WO1998018805A2 - Composes organiques - Google Patents
Composes organiques Download PDFInfo
- Publication number
- WO1998018805A2 WO1998018805A2 PCT/EP1997/005909 EP9705909W WO9818805A2 WO 1998018805 A2 WO1998018805 A2 WO 1998018805A2 EP 9705909 W EP9705909 W EP 9705909W WO 9818805 A2 WO9818805 A2 WO 9818805A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- alkyl
- substituted
- mmol
- solution
- added
- Prior art date
Links
- NIGUVXFURDGQKZ-UQTBNESHSA-N alpha-Neup5Ac-(2->3)-beta-D-Galp-(1->4)-[alpha-L-Fucp-(1->3)]-beta-D-GlcpNAc Chemical compound O[C@H]1[C@H](O)[C@H](O)[C@H](C)O[C@H]1O[C@H]1[C@H](O[C@H]2[C@@H]([C@@H](O[C@]3(O[C@H]([C@H](NC(C)=O)[C@@H](O)C3)[C@H](O)[C@H](O)CO)C(O)=O)[C@@H](O)[C@@H](CO)O2)O)[C@@H](CO)O[C@@H](O)[C@@H]1NC(C)=O NIGUVXFURDGQKZ-UQTBNESHSA-N 0.000 title abstract description 6
- 102000003800 Selectins Human genes 0.000 claims abstract description 7
- 108090000184 Selectins Proteins 0.000 claims abstract description 7
- 230000001413 cellular effect Effects 0.000 claims abstract description 6
- 230000001404 mediated effect Effects 0.000 claims abstract description 5
- AAEVYOVXGOFMJO-UHFFFAOYSA-N prometryn Chemical compound CSC1=NC(NC(C)C)=NC(NC(C)C)=N1 AAEVYOVXGOFMJO-UHFFFAOYSA-N 0.000 claims abstract description 4
- 150000001875 compounds Chemical class 0.000 claims description 62
- 238000002360 preparation method Methods 0.000 claims description 59
- -1 2hydroxyphenyl Chemical group 0.000 claims description 43
- 238000000034 method Methods 0.000 claims description 38
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 35
- 229910052739 hydrogen Inorganic materials 0.000 claims description 35
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 17
- 229910018828 PO3H2 Inorganic materials 0.000 claims description 15
- 150000003839 salts Chemical class 0.000 claims description 14
- 150000001413 amino acids Chemical class 0.000 claims description 10
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 6
- 230000008569 process Effects 0.000 claims description 5
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 4
- 125000003118 aryl group Chemical group 0.000 claims description 4
- 201000010099 disease Diseases 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 4
- 125000002947 alkylene group Chemical group 0.000 claims description 3
- 239000003085 diluting agent Substances 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 239000003814 drug Substances 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 230000005764 inhibitory process Effects 0.000 abstract description 5
- 230000003278 mimic effect Effects 0.000 abstract description 5
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 203
- 239000000243 solution Substances 0.000 description 164
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 135
- 235000019439 ethyl acetate Nutrition 0.000 description 95
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 75
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Substances CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 73
- 239000011541 reaction mixture Substances 0.000 description 72
- 239000000203 mixture Substances 0.000 description 67
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 67
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 58
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 48
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 46
- 238000006243 chemical reaction Methods 0.000 description 44
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 43
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 36
- 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 33
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 33
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 33
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 31
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 31
- 239000002904 solvent Substances 0.000 description 30
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 29
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 27
- 238000003756 stirring Methods 0.000 description 27
- GNGACRATGGDKBX-UHFFFAOYSA-N dihydroxyacetone phosphate Chemical compound OCC(=O)COP(O)(O)=O GNGACRATGGDKBX-UHFFFAOYSA-N 0.000 description 26
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 24
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 24
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 24
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 24
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 24
- 239000010779 crude oil Substances 0.000 description 24
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 23
- 230000003197 catalytic effect Effects 0.000 description 23
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 23
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 23
- 239000012074 organic phase Substances 0.000 description 20
- 150000001299 aldehydes Chemical class 0.000 description 19
- 239000012044 organic layer Substances 0.000 description 18
- 238000010898 silica gel chromatography Methods 0.000 description 18
- 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 18
- 239000002253 acid Substances 0.000 description 17
- 150000001412 amines Chemical class 0.000 description 17
- 239000010410 layer Substances 0.000 description 17
- XMIIGOLPHOKFCH-UHFFFAOYSA-N 3-phenylpropionic acid Chemical compound OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 description 15
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 15
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 15
- 238000003818 flash chromatography Methods 0.000 description 15
- 239000007787 solid Substances 0.000 description 15
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 14
- XXROGKLTLUQVRX-UHFFFAOYSA-N allyl alcohol Chemical compound OCC=C XXROGKLTLUQVRX-UHFFFAOYSA-N 0.000 description 14
- 238000005160 1H NMR spectroscopy Methods 0.000 description 13
- 229910004373 HOAc Inorganic materials 0.000 description 13
- 239000003480 eluent Substances 0.000 description 13
- 238000000746 purification Methods 0.000 description 13
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 239000008346 aqueous phase Substances 0.000 description 12
- 210000004027 cell Anatomy 0.000 description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 12
- 239000003921 oil Substances 0.000 description 12
- 239000000047 product Substances 0.000 description 12
- 239000000741 silica gel Substances 0.000 description 12
- 229910002027 silica gel Inorganic materials 0.000 description 12
- 239000011734 sodium Substances 0.000 description 12
- 230000015572 biosynthetic process Effects 0.000 description 11
- 230000008878 coupling Effects 0.000 description 11
- 238000010168 coupling process Methods 0.000 description 11
- 238000005859 coupling reaction Methods 0.000 description 11
- 238000003786 synthesis reaction Methods 0.000 description 11
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 10
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 10
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 description 10
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 9
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 9
- 150000001336 alkenes Chemical class 0.000 description 9
- 229940024606 amino acid Drugs 0.000 description 9
- 235000001014 amino acid Nutrition 0.000 description 9
- 150000002009 diols Chemical class 0.000 description 9
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 9
- 229910000104 sodium hydride Inorganic materials 0.000 description 9
- FALRKNHUBBKYCC-UHFFFAOYSA-N 2-(chloromethyl)pyridine-3-carbonitrile Chemical compound ClCC1=NC=CC=C1C#N FALRKNHUBBKYCC-UHFFFAOYSA-N 0.000 description 8
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 8
