NO322866B1 - 4-Pyrimidinyl-N-acyl-L-fenylalaniner, anvendelse av disse som medikamenter og for behandling av sykdom, farmasoytiske preparater inneholdende slike, fremgangsmate for fremstilling av farmasoytisk preparat inneholdende disse og anvendelse av disse for fremstilling av medikament for behandling av sykdommer. - Google Patents
4-Pyrimidinyl-N-acyl-L-fenylalaniner, anvendelse av disse som medikamenter og for behandling av sykdom, farmasoytiske preparater inneholdende slike, fremgangsmate for fremstilling av farmasoytisk preparat inneholdende disse og anvendelse av disse for fremstilling av medikament for behandling av sykdommer. Download PDFInfo
- Publication number
- NO322866B1 NO322866B1 NO20022633A NO20022633A NO322866B1 NO 322866 B1 NO322866 B1 NO 322866B1 NO 20022633 A NO20022633 A NO 20022633A NO 20022633 A NO20022633 A NO 20022633A NO 322866 B1 NO322866 B1 NO 322866B1
- Authority
- NO
- Norway
- Prior art keywords
- alkyl
- pyrimidinyl
- carbonyl
- dioxo
- phenylalanine
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 43
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 title claims description 11
- 201000010099 disease Diseases 0.000 title claims description 9
- 239000003814 drug Substances 0.000 title claims description 8
- 238000004519 manufacturing process Methods 0.000 title claims description 5
- 238000002360 preparation method Methods 0.000 title description 98
- 230000008569 process Effects 0.000 title description 2
- 239000008194 pharmaceutical composition Substances 0.000 title 2
- 125000000217 alkyl group Chemical group 0.000 claims description 172
- -1 perfluoro Chemical group 0.000 claims description 161
- 150000001875 compounds Chemical class 0.000 claims description 126
- 239000001257 hydrogen Substances 0.000 claims description 124
- 229910052739 hydrogen Inorganic materials 0.000 claims description 124
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 120
- 125000001624 naphthyl group Chemical group 0.000 claims description 80
- 229960005190 phenylalanine Drugs 0.000 claims description 72
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 71
- 229910052736 halogen Inorganic materials 0.000 claims description 64
- 150000002367 halogens Chemical class 0.000 claims description 64
- 150000002431 hydrogen Chemical class 0.000 claims description 64
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 56
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 40
- 125000004494 ethyl ester group Chemical group 0.000 claims description 33
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 32
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 30
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 29
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 29
- 125000004644 alkyl sulfinyl group Chemical group 0.000 claims description 27
- 125000004414 alkyl thio group Chemical group 0.000 claims description 27
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 27
- 125000003545 alkoxy group Chemical group 0.000 claims description 21
- 108010008212 Integrin alpha4beta1 Proteins 0.000 claims description 20
- 125000003282 alkyl amino group Chemical group 0.000 claims description 20
- 230000027455 binding Effects 0.000 claims description 20
- 108010000134 Vascular Cell Adhesion Molecule-1 Proteins 0.000 claims description 17
