ES2586145T3 - Derivados de 5-(bifenil-4-il)-3-fenil-1,2,4-oxadiazolilo como ligandos en los receptores de esfingosina 1-fosfato (S1P) - Google Patents
Derivados de 5-(bifenil-4-il)-3-fenil-1,2,4-oxadiazolilo como ligandos en los receptores de esfingosina 1-fosfato (S1P) Download PDFInfo
- Publication number
- ES2586145T3 ES2586145T3 ES11729318.3T ES11729318T ES2586145T3 ES 2586145 T3 ES2586145 T3 ES 2586145T3 ES 11729318 T ES11729318 T ES 11729318T ES 2586145 T3 ES2586145 T3 ES 2586145T3
- Authority
- ES
- Spain
- Prior art keywords
- methyl
- formula
- ethyl
- tert
- amino
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- DUYSYHSSBDVJSM-KRWOKUGFSA-N sphingosine 1-phosphate Chemical compound CCCCCCCCCCCCC\C=C\[C@@H](O)[C@@H](N)COP(O)(O)=O DUYSYHSSBDVJSM-KRWOKUGFSA-N 0.000 title claims description 12
- -1 5- (Biphenyl-4-yl) -3-phenyl-1,2,4-oxadiazolyl Chemical class 0.000 title description 83
- 239000003446 ligand Substances 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 205
- 239000000203 mixture Substances 0.000 claims abstract description 52
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims abstract description 42
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 34
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 28
- 150000003839 salts Chemical class 0.000 claims abstract description 15
- 239000012453 solvate Substances 0.000 claims abstract description 13
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims abstract description 9
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 6
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 5
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims abstract description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract 4
- JNCMHMUGTWEVOZ-UHFFFAOYSA-N F[CH]F Chemical compound F[CH]F JNCMHMUGTWEVOZ-UHFFFAOYSA-N 0.000 claims abstract 2
- 108010081348 HRT1 protein Hairy Proteins 0.000 claims abstract 2
- 102100021881 Hairy/enhancer-of-split related with YRPW motif protein 1 Human genes 0.000 claims abstract 2
- 238000000034 method Methods 0.000 claims description 266
- 239000002253 acid Substances 0.000 claims description 8
- 238000011282 treatment Methods 0.000 claims description 8
- 229910052701 rubidium Inorganic materials 0.000 claims description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 4
- 201000006417 multiple sclerosis Diseases 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- 230000008569 process Effects 0.000 claims description 4
- 230000001684 chronic effect Effects 0.000 claims description 3
- 208000035475 disorder Diseases 0.000 claims description 3
- 239000003814 drug Substances 0.000 claims description 3
- 230000028993 immune response Effects 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- 230000001363 autoimmune Effects 0.000 claims description 2
- 208000037979 autoimmune inflammatory disease Diseases 0.000 claims description 2
- 239000003153 chemical reaction reagent Substances 0.000 claims description 2
- 208000037976 chronic inflammation Diseases 0.000 claims description 2
- 208000037893 chronic inflammatory disorder Diseases 0.000 claims description 2
- 238000009833 condensation Methods 0.000 claims description 2
- 230000005494 condensation Effects 0.000 claims description 2
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 2
- 201000000596 systemic lupus erythematosus Diseases 0.000 claims description 2
- 201000001320 Atherosclerosis Diseases 0.000 claims 2
- 230000005856 abnormality Effects 0.000 claims 2
- 239000004480 active ingredient Substances 0.000 claims 2
- 230000004957 immunoregulator effect Effects 0.000 claims 2
- 238000011321 prophylaxis Methods 0.000 claims 2
- 208000023275 Autoimmune disease Diseases 0.000 claims 1
- 206010003827 Autoimmune hepatitis Diseases 0.000 claims 1
- 208000022559 Inflammatory bowel disease Diseases 0.000 claims 1
- 206010039710 Scleroderma Diseases 0.000 claims 1
- 208000034189 Sclerosis Diseases 0.000 claims 1
- 239000002671 adjuvant Substances 0.000 claims 1
- 239000000546 pharmaceutical excipient Substances 0.000 claims 1
- 238000000926 separation method Methods 0.000 claims 1
- DUYSYHSSBDVJSM-KRWOKUGFSA-M sphingosine 1-phosphate(1-) Chemical compound CCCCCCCCCCCCC\C=C\[C@@H](O)[C@@H]([NH3+])COP([O-])([O-])=O DUYSYHSSBDVJSM-KRWOKUGFSA-M 0.000 claims 1
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 144
- 229910052739 hydrogen Inorganic materials 0.000 description 112
- 102100025750 Sphingosine 1-phosphate receptor 1 Human genes 0.000 description 104
- 101710155454 Sphingosine 1-phosphate receptor 1 Proteins 0.000 description 102
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 98
- 239000000543 intermediate Substances 0.000 description 81
- 238000005160 1H NMR spectroscopy Methods 0.000 description 80
- 238000004128 high performance liquid chromatography Methods 0.000 description 74
- 102100025747 Sphingosine 1-phosphate receptor 3 Human genes 0.000 description 67
- 101710155457 Sphingosine 1-phosphate receptor 3 Proteins 0.000 description 67
- 239000000243 solution Substances 0.000 description 49
- 239000011541 reaction mixture Substances 0.000 description 47
- 239000007787 solid Substances 0.000 description 43
- 235000019439 ethyl acetate Nutrition 0.000 description 41
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 40
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 38
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 36
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 34
- 239000002904 solvent Substances 0.000 description 33
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 32
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 28
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 26
- 125000004801 4-cyanophenyl group Chemical group [H]C1=C([H])C(C#N)=C([H])C([H])=C1* 0.000 description 25
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 25
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 25
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 21
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 20
- 239000012267 brine Substances 0.000 description 19
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 19
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 18
- 239000012230 colorless oil Substances 0.000 description 18
- 239000012074 organic phase Substances 0.000 description 17