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 8
- 150000002148 esters Chemical class 0.000 description 8
- 238000005984 hydrogenation reaction Methods 0.000 description 8
- 239000011347 resin Substances 0.000 description 8
- 229920005989 resin Polymers 0.000 description 8
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 8
- 229940014800 succinic anhydride Drugs 0.000 description 8
- 239000003810 Jones reagent Substances 0.000 description 7
- 229910052786 argon Inorganic materials 0.000 description 7
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 7
- 238000004440 column chromatography Methods 0.000 description 7
- 238000010828 elution Methods 0.000 description 7
- 238000004108 freeze drying Methods 0.000 description 7
- 210000000265 leukocyte Anatomy 0.000 description 7
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 7
- FTVLMFQEYACZNP-UHFFFAOYSA-N trimethylsilyl trifluoromethanesulfonate Chemical compound C[Si](C)(C)OS(=O)(=O)C(F)(F)F FTVLMFQEYACZNP-UHFFFAOYSA-N 0.000 description 7
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 description 6
- WDYVUKGVKRZQNM-UHFFFAOYSA-N 6-phosphonohexylphosphonic acid Chemical compound OP(O)(=O)CCCCCCP(O)(O)=O WDYVUKGVKRZQNM-UHFFFAOYSA-N 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- SHZGCJCMOBCMKK-UHFFFAOYSA-N D-mannomethylose Natural products CC1OC(O)C(O)C(O)C1O SHZGCJCMOBCMKK-UHFFFAOYSA-N 0.000 description 6
- 102000015689 E-Selectin Human genes 0.000 description 6
- 108010024212 E-Selectin Proteins 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 6
- 238000006256 asymmetric dihydroxylation reaction Methods 0.000 description 6
- 239000003054 catalyst Substances 0.000 description 6
- 238000005119 centrifugation Methods 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 238000001704 evaporation Methods 0.000 description 6
- 230000008020 evaporation Effects 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- 239000002244 precipitate Substances 0.000 description 6
- 150000003254 radicals Chemical class 0.000 description 6
- 238000010626 work up procedure Methods 0.000 description 6
- AFXKCBFBGDUFAM-UHFFFAOYSA-N 2-methylpropan-2-amine;hydrofluoride Chemical compound [F-].CC(C)(C)[NH3+] AFXKCBFBGDUFAM-UHFFFAOYSA-N 0.000 description 5
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 5
- SHZGCJCMOBCMKK-PQMKYFCFSA-N L-Fucose Natural products C[C@H]1O[C@H](O)[C@@H](O)[C@@H](O)[C@@H]1O SHZGCJCMOBCMKK-PQMKYFCFSA-N 0.000 description 5
- PNNNRSAQSRJVSB-UHFFFAOYSA-N L-rhamnose Natural products CC(O)C(O)C(O)C(O)C=O PNNNRSAQSRJVSB-UHFFFAOYSA-N 0.000 description 5
- 229930182473 O-glycoside Natural products 0.000 description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- 238000003556 assay Methods 0.000 description 5
- 239000012298 atmosphere Substances 0.000 description 5
- 238000001816 cooling Methods 0.000 description 5
- 125000003074 decanoyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C(*)=O 0.000 description 5
- 239000000284 extract Substances 0.000 description 5
- 239000001257 hydrogen Substances 0.000 description 5
- FBBDOOHMGLLEGJ-UHFFFAOYSA-N methane;hydrochloride Chemical compound C.Cl FBBDOOHMGLLEGJ-UHFFFAOYSA-N 0.000 description 5
- 238000005949 ozonolysis reaction Methods 0.000 description 5
- 238000005897 peptide coupling reaction Methods 0.000 description 5
- 229920006395 saturated elastomer Polymers 0.000 description 5
- 229910052938 sodium sulfate Inorganic materials 0.000 description 5
- 239000008279 sol Substances 0.000 description 5
- 239000006228 supernatant Substances 0.000 description 5
- HYWCXWRMUZYRPH-UHFFFAOYSA-N trimethyl(prop-2-enyl)silane Chemical compound C[Si](C)(C)CC=C HYWCXWRMUZYRPH-UHFFFAOYSA-N 0.000 description 5
- HEVMDQBCAHEHDY-UHFFFAOYSA-N (Dimethoxymethyl)benzene Chemical compound COC(OC)C1=CC=CC=C1 HEVMDQBCAHEHDY-UHFFFAOYSA-N 0.000 description 4
- HNTGIJLWHDPAFN-UHFFFAOYSA-N 1-bromohexadecane Chemical compound CCCCCCCCCCCCCCCCBr HNTGIJLWHDPAFN-UHFFFAOYSA-N 0.000 description 4
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- JXYACYYPACQCDM-UHFFFAOYSA-N Benzyl glycinate Chemical compound NCC(=O)OCC1=CC=CC=C1 JXYACYYPACQCDM-UHFFFAOYSA-N 0.000 description 4
- 229930182476 C-glycoside Natural products 0.000 description 4
- WWZKQHOCKIZLMA-UHFFFAOYSA-N Caprylic acid Natural products CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 description 4
- WQZGKKKJIJFFOK-QTVWNMPRSA-N D-mannopyranose Chemical compound OC[C@H]1OC(O)[C@@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-QTVWNMPRSA-N 0.000 description 4
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 4
- 102000001390 Fructose-Bisphosphate Aldolase Human genes 0.000 description 4
- 108010068561 Fructose-Bisphosphate Aldolase Proteins 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- 239000007832 Na2SO4 Substances 0.000 description 4
- 150000007513 acids Chemical class 0.000 description 4
- 150000001408 amides Chemical class 0.000 description 4
- 239000001273 butane Substances 0.000 description 4
- 238000010511 deprotection reaction Methods 0.000 description 4
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 4
- FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical compound CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 description 4
- 229940058172 ethylbenzene Drugs 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 239000008241 heterogeneous mixture Substances 0.000 description 4
- 239000012528 membrane Substances 0.000 description 4
- 229940038384 octadecane Drugs 0.000 description 4
- 229910052763 palladium Inorganic materials 0.000 description 4
- 239000001294 propane Substances 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 4
- 210000001519 tissue Anatomy 0.000 description 4
- LAQPKDLYOBZWBT-NYLDSJSYSA-N (2s,4s,5r,6r)-5-acetamido-2-{[(2s,3r,4s,5s,6r)-2-{[(2r,3r,4r,5r)-5-acetamido-1,2-dihydroxy-6-oxo-4-{[(2s,3s,4r,5s,6s)-3,4,5-trihydroxy-6-methyloxan-2-yl]oxy}hexan-3-yl]oxy}-3,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy}-4-hydroxy-6-[(1r,2r)-1,2,3-trihydrox Chemical compound O[C@H]1[C@H](O)[C@H](O)[C@H](C)O[C@H]1O[C@H]([C@@H](NC(C)=O)C=O)[C@@H]([C@H](O)CO)O[C@H]1[C@H](O)[C@@H](O[C@]2(O[C@H]([C@H](NC(C)=O)[C@@H](O)C2)[C@H](O)[C@H](O)CO)C(O)=O)[C@@H](O)[C@@H](CO)O1 LAQPKDLYOBZWBT-NYLDSJSYSA-N 0.000 description 3
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Chemical group CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 3
- IUVCFHHAEHNCFT-INIZCTEOSA-N 2-[(1s)-1-[4-amino-3-(3-fluoro-4-propan-2-yloxyphenyl)pyrazolo[3,4-d]pyrimidin-1-yl]ethyl]-6-fluoro-3-(3-fluorophenyl)chromen-4-one Chemical compound C1=C(F)C(OC(C)C)=CC=C1C(C1=C(N)N=CN=C11)=NN1[C@@H](C)C1=C(C=2C=C(F)C=CC=2)C(=O)C2=CC(F)=CC=C2O1 IUVCFHHAEHNCFT-INIZCTEOSA-N 0.000 description 3
- WFIYPADYPQQLNN-UHFFFAOYSA-N 2-[2-(4-bromopyrazol-1-yl)ethyl]isoindole-1,3-dione Chemical compound C1=C(Br)C=NN1CCN1C(=O)C2=CC=CC=C2C1=O WFIYPADYPQQLNN-UHFFFAOYSA-N 0.000 description 3
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Chemical group CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 3
- BYHDDXPKOZIZRV-UHFFFAOYSA-N 5-phenylpentanoic acid Chemical group OC(=O)CCCCC1=CC=CC=C1 BYHDDXPKOZIZRV-UHFFFAOYSA-N 0.000 description 3
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Chemical group CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 3
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 3
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- HOVAGTYPODGVJG-ZFYZTMLRSA-N methyl alpha-D-glucopyranoside Chemical compound CO[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O HOVAGTYPODGVJG-ZFYZTMLRSA-N 0.000 description 1
