JP6949967B2 - リン含有化合物及びその製造並びにそれを用いた医薬品 - Google Patents
リン含有化合物及びその製造並びにそれを用いた医薬品 Download PDFInfo
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- JP6949967B2 JP6949967B2 JP2019539245A JP2019539245A JP6949967B2 JP 6949967 B2 JP6949967 B2 JP 6949967B2 JP 2019539245 A JP2019539245 A JP 2019539245A JP 2019539245 A JP2019539245 A JP 2019539245A JP 6949967 B2 JP6949967 B2 JP 6949967B2
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- phosphorus
- phenyl
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- 150000001875 compounds Chemical class 0.000 title claims description 186
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 title claims description 51
- 229910052698 phosphorus Inorganic materials 0.000 title claims description 51
- 239000011574 phosphorus Substances 0.000 title claims description 51
- 238000004519 manufacturing process Methods 0.000 title claims description 22
- 239000003814 drug Substances 0.000 title description 8
- 238000006243 chemical reaction Methods 0.000 claims description 99
- 239000000243 solution Substances 0.000 claims description 70
- 125000000217 alkyl group Chemical group 0.000 claims description 66
- -1 phosphoric acid diester Chemical class 0.000 claims description 57
- 239000000047 product Substances 0.000 claims description 46
- 125000003118 aryl group Chemical group 0.000 claims description 40
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 36
- 125000003545 alkoxy group Chemical group 0.000 claims description 35
- 229910052736 halogen Inorganic materials 0.000 claims description 32
- 150000002367 halogens Chemical class 0.000 claims description 32
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 32
- 208000003556 Dry Eye Syndromes Diseases 0.000 claims description 31
- 206010013774 Dry eye Diseases 0.000 claims description 31
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 26
- 239000002253 acid Substances 0.000 claims description 26
- 125000003277 amino group Chemical group 0.000 claims description 26
- 229910001873 dinitrogen Inorganic materials 0.000 claims description 26
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 23
- 239000012074 organic phase Substances 0.000 claims description 22
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 21
- 238000003756 stirring Methods 0.000 claims description 21
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 19
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 17
- 239000003889 eye drop Substances 0.000 claims description 16
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 15
- 239000007864 aqueous solution Substances 0.000 claims description 13
- 238000001704 evaporation Methods 0.000 claims description 13
- 210000002865 immune cell Anatomy 0.000 claims description 12
- 239000007818 Grignard reagent Substances 0.000 claims description 11
- 239000003153 chemical reaction reagent Substances 0.000 claims description 11