- 238000003818 flash chromatography Methods 0.000 description 16
- 239000003921 oil Substances 0.000 description 16
- 239000000843 powder Substances 0.000 description 16
- 239000000047 product Substances 0.000 description 16
- 239000012044 organic layer Substances 0.000 description 15
- AFABGHUZZDYHJO-UHFFFAOYSA-N 2-Methylpentane Chemical compound CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 description 14
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 14
- OBNCKNCVKJNDBV-UHFFFAOYSA-N ethyl butyrate Chemical compound CCCC(=O)OCC OBNCKNCVKJNDBV-UHFFFAOYSA-N 0.000 description 14
- 239000007788 liquid Substances 0.000 description 14
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 13
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 13
- 235000019341 magnesium sulphate Nutrition 0.000 description 13
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 238000003756 stirring Methods 0.000 description 12
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 11
- 238000005481 NMR spectroscopy Methods 0.000 description 11
- 239000007832 Na2SO4 Substances 0.000 description 11
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 11
- 229940125904 compound 1 Drugs 0.000 description 11
- 230000002829 reductive effect Effects 0.000 description 11
- 235000017557 sodium bicarbonate Nutrition 0.000 description 11
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 11
- 229910052938 sodium sulfate Inorganic materials 0.000 description 11
- 235000011152 sodium sulphate Nutrition 0.000 description 11
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 10
- 230000002209 hydrophobic effect Effects 0.000 description 10
- SJMDMGHPMLKLHQ-UHFFFAOYSA-N tert-butyl 2-aminoacetate Chemical compound CC(C)(C)OC(=O)CN SJMDMGHPMLKLHQ-UHFFFAOYSA-N 0.000 description 10
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 9
- 239000003208 petroleum Substances 0.000 description 9
- 239000007864 aqueous solution Substances 0.000 description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- 238000003786 synthesis reaction Methods 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 7
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 7
- 238000006243 chemical reaction Methods 0.000 description 7
- 239000000706 filtrate Substances 0.000 description 7
- 238000010992 reflux Methods 0.000 description 7
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 7
- NLPHXWGWBKZSJC-UHFFFAOYSA-N 4-acetylbenzonitrile Chemical compound CC(=O)C1=CC=C(C#N)C=C1 NLPHXWGWBKZSJC-UHFFFAOYSA-N 0.000 description 6
- 239000000556 agonist Substances 0.000 description 6
- 150000001298 alcohols Chemical class 0.000 description 6
- 238000004296 chiral HPLC Methods 0.000 description 6
- 239000003480 eluent Substances 0.000 description 6
- 239000000945 filler Substances 0.000 description 6
- 239000012299 nitrogen atmosphere Substances 0.000 description 6
- 150000004866 oxadiazoles Chemical class 0.000 description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 5
- DHMQDGOQFOQNFH-UHFFFAOYSA-M Aminoacetate Chemical compound NCC([O-])=O DHMQDGOQFOQNFH-UHFFFAOYSA-M 0.000 description 5
- QSRRZKPKHJHIRB-UHFFFAOYSA-N methyl 4-[(2,5-dichloro-4-methylthiophen-3-yl)sulfonylamino]-2-hydroxybenzoate Chemical compound C1=C(O)C(C(=O)OC)=CC=C1NS(=O)(=O)C1=C(Cl)SC(Cl)=C1C QSRRZKPKHJHIRB-UHFFFAOYSA-N 0.000 description 5
- 239000012279 sodium borohydride Substances 0.000 description 5
- 229910000033 sodium borohydride Inorganic materials 0.000 description 5
- BNWCETAHAJSBFG-UHFFFAOYSA-N tert-butyl 2-bromoacetate Chemical compound CC(C)(C)OC(=O)CBr BNWCETAHAJSBFG-UHFFFAOYSA-N 0.000 description 5
- WMOVHXAZOJBABW-UHFFFAOYSA-N tert-butyl acetate Chemical compound CC(=O)OC(C)(C)C WMOVHXAZOJBABW-UHFFFAOYSA-N 0.000 description 5
- VXUYXOFXAQZZMF-UHFFFAOYSA-N titanium(IV) isopropoxide Chemical compound CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C VXUYXOFXAQZZMF-UHFFFAOYSA-N 0.000 description 5
- HCGNPQRUNHMUDF-UHFFFAOYSA-N 3-fluoro-4-(methylaminomethyl)benzonitrile Chemical compound CNCC1=CC=C(C#N)C=C1F HCGNPQRUNHMUDF-UHFFFAOYSA-N 0.000 description 4
- OOJCPHNFLMBMNG-UHFFFAOYSA-N 4-[5-[4-(2-methylphenyl)-3-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-3-yl]benzaldehyde Chemical compound CC1=CC=CC=C1C1=CC=C(C=2ON=C(N=2)C=2C=CC(C=O)=CC=2)C=C1C(F)(F)F OOJCPHNFLMBMNG-UHFFFAOYSA-N 0.000 description 4
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 4
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 150000001412 amines Chemical class 0.000 description 4
- 150000001413 amino acids Chemical class 0.000 description 4
- 239000000908 ammonium hydroxide Substances 0.000 description 4
- 238000004440 column chromatography Methods 0.000 description 4
- 229940126214 compound 3 Drugs 0.000 description 4
- 125000000753 cycloalkyl group Chemical group 0.000 description 4
- 239000006260 foam Substances 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- CCLBEXAGIJGEMC-DTIOYNMSSA-N methyl (2s)-2-[1-(3-cyanophenyl)ethyl-methylamino]propanoate Chemical compound COC(=O)[C@H](C)N(C)C(C)C1=CC=CC(C#N)=C1 CCLBEXAGIJGEMC-DTIOYNMSSA-N 0.000 description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 description 4
- IVIQFUCVLFGGLB-UHFFFAOYSA-N tert-butyl 2-[1-(4-cyanophenyl)ethyl-methylamino]acetate Chemical compound CC(C)(C)OC(=O)CN(C)C(C)C1=CC=C(C#N)C=C1 IVIQFUCVLFGGLB-UHFFFAOYSA-N 0.000 description 4
- QWCKQJZIFLGMSD-UHFFFAOYSA-N 2-Aminobutanoic acid Natural products CCC(N)C(O)=O QWCKQJZIFLGMSD-UHFFFAOYSA-N 0.000 description 3
- FZFYFVXVHIGBJC-UHFFFAOYSA-N 3-[1-(methylamino)ethyl]benzonitrile Chemical compound CNC(C)C1=CC=CC(C#N)=C1 FZFYFVXVHIGBJC-UHFFFAOYSA-N 0.000 description 3
- ZESZAIOGACKOMB-UHFFFAOYSA-N 4-(bromomethyl)-3-fluorobenzonitrile Chemical compound FC1=CC(C#N)=CC=C1CBr ZESZAIOGACKOMB-UHFFFAOYSA-N 0.000 description 3
- BVGWYOPERDHROG-UHFFFAOYSA-N 4-[2-(difluoromethyl)phenyl]-3-methylbenzoic acid Chemical compound CC1=CC(C(O)=O)=CC=C1C1=CC=CC=C1C(F)F BVGWYOPERDHROG-UHFFFAOYSA-N 0.000 description 3
- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 description 3
- ZHGDGFWZFRPTRR-UHFFFAOYSA-N CC(C1=CC(=CC=C1)C(=NO)N)N(C)C(C)(C)C(=O)O Chemical compound CC(C1=CC(=CC=C1)C(=NO)N)N(C)C(C)(C)C(=O)O ZHGDGFWZFRPTRR-UHFFFAOYSA-N 0.000 description 3
- QNAYBMKLOCPYGJ-UHFFFAOYSA-N D-alpha-Ala Natural products CC([NH3+])C([O-])=O QNAYBMKLOCPYGJ-UHFFFAOYSA-N 0.000 description 3
