JP5441894B2 - イソファゴミンおよびその誘導体を製造する新規な方法 - Google Patents
イソファゴミンおよびその誘導体を製造する新規な方法 Download PDFInfo
- Publication number
- JP5441894B2 JP5441894B2 JP2010509556A JP2010509556A JP5441894B2 JP 5441894 B2 JP5441894 B2 JP 5441894B2 JP 2010509556 A JP2010509556 A JP 2010509556A JP 2010509556 A JP2010509556 A JP 2010509556A JP 5441894 B2 JP5441894 B2 JP 5441894B2
- Authority
- JP
- Japan
- Prior art keywords
- derivative
- protected
- arabinose
- converting
- xylose
- 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
Links
- QPYJXFZUIJOGNX-HSUXUTPPSA-N afegostat Chemical compound OC[C@H]1CNC[C@@H](O)[C@@H]1O QPYJXFZUIJOGNX-HSUXUTPPSA-N 0.000 title claims description 36
- 238000004519 manufacturing process Methods 0.000 title claims description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 115
- 238000006243 chemical reaction Methods 0.000 claims description 66
- 239000002904 solvent Substances 0.000 claims description 55
- -1 methoxybenzyl Chemical group 0.000 claims description 42
- 239000002253 acid Substances 0.000 claims description 38
- 150000003741 xylose derivatives Chemical class 0.000 claims description 37
- 150000002825 nitriles Chemical class 0.000 claims description 33
- 230000015572 biosynthetic process Effects 0.000 claims description 29
- SRBFZHDQGSBBOR-UHFFFAOYSA-N beta-D-Pyranose-Lyxose Natural products OC1COC(O)C(O)C1O SRBFZHDQGSBBOR-UHFFFAOYSA-N 0.000 claims description 28
- 229930182470 glycoside Natural products 0.000 claims description 24
- 150000002338 glycosides Chemical class 0.000 claims description 24
- 150000002009 diols Chemical class 0.000 claims description 22
- 238000000034 method Methods 0.000 claims description 22
- 230000004913 activation Effects 0.000 claims description 21
- 150000001479 arabinose derivatives Chemical class 0.000 claims description 20
- 150000003839 salts Chemical class 0.000 claims description 19
- PYMYPHUHKUWMLA-UHFFFAOYSA-N arabinose Natural products OCC(O)C(O)C(O)C=O PYMYPHUHKUWMLA-UHFFFAOYSA-N 0.000 claims description 17
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 17
- 150000001875 compounds Chemical class 0.000 claims description 17
- 125000006239 protecting group Chemical group 0.000 claims description 17
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 14
- 239000012190 activator Substances 0.000 claims description 11
- 150000002148 esters Chemical class 0.000 claims description 11
- WURBFLDFSFBTLW-UHFFFAOYSA-N benzil Chemical compound C=1C=CC=CC=1C(=O)C(=O)C1=CC=CC=C1 WURBFLDFSFBTLW-UHFFFAOYSA-N 0.000 claims description 10
- SRBFZHDQGSBBOR-MBMOQRBOSA-N alpha-D-arabinopyranose Chemical compound O[C@@H]1CO[C@H](O)[C@@H](O)[C@@H]1O SRBFZHDQGSBBOR-MBMOQRBOSA-N 0.000 claims description 8
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims description 8
- PYMYPHUHKUWMLA-WISUUJSJSA-N aldehydo-L-xylose Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)C=O PYMYPHUHKUWMLA-WISUUJSJSA-N 0.000 claims description 5
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 5
- PYMYPHUHKUWMLA-WDCZJNDASA-N arabinose Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)C=O PYMYPHUHKUWMLA-WDCZJNDASA-N 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000002924 primary amino group Chemical class [H]N([H])* 0.000 claims description 3
- 238000007127 saponification reaction Methods 0.000 claims description 3
- 230000008569 process Effects 0.000 claims description 2
- 125000004803 chlorobenzyl group Chemical group 0.000 claims 2
- 125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims 2