- 239000003112 inhibitor Substances 0.000 claims description 11
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 claims description 11
- 239000011780 sodium chloride Substances 0.000 claims description 11
- 229940012356 eye drops Drugs 0.000 claims description 10
- 239000013067 intermediate product Substances 0.000 claims description 10
- 238000010791 quenching Methods 0.000 claims description 10
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 9
- 230000012292 cell migration Effects 0.000 claims description 8
- 239000012071 phase Substances 0.000 claims description 8
- 229940126062 Compound A Drugs 0.000 claims description 7
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 claims description 7
- 229920006395 saturated elastomer Polymers 0.000 claims description 7
- 125000000304 alkynyl group Chemical group 0.000 claims description 6
- 239000000758 substrate Substances 0.000 claims description 6
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 5
- NBIIXXVUZAFLBC-UHFFFAOYSA-N phosphoric acid Substances OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 5
- 230000002140 halogenating effect Effects 0.000 claims description 4
- 238000006467 substitution reaction Methods 0.000 claims description 4
- 125000004391 aryl sulfonyl group Chemical group 0.000 claims description 3
- 239000000872 buffer Substances 0.000 claims description 3
- 239000007853 buffer solution Substances 0.000 claims description 3
- 239000003054 catalyst Substances 0.000 claims description 3
- 239000006260 foam Substances 0.000 claims description 3
- 150000004795 grignard reagents Chemical class 0.000 claims description 3
- LBMDZNOARBBHHG-UHFFFAOYSA-N methyl 2-ethynylbenzoate Chemical class COC(=O)C1=CC=CC=C1C#C LBMDZNOARBBHHG-UHFFFAOYSA-N 0.000 claims description 3
- 235000019799 monosodium phosphate Nutrition 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 claims description 3
- 229910000162 sodium phosphate Inorganic materials 0.000 claims description 3
- 239000004480 active ingredient Substances 0.000 claims description 2
- 238000007259 addition reaction Methods 0.000 claims description 2
- 238000007112 amidation reaction Methods 0.000 claims description 2
- 238000005886 esterification reaction Methods 0.000 claims description 2
- 238000006722 reduction reaction Methods 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 8
- 239000002504 physiological saline solution Substances 0.000 claims 2
- XCXJLWLQQPJVDR-UHFFFAOYSA-N 3-(azepan-2-yl)quinoline Chemical compound C1CCCCNC1C1=CN=C(C=CC=C2)C2=C1 XCXJLWLQQPJVDR-UHFFFAOYSA-N 0.000 claims 1
- 125000003172 aldehyde group Chemical group 0.000 claims 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 84
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 60
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 54
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 52