- HOVAGTYPODGVJG-VEIUFWFVSA-N methyl alpha-D-mannoside Chemical compound CO[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]1O HOVAGTYPODGVJG-VEIUFWFVSA-N 0.000 description 1
- HPNSFSBZBAHARI-UHFFFAOYSA-N micophenolic acid Natural products OC1=C(CC=C(C)CCC(O)=O)C(OC)=C(C)C2=C1C(=O)OC2 HPNSFSBZBAHARI-UHFFFAOYSA-N 0.000 description 1
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- HPNSFSBZBAHARI-RUDMXATFSA-N mycophenolic acid Chemical compound OC1=C(C\C=C(/C)CCC(O)=O)C(OC)=C(C)C2=C1C(=O)OC2 HPNSFSBZBAHARI-RUDMXATFSA-N 0.000 description 1
- YGBMCLDVRUGXOV-UHFFFAOYSA-N n-[6-[6-chloro-5-[(4-fluorophenyl)sulfonylamino]pyridin-3-yl]-1,3-benzothiazol-2-yl]acetamide Chemical compound C1=C2SC(NC(=O)C)=NC2=CC=C1C(C=1)=CN=C(Cl)C=1NS(=O)(=O)C1=CC=C(F)C=C1 YGBMCLDVRUGXOV-UHFFFAOYSA-N 0.000 description 1
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- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- WTBAHSZERDXKKZ-UHFFFAOYSA-N octadecanoyl chloride Chemical compound CCCCCCCCCCCCCCCCCC(Cl)=O WTBAHSZERDXKKZ-UHFFFAOYSA-N 0.000 description 1
- IOQPZZOEVPZRBK-UHFFFAOYSA-N octan-1-amine Chemical group CCCCCCCCN IOQPZZOEVPZRBK-UHFFFAOYSA-N 0.000 description 1
- REEZZSHJLXOIHL-UHFFFAOYSA-N octanoyl chloride Chemical compound CCCCCCCC(Cl)=O REEZZSHJLXOIHL-UHFFFAOYSA-N 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 229910000489 osmium tetroxide Inorganic materials 0.000 description 1
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- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
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- QFJCIRLUMZQUOT-HPLJOQBZSA-N sirolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 QFJCIRLUMZQUOT-HPLJOQBZSA-N 0.000 description 1
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- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910001415 sodium ion Inorganic materials 0.000 description 1
- KSAVQLQVUXSOCR-UHFFFAOYSA-M sodium lauroyl sarcosinate Chemical compound [Na+].CCCCCCCCCCCC(=O)N(C)CC([O-])=O KSAVQLQVUXSOCR-UHFFFAOYSA-M 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 239000011343 solid material Substances 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 210000000952 spleen Anatomy 0.000 description 1
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- 239000008117 stearic acid Substances 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 229910052682 stishovite Inorganic materials 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 229960002317 succinimide Drugs 0.000 description 1
- UDYFLDICVHJSOY-UHFFFAOYSA-N sulfur trioxide-pyridine complex Substances O=S(=O)=O.C1=CC=NC=C1 UDYFLDICVHJSOY-UHFFFAOYSA-N 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- MHYGQXWCZAYSLJ-UHFFFAOYSA-N tert-butyl-chloro-diphenylsilane Chemical compound C=1C=CC=CC=1[Si](Cl)(C(C)(C)C)C1=CC=CC=C1 MHYGQXWCZAYSLJ-UHFFFAOYSA-N 0.000 description 1
- QZZGJDVWLFXDLK-UHFFFAOYSA-N tetracosanoic acid Chemical compound CCCCCCCCCCCCCCCCCCCCCCCC(O)=O QZZGJDVWLFXDLK-UHFFFAOYSA-N 0.000 description 1
- TUNFSRHWOTWDNC-HKGQFRNVSA-N tetradecanoic acid Chemical compound CCCCCCCCCCCCC[14C](O)=O TUNFSRHWOTWDNC-HKGQFRNVSA-N 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
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- 238000000954 titration curve Methods 0.000 description 1
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- 229910052905 tridymite Inorganic materials 0.000 description 1
- GGUBFICZYGKNTD-UHFFFAOYSA-N triethyl phosphonoacetate Chemical compound CCOC(=O)CP(=O)(OCC)OCC GGUBFICZYGKNTD-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- JUKPJGZUFHCZQI-UHFFFAOYSA-N undecanoyl chloride Chemical compound CCCCCCCCCCC(Cl)=O JUKPJGZUFHCZQI-UHFFFAOYSA-N 0.000 description 1
- JQSHBVHOMNKWFT-DTORHVGOSA-N varenicline Chemical compound C12=CC3=NC=CN=C3C=C2[C@H]2C[C@@H]1CNC2 JQSHBVHOMNKWFT-DTORHVGOSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/02—Acyclic radicals, not substituted by cyclic structures
- C07H15/04—Acyclic radicals, not substituted by cyclic structures attached to an oxygen atom of the saccharide radical
Definitions
- the present invention relates to compounds that inhibit cellular adhesion. More particularly, the present invention relates to sialyl Lewis X mimetics which mimic the inhibition of selectin-mediated cellular adhesion by sialyl Lewis X.
- the complex process of inflammation which takes place in several stages, is the body's natural reaction to injuries in which, for example, there is also invasion by infectious agents.
- the endothelium which lines the blood vessels expresses adhesion proteins on its surface.
- the P and E selectins bring about, by a protein-carbohydrate interaction with glycolipids and glycoproteins on the leukocyte membrane, the so- called “rolling" of leukocytes.
- the latter are slowed down by this process, and there is activation of certain proteins (integrins) on their surface which ensure firm adhesion of the leukocytes to the endothelium. This is followed by migration of the leukocytes into the damaged tissue.
- SLe x mimetics which are easy to synthesize, more stable and more active than SLe", and preferably orally active.
- Y is -O- or C C ⁇ lkylene which is unsubstituted or substituted by one or two substituents selected from OR 3 and C(O)NH[CH 2 ] m C(O)NHC 10 -C 16 alkyl;
- R 2 is CHOHCHOHC(O)(CH 2 ) n R 5 ;
- R 3 is aralkyl with C r C 6 alkyl and C 6 -C 10 aryl or CH 2 C(O)NHC ⁇ -C 2 oalkyl which is unsubstituted or substituted by one or two OC(O)C ⁇ 0 -C 16 alkyl;
- R 5 is OPO 3 H 2 or PO 3 H 2 ;
- m is a number from 1 to 6; and
- n is 1 or 2; or
- Y is C C ⁇ alkylene which is unsubstituted or substituted by one or two substituents selected from OR 3 and C(O)NH[CH 2 ] rn C(O)NHC 1 o-C 16 alkyl;
- R 2 is -NR 6 R 7 ;
- R 3 is aralkyl with d-C 6 alkyl and C 6 -C ⁇ 0 aryl or CH 2 C(O)NHC 1 -C 20 alkyl which is unsubstituted or substituted by one or two OC(O)C ⁇ 0 -C ⁇ 6 alkyl;
- R 6 is C(O)CHR 8 NHC(O)(CH 2 ) q C(O)OH;
- R 7 is (CH 2 ) m C(O)NHC 4 -C ⁇ 8 alkyl or (CH 2 ) r ⁇ ,C(O)NHC 6 -C ⁇ 0 aryl wherein aryl is optionally substituted by OH or C 5 -C 16 alkyl;
- R 8 is C ⁇ -C 6 alkyl unsubstituted or substituted with one or two OH; m is a number from 0 to 6; and q is 2 or 3; or
- R 1 is OH
- Y is -CH 2 -;
- R 2 is -NR 6 H
- R 6 is C(O)-C 1 -C 30 alkyl which is substituted by C(O)OH; or
- R 1 is a group of formula la
- Y is -CH 2 -; R 2 is OH; and n is 0, 1 or 2; or
- R 1 is Y'-R 2' ;
- Y is -CH 2 -;
- R 2 is H, -OH, -N 3 , -OSO 3 2' , -O-C(O)-C 4 -C 30 alkyl, -O-C r C 30 alkyl which is unsubstituted or substituted with C 6 -C 10 aryl; -O-C 6 -C ⁇ 0 aryl which is unsubstituted or substituted with d-Caalkyl; -O-C(O)-CH 2 CH 2 C(O)NHCH(CH 2 CO 2 H)CO 2 H or NHR 6 ;
- Y' is C ⁇ -C 5 alkylene or O-d-C alkylene ;
- R 2' is -CHOHCHOHC(O)(CH 2 ) n R 5 ; -CHOHCHOHC(O)[CH 2 ] n C(O)OH;
- R 4 is H, C r C 6 alkyl which is substituted by C(O)OH; CH 2 hydroxyphenyl; benzyl or the radical of an amino acid;
- R 5 is OPO 3 H 2 or PO 3 H 2 ;
- R 6 is C C 3 oalkyl which is unsubstituted or substituted by C 6 -C ⁇ 0 aryl, CCOJ-d-Csoalkyl which is unsubstituted or substituted by C 6 -C ⁇ 0 aryl or C(O)OH, C(O)-C -C 3 oalkenyl with 1 to 4 double bonds which is unsubstituted or substituted by C(O)OH, C(O)-C 6 - C 10 aryl which is unsubstituted or substituted by one or two OH, C(O)(CH 2 ) m NHCr C 6 alkyl, C(O)(CH 2 ) r CON(CH 2 CONH(CH 2 )CH 3 )HCONH(CH 2 ) s CH 3 or C(O)(CH 2 ) p NHC(O)(CH 2 ) q C(O)OH; m is a number from 1 to 6; n is 1 or 2
- the compounds of formula I may comprise one or more asymmetric carbon atoms. It will be understood that the present invention includes all individual isomeric forms, enantiomers and diastereoisomers as well as mixtures, e.g. racemates, unless otherwise stated.