- 125000005982 diphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 81
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical class OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 81
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 62
- IWVRQJNSUOIUFV-VGRMVHKJSA-N n-[(2r,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)piperidin-2-yl]acetamide Chemical compound CC(=O)N[C@H]1NC[C@H](CO)[C@H](O)[C@@H]1O IWVRQJNSUOIUFV-VGRMVHKJSA-N 0.000 description 61
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical class CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 50
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 45
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 43
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 42
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 41
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 40
- 239000000203 mixture Substances 0.000 description 37
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 35
- 239000007787 solid Substances 0.000 description 35
- 239000000047 product Substances 0.000 description 33
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 31
- 239000000243 solution Substances 0.000 description 31
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical class OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 30
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 30
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 28
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 28
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 28
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 27
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 25
- 238000003786 synthesis reaction Methods 0.000 description 25
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 25
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 description 24
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 21
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 21
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 21
- 230000002829 reductive effect Effects 0.000 description 20
- 238000000746 purification Methods 0.000 description 18
- 239000011975 tartaric acid Substances 0.000 description 18
- 235000002906 tartaric acid Nutrition 0.000 description 18
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 17
- 125000000217 alkyl group Chemical group 0.000 description 17
- 238000005984 hydrogenation reaction Methods 0.000 description 17
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 16
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 15
- 238000002425 crystallisation Methods 0.000 description 15
- 230000008025 crystallization Effects 0.000 description 15
- 239000012454 non-polar solvent Substances 0.000 description 15
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 14
- 229910052757 nitrogen Inorganic materials 0.000 description 14
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 14
- 239000007858 starting material Substances 0.000 description 14
- 235000019445 benzyl alcohol Nutrition 0.000 description 13
- 229940095064 tartrate Drugs 0.000 description 13
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 13
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 12
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 12
- 239000012346 acetyl chloride Substances 0.000 description 12
- 239000000543 intermediate Substances 0.000 description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- 238000011068 loading method Methods 0.000 description 11
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 10