- 102100023543 Vascular cell adhesion protein 1 Human genes 0.000 claims description 17
- MEWSBKJAUCDJSK-KRWDZBQOSA-N (2s)-2-[(2,6-dichlorobenzoyl)amino]-3-[4-(1,3,4-trimethyl-2,6-dioxopyrimidin-5-yl)phenyl]propanoic acid Chemical compound O=C1N(C)C(=O)N(C)C(C)=C1C(C=C1)=CC=C1C[C@@H](C(O)=O)NC(=O)C1=C(Cl)C=CC=C1Cl MEWSBKJAUCDJSK-KRWDZBQOSA-N 0.000 claims description 15
- 125000004432 carbon atom Chemical group C* 0.000 claims description 14
- 229910052717 sulfur Inorganic materials 0.000 claims description 13
- 208000006673 asthma Diseases 0.000 claims description 12
- 239000000460 chlorine Substances 0.000 claims description 12
- 150000003839 salts Chemical class 0.000 claims description 12
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 11
- 229910052799 carbon Inorganic materials 0.000 claims description 11
- 125000004429 atom Chemical group 0.000 claims description 10
- 125000001072 heteroaryl group Chemical group 0.000 claims description 10
- 229910052757 nitrogen Inorganic materials 0.000 claims description 10
- XWJUDXXALXRTIE-SFHVURJKSA-N (2s)-2-[(2-chloro-6-methylbenzoyl)amino]-3-[4-(1,3,4-trimethyl-2,6-dioxopyrimidin-5-yl)phenyl]propanoic acid Chemical compound CC1=CC=CC(Cl)=C1C(=O)N[C@H](C(O)=O)CC1=CC=C(C=2C(N(C)C(=O)N(C)C=2C)=O)C=C1 XWJUDXXALXRTIE-SFHVURJKSA-N 0.000 claims description 9
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 9
- 229910052760 oxygen Inorganic materials 0.000 claims description 9
- 125000006239 protecting group Chemical group 0.000 claims description 9
- KQFDKGNSBOLNCZ-IBGZPJMESA-N (2s)-2-[(2,6-dichlorobenzoyl)amino]-3-[4-(1,3-diethyl-4-methyl-2,6-dioxopyrimidin-5-yl)phenyl]propanoic acid Chemical compound O=C1N(CC)C(=O)N(CC)C(C)=C1C(C=C1)=CC=C1C[C@@H](C(O)=O)NC(=O)C1=C(Cl)C=CC=C1Cl KQFDKGNSBOLNCZ-IBGZPJMESA-N 0.000 claims description 8
- MWYWLZQVFNXNEI-IBGZPJMESA-N (2s)-2-[(2-chloro-6-methylbenzoyl)amino]-3-[4-(1,3-dimethyl-2,4-dioxopyrimidin-5-yl)-3-methylphenyl]propanoic acid Chemical compound N([C@@H](CC=1C=C(C(=CC=1)C=1C(N(C)C(=O)N(C)C=1)=O)C)C(O)=O)C(=O)C1=C(C)C=CC=C1Cl MWYWLZQVFNXNEI-IBGZPJMESA-N 0.000 claims description 8
- 208000022559 Inflammatory bowel disease Diseases 0.000 claims description 8
- NTFHSUUFBUDKFC-SFHVURJKSA-N (2s)-2-[(2,6-dichlorobenzoyl)amino]-3-[3-methyl-4-(1,3,4-trimethyl-2,6-dioxopyrimidin-5-yl)phenyl]propanoic acid Chemical compound N([C@@H](CC=1C=C(C(=CC=1)C=1C(N(C)C(=O)N(C)C=1C)=O)C)C(O)=O)C(=O)C1=C(Cl)C=CC=C1Cl NTFHSUUFBUDKFC-SFHVURJKSA-N 0.000 claims description 7
- XYXZMKHLXJARTF-SFHVURJKSA-N (2s)-2-[(2,6-dichlorobenzoyl)amino]-3-[4-(1,3-dimethyl-2,4-dioxopyrimidin-5-yl)-3-methylphenyl]propanoic acid Chemical compound N([C@@H](CC=1C=C(C(=CC=1)C=1C(N(C)C(=O)N(C)C=1)=O)C)C(O)=O)C(=O)C1=C(Cl)C=CC=C1Cl XYXZMKHLXJARTF-SFHVURJKSA-N 0.000 claims description 7
- YJBJPRUILPSVFT-IBGZPJMESA-N (2s)-2-[(2-chloro-6-ethylbenzoyl)amino]-3-[4-(1,3,4-trimethyl-2,6-dioxopyrimidin-5-yl)phenyl]propanoic acid Chemical compound CCC1=CC=CC(Cl)=C1C(=O)N[C@H](C(O)=O)CC1=CC=C(C=2C(N(C)C(=O)N(C)C=2C)=O)C=C1 YJBJPRUILPSVFT-IBGZPJMESA-N 0.000 claims description 7
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 7
- 229910052801 chlorine Inorganic materials 0.000 claims description 7
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 7
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 7
