JP5001653B2 - アミノプロパノール誘導体 - Google Patents
アミノプロパノール誘導体 Download PDFInfo
- Publication number
- JP5001653B2 JP5001653B2 JP2006524339A JP2006524339A JP5001653B2 JP 5001653 B2 JP5001653 B2 JP 5001653B2 JP 2006524339 A JP2006524339 A JP 2006524339A JP 2006524339 A JP2006524339 A JP 2006524339A JP 5001653 B2 JP5001653 B2 JP 5001653B2
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- JP
- Japan
- Prior art keywords
- formula
- compound
- phenyl
- enantiomer
- alkyl
- 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.)
- Expired - Fee Related
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- MXZROAOUCUVNHX-UHFFFAOYSA-N 2-Aminopropanol Chemical class CCC(N)O MXZROAOUCUVNHX-UHFFFAOYSA-N 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 107
- 238000000034 method Methods 0.000 claims abstract description 48
- -1 amino, hydroxy Chemical group 0.000 claims description 55
- 125000000217 alkyl group Chemical group 0.000 claims description 28
- 150000003839 salts Chemical group 0.000 claims description 25
- 239000000203 mixture Substances 0.000 claims description 23
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 21
- 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 description 18
- 238000000926 separation method Methods 0.000 claims description 14
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 13
- LOUPRKONTZGTKE-WZBLMQSHSA-N Quinine Chemical compound C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@@H]2[C@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-WZBLMQSHSA-N 0.000 claims description 12
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 12
- 125000006239 protecting group Chemical group 0.000 claims description 12
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 claims description 11
- LOUPRKONTZGTKE-UHFFFAOYSA-N cinchonine Natural products C1C(C(C2)C=C)CCN2C1C(O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-UHFFFAOYSA-N 0.000 claims description 11
- LRFKWQGGENFBFO-UHFFFAOYSA-N fingolimod phosphate Chemical compound CCCCCCCCC1=CC=C(CCC(N)(CO)COP(O)(O)=O)C=C1 LRFKWQGGENFBFO-UHFFFAOYSA-N 0.000 claims description 10
- 229910052736 halogen Inorganic materials 0.000 claims description 10
- LOUPRKONTZGTKE-LHHVKLHASA-N quinidine Chemical compound C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@H]2[C@@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-LHHVKLHASA-N 0.000 claims description 10
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 9
- 210000004369 blood Anatomy 0.000 claims description 8
- 239000008280 blood Substances 0.000 claims description 8
- 229910052799 carbon Inorganic materials 0.000 claims description 8
- 238000004587 chromatography analysis Methods 0.000 claims description 8
- 125000002252 acyl group Chemical group 0.000 claims description 7
- 238000002360 preparation method Methods 0.000 claims description 7
- 235000001258 Cinchona calisaya Nutrition 0.000 claims description 6
- 125000005843 halogen group Chemical group 0.000 claims description 6
- 150000002367 halogens Chemical group 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- 229960000948 quinine Drugs 0.000 claims description 6
- 229920000856 Amylose Polymers 0.000 claims description 5
- 230000005526 G1 to G0 transition Effects 0.000 claims description 5
- 125000003545 alkoxy group Chemical group 0.000 claims description 5
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 5
- 238000005342 ion exchange Methods 0.000 claims description 5