- R 1 is Y'-R 2' ; Y is -CH 2 -; R 2 is H; -OH; -O-C,-C 6 alkyl; -OBn; -N 3 ; -OSO 3 2" ; -O-C(O)- CH 2 CH 2 C(O)NHCH(CH 2 CO 2 H)CO 2 H or NHR 6 ; Y' is C r C 5 alkylene; R 2' is -CHOHCHOHC(O)CH 2 R 5 ; R 5 is OPO 3 H 2 or PO 3 H 2 ; and R 6 is d-C 6 alkyl; acyl; decanoyl, phenylacetyl or C(O)CH 2 CH 2 C(O)OH; or (b1) R 1 is CH 3 ; Y is -CH 2 -; R 2 is CHOHCHOHC(O)CH 2 R 5 ; and R 5 is OPO 3 H 2 or PO 3 H 2 ; or (c1) R 1 is CH 3
- R 1 is Y'-R 2' ; Y is -CH 2 -; R 2 is -OH; Y' is -CH 2 -; R 2' is C(O)NHCHR 4 C(O)OH; and R 4 is the radical of an amino acid selected from the group consisting of Ala, Val, Leu, lie, Pro, Phe, Trp, Met, Gly, Ser, Thr, Cys, Tyr, Asn, Gin, Asp, Glu, Lys, Arg and His; or
- R 1 is Y'-R 2' ; Y is -CH 2 -; R 2 is -OH; Y' is -CH 2 -; R 2' is -CHOHCHOHC(O)NHCHR 4 C(O)OH; and R 4 is the radical of an amino acid selected from the group consisting of Ala, Val, Leu, He, Pro, Phe, Trp, Met, Gly, Ser, Thr, Cys, Tyr, Asn, Gin, Asp, Glu, Lys, Arg and His; or
- R 1 is a group of formula la; Y is -CH 2 -; R 2 is OH; and n is 0, 1 or 2; or (d2) R 1 is OH; Y is -CH 2 -; R 2 is -NR 6 H; and R 6 is C(O)-C 2 -C 3 alkyl which is substituted by C(O)OH.
- R 1 is Y'-R 2' ; Y is -CH 2 -; R 2 is NHR 6 ; Y' is -CH 2 -; R 2' is C(O)NHCHR 4 C(O)OH; R 4 is C 2 alkyl which is substituted by C(O)OH; R 6 is hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, laurate, tridecanoyl, myristate, pentadecanoyl, palmitate, hepta- decanoyl, stearate, nonadecanoyl, eicosanoyl, hexaicosanoyl, docosanoyl, tricosanoyl, tetracosanoyl, hexacosanoyl, heptacosanoyl, octaco
- SUBSTTTUTE SHEET (RULE 25) ane, O-docosane, O-ethyl-naphthalene, O-methyl-naphthalene, O-ethyl-benzene, O-phenyl-propane, O-heptanoyl, O-octanoyl, O-nonaoyl, O-decanoyl, O-undecanoyl, O-lauroyl, O-myristoyl, O-palmitoyl, O-heptadecanoyl or O-stearoyl; Y' is -CH 2 -; R 2 is C(O)NHCHR 4 C(O)OH; and R 4 is C 2 alkyl which is substituted by C(O)OH; or
- R 1 is Y'-R 2 ; Y is -CH 2 -; R 2 is -OH, O-propane, O-butane, O-pentane, O-hexane, O-heptane, O-octane, O-nonane, O-decane, O-undecane, O-dodecane, O-tri- decane, O-tetradecane, O-pentadecane, O-hexadecane, O-octadecane, O-eicos- ane, O-docosane, O-ethyl-naphthalene, O-methyl-naphthalene, O-ethyl-benzene, O-phenyl-propane, O-heptanoyl, O-octanoyl, O-nonaoyl, O-decanoyl, O-undecanoyl, O-lauroy
- R 1 is Y'-R 2' ; Y is -CH 2 -; R 2 is -OH, O-propane, O-butane, O-pentane, O-hexane, O-heptane, O-octane, O-nonane, O-decane, O-undecane, O-dodecane, O-tri- decane, O-tetradecane, O-pentadecane, O-hexadecane, O-octadecane, O-eicos- ane, O-docosane, O-ethyl-naphthalene, O-methyl-naphthalene, O-ethyl-benzene, O-phenyl-propane, O-heptanoyl, O-octanoyl, O-nonaoyl, O-decanoyl, O-undecanoyl, O-lau
- R 1 is Y'-R 2' ; Y is -CH -; R 2 is -OH, O-propane, O-butane, O-pentane, O-hexane, O-heptane, O-octane, O-nonane, O-decane, O-undecane, O-dodecane, O-tri- decane, O-tetradecane, O-pentadecane, O-hexadecane, O-octadecane, O-eicos- ane, O-docosane, O-ethyl-naphthalene, O-methyl-naphthalene, O-ethyl-benzene, O-phenyl-propane, O-heptanoyl, O-octanoyl, O-nonaoyl, O-decanoyl, O-undecanoyl, O-lauroy
- R 1 is CH 3 ; Y is C 2 alkylene; R 2 is -NR 6 R 7 ; R 6 is C(O)CHR 8 NHC(O)(CH 2 ) 3 C(O)OH; R 7 is (CH 2 ) m C(O)R 9 ; R 8 is CHOHCH 2 OH; R 9 is butyl amine, amyl amine, hexyl amine, heptyl amine, octyl amine, nonylamine, octadecyl amine, 1 -amino naphthalene, 2-amino naphthalene, 2-amino-2-naphthol perhydrochloride, 4-pentyl aniline, 4-hexyl aniline, 4-heptyl aniline, 4-octyl aniline, 4-decyl aniline, 4-dodecyl aniline, 4-tetra- decyl aniline or 4-hexadecyl
- R 1 is Y'-R 2' ; Y is -CH 2 -; R 2 is -OH; Y' is -CH 2 -; R 2' is C(O)NHCHR 4 C(O)OH; and R 4 is the radical of an amino acid selected from the group consisting of Ala, Val, Leu, lie, Pro, Phe, Trp, Met, Gly, Ser, Thr, Cys, Tyr, Asn, Gin, Asp, Glu, Lys, Arg and His.