- LYHCGYLAKNFJSM-KRWDZBQOSA-N (2s)-2-[(2,6-difluorobenzoyl)amino]-3-[4-(1,3,4-trimethyl-2,6-dioxopyrimidin-5-yl)phenyl]propanoic acid Chemical compound O=C1N(C)C(=O)N(C)C(C)=C1C(C=C1)=CC=C1C[C@@H](C(O)=O)NC(=O)C1=C(F)C=CC=C1F LYHCGYLAKNFJSM-KRWDZBQOSA-N 0.000 claims description 6
- 125000005842 heteroatom Chemical group 0.000 claims description 6
- 201000006417 multiple sclerosis Diseases 0.000 claims description 6
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 6
- IECKVUVUZIOYDW-FQEVSTJZSA-N (2s)-2-[(2-chloro-6-methylbenzoyl)amino]-3-[4-(1,3-diethyl-4-methyl-2,6-dioxopyrimidin-5-yl)phenyl]propanoic acid Chemical compound O=C1N(CC)C(=O)N(CC)C(C)=C1C(C=C1)=CC=C1C[C@@H](C(O)=O)NC(=O)C1=C(C)C=CC=C1Cl IECKVUVUZIOYDW-FQEVSTJZSA-N 0.000 claims description 5
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 5
- 125000005196 alkyl carbonyloxy group Chemical group 0.000 claims description 5
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 5
- XHXNVXQXRIGHCE-MRNPHLECSA-N 1-acetyloxyethyl (2s)-2-[(2,6-difluorobenzoyl)amino]-3-[4-(1,3,4-trimethyl-2,6-dioxopyrimidin-5-yl)phenyl]propanoate Chemical compound C([C@@H](C(=O)OC(OC(C)=O)C)NC(=O)C=1C(=CC=CC=1F)F)C(C=C1)=CC=C1C1=C(C)N(C)C(=O)N(C)C1=O XHXNVXQXRIGHCE-MRNPHLECSA-N 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- DXBUTWPHLQEKCF-FQEVSTJZSA-N ethyl (2s)-2-[(2-chloro-6-methylbenzoyl)amino]-3-[4-(1,3,4-trimethyl-2,6-dioxopyrimidin-5-yl)phenyl]propanoate Chemical compound C([C@@H](C(=O)OCC)NC(=O)C=1C(=CC=CC=1C)Cl)C(C=C1)=CC=C1C1=C(C)N(C)C(=O)N(C)C1=O DXBUTWPHLQEKCF-FQEVSTJZSA-N 0.000 claims description 4
- 230000001404 mediated effect Effects 0.000 claims description 4
- 125000004738 (C1-C6) alkyl sulfinyl group Chemical group 0.000 claims description 3
- 125000004739 (C1-C6) alkylsulfonyl group Chemical group 0.000 claims description 3
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims description 3
- XUEMABPGUCMTNO-IBGZPJMESA-N ethyl (2s)-2-[(2,6-dichlorobenzoyl)amino]-3-[4-(1,3,4-trimethyl-2,6-dioxopyrimidin-5-yl)phenyl]propanoate Chemical compound C([C@@H](C(=O)OCC)NC(=O)C=1C(=CC=CC=1Cl)Cl)C(C=C1)=CC=C1C1=C(C)N(C)C(=O)N(C)C1=O XUEMABPGUCMTNO-IBGZPJMESA-N 0.000 claims description 3
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims 2
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims 2
- 125000001589 carboacyl group Chemical group 0.000 claims 2
- 125000004769 (C1-C4) alkylsulfonyl group Chemical group 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 165
- 239000000243 solution Substances 0.000 description 131
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 120
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 108
- 239000007787 solid Substances 0.000 description 95
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 77
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 68
- 239000000203 mixture Substances 0.000 description 68
- 239000000725 suspension Substances 0.000 description 65
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 56
- 238000001914 filtration Methods 0.000 description 56
- 239000011541 reaction mixture Substances 0.000 description 55
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 54
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 51
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 48
- 238000001704 evaporation Methods 0.000 description 46
- 230000008020 evaporation Effects 0.000 description 46
- 239000011734 sodium Substances 0.000 description 45
