WO2005082872A1 - ベンゾチアジン-3-オン化合物及びその製造中間体 - Google Patents
ベンゾチアジン-3-オン化合物及びその製造中間体 Download PDFInfo
- Publication number
- WO2005082872A1 WO2005082872A1 PCT/JP2005/003821 JP2005003821W WO2005082872A1 WO 2005082872 A1 WO2005082872 A1 WO 2005082872A1 JP 2005003821 W JP2005003821 W JP 2005003821W WO 2005082872 A1 WO2005082872 A1 WO 2005082872A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- compound
- formula
- group
- methoxyphenyl
- ethyl
- Prior art date
Links
- -1 Benzothiazin-3-one compound Chemical class 0.000 title claims abstract description 95
- 150000001875 compounds Chemical class 0.000 claims abstract description 282
- 238000000034 method Methods 0.000 claims abstract description 119
- 150000003839 salts Chemical class 0.000 claims abstract description 75
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims abstract description 65
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 18
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 14
- 125000005843 halogen group Chemical group 0.000 claims abstract description 12
- 239000004480 active ingredient Substances 0.000 claims abstract description 11
- 230000001225 therapeutic effect Effects 0.000 claims abstract description 7
- 125000001188 haloalkyl group Chemical group 0.000 claims abstract description 6
- 125000004438 haloalkoxy group Chemical group 0.000 claims abstract description 5
- 230000003449 preventive effect Effects 0.000 claims abstract description 3
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 63
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 50
- 125000002349 hydroxyamino group Chemical group [H]ON([H])[*] 0.000 claims description 41
- 125000004432 carbon atom Chemical group C* 0.000 claims description 22
- 125000000217 alkyl group Chemical group 0.000 claims description 18
- 210000000845 cartilage Anatomy 0.000 claims description 14
- 239000011159 matrix material Substances 0.000 claims description 12
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 11
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 10
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 8
- 208000015122 neurodegenerative disease Diseases 0.000 claims description 8
- 125000006503 p-nitrobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1[N+]([O-])=O)C([H])([H])* 0.000 claims description 8
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 7
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 7
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 5
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 4
- 229910052731 fluorine Inorganic materials 0.000 claims description 4
- 125000001153 fluoro group Chemical group F* 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 229940124158 Protease/peptidase inhibitor Drugs 0.000 claims description 3
- 208000027866 inflammatory disease Diseases 0.000 claims description 3
- 239000000137 peptide hydrolase inhibitor Substances 0.000 claims description 3
- NBIVLYUEDPRLGI-UHFFFAOYSA-N 3-oxo-4h-1,4-benzothiazine-6-carboxylic acid Chemical compound S1CC(=O)NC2=CC(C(=O)O)=CC=C21 NBIVLYUEDPRLGI-UHFFFAOYSA-N 0.000 claims 1
- 230000008569 process Effects 0.000 abstract description 26
- 201000008482 osteoarthritis Diseases 0.000 abstract description 11
- 239000003814 drug Substances 0.000 abstract description 10
- 206010028980 Neoplasm Diseases 0.000 abstract description 9
- 201000010099 disease Diseases 0.000 abstract description 8
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical group [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 abstract description 7
- 239000001257 hydrogen Chemical group 0.000 abstract description 7
- 229910052739 hydrogen Chemical group 0.000 abstract description 7
- 230000001684 chronic effect Effects 0.000 abstract 1
- 208000007565 gingivitis Diseases 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 198
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 94
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 93
- 239000000203 mixture Substances 0.000 description 91
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 85
- 239000000243 solution Substances 0.000 description 82
- 238000004519 manufacturing process Methods 0.000 description 71
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 71
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 69
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 68
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 63
- 230000003287 optical effect Effects 0.000 description 59
- 230000002829 reductive effect Effects 0.000 description 52
- 239000002904 solvent Substances 0.000 description 51
- 238000006243 chemical reaction Methods 0.000 description 47
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 45
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 39
- 239000012442 inert solvent Substances 0.000 description 36
- 239000007864 aqueous solution Substances 0.000 description 35
- 239000012044 organic layer Substances 0.000 description 35
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 34
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 34
- 238000001914 filtration Methods 0.000 description 34
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 33
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 33
- 239000013078 crystal Substances 0.000 description 32
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 31
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 31
- 238000005481 NMR spectroscopy Methods 0.000 description 31
- 238000001816 cooling Methods 0.000 description 31
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 30
- 238000005160 1H NMR spectroscopy Methods 0.000 description 29
- 239000002253 acid Substances 0.000 description 29
- 239000000543 intermediate Substances 0.000 description 28
- 239000002585 base Substances 0.000 description 26
- 239000007787 solid Substances 0.000 description 26
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 25
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 24
- 229920006395 saturated elastomer Polymers 0.000 description 22
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
- 238000004458 analytical method Methods 0.000 description 21
- 238000003756 stirring Methods 0.000 description 21
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 20
- 239000002994 raw material Substances 0.000 description 19
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 16
- 239000012071 phase Substances 0.000 description 16
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 16
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 15
- 235000019270 ammonium chloride Nutrition 0.000 description 15
- NAWXUBYGYWOOIX-SFHVURJKSA-N (2s)-2-[[4-[2-(2,4-diaminoquinazolin-6-yl)ethyl]benzoyl]amino]-4-methylidenepentanedioic acid Chemical compound C1=CC2=NC(N)=NC(N)=C2C=C1CCC1=CC=C(C(=O)N[C@@H](CC(=C)C(O)=O)C(O)=O)C=C1 NAWXUBYGYWOOIX-SFHVURJKSA-N 0.000 description 14
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 14
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 14
- 239000003921 oil Substances 0.000 description 14
- 235000019198 oils Nutrition 0.000 description 14
- 238000001514 detection method Methods 0.000 description 13
- 238000004128 high performance liquid chromatography Methods 0.000 description 13
- 239000000706 filtrate Substances 0.000 description 12
- 125000006239 protecting group Chemical group 0.000 description 12
- 238000010898 silica gel chromatography Methods 0.000 description 12
- 239000003153 chemical reaction reagent Substances 0.000 description 11
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 11
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 11
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 10
- 239000010410 layer Substances 0.000 description 10
- 235000017557 sodium bicarbonate Nutrition 0.000 description 10
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 9
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 9
- 239000013543 active substance Substances 0.000 description 9
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 9
- 239000011541 reaction mixture Substances 0.000 description 9
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 9
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
- 102000002274 Matrix Metalloproteinases Human genes 0.000 description 8
- 108010000684 Matrix Metalloproteinases Proteins 0.000 description 8
- 201000011510 cancer Diseases 0.000 description 8
- 229910052799 carbon Inorganic materials 0.000 description 8
- 239000002274 desiccant Substances 0.000 description 8
- 239000012046 mixed solvent Substances 0.000 description 8
- 239000007800 oxidant agent Substances 0.000 description 8
- 238000002360 preparation method Methods 0.000 description 8
- 238000010992 reflux Methods 0.000 description 8
