m. CH=CH2). 6-94 (2H, m, p-FPh-H). 7.09 (2H. m,. NH, p-FPh-H). 7.37 (2H. d. J=8Hz, Ph-H). 8.08 (2H. d, J=8Hz, Ph-H)
In an analagous manner the following chioro compounds were prepared from racemic 4-[(4-ailyloxycarbonyl)benzylthio]-2-oxoazetidin-l-ylacetic acid.
Example 30 (-Ma-S, 4-R, 5-S)- and (+)-(a-R, 4-S, S-R>-N-fM4-
Chlorophenyt)hexyl]-2-[(4-aIlyloxycarbonyl)benzylsulphinyl]-2-oxoazetidJn-
1-ylproptoiuunide a. N-[6-(4-Chlorophenyl)hexyI]-2-[(4-allyJoxycarbonyI)benzylthio]-2" oxoazetidin- 1-ylpropionamide
A mixture of methyl-2-((4-allyloxycarbonyl)benzylthio]-2-oxoazetidin-l-yl}propionate(4.87g), hydroxybenzotriazole (l.88g), DCC (2.89g) in dry DMF (60ml) was treated with 6-(4-ch)orophenyI)hexylamine and stirred at room temperature for 6 days. The orange suspension was diluted with diethyl ether (200ml) and filtered to remove precipitate. Filtrate was washed with dil NaHCC>3 (200ml). brine, dried (MgSC>4), and evaporated to an orange oil. Repeat flash column chromatography on silica gel using P.E 40-60°C:ethyl acetate gave : Diastereoisomer A (RJt/S,S) (0.8 lg. 11%)
IH NMR 6 (CDCI3) 1.25-1.7 (l IH, m. 4xCH2- CH3),2.55 (2H, t, J=7.6Hz, OfcPb). 2.85 (IH, dd. H3). 3.25 (3H. m. NCH2. H3). 3.89 (2H,m. SCH2). 4.05 (IH. m. CH). 4.81 (3H. 4.C02CH2). 5.4 (2H. m, CH=CH2). 6.04 (IH, m, CH=CH2). 6.48 (IH, m, NH), 7.07 (2H. d, J=8.4Hz, p-ClPh-H). 7.22 (2H. d. J=8„8Hz, p-ClPh-H), 7.39 (2H. d. J=8Hz. Ph-H), 8.08 (2H. d. Ph-H) Diasteroisomer B (R,S/S,R) (1.63g. 22%)
IH NMR 6 (CDCI3) 1-25-1.7 (1 IH, m. 4xCH2. CH3),2.55 (2H, t, J=7.6Hz, CH2Ph). 2.83,2.89 (IK. dd, 1= 2.3.15-iHz, H3). 3.25 (3H, m. NCH2, H3). 3.86 (2H, s. SCH2). 4.10 (IH. m, CH). 4.69 (IH. m, 4H). 4.83 (2H. m, C02CH2). 5.4 (2H. m. CH=CH2). 6-04 (IH. m, CH=CH2). 6.43 (IH, m. NH). 7.07 (2H. d, J=8.4Hz, p-ClPh-H). 7.22 (2H. d, J=8.8Hz. p-ClPh-H). 7.39 (2H. d. J=8Hz. Ph-H). 8.08 (2H, m, Ph-H)
b. N-[6-(4-Chlorophenyl)hexyl]-2-[(4-allyloxycarbonyJ)benzylsulphinyl]-2-oxoazetidln-I-ylpropionainide
A solution of (R,S/S.R)-N-[6-(4-chlorophenyl)hexyl)-2-((4-allyloxycarbonyl)-4-benzylthio)-2-oxoazetidin- 1-ylpropionamide (1,60g Kdiastereoisomer B) in
Printed from Mimosa
dichloromethane (30ml), cooled to -75°C, was treated with a solution of racpba (0.92g) in CH2CI2 (30ml) over 45 minutes keeping the temperature below -70°C. The cooling bath was removed and the reaction was stirred for 45 minutes,
diluted with CH2CI2 (20ml), washed with 10%aq. sodium sulphite (50ml), saLNaHCC>3 (50ml), dried (MgSC>4) and evaporated to give the title compound as a mixture of stereoisomers as a coloured oiL(1.6g. 100%). (65%:35% sulfoxide diastereoisomer B2:B1) This material was separated by hplc: Sulfoxide dia B2 was separated from dia B1 using Beckman silica 15cm x 4.6mm eluted with 10:90 ethanolihexane and subsequent enantiomer separation of diasteroisom. '2 used Chiracel OD-4.6mm eluted with 25:75 ethanol:hexane.