- 239000002274 desiccant Substances 0.000 description 44
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 43
- 239000012267 brine Substances 0.000 description 39
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 39
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 36
- 239000000284 extract Substances 0.000 description 32
- 238000010898 silica gel chromatography Methods 0.000 description 31
- 210000004027 cell Anatomy 0.000 description 30
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 30
- 239000012043 crude product Substances 0.000 description 28
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 26
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 25
- 238000006243 chemical reaction Methods 0.000 description 23
- 239000000706 filtrate Substances 0.000 description 23
- 239000002904 solvent Substances 0.000 description 22
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 21
- 239000000872 buffer Substances 0.000 description 19
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 17
- 230000002829 reductive effect Effects 0.000 description 17
- 239000002253 acid Substances 0.000 description 15
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical class [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 14
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 14
- 239000000047 product Substances 0.000 description 14
- 239000012535 impurity Substances 0.000 description 13
- 238000005259 measurement Methods 0.000 description 13
- 230000007935 neutral effect Effects 0.000 description 13
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 239000007864 aqueous solution Substances 0.000 description 12
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 description 12
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 12
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 11
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 11
- 125000003118 aryl group Chemical group 0.000 description 11
- 239000003153 chemical reaction reagent Substances 0.000 description 11
- 238000004809 thin layer chromatography Methods 0.000 description 11
- 239000007858 starting material Substances 0.000 description 10
- DLQYXUGCCKQSRJ-UHFFFAOYSA-N tris(furan-2-yl)phosphane Chemical compound C1=COC(P(C=2OC=CC=2)C=2OC=CC=2)=C1 DLQYXUGCCKQSRJ-UHFFFAOYSA-N 0.000 description 10
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 9
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 9
- 150000001299 aldehydes Chemical class 0.000 description 9
- 238000007796 conventional method Methods 0.000 description 9
- 238000010790 dilution Methods 0.000 description 9
- 239000012895 dilution Substances 0.000 description 9
- 238000012360 testing method Methods 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- 239000002585 base Substances 0.000 description 8
- 230000015572 biosynthetic process Effects 0.000 description 8
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 8
- 238000010992 reflux Methods 0.000 description 8
- JBLIDPPHFGWTKU-UHFFFAOYSA-N 2,6-dichlorobenzoyl chloride Chemical compound ClC(=O)C1=C(Cl)C=CC=C1Cl JBLIDPPHFGWTKU-UHFFFAOYSA-N 0.000 description 7
- 210000003979 eosinophil Anatomy 0.000 description 7
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical group I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 7