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Chemical compound CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 description 3
- WZDFJBMTKHCLGB-UHFFFAOYSA-N [3-[5-[4-(2-methylphenyl)-3-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-3-yl]phenyl]methanol Chemical compound CC1=CC=CC=C1C1=CC=C(C=2ON=C(N=2)C=2C=C(CO)C=CC=2)C=C1C(F)(F)F WZDFJBMTKHCLGB-UHFFFAOYSA-N 0.000 description 3
- BQHFECKBXAKLLH-UHFFFAOYSA-N [4-[5-[3-(methoxymethyl)-4-(2-methylphenyl)phenyl]-1,2,4-oxadiazol-3-yl]phenyl]methanol Chemical compound COCC1=CC(C=2ON=C(N=2)C=2C=CC(CO)=CC=2)=CC=C1C1=CC=CC=C1C BQHFECKBXAKLLH-UHFFFAOYSA-N 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- ACEONLNNWKIPTM-UHFFFAOYSA-N methyl 2-bromopropanoate Chemical compound COC(=O)C(C)Br ACEONLNNWKIPTM-UHFFFAOYSA-N 0.000 description 3
- UUIQMZJEGPQKFD-UHFFFAOYSA-N n-butyric acid methyl ester Natural products CCCC(=O)OC UUIQMZJEGPQKFD-UHFFFAOYSA-N 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 239000000377 silicon dioxide Substances 0.000 description 3
- LSVYCJILORYVCD-UHFFFAOYSA-N tert-butyl 2-amino-2-methylpropanoate Chemical compound CC(C)(C)OC(=O)C(C)(C)N LSVYCJILORYVCD-UHFFFAOYSA-N 0.000 description 3
- RJBVJBGFJIHJSZ-UHFFFAOYSA-N tert-butyl 2-amino-3-methylbutanoate Chemical compound CC(C)C(N)C(=O)OC(C)(C)C RJBVJBGFJIHJSZ-UHFFFAOYSA-N 0.000 description 3
- TWBUVVYSQBFVGZ-UHFFFAOYSA-N tert-butyl butanoate Chemical compound CCCC(=O)OC(C)(C)C TWBUVVYSQBFVGZ-UHFFFAOYSA-N 0.000 description 3
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 3
- IUSARDYWEPUTPN-OZBXUNDUSA-N (2r)-n-[(2s,3r)-4-[[(4s)-6-(2,2-dimethylpropyl)spiro[3,4-dihydropyrano[2,3-b]pyridine-2,1'-cyclobutane]-4-yl]amino]-3-hydroxy-1-[3-(1,3-thiazol-2-yl)phenyl]butan-2-yl]-2-methoxypropanamide Chemical compound C([C@H](NC(=O)[C@@H](C)OC)[C@H](O)CN[C@@H]1C2=CC(CC(C)(C)C)=CN=C2OC2(CCC2)C1)C(C=1)=CC=CC=1C1=NC=CS1 IUSARDYWEPUTPN-OZBXUNDUSA-N 0.000 description 2
- SRUHWBRLAMMJSO-SFHVURJKSA-N (2s)-2-[[2-fluoro-4-[5-[3-(methoxymethyl)-4-(2-methylphenyl)phenyl]-1,2,4-oxadiazol-3-yl]phenyl]methyl-methylamino]propanoic acid Chemical compound COCC1=CC(C=2ON=C(N=2)C=2C=C(F)C(CN(C)[C@@H](C)C(O)=O)=CC=2)=CC=C1C1=CC=CC=C1C SRUHWBRLAMMJSO-SFHVURJKSA-N 0.000 description 2
- BITWDJOPJWSEHI-QHCPKHFHSA-N (2s)-2-[[4-[5-[4-(2-methylphenyl)-3-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-3-yl]phenyl]methylamino]butanoic acid Chemical compound C1=CC(CN[C@@H](CC)C(O)=O)=CC=C1C1=NOC(C=2C=C(C(C=3C(=CC=CC=3)C)=CC=2)C(F)(F)F)=N1 BITWDJOPJWSEHI-QHCPKHFHSA-N 0.000 description 2
- WZZBNLYBHUDSHF-DHLKQENFSA-N 1-[(3s,4s)-4-[8-(2-chloro-4-pyrimidin-2-yloxyphenyl)-7-fluoro-2-methylimidazo[4,5-c]quinolin-1-yl]-3-fluoropiperidin-1-yl]-2-hydroxyethanone Chemical compound CC1=NC2=CN=C3C=C(F)C(C=4C(=CC(OC=5N=CC=CN=5)=CC=4)Cl)=CC3=C2N1[C@H]1CCN(C(=O)CO)C[C@@H]1F WZZBNLYBHUDSHF-DHLKQENFSA-N 0.000 description 2
- YHRHVIQHPYUKDO-UHFFFAOYSA-N 1-[3-[5-[4-(2-methylphenyl)-3-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-3-yl]phenyl]ethanol Chemical compound CC(O)C1=CC=CC(C=2N=C(ON=2)C=2C=C(C(C=3C(=CC=CC=3)C)=CC=2)C(F)(F)F)=C1 YHRHVIQHPYUKDO-UHFFFAOYSA-N 0.000 description 2
- IMQYMMQGSJEFSC-UHFFFAOYSA-N 1-[[4-[5-[3-(methoxymethyl)-4-(2-methylphenyl)phenyl]-1,2,4-oxadiazol-3-yl]phenyl]methyl-methylamino]cyclopentane-1-carboxylic acid Chemical compound COCC1=CC(C=2ON=C(N=2)C=2C=CC(CN(C)C3(CCCC3)C(O)=O)=CC=2)=CC=C1C1=CC=CC=C1C IMQYMMQGSJEFSC-UHFFFAOYSA-N 0.000 description 2
- XCZBTWQEBPAMSS-UHFFFAOYSA-N 2-[[2-fluoro-4-[5-[3-methyl-4-[2-(trifluoromethyl)phenyl]phenyl]-1,2,4-oxadiazol-3-yl]phenyl]methylamino]-2-methylpropanoic acid Chemical compound CC1=CC(C=2ON=C(N=2)C=2C=C(F)C(CNC(C)(C)C(O)=O)=CC=2)=CC=C1C1=CC=CC=C1C(F)(F)F XCZBTWQEBPAMSS-UHFFFAOYSA-N 0.000 description 2
- LLJQFDXIOXMESP-UHFFFAOYSA-N 2-[[3-fluoro-5-[5-[4-(2-methylphenyl)-3-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-3-yl]phenyl]methylamino]-2-methylpropanoic acid Chemical compound CC1=CC=CC=C1C1=CC=C(C=2ON=C(N=2)C=2C=C(CNC(C)(C)C(O)=O)C=C(F)C=2)C=C1C(F)(F)F LLJQFDXIOXMESP-UHFFFAOYSA-N 0.000 description 2
- VEJMNZSNQUQTBE-UHFFFAOYSA-N 3-(aminomethyl)-5-fluorobenzonitrile Chemical compound NCC1=CC(F)=CC(C#N)=C1 VEJMNZSNQUQTBE-UHFFFAOYSA-N 0.000 description 2
- SUIFNMFWHQFXIP-UHFFFAOYSA-N 3-(bromomethyl)-5-fluorobenzonitrile Chemical compound FC1=CC(CBr)=CC(C#N)=C1 SUIFNMFWHQFXIP-UHFFFAOYSA-N 0.000 description 2
- CGYNMXWYNFMIPM-UHFFFAOYSA-N 4-(2-hydroxyacetyl)benzonitrile Chemical compound OCC(=O)C1=CC=C(C#N)C=C1 CGYNMXWYNFMIPM-UHFFFAOYSA-N 0.000 description 2
- FDGMGJFQCFFTAZ-UHFFFAOYSA-N 4-(2-methoxyacetyl)benzonitrile Chemical compound COCC(=O)C1=CC=C(C#N)C=C1 FDGMGJFQCFFTAZ-UHFFFAOYSA-N 0.000 description 2
- AYOYWYXTWZMMGA-UHFFFAOYSA-N 4-(2-methylphenyl)-3-(trifluoromethyl)benzoic acid Chemical compound CC1=CC=CC=C1C1=CC=C(C(O)=O)C=C1C(F)(F)F AYOYWYXTWZMMGA-UHFFFAOYSA-N 0.000 description 2
- ZYDCWMILCKQXDE-UHFFFAOYSA-N 4-[1-(methylamino)ethyl]benzonitrile Chemical compound CNC(C)C1=CC=C(C#N)C=C1 ZYDCWMILCKQXDE-UHFFFAOYSA-N 0.000 description 2
- LOBILSDOITWLGG-UHFFFAOYSA-N 4-[5-[3-(methoxymethyl)-4-(2-methylphenyl)phenyl]-1,2,4-oxadiazol-3-yl]benzaldehyde Chemical compound COCC1=CC(C=2ON=C(N=2)C=2C=CC(C=O)=CC=2)=CC=C1C1=CC=CC=C1C LOBILSDOITWLGG-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- WTSPOFYRDFMEOO-UHFFFAOYSA-N CC(C1=CC=C(C=C1)C(=NO)N)N(C)C(C)(C)C(=O)O Chemical compound CC(C1=CC=C(C=C1)C(=NO)N)N(C)C(C)(C)C(=O)O WTSPOFYRDFMEOO-UHFFFAOYSA-N 0.000 description 2
- 229930195711 D-Serine Natural products 0.000 description 2
- 102000003688 G-Protein-Coupled Receptors Human genes 0.000 description 2
- 108090000045 G-Protein-Coupled Receptors Proteins 0.000 description 2
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 2
- QWCKQJZIFLGMSD-VKHMYHEASA-N L-alpha-aminobutyric acid Chemical compound CC[C@H](N)C(O)=O QWCKQJZIFLGMSD-VKHMYHEASA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 2
- 102100029802 Sphingosine 1-phosphate receptor 5 Human genes 0.000 description 2
- 102000011011 Sphingosine 1-phosphate receptors Human genes 0.000 description 2
- 108050001083 Sphingosine 1-phosphate receptors Proteins 0.000 description 2
- TZHVWYKAIWSQSL-UHFFFAOYSA-N [4-[5-[4-(2-methylphenyl)-3-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-3-yl]phenyl]methanol Chemical compound CC1=CC=CC=C1C1=CC=C(C=2ON=C(N=2)C=2C=CC(CO)=CC=2)C=C1C(F)(F)F TZHVWYKAIWSQSL-UHFFFAOYSA-N 0.000 description 2