- SUBSTITUTE SHEET (RULE 25) Within group (b) the most preferred compounds are 27(15) and 29(15) as exemplified in Examples B.
- Another preferred embodiment comprises compounds of group (d) wherein R 1 is Y'-R 2 ; Y is -CH 2 -; Y' is -CH 2 - or -O-CH 2 -; R 2 is OH; R 2' is CHOHCHOHC(O)(CH 2 ) n R 5 ; R 5 is OPO 3 H 2 or PO 3 H 2 ; and n is 1 or 2.
- Most preferred compounds are 6(14), 4(3), 4a(3), 7(14) and 13(14) as exemplified in Examples B.
- R 1 is Y'-R 2 ; Y is -CH 2 -; R 2 is OH; Y' is -CH 2 -; R 2' is -CHOHCHOHC(O)(CH 2 ) 2 C(O)OH; -C(O)NHCH 2 C(O)OH -CHOHCHOHC(O)CH 2 CH[benzyl]C(O)OH; -CHOHCHOHC(O)NHCHR C(O)OH; or C(O)NHCHR 4 C(O)OH; and R 4 is H, d-C 6 alkyl which is substituted by C(O)OH; CH 2 hydroxy- phenyl or benzyl.
- Most preferred compounds are 5(15), 6(15), 102(3), 103(3), 104(3), 105(3) and 106(3) as exemplified in Examples B.
- Another preferred embodiment comprises compounds of group (d) wherein R 1 is Y'-R 2 ; Y is -CH 2 -; Y' is -CH 2 -; R 2 is -O-d-C ⁇ alkyl and R 2' is -C(O)NHCHR 4 C(O)OH wherein R 4 is CH 2 CH 2 C(O)OH; or -C(O)NHphenyl which is substituted by one C(O)OH.
- Most preferred compounds are 3(3) and 3a(3) as exemplified in Examples B.
- R 1 is Y'-R 2 ; Y is -CH 2 -; Y' is -CH 2 - or -O-CH 2 -; R 2 is -NHR 6 ; R 2' is - CHOHCHOHC(O)CH 2 R 5 or C(O)NHCHR C(O)OH; R 5 is OPO 3 H 2 or PO 3 H 2 ; R 6 is d-Csoalkyl which is unsubstituted or substituted by Ce-Cioaryl, C(O)-d-C 30 alkyl which is unsubstituted or substituted by Ce- Cioaryl or C(O)OH; C(O)(CH 2 ) p NHC(O)(CH 2 ) q C(O)OH; C(O)(CH 2 ) m NHC ⁇ -C 6 alkyl; or C(O)(CH2) r CON(CH 2 CONH(CH 2 )CH 3 )HCON
- the present invention also comprises a process for the preparation of the compounds of the formula I wherein the corresponding radicals -Y-R 2 and -Y'-R 2 are coupled, optionally via more than one step, to the corresponding sugar moiety.
- the procedures are generally known to the skilled person or can be deduced from the Examples, describing further non- limiting details of the preparation.
- the coupling step within the synthesis of C-glycosides of group (d), eg. 6(14) and 4(3) which may be performed in the presence of a DHAP dependent aldolase.
- the DHAP substrate is a compound selected from the group consisting of e.g. dihydroxyacetone phosphate and 3-keto- 4-hydroxy-butanyl-1-phosphonate.
- the DHAP dependent aldolase is selected from the group consisting of FDPA, FucA, RhaA and TagA.
- the compounds of formula I exhibit valuable pharmacological properties as indicated in tests and are therefore indicated for therapy.
- the compounds of formula I inhibit the binding of E-selectin to HL-60 cells as disclosed in Example D.
- the compounds are particularly indicated for preventing or treating conditions or diseases which are mediated by the binding of selectin in cellular adhesion, e.g. acute or chronic inflammatory or autoimmune diseases such as rheumatoid arthritis, asthma, allergy conditions, psoriasis, contact dermatitis, adult respiratory distress syndrome, inflammatory bowel disease and ophthalmic inflammatory diseases, infection diseases such as septic shock, traumatic shock, thrombosis and inappropriate platelet aggregation conditions, cardiovascular diseases such as heart attacks, reperfusion injury, multiple sclerosis and neoplastic diseases including metastasis conditions, strokes and acute or chronic rejection of organ or tissue transplants.
- acute or chronic inflammatory or autoimmune diseases such as rheumatoid arthritis, asthma, allergy conditions, psoriasis, contact dermatitis, adult respiratory distress syndrome, inflammatory bowel disease and ophthalmic inflammatory diseases
- infection diseases such as septic shock, traumatic shock, thrombosis and inappropriate platelet aggregation
- Acute and chronic rejection play a role in the transplantation of organs or tissues from a donor to a recipient of the same species (allograft) or different species (xenograft).
- organs or tissues and given illustratively are heart, lung, combined heart- lung, trachea, liver, kidney, spleen, pancreatic (complete or partial, e.g. Langerhans islets), skin, bowel, or cornea or a combination of any of the foregoing.
- SUBSTTTUTE SHEET (RULE 25) nostimulated in 1 , 2, 3, or 4 doses/day, or in sustained release form.
- Suitable daily dosages for oral administration to larger mammals, e.g., humans, are generally about 50 to 1500 mg, preferably in the order of from 200 to 800 mg.
- Unit dosage forms suitably comprise from about 25 mg to 0.750 g of a compound of the invention, together with a pharmaceutical acceptable diluent or carrier therefor.
- the compounds of formula I may be administered by any conventional route of administration, e.g. enterally, preferably orally, e.g. in the form of tablets or capsules, or parenterally e.g. in form of injectable solutions or suspensions.
- OPO 3 H 2 , PO 3 H 2 and the carboxyl group may be in free acid form or in salt form.
- Pharmaceutically acceptable salts are to be understood as meaning, in particular, the alkali metal and alkaline earth metal salts, for example sodium, potassium, magnesium and calcium salts. Sodium and potassium ions and their salts are preferred.
- the present invention further provides:
- composition comprising a pharmaceutically effective amount of the compound of formula I or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable diluent or carrier;
- the compound may be administered alone or in combination with one or more other anti-inflammatory or immunosuppressive agents, for example in combination with cyclosporin A and analogs thereof, FK-506 and analogs thereof, rapamycin and analogs thereof, myco- phenolic acid, mycophenolate mofetil, mizoribine, 15-deoxyspergualine, leflunomide, steroids, cyclophosphamide, azathioprene (AZA), or anti-lymphocyte antibodies or immuno- toxins such as monoclonal antibodies to leukocyte receptors, e.g. MHC, CD2, CD3, CD4, or CD25; especially in combination with a T-cell suppressant, e.g., cyclosporin A or FK-506.
- anti-inflammatory or immunosuppressive agents for example in combination with cyclosporin A and analogs thereof, FK-506 and analogs thereof, rapamycin and analogs thereof, myco- phenolic acid, mycophenolate mofetil, mizoribine,
- Such combination therapy is further comprised within the scope of the invention, e.g., a method according to 1 above further comprising administration concomitantly or in sequence of a therapeutically or synergistically effective amount of such a second immuno- suppressive or anti-inflammatory agent.