- 229910000027 potassium carbonate Inorganic materials 0.000 description 7
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 7
- 238000003786 synthesis reaction Methods 0.000 description 7
- PAAZPARNPHGIKF-UHFFFAOYSA-N 1,2-dibromoethane Chemical compound BrCCBr PAAZPARNPHGIKF-UHFFFAOYSA-N 0.000 description 6
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 6
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 6
- 239000005977 Ethylene Substances 0.000 description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 6
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical class O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 description 6
- 229910052794 bromium Inorganic materials 0.000 description 6
- 125000004185 ester group Chemical group 0.000 description 6
- 150000002148 esters Chemical class 0.000 description 6
- 239000007789 gas Substances 0.000 description 6
- 238000011534 incubation Methods 0.000 description 6
- 239000012442 inert solvent Substances 0.000 description 6
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 6
- HSZCZNFXUDYRKD-UHFFFAOYSA-M lithium iodide Chemical compound [Li+].[I-] HSZCZNFXUDYRKD-UHFFFAOYSA-M 0.000 description 6
- 210000004698 lymphocyte Anatomy 0.000 description 6
- IWNHLNMIUYBYEW-ZDUSSCGKSA-N methyl (2s)-2-amino-3-[4-(1,3,4-trimethyl-2,6-dioxopyrimidin-5-yl)phenyl]propanoate Chemical compound C1=CC(C[C@H](N)C(=O)OC)=CC=C1C1=C(C)N(C)C(=O)N(C)C1=O IWNHLNMIUYBYEW-ZDUSSCGKSA-N 0.000 description 6
- NOQQXVTTXMDLPV-ZOWNYOTGSA-N methyl (2s)-2-amino-3-[4-(1,3,4-trimethyl-2,6-dioxopyrimidin-5-yl)phenyl]propanoate;hydrochloride Chemical compound Cl.C1=CC(C[C@H](N)C(=O)OC)=CC=C1C1=C(C)N(C)C(=O)N(C)C1=O NOQQXVTTXMDLPV-ZOWNYOTGSA-N 0.000 description 6
- 229910052763 palladium Inorganic materials 0.000 description 6
- 239000002244 precipitate Substances 0.000 description 6
- 235000017557 sodium bicarbonate Nutrition 0.000 description 6
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 6
- 159000000000 sodium salts Chemical class 0.000 description 6
- 239000005051 trimethylchlorosilane Substances 0.000 description 6
- 150000003752 zinc compounds Chemical class 0.000 description 6
- SSWYXDSEGDETGF-HNNXBMFYSA-N (2s)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-3-[4-(1,3,4-trimethyl-2,6-dioxopyrimidin-5-yl)phenyl]propanoic acid Chemical compound O=C1N(C)C(=O)N(C)C(C)=C1C1=CC=C(C[C@H](NC(=O)OC(C)(C)C)C(O)=O)C=C1 SSWYXDSEGDETGF-HNNXBMFYSA-N 0.000 description 5
- CEFMMQYDPGCYMG-UHFFFAOYSA-N 2-chloro-6-methylbenzoic acid Chemical compound CC1=CC=CC(Cl)=C1C(O)=O CEFMMQYDPGCYMG-UHFFFAOYSA-N 0.000 description 5
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/52—Two oxygen atoms
- C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
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- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- A—HUMAN NECESSITIES
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- 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]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/52—Two oxygen atoms
- C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
- C07D239/545—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/553—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms with halogen atoms or nitro radicals directly attached to ring carbon atoms, e.g. fluorouracil
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06139—Dipeptides with the first amino acid being heterocyclic