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 45
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 40
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 36
- 238000005160 1H NMR spectroscopy Methods 0.000 description 30
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 25
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 25
- QPJVMBTYPHYUOC-UHFFFAOYSA-N methyl benzoate Chemical compound COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 description 22
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 19
- 239000000203 mixture Substances 0.000 description 19
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 19
- 0 CCCCP(CCc1cc(Cl)c(C(N[C@@](Cc2cccc(*)c2)C(O)=O)=O)c(Cl)c1)(c1cc(O)ccc1)=O Chemical compound CCCCP(CCc1cc(Cl)c(C(N[C@@](Cc2cccc(*)c2)C(O)=O)=O)c(Cl)c1)(c1cc(O)ccc1)=O 0.000 description 18
- 229940095102 methyl benzoate Drugs 0.000 description 15
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 15
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 15
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 14
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 14
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 14
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 12
- 125000004432 carbon atom Chemical group C* 0.000 description 12
- HSZCZNFXUDYRKD-UHFFFAOYSA-M lithium iodide Chemical compound [Li+].[I-] HSZCZNFXUDYRKD-UHFFFAOYSA-M 0.000 description 12
- QMFDSGLDMSBMLX-NTISSMGPSA-N benzyl (2s)-2-amino-3-(3-methylsulfonylphenyl)propanoate;hydrochloride Chemical compound Cl.CS(=O)(=O)C1=CC=CC(C[C@H](N)C(=O)OCC=2C=CC=CC=2)=C1 QMFDSGLDMSBMLX-NTISSMGPSA-N 0.000 description 11
- 239000012043 crude product Substances 0.000 description 11
- 239000007789 gas Substances 0.000 description 11
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 10
- 238000000034 method Methods 0.000 description 10
- 238000000746 purification Methods 0.000 description 10
- 238000005481 NMR spectroscopy Methods 0.000 description 9
- 238000000605 extraction Methods 0.000 description 9
- LFGREXWGYUGZLY-UHFFFAOYSA-N phosphoryl Chemical group [P]=O LFGREXWGYUGZLY-UHFFFAOYSA-N 0.000 description 9
- 125000001424 substituent group Chemical group 0.000 description 9
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 8
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 8
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 8
- 229940079593 drug Drugs 0.000 description 7
- 230000008020 evaporation Effects 0.000 description 7
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 7
- 229910052757 nitrogen Inorganic materials 0.000 description 7
- 239000012044 organic layer Substances 0.000 description 7
- 235000019260 propionic acid Nutrition 0.000 description 7
- 230000000171 quenching effect Effects 0.000 description 7
- 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 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 6