- 238000012360 testing method Methods 0.000 description 8
- 102100027995 Collagenase 3 Human genes 0.000 description 7
- 102000035195 Peptidases Human genes 0.000 description 7
- 108091005804 Peptidases Proteins 0.000 description 7
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 7
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 7
- 239000012043 crude product Substances 0.000 description 7
- 239000007924 injection Substances 0.000 description 7
- 238000002347 injection Methods 0.000 description 7
- DNIAPMSPPWPWGF-UHFFFAOYSA-N propylene glycol Substances CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 7
- 238000000746 purification Methods 0.000 description 7
- 230000035484 reaction time Effects 0.000 description 7
- 238000005406 washing Methods 0.000 description 7
- ZCDYTNZJBGSKFI-UHFFFAOYSA-N 1-(2-methylphenyl)ethanamine Chemical compound CC(N)C1=CC=CC=C1C ZCDYTNZJBGSKFI-UHFFFAOYSA-N 0.000 description 6
- BGPOHJSGSYVQSU-UHFFFAOYSA-N 5-(4-methoxyphenyl)pentanoic acid Chemical compound COC1=CC=C(CCCCC(O)=O)C=C1 BGPOHJSGSYVQSU-UHFFFAOYSA-N 0.000 description 6
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 6
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 6
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 6
- 239000004365 Protease Substances 0.000 description 6
- 239000002775 capsule Substances 0.000 description 6
- 230000008034 disappearance Effects 0.000 description 6
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 6
- 238000001727 in vivo Methods 0.000 description 6
- 230000002401 inhibitory effect Effects 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
- 239000012299 nitrogen atmosphere Substances 0.000 description 6
- 239000002244 precipitate Substances 0.000 description 6
- 206010039073 rheumatoid arthritis Diseases 0.000 description 6
- 239000002562 thickening agent Substances 0.000 description 6
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 5
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 5
- 108050005238 Collagenase 3 Proteins 0.000 description 5
- 229940124761 MMP inhibitor Drugs 0.000 description 5
- 241000700159 Rattus Species 0.000 description 5
- FFBHFFJDDLITSX-UHFFFAOYSA-N benzyl N-[2-hydroxy-4-(3-oxomorpholin-4-yl)phenyl]carbamate Chemical compound OC1=C(NC(=O)OCC2=CC=CC=C2)C=CC(=C1)N1CCOCC1=O FFBHFFJDDLITSX-UHFFFAOYSA-N 0.000 description 5
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 5
- 229910000024 caesium carbonate Inorganic materials 0.000 description 5
- 239000003054 catalyst Substances 0.000 description 5
- 230000007850 degeneration Effects 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 150000002148 esters Chemical class 0.000 description 5
- 238000000605 extraction Methods 0.000 description 5
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 5
- 229910052751 metal Inorganic materials 0.000 description 5
- 239000002184 metal Substances 0.000 description 5
- SJGALSBBFTYSBA-UHFFFAOYSA-N oxaziridine Chemical compound C1NO1 SJGALSBBFTYSBA-UHFFFAOYSA-N 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 230000006340 racemization Effects 0.000 description 5
- 239000000741 silica gel Substances 0.000 description 5
- 229910002027 silica gel Inorganic materials 0.000 description 5
- 239000011780 sodium chloride Substances 0.000 description 5
- 229940124597 therapeutic agent Drugs 0.000 description 5
- 125000005951 trifluoromethanesulfonyloxy group Chemical group 0.000 description 5
- 239000011701 zinc Substances 0.000 description 5
- 229910052725 zinc Inorganic materials 0.000 description 5
- FNLPJNRBORUCRK-LLVKDONJSA-N (2r)-2-hydroxy-5-(4-methoxyphenyl)pentanoic acid Chemical compound COC1=CC=C(CCC[C@@H](O)C(O)=O)C=C1 FNLPJNRBORUCRK-LLVKDONJSA-N 0.000 description 4
- AVSJXWWJPUEEDO-IBGZPJMESA-N (4r)-3-[5-(4-methoxyphenyl)pentanoyl]-4-phenyl-1,3-oxazolidin-2-one Chemical compound C1=CC(OC)=CC=C1CCCCC(=O)N1C(=O)OC[C@H]1C1=CC=CC=C1 AVSJXWWJPUEEDO-IBGZPJMESA-N 0.000 description 4
- OWOUKRYOZIZVFK-UHFFFAOYSA-N 2-methylphenethylamine Chemical group CC1=CC=CC=C1CCN OWOUKRYOZIZVFK-UHFFFAOYSA-N 0.000 description 4
- AFPHTEQTJZKQAQ-UHFFFAOYSA-M 3-nitrobenzoate Chemical compound [O-]C(=O)C1=CC=CC([N+]([O-])=O)=C1 AFPHTEQTJZKQAQ-UHFFFAOYSA-M 0.000 description 4
- QRAOZQGIUIDZQZ-UHFFFAOYSA-N 4-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1,4-benzoxazine Chemical compound C=1C=C2N(C)CCOC2=CC=1B1OC(C)(C)C(C)(C)O1 QRAOZQGIUIDZQZ-UHFFFAOYSA-N 0.000 description 4
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 241001000171 Chira Species 0.000 description 4
- XPDWGBQVDMORPB-UHFFFAOYSA-N Fluoroform Chemical compound FC(F)F XPDWGBQVDMORPB-UHFFFAOYSA-N 0.000 description 4
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- 238000010521 absorption reaction Methods 0.000 description 4
- 239000005456 alcohol based solvent Substances 0.000 description 4
- 150000001412 amines Chemical class 0.000 description 4
- 239000012298 atmosphere Substances 0.000 description 4
- 238000009835 boiling Methods 0.000 description 4
- 239000000872 buffer Substances 0.000 description 4
- 238000004440 column chromatography Methods 0.000 description 4
- 238000010511 deprotection reaction Methods 0.000 description 4
- 239000004210 ether based solvent Substances 0.000 description 4
- 229910052740 iodine Inorganic materials 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 4
- 239000000546 pharmaceutical excipient Substances 0.000 description 4
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Chemical compound [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 230000000069 prophylactic effect Effects 0.000 description 4
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 4
- 238000010186 staining Methods 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- HJUGFYREWKUQJT-UHFFFAOYSA-N tetrabromomethane Chemical compound BrC(Br)(Br)Br HJUGFYREWKUQJT-UHFFFAOYSA-N 0.000 description 4
- 210000001519 tissue Anatomy 0.000 description 4
- 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 4
- KAPYPIXVCPGDFE-UYAOXDASSA-N (4r)-4-benzyl-3-[(2r)-2-bromo-5-(4-methoxyphenyl)pentanoyl]-1,3-oxazolidin-2-one Chemical compound C1=CC(OC)=CC=C1CCC[C@@H](Br)C(=O)N1C(=O)OC[C@H]1CC1=CC=CC=C1 KAPYPIXVCPGDFE-UYAOXDASSA-N 0.000 description 3
- ISGGVRGCLXXWPU-LJQANCHMSA-N (4r)-4-benzyl-3-[5-(4-methoxyphenyl)pentanoyl]-1,3-oxazolidin-2-one Chemical compound C1=CC(OC)=CC=C1CCCCC(=O)N1C(=O)OC[C@H]1CC1=CC=CC=C1 ISGGVRGCLXXWPU-LJQANCHMSA-N 0.000 description 3
- LZHMNCJMXQKSBY-UHFFFAOYSA-N 4-(4-methoxyphenyl)butanoic acid Chemical compound COC1=CC=C(CCCC(O)=O)C=C1 LZHMNCJMXQKSBY-UHFFFAOYSA-N 0.000 description 3
- WAOMRGJPKKYYLW-UHFFFAOYSA-N 4-[2-(hydroxyamino)-2-oxoethyl]-2-[3-(4-methoxyphenyl)propyl]-3-oxo-1,4-benzothiazine-6-carboxylic acid Chemical compound C1=CC(OC)=CC=C1CCCC1C(=O)N(CC(=O)NO)C2=CC(C(O)=O)=CC=C2S1 WAOMRGJPKKYYLW-UHFFFAOYSA-N 0.000 description 3
- XQIRIYJOVQEBDL-UHFFFAOYSA-N 4h-1,2-benzothiazin-3-one Chemical class C1=CC=C2SNC(=O)CC2=C1 XQIRIYJOVQEBDL-UHFFFAOYSA-N 0.000 description 3
- 102100026802 72 kDa type IV collagenase Human genes 0.000 description 3
- 241000766026 Coregonus nasus Species 0.000 description 3
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- 230000003213 activating effect Effects 0.000 description 3
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 3
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 3
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- 238000004587 chromatography analysis Methods 0.000 description 3
- 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 description 3
- 239000003086 colorant Substances 0.000 description 3
- 239000006071 cream Substances 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 229940088598 enzyme Drugs 0.000 description 3
- 239000003759 ester based solvent Substances 0.000 description 3
- 125000004494 ethyl ester group Chemical group 0.000 description 3
- 238000011156 evaluation Methods 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 239000003112 inhibitor Substances 0.000 description 3
- 229910052742 iron Inorganic materials 0.000 description 3
- 235000019359 magnesium stearate Nutrition 0.000 description 3
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 3
- 235000019341 magnesium sulphate Nutrition 0.000 description 3
- 230000005499 meniscus Effects 0.000 description 3
- PJGHOJKPGBATRF-GFCCVEGCSA-N methyl (2r)-2-hydroxy-5-(4-methoxyphenyl)pentanoate Chemical compound COC(=O)[C@H](O)CCCC1=CC=C(OC)C=C1 PJGHOJKPGBATRF-GFCCVEGCSA-N 0.000 description 3
- HHKQJRYPUGNIQN-UHFFFAOYSA-N methyl 5-(4-methoxyphenyl)pentanoate Chemical compound COC(=O)CCCCC1=CC=C(OC)C=C1 HHKQJRYPUGNIQN-UHFFFAOYSA-N 0.000 description 3
- 229920000609 methyl cellulose Polymers 0.000 description 3
- 239000001923 methylcellulose Substances 0.000 description 3