- SMNRFWMNPDABKZ-WVALLCKVSA-N [[(2R,3S,4R,5S)-5-(2,6-dioxo-3H-pyridin-3-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [[[(2R,3S,4S,5R,6R)-4-fluoro-3,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-hydroxyphosphoryl]oxy-hydroxyphosphoryl] hydrogen phosphate Chemical compound OC[C@H]1O[C@H](OP(O)(=O)OP(O)(=O)OP(O)(=O)OP(O)(=O)OC[C@H]2O[C@H]([C@H](O)[C@@H]2O)C2C=CC(=O)NC2=O)[C@H](O)[C@@H](F)[C@@H]1O SMNRFWMNPDABKZ-WVALLCKVSA-N 0.000 description 2
- 150000001299 aldehydes Chemical class 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 2
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 2
- XJHCXCQVJFPJIK-UHFFFAOYSA-M caesium fluoride Chemical compound [F-].[Cs+] XJHCXCQVJFPJIK-UHFFFAOYSA-M 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 229940125807 compound 37 Drugs 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical group C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- KKGQTZUTZRNORY-UHFFFAOYSA-N fingolimod Chemical compound CCCCCCCCC1=CC=C(CCC(N)(CO)CO)C=C1 KKGQTZUTZRNORY-UHFFFAOYSA-N 0.000 description 2
- 229960000556 fingolimod Drugs 0.000 description 2
- 150000004677 hydrates Chemical class 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 230000001506 immunosuppresive effect Effects 0.000 description 2
- IUYHWZFSGMZEOG-UHFFFAOYSA-M magnesium;propane;chloride Chemical compound [Mg+2].[Cl-].C[CH-]C IUYHWZFSGMZEOG-UHFFFAOYSA-M 0.000 description 2
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 229910000000 metal hydroxide Inorganic materials 0.000 description 2
- 150000004692 metal hydroxides Chemical class 0.000 description 2
- VSJNWVCUBPAENV-DTIOYNMSSA-N methyl (2s)-2-[1-(4-cyanophenyl)ethyl-methylamino]propanoate Chemical compound COC(=O)[C@H](C)N(C)C(C)C1=CC=C(C#N)C=C1 VSJNWVCUBPAENV-DTIOYNMSSA-N 0.000 description 2
- PYFSLJVSCGXYAJ-UHFFFAOYSA-N methyl 2-hydroxy-4-[[3-(2-hydroxyphenyl)phenyl]sulfonylamino]benzoate Chemical compound C1=C(O)C(C(=O)OC)=CC=C1NS(=O)(=O)C1=CC=CC(C=2C(=CC=CC=2)O)=C1 PYFSLJVSCGXYAJ-UHFFFAOYSA-N 0.000 description 2
- FPYOTPGYISYHLH-UHFFFAOYSA-N methyl 4-(2-methylphenyl)-3-(trifluoromethyl)benzoate Chemical compound FC(F)(F)C1=CC(C(=O)OC)=CC=C1C1=CC=CC=C1C FPYOTPGYISYHLH-UHFFFAOYSA-N 0.000 description 2
- DTVRLJMSCKUEEN-UHFFFAOYSA-N methyl 4-bromo-3-(trifluoromethyl)benzoate Chemical compound COC(=O)C1=CC=C(Br)C(C(F)(F)F)=C1 DTVRLJMSCKUEEN-UHFFFAOYSA-N 0.000 description 2
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 238000002953 preparative HPLC Methods 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 150000003254 radicals Chemical class 0.000 description 2
- 102000005962 receptors Human genes 0.000 description 2
- 108020003175 receptors Proteins 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 239000012047 saturated solution Substances 0.000 description 2
- KZNICNPSHKQLFF-UHFFFAOYSA-N succinimide Chemical compound O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 2
- XPROUDBFRJFPDJ-UHFFFAOYSA-N tert-butyl 2-(benzylamino)-2-methylpropanoate Chemical compound CC(C)(C)OC(=O)C(C)(C)NCC1=CC=CC=C1 XPROUDBFRJFPDJ-UHFFFAOYSA-N 0.000 description 2
- JZOBAXQZAHIFSC-UHFFFAOYSA-N tert-butyl 2-[(3-cyano-5-fluorophenyl)methylamino]-4-methylpentanoate Chemical compound CC(C)(C)OC(=O)C(CC(C)C)NCC1=CC(F)=CC(C#N)=C1 JZOBAXQZAHIFSC-UHFFFAOYSA-N 0.000 description 2
- YQIKHHMKHKRGAI-UHFFFAOYSA-N tert-butyl 2-[(4-cyano-2-fluorophenyl)methylamino]-2-methylpropanoate Chemical compound CC(C)(C)OC(=O)C(C)(C)NCC1=CC=C(C#N)C=C1F YQIKHHMKHKRGAI-UHFFFAOYSA-N 0.000 description 2
- KTQLOPNHSRZIHW-UHFFFAOYSA-N tert-butyl 2-[(4-cyano-2-fluorophenyl)methylamino]-3-methylbutanoate Chemical compound CC(C)(C)OC(=O)C(C(C)C)NCC1=CC=C(C#N)C=C1F KTQLOPNHSRZIHW-UHFFFAOYSA-N 0.000 description 2
- WNUQAKWJHFOTAN-UHFFFAOYSA-N tert-butyl 2-[1-(3-cyanophenyl)ethylamino]acetate Chemical compound CC(C)(C)OC(=O)CNC(C)C1=CC=CC(C#N)=C1 WNUQAKWJHFOTAN-UHFFFAOYSA-N 0.000 description 2
- PRYVBGSLLFOVKD-UHFFFAOYSA-N tert-butyl 2-[1-(4-cyanophenyl)ethylamino]acetate Chemical compound CC(C)(C)OC(=O)CNC(C)C1=CC=C(C#N)C=C1 PRYVBGSLLFOVKD-UHFFFAOYSA-N 0.000 description 2
- IGVNJALYNQVQIT-UHFFFAOYSA-N tert-butyl 2-bromo-2-methylpropanoate Chemical compound CC(C)(C)OC(=O)C(C)(C)Br IGVNJALYNQVQIT-UHFFFAOYSA-N 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- 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 2
- ASGMFNBUXDJWJJ-JLCFBVMHSA-N (1R,3R)-3-[[3-bromo-1-[4-(5-methyl-1,3,4-thiadiazol-2-yl)phenyl]pyrazolo[3,4-d]pyrimidin-6-yl]amino]-N,1-dimethylcyclopentane-1-carboxamide Chemical compound BrC1=NN(C2=NC(=NC=C21)N[C@H]1C[C@@](CC1)(C(=O)NC)C)C1=CC=C(C=C1)C=1SC(=NN=1)C ASGMFNBUXDJWJJ-JLCFBVMHSA-N 0.000 description 1
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 1
- NSJVYHOPHZMZPN-UHFFFAOYSA-N (2-methylphenyl)boronic acid Chemical compound CC1=CC=CC=C1B(O)O NSJVYHOPHZMZPN-UHFFFAOYSA-N 0.000 description 1
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 1
- FHNOCOMKDZBPED-IAGOWNOFSA-N (2r)-2-[[(1r)-1-[4-[5-[4-[2-(difluoromethyl)phenyl]-3-methylphenyl]-1,2,4-oxadiazol-3-yl]phenyl]ethyl]amino]propanoic acid Chemical compound C1=CC([C@@H](C)N[C@H](C)C(O)=O)=CC=C1C1=NOC(C=2C=C(C)C(=CC=2)C=2C(=CC=CC=2)C(F)F)=N1 FHNOCOMKDZBPED-IAGOWNOFSA-N 0.000 description 1
- AQHRZSDIYFOKKH-RBUKOAKNSA-N (2r)-2-[[(1s)-1-[4-[5-[3-(methoxymethyl)-4-(2-methylphenyl)phenyl]-1,2,4-oxadiazol-3-yl]phenyl]ethyl]amino]propanoic acid Chemical compound COCC1=CC(C=2ON=C(N=2)C=2C=CC(=CC=2)[C@H](C)N[C@H](C)C(O)=O)=CC=C1C1=CC=CC=C1C AQHRZSDIYFOKKH-RBUKOAKNSA-N 0.000 description 1
- LXUUXXCBMHIPDA-KRWDZBQOSA-N (2s)-2-[2-[3-[5-[4-(2-methylphenyl)-3-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-3-yl]phenyl]ethylamino]propanoic acid Chemical compound OC(=O)[C@H](C)NCCC1=CC=CC(C=2N=C(ON=2)C=2C=C(C(C=3C(=CC=CC=3)C)=CC=2)C(F)(F)F)=C1 LXUUXXCBMHIPDA-KRWDZBQOSA-N 0.000 description 1
- DYZJTXQWJDJFJX-QHCPKHFHSA-N (2s)-2-[[2-fluoro-4-[5-[4-(2-methylphenyl)-3-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-3-yl]phenyl]methyl-methylamino]-3-hydroxypropanoic acid Chemical compound C1=C(F)C(CN(C)[C@@H](CO)C(O)=O)=CC=C1C1=NOC(C=2C=C(C(C=3C(=CC=CC=3)C)=CC=2)C(F)(F)F)=N1 DYZJTXQWJDJFJX-QHCPKHFHSA-N 0.000 description 1