c. (-)-(a-S, 4-R, 5-S)-N-[6-(4-Chlorophenyl)hexyl]-2-{(4-alIyloxycarbonyl)benzylsu]phinyt]-2-oxoazetidJn-l-y)propionamide ((-)B2) Enantiomerically pure, colourless oil, 148mg, [a]D= -4.2° (c=0.4%w/v in CHCI3) IH NMR 5 (CDCI3) 1.25-1.7 (1 IH, a». 4xCU2. CH3).2.55 (2H. t, J=7.6Hz, CH2Ph), 2.83,2.89 (IH, ddj= 2.4. 15.3Hz, H3). 3.24 (3H, m. NCH2. H3). 4.08 (2H, m). 4.60 (IH. m. CH). 4.69 (IH, m, 4H). 4.83 (2H. m. CC^Qfc). 5.4 (2H. m. CH=CH2). 6 04 (IH, m. CH=CH2), 6.95 (IH, m. NH), 7.08 (2H, d, J=8.4Hz, p-ClPh-H). 7.22 (2H, d. J=8.8Hz, p-ClPh-E), 7.39 (2H. d, J=8Hz, Ph-H), 8.08 (2H. d. J«8Hz, Ph-H)
d. (+Ma-R, 4-S, S-R)--N-[M4-Chlorophenyl)hexy)]-2-[(4-allyloxycarbonyl)benzylsulphinyl]-2-oxoazetidin-1 •ylpropionamide ((+)B2) Sample contains 0.83% of the other enantiomer, colourless oil,145mg, [a]D-+4.3° (c=0.4%w/v in CHCI3)
IH NMR 6 (CDCI3) 1.25-1.7 (1 IH. m. 4xCH2> CH3X.2.55 (2H. t, J=7.6Hz, CH2Ph), 2.83, 2.89 (IH, dd,J= 2.4, 15.3Hz, H3), 3.24 (3H. ra, NCH2, H3). 4-08 (2H, m), 4.60 (IH. m. CH). 4.69 (IH, m. 4H), 4.83 (2H. m, CO2CH2). 5.4 (2H, m, CH=CH2). 6.04 (IH. in. CH=CH2), 6.95 (IH. m. NH). 7.08 (2H. d, J=8.4Hz, p-QPh-H), 7.22 (2H, d. J=8.8Hz. p-ClPh-H), 7.39 (2H, d, J=8Hz, Ph-H), 8.08 (2H. d. J=8Hz. Ph-H)
Example 31 (-)-(a-S, 4-R, S-S)-[6-(4-Chlorophenyl)hexyl>2-<4-carboxybenzylsalphinyl)-2-oxoazetidln-1 -ylpropionamide
A solution of (-Ma-S, 4-R, S-S)-N-[6-(4-chlorophenyl)hexyf]-2-[(4-allyloxycarbonyl)benzylsulphinyl]-2-oxoazetidin- 1-ylpropionamide (I25mg), triphenylphosphine (6mg), tetrakis(triphenylphosphine)palladium (0) (8mg) in dry CH2CI2 (2ml) under nitrogen was treated with pyrrolidine (19.5^il) and the mixture was stirred at room temperature for 19 hours. Purification by flash column chromatography eluted with a CH2Cl2:acetone:acetic acid gradient elution gave the product as an oil. The oil was dissolved in CH2CI2 (2ml) and diluted with diethyl ether (50ml), washed with, brine (x2), dried (MgSCX}),
Printed from Mimosa
filtered and evaporated to givee the title compound as a yellow foam (104mg, 87%)
[a]D= -3.7° (c=0.5%w/v in CHCI3)
IH NMR 5 (CDCI3) 1.25-1.6 (8H, m, 4xCH2.). 1-62 (3H. d. J=7.2Hz, CH3),2.55 (2H, t, J=7.6Hz, CifcPh). 186, 2.89 (IH. dd. J=2.4, 15^Hzii3). 3.20 (3a m. NCJfe. H3). 4.06 (2H, m. SOCH2). 4-45 (IH, m, CH). 4.66 (IH. m. 4H). 6.95 (IH. m. NH). 7.08 (2a d. J=8.4Hz, p-ClPh-H). 7.22 (2H, d, J=8.8Hz, p-ClPh-H). 7.39 (2H. d, J=8Hz, Ph-H). 8.08 (2H. d, J=SHz, Pb-H)
Example 32 (+Ma-R, 4S, S-R)-N-[6-(4-Chlorophenyi)hexyl]-2-(4-carboxybenzylsulphinyl)-2-oxoazetidln- 1-ylpropiona ilde A solution of (+)-(o-R. 4-S. 5-R)-N-[6-(4-chlorophenyl)aexyl]-2-[(4-allyloxycarbonyl)benzylsulphinyl]-2-oxoazetidtn-l-ylpropionsmide (123mg), triphenylphosphine (6mg). tetrakis(triphenylphosphine)palladium (O) (8mg) in dry CH2CI2 (2ml) under nitrogen was treated with pyrrolidine (19.5pJ) and the mixture was stirred at room temperature for 19 hours. Purification by flash column chromatography eluted with a CH2Cl2:acetone:acetic acid gradient elution gave the product as an oil. The oil was dissolved in CH2C12 (2ml) and diluted with diethyl ether (50ml). washed with, brine (x2), dried (MgSOj}),
filtered and evaporated to a yellow foam (lOlmg, 89%)
[a]0= +3.3° (c=0.3%w/v in CHC13)
IH NMR 5 (CDCI3) 1.25-1.6 (8H. m. 4xCH2«). 1-62 (3H. d. J=7.2Hz, CH3).2.55 (2H, t. J=7.6Hz. CH2Ph), 2.88 (IH. dd. H3), 3.20 (3H, m. NCfo. H3). 4.06 (2H. m. SOCH2). 4-45 (IH. m. CH). 4.69 (IH. m. 4H). 6.95 (IH. m. NH). 7.08 (2H. d, J=8.4Hz, p-ClPh-H). 7.22 (2H. d. J=8.8Hz, p-ClPh-H). 7.39 (2H. d. J=8Hz, Ph-H). 8.08 (2H, d. J=8Hz, Ph-H)
The following 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.
Description 1 fX,5/S,/?J-l-(2-(6-Chlorophenyl)hexyloxy)ethyl-4-(4-carboxybenzylsulphinyl)-2-oxoazetidine (diast 2)
(R.S/S.Ry 1 -(2-(6-Chlorophenyl)hexyloxy)ethyl-4-(4-allyloxycarbonylbenzylsulphinyl)~2-oxoazetidine (220mg), triphenylphosphine (1 lmg), tetrakis(tnpheny(phosphine)palladiura (0) (15mg) in dry CH2Cl2 (5ml) under nitrogen was treated with pyrrolidine (37|il) 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. The oil was dissolved in CH2CI2 (4ml) and diluted with diethyl
Printed from Mimosa
ether (75ml), washed with water, brine, dried (MgSC>4), filtered and evaporated to an oil which solidified on cooling. Trituration with diethyl ether gave the title compound as a cream solid (149mg, 75%) ra.p.l07-108°C IH NMR 8 (CDClj) 1.25-1.6 (8H, m, 4xCH2-). 2.56 (2H, t, J = 7.8Hz, CH2Ph). 2.71,2.74 (IH, dd, J=2,15.2Hz,H3), 3.12, 3.15 (IH. dd. J=5.2. 15.2Hz.H3). 3.38-3.72 (6H, m. NCikQfe. OCH2). 4.10 (2H, m. SOCH2). 4.63 (IH. m, H4). 7.09 (2H, d, J=8.8Hz, p-ClPh-fl), 7.22 (2H, d, J=8.8Hz, p-CIPh-H), 7.40 (2H, d, J=8Hz, Ph-H). 8.08 (2H, d, J=8Hz, Ph-H)
Description 2 (/?,5/Srff)-l-(2-(6-Chlorophenyl)hexyloxy)ethyl-4-(4-ethoxycarbonylbenzyisolphinyI)-2-oxoazetidine (diast 2)
a. l-(2"(6-ChlorophenyI)hexyIoxy)ethyl-4-(4-ethoxycflrbonyIbenzylthio)-2-oxoazetidine
A solution of 6-(4-chlorophenyl)hexyloxy triflate (3.62g), 4-(4-ethoxycarbonylbenztlthio)azetidin-2-one (2.47g) and tetrabutylammonium bromide (0.30g) in dry THF (70ml) was cooled to 10°C under nitrogen and was treated with powdered potassium hydroxide (0.62g). The cooling bath was removed and the reaction was stirred for 2 hours . The mixture was partitioned between brine (200ml) and ethyl acetate (200ml) and filtered through celite. The layers were separated and the aqueous was washed with ethyl acetate (100ml). The organic extracts were combined, dried (MgSCX*) and evaporated to a dark oil. Purification by flash column chromatography on silica gel eluted with [2:1] to [1:1] P.E. 40-60°C: ethyl acetate gave the title compound as a yellow oil (2.41g, 51%).
