JP2014523887A5 - - Google Patents
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- Publication number
- JP2014523887A5 JP2014523887A5 JP2014517431A JP2014517431A JP2014523887A5 JP 2014523887 A5 JP2014523887 A5 JP 2014523887A5 JP 2014517431 A JP2014517431 A JP 2014517431A JP 2014517431 A JP2014517431 A JP 2014517431A JP 2014523887 A5 JP2014523887 A5 JP 2014523887A5
- Authority
- JP
- Japan
- Prior art keywords
- group
- butyl
- butoxy
- butylamino
- 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.)
- Pending
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- -1 hydroxy, mercapto, cyano, amino Chemical group 0.000 claims description 810
- 150000001875 compounds Chemical class 0.000 claims description 218
- 239000001257 hydrogen Substances 0.000 claims description 135
- 229910052739 hydrogen Inorganic materials 0.000 claims description 135
- 150000002431 hydrogen Chemical group 0.000 claims description 111
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims description 107
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 99
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 95
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 94
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 94
- 125000003282 alkyl amino group Chemical group 0.000 claims description 88
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 84
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 77
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 77
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 69
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 56
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 54
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 53
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 48
- 229910052736 halogen Inorganic materials 0.000 claims description 48
- 150000002367 halogens Chemical class 0.000 claims description 48
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 48
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 47
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 claims description 47
- 125000004369 butenyl group Chemical group C(=CCC)* 0.000 claims description 47
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 47
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 claims description 47
- 125000001153 fluoro group Chemical group F* 0.000 claims description 47
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 claims description 47
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 claims description 47
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 38
- 125000002861 (C1-C4) alkanoyl group Chemical group 0.000 claims description 37
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 35
- 150000003839 salts Chemical class 0.000 claims description 35
- 150000001336 alkenes Chemical class 0.000 claims description 34
- 125000004442 acylamino group Chemical group 0.000 claims description 32
- 125000004423 acyloxy group Chemical group 0.000 claims description 32
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 30
- 150000002148 esters Chemical class 0.000 claims description 29
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims description 28
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 24
- 229910052717 sulfur Inorganic materials 0.000 claims description 22
- 229910052760 oxygen Inorganic materials 0.000 claims description 20
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 16
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 16
- UNLBRWACURAHRZ-UHFFFAOYSA-N oxo-[[1-[[5-[[4-(oxoazaniumylmethylidene)pyridin-1-yl]methyl]thiophen-2-yl]methyl]pyridin-4-ylidene]methyl]azanium;diperchlorate Chemical group [O-]Cl(=O)(=O)=O.[O-]Cl(=O)(=O)=O.C1=CC(=C[NH+]=O)C=CN1CC(S1)=CC=C1CN1C=CC(=C[NH+]=O)C=C1 UNLBRWACURAHRZ-UHFFFAOYSA-N 0.000 claims description 16
- 239000011593 sulfur Chemical group 0.000 claims description 16
- 125000000217 alkyl group Chemical group 0.000 claims description 15
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 15