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 10
- 239000012458 free base Substances 0.000 description 10
- 239000011541 reaction mixture Substances 0.000 description 10
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 description 9
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 150000007513 acids Chemical class 0.000 description 9
- 150000001298 alcohols Chemical class 0.000 description 9
- 230000000694 effects Effects 0.000 description 9
- 239000012074 organic phase Substances 0.000 description 9
- 239000000376 reactant Substances 0.000 description 9
- 238000006467 substitution reaction Methods 0.000 description 9
- 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 9
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 8
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 8
- 229910052799 carbon Inorganic materials 0.000 description 8
- 239000003054 catalyst Substances 0.000 description 8
- 238000001914 filtration Methods 0.000 description 8
- FGIUAXJPYTZDNR-UHFFFAOYSA-N potassium nitrate Chemical group [K+].[O-][N+]([O-])=O FGIUAXJPYTZDNR-UHFFFAOYSA-N 0.000 description 8
- 238000006722 reduction reaction Methods 0.000 description 8
- QWOJMRHUQHTCJG-UHFFFAOYSA-N CC([CH2-])=O Chemical compound CC([CH2-])=O QWOJMRHUQHTCJG-UHFFFAOYSA-N 0.000 description 7
- SRBFZHDQGSBBOR-IOVATXLUSA-N D-xylopyranose Chemical compound O[C@@H]1COC(O)[C@H](O)[C@H]1O SRBFZHDQGSBBOR-IOVATXLUSA-N 0.000 description 7
- 102000004190 Enzymes Human genes 0.000 description 7
- 108090000790 Enzymes Proteins 0.000 description 7
- 239000006184 cosolvent Substances 0.000 description 7
- 238000010511 deprotection reaction Methods 0.000 description 7
- 229910052500 inorganic mineral Inorganic materials 0.000 description 7
- 235000010755 mineral Nutrition 0.000 description 7
- 239000011707 mineral Substances 0.000 description 7
- 229910052763 palladium Inorganic materials 0.000 description 7
- 230000009467 reduction Effects 0.000 description 7
- RWHQMRRVZJSKGX-UHFFFAOYSA-N 2-oxobutanal Chemical compound CCC(=O)C=O RWHQMRRVZJSKGX-UHFFFAOYSA-N 0.000 description 6
- SRBFZHDQGSBBOR-OWMBCFKOSA-N L-ribopyranose Chemical compound O[C@H]1COC(O)[C@@H](O)[C@H]1O SRBFZHDQGSBBOR-OWMBCFKOSA-N 0.000 description 6
- 150000001412 amines Chemical class 0.000 description 6
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 6
- 239000002585 base Substances 0.000 description 6
- 239000003153 chemical reaction reagent Substances 0.000 description 6
- 229910052739 hydrogen Inorganic materials 0.000 description 6
- 239000001257 hydrogen Substances 0.000 description 6
- 229910052760 oxygen Inorganic materials 0.000 description 6
- 239000001301 oxygen Substances 0.000 description 6
- 238000001556 precipitation Methods 0.000 description 6
- 239000000741 silica gel Substances 0.000 description 6
- 229910002027 silica gel Inorganic materials 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 238000004809 thin layer chromatography Methods 0.000 description 6
- GLNXCVYWFLIUFZ-IJLUTSLNSA-N (2s,3r,4r)-2-benzyl-2,3,4,5-tetrahydroxypentanal Chemical compound OC[C@@H](O)[C@@H](O)[C@](O)(C=O)CC1=CC=CC=C1 GLNXCVYWFLIUFZ-IJLUTSLNSA-N 0.000 description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 5
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 5
- 229910052783 alkali metal Inorganic materials 0.000 description 5
- 150000001340 alkali metals Chemical class 0.000 description 5
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 description 5
- 229940073608 benzyl chloride Drugs 0.000 description 5