- 229960001404 quinidine Drugs 0.000 claims description 5
- 125000003302 alkenyloxy group Chemical group 0.000 claims description 4
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 4
- 125000003118 aryl group Chemical group 0.000 claims description 4
- 125000003884 phenylalkyl group Chemical group 0.000 claims description 4
- 150000004676 glycans Chemical class 0.000 claims description 3
- 125000000623 heterocyclic group Chemical group 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
- 229910052760 oxygen Inorganic materials 0.000 claims description 3
- 229920001282 polysaccharide Polymers 0.000 claims description 3
- 239000005017 polysaccharide Substances 0.000 claims description 3
- 125000004442 acylamino group Chemical group 0.000 claims description 2
- 125000004423 acyloxy group Chemical group 0.000 claims description 2
- 125000004466 alkoxycarbonylamino group Chemical group 0.000 claims description 2
- 125000003282 alkyl amino group Chemical group 0.000 claims description 2
- 125000005115 alkyl carbamoyl group Chemical group 0.000 claims description 2
- 125000004414 alkyl thio group Chemical group 0.000 claims description 2
- 125000005133 alkynyloxy group Chemical group 0.000 claims description 2
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 2
- 125000002102 aryl alkyloxo group Chemical group 0.000 claims description 2
- 125000004122 cyclic group Chemical group 0.000 claims description 2
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 2
- 125000004446 heteroarylalkyl group Chemical group 0.000 claims description 2
- 125000005842 heteroatom Chemical group 0.000 claims description 2
- 125000005343 heterocyclic alkyl group Chemical group 0.000 claims description 2
- 125000005359 phenoxyalkyl group Chemical group 0.000 claims description 2
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 claims description 2
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 2
- 229910052717 sulfur Inorganic materials 0.000 claims description 2
- 238000003379 elimination reaction Methods 0.000 claims 1
- 238000012544 monitoring process Methods 0.000 claims 1
- 125000002071 phenylalkoxy group Chemical group 0.000 claims 1
- 125000001424 substituent group Chemical group 0.000 claims 1
- 239000008194 pharmaceutical composition Substances 0.000 abstract description 5
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 84
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 54
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 42
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 42
- 239000000243 solution Substances 0.000 description 40
- 239000011541 reaction mixture Substances 0.000 description 39
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 33
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 30
- 150000002148 esters Chemical class 0.000 description 18
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 17
- 239000012267 brine Substances 0.000 description 16
- 239000012044 organic layer Substances 0.000 description 16
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 16
- 239000011734 sodium Substances 0.000 description 15
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 13
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- 238000002425 crystallisation Methods 0.000 description 12
- 230000008025 crystallization Effects 0.000 description 12
- ZWLUXSQADUDCSB-UHFFFAOYSA-N phthalaldehyde Chemical compound O=CC1=CC=CC=C1C=O ZWLUXSQADUDCSB-UHFFFAOYSA-N 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 11