- 239000001301 oxygen Substances 0.000 claims description 15
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 14
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 claims description 14
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 12
- 125000003118 aryl group Chemical group 0.000 claims description 12
- 239000008194 pharmaceutical composition Substances 0.000 claims description 12
- 125000002252 acyl group Chemical group 0.000 claims description 11
- 239000003795 chemical substances by application Substances 0.000 claims description 11
- 125000003396 thiol group Chemical group [H]S* 0.000 claims description 10
- 125000003277 amino group Chemical group 0.000 claims description 8
- 125000005842 heteroatom Chemical group 0.000 claims description 8
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 8
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 6
- 201000010099 disease Diseases 0.000 claims description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 6
- 239000004480 active ingredient Substances 0.000 claims description 5
- 125000000623 heterocyclic group Chemical group 0.000 claims description 5
- 230000001225 therapeutic effect Effects 0.000 claims description 5
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 125000004414 alkyl thio group Chemical group 0.000 claims description 4
- 238000012217 deletion Methods 0.000 claims description 4
- 230000037430 deletion Effects 0.000 claims description 4
- 239000002955 immunomodulating agent Substances 0.000 claims description 4
- 230000001506 immunosuppresive effect Effects 0.000 claims description 4
- 229910052727 yttrium Inorganic materials 0.000 claims description 4
- 208000026278 immune system disease Diseases 0.000 claims description 3
- 229940121354 immunomodulator Drugs 0.000 claims description 3
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims description 2
- 208000023275 Autoimmune disease Diseases 0.000 claims description 2
- 210000000056 organ Anatomy 0.000 claims description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 2
- 238000002054 transplantation Methods 0.000 claims description 2
- 238000006467 substitution reaction Methods 0.000 claims 8
- 125000001273 sulfonato group Chemical group [O-]S(*)(=O)=O 0.000 claims 8
- 238000004519 manufacturing process Methods 0.000 claims 2
- BUYUFJZVMVFQLQ-UHFFFAOYSA-N 4-[2-(5,5,8,8-tetramethyl-6,7-dihydroquinoxalin-2-yl)ethynyl]benzoic acid Chemical compound CC1(C=2N=CC(=NC=2C(CC1)(C)C)C#CC1=CC=C(C(=O)O)C=C1)C BUYUFJZVMVFQLQ-UHFFFAOYSA-N 0.000 claims 1
- 206010062016 Immunosuppression Diseases 0.000 claims 1
- 125000006309 butyl amino group Chemical group 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 230000002584 immunomodulator Effects 0.000 claims 1
- 230000000069 prophylactic effect Effects 0.000 claims 1
- 239000000243 solution Substances 0.000 description 218
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical group [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 186
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 147
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 147
- 238000002360 preparation method Methods 0.000 description 140
- 239000011734 sodium Substances 0.000 description 133
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 123
- 239000000203 mixture Substances 0.000 description 114
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 112
- 229910052753 mercury Inorganic materials 0.000 description 112
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 105
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 101
- 238000010992 reflux Methods 0.000 description 81
- 235000019439 ethyl acetate Nutrition 0.000 description 73
- 239000000460 chlorine Substances 0.000 description 71
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 59
- 238000010898 silica gel chromatography Methods 0.000 description 58
- 239000012043 crude product Substances 0.000 description 56
- 239000007787 solid Substances 0.000 description 54
- 230000007935 neutral effect Effects 0.000 description 50
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 48