- 235000010981 methylcellulose Nutrition 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 239000002674 ointment Substances 0.000 description 3
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 3
- 239000012188 paraffin wax Substances 0.000 description 3
- 230000000144 pharmacologic effect Effects 0.000 description 3
- 239000006187 pill Substances 0.000 description 3
- 239000011591 potassium Substances 0.000 description 3
- 229910052700 potassium Inorganic materials 0.000 description 3
- 239000000651 prodrug Substances 0.000 description 3
- 229940002612 prodrug Drugs 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 239000002002 slurry Substances 0.000 description 3
- 229910000104 sodium hydride Inorganic materials 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- 239000003381 stabilizer Substances 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- 239000000375 suspending agent Substances 0.000 description 3
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 description 2
- ZCLZYIZDVMSKPA-GOSISDBHSA-N (4-nitrophenyl)methyl (2r)-2-hydroxy-5-(4-methoxyphenyl)pentanoate Chemical compound C1=CC(OC)=CC=C1CCC[C@@H](O)C(=O)OCC1=CC=C([N+]([O-])=O)C=C1 ZCLZYIZDVMSKPA-GOSISDBHSA-N 0.000 description 2
- HAMBQYFZDBYWHU-CNLAJYNUSA-N (4as,7s,8ar)-8,8-dichloro-9,9-dimethyltetrahydro-4h-4a,7-methanobenzo[c][1,2]oxazireno[2,3-b]isothiazole 3,3-dioxide Chemical group C1S(=O)(=O)N2O[C@@]32C(Cl)(Cl)[C@@H]2C(C)(C)[C@]13CC2 HAMBQYFZDBYWHU-CNLAJYNUSA-N 0.000 description 2
- PZHUJARCDNEXCN-RBUKOAKNSA-N (4r)-3-[(2r)-2-hydroxy-5-(4-methoxyphenyl)pentanoyl]-4-phenyl-1,3-oxazolidin-2-one Chemical compound C1=CC(OC)=CC=C1CCC[C@@H](O)C(=O)N1C(=O)OC[C@H]1C1=CC=CC=C1 PZHUJARCDNEXCN-RBUKOAKNSA-N 0.000 description 2
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 2
- ORLCYMQZIPSODD-UHFFFAOYSA-N 1-chloro-2-[chloro(2,2,2-trichloroethoxy)phosphoryl]oxybenzene Chemical compound ClC1=CC=CC=C1OP(Cl)(=O)OCC(Cl)(Cl)Cl ORLCYMQZIPSODD-UHFFFAOYSA-N 0.000 description 2
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 description 2
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 2
- VKUYLANQOAKALN-UHFFFAOYSA-N 2-[benzyl-(4-methoxyphenyl)sulfonylamino]-n-hydroxy-4-methylpentanamide Chemical compound C1=CC(OC)=CC=C1S(=O)(=O)N(C(CC(C)C)C(=O)NO)CC1=CC=CC=C1 VKUYLANQOAKALN-UHFFFAOYSA-N 0.000 description 2
- YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical compound CC(C)COC(Cl)=O YOETUEMZNOLGDB-UHFFFAOYSA-N 0.000 description 2
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 description 2
- FWMNVWWHGCHHJJ-SKKKGAJSSA-N 4-amino-1-[(2r)-6-amino-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-amino-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]piperidine-4-carboxylic acid Chemical compound C([C@H](C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N1CCC(N)(CC1)C(O)=O)NC(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 FWMNVWWHGCHHJJ-SKKKGAJSSA-N 0.000 description 2
- AXCXHFKZHDEKTP-NSCUHMNNSA-N 4-methoxycinnamaldehyde Chemical compound COC1=CC=C(\C=C\C=O)C=C1 AXCXHFKZHDEKTP-NSCUHMNNSA-N 0.000 description 2
- GEKATFHSQNGKLM-UHFFFAOYSA-N 5-(4-methoxyphenyl)-2-oxopentanoic acid Chemical compound COC1=CC=C(CCCC(=O)C(O)=O)C=C1 GEKATFHSQNGKLM-UHFFFAOYSA-N 0.000 description 2
- 206010002091 Anaesthesia Diseases 0.000 description 2
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 2
- 101100274581 Caenorhabditis elegans chc-1 gene Proteins 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 2
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 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
- 108090000371 Esterases Proteins 0.000 description 2
- 108010037362 Extracellular Matrix Proteins Proteins 0.000 description 2
- 102000010834 Extracellular Matrix Proteins Human genes 0.000 description 2
- 101000577887 Homo sapiens Collagenase 3 Proteins 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- 239000004166 Lanolin Substances 0.000 description 2
- 108010076503 Matrix Metalloproteinase 13 Proteins 0.000 description 2
- 108010076557 Matrix Metalloproteinase 14 Proteins 0.000 description 2
- 108010016165 Matrix Metalloproteinase 2 Proteins 0.000 description 2
- 102000000422 Matrix Metalloproteinase 3 Human genes 0.000 description 2
- 102100030216 Matrix metalloproteinase-14 Human genes 0.000 description 2
- 108010015302 Matrix metalloproteinase-9 Proteins 0.000 description 2
- 206010027476 Metastases Diseases 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- AMQJEAYHLZJPGS-UHFFFAOYSA-N N-Pentanol Chemical compound CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- 101710180319 Protease 1 Proteins 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 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 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 102100030416 Stromelysin-1 Human genes 0.000 description 2
- 101710108790 Stromelysin-1 Proteins 0.000 description 2
- 101710137710 Thioesterase 1/protease 1/lysophospholipase L1 Proteins 0.000 description 2
- VJHCJDRQFCCTHL-UHFFFAOYSA-N acetic acid 2,3,4,5,6-pentahydroxyhexanal Chemical compound CC(O)=O.OCC(O)C(O)C(O)C(O)C=O VJHCJDRQFCCTHL-UHFFFAOYSA-N 0.000 description 2
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 2
- 239000012190 activator Substances 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 2
- 230000037005 anaesthesia Effects 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 150000001718 carbodiimides Chemical class 0.000 description 2
- MMCOUVMKNAHQOY-UHFFFAOYSA-N carbonoperoxoic acid Chemical compound OOC(O)=O MMCOUVMKNAHQOY-UHFFFAOYSA-N 0.000 description 2
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 2
- 229950008138 carmellose Drugs 0.000 description 2
- KMPWYEUPVWOPIM-KODHJQJWSA-N cinchonidine Chemical compound C1=CC=C2C([C@H]([C@H]3[N@]4CC[C@H]([C@H](C4)C=C)C3)O)=CC=NC2=C1 KMPWYEUPVWOPIM-KODHJQJWSA-N 0.000 description 2
- KMPWYEUPVWOPIM-UHFFFAOYSA-N cinchonidine Natural products C1=CC=C2C(C(C3N4CCC(C(C4)C=C)C3)O)=CC=NC2=C1 KMPWYEUPVWOPIM-UHFFFAOYSA-N 0.000 description 2
- 210000004439 collateral ligament Anatomy 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 210000002808 connective tissue Anatomy 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 239000002270 dispersing agent Substances 0.000 description 2
- 239000006196 drop Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 239000003995 emulsifying agent Substances 0.000 description 2
- KZEQVOVSYJIYHW-IBGZPJMESA-N ethyl (2s)-2-[3-(4-methoxyphenyl)propyl]-3-oxo-4h-1,4-benzothiazine-6-carboxylate Chemical compound C([C@@H]1SC2=CC=C(C=C2NC1=O)C(=O)OCC)CCC1=CC=C(OC)C=C1 KZEQVOVSYJIYHW-IBGZPJMESA-N 0.000 description 2
- HDZHUUUOOPAAEQ-UHFFFAOYSA-N ethyl 2-[3-(4-chlorophenyl)propyl]-4-[2-(hydroxyamino)-2-oxoethyl]-3-oxo-1,4-benzothiazine-6-carboxylate Chemical compound O=C1N(CC(=O)NO)C2=CC(C(=O)OCC)=CC=C2SC1CCCC1=CC=C(Cl)C=C1 HDZHUUUOOPAAEQ-UHFFFAOYSA-N 0.000 description 2
- DGNUAQXGWVCHRS-UHFFFAOYSA-N ethyl 2-bromo-5-(4-methoxyphenyl)pentanoate Chemical compound CCOC(=O)C(Br)CCCC1=CC=C(OC)C=C1 DGNUAQXGWVCHRS-UHFFFAOYSA-N 0.000 description 2
- VJQKIIZWMZXAPZ-UHFFFAOYSA-N ethyl 3-bromo-4-sulfanylbenzoate Chemical compound CCOC(=O)C1=CC=C(S)C(Br)=C1 VJQKIIZWMZXAPZ-UHFFFAOYSA-N 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 210000002744 extracellular matrix Anatomy 0.000 description 2
- 210000003195 fascia Anatomy 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 235000019634 flavors Nutrition 0.000 description 2
- 238000010575 fractional recrystallization Methods 0.000 description 2
- ZTVZLYBCZNMWCF-UHFFFAOYSA-N homocystine Chemical compound [O-]C(=O)C([NH3+])CCSSCCC([NH3+])C([O-])=O ZTVZLYBCZNMWCF-UHFFFAOYSA-N 0.000 description 2
- 229920002674 hyaluronan Polymers 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 2
- 150000002443 hydroxylamines Chemical class 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 229940039717 lanolin Drugs 0.000 description 2
- 235000019388 lanolin Nutrition 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- AMXOYNBUYSYVKV-UHFFFAOYSA-M lithium bromide Chemical compound [Li+].[Br-] AMXOYNBUYSYVKV-UHFFFAOYSA-M 0.000 description 2
- 239000006210 lotion Substances 0.000 description 2
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 230000009401 metastasis Effects 0.000 description 2
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 2
- 125000005948 methanesulfonyloxy group Chemical group 0.000 description 2
- 239000011812 mixed powder Substances 0.000 description 2
- 239000002808 molecular sieve Substances 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 2
- AEKHNNJSMVVESS-UHFFFAOYSA-N o-trimethylsilylhydroxylamine Chemical compound C[Si](C)(C)ON AEKHNNJSMVVESS-UHFFFAOYSA-N 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 description 2