- C07K5/06165—Dipeptides with the first amino acid being heterocyclic and Pro-amino acid; Derivatives thereof
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
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- Molecular Biology (AREA)
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- Immunology (AREA)
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- Biochemistry (AREA)
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- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicinal Preparation (AREA)
- Peptides Or Proteins (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US16908999P | 1999-12-06 | 1999-12-06 | |
| PCT/EP2000/011884 WO2001042225A2 (en) | 1999-12-06 | 2000-11-28 | 4-pyrimidinyl-n-acyl-l-phenylalanines |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| NO20022633L NO20022633L (no) | 2002-06-04 |
| NO20022633D0 NO20022633D0 (no) | 2002-06-04 |
| NO322866B1 true NO322866B1 (no) | 2006-12-18 |
Family
ID=22614222
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO20022633A NO322866B1 (no) | 1999-12-06 | 2002-06-04 | 4-Pyrimidinyl-N-acyl-L-fenylalaniner, anvendelse av disse som medikamenter og for behandling av sykdom, farmasoytiske preparater inneholdende slike, fremgangsmate for fremstilling av farmasoytisk preparat inneholdende disse og anvendelse av disse for fremstilling av medikament for behandling av sykdommer. |
Country Status (35)
| Country | Link |
|---|---|
| EP (1) | EP1237878B1 (cs) |
| JP (1) | JP3824935B2 (cs) |
| KR (1) | KR100522344B1 (cs) |
| CN (1) | CN1218943C (cs) |
| AR (1) | AR034401A1 (cs) |
| AT (1) | ATE357433T1 (cs) |
| AU (1) | AU783348B2 (cs) |
| BR (1) | BR0016195A (cs) |
| CA (1) | CA2392570C (cs) |
| CO (1) | CO5080772A1 (cs) |
| CY (1) | CY1106626T1 (cs) |
| CZ (1) | CZ303435B6 (cs) |
| DE (1) | DE60034061T2 (cs) |
| DK (1) | DK1237878T3 (cs) |
| EG (1) | EG24361A (cs) |
| ES (1) | ES2282162T3 (cs) |
| HK (1) | HK1054384B (cs) |
| HR (1) | HRP20020468B1 (cs) |
| HU (1) | HU229105B1 (cs) |
| IL (2) | IL149617A0 (cs) |
| JO (1) | JO2283B1 (cs) |
| MA (1) | MA26850A1 (cs) |
| MX (1) | MXPA02005564A (cs) |
| MY (1) | MY126972A (cs) |
| NO (1) | NO322866B1 (cs) |
| NZ (1) | NZ518828A (cs) |
| PE (1) | PE20010961A1 (cs) |
| PL (1) | PL207160B1 (cs) |
| PT (1) | PT1237878E (cs) |
| RS (1) | RS50371B (cs) |
| RU (1) | RU2266901C2 (cs) |
| SI (1) | SI1237878T1 (cs) |
| TW (1) | TWI256387B (cs) |
| WO (1) | WO2001042225A2 (cs) |
| ZA (1) | ZA200203533B (cs) |
Families Citing this family (32)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6960597B2 (en) | 2000-06-30 | 2005-11-01 | Orth-Mcneil Pharmaceutical, Inc. | Aza-bridged-bicyclic amino acid derivatives as α4 integrin antagonists |
| CN1325480C (zh) * | 2000-08-18 | 2007-07-11 | 味之素株式会社 | 苯基丙氨酸衍生物 |
| AR033765A1 (es) * | 2001-05-22 | 2004-01-07 | Syngenta Participations Ag | Procedimiento para la preparacion de derivados 3-alquil-3h-isobenzofuran-1-ona 7-sustituidos. |
| WO2003053926A1 (en) | 2001-12-13 | 2003-07-03 | Ajinomoto Co.,Inc. | Novel phenylalanine derivative |
| CA2550843C (en) | 2003-12-22 | 2013-04-02 | Ajinomoto Co., Inc. | Novel phenylalanine derivatives |
| US7618981B2 (en) * | 2004-05-06 | 2009-11-17 | Cytokinetics, Inc. | Imidazopyridinyl-benzamide anti-cancer agents |