- BnBr benzyl bromide
- CSA camphorsulfonic acid
- DCM dichloro- methane
- DEAD diethylazodicarboxylate
- C-DHAP 3-keto-4-hydroxy-butanyl-1-phosphon- ate
- DHAP dihydroxyacetone phosphate
- dppb 1 ,4-bis(diphenylphosphino)butane
- DMAP 4-dimethylaminopyridine
- DMF dimethylformamide
- DMS dimethylsulfide
- EDC 1-(3-di- methylaminopropyl)-3-ethylcarbodiimide hydrochloride; eq: equivalent
- ESI electrospray ionization
- HOBt 1-hydroxybenzotriazole
- HOSu N-hydroxy succinimide
- NBA m-nitro- benzylalcohol
- NMM 4-methyl morpholine
- PPh 3 4-methyl morpholine
- the diols are prepared from the unsaturated esters according to the literature protocol as follows: A solution of AD-mix ( ⁇ or ⁇ ) (1.4 g/mmol olefin) in tert.-butanol (5 ml) and H 2 O (5 ml) is cooled to 0°C, MeSO 2 NH 2 and the olefin (1 mmol) are added and the heterogeneous mixture is stirred at 4°C until completion is indicated by tic (up to 48 h, to avoid very slow conversion, addition of extra potassium osmate (1.3 mg) is recommended). Sodium sulfite (1.5 g) is added at 4°C and stirring is continued at 23°C for 30 min.
- GP B A solution of the amine, HOBt, the carboxylic acid and NMM in dry CH 2 CI 2 is cooled to 0°C and EDC is added in one portion. The reaction mixture is stirred several h at 0°C and
- An aqueous solution of the residue is either directly filtered through a Whatman ® Anotop inorganic membrane filter (Anotop 25 (0.2 ⁇ m) or Anotop 10 (0.02 ⁇ m)) or, if necessary, purified by Biogel P2 or Sephadex G10 column chromatography (H 2 O as eluent) and lyophilized to give the completely deprotected compound as a white solid.
- GP B A solution of the benzyl protected compound in EtOH/H 2 O (2:1 ) is hydrogenated at 1 atm in the presence of Pd(OH) 2 /C (Degussa type, 20% Pd(OH) 2 on activated carbon) for several hours. The reaction is worked up as described above in GP A.
- the reaction mixture is stirred at -20°C for 1 h and then allowed to reach 23°C slowly. After 16 to 36 h the reaction is taken up in ethyl acetate and extracted with 5% w/v citric acid solution (20 ml). The aqueous layer is further extracted with ethyl acetate (4 x 20 ml) and the combined oranic layers are washed with sat. NaHCO 3 -sol. (40 ml) and brine (40 ml) followed by drying over MgSO 4 . After evaporation under reduced pressure the residual oil is purified by SGCC (gradient elution with 30% ⁇ 100% EtOAc in hexanes) to give the coupled protected mimetic.
- SGCC gradient elution with 30% ⁇ 100% EtOAc in hexanes
- An aqueous solution of the residue is either directly filtered through a Whatman ® Anotop inorganic membrane filter (Anotop 25 (0.2 ⁇ m) or Anotop 10 (0.02 ⁇ m)) or, if necessary, purified by Biogel P2 or Sephadex G10 column chromatography (H 2 O as eluent) and lyophilized to give the completely deprotected compound as a white solid.
- SUBSTTTUTE SHEET (RULE 25) tion is indicated by tic (up to 48h, to avoid very slow conversion, addition of extra potassium osmate (1.3 mg) is recommended). Sodium sulfite (1.5g) is added at 4°C and stirring is continued at 23°C for 30min. Triple extraction with EtOAc is followed by washings with 1 N NaOH and brine. After drying over Na 2 SO and removal of the solvent in vacuo the residual slightly yellow solid is purified by SGCC (gradient elution EtOAc in hexanes) to give the desired diol.
- SGCC gradient elution EtOAc in hexanes
- Procedure B A solution of the amine, HOBt, the carboxylic acid and NMM in dry CH 2 CI 2 is cooled to 0°C and EDC is added in one portion. The reaction mixture is stirred several h at 0°C and then allowed to reach 23°C slowly. After 4 to 18h the reaction is worked up as described above in Procedure A.
- the reaction mixture is treated with NMM until a basic pH is achieved.
- the reaction mixture is stirred at 0°C for several h and then allowed to reach 23°C slowly.
- the reaction is taken up in ethyl acetate and extracted with 5% w/v citric acid solution (20 ml).
- the aqueous layer is further extracted with ethyl acetate (4 x 20 ml) and the combined organic layers are washed with sat. NaHCO 3 -sol. (40 ml) and brine (40 ml) followed by drying over MgSO 4 or Na 2 SO in the case of unprotected diols.
- the residual oil is purified by SGCC (gradient elution with 40% ⁇ 100% EtOAc in hexanes) to give the coupled compound.
- SUBSTITUTE SHEET (RULE 25) (d) 2 mol (1132mg) of 4(14) is dissolved in a mixture of THF and water (3:1) and hydrogenated at 1 atm in the presence of a catalytic amount of Pd/C (Aldrich; 10% Pd/C). The mixture is allowed to react overnight and the catalyst is filtered off using a celite pad. The solvent is evaporated under vacuum and 5(14) is isolated as a mixture of aldehyde and dihydrate.
- Example A4 Preparation of Compound 22(14) 20(14) is treated with 1.1 eq of succinic anhydride in pyridine as solvent and in the presence of a catalytic amount of DMAP; conditions and workup are as above.
- the product so obtained is subjected to ozonolysis in DCM/MeOH (5:1), quenched by DMS and extracted from ether. Hydrogenation of the benzyl groups is carried out in THF:H 2 O mixture under 50 psi of H 2 to yield 22(14).
- the O-allyl, O-propenyl, O-butenyl, and O-pentenyl ⁇ -(D)-glucoside 23(14) is prepared according to Fraser-Reid et al [Syntlett 927 (1992)] wherein the O-methyl ⁇ -(D)-mannoside is stirred in neat solvent (e.g. 1.0 propenol (for the O-propenyl derivative), 1.0 allyl alcohol (for the O-allyl derivative), 1.0 butenol (for the O-butenyl derivative) or 1.0 O-pentenol (for the O-pentenyl derivative) at 90°C for 12 h.
- solvent e.g. 1.0 propenol (for the O-propenyl derivative), 1.0 allyl alcohol (for the O-allyl derivative), 1.0 butenol (for the O-butenyl derivative) or 1.0 O-pentenol (for the O-pentenyl derivative) at 90°C for
- the crude oil is purified by SGFC (CH 2 CI 2 :MeOH) giving the perbenzyl aldehyde.
- the tertbutyldiphenylsilyl moiety is then removed by adding 1.0 M solvent THF to the perbenzyl aldehyde followed by the addition of TBAF (1.0 eq; 1.0 M solution).
- the reaction mixture is stirred for 2 h at 0°C.
- the reaction mixture is evaporated and partitioned between a saturated NaHCO 3 solution (50ml) and EtOAc (5ml).
- the aqueous phase is extracted with EtOAc (2x30ml) and the combined organic phases are dried and concentrated under reduced pressure.
- the crude oil is purified by SGFC (CH 2 CI 2 :MeOH) giving the perbenzylated aldehyde 25(14).
- R'-bromide chloride or iodide is also acceptable
- the reaction mixture is warmed to 23°C, diluted with CH 2 CI 2 (100 ml), washed with saturated NaHCO 3 (50 ml), and dried (MgSO 4 ).
- the crude product is used directly in the next step without further purification.
- the aldehyde prepared above is dissolved in acetone (3 ml) and cooled to 0°C. Jones reagent is added drop-wise until a orange color persists. iPrOH (1 ml) is added to quench any excess Jones reagent and the reaction mixture is then partitioned between methylene chloride (50 ml) and 1 N HCI (50 ml). The aqueous layer is extracted with CH 2 CI 2 (50 ml) and the combined organic phases are dried (MgSO 4 ), concentrated under reduced pressure, and purified by SGFC (100% EtOAc) giving 18(15).