- NWVVVBRKAWDGAB-UHFFFAOYSA-N p-methoxyphenol Chemical compound COC1=CC=C(O)C=C1 NWVVVBRKAWDGAB-UHFFFAOYSA-N 0.000 description 2
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 2
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- CHKVPAROMQMJNQ-UHFFFAOYSA-M potassium bisulfate Chemical compound [K+].OS([O-])(=O)=O CHKVPAROMQMJNQ-UHFFFAOYSA-M 0.000 description 2
- 229910000343 potassium bisulfate Inorganic materials 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 230000001376 precipitating effect Effects 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 108090000765 processed proteins & peptides Proteins 0.000 description 2
- 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 description 2
- 238000006722 reduction reaction Methods 0.000 description 2
- 230000002441 reversible effect Effects 0.000 description 2
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 2
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical compound [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 description 2
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 2
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- 235000010288 sodium nitrite Nutrition 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- 239000012453 solvate Substances 0.000 description 2
- 239000007921 spray Substances 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 108091007196 stromelysin Proteins 0.000 description 2
- QMGVPVSNSZLJIA-FVWCLLPLSA-N strychnine Chemical compound O([C@H]1CC(N([C@H]2[C@H]1[C@H]1C3)C=4C5=CC=CC=4)=O)CC=C1CN1[C@@H]3[C@]25CC1 QMGVPVSNSZLJIA-FVWCLLPLSA-N 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 210000002303 tibia Anatomy 0.000 description 2
- 238000011200 topical administration Methods 0.000 description 2
- 230000000699 topical effect Effects 0.000 description 2
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 239000008215 water for injection Substances 0.000 description 2
- KYLUAQBYONVMCP-UHFFFAOYSA-N (2-methylphenyl)phosphane Chemical compound CC1=CC=CC=C1P KYLUAQBYONVMCP-UHFFFAOYSA-N 0.000 description 1
- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 description 1
- FNLPJNRBORUCRK-NSHDSACASA-N (2s)-2-hydroxy-5-(4-methoxyphenyl)pentanoic acid Chemical compound COC1=CC=C(CCC[C@H](O)C(O)=O)C=C1 FNLPJNRBORUCRK-NSHDSACASA-N 0.000 description 1
- OJOFMLDBXPDXLQ-SECBINFHSA-N (4r)-4-benzyl-1,3-oxazolidin-2-one Chemical compound C1OC(=O)N[C@@H]1CC1=CC=CC=C1 OJOFMLDBXPDXLQ-SECBINFHSA-N 0.000 description 1
- QDMNNMIOWVJVLY-QMMMGPOBSA-N (4r)-4-phenyl-1,3-oxazolidin-2-one Chemical compound C1OC(=O)N[C@@H]1C1=CC=CC=C1 QDMNNMIOWVJVLY-QMMMGPOBSA-N 0.000 description 1
- SYTBZMRGLBWNTM-SNVBAGLBSA-N (R)-flurbiprofen Chemical compound FC1=CC([C@H](C(O)=O)C)=CC=C1C1=CC=CC=C1 SYTBZMRGLBWNTM-SNVBAGLBSA-N 0.000 description 1
- 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 1
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 1
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 1
- TUSDEZXZIZRFGC-UHFFFAOYSA-N 1-O-galloyl-3,6-(R)-HHDP-beta-D-glucose Natural products OC1C(O2)COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC1C(O)C2OC(=O)C1=CC(O)=C(O)C(O)=C1 TUSDEZXZIZRFGC-UHFFFAOYSA-N 0.000 description 1
- 125000004797 2,2,2-trichloroethoxy group Chemical group ClC(CO*)(Cl)Cl 0.000 description 1
- 125000000453 2,2,2-trichloroethyl group Chemical group [H]C([H])(*)C(Cl)(Cl)Cl 0.000 description 1
- 125000004793 2,2,2-trifluoroethoxy group Chemical group FC(CO*)(F)F 0.000 description 1
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 1
- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 description 1
- 125000001917 2,4-dinitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C(=C1*)[N+]([O-])=O)[N+]([O-])=O 0.000 description 1
- JYWKEVKEKOTYEX-UHFFFAOYSA-N 2,6-dibromo-4-chloroiminocyclohexa-2,5-dien-1-one Chemical compound ClN=C1C=C(Br)C(=O)C(Br)=C1 JYWKEVKEKOTYEX-UHFFFAOYSA-N 0.000 description 1
- MMGQBQAKOXSVRY-UHFFFAOYSA-M 2-(4-aminophenyl)acetate;mercury(1+) Chemical compound [Hg+].NC1=CC=C(CC([O-])=O)C=C1 MMGQBQAKOXSVRY-UHFFFAOYSA-M 0.000 description 1
- FALRKNHUBBKYCC-UHFFFAOYSA-N 2-(chloromethyl)pyridine-3-carbonitrile Chemical compound ClCC1=NC=CC=C1C#N FALRKNHUBBKYCC-UHFFFAOYSA-N 0.000 description 1
- NCRFTSZYJRHCJD-FQEVSTJZSA-N 2-[(2s)-6-ethoxycarbonyl-2-[3-(4-methoxyphenyl)propyl]-3-oxo-1,4-benzothiazin-4-yl]acetic acid Chemical compound C([C@@H]1SC2=CC=C(C=C2N(CC(O)=O)C1=O)C(=O)OCC)CCC1=CC=C(OC)C=C1 NCRFTSZYJRHCJD-FQEVSTJZSA-N 0.000 description 1
- IEQAICDLOKRSRL-UHFFFAOYSA-N 2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-(2-dodecoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethanol Chemical compound CCCCCCCCCCCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCO IEQAICDLOKRSRL-UHFFFAOYSA-N 0.000 description 1
- CGQWXVCWKIXXOO-UHFFFAOYSA-N 2-[3-(4-chlorophenyl)propyl]-4-[2-(hydroxyamino)-2-oxoethyl]-3-oxo-1,4-benzothiazine-6-carboxylic acid Chemical compound S1C2=CC=C(C(O)=O)C=C2N(CC(=O)NO)C(=O)C1CCCC1=CC=C(Cl)C=C1 CGQWXVCWKIXXOO-UHFFFAOYSA-N 0.000 description 1
- SBAKOAWPWXUPSO-UHFFFAOYSA-N 2-[3-(4-fluorophenyl)propyl]-4-[2-(hydroxyamino)-2-oxoethyl]-3-oxo-1,4-benzothiazine-6-carboxylic acid Chemical compound S1C2=CC=C(C(O)=O)C=C2N(CC(=O)NO)C(=O)C1CCCC1=CC=C(F)C=C1 SBAKOAWPWXUPSO-UHFFFAOYSA-N 0.000 description 1
- FYELSNVLZVIGTI-UHFFFAOYSA-N 2-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]-5-ethylpyrazol-1-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C=1C=NN(C=1CC)CC(=O)N1CC2=C(CC1)NN=N2 FYELSNVLZVIGTI-UHFFFAOYSA-N 0.000 description 1
- MFGOFGRYDNHJTA-UHFFFAOYSA-N 2-amino-1-(2-fluorophenyl)ethanol Chemical compound NCC(O)C1=CC=CC=C1F MFGOFGRYDNHJTA-UHFFFAOYSA-N 0.000 description 1
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 1
- GXLQOYDRTANCON-UHFFFAOYSA-N 2-benzyl-4h-1,2-benzothiazin-3-one Chemical class O=C1CC2=CC=CC=C2SN1CC1=CC=CC=C1 GXLQOYDRTANCON-UHFFFAOYSA-N 0.000 description 1
- KGHPRMWTRGCJCG-UHFFFAOYSA-N 2-bromo-5-(4-methoxyphenyl)pentanoic acid Chemical compound COC1=CC=C(CCCC(Br)C(O)=O)C=C1 KGHPRMWTRGCJCG-UHFFFAOYSA-N 0.000 description 1
- 125000004791 2-fluoroethoxy group Chemical group FCCO* 0.000 description 1
- 125000004777 2-fluoroethyl group Chemical group [H]C([H])(F)C([H])([H])* 0.000 description 1
- FNLPJNRBORUCRK-UHFFFAOYSA-N 2-hydroxy-5-(4-methoxyphenyl)pentanoic acid Chemical compound COC1=CC=C(CCCC(O)C(O)=O)C=C1 FNLPJNRBORUCRK-UHFFFAOYSA-N 0.000 description 1
- QTWJRLJHJPIABL-UHFFFAOYSA-N 2-methylphenol;3-methylphenol;4-methylphenol Chemical compound CC1=CC=C(O)C=C1.CC1=CC=CC(O)=C1.CC1=CC=CC=C1O QTWJRLJHJPIABL-UHFFFAOYSA-N 0.000 description 1
- NPQTWVMBANUGAG-UHFFFAOYSA-N 2-oxo-3,4-dihydro-1,4-benzothiazine-6-carboxylic acid Chemical compound OC(=O)c1ccc2SC(=O)CNc2c1 NPQTWVMBANUGAG-UHFFFAOYSA-N 0.000 description 1
- UJVBZCCNLAAMOV-UHFFFAOYSA-N 2h-1,2-benzothiazine Chemical group C1=CC=C2C=CNSC2=C1 UJVBZCCNLAAMOV-UHFFFAOYSA-N 0.000 description 1
- OUNDGARMZDNTFJ-UHFFFAOYSA-N 2h-1,2-benzothiazine-6-carboxylic acid Chemical compound S1NC=CC2=CC(C(=O)O)=CC=C21 OUNDGARMZDNTFJ-UHFFFAOYSA-N 0.000 description 1
- YLZOPXRUQYQQID-UHFFFAOYSA-N 3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)-1-[4-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidin-5-yl]piperazin-1-yl]propan-1-one Chemical compound N1N=NC=2CN(CCC=21)CCC(=O)N1CCN(CC1)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F YLZOPXRUQYQQID-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- AONUGCJCKAIQBI-UHFFFAOYSA-N 3-bromo-4-sulfanylbenzonitrile Chemical compound SC1=CC=C(C#N)C=C1Br AONUGCJCKAIQBI-UHFFFAOYSA-N 0.000 description 1
- CSIFGMFVGDBOQC-UHFFFAOYSA-N 3-iminobutanenitrile Chemical compound CC(=N)CC#N CSIFGMFVGDBOQC-UHFFFAOYSA-N 0.000 description 1
- XMIIGOLPHOKFCH-UHFFFAOYSA-N 3-phenylpropionic acid Chemical compound OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 description 1
- XVAABEUFZBUUOF-UHFFFAOYSA-N 4-(4-methoxyphenyl)pentanoic acid Chemical compound COC1=CC=C(C(C)CCC(O)=O)C=C1 XVAABEUFZBUUOF-UHFFFAOYSA-N 0.000 description 1
- HCMXMCIPMZNCKG-UHFFFAOYSA-N 4-[2-(hydroxyamino)-2-oxoethyl]-2-[4-(4-methoxyphenyl)butyl]-3-oxo-1,4-benzothiazine-6-carboxylic acid Chemical compound C1=CC(OC)=CC=C1CCCCC1C(=O)N(CC(=O)NO)C2=CC(C(O)=O)=CC=C2S1 HCMXMCIPMZNCKG-UHFFFAOYSA-N 0.000 description 1
- VOLRSQPSJGXRNJ-UHFFFAOYSA-N 4-nitrobenzyl bromide Chemical compound [O-][N+](=O)C1=CC=C(CBr)C=C1 VOLRSQPSJGXRNJ-UHFFFAOYSA-N 0.000 description 1
- QDMNNMIOWVJVLY-UHFFFAOYSA-N 4-phenyl-1,3-oxazolidin-2-one Chemical compound C1OC(=O)NC1C1=CC=CC=C1 QDMNNMIOWVJVLY-UHFFFAOYSA-N 0.000 description 1
- 125000004199 4-trifluoromethylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C(F)(F)F 0.000 description 1