- OILAIQUEIWYQPH-UHFFFAOYSA-N cyclohexane-1,2-dione Chemical compound O=C1CCCCC1=O OILAIQUEIWYQPH-UHFFFAOYSA-N 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- NHGXDBSUJJNIRV-UHFFFAOYSA-M tetrabutylammonium chloride Chemical compound [Cl-].CCCC[N+](CCCC)(CCCC)CCCC NHGXDBSUJJNIRV-UHFFFAOYSA-M 0.000 description 5
- PCZOZSATUTWXIC-UHFFFAOYSA-N tetraethylazanium;cyanide Chemical compound N#[C-].CC[N+](CC)(CC)CC PCZOZSATUTWXIC-UHFFFAOYSA-N 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- JQPFYXFVUKHERX-UHFFFAOYSA-N 2-hydroxy-2-cyclohexen-1-one Natural products OC1=CCCCC1=O JQPFYXFVUKHERX-UHFFFAOYSA-N 0.000 description 4
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 4
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 4
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 4
- QSJXEFYPDANLFS-UHFFFAOYSA-N Diacetyl Chemical compound CC(=O)C(C)=O QSJXEFYPDANLFS-UHFFFAOYSA-N 0.000 description 4
- 208000015872 Gaucher disease Diseases 0.000 description 4
- 239000002841 Lewis acid Substances 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 238000007792 addition Methods 0.000 description 4
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 4
- 150000004703 alkoxides Chemical class 0.000 description 4
- 230000029936 alkylation Effects 0.000 description 4
- 238000005804 alkylation reaction Methods 0.000 description 4
- 239000000908 ammonium hydroxide Substances 0.000 description 4
- 150000008064 anhydrides Chemical class 0.000 description 4
- HOPRXXXSABQWAV-UHFFFAOYSA-N anhydrous collidine Natural products CC1=CC=NC(C)=C1C HOPRXXXSABQWAV-UHFFFAOYSA-N 0.000 description 4
- 239000000010 aprotic solvent Substances 0.000 description 4
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 4
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 4
- 239000012267 brine Substances 0.000 description 4
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 4
- XJHCXCQVJFPJIK-UHFFFAOYSA-M cesium fluoride Substances [F-].[Cs+] XJHCXCQVJFPJIK-UHFFFAOYSA-M 0.000 description 4
- UTBIMNXEDGNJFE-UHFFFAOYSA-N collidine Natural products CC1=CC=C(C)C(C)=N1 UTBIMNXEDGNJFE-UHFFFAOYSA-N 0.000 description 4
- QILSFLSDHQAZET-UHFFFAOYSA-N diphenylmethanol Chemical compound C=1C=CC=CC=1C(O)C1=CC=CC=C1 QILSFLSDHQAZET-UHFFFAOYSA-N 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- 150000007517 lewis acids Chemical class 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 230000004048 modification Effects 0.000 description 4
- 238000012986 modification Methods 0.000 description 4
- 150000007530 organic bases Chemical class 0.000 description 4
- 239000002798 polar solvent Substances 0.000 description 4
- 239000004323 potassium nitrate Chemical group 0.000 description 4
- 235000010333 potassium nitrate Nutrition 0.000 description 4
- 239000012264 purified product Substances 0.000 description 4
- VWDWKYIASSYTQR-UHFFFAOYSA-N sodium nitrate Inorganic materials [Na+].[O-][N+]([O-])=O VWDWKYIASSYTQR-UHFFFAOYSA-N 0.000 description 4
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 4
- 235000000346 sugar Nutrition 0.000 description 4
- GFYHSKONPJXCDE-UHFFFAOYSA-N sym-collidine Natural products CC1=CN=C(C)C(C)=C1 GFYHSKONPJXCDE-UHFFFAOYSA-N 0.000 description 4
- PYOKUURKVVELLB-UHFFFAOYSA-N trimethyl orthoformate Chemical compound COC(OC)OC PYOKUURKVVELLB-UHFFFAOYSA-N 0.000 description 4
- XXPFHYCYDUDOIS-RWOHWRPJSA-N (3r,4r,5r)-5-(hydroxymethyl)piperidine-3,4-diol;hydrochloride Chemical compound Cl.OC[C@H]1CNC[C@@H](O)[C@@H]1O XXPFHYCYDUDOIS-RWOHWRPJSA-N 0.000 description 3