- DFFTUUPJPLRTOW-INIZCTEOSA-N (2s)-2-[[2-fluoro-4-[5-[4-(2-methylphenyl)-3-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-3-yl]phenyl]methyl-methylamino]propanoic acid Chemical compound C1=C(F)C(CN(C)[C@@H](C)C(O)=O)=CC=C1C1=NOC(C=2C=C(C(C=3C(=CC=CC=3)C)=CC=2)C(F)(F)F)=N1 DFFTUUPJPLRTOW-INIZCTEOSA-N 0.000 description 1
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 description 1
- HUWSZNZAROKDRZ-RRLWZMAJSA-N (3r,4r)-3-azaniumyl-5-[[(2s,3r)-1-[(2s)-2,3-dicarboxypyrrolidin-1-yl]-3-methyl-1-oxopentan-2-yl]amino]-5-oxo-4-sulfanylpentane-1-sulfonate Chemical compound OS(=O)(=O)CC[C@@H](N)[C@@H](S)C(=O)N[C@@H]([C@H](C)CC)C(=O)N1CCC(C(O)=O)[C@H]1C(O)=O HUWSZNZAROKDRZ-RRLWZMAJSA-N 0.000 description 1
- LZHZRUMDTRUWCF-UHFFFAOYSA-N 1-[4-[5-[4-(2-methylphenyl)-3-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-3-yl]phenyl]ethanol Chemical compound C1=CC(C(O)C)=CC=C1C1=NOC(C=2C=C(C(C=3C(=CC=CC=3)C)=CC=2)C(F)(F)F)=N1 LZHZRUMDTRUWCF-UHFFFAOYSA-N 0.000 description 1
- NILQLFBWTXNUOE-UHFFFAOYSA-N 1-aminocyclopentanecarboxylic acid Chemical compound OC(=O)C1(N)CCCC1 NILQLFBWTXNUOE-UHFFFAOYSA-N 0.000 description 1
- LLAPDLPYIYKTGQ-UHFFFAOYSA-N 1-aminoethyl Chemical group C[CH]N LLAPDLPYIYKTGQ-UHFFFAOYSA-N 0.000 description 1
- RMYPQIOCZSWSDG-UHFFFAOYSA-N 1-bromo-2-(difluoromethyl)benzene Chemical compound FC(F)C1=CC=CC=C1Br RMYPQIOCZSWSDG-UHFFFAOYSA-N 0.000 description 1
- ILELRQCKXAXPJH-UHFFFAOYSA-N 1-methyl-2-[2-(trifluoromethyl)phenyl]benzene Chemical group CC1=CC=CC=C1C1=CC=CC=C1C(F)(F)F ILELRQCKXAXPJH-UHFFFAOYSA-N 0.000 description 1
- OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 1
- SROUFENEQQOQIW-UHFFFAOYSA-N 2-(bromomethyl)-5-fluorobenzonitrile Chemical compound FC1=CC=C(CBr)C(C#N)=C1 SROUFENEQQOQIW-UHFFFAOYSA-N 0.000 description 1
- FUOOLUPWFVMBKG-UHFFFAOYSA-N 2-Aminoisobutyric acid Chemical compound CC(C)(N)C(O)=O FUOOLUPWFVMBKG-UHFFFAOYSA-N 0.000 description 1
- JAZOVBUNFUGASA-LJQANCHMSA-N 2-[[(1r)-1-[4-[5-[3-(methoxymethyl)-4-(2-methylphenyl)phenyl]-1,2,4-oxadiazol-3-yl]phenyl]ethyl]-methylamino]acetic acid Chemical compound COCC1=CC(C=2ON=C(N=2)C=2C=CC(=CC=2)[C@@H](C)N(C)CC(O)=O)=CC=C1C1=CC=CC=C1C JAZOVBUNFUGASA-LJQANCHMSA-N 0.000 description 1
- ADEFKSGWKUVQBO-UHFFFAOYSA-N 2-[[2-fluoro-4-[5-[3-(methoxymethyl)-4-(2-methylphenyl)phenyl]-1,2,4-oxadiazol-3-yl]phenyl]methyl-methylamino]-2-methylpropanoic acid Chemical compound COCC1=CC(C=2ON=C(N=2)C=2C=C(F)C(CN(C)C(C)(C)C(O)=O)=CC=2)=CC=C1C1=CC=CC=C1C ADEFKSGWKUVQBO-UHFFFAOYSA-N 0.000 description 1
- RHRYVABABYPEGG-UHFFFAOYSA-N 2-[[2-fluoro-4-[5-[4-(2-methylphenyl)-3-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-3-yl]phenyl]methylamino]-2-methylpropanoic acid Chemical compound CC1=CC=CC=C1C1=CC=C(C=2ON=C(N=2)C=2C=C(F)C(CNC(C)(C)C(O)=O)=CC=2)C=C1C(F)(F)F RHRYVABABYPEGG-UHFFFAOYSA-N 0.000 description 1
- JCSQZHKFMKHKSM-UHFFFAOYSA-N 2-[[3-fluoro-5-(N'-hydroxycarbamimidoyl)phenyl]methylamino]-4-methylpentanoic acid Chemical compound CC(C)CC(NCc1cc(F)cc(c1)C(N)=NO)C(O)=O JCSQZHKFMKHKSM-UHFFFAOYSA-N 0.000 description 1
- YSUIQYOGTINQIN-UZFYAQMZSA-N 2-amino-9-[(1S,6R,8R,9S,10R,15R,17R,18R)-8-(6-aminopurin-9-yl)-9,18-difluoro-3,12-dihydroxy-3,12-bis(sulfanylidene)-2,4,7,11,13,16-hexaoxa-3lambda5,12lambda5-diphosphatricyclo[13.2.1.06,10]octadecan-17-yl]-1H-purin-6-one Chemical compound NC1=NC2=C(N=CN2[C@@H]2O[C@@H]3COP(S)(=O)O[C@@H]4[C@@H](COP(S)(=O)O[C@@H]2[C@@H]3F)O[C@H]([C@H]4F)N2C=NC3=C2N=CN=C3N)C(=O)N1 YSUIQYOGTINQIN-UZFYAQMZSA-N 0.000 description 1
- TVTJUIAKQFIXCE-HUKYDQBMSA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynyl-1H-purine-6,8-dione Chemical compound NC=1NC(C=2N(C(N(C=2N=1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C)=O TVTJUIAKQFIXCE-HUKYDQBMSA-N 0.000 description 1
- IVLXQGJVBGMLRR-UHFFFAOYSA-N 2-aminoacetic acid;hydron;chloride Chemical class Cl.NCC(O)=O IVLXQGJVBGMLRR-UHFFFAOYSA-N 0.000 description 1
- ZABVLYIZEBHGTJ-UHFFFAOYSA-N 2-aminobutanoic acid Chemical compound [CH2]CC(N)C(O)=O ZABVLYIZEBHGTJ-UHFFFAOYSA-N 0.000 description 1
- XXSPGBOGLXKMDU-UHFFFAOYSA-M 2-bromo-2-methylpropanoate Chemical compound CC(C)(Br)C([O-])=O XXSPGBOGLXKMDU-UHFFFAOYSA-M 0.000 description 1
- YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical compound CC(C)COC(Cl)=O YOETUEMZNOLGDB-UHFFFAOYSA-N 0.000 description 1
- PCOFIIVWHXIDGT-UHFFFAOYSA-N 3-(hydroxymethyl)benzonitrile Chemical compound OCC1=CC=CC(C#N)=C1 PCOFIIVWHXIDGT-UHFFFAOYSA-N 0.000 description 1
- YMNGMGLZWKUGGJ-UHFFFAOYSA-N 3-(methoxymethyl)-4-(2-methylphenyl)benzoic acid Chemical compound COCC1=CC(C(O)=O)=CC=C1C1=CC=CC=C1C YMNGMGLZWKUGGJ-UHFFFAOYSA-N 0.000 description 1
- VZLWLSLMIKXXHL-UHFFFAOYSA-N 3-[5-[4-(2-methylphenyl)-3-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-3-yl]benzaldehyde Chemical compound CC1=CC=CC=C1C1=CC=C(C=2ON=C(N=2)C=2C=C(C=O)C=CC=2)C=C1C(F)(F)F VZLWLSLMIKXXHL-UHFFFAOYSA-N 0.000 description 1
- SBCFGFDAZCTSRH-UHFFFAOYSA-N 3-acetylbenzonitrile Chemical compound CC(=O)C1=CC=CC(C#N)=C1 SBCFGFDAZCTSRH-UHFFFAOYSA-N 0.000 description 1
- GKUQCZSZQBEHCP-UHFFFAOYSA-N 3-fluoro-5-methylbenzonitrile Chemical compound CC1=CC(F)=CC(C#N)=C1 GKUQCZSZQBEHCP-UHFFFAOYSA-N 0.000 description 1
- DSGKWQYXNJZEBE-UHFFFAOYSA-N 3-methoxy-2-[[3-[5-[4-(2-methylphenyl)-3-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-3-yl]phenyl]methylamino]propanoic acid Chemical compound COCC(C(O)=O)NCC1=CC=CC(C=2N=C(ON=2)C=2C=C(C(C=3C(=CC=CC=3)C)=CC=2)C(F)(F)F)=C1 DSGKWQYXNJZEBE-UHFFFAOYSA-N 0.000 description 1
- ORMMKYADNPXZNO-UHFFFAOYSA-N 3-methyl-4-[2-(trifluoromethyl)phenyl]benzoic acid Chemical compound CC1=CC(C(O)=O)=CC=C1C1=CC=CC=C1C(F)(F)F ORMMKYADNPXZNO-UHFFFAOYSA-N 0.000 description 1
- CANLULJYEHSQFU-UHFFFAOYSA-N 4-(1-aminoethyl)benzonitrile Chemical compound CC(N)C1=CC=C(C#N)C=C1 CANLULJYEHSQFU-UHFFFAOYSA-N 0.000 description 1
- BZBALHIGUYHQAN-UHFFFAOYSA-N 4-[2-(1,1-difluoroethyl)phenyl]-3-methylbenzoic acid Chemical compound CC1=C(C=CC(=C1)C(=O)O)C2=CC=CC=C2C(C)(F)F BZBALHIGUYHQAN-UHFFFAOYSA-N 0.000 description 1
- GPBPFDPENZHCPR-UHFFFAOYSA-N 4-bromo-3-(trifluoromethyl)benzoic acid Chemical compound OC(=O)C1=CC=C(Br)C(C(F)(F)F)=C1 GPBPFDPENZHCPR-UHFFFAOYSA-N 0.000 description 1
- XAASLEJRGFPHEV-UHFFFAOYSA-N 4-cyanobenzyl alcohol Chemical compound OCC1=CC=C(C#N)C=C1 XAASLEJRGFPHEV-UHFFFAOYSA-N 0.000 description 1
- XOKDXPVXJWTSRM-UHFFFAOYSA-N 4-iodobenzonitrile Chemical compound IC1=CC=C(C#N)C=C1 XOKDXPVXJWTSRM-UHFFFAOYSA-N 0.000 description 1