- AFVLYAZCZXVTAB-UHFFFAOYSA-N ClC1=C(C(=O)OC)C(=CC(=C1)C#C)Cl Chemical compound ClC1=C(C(=O)OC)C(=CC(=C1)C#C)Cl AFVLYAZCZXVTAB-UHFFFAOYSA-N 0.000 description 6
- 239000007821 HATU Substances 0.000 description 6
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 6
- 229910052799 carbon Inorganic materials 0.000 description 6
- 125000000753 cycloalkyl group Chemical group 0.000 description 6
- 239000012530 fluid Substances 0.000 description 6
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 6
- 125000001624 naphthyl group Chemical group 0.000 description 6
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 6
- 229910052760 oxygen Inorganic materials 0.000 description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 6
- 238000010898 silica gel chromatography Methods 0.000 description 6
- 229910052717 sulfur Inorganic materials 0.000 description 6
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 5
- 210000004027 cell Anatomy 0.000 description 5
- 238000004007 reversed phase HPLC Methods 0.000 description 5
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- RJUFJBKOKNCXHH-UHFFFAOYSA-N Methyl propionate Chemical compound CCC(=O)OC RJUFJBKOKNCXHH-UHFFFAOYSA-N 0.000 description 4
- 239000012131 assay buffer Substances 0.000 description 4
- 210000005252 bulbus oculi Anatomy 0.000 description 4
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 4
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 4
- 210000001508 eye Anatomy 0.000 description 4
- 125000000623 heterocyclic group Chemical group 0.000 description 4
- 229940017219 methyl propionate Drugs 0.000 description 4
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
- 125000005493 quinolyl group Chemical group 0.000 description 4
- 230000002829 reductive effect Effects 0.000 description 4
- ONDSBJMLAHVLMI-UHFFFAOYSA-N trimethylsilyldiazomethane Chemical compound C[Si](C)(C)[CH-][N+]#N ONDSBJMLAHVLMI-UHFFFAOYSA-N 0.000 description 4
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 4
- 229920002554 vinyl polymer Polymers 0.000 description 4
- WORJRXHJTUTINR-UHFFFAOYSA-N 1,4-dioxane;hydron;chloride Chemical compound Cl.C1COCCO1 WORJRXHJTUTINR-UHFFFAOYSA-N 0.000 description 3
- BGOVMHWFMVXAIR-UHFFFAOYSA-N 2-chloropropane;magnesium Chemical compound [Mg].CC(C)Cl BGOVMHWFMVXAIR-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 235000019270 ammonium chloride Nutrition 0.000 description 3
- 229910052786 argon Inorganic materials 0.000 description 3
- 125000000043 benzamido group Chemical group [H]N([*])C(=O)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 3
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 3
- 229940125782 compound 2 Drugs 0.000 description 3
- 229940125810 compound 20 Drugs 0.000 description 3
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- YZLUEUFLDIQJCG-UHFFFAOYSA-N ethyl (3-methoxyphenyl) methyl phosphate Chemical compound CCOP(=O)(OC)OC1=CC=CC(=C1)OC YZLUEUFLDIQJCG-UHFFFAOYSA-N 0.000 description 3