- OMNGRPHPKWAMSY-UHFFFAOYSA-N 1-chloroprop-1-yne Chemical compound CC#CCl OMNGRPHPKWAMSY-UHFFFAOYSA-N 0.000 description 3
- MSHFRERJPWKJFX-UHFFFAOYSA-N 4-Methoxybenzyl alcohol Chemical compound COC1=CC=C(CO)C=C1 MSHFRERJPWKJFX-UHFFFAOYSA-N 0.000 description 3
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 description 3
- OTLNPYWUJOZPPA-UHFFFAOYSA-N 4-nitrobenzoic acid Chemical compound OC(=O)C1=CC=C([N+]([O-])=O)C=C1 OTLNPYWUJOZPPA-UHFFFAOYSA-N 0.000 description 3
- LGCBVEQNSDSLIH-UHFFFAOYSA-N 4-pyridin-3-ylbutanal Chemical compound O=CCCCC1=CC=CN=C1 LGCBVEQNSDSLIH-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 241000551547 Dione <red algae> Species 0.000 description 3
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 3
- 239000005909 Kieselgur Substances 0.000 description 3
- 239000001358 L(+)-tartaric acid Substances 0.000 description 3
- 235000011002 L(+)-tartaric acid Nutrition 0.000 description 3
- FEWJPZIEWOKRBE-LWMBPPNESA-N L-(+)-Tartaric acid Natural products OC(=O)[C@@H](O)[C@H](O)C(O)=O FEWJPZIEWOKRBE-LWMBPPNESA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 125000001931 aliphatic group Chemical group 0.000 description 3
- 239000002168 alkylating agent Substances 0.000 description 3
- 229940100198 alkylating agent Drugs 0.000 description 3
- 125000003118 aryl group Chemical group 0.000 description 3
- 150000003938 benzyl alcohols Chemical class 0.000 description 3
- 150000001805 chlorine compounds Chemical class 0.000 description 3
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- 125000003545 alkoxy group Chemical group 0.000 description 1
- 150000008055 alkyl aryl sulfonates Chemical class 0.000 description 1
- 229940045714 alkyl sulfonate alkylating agent Drugs 0.000 description 1
- 150000008052 alkyl sulfonates Chemical class 0.000 description 1
- 125000000304 alkynyl group Chemical group 0.000 description 1
- 102000003802 alpha-Synuclein Human genes 0.000 description 1
- 108090000185 alpha-Synuclein Proteins 0.000 description 1
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 238000010936 aqueous wash Methods 0.000 description 1
- 150000008365 aromatic ketones Chemical class 0.000 description 1
- 208000037875 astrocytosis Diseases 0.000 description 1
- 230000007341 astrogliosis Effects 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- RWCCWEUUXYIKHB-UHFFFAOYSA-N benzophenone Chemical compound C=1C=CC=CC=1C(=O)C1=CC=CC=C1 RWCCWEUUXYIKHB-UHFFFAOYSA-N 0.000 description 1
- 239000012965 benzophenone Substances 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 125000006267 biphenyl group Chemical group 0.000 description 1
- 238000006664 bond formation reaction Methods 0.000 description 1
- 229910000085 borane Inorganic materials 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 150000007942 carboxylates Chemical class 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000005285 chemical preparation method Methods 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- XLJMAIOERFSOGZ-UHFFFAOYSA-M cyanate Chemical compound [O-]C#N XLJMAIOERFSOGZ-UHFFFAOYSA-M 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 150000001983 dialkylethers Chemical class 0.000 description 1
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- LQRUPWUPINJLMU-UHFFFAOYSA-N dioctyl(oxo)tin Chemical compound CCCCCCCC[Sn](=O)CCCCCCCC LQRUPWUPINJLMU-UHFFFAOYSA-N 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000009881 electrostatic interaction Effects 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 150000002084 enol ethers Chemical class 0.000 description 1
- 238000001952 enzyme assay Methods 0.000 description 1