- 210000004027 cell Anatomy 0.000 description 10
- 238000000746 purification Methods 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 238000013375 chromatographic separation Methods 0.000 description 9
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 8
- 239000003795 chemical substances by application Substances 0.000 description 8
- 239000012141 concentrate Substances 0.000 description 8
- 239000012467 final product Substances 0.000 description 8
- 238000003818 flash chromatography Methods 0.000 description 8
- 239000010410 layer Substances 0.000 description 8
- 102000011011 Sphingosine 1-phosphate receptors Human genes 0.000 description 7
- 239000004480 active ingredient Substances 0.000 description 7
- FBADWCHAKCHONV-UHFFFAOYSA-N 2-amino-2-[2-(4-phenylmethoxyphenyl)ethyl]propane-1,3-diol Chemical compound C1=CC(CCC(CO)(CO)N)=CC=C1OCC1=CC=CC=C1 FBADWCHAKCHONV-UHFFFAOYSA-N 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 229960000583 acetic acid Drugs 0.000 description 6
- 239000012298 atmosphere Substances 0.000 description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 6
- 239000000284 extract Substances 0.000 description 6
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- XOFLBQFBSOEHOG-UUOKFMHZSA-N γS-GTP Chemical compound C1=2NC(N)=NC(=O)C=2N=CN1[C@@H]1O[C@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=S)[C@@H](O)[C@H]1O XOFLBQFBSOEHOG-UUOKFMHZSA-N 0.000 description 6
- 108050001083 Sphingosine 1-phosphate receptors Proteins 0.000 description 5
- 238000004458 analytical method Methods 0.000 description 5
- 239000002246 antineoplastic agent Substances 0.000 description 5
- 229940127089 cytotoxic agent Drugs 0.000 description 5
- 230000001506 immunosuppresive effect Effects 0.000 description 5
- 230000002757 inflammatory effect Effects 0.000 description 5
- 230000001404 mediated effect Effects 0.000 description 5
- 239000012528 membrane Substances 0.000 description 5
- 229920006395 saturated elastomer Polymers 0.000 description 5
- 239000000741 silica gel Substances 0.000 description 5
- 229910002027 silica gel Inorganic materials 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- YEEFLZIZMHPFFY-UHFFFAOYSA-N 1-(2-iodoethyl)-4-phenylmethoxybenzene Chemical compound C1=CC(CCI)=CC=C1OCC1=CC=CC=C1 YEEFLZIZMHPFFY-UHFFFAOYSA-N 0.000 description 4
- YCCILVSKPBXVIP-UHFFFAOYSA-N 2-(4-hydroxyphenyl)ethanol Chemical compound OCCC1=CC=C(O)C=C1 YCCILVSKPBXVIP-UHFFFAOYSA-N 0.000 description 4
- JCUJAHLWCDISCC-UHFFFAOYSA-N 2-(4-phenylmethoxyphenyl)ethanol Chemical compound C1=CC(CCO)=CC=C1OCC1=CC=CC=C1 JCUJAHLWCDISCC-UHFFFAOYSA-N 0.000 description 4
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- 0 CC(C)(C)*C(O*C(C=CC)=C(C=C(CC1)O*)C1=C)=O Chemical compound CC(C)(C)*C(O*C(C=CC)=C(C=C(CC1)O*)C1=C)=O 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 4
- 239000005557 antagonist Substances 0.000 description 4
- 239000002260 anti-inflammatory agent Substances 0.000 description 4
- 229940121363 anti-inflammatory agent Drugs 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 230000001684 chronic effect Effects 0.000 description 4
- 239000012230 colorless oil Substances 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- CMBKNTZEFNLDIN-UHFFFAOYSA-N diethyl 2-acetamido-2-[2-(4-phenylmethoxyphenyl)ethyl]propanedioate Chemical compound C1=CC(CCC(C(=O)OCC)(NC(C)=O)C(=O)OCC)=CC=C1OCC1=CC=CC=C1 CMBKNTZEFNLDIN-UHFFFAOYSA-N 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 238000005516 engineering process Methods 0.000 description 4