- OZAIFHULBGXAKX-VAWYXSNFSA-N AIBN Substances N#CC(C)(C)\N=N\C(C)(C)C#N OZAIFHULBGXAKX-VAWYXSNFSA-N 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 208000008439 Biliary Liver Cirrhosis Diseases 0.000 description 1
- 206010004659 Biliary cirrhosis Diseases 0.000 description 1
- OHZYBVJLACKLBS-UHFFFAOYSA-N C1=CC=CC=C1.FC(C(=O)OIOC(C(F)(F)F)=O)(F)F Chemical compound C1=CC=CC=C1.FC(C(=O)OIOC(C(F)(F)F)=O)(F)F OHZYBVJLACKLBS-UHFFFAOYSA-N 0.000 description 1
- BQXUPNKLZNSUMC-YUQWMIPFSA-N CCN(CCCCCOCC(=O)N[C@H](C(=O)N1C[C@H](O)C[C@H]1C(=O)N[C@@H](C)c1ccc(cc1)-c1scnc1C)C(C)(C)C)CCOc1ccc(cc1)C(=O)c1c(sc2cc(O)ccc12)-c1ccc(O)cc1 Chemical compound CCN(CCCCCOCC(=O)N[C@H](C(=O)N1C[C@H](O)C[C@H]1C(=O)N[C@@H](C)c1ccc(cc1)-c1scnc1C)C(C)(C)C)CCOc1ccc(cc1)C(=O)c1c(sc2cc(O)ccc12)-c1ccc(O)cc1 BQXUPNKLZNSUMC-YUQWMIPFSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- ABGKEOBGBPJMQD-UHFFFAOYSA-N Cl.FC1=C(CNC(C)(C(=O)O)C)C=CC(=C1)C1=NOC(=N1)C1=CC(=C(C=C1)C1=C(C=CC=C1)C)C(F)(F)F Chemical compound Cl.FC1=C(CNC(C)(C(=O)O)C)C=CC(=C1)C1=NOC(=N1)C1=CC(=C(C=C1)C1=C(C=CC=C1)C)C(F)(F)F ABGKEOBGBPJMQD-UHFFFAOYSA-N 0.000 description 1
- 206010009900 Colitis ulcerative Diseases 0.000 description 1
- 229940126639 Compound 33 Drugs 0.000 description 1
- 229940127007 Compound 39 Drugs 0.000 description 1
- 208000011231 Crohn disease Diseases 0.000 description 1
- MTCFGRXMJLQNBG-UWTATZPHSA-N D-Serine Chemical compound OC[C@@H](N)C(O)=O MTCFGRXMJLQNBG-UWTATZPHSA-N 0.000 description 1
- QNAYBMKLOCPYGJ-UWTATZPHSA-N D-alanine Chemical compound C[C@@H](N)C(O)=O QNAYBMKLOCPYGJ-UWTATZPHSA-N 0.000 description 1
- ROHFNLRQFUQHCH-RXMQYKEDSA-N D-leucine Chemical compound CC(C)C[C@@H](N)C(O)=O ROHFNLRQFUQHCH-RXMQYKEDSA-N 0.000 description 1
- 229930182819 D-leucine Natural products 0.000 description 1
- 125000000734 D-serino group Chemical group [H]N([H])[C@@]([H])(C(=O)[*])C(O[H])([H])[H] 0.000 description 1
- 206010012438 Dermatitis atopic Diseases 0.000 description 1
- 102000036530 EDG receptors Human genes 0.000 description 1
- 108091007263 EDG receptors Proteins 0.000 description 1
- 206010072579 Granulomatosis with polyangiitis Diseases 0.000 description 1
- 208000003084 Graves Ophthalmopathy Diseases 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- PIWKPBJCKXDKJR-UHFFFAOYSA-N Isoflurane Chemical compound FC(F)OC(Cl)C(F)(F)F PIWKPBJCKXDKJR-UHFFFAOYSA-N 0.000 description 1
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 description 1
- 206010025323 Lymphomas Diseases 0.000 description 1
- 206010025327 Lymphopenia Diseases 0.000 description 1
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 1
- 201000002481 Myositis Diseases 0.000 description 1
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 101100030361 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) pph-3 gene Proteins 0.000 description 1
- KNTFCRCCPLEUQZ-VKHMYHEASA-N O-methylserine Chemical compound COC[C@H](N)C(O)=O KNTFCRCCPLEUQZ-VKHMYHEASA-N 0.000 description 1
- 229930040373 Paraformaldehyde Natural products 0.000 description 1
- 229910002666 PdCl2 Inorganic materials 0.000 description 1
- 206010034277 Pemphigoid Diseases 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- 101150043606 S1pr5 gene Proteins 0.000 description 1
- PNUZDKCDAWUEGK-CYZMBNFOSA-N Sitafloxacin Chemical compound C([C@H]1N)N(C=2C(=C3C(C(C(C(O)=O)=CN3[C@H]3[C@H](C3)F)=O)=CC=2F)Cl)CC11CC1 PNUZDKCDAWUEGK-CYZMBNFOSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 102100025749 Sphingosine 1-phosphate receptor 2 Human genes 0.000 description 1
- 101710155462 Sphingosine 1-phosphate receptor 2 Proteins 0.000 description 1
- 102100029803 Sphingosine 1-phosphate receptor 4 Human genes 0.000 description 1
- 101710155458 Sphingosine 1-phosphate receptor 4 Proteins 0.000 description 1
- 101710155451 Sphingosine 1-phosphate receptor 5 Proteins 0.000 description 1
- 238000006859 Swern oxidation reaction Methods 0.000 description 1
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 1
- 201000006704 Ulcerative Colitis Diseases 0.000 description 1
- 206010046851 Uveitis Diseases 0.000 description 1
- AVPMRIWGOGRNBF-UHFFFAOYSA-N [bromo(fluoro)methyl]benzene Chemical compound FC(Br)C1=CC=CC=C1 AVPMRIWGOGRNBF-UHFFFAOYSA-N 0.000 description 1
- 125000003158 alcohol group Chemical group 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 150000001499 aryl bromides Chemical class 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 201000008937 atopic dermatitis Diseases 0.000 description 1
- JXLHNMVSKXFWAO-UHFFFAOYSA-N azane;7-fluoro-2,1,3-benzoxadiazole-4-sulfonic acid Chemical compound N.OS(=O)(=O)C1=CC=C(F)C2=NON=C12 JXLHNMVSKXFWAO-UHFFFAOYSA-N 0.000 description 1
- 150000008359 benzonitriles Chemical class 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- 150000003938 benzyl alcohols Chemical class 0.000 description 1
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 230000008033 biological extinction Effects 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 125000000319 biphenyl-4-yl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 208000000594 bullous pemphigoid Diseases 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000003915 cell function Effects 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- SFZULDYEOVSIKM-UHFFFAOYSA-N chembl321317 Chemical compound C1=CC(C(=N)NO)=CC=C1C1=CC=C(C=2C=CC(=CC=2)C(=N)NO)O1 SFZULDYEOVSIKM-UHFFFAOYSA-N 0.000 description 1
- 238000001311 chemical methods and process Methods 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 230000000973 chemotherapeutic effect Effects 0.000 description 1
- 229940125773 compound 10 Drugs 0.000 description 1
- 229940125797 compound 12 Drugs 0.000 description 1
- 229940126543 compound 14 Drugs 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 229940125851 compound 27 Drugs 0.000 description 1
- 229940127573 compound 38 Drugs 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000012039 electrophile Substances 0.000 description 1
- NFWQATGYWOTOHB-BXUZGUMPSA-N ethyl (2r)-2-[[(1r)-1-(4-cyanophenyl)ethyl]amino]butanoate Chemical compound CCOC(=O)[C@@H](CC)N[C@H](C)C1=CC=C(C#N)C=C1 NFWQATGYWOTOHB-BXUZGUMPSA-N 0.000 description 1
- NFWQATGYWOTOHB-RISCZKNCSA-N ethyl (2s)-2-[[(1r)-1-(4-cyanophenyl)ethyl]amino]butanoate Chemical compound CCOC(=O)[C@H](CC)N[C@H](C)C1=CC=C(C#N)C=C1 NFWQATGYWOTOHB-RISCZKNCSA-N 0.000 description 1