- 239000002532 enzyme inhibitor Substances 0.000 description 1
- 125000003700 epoxy group Chemical group 0.000 description 1
- FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical compound CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 210000002950 fibroblast Anatomy 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 125000001475 halogen functional group Chemical group 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000036571 hydration Effects 0.000 description 1
- 238000006703 hydration reaction Methods 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 125000001841 imino group Chemical group [H]N=* 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 230000002132 lysosomal effect Effects 0.000 description 1
- RMGJCSHZTFKPNO-UHFFFAOYSA-M magnesium;ethene;bromide Chemical compound [Mg+2].[Br-].[CH-]=C RMGJCSHZTFKPNO-UHFFFAOYSA-M 0.000 description 1
- 230000035800 maturation Effects 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 229910052987 metal hydride Inorganic materials 0.000 description 1
- 150000004681 metal hydrides Chemical class 0.000 description 1
- 229960001238 methylnicotinate Drugs 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 230000004770 neurodegeneration Effects 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 150000005440 nitrobenzoic acid derivatives Chemical class 0.000 description 1
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 1
- 125000002868 norbornyl group Chemical group C12(CCC(CC1)C2)* 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 238000007248 oxidative elimination reaction Methods 0.000 description 1
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 1
- 238000005949 ozonolysis reaction Methods 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- RGSFGYAAUTVSQA-UHFFFAOYSA-N pentamethylene Natural products C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 1
- 150000003003 phosphines Chemical class 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 229910003446 platinum oxide Inorganic materials 0.000 description 1
- 239000003880 polar aprotic solvent Substances 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- XOJVVFBFDXDTEG-UHFFFAOYSA-N pristane Chemical compound CC(C)CCCC(C)CCCC(C)CCCC(C)C XOJVVFBFDXDTEG-UHFFFAOYSA-N 0.000 description 1
- 230000012846 protein folding Effects 0.000 description 1
- 238000010926 purge Methods 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 238000003385 ring cleavage reaction Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 238000007142 ring opening reaction Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 229910001923 silver oxide Inorganic materials 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 238000000935 solvent evaporation Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- 125000005346 substituted cycloalkyl group Chemical group 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- FKHIFSZMMVMEQY-UHFFFAOYSA-N talc Chemical compound [Mg+2].[O-][Si]([O-])=O FKHIFSZMMVMEQY-UHFFFAOYSA-N 0.000 description 1
- YMBCJWGVCUEGHA-UHFFFAOYSA-M tetraethylammonium chloride Chemical compound [Cl-].CC[N+](CC)(CC)CC YMBCJWGVCUEGHA-UHFFFAOYSA-M 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- HZPNJVXVIFRTRF-UHFFFAOYSA-N tetrapropylazanium;nitrate Chemical compound [O-][N+]([O-])=O.CCC[N+](CCC)(CCC)CCC HZPNJVXVIFRTRF-UHFFFAOYSA-N 0.000 description 1
- ZMZDMBWJUHKJPS-UHFFFAOYSA-M thiocyanate group Chemical group [S-]C#N ZMZDMBWJUHKJPS-UHFFFAOYSA-M 0.000 description 1