- 238000001914 filtration Methods 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
- 229960000556 fingolimod Drugs 0.000 description 4
- 210000004698 lymphocyte Anatomy 0.000 description 4
- FTDWNMSHJXLOKK-UHFFFAOYSA-N n-[1-hydroxy-2-(hydroxymethyl)-4-(4-phenylmethoxyphenyl)butan-2-yl]acetamide Chemical compound C1=CC(CCC(CO)(CO)NC(=O)C)=CC=C1OCC1=CC=CC=C1 FTDWNMSHJXLOKK-UHFFFAOYSA-N 0.000 description 4
- 230000000865 phosphorylative effect Effects 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- 238000011282 treatment Methods 0.000 description 4
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 3
- 208000023275 Autoimmune disease Diseases 0.000 description 3
- 239000007995 HEPES buffer Substances 0.000 description 3
- 229910019142 PO4 Inorganic materials 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- 239000007983 Tris buffer Substances 0.000 description 3
- 230000001154 acute effect Effects 0.000 description 3
- 230000003110 anti-inflammatory effect Effects 0.000 description 3
- 238000004296 chiral HPLC Methods 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
- 238000001212 derivatisation Methods 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000035475 disorder Diseases 0.000 description 3
- 230000007062 hydrolysis Effects 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- 230000002519 immonomodulatory effect Effects 0.000 description 3
- 239000002955 immunomodulating agent Substances 0.000 description 3
- 239000003018 immunosuppressive agent Substances 0.000 description 3
- 208000027866 inflammatory disease Diseases 0.000 description 3
- 239000003446 ligand Substances 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 3
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 3
- 239000010452 phosphate Substances 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 229910000104 sodium hydride Inorganic materials 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- IAWVFXPPNCZKDM-UHFFFAOYSA-N tert-butyl 4-(hydroxymethyl)-4-[2-(4-hydroxyphenyl)ethyl]-2,2-dimethyl-1,3-oxazolidine-3-carboxylate Chemical compound CC(C)(C)OC(=O)N1C(C)(C)OCC1(CO)CCC1=CC=C(O)C=C1 IAWVFXPPNCZKDM-UHFFFAOYSA-N 0.000 description 3
- 150000003536 tetrazoles Chemical class 0.000 description 3
- CNCUKGDUDOASDV-UHFFFAOYSA-N 1-bromo-6-fluorohexane Chemical compound FCCCCCCBr CNCUKGDUDOASDV-UHFFFAOYSA-N 0.000 description 2
- IZXIZTKNFFYFOF-UHFFFAOYSA-N 2-Oxazolidone Chemical compound O=C1NCCO1 IZXIZTKNFFYFOF-UHFFFAOYSA-N 0.000 description 2
- GUXJXWKCUUWCLX-UHFFFAOYSA-N 2-methyl-2-oxazoline Chemical compound CC1=NCCO1 GUXJXWKCUUWCLX-UHFFFAOYSA-N 0.000 description 2
- JVIUOMCSCXPLGW-UHFFFAOYSA-N 4-[2-[4-(hydroxymethyl)-2-methyl-5h-1,3-oxazol-4-yl]ethyl]phenol Chemical compound C1OC(C)=NC1(CO)CCC1=CC=C(O)C=C1 JVIUOMCSCXPLGW-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 102100039498 Cytotoxic T-lymphocyte protein 4 Human genes 0.000 description 2
- 201000004624 Dermatitis Diseases 0.000 description 2
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 101000889276 Homo sapiens Cytotoxic T-lymphocyte protein 4 Proteins 0.000 description 2
- 101100236683 Homo sapiens MBTPS1 gene Proteins 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 206010040070 Septic Shock Diseases 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- LRFKWQGGENFBFO-IBGZPJMESA-N [(2s)-2-amino-2-(hydroxymethyl)-4-(4-octylphenyl)butyl] dihydrogen phosphate Chemical compound CCCCCCCCC1=CC=C(CC[C@](N)(CO)COP(O)(O)=O)C=C1 LRFKWQGGENFBFO-IBGZPJMESA-N 0.000 description 2