- DEXFNLNNUZKHNO-UHFFFAOYSA-N 6-[3-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperidin-1-yl]-3-oxopropyl]-3H-1,3-benzoxazol-2-one Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C1CCN(CC1)C(CCC1=CC2=C(NC(O2)=O)C=C1)=O DEXFNLNNUZKHNO-UHFFFAOYSA-N 0.000 description 1
- 101710151806 72 kDa type IV collagenase Proteins 0.000 description 1
- HGINCPLSRVDWNT-UHFFFAOYSA-N Acrolein Chemical compound C=CC=O HGINCPLSRVDWNT-UHFFFAOYSA-N 0.000 description 1
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 1
- 239000005695 Ammonium acetate Substances 0.000 description 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 101150041968 CDC13 gene Proteins 0.000 description 1
- 208000019300 CLIPPERS Diseases 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 241000282552 Chlorocebus aethiops Species 0.000 description 1
- 235000001258 Cinchona calisaya Nutrition 0.000 description 1
- 101100007328 Cocos nucifera COS-1 gene Proteins 0.000 description 1
- 102000008186 Collagen Human genes 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- 108060005980 Collagenase Proteins 0.000 description 1
- 102000029816 Collagenase Human genes 0.000 description 1
- VVNCNSJFMMFHPL-VKHMYHEASA-N D-penicillamine Chemical compound CC(C)(S)[C@@H](N)C(O)=O VVNCNSJFMMFHPL-VKHMYHEASA-N 0.000 description 1
- 201000004624 Dermatitis Diseases 0.000 description 1
- 239000004375 Dextrin Substances 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- 208000030814 Eating disease Diseases 0.000 description 1
- 241000792859 Enema Species 0.000 description 1
- 239000001263 FEMA 3042 Substances 0.000 description 1
- 208000019454 Feeding and Eating disease Diseases 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 238000003747 Grignard reaction Methods 0.000 description 1
- 101100184232 Homo sapiens MMP13 gene Proteins 0.000 description 1
- 101000958041 Homo sapiens Musculin Proteins 0.000 description 1
- 102000004157 Hydrolases Human genes 0.000 description 1
- 108090000604 Hydrolases Proteins 0.000 description 1
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical class NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- 239000004367 Lipase Substances 0.000 description 1
- 108090001060 Lipase Proteins 0.000 description 1
- 102000004882 Lipase Human genes 0.000 description 1
- 102000000380 Matrix Metalloproteinase 1 Human genes 0.000 description 1
- 108010016113 Matrix Metalloproteinase 1 Proteins 0.000 description 1
- 102000001776 Matrix metalloproteinase-9 Human genes 0.000 description 1
- 102100030412 Matrix metalloproteinase-9 Human genes 0.000 description 1
- ZRVUJXDFFKFLMG-UHFFFAOYSA-N Meloxicam Chemical compound OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC1=NC=C(C)S1 ZRVUJXDFFKFLMG-UHFFFAOYSA-N 0.000 description 1
- 102000005741 Metalloproteases Human genes 0.000 description 1
- 108010006035 Metalloproteases Proteins 0.000 description 1
- 208000000112 Myalgia Diseases 0.000 description 1
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 description 1
- NIPNSKYNPDTRPC-UHFFFAOYSA-N N-[2-oxo-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 NIPNSKYNPDTRPC-UHFFFAOYSA-N 0.000 description 1
- AFCARXCZXQIEQB-UHFFFAOYSA-N N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CCNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 AFCARXCZXQIEQB-UHFFFAOYSA-N 0.000 description 1
- PHSPJQZRQAJPPF-UHFFFAOYSA-N N-alpha-Methylhistamine Chemical compound CNCCC1=CN=CN1 PHSPJQZRQAJPPF-UHFFFAOYSA-N 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- CMWTZPSULFXXJA-UHFFFAOYSA-N Naproxen Natural products C1=C(C(C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-UHFFFAOYSA-N 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- QMGVPVSNSZLJIA-UHFFFAOYSA-N Nux Vomica Natural products C1C2C3C4N(C=5C6=CC=CC=5)C(=O)CC3OCC=C2CN2C1C46CC2 QMGVPVSNSZLJIA-UHFFFAOYSA-N 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- 229930012538 Paclitaxel Natural products 0.000 description 1
- 208000031481 Pathologic Constriction Diseases 0.000 description 1
- LRBQNJMCXXYXIU-PPKXGCFTSA-N Penta-digallate-beta-D-glucose Natural products OC1=C(O)C(O)=CC(C(=O)OC=2C(=C(O)C=C(C=2)C(=O)OC[C@@H]2[C@H]([C@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)O2)OC(=O)C=2C=C(OC(=O)C=3C=C(O)C(O)=C(O)C=3)C(O)=C(O)C=2)O)=C1 LRBQNJMCXXYXIU-PPKXGCFTSA-N 0.000 description 1
- 235000019496 Pine nut oil Nutrition 0.000 description 1
- 208000025747 Rheumatic disease Diseases 0.000 description 1
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 1
- 235000014680 Saccharomyces cerevisiae Nutrition 0.000 description 1
- 206010040047 Sepsis Diseases 0.000 description 1
- 241001279009 Strychnos toxifera Species 0.000 description 1
- 108700012920 TNF Proteins 0.000 description 1
- QJJXYPPXXYFBGM-LFZNUXCKSA-N Tacrolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1\C=C(/C)[C@@H]1[C@H](C)[C@@H](O)CC(=O)[C@H](CC=C)/C=C(C)/C[C@H](C)C[C@H](OC)[C@H]([C@H](C[C@H]2C)OC)O[C@@]2(O)C(=O)C(=O)N2CCCC[C@H]2C(=O)O1 QJJXYPPXXYFBGM-LFZNUXCKSA-N 0.000 description 1
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- 206010052428 Wound Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- FHKPLLOSJHHKNU-INIZCTEOSA-N [(3S)-3-[8-(1-ethyl-5-methylpyrazol-4-yl)-9-methylpurin-6-yl]oxypyrrolidin-1-yl]-(oxan-4-yl)methanone Chemical compound C(C)N1N=CC(=C1C)C=1N(C2=NC=NC(=C2N=1)O[C@@H]1CN(CC1)C(=O)C1CCOCC1)C FHKPLLOSJHHKNU-INIZCTEOSA-N 0.000 description 1
- 229960001138 acetylsalicylic acid Drugs 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 238000007259 addition reaction Methods 0.000 description 1
- 229940009456 adriamycin Drugs 0.000 description 1
- 239000003463 adsorbent Substances 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 150000004703 alkoxides Chemical class 0.000 description 1
- 125000005278 alkyl sulfonyloxy group Chemical group 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- CEGOLXSVJUTHNZ-UHFFFAOYSA-K aluminium tristearate Chemical compound [Al+3].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CEGOLXSVJUTHNZ-UHFFFAOYSA-K 0.000 description 1
- 229940063655 aluminum stearate Drugs 0.000 description 1
- 238000007112 amidation reaction Methods 0.000 description 1
- 238000010976 amide bond formation reaction Methods 0.000 description 1
- 235000019257 ammonium acetate Nutrition 0.000 description 1
- 229940043376 ammonium acetate Drugs 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 239000002257 antimetastatic agent Substances 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 239000011260 aqueous acid Substances 0.000 description 1
- 210000001188 articular cartilage Anatomy 0.000 description 1
- 125000004391 aryl sulfonyl group Chemical group 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 238000009876 asymmetric hydrogenation reaction Methods 0.000 description 1
- 150000003851 azoles Chemical class 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- RQPZNWPYLFFXCP-UHFFFAOYSA-L barium dihydroxide Chemical compound [OH-].[OH-].[Ba+2] RQPZNWPYLFFXCP-UHFFFAOYSA-L 0.000 description 1
- 229910001863 barium hydroxide Inorganic materials 0.000 description 1
- 210000002469 basement membrane Anatomy 0.000 description 1
- UIJGNTRUPZPVNG-UHFFFAOYSA-N benzenecarbothioic s-acid Chemical class SC(=O)C1=CC=CC=C1 UIJGNTRUPZPVNG-UHFFFAOYSA-N 0.000 description 1
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 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
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 1
- RLECCBFNWDXKPK-UHFFFAOYSA-N bis(trimethylsilyl)sulfide Chemical compound C[Si](C)(C)S[Si](C)(C)C RLECCBFNWDXKPK-UHFFFAOYSA-N 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 239000001273 butane Substances 0.000 description 1
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- TVFDJXOCXUVLDH-UHFFFAOYSA-N caesium atom Chemical class [Cs] TVFDJXOCXUVLDH-UHFFFAOYSA-N 0.000 description 1
- HUCVOHYBFXVBRW-UHFFFAOYSA-M caesium hydroxide Inorganic materials [OH-].[Cs+] HUCVOHYBFXVBRW-UHFFFAOYSA-M 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 235000019438 castor oil Nutrition 0.000 description 1
- RZEKVGVHFLEQIL-UHFFFAOYSA-N celecoxib Chemical compound C1=CC(C)=CC=C1C1=CC(C(F)(F)F)=NN1C1=CC=C(S(N)(=O)=O)C=C1 RZEKVGVHFLEQIL-UHFFFAOYSA-N 0.000 description 1
- 229960000590 celecoxib Drugs 0.000 description 1
- 229920001429 chelating resin Polymers 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 210000001612 chondrocyte Anatomy 0.000 description 1
- 208000021930 chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids Diseases 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 229960002424 collagenase Drugs 0.000 description 1
- 239000002299 complementary DNA Substances 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 239000003246 corticosteroid Substances 0.000 description 1
- 229960001334 corticosteroids Drugs 0.000 description 1