- Example A17 Preparation of methyl-2-[N-(2,3,4,6-tetrabenzyloxy- ⁇ -D-mannopyran- oside)carbonyl]amino-3-[(2-acetic acid)oxy]-4,6-0-dibenzylidine-galac- topyranoside 13(3)
- reaction is diluted with CH CI 2 (10 ml) and the resulting solution is quenched by saturated NaHCO.
- the aqueous layer is extracted with CH 2 CI 2 (2 x 10 ml) and the combined organic layers are washed with brine, dried with MgSO 4 , filtered, evaporated and purified by column chromatography to provide 8(3).
- alkyl halide or acyl halide may be used in lieu of 1 -bromohexadecane: 1-chloropropane, 1-chlorobutane, 1-chloropentane, 1-chlorohexane, 1-chloro- heptane, 1-chlorooctane, 1-chlorononane, 1-chlorodecane, 1-bromoundecane, 1-bromo- dodecane, 1-bromotridecane, 1-bromotetradecane, 1-bromopentadecane, 1 -bromohexadecane, 1 -bromooctadecane, 1-bromoeicosane, 1-bromodocosane, 2-bromomethyl-naph- thalene, 1-chloromethyl-naphthalene, 2-bromoethyl-benzene, 1-bromo-3-phenyl-propane, h
- D-Mannose (1500 mg, 8.3 mmol) is added to 10 ml of allyl alcohol together with a catalytic amount (10 mg) of camphorsulfonic acid. The mixture is heated to 90°C overnight and then the excess allyl alcohol is evaporated in vacuo. Flash chromatography of the residue (EtOAc:MeOH, 6:1 -4:1) gives 1400 mg (76%) of ⁇ -O-allylmannopyranoside. To a solution of the above compound is added 1.1 eq TBDPSOTf (1.1 eq) in anhydrous methylene chloride (.10 M) at 0°C and allowed to stir for 2 h.
- TBDPSOTf 1.1 eq
- the ozonolysis of 9a(3) is performed as described above.
- the aldehyde product (2 mmol, 1.1 g) is dissolved in a 3:1 mixture of THF and water and hydrogenated overnight at 1 atm in the presence of a catalytic amount of Pd-C. After filtration through Celite and evaporation of the solvent, the deprotected aldehyde 18a(3) is isolated.
- reaction is diluted with CH 2 CI 2 (10 ml) and the resulting solution is quenched by saturated NaHCO 3 .
- the aqueous layer is extracted with CH 2 CI 2 (2 x 10 ml) and the combined organic layers are washed with brine, dried with MgSO , filtered, evaporated and purified by column chromatography to provide the acetate.
- the crude acetate is dissolved in MeOH and a catalytic amount of 25% NaOMe by weight is added in MeOH. After 2 h Dowex H + resin is added until the pH of the solution is approximately 1-2. The residue is then dissolved in CH 2 CI 2 and the solution is washed with 5% aq. citric acid solution , sat. NaHCO 3 soln., and brine. This solution is then dried over Na 2 SO and concentrated under reduced pressure. The crude material is purified by flash chromatography with silica gel using 25%-35% ethyl acetate in hexane as the eluent.
- reaction After stirring overnight, the reaction is quenched by the addition of 1 g Na 2 S 2 Os, 10 g Florisil and 25 ml of H 2 O. After 30 min, the reaction mixture is concentrated under reduced pressure and the residue is treated with EtOAc and water. The solution is decanted away from the Florisil and the aqueous portion is extracted four times with EtOAc. The combined organic extracts are dried over MgSO 4 and concentrated under reduced pressure. The diol is immediately used in the next reaction.
- the reaction is quenched with isopropanol, 5 g of celite is added and the reaction is stirred for 20 min.
- the solution is decanted into a separatory funnel and EtOAc is added.
- the aqueous portion is extracted three times with EtOAc.
- the combined organic extracts are dried over MgSO 4 and concentrated under reduced pressure. The acid is sufficiently pure for use in the next reaction.
- reaction is allowed to stir for 24 h before being diluted with CH 2 CI 2 (20 ml) and washed successively with a 1 N hydrochloric acid solution (15 ml), saturated NaHCO 3 solution (15 ml) and brine (15 ml).
- the organic phase is dried with MgSO 4 , concentrated and purified by silica gel chromatoaraphy to yield 81(3).
- the reaction is allowed to stir for 24 h before being diluted with CH 2 CI 2 (50 ml) and washed successively with a 5% citric acid solution (25 ml), saturated NaHCO 3 solution (25 ml), and brine (25 ml).
- the organic phase is dried (MgSO 4 ), concentrated under reduced pressure, and purified by silica gel chromatography (EtOAc:Hexane 1 :1) giving 102i(3).
- the ⁇ , ⁇ -unsaturated ester (211 mg, 331 ⁇ mol) is subjected to the general procedure described for the asymmetric dihydroxylation reaction (AD-reaction) to provide diol 113(3).
- Example B5 Preparation of (2S,3fl)-N-carboxylmethyl-2,3-dihydroxy-4-( ⁇ -D-manno- pyranosyl)-butyramide 5(15)
- 26(15) (61 mg, 0.169 mmol) is dissolved in 90% TFA:water (3 ml) and stirred for 4 h. The reaction mixture is evaporated down under reduced pressure and any residual TFA is removed by two co-evaporations with toluene (2 x 25 ml). The crude mimic is dissolved in water (10 ml), filtered, and lyophilized giving 27(15): HRMS calcd for C 10 H 18 O 8 N (M + H), 280.1032, found 280.1038.
- Example B11 Preparation of methyl-2-[N-(2,3,4,6-hydroxy- ⁇ -D-mannopyranoside) carbonyl]amino-3-[(2-aceticacid)oxy]-4,6-hydroxy-galactopyranoside
- DHAP 1.2-1.5 mmol of 18(3) is dissolved in a solution of DHAP, (1 mmol, 3 ml of a 330 mM solution).
- the pH is adjusted to 6.7 by adding NaOH and 200 u of FDP aldolase (Sigma) is added.
- FDP aldolase Sigma
- the pH is adjusted to 8 and 1 g of BaCI 2 • 2 H 2 O (4.4 mmol) in 5 ml of water is added slowly.
- the cloudy mixture is kept in an ice bath for 15 min and the precipitates are removed by centrifugation. Two volumes of acetone are added to the supernate and the mixture is stored at 0°C for 1 h.
- the precipitates are collected by centrifugation and the supernatant is discarded.
- the pellet is treated with Dowex-50 H + until the solid is completely dissolved (ca. 30min), and the resin is filtered off.
- the pH of the filtrate is adjusted to 7.0 by adding NaOH. Lyophilisation of the solution yields a mixture of the phosphonates that are
- SUBSTITUTE SHEET (RULE 25) mixture is filtered off using celite pad. The solvent is removed under vacuum to give free amine compound which can be used in the next step without further purification.
- OSu activated ester RCOOSu (1.1 eq; R is a radical derived from the following acids; the activated ester is derived by reacting 1.1 eq of succinic anhydride with 1.0 eq of the following commercially available acids in 0.10 M methylene chloride at 0°C for 6 h: the acids are as follows: hexanoic acid, heptan- oic acid, octanoic acid, nonanoic acid, decanoic acid, undecanoic acid, lauric acid, tri- decanoic acid, myristic acid, pentadecanoic acid, palmitic acid, heptadecanoic acid, stearic acid, nonadecanoic acid
- the Boc compound 71(3) (1.0 mmol) is dissolved in a 50:50 mixture of CH 2 CI 2 :TFA and the mixture is cooled to 0°C. After 30 min, the residue is concentrated to remove the excess TFA and CH 2 CI 2 and the residue is rinsed with CHCI 3 and concentrated to remove any traces of TFA.