- 229910001887 tin oxide Inorganic materials 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- FTVLMFQEYACZNP-UHFFFAOYSA-N trimethylsilyl trifluoromethanesulfonate Chemical compound C[Si](C)(C)OS(=O)(=O)C(F)(F)F FTVLMFQEYACZNP-UHFFFAOYSA-N 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/40—Oxygen atoms
- C07D211/42—Oxygen atoms attached in position 3 or 5
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/40—Oxygen atoms
- C07D211/44—Oxygen atoms attached in position 4
- C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/18—Acyclic radicals, substituted by carbocyclic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/20—Carbocyclic rings
- C07H15/203—Monocyclic carbocyclic rings other than cyclohexane rings; Bicyclic carbocyclic ring systems
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biotechnology (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Hydrogenated Pyridines (AREA)
Description
本出願は、全体が、参照により本明細書に援用される2007年5月22日出願の米国特許仮出願第60/939,519号の利益を主張するものである。
IFGおよび/またはN−アルキル化IFG誘導体は、Sierksによる特許文献1、Lundgrenによる特許文献2およびKristiansenらによる特許文献4、非特許文献1、非特許文献2、非特許文献3、非特許文献4、非特許文献5、非特許文献6、非特許文献7、非特許文献8、非特許文献9、非特許文献10、非特許文献11、非特許文献12および最近の非特許文献13に記載されている。L立方異性体の合成は、非特許文献14に記載されている。この段落の参考文献は全て、参照により本明細書に援用される。
イソファゴミンおよび関連の化合物は、リソソーム酵素β−グルコセレブロシダーゼ(GCアーゼとしても知られている)の活性を増大させるのに有効であることが示されている。特許文献5、特許文献6および特許文献7ならびに2004年11月12日出願の特許文献8および特許文献9を参照のこと(全て参照により本明細書に援用される)。意外なことに、特定の酵素阻害剤が、その合成中、酵素に特異的に結合して、ERにおけるタンパク質折り畳みを安定化するが、リソソームの元の位置で酵素から解離して、分解の代わりに、処理された酵素のレベルを増大することにより、酵素活性を増大することが見出された。GCアーゼの阻害剤であるIFGは、野生型と突然変異体のGCアーゼの両方の活性部位で結合し、合成および処理中、酵素を安定化する(非特許文献15、非特許文献16)。IFGは、活性部位から解離できるため、IFG結合の正味の効果は、GCアーゼ処理、リソソームへの輸送および活性の増大である。
本明細書で用いる用語および略記は、各用語が用いられる本発明の文脈内および特定の脈略において、概して、当該技術分野における通常の意味を有している。特定の用語および略記を、本発明の方法および組成を説明するのに実務者のさらなる指針となるよう、以下、あるいは明細書の他の部分に示す。
「CsF」は、フッ化セシウムを意味する。
「DMA」は、N,N−ジメチルアニリンを意味する。
「DMF」は、N,N−ジメチルホルムアミドを意味する。
「NMP」は、N−メチルピロリドンを意味する。
「DMSO」は、ジメチルスルホキシドを意味する。
「LG」は、脱離基を意味する。
「MTBE」は、メチルtertブチルエーテルを意味する。
「Pd/C」は、パラジウム炭素を意味する。
「Pd(OH)2/C」は、パールマン触媒またはデグサ触媒と呼ばれる発現のいずれかを含む様々な形態のいずれかにおける水酸化パラジウム炭素を意味する。
「PG」および「PG2」は、ヒドロキシル保護基を意味する。
「PtO2」は、水和形態を含む酸化白金を意味する。
「THF」は、テトラヒドロフランを意味する。
「TLC」は、薄層クロマトグラフィーを意味する。
「Bn」は、ベンジルを意味する。
1,2−ジオンで保護されたD−アラビノースによるIFGの合成
Claims (14)
- D−(−)−アラビノースのアノマーヒドロキシル基を保護基により保護して、グリコシドを形成し;前記グリコシドの2−および3−ヒドロキシル基を1,2−ジオンを用いて保護して、トリ保護アラビノース誘導体を形成し;前記アラビノース誘導体をトリ保護キシロース誘導体に変換し;前記キシロース誘導体をトリ保護ニトリルに変換し;前記ニトリルを保護ジオールに変換し、次いで、前記ジオールを脱保護することを含むことを特徴とするイソファゴミンまたはその酸塩を製造する方法。
- 変換前は任意で分離されている活性化系により、前記アラビノース誘導体を前記キシロース誘導体に変換することをさらに含むことを特徴とする請求項1に記載の方法。
- 変換前は任意で分離されていて、後に、シアノ源により置換される活性化系を用いて、前記キシロース誘導体を前記ニトリルに変換することをさらに含むことを特徴とする請求項1に記載の方法。
- 前記キシロース誘導体を精製した後、前記ニトリルを得ることをさらに含むことを特徴とする請求項1に記載の方法。
- 光延反転反応により、前記アラビノース誘導体を前記キシロース誘導体に変換して、反転エステル誘導体を形成し、鹸化することをさらに含むことを特徴とする請求項1に記載の方法。
- D−(−)−アラビノースのアノマーヒドロキシル基を保護基により保護して、グリコシドを形成し;前記グリコシドの2−および3−ヒドロキシル基を1,2−ジオンを用いて保護して、トリ保護アラビノース誘導体を形成し;前記アラビノース誘導体をトリ保護キシロース誘導体に変換し;前記キシロース誘導体をトリ保護ニトリルに変換する工程と、前記ニトリルを保護イソファゴミン塩に変換し、次いで、前記イソファゴミン塩を脱保護することを含むことを特徴とするイソファゴミンまたはその酸塩を製造する方法。
- D−(−)−アラビノースのアノマーヒドロキシル基を保護基により保護して、グリコシドを形成し;前記グリコシドの2−および3−ヒドロキシル基を1,2−ジオンを用いて保護して、トリ保護アラビノース誘導体を形成し;前記アラビノース誘導体をトリ保護キシロース誘導体に変換し;前記キシロース誘導体をトリ保護ニトリルに変換し;前記ニトリルをトリ保護第1級アミンまで還元し;前記第1級アミンをジオールに脱保護し、次いで、触媒水素化を用いることを含むことを特徴とするイソファゴミンまたはその酸塩を製造する方法。
- D−(−)−アラビノースの前記アノマーヒドロキシル基の保護が、アルコール、活性化剤および任意で溶媒を用いて行われ、前記アラビノース誘導体の形成が、酸およびアルコールを用いて行われることを特徴とする請求項1、6および7のいずれか一項に記載の方法。
- L−(−)−キシロースを、アルコール、活性化剤および任意で溶媒と接触させて、保護されたグリコシドを形成し;1,2−ジオンを用いて、前記グリコシドをトリ保護キシロース誘導体に変換し;前記キシロース誘導体をトリ保護ニトリルに変換し;前記ニトリルを保護されたジオールに変換し、次いで、前記ジオールを脱保護することを含むことを特徴とするイソファゴミンまたはその酸塩を製造する方法。
- PGがベンジルである請求項10に記載の化合物。