IH NMR 8 (CDCI3) 1.25-1.6 (1 IH. m, CH3.4xCH2.)> 2-55 (2H, t, J =7.6Hz, CH2Ph), 2.85 (IH, dd, H3), 3 05 (IH, m), 3.25. 3.30 (IH. dd, H3), 3.36-3.72 (5H. m. NCH2CH2. OCH2). 3.85 (2H. s. SCH2). 4.37 (2H. q. J=7.1Hz, CO2CH3) 4.76 (IH. m. H4). 7.07 (2H, d, J=8.4Hz. p-CIPh-H). 7.22 (2H, ra, p-OPh-H), 7.39 (2H, d. J=8Hz, Ph-H), 8.08 (2H. d. J=8Hz, Ph-H)
b. (7i,S/S,*)-l-(2-(6-Chlorophenyl)hexyloxy)ethyl-4-(4-ethoxycarbonylbenzylsulphinyl)-2-oxoazetldine (diast 2)
A solution of l-(2-(6-chlorophenyl)hexyloxy)ethyl-4-(4-ethoxycarbonylbenzylthio)-2-oxoazetidine (2.37g) in dichloromethane (75ml). cooled to -70°C, was treated with a solution of mcpba (I.Og) in CH2Q2 (75ml) dropwise over 1 hour maintaining the temperature at below -70°C. The cooling bath was removed and the reaction was stirred for 2 hours, washed with a solution of 10% aq.sodium hydrogen carbonate(50ml) + 10% aq. sodium sulphite (50ml). The layers were separated and the organic layer was washed with brine, dried (MgSC>4) and evaporated to an oil. Recrystallisation from diethyl ether '40ml) gave a colourless solid (0.91g). Purification by flash column chromatography
Printed from Mimosa
PCT/EP97/0189S
eluted on silica gel with [2; 1} ethyl acetaterhexane and rccysallisation of the less polar product from diethyl ether (15ml) gave diastereoisomer 2 as a colourless solid (0.40g,15%).m.p. 81-82°C
IH NMR 5 (CDCIj) 1.25-1.6 (11H, m, CH3.4xCH2.). 2-55 (2H- * «7.8Hz, CtfcPh), 2.63,2.69 (IH, dd, J-2.2,15.1Hz,H3). 3.05,3.11 (IH, dd, J=5.1. 15.lHz.H3). 3.36-3.74 (6a m, NCH2CH2. OCH2).375 <2H-SOCH2), 4J9 (2H, q, J=7.1Hz. CO2CH3) 4-*4 (ia m. H4). 7.09 (2H. d, J=8.4Hz, p-CIPh-H). 7.22 (2H. m, p-CIPh-H). 7.37 (2H. d, J=8.3Hz, Ph-H), 8.06 (2H, in, Ph-H)
Printed from Mimosa
Biological Data
1. Screen for Lp-PLA2 inhibition.
Enzyme activity was determined by measuring the rate of turnover of the artificial substrate (A) at 37 °C in 50mM HEPES (N-2-hydroxyethylpiperazine-N'-2-ethanesulphonic acid) buffer containing 150mM NaCl. pH 7.4.
Assays were performed in 96 well litre plates.
Lp-PLA2 was partially purified by density gradient centrifugaticn 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 fxL The reaction was then initiated by the addition of 20 pJ lOx substrate (A) to jive a final substrate concentration of 20 iiM. 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)hcx-l-yl]-4-(4-carboxybenzylsulphinyl)-2-oxoazetidin-l-yl)acetamide and the carboxylic acid (4R, SS)-N-[6-(4-fluorophenyl)hex-l-yl]-4-(4-carboxybenzylsulphinyI)-2-oxoazetidin-l-yi)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.
2. Evaluation of Bioavailability
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.
OPO(CH2)2NMe3®
cP
(A)
Results:
Printed from Mimosa
v-oc
Example
Add production
Buffer
SGF
pH 7.5
pH 1.2
R
Dog mic
Human mic tl/2 h tl/2h
9
100%
80%
3
3.5
°-Vi<
0 *
100%
75%
1
1
11
100%
65%
3.5
2.5
12
100%
60%
>4
1.5
o
13
100%
50%
3
7
o
14
100%
70%
-7
58
°-°Ykr
0
100%
100%
8-9
°yy
16
100%
45%
1.5
OEt
6
%
<2%
Acid production - % conversion of test ester to parent acid by r ive • microsomes after incubation ofl^m test compound for 15 min, . .^d by measuring the concentration of parent acid produced by HPLC detection of acid (100% = ljxM acid produced). Figures are rounded to nearest 5%.