- XIMFCGSNSKXPBO-UHFFFAOYSA-N ethyl 2-bromobutanoate Chemical compound CCOC(=O)C(Br)CC XIMFCGSNSKXPBO-UHFFFAOYSA-N 0.000 description 1
- 208000024711 extrinsic asthma Diseases 0.000 description 1
- 125000004175 fluorobenzyl group Chemical group 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 230000008570 general process Effects 0.000 description 1
- 229930182480 glucuronide Natural products 0.000 description 1
- 150000008134 glucuronides Chemical class 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 210000003958 hematopoietic stem cell Anatomy 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 206010021198 ichthyosis Diseases 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 229940125721 immunosuppressive agent Drugs 0.000 description 1
- 239000003018 immunosuppressive agent Substances 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 230000008611 intercellular interaction Effects 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 229960002725 isoflurane Drugs 0.000 description 1
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 210000000265 leukocyte Anatomy 0.000 description 1
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 description 1
- 210000004698 lymphocyte Anatomy 0.000 description 1
- 210000003563 lymphoid tissue Anatomy 0.000 description 1
- 231100001023 lymphopenia Toxicity 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- RDBWYSWPXDSHOE-UHFFFAOYSA-N methyl 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate Chemical compound CC1=CC(C(=O)OC)=CC=C1B1OC(C)(C)C(C)(C)O1 RDBWYSWPXDSHOE-UHFFFAOYSA-N 0.000 description 1
- VLFRBILAMCQAFC-UHFFFAOYSA-N methyl 4-[2-(difluoromethyl)phenyl]-3-methylbenzoate Chemical compound CC1=CC(C(=O)OC)=CC=C1C1=CC=CC=C1C(F)F VLFRBILAMCQAFC-UHFFFAOYSA-N 0.000 description 1
- DKSFMGRTWCDFRB-UHFFFAOYSA-N n'-hydroxy-3-(hydroxymethyl)benzenecarboximidamide Chemical compound ON=C(N)C1=CC=CC(CO)=C1 DKSFMGRTWCDFRB-UHFFFAOYSA-N 0.000 description 1
- XAVQRXUCPQYHBS-UHFFFAOYSA-N n'-hydroxy-4-(hydroxymethyl)benzenecarboximidamide Chemical compound OCC1=CC=C(C(=N)NO)C=C1 XAVQRXUCPQYHBS-UHFFFAOYSA-N 0.000 description 1
- DUWWHGPELOTTOE-UHFFFAOYSA-N n-(5-chloro-2,4-dimethoxyphenyl)-3-oxobutanamide Chemical compound COC1=CC(OC)=C(NC(=O)CC(C)=O)C=C1Cl DUWWHGPELOTTOE-UHFFFAOYSA-N 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- PIDFDZJZLOTZTM-KHVQSSSXSA-N ombitasvir Chemical compound COC(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@H]1C(=O)NC1=CC=C([C@H]2N([C@@H](CC2)C=2C=CC(NC(=O)[C@H]3N(CCC3)C(=O)[C@@H](NC(=O)OC)C(C)C)=CC=2)C=2C=CC(=CC=2)C(C)(C)C)C=C1 PIDFDZJZLOTZTM-KHVQSSSXSA-N 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 1
- CHKVPAROMQMJNQ-UHFFFAOYSA-M potassium bisulfate Chemical compound [K+].OS([O-])(=O)=O CHKVPAROMQMJNQ-UHFFFAOYSA-M 0.000 description 1
- 229910000343 potassium bisulfate Inorganic materials 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000000018 receptor agonist Substances 0.000 description 1
- 229940044601 receptor agonist Drugs 0.000 description 1
- 238000006268 reductive amination reaction Methods 0.000 description 1
- 238000004007 reversed phase HPLC Methods 0.000 description 1
- 101150024819 s1pr1 gene Proteins 0.000 description 1
- 101150079914 s1pr2 gene Proteins 0.000 description 1
- 201000000306 sarcoidosis Diseases 0.000 description 1
- 230000009919 sequestration Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 150000003408 sphingolipids Chemical class 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 229960002317 succinimide Drugs 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- FXFXLPOHFVEXHX-ZETCQYMHSA-N tert-butyl (2S)-2-(dimethylamino)propanoate Chemical compound CN(C)[C@@H](C)C(=O)OC(C)(C)C FXFXLPOHFVEXHX-ZETCQYMHSA-N 0.000 description 1
- BKDAAQBTWCKCKR-VTBWFHPJSA-N tert-butyl (2r)-2-[[2-[tert-butyl(dimethyl)silyl]oxy-1-(4-cyanophenyl)ethyl]amino]propanoate Chemical compound CC(C)(C)OC(=O)[C@@H](C)NC(CO[Si](C)(C)C(C)(C)C)C1=CC=C(C#N)C=C1 BKDAAQBTWCKCKR-VTBWFHPJSA-N 0.000 description 1
- PAWKLFLVSVNNPA-UHFFFAOYSA-N tert-butyl 2-[(2-fluoro-4-isocyanophenyl)methyl-methylamino]-2-methylpropanoate Chemical compound CC(C)(C)OC(=O)C(C)(C)N(C)CC1=CC=C([N+]#[C-])C=C1F PAWKLFLVSVNNPA-UHFFFAOYSA-N 0.000 description 1
- DRUGLDXGMFFYMK-UHFFFAOYSA-N tert-butyl 2-[(3-cyano-5-fluorophenyl)methylamino]-2-methylpropanoate Chemical compound CC(C)(C)OC(=O)C(C)(C)NCC1=CC(F)=CC(C#N)=C1 DRUGLDXGMFFYMK-UHFFFAOYSA-N 0.000 description 1
- MUMVLEWLOTZJOL-UHFFFAOYSA-N tert-butyl 2-[(4-cyano-2-fluorophenyl)methyl-methylamino]-3-methylbutanoate Chemical compound CC(C)(C)OC(=O)C(C(C)C)N(C)CC1=CC=C(C#N)C=C1F MUMVLEWLOTZJOL-UHFFFAOYSA-N 0.000 description 1
- SEMQOVVLEJTZQT-UHFFFAOYSA-N tert-butyl 2-[[1-(4-cyanophenyl)-2-hydroxyethyl]amino]acetate Chemical compound CC(C)(C)OC(=O)CNC(CO)C1=CC=C(C#N)C=C1 SEMQOVVLEJTZQT-UHFFFAOYSA-N 0.000 description 1
- RIUJWUWLGXBICR-UHFFFAOYSA-N tert-butyl 2-bromobutanoate Chemical compound CCC(Br)C(=O)OC(C)(C)C RIUJWUWLGXBICR-UHFFFAOYSA-N 0.000 description 1
- 125000006318 tert-butyl amino group Chemical group [H]N(*)C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- SYCYTDVODOGBBU-UHFFFAOYSA-N tert-butyl n-[1-(4-cyanophenyl)ethyl]carbamate Chemical compound CC(C)(C)OC(=O)NC(C)C1=CC=C(C#N)C=C1 SYCYTDVODOGBBU-UHFFFAOYSA-N 0.000 description 1
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 230000032258 transport Effects 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
- C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
- C07D271/06—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4245—Oxadiazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
- A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Immunology (AREA)
- Epidemiology (AREA)
- Physical Education & Sports Medicine (AREA)
- Rheumatology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Pain & Pain Management (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Biomedical Technology (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Cardiology (AREA)
- Dermatology (AREA)
- Heart & Thoracic Surgery (AREA)
- Gastroenterology & Hepatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP10168833 | 2010-07-08 | ||
| EP10168833 | 2010-07-08 | ||
| US36274610P | 2010-07-09 | 2010-07-09 | |
| US362746P | 2010-07-09 | ||