- JBTWLSYIZRCDFO-UHFFFAOYSA-N ethyl methyl carbonate Chemical compound CCOC(=O)OC JBTWLSYIZRCDFO-UHFFFAOYSA-N 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- JAXFJECJQZDFJS-XHEPKHHKSA-N gtpl8555 Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)N[C@H](B1O[C@@]2(C)[C@H]3C[C@H](C3(C)C)C[C@H]2O1)CCC1=CC=C(F)C=C1 JAXFJECJQZDFJS-XHEPKHHKSA-N 0.000 description 3
- 239000001307 helium Substances 0.000 description 3
- 229910052734 helium Inorganic materials 0.000 description 3
- SWQJXJOGLNCZEY-UHFFFAOYSA-N helium atom Chemical compound [He] SWQJXJOGLNCZEY-UHFFFAOYSA-N 0.000 description 3
- 229910001629 magnesium chloride Inorganic materials 0.000 description 3
- HNQIVZYLYMDVSB-UHFFFAOYSA-N methanesulfonimidic acid Chemical compound CS(N)(=O)=O HNQIVZYLYMDVSB-UHFFFAOYSA-N 0.000 description 3
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 3
- 150000007522 mineralic acids Chemical class 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical group CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- SSOLNOMRVKKSON-UHFFFAOYSA-N proguanil Chemical compound CC(C)\N=C(/N)N=C(N)NC1=CC=C(Cl)C=C1 SSOLNOMRVKKSON-UHFFFAOYSA-N 0.000 description 3
- 230000001681 protective effect Effects 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- QERYCTSHXKAMIS-UHFFFAOYSA-N thiophene-2-carboxylic acid Chemical compound OC(=O)C1=CC=CS1 QERYCTSHXKAMIS-UHFFFAOYSA-N 0.000 description 3
- APGOHCBEJDAUOM-VYIIXAMBSA-N (2S)-2-amino-N-(1-diphenoxyphosphorylethyl)butanediamide Chemical compound C=1C=CC=CC=1OP(=O)(C(NC(=O)[C@@H](N)CC(N)=O)C)OC1=CC=CC=C1 APGOHCBEJDAUOM-VYIIXAMBSA-N 0.000 description 2
- YOLVBJUSDXESQT-LSLKUGRBSA-N (2S)-2-amino-N-(1-diphenoxyphosphorylethyl)propanamide Chemical compound C=1C=CC=CC=1OP(=O)(C(C)NC(=O)[C@@H](N)C)OC1=CC=CC=C1 YOLVBJUSDXESQT-LSLKUGRBSA-N 0.000 description 2
- JHHZLHWJQPUNKB-SCSAIBSYSA-N (3r)-pyrrolidin-3-ol Chemical compound O[C@@H]1CCNC1 JHHZLHWJQPUNKB-SCSAIBSYSA-N 0.000 description 2
- 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 2
- YSUIQYOGTINQIN-UZFYAQMZSA-N 2-amino-9-[(1S,6R,8R,9S,10R,15R,17R,18R)-8-(6-aminopurin-9-yl)-9,18-difluoro-3,12-dihydroxy-3,12-bis(sulfanylidene)-2,4,7,11,13,16-hexaoxa-3lambda5,12lambda5-diphosphatricyclo[13.2.1.06,10]octadecan-17-yl]-1H-purin-6-one Chemical compound NC1=NC2=C(N=CN2[C@@H]2O[C@@H]3COP(S)(=O)O[C@@H]4[C@@H](COP(S)(=O)O[C@@H]2[C@@H]3F)O[C@H]([C@H]4F)N2C=NC3=C2N=CN=C3N)C(=O)N1 YSUIQYOGTINQIN-UZFYAQMZSA-N 0.000 description 2
- UYEMGAFJOZZIFP-UHFFFAOYSA-N 3,5-dihydroxybenzoic acid Chemical compound OC(=O)C1=CC(O)=CC(O)=C1 UYEMGAFJOZZIFP-UHFFFAOYSA-N 0.000 description 2
- QBWKPGNFQQJGFY-QLFBSQMISA-N 3-[(1r)-1-[(2r,6s)-2,6-dimethylmorpholin-4-yl]ethyl]-n-[6-methyl-3-(1h-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]-1,2-thiazol-5-amine Chemical compound N1([C@H](C)C2=NSC(NC=3C4=NC=C(N4C=C(C)N=3)C3=CNN=C3)=C2)C[C@H](C)O[C@H](C)C1 QBWKPGNFQQJGFY-QLFBSQMISA-N 0.000 description 2