3. Evaluation of stability
Printed from Mimosa
Claims (25)
1.2 + pepsin). Initial concentration = 50 uM and compound monitored by HPLC. Figures rounded to nearest 0.5 h. 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). ■ .50- Printed from Mimosa Claims L A compound of the formula CI): 332476 SOCH. 2 co2R* o CR*R' —XY (D in which: Rl is hydrogen or a corresponding pharmaceutical^ acceptable ester or a pharmaceutically acceptable salt thereof; R2 and R^ which may be the same or different is each selected from hydrogen or optionally substituted C(i_6)alkyl; X is a group X'(CH2)m in which X' is CO. CONR4. COO, CONR^O, CONHO or CH2O in which R4 is hydrogen or C(i.6)alkyl and m is 0 or an integer from 1 to 12; or a C(i.i2)alkylene chain optionally interupted by X'; and Y is an optionally substituted aryl group; having the absolute configuration (4i?,S30.
2. A compound as claimed in claim I in which R2 and is each hydrogen or R2 is hydrogen and R^ is methyl.
3. A compound of formula (I) as claimed in claim 1 or 2 in which X is CO(CH2)m. CONH(CH2)m, COO(CH2)m. CONHCO(CH2)m, CONHO(CH2)m, CH20(CH2)m, or C(i _j2)alkylene.
4. A compound of formula (I) as claimed in any one of claims 1 to 3 in which X is CONH(CH2)m or CH20(CH2)m.
5. A compound of formula (I) as claimed in any one of claims 1 to 4 in which X is CONH(CH2)6-
6. A compound of formula (I) as claimed in any one of claims 1 to 5 in which Y is phenyl, optionally substituted by up tc three further substituents. -51- INTELLECTUAL PROPERTY OFFICE OF N2. 16 MAY 2000 RECEIVED 332476
7. A compound of fonnula (I) as claimed in any one of claims 1 to 6 in which Y is phenyl optionally substituted by halo.
8. A compound of fonnula (I) as claimed in any one of claims 1 to 7 in which X-Y is CONH(CH2)6Ph(4-F)/(4-Cl).
9. A compound of fonnula (I) as claimed in any one of claims 1 to 8 in which the pharmaceutically acceptable ester is a C(i_6)alkyl or C(2-6)aIkenyl ester or a pharmaceutically acceptable in vivo hydrolysable ester.
10. A compound of fonnula (I) as claimed in claim 9 in which R' is an in vivo hydrolysable ester selected from: -CH(R&X).CO.Rb; -CH(Ra)O.CO.ORc; -CH(Ra)CO.NReRf -RdNRCRf; -CH2OR«; ch, y X Y o -CH(Ra)O.CO.C6H4YlCOCH(R«)NH2; and O in which: Ra is hydrogen, (Chalky!, in particular methyl, (C3-7)cycloaUcyl, or phenyl, each of which may be optionally substituted; Rb is (Ci-6>alkyl, (C j-^)a]koxy(C \ -6)alkyl, phenyl, benzyl, (C3*7)cycloalkyi, (Ci-6)alkyl(C3-7)cycloallcyI, l-amino(Ci-6)alkyl. or 1 -(C i-galkyI)amino(C \-g)alkyI, each of which may be optionally substituted; or Ra and R*5 together form a 1,2-phenyIene group optionally substituted by one or two methoxy groups; Rc is (Ci-5)alkyl, (C3-7>cycloalkyl, (C]-6)alkyl(C3-7)cycloalkyl; 52- INTELLECTUAL PROPERTY QFRCE OF NZ 16 MAY 2000 o rr r* <- i v / r- r\ WO 97/41098 PCT/EP97/01S98 Rd is (Ci-6)alkylene optionally substituted with a methyl or ethyl group; Rc and Rf which may be the same or different is each (Ci-gjalkyl; or aryKCi-4) alkyl, optionally substituted with e.g. hydroxy; R£ is (Cj-6)alkyl; Rh is hydrogen, (Ci-5)alkyl or phenyl; R' is hydrogen or phenyl optionally substituted by up to three groups selected from halogen, (Cj-gJ-alkyl, or (C i-g)alkoxy; and Yl is oxygen or NH. I
11. A compound of fonnula (I) as claimed in claim 10 in which R* is: (a) acyloxyalkyl groups such as acetoxymethyl, isobutyryloxymethyl. pivaloyloxymethyl. bekzoyloxymethyl. ot-acetoxyethyl. a-pivaloyloxyethyl, 1 -(cyclohexylcarbonyloxy)ethyl, (1 -arainoethyljcarbonyloxyraethyl, 2-methoxyprop-2-ylcarbonyloxymethyI, phenylcarbonyloxymethyl and 4-methoxyphenyl-carbonyloxymethyl; (b) alkoxy/tycloalkoxycarbonyloxyalkyl groups, such as ethoxycarbonyloxymethyl, t-butyloxycarbonyloxymethyl, cyclohexyloxycarbonytoxymethyl, 1-methylcyclohexyloxycarbonyloxymethyl and a-cthoxycarbonyloxyethyl; (c) dialkylaminoalkyl, especially di-loweralkylamino alkyl groups such as dimethylaminomethyl, dimethylamincethyl, diethylaminomethyl or diethylaminoethyl; (d) acetamido groups such as N,N-dimethylaminocarbonylmethyl, N,N-(2-hydroxyethyl)aminocarbonylmethyl: (e) lactone groups such as phthalidyl and dimethoxyphthalidyl; (0 (5-methyl-2-oxo-13-dioxolen-4-yJ)methyl; and (g) (2-methoxycarbonyl-£-but-2-en-yl)methyl.
12. Acompound of formula (I) as claimed in claim 11 in which R' is: (2-methoxycarbonyl-£-but-2-en-yl)methyl, isobutyryloxymethyl, 2-methoxyprop-2-ylcarbonyloxymethyl, phenylcarbonyloxymethyl, 4-methoxyphenyl-carbonyloxymethyl, t-butyloxycarbonyloxymethyl, cyclohexyloxy-caibonyloxymcthyl. 1 -methylcyclohexyloxycarbonyloxymethyl. -53- Printed from Mimosa 332476 N,N-dimethylaminocarbonylmethyl, N-N-di-(2-hydroxyethyl)aminocarbonyl-methyloxy or (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl.