- the TFA amine salt is the one used in the general procedure for coupling a carboxylic acid and an amine, using an additional equivalent of NMM.
- the activated ester is derived by reacting 1.1 eq of succinic anhydride with 1.0 eq of an acid in 0.10 M methylene chloride at 0°C for 6 h: useful acids are mentioned in example B14), HOBt (1.2 mmol), the amine (2.0 mmol) and NMM (2.5 mmol) in CH 2 CI 2 (0.5 M) is added EDC (1.3 mmol). After stirring overnight and subsequent warming to RT sat. NaHCO 3 soln. and CH 2 CI 2 are added to the reaction mixture. The aqueous portion is extracted twice with CH 2 CI 2 .
- Example B17 Preparation of 3- ⁇ N-[1-(6-O-Hexadecanyl- ⁇ -D-mannopyranosyl)]- acetyl)aminobenzoic acid 3a(3)
- a soluble form of E-selectin (sol-E-selectin) is prepared for inhibition assays of the SLe x mimetics.
- a 1.67 kbp DNA fragment encoding a truncated structural gene for E-selectin is isolated by PCR amplification of cDNA derived from mRNA that is isolated from IL-1 activated human endotheiial cells.
- the cDNA is subcloned into the vector pBluescript II and is trans- fected into 293 cells.
- the clones are screened for the production of sol-E-selectin, and the clone 293#3 is selected as the stable cell line that produces the greatest amount of sol-E- selectin per cell.
- Sol-E-selectin is produced on a large scale from this line using a Nunc cell factory. Recombinant sol-E-selectin is isolated from the media using immunoaffinity chromatography.
- the SLe mimetics are assayed for ability to block the adhesion of HL-60 cells to immobilized sol-E-selectin.
- Immobilized E-selectin is incubated first with inhibitor and then with HL- 60 cells.
- the bound cells are lysed, and myeloperoxidase released from the bound cells is detected with o-phenylenediamine and hydrogen peroxide.
- the percentage inhibition is determined by comparing the absorbance of the resulting solution at 492 nm to that in wells containing no inhibitor.
- Each data point in the E-selectin assay is a direct measure of cells bound using a quantitative enzyme assay. The values are then plotted to give the titration curve and IC 50 values.
- the procedure described herein is adopted from Wong et. al. [J. Am. Chem. Soc. 177:66- 79 (1995)].
- the compounds of formula I show an inhibition at 3 mM of 70% to 80%, or an IC 50 value of from 0.1 mM to 0.2 mM.
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- Molecular Biology (AREA)
- Crystallography & Structural Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
Abstract
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU53137/98A AU5313798A (en) | 1996-10-28 | 1997-10-27 | Organic compounds |
Applications Claiming Priority (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US08/744,744 US5830871A (en) | 1996-10-28 | 1996-10-28 | Inhibitors of E-, P- and L-selectin binding |
US08/744,744 | 1996-10-28 | ||
US08/764,315 | 1996-12-12 | ||
US08/764,315 US5837862A (en) | 1996-12-12 | 1996-12-12 | Sialyl Lewis X mimetics incorporating mannopeptides |
US89645297A | 1997-07-18 | 1997-07-18 | |
US08/896,452 | 1997-07-18 |
Publications (2)
Publication Number | Publication Date |
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WO1998018805A2 true WO1998018805A2 (fr) | 1998-05-07 |
WO1998018805A3 WO1998018805A3 (fr) | 2003-04-17 |
Family
ID=27419313
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP1997/005909 WO1998018805A2 (fr) | 1996-10-28 | 1997-10-27 | Composes organiques |
Country Status (2)
Country | Link |
---|---|
AU (1) | AU5313798A (fr) |
WO (1) | WO1998018805A2 (fr) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1999010359A3 (fr) * | 1997-08-26 | 1999-11-11 | Novartis Ag | Composes organiques |
EP2608796A2 (fr) * | 2010-08-05 | 2013-07-03 | Seattle Genetics, Inc. | Procédés d'inhibition de la fucosylation in vivo de protéines en utilisant des analogues du fucose |
-
1997
- 1997-10-27 WO PCT/EP1997/005909 patent/WO1998018805A2/fr active Application Filing
- 1997-10-27 AU AU53137/98A patent/AU5313798A/en not_active Abandoned
Non-Patent Citations (4)
Title |
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LUENGO, JUAN I. ET AL: "Synthesis of C-fucopyranosyl analogs of GDP-L-fucose as inhibitors of fucosyltransferases" TETRAHEDRON LETT. (1992), 33(46), 6911-14 CODEN: TELEAY;ISSN: 0040-4039, 1992, XP002054598 * |
UCHIYAMA, TAKETO ET AL: "Design and Synthesis of Sialyl Lewis X Mimetics" J. AM. CHEM. SOC. (1995), 117(19), 5395-6 CODEN: JACSAT;ISSN: 0002-7863, 1995, XP000570082 * |
UCHIYAMA, TRAKETO ET AL: "Design and synthesis of C-linked fucosides as inhibitors of E-selectin" BIOORG. MED. CHEM. (1996), 4(7), 1149-1165 CODEN: BMECEP;ISSN: 0968-0896, 9 July 1996, XP002054353 * |
WONG, CHI-HUEY ET AL: "Small Molecules as Structural and Functional Mimics of Sialyl Lewis X in Selectin Inhibition: A Remarkable Enhancement of Inhibition by Additional Negative Charge and/or Hydrophobic Group" J. AM. CHEM. SOC. (1997), 119(35), 8152-8158 CODEN: JACSAT;ISSN: 0002-7863, 1997, XP002054599 * |
Cited By (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1999010359A3 (fr) * | 1997-08-26 | 1999-11-11 | Novartis Ag | Composes organiques |
EP2608796A2 (fr) * | 2010-08-05 | 2013-07-03 | Seattle Genetics, Inc. | Procédés d'inhibition de la fucosylation in vivo de protéines en utilisant des analogues du fucose |
CN103402525A (zh) * | 2010-08-05 | 2013-11-20 | 西雅图基因公司 | 使用岩藻糖类似物在体内抑制蛋白质岩藻糖基化的方法 |
EP2608796A4 (fr) * | 2010-08-05 | 2014-06-11 | Seattle Genetics Inc | Procédés d'inhibition de la fucosylation in vivo de protéines en utilisant des analogues du fucose |
AU2011285490B2 (en) * | 2010-08-05 | 2016-04-21 | Seagen Inc. | Methods of inhibition of protein fucosylation in vivo using fucose analogs |
US9504702B2 (en) | 2010-08-05 | 2016-11-29 | Seattle Genetics, Inc. | Methods of inhibition of protein fucosylation in vivo using fucose analogs |
CN103402525B (zh) * | 2010-08-05 | 2017-03-01 | 西雅图基因公司 | 使用岩藻糖类似物在体内抑制蛋白质岩藻糖基化的方法 |
RU2625768C2 (ru) * | 2010-08-05 | 2017-07-18 | Сиэтл Дженетикс, Инк. | Способы ингибирования фукозилирования белков in vivo с использованием аналогов фукозы |
US10342811B2 (en) | 2010-08-05 | 2019-07-09 | Seattle Genetics, Inc. | Methods of inhibition of protein fucosylation in vivo using fucose analogs |
EP3513794A3 (fr) * | 2010-08-05 | 2019-10-16 | Seattle Genetics, Inc. | Analogues du fucose pour inhibition de la fucosylation de protéines in vivo |
US11033561B2 (en) | 2010-08-05 | 2021-06-15 | Seagen Inc. | Methods of inhibition of protein fucosylation in vivo using fucose analogs |
Also Published As
Publication number | Publication date |
---|---|
AU5313798A (en) | 1998-05-22 |
WO1998018805A3 (fr) | 2003-04-17 |
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