- IJFXRHURBJZNAO-UHFFFAOYSA-N 3-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=CC(O)=C1 IJFXRHURBJZNAO-UHFFFAOYSA-N 0.000 description 2
- WYFCZWSWFGJODV-MIANJLSGSA-N 4-[[(1s)-2-[(e)-3-[3-chloro-2-fluoro-6-(tetrazol-1-yl)phenyl]prop-2-enoyl]-5-(4-methyl-2-oxopiperazin-1-yl)-3,4-dihydro-1h-isoquinoline-1-carbonyl]amino]benzoic acid Chemical compound O=C1CN(C)CCN1C1=CC=CC2=C1CCN(C(=O)\C=C\C=1C(=CC=C(Cl)C=1F)N1N=NN=C1)[C@@H]2C(=O)NC1=CC=C(C(O)=O)C=C1 WYFCZWSWFGJODV-MIANJLSGSA-N 0.000 description 2
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- MLMQRMHAAAUCMB-UHFFFAOYSA-N dimethoxyphosphoryloxymethyl dimethyl phosphate Chemical compound COP(=O)(OC)OCOP(=O)(OC)OC MLMQRMHAAAUCMB-UHFFFAOYSA-N 0.000 description 1
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- 238000005259 measurement Methods 0.000 description 1
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- KBMZQFQCPXVGJR-UHFFFAOYSA-N methyl 4-amino-2,6-dichlorobenzoate Chemical compound COC(=O)C1=C(Cl)C=C(N)C=C1Cl KBMZQFQCPXVGJR-UHFFFAOYSA-N 0.000 description 1
- TZIHFWKZFHZASV-UHFFFAOYSA-N methyl formate Chemical group COC=O TZIHFWKZFHZASV-UHFFFAOYSA-N 0.000 description 1
- QJQYPZZUKLQGGT-UHFFFAOYSA-N methyl hypobromite Chemical compound COBr QJQYPZZUKLQGGT-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C07F9/306—Arylalkanephosphinic acids, e.g. Ar-(CH2)n-P(=X)(R)(XH), (X = O,S, Se; n>=1)
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Description
そのうち、前記誘導体は芳香環上のいずれか一つまたは複数が、H、アルキル基、アルコキシ基、ハロゲン、アミノ基、シアノ基、ヒドロキシ基、ニトロ基、アリール基、アルキルスルホニル基、フェニルスルホニル基によって置換されたものである。
化合物A及び化合物Cから、順次化合物B上にある活性部位と反応することにより前記リン含有化合物を得る;
前記L1とL1′及びL2とL2′との間に、置換反応(substitution reaction)、付加反応、脱離反応または単置換反応(single displacement reaction)が起きることにより、L1とL1′及びL2とL2′との間に結合を形成する。
前記化合物Aと化合物Cとのモル比は1:0.1−10である;
前記化合物Cと化合物Bとのモル比は1:0.1−10である。
ステップ1、リン酸ジエステルの誘導体中にハロゲン化試薬を入れ、50−100℃の温度下において1−5時間反応した後、直接ロータリーエバポレータを用いてエバポレーションして基質1を得る;
さらには、本発明はリン含有化合物を含む免疫細胞移動阻害剤を提供する。
さらには、本発明はリン含有化合物の免疫細胞移動阻害剤としての使用を提供する。
さらには、本発明はリン含有化合を含む医薬組成物を提供する。
さらには、本発明はドライアイの緩和及び治療に用いられる目薬を提供する。
さらには、本発明はリン含有化合物を有効成分として含有する、ドライアイの緩和及び治療に用いられる目薬を提供する。
さらには、本発明はリン含有化合物の、ドライアイの緩和及び治療に用いられる目薬の製造における使用を提供する。
さらには、本発明はドライアイの緩和及び治療に用いられる目薬の製造方法であって、
リン含有化合物を無菌生理塩水中に入れた後、水酸化ナトリウムを入れて攪拌して透明溶液を得るステップ;
上記により得られた溶液中においてNaH2PO4飽和水溶液を入れ、溶液のpHが6.75−7.25の間となるようにするステップ;
無菌生理塩水で定容した後、上記溶液中に窒素ガスを通気し、0.1−5時間泡を吹き込み、得られた溶液を密封し、5℃において光を避けて保存し使用に備えるステップ;
前記ステップを含むことを特徴とする、前記製造方法を提供する。
さらには、本発明は他の緩衝液を用いて水酸化ナトリウム及びNaH2PO4を置き換えられることを特徴とする、請求項19に記載のドライアイの緩和及び治療に用いられる目薬の製造方法を提供する。
ステップB:エチル(3−メトキシフェニル)塩化ホスホリル(化合物20.2)
実施例14及び11における(2s)−2−アミノ−3−(3−(メタンスルホニル)フェニル)プロピオン酸ベンジルエステル塩酸塩を(2s)−2−アミノ−3−(1−(メタンスルホニル)−1H−ピラゾール−4−イル)プロピオン酸塩酸塩に換えて実施例41を得る。
実施例11とまったく同じステップを用いて、「m−メトキシリン酸ジエチル」を「4−メトキシ−3−クロロリン酸ジエチル」に換えて実施例48を製造する。LCMS ESI(+)m/z:628.1(M+1)である。
Claims (15)