13. A compound of fonnula (I) selected from: (4/?, SS)-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); (4/?, SS> N-[6-(4-FIuoropheny l)hex-1 -yI]-4-(4-alloxycarbonylbenzylsulphinyl)-2-oxoazetidin-1 -yl)acetamide; (4R, S5>N-(6-(4-Fluorophenyl)hexyl)-4-(4-ethoxycarbonylbenzylsulphinyl)-2-oxoazetidin-1 -ylacetamide; (4/?, SS)-N-(6-(4-Chlorophenyl)hexyl)-4-(4-ethoxycarbonylbenzylsulphinyl)-2-oxoazetidin-1 -ylacetamide; (-)-1 -(2-(6-Fluorophenyl)hexyloxy)ethyl-4-(4-carboxybenzylsulphinyl)-2-oxoazetidine (diast. 2); (+)-1 -(2-(6-Fluorophenyl)hexyloxy)ethyl-4-(4-carboxybenzylsulphinyl)-2-oxoazetidine (diast. 2); (+)-l-(2-(6-Fluorophenyl)hexyloxy)ethyl-4-(4-allyloxycarbonylbenzylsulphinyl)-2-oxoazetidine (dias' 2); (-H-(2-(6-Fluorophenyl)hexyloxy)ethyl-4-(4-allyloxycarbonylbenzylsulphinyI)-2-oxoazetidine (diast 2); (-)-1 -(2-(6-ChlorophenyI)hexyloxy)ethy l-4-(4-carboxybenzylsulphinyI)-2-oxoazetidine (diast. 2); (•»-)-l-(2-(6-Chlorophcnyl)hexyloxy )ethyl-4-(4-carboxybenzylsulphinyl)-2-oxoazetidine (diast. 2); (+)-l-(2-(6-ChlorophenyI)hexyIoxy)ethyl-4-(4-allyloxycarbonylbenzyLsulphinyl)-2-oxoazetidine; (-H-(2-(6-Chlorophenyl)hexyloxy)ethyI-4-(4-allyloxycarbonylbenzylsulphinyl)-2-oxoazetidine; (a-S, 4-R, 5-S)-N-[6-(4-fluorophenyl)hexyl]-2-[(4-allyloxycarbonyl)benzylsulphinyl)]-2-oxoazetidin- 1-ylpropionamide; (a-S, 4-R, 5-S)-N-[6-(4-Fluorophenyl)hexyl]-2-[(4-carboxybenzylsulphinyl)-2-oxoazetidin-1 -ylpropionamide; INTELLECTUAL PROPERTY OFFICE OF N.Z. RECEIVED WO 97/41098 PCT/EP97/01898 (a-R, 4- R, S-R)—N-[6-(4-Fluorophenyl)hexyI]-2-[(4-aIlyloxycarbonyI)benzylsulphinyl)]-2-o*oazetidin-1 -ylpropionamide; (a-R, 4-R, J-S)-N-[6-(4-Fluorophenyl)hexyI]-2-[(4-allyloxycarboayl)benzylsulphinyl)]-2-oxoazetidin-1 -ylpropionamide; (-)-(a-S, 4-K, S-S)-N-(6-(4-Chlorophenyl)hexyl]-2-((4-allyloxycarbonyl)benzylsulphinyl]-2-oxoazetidin-1 -ylpropionamide ((-)B2); (-Ha-S, 4-R. 5-S)-[6-(4-Chlorophenyl)hexyl]-2-(4-carboxybeazylsulphinyl}-2-oxoazetidin-1 -ylpropionamide; (+)-(a-R, 4-S, S-R)-N-[6-(4-Chlorophenyl)hexyl]-2-I(4-allyloxycarbonyl)benzylsulphinyl]-2-oxoazetidin- 1-ylpropionamide ((+)B2); and (+)-(a-R, 4-S, S-R)-N-|6-(4-Chlorophenyl)hexy!)-2-(4-carboxybenzylsulphinyl)-2-oxoazetidin- 1-ylpropionamide.
14. A compound of fonnula (I) selected from: (4R, SS)-N-(6-(4-FluorophertyV)hex-1 -yl)-4-(4- (cyclobexyloxycarbonyloxymethyloxycarbonyl)benzylsulphinyl)-2-oxoazetidin-l-yl)acetaraide; (4/?, S5)-N-(6-[4-Fluorophenyl]hex- l-yl)-4-(4-(tert-butyloxycaxbonyloxymethyloxycarbonyl)benzylsulphinyl)-2-oxoazetidin-1 -yl)acetamide; (4/?, S5>N-(6-[4-Fluorophenyl]hex-1 -yl)-4-<4-( 1 -methylcyclohexyloxycarbonyloxymethyloxycarbonyl)benzylsulphinyI)-2-oxoazetidin-1 -yl)acetamide; (4R, SS)-N-(6-[4-Fluorophtryl]hex-1 -yl)-4-(4- (phenylcarbonyloxymethyloxycarbonyl)benzylsulphiny l)-2-oxoazetidin-1 -yl)acetamide; (4R, SS)-N-(6-[4-Flucrophenyl]hex-l-yl)-4~{4-(4- methoxyphenylcarbonyloxymethyloxycarbonyl)benzylsulphinyl)-2-oxoazeudin-l-yl)acetamide; (4R, S5)-N-(6-[4-Fluorophenyl]hex-1 -yl)-4-(4-(iso-butyryloxymethyloxycarbonyl)benzylsulphiny l)-2-oxoazetidin-1 -yDscetamide; (4/f. S5)-N-(6-[4-FluorophenyI)hex-l-yl)-4-(4-(2-meu»oxyprop-2-ylcarbonyloxymethyloxycarbonyI)benzylsulphinyI)-2-oxoazetidin-1 -yl)2ceumide; (4R, S5>N-(6-f4-Fluorophenyl]hex-1 -yl)-4-(4-((5-methy 1-2-oxo-1,3-dioxoien~4-yi)methyloxycarbonyl)benzylsulphinyl)-2-oxoazetidin-1 -yl)acetamide; -55- Printed from Mimosa 332476 (4/?, S5)-N-(6-[4-Huorophenyl)hex-1 -yl)-4-(4-((2-methoxycarbonyl-E-but-2-en-yl)methy loxycarbonyl)benzylsulphinyl)-2-oxoazetidin-1 -yl)acetaraide; (4R, SS)-N-(6-{4-Fluorophenyl]hex-l-yl)-4-(4-( N-N-dimethylaminocarbonylmethyloxycarbonyI)benzylsulphinyl)-2-oxoazetidin-l-yl)acetamide; and (4/f, Si>N-(6-[4-FluorophenyI]hex-l-yl)-4-(4-( N-N-di-(2- hydroxyethyl)arainocarbonylmethyloxycarbonyl)benzylsulphinyl)-2-oxoazetidin-l- yl)acetamide;
15. A pharmaceutical composition comprising a compound of formula (I) as defined in any of the preceding claims and a pharmaceutically acceptable carrier.