| EP1781686B1 (en) * | 2004-08-16 | 2009-05-06 | Merck & Co., Inc. | Vla-4 antagonists |
| JP4784224B2 (ja) | 2004-09-24 | 2011-10-05 | 味の素株式会社 | 糖鎖転移方法および糖鎖転移酵素 |
| WO2007060408A2 (en) * | 2005-11-23 | 2007-05-31 | Astrazeneca Ab | L-phenylalanine derivatives and their use as integrin antagonists |
| AR059224A1 (es) * | 2006-01-31 | 2008-03-19 | Jerini Ag | Compuestos para la inhibicion de integrinas y uso de estas |
| WO2007091046A1 (en) * | 2006-02-09 | 2007-08-16 | Astrazeneca Ab | Chemical compounds |
| US7879837B2 (en) | 2006-06-19 | 2011-02-01 | Toray Industries, Inc. | Therapeutic or prophylactic agent for multiple sclerosis |
| DK2203431T3 (da) | 2007-09-17 | 2011-11-21 | Abbott Lab | Antiinfektiøse pyrimidiner og anvendelser heraf |
| MX2010002905A (es) * | 2007-09-17 | 2010-07-05 | Abbott Lab | Derivados de uracilo o timina para tratar la hepatitis c. |
| CN105294569A (zh) | 2007-09-17 | 2016-02-03 | 艾伯维巴哈马有限公司 | 治疗丙型肝炎的尿嘧啶或胸腺嘧啶衍生物 |
| PL2382222T3 (pl) * | 2008-12-22 | 2013-09-30 | Icl Ip America Inc | Proces oczyszczania bisfosforanu na bazie rozpuszczalnika mieszalnego z wodą |
| US9216952B2 (en) | 2010-03-23 | 2015-12-22 | Abbvie Inc. | Process for preparing antiviral compound |
| US8975443B2 (en) | 2010-07-16 | 2015-03-10 | Abbvie Inc. | Phosphine ligands for catalytic reactions |
| CN105622525B (zh) | 2010-07-16 | 2019-02-15 | 艾伯维巴哈马有限公司 | 用于制备抗病毒化合物的方法 |
| PE20131095A1 (es) | 2010-07-16 | 2013-10-27 | Abbvie Bahamas Ltd | Ligandos fosfina para reacciones cataliticas |
| US9255074B2 (en) | 2010-07-16 | 2016-02-09 | Abbvie Inc. | Process for preparing antiviral compounds |
| US8877815B2 (en) | 2010-11-16 | 2014-11-04 | Novartis Ag | Substituted carbamoylcycloalkyl acetic acid derivatives as NEP |
| US9447035B2 (en) * | 2012-01-27 | 2016-09-20 | Hoffmann-La Roche Inc. | Integrin antagonist conjugates for targeted delivery to cells expressing VLA-4 |
| BR112014013135A2 (pt) * | 2012-01-27 | 2017-12-05 | Hoffmann La Roche | composto, composição farmacêutica, método para o tratamento da inflamação, uso de um composto e invenção |
| WO2015048819A1 (en) | 2013-09-30 | 2015-04-02 | The Regents Of The University Of California | Anti-alphavbeta1 integrin compounds and methods |
| MX373389B (es) * | 2013-10-29 | 2020-05-12 | Ea Pharma Co Ltd | Derivado de sulfonamida y uso farmaceutico del mismo. |
| WO2016145258A1 (en) | 2015-03-10 | 2016-09-15 | The Regents Of The University Of California | Anti-alphavbeta1 integrin inhibitors and methods of use |
| PL3873900T3 (pl) | 2018-10-30 | 2025-06-02 | Gilead Sciences, Inc. | Imidazo[1,2-a]pirydynowe pochodne jako inhibitory integryny alpha4beta7 do leczenia chorób zapalnych |
| AU2019373245C1 (en) | 2018-10-30 | 2022-10-27 | Gilead Sciences, Inc. | Compounds for inhibition of alpha 4β7 integrin |
| WO2020092383A1 (en) | 2018-10-30 | 2020-05-07 | Gilead Sciences, Inc. | Compounds for inhibition of alpha 4 beta 7 integrin |
| DK3873884T3 (da) | 2018-10-30 | 2025-02-17 | Gilead Sciences Inc | 3-(quinolin-8-yl)-1,4-dihydropyrido[3,4-d]pyrimidin-2,4-dion-derivater som alpha4beta7-integrinhæmmere til behandling af inflammatoriske sygdomme |
| CN119431230A (zh) | 2019-08-14 | 2025-02-14 | 吉利德科学公司 | 用于抑制α4β7整合素的化合物 |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CH516578A (de) * | 1967-11-02 | 1971-12-15 | Bayer Ag | Verfahren zur Herstellung von heterocyclische Acylaminogruppen enthaltenden Arylsulfonylharnstoffen mit blutdrucksenkender Wirkung |