- PGがベンジルである請求項12に記載の化合物。
- 請求項10〜13のいずれか一項に記載の化合物を変換して、イソファゴミンまたはその酸塩を製造する工程を含むことを特徴とするイソファゴミンまたはその酸塩を製造する方法。
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US93951907P | 2007-05-22 | 2007-05-22 | |
US60/939,519 | 2007-05-22 | ||
PCT/US2008/064559 WO2008144773A1 (en) | 2007-05-22 | 2008-05-22 | New method for preparing isofagomine and its derivatives |
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US (3) | US8487110B2 (ja) |
EP (1) | EP2152265B1 (ja) |
JP (1) | JP5441894B2 (ja) |
KR (4) | KR101650726B1 (ja) |
CN (2) | CN104530068B (ja) |
AU (1) | AU2008254594B2 (ja) |
BR (1) | BRPI0812381A2 (ja) |
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HK (2) | HK1141719A1 (ja) |
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US7964617B2 (en) | 2005-06-08 | 2011-06-21 | Amicus Therapeutics, Inc. | Methods for treating parkinsons disease and parkinsonism |
WO2007150064A2 (en) * | 2006-06-23 | 2007-12-27 | Amicus Therapeutics, Inc. | METHOD FOR THE TREATMENT OF NEUROLOGICAL DISORDERS BY ENHANCING THE ACTIVITY OF β-GLUCOCEREBROSIDASE |
HUE030932T2 (en) * | 2010-11-08 | 2017-06-28 | Amicus Therapeutics Inc | Increased stability and increased catalytic activity, altered, recombinant, β-glucocerebrosidase proteins |
WO2012177997A1 (en) | 2011-06-22 | 2012-12-27 | The General Hospital Corporation | Treatment of proteinopathies |
WO2016144773A1 (en) | 2015-03-06 | 2016-09-15 | Abbvie Inc. | Arabinosylated glycoproteins |
US11643265B1 (en) * | 2017-02-06 | 2023-05-09 | Rational Packaging Llc | Corrugated offset corner elements |
CN112625010B (zh) * | 2020-12-31 | 2023-03-03 | 中山大学 | 一种9-羟基菲醌衍生物及其制备方法和应用 |
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US5863903A (en) | 1994-03-09 | 1999-01-26 | Novo Nordisk A/S | Use of hydroxy alkyl piperidine and pyrrolidine compounds to treat diabetes |
US5844102A (en) | 1994-07-07 | 1998-12-01 | University Of Maryland Baltimore County | Glycohydrolase inhibitors, their preparation and use thereof |
FR2751863B1 (fr) | 1996-08-01 | 1999-01-22 | Vitalitec International | Support de clips hemostatiques |
EP0983239A1 (en) | 1997-05-06 | 2000-03-08 | Novo Nordisk A/S | Novel heterocyclic compounds |
US6274597B1 (en) | 1998-06-01 | 2001-08-14 | Mount Sinai School Of Medicine Of New York University | Method of enhancing lysosomal α-Galactosidase A |
JP2001172250A (ja) * | 1999-12-14 | 2001-06-26 | Ono Pharmaceut Co Ltd | グルコピラノース誘導体 |
US8389565B2 (en) * | 2000-01-07 | 2013-03-05 | Simon Fraser University | Glycosidase inhibitors and methods of synthesizing same |
US6455573B1 (en) * | 2000-01-07 | 2002-09-24 | Simon Fraser University | Glycosidase inhibitors and methods of synthesizing same |
US6960654B2 (en) * | 2002-06-11 | 2005-11-01 | The Board Of Trustees Of The University Of Illinois | Method of forming glycosidic bonds from thioglycosides using an N,N-dialkylsulfinamide |
CH697574B1 (de) | 2003-01-07 | 2008-12-15 | Lanxess Deutschland Gmbh | Pyrazolylarylalkine. |
WO2005046612A2 (en) | 2003-11-12 | 2005-05-26 | Amicus Therapeutics Inc. | Hydroxy piperidine derivatives to treat gaucher disease |
US20070065922A1 (en) * | 2005-09-21 | 2007-03-22 | Metkinen Oy | Biocatalytic synthesis of aminodeoxy purine N9-beta-D-nucleosides containing 3-amino-3-deoxy-beta-D-ribofuranose, 3-amino-2,3-dideoxy-beta-D-ribofuranose, and 2-amino-2-deoxy-beta-D-ribofuranose as sugar moieties |
WO2007140212A2 (en) * | 2006-05-24 | 2007-12-06 | Amicus Therapeutics, Inc. | Tartrate salt of isofagomine and methods of use |
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