16. A compound of formula (I) as defined in claim 1 for use in therapy.
17. The use of a compound of fonnula (I) as defined in claim I in the manufacture of a medicament for treating atheroscelrosis.
18. The use of a compound of fonnula (I) as defined in claim 1 in the manufacture of a medicament for treating diabetes, hypertension, angina pectoris, after ischaemia. reperfusion, rheumatoid arthritis, stroke, myocardial infarction, reperfusion injury, sepsis, and acute and chronic inflammation, inflammatory conditions of the brain such as Alzheimer's Disease, neuropsychiatry disorders such as schizophrenia, and psoriasis.
19. A process for preparing a compound of formula (I) as defined in claim 1 and in which X is an amide CONH which comprises treating a compound of formula 01): o 2' (II) in which R1 is C(i.6)alkyl or C(2-6)al*enyl and R2 and R^ arc as defined in claim 1, and having the absolute configuration (4R,SS)\ with an amine of the fonnula (HI): H2N(CH2)nY INTELLECTUAL PROPEflMWRCE OF NZ -56- 16 MAY 2000 RECEIVED 332476 under suitable amide forming conditions, for instance in the presence of an activating agent such as N,N-dicyclohexylcarbodiimide and l-hydroxybenzouiazole in a suitable solvent such as dry dimeihylfonnamide; and thereafter, and if necessary, (a) removing the ester group under suitable de-esterifying conditions to form the acid; (b) convening the acid to a pharmaceutically acceptable salt; and/or (c) convening the acid, a suitable salt, the ester or an activated derivative of the acid, to an in vivo hydrolysable ester by reaction with a compound of fonnula (IV): in which: R4 is a reactive esterifying leaving group; and R1 is as hereinbefore defined; under ester forming conditions.
20. A compound of formula (II): in which R1 is C(1^}alkyl or C^^alkenyl and R2 and R3 are as defined in claim 1.
21. A compound of formula (V): r!R4 (IV) 01) (V) -57- INTELLECTUAL PROPERTY OFFICE OF N2. 16 MAY 2000 332476 in which R*, R2 and R^ are as defined in claim 1, and having the absolute configuration (4R).
22. a diastereoisomeric salt formed from a compound of fonnula (VI): ^SCHjCgH, COjR* CFtV COjH (VI) in which R* is a carboxy protecting group, for instance C(i.g)alkyl or C(2-6)alkenyl and R2 and R^ are as defined in claim 1; and a chiral base.
23. A process for resolving an intermediate compound of formula (VI): ^SCHaC,H,~ COaR' » \ cr'r'— co.h in which R* is carboxy protecting group, for instance a C(i.6)alkyl or C(2-6)alkenyl and R2 and R3 are as defined in claim 1; which process comprises the formation of a diastereoisomeric salt with a chiral base such as (-)-cinchonidine; and thereafter (a) isolating the preferred diastereoisomeric salt obtained by fractional crystallisation; and then (b) generating the enantiomeric free acid therefrom by acidification. (VI)
24. A process for preparing a compound of formula (I) as defined in claim 1 and in which X is an amide CONH which comprises the process defined in claim 23.
25. A process for preparing a compound of formula (I) as defined in claim 1, substantially as hereinbefore described with particular reference to any one of the foregoing Examples 1 to 32. • .' J f LLLECI UAL PROPERTY OFFICE OF NZ 16 MAY 2000 RECEIVED
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GBGB9608646.7A GB9608646D0 (en) | 1996-04-26 | 1996-04-26 | Novel compounds |
| GBGB9623756.5A GB9623756D0 (en) | 1996-11-15 | 1996-11-15 | Novel compounds |
| GBGB9625121.0A GB9625121D0 (en) | 1996-12-03 | 1996-12-03 | Novel compounds |
| PCT/EP1997/001898 WO1997041098A1 (en) | 1996-04-26 | 1997-04-15 | Azetidinone derivatives for the treatment of atherosclerosis |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| NZ332476A true NZ332476A (en) | 2000-06-23 |
Family
ID=27268259
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NZ332476A NZ332476A (en) | 1996-04-26 | 1997-04-15 | substituted 4-(carboxybenzylsulphinyl)-2-oxo-azetidine derivatives |
Country Status (17)
| Country | Link |
|---|---|
| EP (1) | EP0915843A1 (en) |
| JP (1) | JP2000509049A (en) |
| AR (1) | AR006833A1 (en) |
| AU (1) | AU2698697A (en) |
| BR (1) | BR9709196A (en) |
| CA (1) | CA2252696A1 (en) |
| CZ (1) | CZ341098A3 (en) |
| HU (1) | HUP9901359A3 (en) |
| ID (1) | ID16660A (en) |
| IL (1) | IL126696A0 (en) |
| MA (1) | MA26426A1 (en) |
| NO (1) | NO984939L (en) |
| NZ (1) | NZ332476A (en) |
| PE (1) | PE64398A1 (en) |
| PL (1) | PL329530A1 (en) |
| TR (1) | TR199802160T2 (en) |
| WO (1) | WO1997041098A1 (en) |