- OODGLKXIVVEXCZ-UHFFFAOYSA-N [2-(hydroxymethyl)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-4-(4-phenylmethoxyphenyl)butyl] 2-nitrobenzoate Chemical compound C=1C=CC=C([N+]([O-])=O)C=1C(=O)OCC(CO)(NC(=O)OC(C)(C)C)CCC(C=C1)=CC=C1OCC1=CC=CC=C1 OODGLKXIVVEXCZ-UHFFFAOYSA-N 0.000 description 2
- ZAFLJLGNVIFOMX-UHFFFAOYSA-N [2-methyl-4-[2-(4-phenylmethoxyphenyl)ethyl]-5h-1,3-oxazol-4-yl]methanol Chemical compound C1OC(C)=NC1(CO)CCC(C=C1)=CC=C1OCC1=CC=CC=C1 ZAFLJLGNVIFOMX-UHFFFAOYSA-N 0.000 description 2
- 239000008186 active pharmaceutical agent Substances 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 229910052786 argon Inorganic materials 0.000 description 2
- 208000006673 asthma Diseases 0.000 description 2
- RQPZNWPYLFFXCP-UHFFFAOYSA-L barium dihydroxide Chemical compound [OH-].[OH-].[Ba+2] RQPZNWPYLFFXCP-UHFFFAOYSA-L 0.000 description 2
- 229910001863 barium hydroxide Inorganic materials 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 2
- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 238000011260 co-administration Methods 0.000 description 2
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Description
より特には、本発明は、式I:
mおよびnはそれぞれ、独立して、1、2または3であり;
Xは、Oまたは直接結合であり;
R1は、
−フェニルアルキル(ここで、アルキルは、直鎖または分岐(C6−20)炭素鎖である)であるか;または
−フェニルアルキル(ここで、アルキルは、直鎖または分岐(C1−30)炭素鎖である)であり、ここで該フェニルアルキルは、
−所望によりハロゲンにより置換されていて良い直鎖または分岐(C6−20)炭素鎖、
−所望によりハロゲンにより置換されていて良い直鎖または分岐(C6−20)アルコキシ鎖、
−直鎖または分岐(C6−20)アルケニルオキシ、
−フェニルアルコキシ、ハロフェニルアルコキシ、フェニルアルコキシアルキル、フェノキシアルコキシまたはフェノキシアルキル、
−C6−20アルキルにより置換されるシクロアルキルアルキル、
−C6−20アルキルにより置換されるヘテロアリールアルキル、
−ヘテロ環式C6−20アルキル、または
−C2−20アルキルにより置換されるヘテロ環式アルキル
によりフェニル残基にて置換されており、
かつ、前記アルキル部分は、
−炭素鎖にて、二重結合、三重結合、O、S、スルフィニル、スルホニルまたはNR5(ここで、R5は、H、アルキル、アラルキル、アシルまたはアルコキシカルボニルである)から選択される結合またはヘテロ原子、および
−置換基として、アルコキシ、アルケニルオキシ、アルキニルオキシ、アラルキルオキシ、アシル、アルキルアミノ、アルキルチオ、アシルアミノ、アルコキシカルボニル、アルコキシカルボニルアミノ、アシルオキシ、アルキルカルバモイル、ニトロ、ハロゲン、アミノ、ヒドロキシまたはカルボキシ、
を有し得、そして
で示される、遊離型または塩形態の化合物を提供する。
シクロアルキルは、好ましくはC3−10シクロアルキル、より好ましくはC3−8シクロアルキルであり、例えば、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシルまたはシクロヘプチルが含まれる。
アシルは、基Ry−CO−(ここで、RyはC1−6アルキル、C3−6シクロアルキル、フェニルまたはフェニル−C1−4アルキルである)であり得る。
1.mおよびnはそれぞれ1または2、好ましくは1である。
2.XはOである。
3.R1は、C13−20アルキルであり、所望によりニトロ、ハロゲン、アミノ、ヒドロキシまたはカルボキシにより置換されていてよく、より好ましくはR1は、所望によりハロゲンにより置換されていてよいC6−14−アルキル鎖により置換されるフェニルアルキルであり、前記アルキル部分は、所望によりヒドロキシにより置換されていてよいC1−6アルキルである。より好ましくは、R1は、直鎖または分岐鎖、好ましくは直鎖C6−14アルキル鎖によりフェニルを置換されるフェニル−C1−6アルキル、例えば、フェニル−C1−6アルキル、例えば、フェニル−C2アルキルである。前記C6−14アルキル鎖は、オルト、メタまたはパラ、好ましくはパラであり得る。
4.R3およびR4はそれぞれHである。
式Iの化合物は、遊離型または塩形態で、例えば、塩酸、臭化水素または硫酸などの例えば無機酸との付加塩、酢酸、フマル酸、マレイン酸、安息香酸、クエン酸、リンゴ酸、メタンスルホン酸またはベンゼンスルホン酸塩などの有機酸との塩で存在し得る;R3またはR4がHであるとき、R2は、例えばアンモニウム塩またはナトリウム、カリウム、カルシウム、亜鉛あるいはマグネシウム、またはその混合物などの金属との塩などの塩形態でも存在し得る。式Iの化合物、および水和物または溶媒和物の形態のその塩もまた、本発明の一部である。
で示される化合物と、芳香族1,2−ジカルバルデヒド、例えば、ベンゼン−1,2−ジカルバルデヒドを反応させ、得られる式Iの化合物を遊離型または塩形態で回収することにより製造され得る。
式IIの化合物(例えば、そのラセミ混合物)を、WO 02/18395またはWO 02/076995に記載の通りに得ることができる。
a)キラル固定相のクロマトグラフィーを用いて、式Iの化合物のラセミ混合物にてRエナンチオマーからSエナンチオマーを分離すること;または
b)前記化合物の70重量%以上がRまたはSエナンチオマーの形態である式IIの化合物、例えば、式IIの化合物の本質的に純粋なRまたはSエナンチオマーと、芳香族1,2−ジカルバルデヒド、例えば、ベンゼン−1,2−ジカルバルデヒドを反応させること
により得ることができる。
で示される化合物(ここで、式IIIの化合物の70重量%以上がRまたはSエナンチオマーの形態である)を脱保護すること、および要すれば、遊離型で得られる式Iの化合物を所望の塩形態に変換すること、またはその逆により得ることができる。
で示される化合物(ここで、式IIIaまたはIIIbの化合物の70重量%以上がRまたはSエナンチオマーの形態である)を脱保護することにより得ることができる。
で示される化合物にてR2’に存在する加水分解性基を除去することにより得ることができる。