- 以下の構造に示されたリン含有化合物であって、
R2はヒドロキシ基、アルキル基、アルコキシ基から選ばれるものである;
R3はベンゼン環上におけるいずれか一つまたは複数の水素原子を置換してもよい、アルキル基、アルコキシ基、ハロゲン、アミノ基、シアノ基、ヒドロキシ基、ニトロ基、アリール基である;
Y1はH、アルキル基から選ばれるものである;
R41はベンゼン環上におけるいずれか一つまたは複数の水素原子を置換してもよい、H、アルキル基、アルコキシ基、アルキルスルホニル基、アリールスルホニル基、ハロゲン、アミノ基、シアノ基、ヒドロキシ基、ニトロ基から選ばれるものである;
R5はH、アルキル基、アリール基、ベンジル基から選ばれるものである
ことを特徴とする、前記リン含有化合物。 - 以下の構造に示される化合物であり、
R11はベンゼン環上におけるいずれか一つまたは複数の水素原子を置換してもよい、アルキル基、アルコキシ基、ハロゲン、アミノ基、シアノ基、ヒドロキシ基、ニトロ基から選ばれたものである;
R2はヒドロキシ基、アルキル基、アルコキシ基から選ばれるものである;
R3はベンゼン環上におけるいずれか一つまたは複数の水素原子を置換してもよい、アルキル基、アルコキシ基、ハロゲン、アミノ基、シアノ基、ヒドロキシ基、ニトロ基、アリール基である;
Y1はH、アルキル基から選ばれるものである;
R41はベンゼン環上におけるいずれか一つまたは複数の水素原子を置換してもよい、H、アルキル基、アルコキシ基、アルキルスルホニル基、アリールスルホニル基、ハロゲン、アミノ基、シアノ基、ヒドロキシ基、ニトロ基から選ばれるものである;
R5はH、アルキル基、アリール基、ベンジル基から選ばれるものである
ことを特徴とする、前記リン含有化合物。 - 請求項1〜4に記載のリン含有化合物の製造方法であって、
化合物A及び化合物Cが、順次化合物B上にある活性部位と反応することで得られる;
そのうち、
前記化合物Aは下記構造に示される化合物である:
R2はヒドロキシ基、アルキル基、アルコキシ基、ハロゲンから選ばれるものである;
nは1である;
R3はベンゼン環上におけるいずれか一つまたは複数の水素原子を置換してもよい、アルキル基、アルコキシ基、ハロゲン、アミノ基、シアノ基、ヒドロキシ基、ニトロ基、アリール基である;
R4はアルキル基、アルコキシ基、アリール基、ベンジル基から選ばれるものである;
R5はH、アルキル基、アリール基、ベンジル基から選ばれるものである、
また、L1とL1′及びL2とL2′はそれぞれ反応し得る一対の活性基であり、
前記L1はハロゲン、メチレンジホスホン酸テトラエチルから選ばれるもの、
前記L1′はアルキニル基、ヒドロキシ基、アミノ基、アルデヒド基から選ばれるもの;
前記L2はアミノ基、
前記L2′はヒドロキシ基である、
L1とL1′の間、及びL2とL2′の間は反応より安定的な結合が形成され,
反応過程において、L1とL1′の反応、L2とL2′の反応により目的生成物を得ることができることを特徴とする、前記リン含有化合物の製造方法。 - 前記化合物Aと化合物Cとのモル比は1:0.1−10である;
前記化合物Cと化合物Bとのモル比は1:0.1−10であることを特徴とする、請求項5に記載のリン含有化合物の製造方法。 - ステップ1、リン酸ジエステルの誘導体中にハロゲン化試薬を入れ、50−100℃の温度下において1−5時間反応した後、直接ロータリーエバポレータを用いてエバポレーションし基質1を得るステップ;
ステップ2、0℃以下の温度下において、エチニル安息香酸メチルの誘導体中において、順次グリニャール試薬及び基質1を入れ、0.1−2時間反応させ、酸溶液を用いて反応をクエンチングし、有機相を抽出してロータリーエバポレータを用いてエバポレーションし、中間生成物1を得るステップ;
ステップ3、中間生成物1と脱エステル基試薬を反応させ、100−150℃の温度下において2−5時間反応させ、酸溶液を入れ、有機相を抽出してロータリーエバポレータを用いてエバポレーションし、中間生成物2を得るステップ;
ステップ4、中間生成物2中において、順次L2がアミノ基の化合物C、アルカリ性触媒を入れ、20−50℃の温度下において、1−10時間反応させ、酸溶液で反応をクエンチングし、有機相を抽出してロータリーエバポレータを用いてエバポレーションし、アルキニル基を有するリン含有化合物を得るステップ;
上記ステップの後、前記アルキニル基を有するリン含有化合物が、還元反応、エステル化反応、アミド化反応、置換反応、付加反応中の一種類または複数種類の反応を行った後、対応のリン含有化合物を得ることを特徴とする、請求項1〜4に記載のリン含有化合物の製造方法。 - 請求項1〜4のいずれかに記載のリン含有化合物を含む免疫細胞移動阻害剤。
- 請求項1〜4のいずれかに記載のリン含有化合物の免疫細胞移動阻害剤としての使用。
- 請求項1〜4のいずれかに記載のリン含有化合を含む医薬組成物。
- ドライアイの緩和及び治療に用いられる目薬であることを特徴とする、請求項10に記載の医薬組成物。
- 請求項1〜4のいずれかに記載のリン含有化合物を有効成分として含有する、ドライアイの緩和及び治療に用いられる目薬。
- 請求項1〜4のいずれかに記載のリン含有化合物の、ドライアイの緩和及び治療に用いられる目薬の製造における使用。
- ドライアイの緩和及び治療に用いられる目薬の製造方法であって、
請求項1−4のいずれかに記載のリン含有化合物を無菌生理塩水中に入れた後、第一の緩衝液を入れて攪拌して透明溶液を得るステップ;
上記により得られた溶液中において第二の緩衝液を入れ、溶液のpHが6.75−7.25の間となるようにするステップ;
無菌生理塩水で定容した後、上記溶液中に窒素ガスを通気し、0.1−5時間泡を吹き込み、得られた溶液を密封し、5℃において光を避けて保存し使用に備えるステップ;
前記ステップを含むことを特徴とする、前記製造方法。 - ドライアイの緩和及び治療に用いられる目薬の製造方法であって、
請求項1−4のいずれかに記載のリン含有化合物を無菌生理塩水中に入れた後、水酸化ナトリウムを入れて攪拌して透明溶液を得るステップ;
上記により得られた溶液中においてNaH2PO4飽和水溶液を入れ、溶液のpHが6.75−7.25の間となるようにするステップ;
無菌生理塩水で定容した後、上記溶液中に窒素ガスを通気し、0.1−5時間泡を吹き込み、得られた溶液を密封し、5℃において光を避けて保存し使用に備えるステップ;
前記ステップを含むことを特徴とする、前記製造方法。
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