- 239000012044 organic layer Substances 0.000 description 46
- 239000006188 syrup Substances 0.000 description 43
- 235000020357 syrup Nutrition 0.000 description 43
- 238000006243 chemical reaction Methods 0.000 description 35
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 34
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 34
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 32
- DZGCGKFAPXFTNM-UHFFFAOYSA-N ethanol;hydron;chloride Chemical compound Cl.CCO DZGCGKFAPXFTNM-UHFFFAOYSA-N 0.000 description 29
- 239000002198 insoluble material Substances 0.000 description 29
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 29
- 239000012153 distilled water Substances 0.000 description 28
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 25
- 239000012267 brine Substances 0.000 description 25
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 25
- 235000002639 sodium chloride Nutrition 0.000 description 23
- 239000008346 aqueous phase Substances 0.000 description 22
- 239000003921 oil Substances 0.000 description 21
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 20
- 239000000843 powder Substances 0.000 description 20
- 239000008096 xylene Substances 0.000 description 20
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 18
- 239000007810 chemical reaction solvent Substances 0.000 description 18
- 239000003814 drug Substances 0.000 description 18
- 238000000746 purification Methods 0.000 description 18
- 150000001299 aldehydes Chemical class 0.000 description 17
- 239000000126 substance Substances 0.000 description 16
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- 241000700159 Rattus Species 0.000 description 14
- 239000003054 catalyst Substances 0.000 description 14
- 239000003638 chemical reducing agent Substances 0.000 description 14
- 239000002585 base Substances 0.000 description 13
- 239000003826 tablet Substances 0.000 description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 12
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 12
- 229940079593 drug Drugs 0.000 description 11
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 10
- 230000000694 effects Effects 0.000 description 10
- 238000000034 method Methods 0.000 description 10
- QGJOPFRUJISHPQ-UHFFFAOYSA-N Carbon disulfide Chemical compound S=C=S QGJOPFRUJISHPQ-UHFFFAOYSA-N 0.000 description 9
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 description 9
- 229960004592 isopropanol Drugs 0.000 description 9
- 238000003786 synthesis reaction Methods 0.000 description 9
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 8
- KQNPFQTWMSNSAP-UHFFFAOYSA-N isobutyric acid Chemical compound CC(C)C(O)=O KQNPFQTWMSNSAP-UHFFFAOYSA-N 0.000 description 8
- 150000003871 sulfonates Chemical class 0.000 description 8
- 0 *C(CC(CO)(CO)N)c1ccc(*c(cc2)ccc2-c2ncc[s]2)cc1 Chemical compound *C(CC(CO)(CO)N)c1ccc(*c(cc2)ccc2-c2ncc[s]2)cc1 0.000 description 7
- ISOLMABRZPQKOV-UHFFFAOYSA-N diethyl 2-acetamidopropanedioate Chemical compound CCOC(=O)C(NC(C)=O)C(=O)OCC ISOLMABRZPQKOV-UHFFFAOYSA-N 0.000 description 7
- ZZIKIHCNFWXKDY-GNTQXERDSA-N myriocin Chemical compound CCCCCCC(=O)CCCCCC\C=C\C[C@@H](O)[C@H](O)[C@@](N)(CO)C(O)=O ZZIKIHCNFWXKDY-GNTQXERDSA-N 0.000 description 7
- 206010020772 Hypertension Diseases 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical group Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 6
- 125000001769 aryl amino group Chemical group 0.000 description 6
- 238000006482 condensation reaction Methods 0.000 description 6
- USIUVYZYUHIAEV-UHFFFAOYSA-N diphenyl ether Chemical compound C=1C=CC=CC=1OC1=CC=CC=C1 USIUVYZYUHIAEV-UHFFFAOYSA-N 0.000 description 6
- 238000006460 hydrolysis reaction Methods 0.000 description 6
- 239000000314 lubricant Substances 0.000 description 6
- 229910052751 metal Inorganic materials 0.000 description 6
- 239000002184 metal Substances 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 239000003085 diluting agent Substances 0.000 description 5
- 238000009472 formulation Methods 0.000 description 5