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| ATE333446T1 (en) * | 2000-02-16 | 2006-08-15 | Smithkline Beecham Plc | PYRIMIDINE-4-ONE DERIVATIVE AS LDL-PLA2 INHIBITOR |
| US6982251B2 (en) | 2000-12-20 | 2006-01-03 | Schering Corporation | Substituted 2-azetidinones useful as hypocholesterolemic agents |
| AR033855A1 (en) | 2001-01-26 | 2004-01-07 | Schering Corp | COMPOSITIONS AND COMBINATIONS OF ACTIVATOR (ES) OF THE PEROXIS0MAL PROPELLERATION ACTIVATION RECEPTOR (PPAR) AND STEROL ABSORPTION INHIBITOR (ES), THE USE OF SUCH COMPOSITIONS OR COMBINATIONS FOR THE MANUFACTURE OF A MEDICINAL TREATMENT FOR VASCAS INDICATIONS, BASIC INDICATIONS, OBES |
| TWI337076B (en) | 2001-01-26 | 2011-02-11 | Schering Corp | The use of substituted azetidinone compounds for the treatment of sitosterolemia |
| US7071181B2 (en) | 2001-01-26 | 2006-07-04 | Schering Corporation | Methods and therapeutic combinations for the treatment of diabetes using sterol absorption inhibitors |
| ES2245733T3 (en) | 2001-03-28 | 2006-01-16 | Schering Corporation | ENANTIOSELECTIVE SYNTHESIS OF MIDDLE COMPOUNDS OF AZETIDINONA |
| AR038956A1 (en) * | 2001-05-25 | 2005-02-02 | Schering Corp | USE OF A COMPOUND REGULATING THE PRODUCTION OR LEVELS OF BETA AMILOID PEPTIDES FOR THE MANUFACTURE OF A MEDICINAL PRODUCT TO TREAT ALZHEIMER'S DISEASE AND / OR TO REGULATE SUCH LEVELS OF BETA AMILOID PEPTIDES IN A SUBJECT |
| PT1429756E (en) | 2001-09-21 | 2007-01-31 | Schering Corp | Treatment of xanthoma with azetidinone derivatives as sterol absorption inhibitors |
| US7053080B2 (en) | 2001-09-21 | 2006-05-30 | Schering Corporation | Methods and therapeutic combinations for the treatment of obesity using sterol absorption inhibitors |
| US7056906B2 (en) | 2001-09-21 | 2006-06-06 | Schering Corporation | Combinations of hormone replacement therapy composition(s) and sterol absorption inhibitor(s) and treatments for vascular conditions in post-menopausal women |
| AU2003291719A1 (en) | 2002-11-06 | 2004-06-03 | Schering Corporation | Cholesterol absorptions inhibitors for the treatment of autoimmune disorders |
| US7459442B2 (en) | 2003-03-07 | 2008-12-02 | Schering Corporation | Substituted azetidinone compounds, processes for preparing the same, formulations and uses thereof |
| MXPA05009503A (en) | 2003-03-07 | 2005-10-18 | Schering Corp | Substituted azetidinone compounds, formulations and uses thereof for the treatment of hypercholesterolemia. |
| CA2517572C (en) | 2003-03-07 | 2011-12-13 | Schering Corporation | Substituted azetidinone compounds, formulations and uses thereof for the treatment of hypercholesterolemia |
| CN1756755A (en) | 2003-03-07 | 2006-04-05 | 先灵公司 | Substituted azetidinone compounds, formulations and uses thereof for the treatment of hypercholesterolemia |
| US8962633B2 (en) | 2007-05-11 | 2015-02-24 | Thomas Jefferson University | Methods of treatment and prevention of metabolic bone diseases and disorders |
| EA018101B1 (en) | 2007-05-11 | 2013-05-30 | Дзе Трастиз Оф Дзе Юниверсити Оф Пенсильвания | Methods of treatment of skin ulcers |
| BRPI0721697A2 (en) | 2007-05-11 | 2014-08-05 | Univ Jefferson | "METHODS FOR TREATING AND / OR PREVENTING NEURODEGENERATIVE DISEASE OR DISORDER IN AN INDIVIDUAL, TO TREAT AND / OR PREVENTING AN INDIVIDUAL WITH OR AT RISK OF VASCULAR DEMENTIA, TO TREAT AND / OR PREVENTING A BARRIERAL DISORDER OR DISORDER AN INDIVIDUAL, TO REDUCE BETA AMILOID ACCUMULATION IN THE BRAIN OF AN INDIVIDUAL, TO TREAT AND / OR PREVENT ALZHEIMER IN AN INDIVIDUAL AND TO PREVENT OR REDUCE THE RISK OF DEVELOPING ALZHHEIMER MISUSE, AND IN USE OF AND / OR LP-PLA2 PROTEIN ACTIVITY. " |
| EA023796B1 (en) | 2010-12-06 | 2016-07-29 | Глэксо Груп Лимитед | PYRIMIDINONE COMPOUNDS FOR USE IN THE TREATMENT OF DISEASES OR CONDITIONS MEDIATED BY Lp-PLA |
| ES2847883T3 (en) | 2010-12-17 | 2021-08-04 | Glaxo Group Ltd | Use of LP-PLA2 inhibitors in the treatment and prevention of eye diseases |
| US20140171431A1 (en) | 2011-06-27 | 2014-06-19 | Jianhua Shen | Azole heterocyclic compound, preparation method, pharmaceutical composition and use |
| EP2739627A4 (en) | 2011-07-27 | 2015-01-21 | Glaxo Group Ltd | 2,3-dihydroimidazo[1,2-c]pyrimidin-5(1h)-one compounds use as lp-pla² inhibitors |
| EP2736908A1 (en) | 2011-07-27 | 2014-06-04 | Glaxo Group Limited | Bicyclic pyrimidone compounds |
| US20150344485A1 (en) | 2013-01-25 | 2015-12-03 | Glaxosmithkline Intellectual Property Development Limited | Bicyclic pyrimidone compounds as inhibitors of lp-pla2 |