で示される化合物を、リン酸化試薬、例えば、ホスホロクロリデート、例えば、ジフェニルクロロホスフェートまたはジベンジルクロロホスフェート、シアノエチルホスフェート、N−フェニルホスホラミデートなどのホスホラミデート、3−(ジエチルアミノ)−1,5−ジヒドロ−2,4,3−ベンゾジオキサホスフェピンなどと反応させることにより得ることができる。前記反応を、当技術分野で公知の方法、例えば、上記のJ.Org.Chem.に開示のように行うことができる。式IIIaの化合物にて、前記アミノ基は、好ましくは、R4がアシル以外のときR’4としての保護形態である。
で示される化合物を、還元条件下、例えばNaHの存在下、リン酸化試薬、例えば、亜リン酸ジエチルと反応させることにより得ることができる。前記反応を、当技術分野で公知の方法により行うことができる。
で示される化合物を、アミノ保護基供与化合物と反応させることにより製造することができる。式Va、Va’、VbまたはVb’の化合物を、式VIの化合物をOHおよびアミノ保護化合物と反応させることにより製造することができ、例えばOHおよびアミノ保護を、環状基、例えば5から7員のヘテロ環、例えば、オキサゾリジン−2−オンまたは2−メチル−4,5−ジヒドロ−オキサゾールを得るために、式VIの遊離アミノアルコールまたはアミノジオールを、例えば、Cbo−Cl、Boc無水物、オルト酢酸トリエチルおよびアセトニトリル、またはホスゲンと塩基性条件下で反応させることにより同時に行うことができる。
で示される化合物(ここで、化合物の70重量%以上がRまたはSエナンチオマー形態である)を脱保護し、加水分解することにより得ることができる。
RT = 室温
CBO = ベンジルオキシカルボニル
FTY720 = 2−アミノ−2−[2−(4−オクチルフェニル)エチル]プロパン−1,3−ジオール
EDTA = エチレンジアミンテトラ酢酸
OPA = オルト−フタルアルデヒド(ベンゼン−1,2−ジカルバルデヒド)
クロロギ酸ベンジル(0.45ml;3.2mmol)を、FTY720.HCl(1.03g、3mmol)の2N NaOH(20ml)懸濁液に加える。反応を一晩RTに維持し、反応を完全にするためにさらにクロロギ酸ベンジル(0.9ml;6.4mmol)を加える。RTで2日後、反応物を1N HClで酸性化し、塩化メチレンで抽出し、移動相として塩化メチレン/メタノール/酢酸50%(9/1/0.125)を用いたシリカゲルのカラムで精製する。
[M+H]+:334(ESI−MS)
a)の最終産物(2.4g;7.2mmol)の塩化メチレン/THF 1/1(100ml)溶液に、0℃で、テトラゾール(再結晶化;2.52g;36mmol)および3−(ジエチルアミノ)−1,5−ジヒドロ−2,4,3−ベンゾジオキサホスフェピントリフェニル−亜リン酸塩(5.17g;21.6mmol)を加える。RTで18時間後、H2O2(8.2ml[30%水溶液];72mmol)を、(冷ましながら)溶液に加え、さらに90分間RTで維持する。飽和Na2S2O3溶液(100ml)でクエンチ後、反応物を酢酸エチル(3回)で抽出する。有機層をNa2SO4で乾燥させ、化合物を移動相としてシクロヘキサン/酢酸エチル 1/1を用いて精製する。
工程b)の最終産物(1.03g;2mmol)を、通常の圧力(Pd/C10%;50mg)で90分かけて水素化する。ろ過後、反応物を濃縮し、さらなる精製なしに工程d)に用いる。
工程c)の最終産物のエタノール溶液(20ml)に、LiOH(20ml;10%水溶液)を加える。還流にて24時間後、反応物をHCl(水中1N)で中和し濃縮する。残渣を氷酢酸(5ml)で処理し、水(50ml)の添加後に生じる最終産物を沈殿させる。ろ過後、(水で)洗浄し乾燥させることにより、純粋な最終産物をさらなる精製なしに得る。
工程d)の最終産物((R/S)−FTY720−リン酸塩)(50mg;0.125mmol)を、EDTA(0.5ml;水中10mM)およびホウ酸水溶液(0.5ml;水中3%;KOH10%水溶液でpH10.5に合わせた)の溶液に懸濁する。OPA(33mg、0.25mmol)を添加後、エタノール(0.5ml)に溶解し、反応を1時間RTに維持する(超音波)。その後、pHを3.5に合わせ(HCl水溶液;1N)、酢酸エチル(3回)で抽出する。有機層をNa2SO4で乾燥させ、前記化合物を移動相として塩化メチレン/メタノール(95/5→0/100)を用いてシリカゲルで精製する。
[M−H]−:502.5(ESI−MS)
a)4−(2−ヒドロキシ−エチル)−フェノール(50g、0.36mol)のエタノール溶液(400ml)に、炭酸カリウム(75g、0.54mol、1.5当量)および臭化ベンジル(47.2ml、0.39mol、1.1当量)を加え、反応混合物をRTで一晩撹拌する。その後、反応混合物をセライトを通してろ過し、真空下で濃縮する。2−(4−ベンジルオキシ−フェニル)−エタノールを、ジエチルエーテルで結晶化後に単離する。
ラセミ体 4−ヒドロキシメチル−4−[2−(4−ヒドロキシ−フェニル)−エチル]−2,2−ジメチル−オキサゾリジン−3−カルボン酸tert−ブチルエステルの0.1%エタノール溶液10マイクロリットルを、Chiralcel OD−Hカラム(0.46×25cm;Chiral Technologiesにより市販されている)に注入する。クロマトグラフィー分離を、室温にて、移動相としてn−ヘキサン/エタノール 90/10(容量)混合物含有0.1%トリフルオロ酢酸(TFA)を用いて1ml/分の流速で行う。検出を、210nmのUVにより行う。エナンチオマーは、7.23分および9.39分後にそれぞれ溶出する(分離係数α:1.52)。
ラセミ体 リン酸ジエチルエステル4−(2−{4−[2−(3−フルオロ−4−メトキシ−フェニル)−エトキシ]−フェニル}−エチル)−2−メチル−4,5−ジヒドロ−オキサゾール−4−イルメチルエステルの0.1%エタノール溶液10マイクロリットルを、Chiralcel OD−Hカラム(0.46×25cm;Chiral Technologiesから市販されている)に注入する。クロマトグラフィー分離を、室温にて、移動相としてn−ヘキサン/エタノール 95/5(容量)混合物を用いて1ml/分の流速で行う。検出を、210nmのUVにより行う。エナンチオマーは、31.17分および35.44分後にそれぞれ溶出する(分離係数α:1.15)。
エナンチオマー リン酸ジエチルエステル4−(2−{4−[2−(3−フルオロ−4−メトキシ−フェニル)−エトキシ]−フェニル}−エチル)−2−メチル−4,5−ジヒドロ−オキサゾール−4−イルメチルエステルの混合物の0.1%エタノール溶液10マイクロリットルを、Chiralcel OJ−Hカラム(0.46×25cm;Chiral Technologiesから市販されている)に注入する。クロマトグラフィー分離を、室温にて、移動相としてn−ヘキサン/2−プロパノール 75/25(容量)混合物を用いて1ml/分の流速で行う。検出を、210nmのUVにより行う。エナンチオマーは、13.89分および16.77分後にそれぞれ溶出する(分離係数α:1.27)。
エナンチオマー リン酸ジエチルエステル(S)−2−メチル−4−[2−(4−オクチル−フェニル)−エチル]−4,5−ジヒドロ−オキサゾール−4−イルメチルエステルの混合物の0.1%エタノール溶液10マイクロリットルを、Chiralpak AD−Hカラム(0.46×25cm;Chiral Technologiesから市販されている)に注入する。クロマトグラフィー分離を、室温にて、移動相としてn−ヘキサン/エタノール 95/5(容量)混合物を用いて1ml/分の流速で行う。検出を、210nmのUVにより行う。エナンチオマーは、10.35分および12.32分後にそれぞれ溶出する(分離係数α:1.27)。
本発明の化合物は、下記の分析にて決定されるように個々のヒトS1P受容体に対する結合親和力を有する:
HEK293細胞へのヒトS1P受容体の一過性トランスフェクション
S1P受容体およびGiタンパク質をクローニングし、等量のS1P受容体の4個のcDNA、Gi−α、Gi−βおよびGi−γを混合し、そしてリン酸カルシウム沈殿法(M. Wigler et al., Cell. 1977,;11;223およびDS. Im et al., Mol. Pharmacol. 2000;57;753)を用いてHEK293細胞の単層にトランスフェクトするために用いる。簡単には、25μgのDNAを含むDNA混合物および0.25M CaClを、HEPES緩衝2mM Na2HPO4に加える。HEK293細胞のサブコンフルエントな単層を25mM クロロキンで毒化し、その後DNA沈殿物を前記細胞に用いる。4時間後、前記単層をリン酸緩衝食塩水およびrefed培地(90% 1:1 ダルベッコの修飾必須培地(DMEM):F−12+10%ウシ胎児血清)で洗浄する。細胞を、DNAの添加後48−72時間で、10%スクロースを含むHME緩衝液(1mM中:20 HEPES、5 MgCl2、1 EDTA、pH7.4)中に氷上で剥離することにより集め、Dounce ホモジナイザーを用いて破壊する。800×gで遠心後、上清をスクロース不含有HMEで希釈し、100,000×gで1時間遠心する。得られるペレットを再ホモジナイズし、100,000×gでさらに1時間遠心する。この粗膜ペレットをスクロース含有HMEに再懸濁し、アリコートに分け、液体窒素に浸して簡易に凍結する。その膜を−70℃で保存する。タンパク質濃度を、Bradfordタンパク質分析により分光学的に測定する。
GTPγS結合実験を、DS. Im et al., Mol. Pharmacol. 2000; 57:753に記載の通りに行う。Gタンパク質とのリガンド仲介GTPγS結合を、一過性トランスフェクションしたHEK293細胞からの膜調製物25μgを用いて、GTP結合緩衝液(1mM中:50 HEPES、100 NaCl、10 MgCl2、pH7.5)にて測定する。リガンドを、10μM GDPおよび0.1nM[35S]GTPγS(1200Ci/mmol)の存在下で膜に加え、30℃で30分間インキュベートする。結合GTPγSを、ブランデル・ハーベスター(Gaithersburg、MD)を用いて非結合のものから分け、液体シンチレーションカウンターで計測する。
これらの分析にて、本発明の化合物は、マイクロMより低い範囲でS1P受容体との結合親和性を有する。
S1P受容体に非常に高濃度でのみアゴニスト作用を示す(R)−FTY720−リン酸塩とは対照的に、(S)−FTY720−リン酸塩は、S1P1およびS1P3の完全なアゴニストであり、低いナノモル範囲でS1P4およびS1P5の部分的アゴニストである。
本発明の化合物またはビヒクルを、ラットに強制経口投与により投与する。血液測定のための尾の血液を個々の基準値を得るために−1日目に、そして薬剤投与後2、6、24、48および72時間後に得る。この分析にて、本発明の化合物は、0.03から3mg/kgの投与量で投与したとき、末梢血リンパ球を枯渇させる。
1.1 例えば上記のような、リンパ球により仲介される障害または疾患を予防または処置するための方法であって、かかる処置を必要とする対象にて、70重量%以上のRまたはSエナンチオマーを含む式IIの化合物またはその薬学的に許容される塩の有効量を該対象に投与することを含む方法;
3. 例えば、上記の1.1または1.2のいずれかの方法における使用のための、薬学的に許容される希釈剤またはその担体と共に遊離型または薬学的に許容される塩形態の70重量%以上のRまたはSエナンチオマーを含む式IIの化合物を含む医薬組成物。
を提供する。前記キットは、その投与のための説明書を含み得る。
Claims (13)
- 遊離形または塩形の、式I:
mおよびnは、それぞれ独立して、1、2または3であり;
Xは、Oまたは直接結合であり;
R1は、
フェニルアルキル(ここで、アルキルは、直鎖または分岐(C6−20)炭素鎖である)であるか;または
フェニルアルキル(ここで、アルキルは、直鎖または分岐(C1−30)炭素鎖である)であり、ここで該フェニルアルキルは、フェニル部分において、
所望によりハロゲンにより置換されていてもよい直鎖または分岐(C6−20)炭素鎖、
所望によりハロゲンにより置換されていてもよい直鎖または分岐(C6−20)アルコキシ鎖、
直鎖または分岐(C6−20)アルケニルオキシ、
フェニルアルコキシ、ハロフェニルアルコキシ、フェニルアルコキシアルキル、フェノ キシアルコキシまたはフェノキシアルキル、
C6−20アルキルにより置換されているシクロアルキルアルキル、
C6−20アルキルにより置換されているヘテロアリールアルキル、
ヘテロ環式C6−20アルキル、または
C2−20アルキルにより置換されているヘテロ環式アルキル
により置換されており、
そして、前記アルキル部分において、
炭素鎖に、二重結合、三重結合、O、S、スルフィニル、スルホニルまたはNR5(ここで、R5は、H、アルキル、アラルキル、アシルまたはアルコキシカルボニルである)から選択される結合またはヘテロ原子、および
置換基として、アルコキシ、アルケニルオキシ、アルキニルオキシ、アラルキルオキシ 、アシル、アルキルアミノ、アルキルチオ、アシルアミノ、アルコキシカルボニル、ア ルコキシカルボニルアミノ、アシルオキシ、アルキルカルバモイル、ニトロ、ハロゲン 、アミノ、ヒドロキシまたはカルボキシ
を有することができるものであり;
そして
R2は、
で示される、化合物。 - 式IIで示される化合物が、リン酸モノ−[2−アミノ−2−ヒドロキシメチル−4−(4−オクチル−フェニル)−ブチル]エステルである、請求項3に記載の方法。
- 請求項3に記載の式III、IIIaまたはIIIbで示される化合物であって、その70重量%以上がRまたはSエナンチオマーであるものの製造法であって、
式III、IIIaまたはIIIbで示される化合物のラセミ混合物中のRエナンチオマーからSエナンチオマーを、ポリサッカライドに基づくキラル固定相を有するクロマトグラフィーまたは疑似移動床クロマトグラフィーの使用により分離することを特徴とする方法。 - 固定相がアミロース型相である、請求項5に記載の方法。
- 請求項1に記載の式Iで示される化合物のラセミ混合物からRまたはSエナンチオマーを分離する方法であって、
当該分離を、カルバミン酸キニーネまたはカルバミン酸キニジンに基づくキラルイオン交換相を用いる高速液体クロマトグラフィー(HPLC)により行うことを特徴とする方法。 - 試料中に存在する請求項2に記載の式IIで示される化合物のRおよび/またはS異性体の量を測定する方法であって、
(a)試料中に存在する請求項2に記載の式IIで示される化合物と芳香族1,2−ジカルバルデヒドを反応させて、請求項1に記載の式Iで示される化合物を形成し、そして(b)HPLCにより当該化合物のRおよびS異性体を分離することを特徴とする方法。 - HPLCがカルバミン酸キニーネまたはカルバミン酸キニジンに基づくキラルイオン交換相を用いて行われる、請求項9に記載の方法。
- 式IIで示される化合物がリン酸モノ−[2−アミノ−2−ヒドロキシメチル−4−(4−オクチル−フェニル)−ブチル]エステルである、請求項9または10に記載の方法。
- Sエナンチオマーの血中濃度をモニターするための、請求項9〜11のいずれかに記載の方法。
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WO2006009092A1 (ja) * | 2004-07-16 | 2006-01-26 | Kyorin Pharmaceutical Co., Ltd. | 効果的な医薬の使用法及び副作用発現の防御に関する方法 |