| PCT/EP2011/061372 WO2012004287A1 (en) | 2010-07-08 | 2011-07-06 | 5-(biphenyl-4-yl)-3-phenyl-1,2,4-oxadiazolyl derivatives as ligands on the sphingosine 1-phosphate (s1p) receptors |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ES2586145T3 true ES2586145T3 (es) | 2016-10-11 |
Family
ID=42341535
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ES11729318.3T Active ES2586145T3 (es) | 2010-07-08 | 2011-07-06 | Derivados de 5-(bifenil-4-il)-3-fenil-1,2,4-oxadiazolilo como ligandos en los receptores de esfingosina 1-fosfato (S1P) |
Country Status (15)
| Country | Link |
|---|---|
| US (1) | US9029405B2 (enExample) |
| EP (1) | EP2590956B1 (enExample) |
| JP (1) | JP6014589B2 (enExample) |
| KR (1) | KR20140003379A (enExample) |
| CN (1) | CN103097365B (enExample) |
| AR (1) | AR082132A1 (enExample) |
| AU (1) | AU2011275854B2 (enExample) |
| CA (1) | CA2804473C (enExample) |
| EA (1) | EA201300092A1 (enExample) |
| ES (1) | ES2586145T3 (enExample) |
| IL (1) | IL224071B (enExample) |
| MX (1) | MX2012015021A (enExample) |
| SG (1) | SG186872A1 (enExample) |
| TW (1) | TW201206429A (enExample) |
| WO (1) | WO2012004287A1 (enExample) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102250035A (zh) * | 2011-06-10 | 2011-11-23 | 北京富卡生物技术有限公司 | 二芳基取代-1，3，4-噁二唑化合物的合成方法和其药物用途 |
| CN107857760A (zh) * | 2017-11-21 | 2018-03-30 | 南京天翔医药科技有限公司 | 鞘氨醇‑1‑磷酸受体调节剂及其应用 |
| TWI891696B (zh) * | 2019-12-23 | 2025-08-01 | 英商喜翠克斯治療有限公司 | 新穎之化合物 |
| EP4126827B1 (en) * | 2020-03-27 | 2024-11-20 | Receptos LLC | Sphingosine 1 phosphate receptor modulators |
| US20240228448A1 (en) * | 2021-03-31 | 2024-07-11 | Washington University | Compositions for binding sphingosine-1-phosphate receptor 1 (s1p1), imaging of s1p1, and processes for preparation thereof |
| WO2022220608A1 (ko) * | 2021-04-14 | 2022-10-20 | 주식회사 엘지화학 | 스핑고신-1-인산 수용체 효능제 합성을 위한 중간체의 제조방법 |
Family Cites Families (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0711792B1 (de) | 1994-11-05 | 1999-03-10 | BASF Aktiengesellschaft | Melaminharze |
| JP4773972B2 (ja) * | 2003-12-17 | 2011-09-14 | メルク・シャープ・エンド・ドーム・コーポレイション | Ｓ１Ｐ（Ｅｄｇ）受容体作働薬としての（３，４−ジ置換）プロパンカルボン酸 |
| US20060223866A1 (en) * | 2004-08-13 | 2006-10-05 | Praecis Pharmaceuticals, Inc. | Methods and compositions for modulating sphingosine-1-phosphate (S1P) receptor activity |
| JP2008545767A (ja) * | 2005-06-08 | 2008-12-18 | ノバルティス アクチエンゲゼルシャフト | 多環式オキサジアゾールまたはイソキサゾールおよびｓｉｐ受容体リガンドとしてのそれらの使用 |
| GB0511684D0 (en) * | 2005-06-08 | 2005-07-13 | Novartis Ag | Organic compounds |
| TWI404706B (zh) * | 2006-01-11 | 2013-08-11 | Actelion Pharmaceuticals Ltd | 新穎噻吩衍生物 |
| GB0601744D0 (en) * | 2006-01-27 | 2006-03-08 | Novartis Ag | Organic compounds |
| JP2009269819A (ja) * | 2006-08-25 | 2009-11-19 | Asahi Kasei Pharma Kk | アミン化合物 |
| KR20090057070A (ko) * | 2006-09-29 | 2009-06-03 | 노파르티스 아게 | 소염성 및 면역억제성을 갖는 옥사디아졸 유도체 |
| CA2696863C (en) | 2007-10-04 | 2016-10-18 | Anna Quattropani | Oxadiazole derivatives |
| TW201000099A (en) * | 2008-06-20 | 2010-01-01 | Amgen Inc | S1P1 receptor agonists and use thereof |
| EP2241558A1 (en) | 2009-04-03 | 2010-10-20 | Merck Serono SA | Oxadiazole derivatives |
-
2011
- 2011-07-01 TW TW100122179A patent/TW201206429A/zh unknown
- 2011-07-06 MX MX2012015021A patent/MX2012015021A/es not_active Application Discontinuation
- 2011-07-06 WO PCT/EP2011/061372 patent/WO2012004287A1/en not_active Ceased
- 2011-07-06 EA EA201300092A patent/EA201300092A1/ru unknown
- 2011-07-06 US US13/809,013 patent/US9029405B2/en not_active Expired - Fee Related
- 2011-07-06 JP JP2013517372A patent/JP6014589B2/ja not_active Expired - Fee Related
- 2011-07-06 ES ES11729318.3T patent/ES2586145T3/es active Active
- 2011-07-06 KR KR20137003335A patent/KR20140003379A/ko not_active Withdrawn
- 2011-07-06 CA CA2804473A patent/CA2804473C/en not_active Expired - Fee Related
- 2011-07-06 SG SG2012096533A patent/SG186872A1/en unknown
- 2011-07-06 AU AU2011275854A patent/AU2011275854B2/en not_active Ceased
- 2011-07-06 EP EP11729318.3A patent/EP2590956B1/en not_active Not-in-force
- 2011-07-06 CN CN201180033823.9A patent/CN103097365B/zh not_active Expired - Fee Related
- 2011-07-08 AR ARP110102449 patent/AR082132A1/es not_active Application Discontinuation
-
2012
- 2012-12-31 IL IL224071A patent/IL224071B/en active IP Right Grant
Also Published As
| Publication number | Publication date |
|---|---|
| AU2011275854B2 (en) | 2015-08-27 |
| CA2804473A1 (en) | 2012-01-12 |
| EP2590956A1 (en) | 2013-05-15 |
| US20130116289A1 (en) | 2013-05-09 |
| CN103097365B (zh) | 2016-02-24 |
| JP6014589B2 (ja) | 2016-10-25 |
| EA201300092A1 (ru) | 2013-06-28 |
| MX2012015021A (es) | 2013-04-03 |
| US9029405B2 (en) | 2015-05-12 |
| AR082132A1 (es) | 2012-11-14 |
| WO2012004287A1 (en) | 2012-01-12 |
| CN103097365A (zh) | 2013-05-08 |
| TW201206429A (en) | 2012-02-16 |
| IL224071B (en) | 2018-06-28 |
| CA2804473C (en) | 2019-04-02 |
| KR20140003379A (ko) | 2014-01-09 |
| AU2011275854A1 (en) | 2013-02-21 |
| SG186872A1 (en) | 2013-02-28 |
| EP2590956B1 (en) | 2016-05-04 |
| JP2013530202A (ja) | 2013-07-25 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| ES2586145T3 (es) | Derivados de 5-(bifenil-4-il)-3-fenil-1,2,4-oxadiazolilo como ligandos en los receptores de esfingosina 1-fosfato (S1P) | |
| US7351725B2 (en) | N-(benzyl)aminoalkylcarboxylates, phosphinates, phosphonates and tetrazoles as Edg receptor agonists | |
| US8993631B2 (en) | Method of treating contrast-induced nephropathy | |
| US7309721B2 (en) | Aminoalkylphosphonates and related compounds as Edg receptor agonists | |
| ES2632600T3 (es) | Inhibidores de neprilisina | |
| ES2673160T5 (es) | Moduladores selectivos del receptor de la esfingosina 1 fosfato y métodos de síntesis quiral | |
| ES2446970T3 (es) | Ácidos 3-fenilpropiónicos sustituidos y su uso | |
| AU2010233932B2 (en) | Oxadiazole derivatives | |
| AU2005299851A1 (en) | 2-(aryl)azacyclylmethyl carboxylates, sulfonates, phosphonates, phosphinates and heterocycles as S1P receptor agonists | |
| US20050107345A1 (en) | Aminoalkylphosphonates and related compounds as edg receptor agonists | |
| CA3152836A1 (en) | Substituted urea dihydroorotate dehydrogenase inhibitors | |
| HK1181035A (en) | 5-(biphenyl-4-yl)-3-phenyl-1,2,4-oxadiazolyl derivatives as ligands on the sphingosine 1-phosphate (s1p) receptors |