- 229930003836 cresol Natural products 0.000 description 1
- 239000012228 culture supernatant Substances 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 238000005828 desilylation reaction Methods 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- 229960001259 diclofenac Drugs 0.000 description 1
- DCOPUUMXTXDBNB-UHFFFAOYSA-N diclofenac Chemical compound OC(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl DCOPUUMXTXDBNB-UHFFFAOYSA-N 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 235000014632 disordered eating Nutrition 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- VHJLVAABSRFDPM-QWWZWVQMSA-N dithiothreitol Chemical compound SC[C@@H](O)[C@H](O)CS VHJLVAABSRFDPM-QWWZWVQMSA-N 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 239000012156 elution solvent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 210000003989 endothelium vascular Anatomy 0.000 description 1
- 239000007920 enema Substances 0.000 description 1
- 229940079360 enema for constipation Drugs 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- GCFHZZWXZLABBL-UHFFFAOYSA-N ethanol;hexane Chemical compound CCO.CCCCCC GCFHZZWXZLABBL-UHFFFAOYSA-N 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- XPJLOINLVSTSQQ-YDFGWWAZSA-N ethyl (2e,4e)-5-(4-methoxyphenyl)penta-2,4-dienoate Chemical compound CCOC(=O)\C=C\C=C\C1=CC=C(OC)C=C1 XPJLOINLVSTSQQ-YDFGWWAZSA-N 0.000 description 1
- TZZHWCYLBJRPSM-CYBMUJFWSA-N ethyl (2r)-2-hydroxy-5-(4-methoxyphenyl)pentanoate Chemical compound CCOC(=O)[C@H](O)CCCC1=CC=C(OC)C=C1 TZZHWCYLBJRPSM-CYBMUJFWSA-N 0.000 description 1
- XHHMQNRSMWYAGX-UHFFFAOYSA-N ethyl 4-(4-methoxyphenyl)butanoate Chemical compound CCOC(=O)CCCC1=CC=C(OC)C=C1 XHHMQNRSMWYAGX-UHFFFAOYSA-N 0.000 description 1
- UXDHYPLTATYEPM-UHFFFAOYSA-N ethyl 4-[2-(hydroxyamino)-2-oxoethyl]-2-[3-(4-methoxyphenyl)propyl]-3-oxo-1,4-benzothiazine-6-carboxylate Chemical compound O=C1N(CC(=O)NO)C2=CC(C(=O)OCC)=CC=C2SC1CCCC1=CC=C(OC)C=C1 UXDHYPLTATYEPM-UHFFFAOYSA-N 0.000 description 1
- QXQJPCBNACBGGR-UHFFFAOYSA-N ethyl 4-[2-(hydroxyamino)-2-oxoethyl]-2-[4-(4-methoxyphenyl)butyl]-3-oxo-1,4-benzothiazine-6-carboxylate Chemical compound O=C1N(CC(=O)NO)C2=CC(C(=O)OCC)=CC=C2SC1CCCCC1=CC=C(OC)C=C1 QXQJPCBNACBGGR-UHFFFAOYSA-N 0.000 description 1
- JZOFDHXGRONGQF-UHFFFAOYSA-N ethyl 4-[2-(hydroxyamino)-2-oxoethyl]-3-oxo-2-[3-[4-(trifluoromethoxy)phenyl]propyl]-1,4-benzothiazine-6-carboxylate Chemical compound O=C1N(CC(=O)NO)C2=CC(C(=O)OCC)=CC=C2SC1CCCC1=CC=C(OC(F)(F)F)C=C1 JZOFDHXGRONGQF-UHFFFAOYSA-N 0.000 description 1
- BLNLZRQIUGDTAO-UHFFFAOYSA-N ethyl 4-chloro-3-nitrobenzoate Chemical compound CCOC(=O)C1=CC=C(Cl)C([N+]([O-])=O)=C1 BLNLZRQIUGDTAO-UHFFFAOYSA-N 0.000 description 1
- JBTWLSYIZRCDFO-UHFFFAOYSA-N ethyl methyl carbonate Chemical compound CCOC(=O)OC JBTWLSYIZRCDFO-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000003818 flash chromatography Methods 0.000 description 1
- 229960002390 flurbiprofen Drugs 0.000 description 1
- SYTBZMRGLBWNTM-UHFFFAOYSA-N flurbiprofen Chemical compound FC1=CC(C(C(O)=O)C)=CC=C1C1=CC=CC=C1 SYTBZMRGLBWNTM-UHFFFAOYSA-N 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- FATAVLOOLIRUNA-UHFFFAOYSA-N formylmethyl Chemical group [CH2]C=O FATAVLOOLIRUNA-UHFFFAOYSA-N 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000003349 gelling agent Substances 0.000 description 1
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 1
- 239000003966 growth inhibitor Substances 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 230000020169 heat generation Effects 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 235000012907 honey Nutrition 0.000 description 1
- 229940018991 hyalgan Drugs 0.000 description 1
- 229960003160 hyaluronic acid Drugs 0.000 description 1
- 150000001469 hydantoins Chemical class 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 229960001680 ibuprofen Drugs 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 229960003444 immunosuppressant agent Drugs 0.000 description 1
- 239000003018 immunosuppressive agent Substances 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000009545 invasion Effects 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 238000004255 ion exchange chromatography Methods 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 description 1
- 239000005453 ketone based solvent Substances 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 210000000629 knee joint Anatomy 0.000 description 1
- 229940041476 lactose 100 mg Drugs 0.000 description 1
- 229960000681 leflunomide Drugs 0.000 description 1
- VHOGYURTWQBHIL-UHFFFAOYSA-N leflunomide Chemical compound O1N=CC(C(=O)NC=2C=CC(=CC=2)C(F)(F)F)=C1C VHOGYURTWQBHIL-UHFFFAOYSA-N 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 210000003041 ligament Anatomy 0.000 description 1
- 235000019421 lipase Nutrition 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 229940057995 liquid paraffin Drugs 0.000 description 1
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 210000003141 lower extremity Anatomy 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229960001929 meloxicam Drugs 0.000 description 1
- 210000004379 membrane Anatomy 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- XELZGAJCZANUQH-UHFFFAOYSA-N methyl 1-acetylthieno[3,2-c]pyrazole-5-carboxylate Chemical compound CC(=O)N1N=CC2=C1C=C(C(=O)OC)S2 XELZGAJCZANUQH-UHFFFAOYSA-N 0.000 description 1
- PJGHOJKPGBATRF-UHFFFAOYSA-N methyl 2-hydroxy-5-(4-methoxyphenyl)pentanoate Chemical compound COC(=O)C(O)CCCC1=CC=C(OC)C=C1 PJGHOJKPGBATRF-UHFFFAOYSA-N 0.000 description 1
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 1
- 235000019799 monosodium phosphate Nutrition 0.000 description 1
- 239000002324 mouth wash Substances 0.000 description 1
- 201000006417 multiple sclerosis Diseases 0.000 description 1
- 208000013465 muscle pain Diseases 0.000 description 1
- WCYMWQIUHPXBKM-UHFFFAOYSA-N n,n-diethylethanamine;ethoxyethane Chemical compound CCOCC.CCN(CC)CC WCYMWQIUHPXBKM-UHFFFAOYSA-N 0.000 description 1
- WAHWCUPSBZVYPH-UHFFFAOYSA-N n,n-diethylethanamine;sodium Chemical compound [Na].CCN(CC)CC WAHWCUPSBZVYPH-UHFFFAOYSA-N 0.000 description 1
- HWYHDWGGACRVEH-UHFFFAOYSA-N n-methyl-n-(4-pyrrolidin-1-ylbut-2-ynyl)acetamide Chemical compound CC(=O)N(C)CC#CCN1CCCC1 HWYHDWGGACRVEH-UHFFFAOYSA-N 0.000 description 1
- 229960002009 naproxen Drugs 0.000 description 1
- CMWTZPSULFXXJA-VIFPVBQESA-N naproxen Chemical compound C1=C([C@H](C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-VIFPVBQESA-N 0.000 description 1
- 239000007923 nasal drop Substances 0.000 description 1
- 229940100662 nasal drops Drugs 0.000 description 1
- 229940037525 nasal preparations Drugs 0.000 description 1
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical group [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 1
- 235000020925 non fasting Nutrition 0.000 description 1
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 1
- 239000012038 nucleophile Substances 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 239000012074 organic phase Substances 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
- BAQNULZQXCKSQW-UHFFFAOYSA-N oxygen(2-);titanium(4+) Chemical compound [O-2].[O-2].[O-2].[O-2].[Ti+4].[Ti+4] BAQNULZQXCKSQW-UHFFFAOYSA-N 0.000 description 1
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 1
- 229960001592 paclitaxel Drugs 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 238000005192 partition Methods 0.000 description 1
- 239000001814 pectin Substances 0.000 description 1
- 229920001277 pectin Polymers 0.000 description 1
- 235000010987 pectin Nutrition 0.000 description 1
- 229960001639 penicillamine Drugs 0.000 description 1
- 238000010647 peptide synthesis reaction Methods 0.000 description 1
- 208000028169 periodontal disease Diseases 0.000 description 1
- 239000012450 pharmaceutical intermediate Substances 0.000 description 1
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 1
- RPGWZZNNEUHDAQ-UHFFFAOYSA-N phenylphosphine Chemical compound PC1=CC=CC=C1 RPGWZZNNEUHDAQ-UHFFFAOYSA-N 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 239000010490 pine nut oil Substances 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- BDAWXSQJJCIFIK-UHFFFAOYSA-N potassium methoxide Chemical compound [K+].[O-]C BDAWXSQJJCIFIK-UHFFFAOYSA-N 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- ALDITMKAAPLVJK-UHFFFAOYSA-N prop-1-ene;hydrate Chemical group O.CC=C ALDITMKAAPLVJK-UHFFFAOYSA-N 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- IVRIRQXJSNCSPQ-UHFFFAOYSA-N propan-2-yl carbonochloridate Chemical compound CC(C)OC(Cl)=O IVRIRQXJSNCSPQ-UHFFFAOYSA-N 0.000 description 1
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 1
- 229960003415 propylparaben Drugs 0.000 description 1