EP1806338B1 (en) | 2004-10-12 | 2016-01-20 | Kyorin Pharmaceutical Co., Ltd. | Process for producing 2-amino-2-[2-[4-(3-benzyloxy-phenylthio)-2-chlorophenyl[ethyl]-1,3-propanediol hydrochloride and hydrates thereof. and intermediates the production thereof |
DK2295049T3 (en) * | 2005-09-09 | 2015-02-23 | Novartis Ag | Treatment of autoimmune diseases |
CN101277687B (zh) * | 2005-10-07 | 2012-07-18 | 杏林制药株式会社 | 以2-氨基-1,3-丙二醇衍生物作为有效成分的肝脏疾病治疗剂及肝脏疾病治疗方法 |
TWI389683B (zh) * | 2006-02-06 | 2013-03-21 | Kyorin Seiyaku Kk | A therapeutic agent for an inflammatory bowel disease or an inflammatory bowel disease treatment using a 2-amino-1,3-propanediol derivative as an active ingredient |
MX2009001457A (es) * | 2006-08-08 | 2009-02-19 | Kyorin Seiyaku Kk | Derivados de aminoalcohol e inmunosupresores que contienen lo mismo como ingrediente activo. |
SG174028A1 (en) | 2006-08-08 | 2011-09-29 | Kyorin Seiyaku Kk | Aminophosphoric acid ester derivative and s1p receptor modulator containing the same as active ingredient |
AU2008310846C1 (en) | 2007-10-12 | 2022-10-06 | Novartis Ag | Compositions comprising sphingosine 1 phosphate (S1P) receptor modulators |
TW200946105A (en) | 2008-02-07 | 2009-11-16 | Kyorin Seiyaku Kk | Therapeutic agent or preventive agent for inflammatory bowel disease containing amino alcohol derivative as active ingredient |
MX354134B (es) | 2008-07-23 | 2018-02-14 | Arena Pharm Inc | Derivados de acido 1,2,3,4-tetrahidrociclopenta [b] indol-3-il) acetico sustituidos utiles en el tratamiento de enfermedades autoinmune e inflamatorias. |
CA2733671C (en) | 2008-08-27 | 2018-01-02 | Arena Pharmaceuticals, Inc. | Substituted tricyclic acid derivatives as s1p1 receptor agonists useful in the treatment of autoimmune and inflammatory disorders |
WO2011070066A1 (en) * | 2009-12-10 | 2011-06-16 | Novartis Ag | Fty720 halogenated derivatives |
EP4148045A1 (en) | 2010-01-27 | 2023-03-15 | Arena Pharmaceuticals, Inc. | Intermediate compounds for the preparation of (r)-2-(7-(4-cyclopentyl-3- (trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b] indol-3-yl)acetic acid and salts thereof |
SG10201501575VA (en) | 2010-03-03 | 2015-04-29 | Arena Pharm Inc | Processes for the preparation of s1p1 receptor modulators and crystalline forms thereof |
MA34285B1 (fr) | 2010-05-06 | 2013-06-01 | Novartis Ag | Traitement de maladies autoimmunes |
JP2013525469A (ja) | 2010-05-06 | 2013-06-20 | ノバルティス アーゲー | ジアリールスルフィド誘導体の投与レジメン |
JPWO2012105574A1 (ja) * | 2011-01-31 | 2014-07-03 | 国立大学法人 長崎大学 | 光学活性化合物又はその塩の製造方法 |
AU2016205361C1 (en) | 2015-01-06 | 2021-04-08 | Arena Pharmaceuticals, Inc. | Methods of treating conditions related to the S1P1 receptor |
IL285890B (en) | 2015-06-22 | 2022-07-01 | Arena Pharm Inc | Slate-free crystal of the arginine salt of (Ar)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-4,3,2,1-tetrahydro-cyclopent[b]indole-3-yl ) acetic acid |
US11534424B2 (en) | 2017-02-16 | 2022-12-27 | Arena Pharmaceuticals, Inc. | Compounds and methods for treatment of primary biliary cholangitis |
US11478448B2 (en) | 2017-02-16 | 2022-10-25 | Arena Pharmaceuticals, Inc. | Compounds and methods for treatment of inflammatory bowel disease with extra-intestinal manifestations |
GB201715786D0 (en) * | 2017-09-29 | 2017-11-15 | Univ College Cardiff Consultants Ltd | Compounds |
US11555015B2 (en) | 2018-09-06 | 2023-01-17 | Arena Pharmaceuticals, Inc. | Compounds useful in the treatment of autoimmune and inflammatory disorders |
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