| WO1998053814A1 (en) * | 1997-05-29 | 1998-12-03 | Merck & Co., Inc. | Heterocyclic amide compounds as cell adhesion inhibitors |
| EP1017382B1 (en) * | 1997-05-29 | 2006-03-01 | Merck & Co., Inc. (a New Jersey corp.) | Biarylalkanoic acids as cell adhesion inhibitors |
| WO1999010313A1 (en) * | 1997-08-22 | 1999-03-04 | F.Hoffmann-La Roche Ag | N-aroylphenylalanine derivatives |
| RU2220950C2 (ru) * | 1997-08-22 | 2004-01-10 | Ф.Хоффманн-Ля Рош Аг | N-алканоилфенилаланиновые производные |
| CN1231212C (zh) * | 1999-01-22 | 2005-12-14 | 依兰制药公司 | 抑制vla－4介导的白细胞粘着的多环化合物 |
-
2000
- 2000-11-28 EP EP00989906A patent/EP1237878B1/en not_active Expired - Lifetime
- 2000-11-28 MX MXPA02005564A patent/MXPA02005564A/es active IP Right Grant
- 2000-11-28 CZ CZ20022351A patent/CZ303435B6/cs not_active IP Right Cessation
- 2000-11-28 ES ES00989906T patent/ES2282162T3/es not_active Expired - Lifetime
- 2000-11-28 HU HU0204081A patent/HU229105B1/hu not_active IP Right Cessation
- 2000-11-28 HR HR20020468A patent/HRP20020468B1/xx not_active IP Right Cessation
- 2000-11-28 CA CA2392570A patent/CA2392570C/en not_active Expired - Fee Related
- 2000-11-28 PL PL357601A patent/PL207160B1/pl unknown
- 2000-11-28 CN CNB008167958A patent/CN1218943C/zh not_active Expired - Fee Related
- 2000-11-28 IL IL14961700A patent/IL149617A0/xx active IP Right Grant
- 2000-11-28 HK HK03106628.4A patent/HK1054384B/zh not_active IP Right Cessation
- 2000-11-28 AU AU26696/01A patent/AU783348B2/en not_active Ceased
- 2000-11-28 SI SI200030948T patent/SI1237878T1/sl unknown
- 2000-11-28 RS YUP-404/02A patent/RS50371B/sr unknown
- 2000-11-28 DK DK00989906T patent/DK1237878T3/da active
- 2000-11-28 AT AT00989906T patent/ATE357433T1/de active
- 2000-11-28 JP JP2001543526A patent/JP3824935B2/ja not_active Expired - Fee Related
- 2000-11-28 KR KR10-2002-7007175A patent/KR100522344B1/ko not_active Expired - Fee Related
- 2000-11-28 NZ NZ518828A patent/NZ518828A/en not_active IP Right Cessation
- 2000-11-28 WO PCT/EP2000/011884 patent/WO2001042225A2/en not_active Ceased
- 2000-11-28 DE DE60034061T patent/DE60034061T2/de not_active Expired - Lifetime
- 2000-11-28 RU RU2002117422/04A patent/RU2266901C2/ru not_active IP Right Cessation
- 2000-11-28 BR BR0016195-0A patent/BR0016195A/pt active Search and Examination
- 2000-11-28 PT PT00989906T patent/PT1237878E/pt unknown
- 2000-11-29 JO JO2000190A patent/JO2283B1/en active
- 2000-12-03 EG EG20001502A patent/EG24361A/xx active
- 2000-12-04 AR ARP000106415A patent/AR034401A1/es not_active Application Discontinuation
- 2000-12-04 MY MYPI20005690A patent/MY126972A/en unknown
- 2000-12-05 PE PE2000001293A patent/PE20010961A1/es not_active Application Discontinuation
- 2000-12-05 TW TW089125890A patent/TWI256387B/zh not_active IP Right Cessation
- 2000-12-05 CO CO00092691A patent/CO5080772A1/es unknown
-
2002
- 2002-05-03 ZA ZA200203533A patent/ZA200203533B/en unknown
- 2002-05-13 IL IL149617A patent/IL149617A/en not_active IP Right Cessation
- 2002-06-04 NO NO20022633A patent/NO322866B1/no not_active IP Right Cessation
- 2002-06-05 MA MA26673A patent/MA26850A1/fr unknown
-
2007
- 2007-05-29 CY CY20071100715T patent/CY1106626T1/el unknown
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| MM1K | Lapsed by not paying the annual fees |