- 239000002599 prostaglandin synthase inhibitor Substances 0.000 description 1
- 229940024999 proteolytic enzymes for treatment of wounds and ulcers Drugs 0.000 description 1
- 210000001747 pupil Anatomy 0.000 description 1
- 238000010926 purge Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 229960001404 quinidine Drugs 0.000 description 1
- 229960000948 quinine Drugs 0.000 description 1
- 239000002516 radical scavenger Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000001226 reprecipitation Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 150000003870 salicylic acids Chemical class 0.000 description 1
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical compound CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 229940048181 sodium sulfide nonahydrate Drugs 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- YWIVKILSMZOHHF-QJZPQSOGSA-N sodium;(2s,3s,4s,5r,6r)-6-[(2s,3r,4r,5s,6r)-3-acetamido-2-[(2s,3s,4r,5r,6r)-6-[(2r,3r,4r,5s,6r)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2- Chemical compound [Na+].CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 YWIVKILSMZOHHF-QJZPQSOGSA-N 0.000 description 1
- WMDLZMCDBSJMTM-UHFFFAOYSA-M sodium;sulfanide;nonahydrate Chemical compound O.O.O.O.O.O.O.O.O.[Na+].[SH-] WMDLZMCDBSJMTM-UHFFFAOYSA-M 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 238000009987 spinning Methods 0.000 description 1
- 201000005671 spondyloarthropathy Diseases 0.000 description 1
- 230000036262 stenosis Effects 0.000 description 1
- 208000037804 stenosis Diseases 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 229960005453 strychnine Drugs 0.000 description 1
- 229940014800 succinic anhydride Drugs 0.000 description 1
- 230000006103 sulfonylation Effects 0.000 description 1
- 238000005694 sulfonylation reaction Methods 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 229960001967 tacrolimus Drugs 0.000 description 1
- QJJXYPPXXYFBGM-SHYZHZOCSA-N tacrolimus Natural products CO[C@H]1C[C@H](CC[C@@H]1O)C=C(C)[C@H]2OC(=O)[C@H]3CCCCN3C(=O)C(=O)[C@@]4(O)O[C@@H]([C@H](C[C@H]4C)OC)[C@@H](C[C@H](C)CC(=C[C@@H](CC=C)C(=O)C[C@H](O)[C@H]2C)C)OC QJJXYPPXXYFBGM-SHYZHZOCSA-N 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- FKHIFSZMMVMEQY-UHFFFAOYSA-N talc Chemical compound [Mg+2].[O-][Si]([O-])=O FKHIFSZMMVMEQY-UHFFFAOYSA-N 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- LRBQNJMCXXYXIU-NRMVVENXSA-N tannic acid Chemical compound OC1=C(O)C(O)=CC(C(=O)OC=2C(=C(O)C=C(C=2)C(=O)OC[C@@H]2[C@H]([C@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)O2)OC(=O)C=2C=C(OC(=O)C=3C=C(O)C(O)=C(O)C=3)C(O)=C(O)C=2)O)=C1 LRBQNJMCXXYXIU-NRMVVENXSA-N 0.000 description 1
- 229920002258 tannic acid Polymers 0.000 description 1
- 229940033123 tannic acid Drugs 0.000 description 1
- 235000015523 tannic acid Nutrition 0.000 description 1
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- OSWULUXZFOQIRU-UHFFFAOYSA-N tert-butyl 2-aminoacetate;hydrochloride Chemical compound Cl.CC(C)(C)OC(=O)CN OSWULUXZFOQIRU-UHFFFAOYSA-N 0.000 description 1
- BNWCETAHAJSBFG-UHFFFAOYSA-N tert-butyl 2-bromoacetate Chemical compound CC(C)(C)OC(=O)CBr BNWCETAHAJSBFG-UHFFFAOYSA-N 0.000 description 1
- CIHOLLKRGTVIJN-UHFFFAOYSA-N tert‐butyl hydroperoxide Chemical compound CC(C)(C)OO CIHOLLKRGTVIJN-UHFFFAOYSA-N 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- HFRXJVQOXRXOPP-UHFFFAOYSA-N thionyl bromide Chemical compound BrS(Br)=O HFRXJVQOXRXOPP-UHFFFAOYSA-N 0.000 description 1
- RMVRSNDYEFQCLF-UHFFFAOYSA-N thiophenol Chemical class SC1=CC=CC=C1 RMVRSNDYEFQCLF-UHFFFAOYSA-N 0.000 description 1
- 239000010936 titanium Substances 0.000 description 1
- 229910052719 titanium Inorganic materials 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- FAQYAMRNWDIXMY-UHFFFAOYSA-N trichloroborane Chemical compound ClB(Cl)Cl FAQYAMRNWDIXMY-UHFFFAOYSA-N 0.000 description 1
- GGUBFICZYGKNTD-UHFFFAOYSA-N triethyl phosphonoacetate Chemical compound CCOC(=O)CP(=O)(OCC)OCC GGUBFICZYGKNTD-UHFFFAOYSA-N 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical class OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
- C07C57/52—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing halogen
- C07C57/58—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing halogen containing six-membered aromatic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
- A61F7/00—Heating or cooling appliances for medical or therapeutic treatment of the human body
- A61F7/007—Heating or cooling appliances for medical or therapeutic treatment of the human body characterised by electric heating
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
- C07C205/49—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups
- C07C205/57—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups having nitro groups and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
- C07C205/58—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups having nitro groups and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton the carbon skeleton being further substituted by halogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/41—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by hydrogenolysis or reduction of carboxylic groups or functional derivatives thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/40—Unsaturated compounds
- C07C59/42—Unsaturated compounds containing hydroxy or O-metal groups
- C07C59/48—Unsaturated compounds containing hydroxy or O-metal groups containing six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/40—Unsaturated compounds
- C07C59/58—Unsaturated compounds containing ether groups, groups, groups, or groups
- C07C59/64—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings
- C07C59/66—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings the non-carboxylic part of the ether containing six-membered aromatic rings
- C07C59/68—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings the non-carboxylic part of the ether containing six-membered aromatic rings the oxygen atom of the ether group being bound to a non-condensed six-membered aromatic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
- C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
- C07C69/732—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids of unsaturated hydroxy carboxylic acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
- C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
- C07C69/734—Ethers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
- C07D279/10—1,4-Thiazines; Hydrogenated 1,4-thiazines
- C07D279/14—1,4-Thiazines; Hydrogenated 1,4-thiazines condensed with carbocyclic rings or ring systems
- C07D279/16—1,4-Thiazines; Hydrogenated 1,4-thiazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring
-
- G—PHYSICS
- G02—OPTICS
- G02B—OPTICAL ELEMENTS, SYSTEMS OR APPARATUS
- G02B27/00—Optical systems or apparatus not provided for by any of the groups G02B1/00 - G02B26/00, G02B30/00
- G02B27/09—Beam shaping, e.g. changing the cross-sectional area, not otherwise provided for
- G02B27/0938—Using specific optical elements
- G02B27/095—Refractive optical elements
- G02B27/0972—Prisms
-
- G—PHYSICS
- G02—OPTICS
- G02B—OPTICAL ELEMENTS, SYSTEMS OR APPARATUS
- G02B27/00—Optical systems or apparatus not provided for by any of the groups G02B1/00 - G02B26/00, G02B30/00
- G02B27/09—Beam shaping, e.g. changing the cross-sectional area, not otherwise provided for
- G02B27/0938—Using specific optical elements
- G02B27/0994—Fibers, light pipes
-
- H—ELECTRICITY
- H05—ELECTRIC TECHNIQUES NOT OTHERWISE PROVIDED FOR
- H05B—ELECTRIC HEATING; ELECTRIC LIGHT SOURCES NOT OTHERWISE PROVIDED FOR; CIRCUIT ARRANGEMENTS FOR ELECTRIC LIGHT SOURCES, IN GENERAL
- H05B3/00—Ohmic-resistance heating
- H05B3/10—Heating elements characterised by the composition or nature of the materials or by the arrangement of the conductor
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
- A61F7/00—Heating or cooling appliances for medical or therapeutic treatment of the human body
- A61F2007/0001—Body part
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
- A61F7/00—Heating or cooling appliances for medical or therapeutic treatment of the human body
- A61F7/02—Compresses or poultices for effecting heating or cooling
- A61F2007/0225—Compresses or poultices for effecting heating or cooling connected to the body or a part thereof
- A61F2007/0228—Compresses or poultices for effecting heating or cooling connected to the body or a part thereof with belt or strap, e.g. with buckle
Definitions
- the present invention relates to a novel benzothiazin-3-one compound or a pharmaceutically acceptable salt thereof, a production intermediate thereof, and a production method thereof, which are useful as a matrix meta-oral protease inhibitor.