| SG11201505520WA (en) | 2013-01-25 | 2015-08-28 | Glaxosmithkline Ip Dev Ltd | 2,3-DIHYDROIMIDAZOL[1,2-C]PYRIMIDIN-5(1H)-ONE BASED LIPOPROTEIN-ASSOCIATED PHOSPHOLIPASE A2 (LP-PLA<sb>2</sb>) INHIBITORS |
| EP2948457A4 (en) | 2013-01-25 | 2016-09-07 | Glaxosmithkline Ip Dev Ltd | Compounds |
| 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 |
| 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 |
| PE20230092A1 (en) | 2019-11-09 | 2023-01-16 | Shanghai Simr Biotechnology Co Ltd | DIHYDROIMIDAZOPYRIMIDONE TRICYCLIC DERIVATIVE, METHOD OF PREPARATION THEREOF, PHARMACEUTICAL COMPOSITION AND USE THEREOF |
| CN115304620A (en) | 2021-05-07 | 2022-11-08 | 上海赛默罗生物科技有限公司 | Pyrimidone derivatives, preparation method, pharmaceutical composition and application thereof |
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| US4680391A (en) * | 1983-12-01 | 1987-07-14 | Merck & Co., Inc. | Substituted azetidinones as anti-inflammatory and antidegenerative agents |
| NZ228600A (en) * | 1988-04-11 | 1992-02-25 | Merck & Co Inc | 1-(benzylaminocarbonyl)-4-phenoxy-azetidin-2-one derivatives |
| IL99658A0 (en) * | 1990-10-15 | 1992-08-18 | Merck & Co Inc | Substituted azetidinones and pharmaceutical compositions containing them |
| WO1993000332A1 (en) * | 1991-06-25 | 1993-01-07 | Merck & Co., Inc. | Substituted azetidinones as anti-inflammatory and antidegenerative agents |
| ES2107548T3 (en) * | 1991-07-23 | 1997-12-01 | Schering Corp | SUBSTITUTED BETA-LACTAMA COMPOUNDS USEFUL AS HYPOCHOLESTEROLEMIC AGENTS AND PROCEDURES FOR THEIR PREPARATION. |
| MY128261A (en) * | 1992-10-27 | 2007-01-31 | Merck Sharp & Dohme | New substituted azetidinones as anti-inflammatory and antidegenerative agents |
| AU5802894A (en) * | 1992-12-17 | 1994-07-04 | Merck & Co., Inc. | New substituted azetidinones as anti-inflammatory and antidegenerative agents |
| EP0658205B1 (en) * | 1993-06-25 | 2000-03-15 | Smithkline Beecham Plc | Lipoprotein associated phospholipase a2, inhibitors thereof and use of the same in diagnosis and therapy |
| ES2159573T3 (en) * | 1993-10-06 | 2001-10-16 | Icos Corp | ACETILHIDROLASA OF THE PLATE ACTIVATOR FACTOR. |
| GB9421816D0 (en) * | 1994-10-29 | 1994-12-14 | Smithkline Beecham Plc | Novel compounds |
| CA2208530A1 (en) * | 1994-12-22 | 1996-06-27 | Smithkline Beecham P.L.C. | Substituted azetidin-2-ones for treatment of atherosclerosis |
| WO1996029307A1 (en) * | 1995-03-23 | 1996-09-26 | Japan Tobacco Inc. | Diphenylmethyl-azetidinone compounds and elastase inhibitor |
| EA199800109A1 (en) * | 1995-07-01 | 1998-10-29 | Смитклайн Бичам Плс | Azetidinone derivatives for the treatment of atherosclerosis |
| JP2000505063A (en) * | 1995-12-08 | 2000-04-25 | スミスクライン・ビーチャム・パブリック・リミテッド・カンパニー | Azetidinone compounds for the treatment of atherosclerosis |
-
1997
- 1997-04-15 HU HU9901359A patent/HUP9901359A3/en unknown
- 1997-04-15 JP JP9538507A patent/JP2000509049A/en active Pending
- 1997-04-15 IL IL12669697A patent/IL126696A0/en unknown
- 1997-04-15 PL PL97329530A patent/PL329530A1/en unknown
- 1997-04-15 AU AU26986/97A patent/AU2698697A/en not_active Abandoned
- 1997-04-15 CA CA002252696A patent/CA2252696A1/en not_active Abandoned
- 1997-04-15 NZ NZ332476A patent/NZ332476A/en unknown
- 1997-04-15 EP EP97920699A patent/EP0915843A1/en not_active Withdrawn
- 1997-04-15 CZ CZ983410A patent/CZ341098A3/en unknown
- 1997-04-15 TR TR1998/02160T patent/TR199802160T2/en unknown
- 1997-04-15 WO PCT/EP1997/001898 patent/WO1997041098A1/en not_active Application Discontinuation
- 1997-04-15 BR BR9709196A patent/BR9709196A/en not_active Application Discontinuation
- 1997-04-24 AR ARP970101682A patent/AR006833A1/en unknown
- 1997-04-24 MA MA24565A patent/MA26426A1/en unknown
- 1997-04-24 PE PE1997000311A patent/PE64398A1/en not_active Application Discontinuation
- 1997-04-25 ID IDP971394A patent/ID16660A/en unknown
-
1998
- 1998-10-23 NO NO984939A patent/NO984939L/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| EP0915843A1 (en) | 1999-05-19 |
| BR9709196A (en) | 1999-05-25 |
| NO984939L (en) | 1998-12-23 |
| MA26426A1 (en) | 2004-12-20 |
| AU2698697A (en) | 1997-11-19 |
| CA2252696A1 (en) | 1997-11-06 |
| HUP9901359A3 (en) | 2000-03-28 |
| IL126696A0 (en) | 1999-08-17 |
| ID16660A (en) | 1997-10-30 |
| NO984939D0 (en) | 1998-10-23 |
| PL329530A1 (en) | 1999-03-29 |
| JP2000509049A (en) | 2000-07-18 |
| PE64398A1 (en) | 1999-01-06 |
| HUP9901359A2 (en) | 1999-08-30 |
| TR199802160T2 (en) | 1999-04-21 |
| CZ341098A3 (en) | 1999-03-17 |
| AR006833A1 (en) | 1999-09-29 |
| WO1997041098A1 (en) | 1997-11-06 |
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