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
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- 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
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- ethyl
- tert
- amino
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- 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
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- 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
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- 125000000753 cycloalkyl group Chemical group 0.000 description 4
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- 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
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- 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
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- 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)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Immunology (AREA)
- Epidemiology (AREA)
- Neurology (AREA)
- Physical Education & Sports Medicine (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Urology & Nephrology (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Dermatology (AREA)
- Gastroenterology & Hepatology (AREA)
- Vascular Medicine (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 (7)
| 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 |
| FI4081511T6 (fi) * | 2019-12-23 | 2026-06-09 | Sitryx Therapeutics Ltd | Karboksijohdannaisia, joilla on anti-inflammatorisia ominaisuuksia |
| KR20220158743A (ko) * | 2020-03-27 | 2022-12-01 | 리셉토스 엘엘씨 | 스핑고신 1 포스페이트 수용체 조절제 |
| 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 |
| US12571867B2 (en) | 2022-04-14 | 2026-03-10 | United States Pharmacopeial Convention | Nuclear magnetic resonance analysis systems and methods |
Family Cites Families (12)
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| EP0711792B1 (de) | 1994-11-05 | 1999-03-10 | BASF Aktiengesellschaft | Melaminharze |
| US7605171B2 (en) * | 2003-12-17 | 2009-10-20 | Merck & Co., Inc. | (3,4-disubstituted)propanoic carboxylates as S1P (Edg) receptor agonists |
| US20060223866A1 (en) * | 2004-08-13 | 2006-10-05 | Praecis Pharmaceuticals, Inc. | Methods and compositions for modulating sphingosine-1-phosphate (S1P) receptor activity |
| US20080306124A1 (en) | 2005-06-08 | 2008-12-11 | Rainer Albert | Polycyclic Oxadiazoles or I Soxazoles and Their Use as Sip Receptor Ligands |
| 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 |
| CN101522646A (zh) * | 2006-09-29 | 2009-09-02 | 诺瓦提斯公司 | 具有抗炎和免疫抑制特性的二唑衍生物 |
| CN101970420B (zh) | 2007-10-04 | 2014-09-24 | 默克雪兰诺有限公司 | 噁二唑衍生物 |
| 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 SG SG2012096533A patent/SG186872A1/en unknown
- 2011-07-06 JP JP2013517372A patent/JP6014589B2/ja not_active Expired - Fee Related
- 2011-07-06 US US13/809,013 patent/US9029405B2/en not_active Expired - Fee Related
- 2011-07-06 EA EA201300092A patent/EA201300092A1/ru unknown
- 2011-07-06 AU AU2011275854A patent/AU2011275854B2/en not_active Ceased
- 2011-07-06 KR KR20137003335A patent/KR20140003379A/ko not_active Withdrawn
- 2011-07-06 ES ES11729318.3T patent/ES2586145T3/es active Active
- 2011-07-06 CA CA2804473A patent/CA2804473C/en not_active Expired - Fee Related
- 2011-07-06 CN CN201180033823.9A patent/CN103097365B/zh not_active Expired - Fee Related
- 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 EP EP11729318.3A patent/EP2590956B1/en not_active Not-in-force
- 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 |
|---|---|
| EA201300092A1 (ru) | 2013-06-28 |
| AU2011275854B2 (en) | 2015-08-27 |
| SG186872A1 (en) | 2013-02-28 |
| US9029405B2 (en) | 2015-05-12 |
| EP2590956B1 (en) | 2016-05-04 |
| JP2013530202A (ja) | 2013-07-25 |
| AR082132A1 (es) | 2012-11-14 |
| AU2011275854A1 (en) | 2013-02-21 |
| MX2012015021A (es) | 2013-04-03 |
| JP6014589B2 (ja) | 2016-10-25 |
| KR20140003379A (ko) | 2014-01-09 |
| IL224071B (en) | 2018-06-28 |
| CA2804473C (en) | 2019-04-02 |
| WO2012004287A1 (en) | 2012-01-12 |
| TW201206429A (en) | 2012-02-16 |
| US20130116289A1 (en) | 2013-05-09 |
| CN103097365B (zh) | 2016-02-24 |
| CA2804473A1 (en) | 2012-01-12 |
| EP2590956A1 (en) | 2013-05-15 |
| CN103097365A (zh) | 2013-05-08 |
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