- 230000002265 prevention Effects 0.000 description 5
- RVYNIIJBIAINNT-UHFFFAOYSA-N propane-1,3-diol;hydrochloride Chemical compound Cl.OCCCO RVYNIIJBIAINNT-UHFFFAOYSA-N 0.000 description 5
- 235000019260 propionic acid Nutrition 0.000 description 5
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- 125000001424 substituent group Chemical group 0.000 description 5
- KXYJNSJYQCRPRE-UHFFFAOYSA-N 2-chloro-1-(4-phenoxyphenyl)ethanone Chemical compound C1=CC(C(=O)CCl)=CC=C1OC1=CC=CC=C1 KXYJNSJYQCRPRE-UHFFFAOYSA-N 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 4
- 206010019233 Headaches Diseases 0.000 description 4
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 4
- 239000002841 Lewis acid Substances 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
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- 229920002472 Starch Polymers 0.000 description 4
- 238000010171 animal model Methods 0.000 description 4
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 235000012000 cholesterol Nutrition 0.000 description 4
- 239000012230 colorless oil Substances 0.000 description 4
- YMGUBTXCNDTFJI-UHFFFAOYSA-N cyclopropanecarboxylic acid Chemical compound OC(=O)C1CC1 YMGUBTXCNDTFJI-UHFFFAOYSA-N 0.000 description 4
- KKGQTZUTZRNORY-UHFFFAOYSA-N fingolimod Chemical compound CCCCCCCCC1=CC=C(CCC(N)(CO)CO)C=C1 KKGQTZUTZRNORY-UHFFFAOYSA-N 0.000 description 4
- 239000008103 glucose Substances 0.000 description 4
- 229960001031 glucose Drugs 0.000 description 4
- 235000001727 glucose Nutrition 0.000 description 4
- 231100000869 headache Toxicity 0.000 description 4
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- 239000007924 injection Substances 0.000 description 4
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- 229910052708 sodium Inorganic materials 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 239000008107 starch Substances 0.000 description 4
- 235000019698 starch Nutrition 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- 101100283604 Caenorhabditis elegans pigk-1 gene Proteins 0.000 description 3
- QSJXEFYPDANLFS-UHFFFAOYSA-N Diacetyl Chemical compound CC(=O)C(C)=O QSJXEFYPDANLFS-UHFFFAOYSA-N 0.000 description 3
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- 239000012448 Lithium borohydride Substances 0.000 description 3
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- ZZIKIHCNFWXKDY-UHFFFAOYSA-N Myriocin Natural products CCCCCCC(=O)CCCCCCC=CCC(O)C(O)C(N)(CO)C(O)=O ZZIKIHCNFWXKDY-UHFFFAOYSA-N 0.000 description 3
- 206010030113 Oedema Diseases 0.000 description 3
- 229910019142 PO4 Inorganic materials 0.000 description 3
- 239000004698 Polyethylene Substances 0.000 description 3
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- 239000000654 additive Substances 0.000 description 3
- 239000011230 binding agent Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- RSYWMSKMNWLWCR-UHFFFAOYSA-N diethyl 2-acetamido-2-[2-[4-[4-(2-chloroacetyl)phenyl]sulfanylphenyl]-2-oxoethyl]propanedioate Chemical compound CCOC(=O)C(CC(=O)c1ccc(Sc2ccc(cc2)C(=O)CCl)cc1)(NC(C)=O)C(=O)OCC RSYWMSKMNWLWCR-UHFFFAOYSA-N 0.000 description 3
- 239000007884 disintegrant Substances 0.000 description 3
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- 238000005886 esterification reaction Methods 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 230000007062 hydrolysis Effects 0.000 description 3
- 230000028993 immune response Effects 0.000 description 3
- 239000003018 immunosuppressive agent Substances 0.000 description 3
- 239000011968 lewis acid catalyst Substances 0.000 description 3
- 239000012280 lithium aluminium hydride Substances 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 3
- 239000008108 microcrystalline cellulose Substances 0.000 description 3
- 229940016286 microcrystalline cellulose Drugs 0.000 description 3
- 231100000417 nephrotoxicity Toxicity 0.000 description 3
- 239000010452 phosphate Substances 0.000 description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 3
- 229910052707 ruthenium Inorganic materials 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 239000012279 sodium borohydride Substances 0.000 description 3
- 229910000033 sodium borohydride Inorganic materials 0.000 description 3
- 239000007901 soft capsule Substances 0.000 description 3
- 239000000080 wetting agent Substances 0.000 description 3
- KFXUHRXGLWUOJT-UHFFFAOYSA-N (4-phenoxyphenyl)boronic acid Chemical compound C1=CC(B(O)O)=CC=C1OC1=CC=CC=C1 KFXUHRXGLWUOJT-UHFFFAOYSA-N 0.000 description 2
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| WO2014175287A1 (ja) | 2013-04-26 | 2014-10-30 | 国立大学法人 京都大学 | 脳動脈瘤の形成および／または増大の抑制若しくは縮小用医薬組成物 |
| CN104844533B (zh) * | 2014-02-17 | 2019-04-09 | 中国医学科学院药物研究所 | 含五元芳杂环的氨基丙二醇类化合物、其制备方法及其医药用途 |
| WO2020039094A1 (en) * | 2018-08-24 | 2020-02-27 | Xeniopro GmbH | Phenoxy(hetero)aryl ethers of antiproliferative activity |
| IL315313A (en) * | 2018-08-24 | 2024-10-01 | Xeniopro GmbH | Aromatic molecules for use in the treatment of pathological conditions |
| CN111087358B (zh) * | 2018-10-24 | 2022-06-21 | 中国医学科学院药物研究所 | 普赛莫德的制备方法 |
| CN111087356B (zh) * | 2018-10-24 | 2022-06-21 | 中国医学科学院药物研究所 | 一种艾托莫德的制备方法 |
| CN111087359B (zh) * | 2018-10-24 | 2022-06-21 | 中国医学科学院药物研究所 | 艾托莫德的制备方法 |
| CN115974803B (zh) * | 2022-12-12 | 2024-04-09 | 渐宽(苏州)生物科技有限公司 | 一种普赛莫德的晶型及其制备方法和用途 |
| CN116217507B (zh) * | 2022-12-22 | 2024-12-20 | 渐宽(苏州)生物科技有限公司 | 一种艾托莫德的晶型及其制备方法和应用 |
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| AUPP796798A0 (en) * | 1998-12-30 | 1999-01-28 | Fujisawa Pharmaceutical Co., Ltd. | New compound |
| WO2003029205A1 (fr) * | 2001-09-27 | 2003-04-10 | Kyorin Pharmaceutical Co., Ltd. | Derive de sulfure de diaryle, son sel d'addition et immunosuppresseur |
| CA2460640C (en) * | 2001-09-27 | 2011-03-29 | Kyorin Pharmaceutical Co., Ltd. | Diaryl ether derivatives, salts thereof and immunosuppressive agents using the same |
| WO2003099192A2 (en) * | 2002-05-27 | 2003-12-04 | Novartis Ag | Bis-aromatic alkanols |
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| WO2005014525A2 (en) * | 2003-08-12 | 2005-02-17 | Mitsubishi Pharma Corporation | Bi-aryl compound having immunosuppressive activity |
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| JP2007001921A (ja) * | 2005-06-23 | 2007-01-11 | Kyorin Pharmaceut Co Ltd | アミノスルホン酸誘導体とその付加塩及びｓ１ｐ受容体調節剤 |
| EP2066800A2 (en) * | 2006-08-04 | 2009-06-10 | Decode Genetics EHF | Aryl amino acid derivatives as inhibitors of lta4h (leukotriene a4 hydrolase) for treating inflammation |
| KR101339976B1 (ko) * | 2006-08-08 | 2013-12-10 | 교린 세이야꾸 가부시키 가이샤 | 아미노인산에스테르 유도체 및 그들을 유효성분으로 하는 ｓ1ｐ 수용체 조절제 |
| US20100093745A1 (en) * | 2007-02-13 | 2010-04-15 | Kazuhiko Kuriyama | Therapeutic agent or prophylactic agent for demyelinating disease comprising amino alcohol derivative as active ingredient |
| JP5452237B2 (ja) * | 2008-02-07 | 2014-03-26 | 杏林製薬株式会社 | アミノアルコール誘導体を有効成分とする炎症性腸疾患の治療剤又は予防剤 |
| JPWO2009142194A1 (ja) * | 2008-05-19 | 2011-09-29 | 杏林製薬株式会社 | 光学活性アミノアルコール誘導体の製造方法 |
| JP2010013407A (ja) * | 2008-07-04 | 2010-01-21 | Kyorin Pharmaceut Co Ltd | アミノアルコール誘導体 |
| JP2010077053A (ja) * | 2008-09-25 | 2010-04-08 | Kyorin Pharmaceut Co Ltd | フェノール誘導体及びそれらを有効成分とする医薬 |
| CA2739901A1 (en) * | 2008-10-17 | 2010-04-22 | Akaal Pharma Pty Ltd | S1p receptors modulators |
| CN102471355B (zh) * | 2009-07-09 | 2015-10-07 | 杏林制药株式会社 | 二苯硫醚衍生物和含有其作为活性成分的药物 |
| JP2011032226A (ja) * | 2009-08-03 | 2011-02-17 | Kyorin Pharmaceutical Co Ltd | ジフェニルスルフィド誘導体及びそれらを有効成分とする医薬 |
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2011
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2012
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- 2012-07-05 WO PCT/CN2012/078244 patent/WO2013004190A1/zh not_active Ceased
- 2012-07-05 JP JP2014517431A patent/JP2014523887A/ja active Pending
- 2012-07-05 EP EP12808109.8A patent/EP2786982A4/en not_active Withdrawn
- 2012-07-05 EA EA201490221A patent/EA201490221A1/ru unknown
- 2012-07-05 KR KR1020147003101A patent/KR20140048239A/ko not_active Ceased
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