- MMPs matrix meta-oral proteases
- MMPs include collagenase (also referred to as matrix meta-oral protease 11 or MMP-1), gelatinase A (also referred to as matrix meta-oral protease 1 or MMP-2), stromelysin (as matrix meta-oral protease) 3 or MMP-3), gelatinase B (also referred to as matrix meta-oral protease 9 or MMP-9), collagenase-3 (also referred to as matrix meta-oral protease 13 or MMP-13), and At present 23 types are known, including membrane-bound matrix meta-oral protease 1 (MT1-MMP, MMP-14).
- MMP tissue Inhibitor of matrix metallo-protease
- Such diseases include, for example, osteoarthritis with destruction of articular cartilage and rheumatoid arthritis.
- MMPs involved in osteoarthritis and rheumatoid arthritis include stromelysin and collagenase-3 (Annals of. The Rheumatic Diseases. 59 (6): 455-61 (2000) and Journal of Clinical Investigation). 99 (7): 1534-45 (1997)).
- MMP is an enzyme that degrades the basement membrane, and is involved in the invasion of cancer cells from surrounding tissues to the vascular endothelium, ie, cancer metastasis. Gelatinase A, B etc. (See Pancreas. 24 (2): 169-78 (2002)).
- MMP inhibitors are considered to be effective as therapeutic or prophylactic agents for cartilage degenerative diseases such as osteoarthritis and rheumatoid arthritis or cancer.
- MMP inhibitors Many compounds are known as MMP inhibitors (see Exp. Op in. Ther. Patents, 8, 259-282 (1998)).
- 2-benzylbenzothiazin-3-one compounds International Publication Pamphlet No. 00/631197 and Japanese Patent Publication: JP-A-2002-12876) can be mentioned.
- Examples of a method for producing an ⁇ -hydroxycarboxylic acid which is a production intermediate for producing the benzothiazin-3-one compound, include, for example, a baker's yeast described in JP-A-10-84987.
- Japanese Patent Publication No. JP-A-10-120621 describes an asymmetric hydrogenation reaction using a catalyst.
- Japanese Patent Publication No. JP-A-2000-309575 describes a method using a hydantoin derivative.
- This patent publication: a method using a Grignard reaction of a chiral epoxide compound described in JP-A-2002-37761, or a method using DIP-C1 described in Tetrahedron Lett., 39, 5501 (1998) is known. I have. However, there has been a demand for a method for producing hydroxyhydroxycarboxylic acid having a high optical purity with a higher yield. Disclosure of the invention
- An object of the present invention is to provide a novel pharmaceutical intermediate useful for treating or preventing a cartilage degenerative disease such as osteoarthritis or rheumatoid arthritis, or a cancer or the like, an intermediate for producing the same, and a method for producing the same. .
- the present inventors have conducted intensive studies in order to solve the above-mentioned problems.
- the benzothiazin-3-one compound of the present invention has excellent pharmacological properties by oral administration to an osteoarthritis animal model. It was found to show activity. Furthermore, it was found that the compound was metabolized in vivo to hydrolyze an ethoxycarbonyl group to be converted into a highly active carboxylic acid compound, and to act as a prodrug.
- the present invention has been completed based on the above findings.
- the present invention relates to a medicament represented by the following [1] to [22], which is useful as an MMP inhibitor.
- -It relates to a 3-one compound or a pharmaceutically acceptable salt thereof. That is,
- n 3 or 4
- R represents an ethyl group or a hydrogen atom
- R 1 represents a halogen atom, an alkoxy group, a haloalkyl group, or an octaalkoxy group.
- n, R and R 1 are as defined above.
- the compound represented by the formula (1) includes the following compound group:
- the compound represented by the formula (1) is (1-)-ethyl 4- [2- (heptadroxyamino) -2-oxodiol] -2- [3- (4-methoxyphenyl) propyl] _3-
- the compound according to [1] which is oxo-3,4-dihydroxy-2H-1,4_benzothiazine-6-carboxylate, or a pharmaceutically acceptable salt thereof;
- the compound represented by the formula (1) is a compound of the following group: 4- [2- (Hydroxyamino) -2-oxoethyl] -2- [3- (4-methoxyphenyl) propyl] -3-oxo-3,4-dihydro-2H-1,4-benzothiazine-6 —Carboxylic acid, 2_ [3- (4-chlorophenyl) propyl] -4- [2- (hydroxyamino) -2-oxoethyl] -3-oxo-3,4-dihydro-2H-1,4 -Benzothiazine-6-carboxylic acid, 2- [3- (4-fluorophenyl) propyl] -4- [2- (hydroxyamino) -2-oxoethyl] -3-oxo-3,4-dihydro-2H -1, 4-benzothiazine-6-carboxylic acid, 4- [2- (hydroxyamino)
- the compound represented by the formula (1) is (1-)-4- [2- (hydroxyamino) -2-oxoethyl] -2- [3- (4-methoxyphenyl) propyl 3-
- the compound according to [1] which is oxo-3,4-dihydro-2H-1,4-benzothiazine-6-carboxylic acid, or a pharmaceutically acceptable salt thereof;
- the present invention relates to a pharmaceutical composition or a therapeutic agent represented by the following [10] to [14]. That is,
- a pharmaceutical composition comprising, as an active ingredient, the benzothiazin-3-one compound or the pharmaceutically acceptable salt thereof according to any of [1] to [9];
- a matrix meta-oral protease inhibitor comprising, as an active ingredient, the benzothiazin-3-one compound or the pharmaceutically acceptable salt thereof according to any of [1] to [9];
- a therapeutic or prophylactic agent for a cartilage degenerative disease or an inflammatory disease comprising, as an active ingredient, the benzothiazin-3-one compound or the pharmaceutically acceptable salt thereof according to any of [1] to [9];
- a cancer metastasis inhibitor comprising, as an active ingredient, the benzothiazin-3-one compound according to any one of [1] to [9] or a pharmaceutically acceptable salt thereof;
- n and R 1 have the same meanings as in formula (1), and R 2 represents an alkyl group having 2 or 3 carbon atoms, a 4-nitrobenzyl group, or a 2,2,2-trichloromethyl group
- n and R 1 have the same meanings as in formula (1), and R 10 is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, a 4-nitrobenzyl group, or a 2,2,2-trichloro group.
- R 10 is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, a 4-nitrobenzyl group, or a 2,2,2-trichloro group.
- the present invention also relates to a method for producing the benzothiazin-3-one compound or an intermediate for producing the benzothiazin-3-one compound according to any one of [1] to [9], represented by the following [23] to [24]. is there. That is,
- n, R and R 1 have the same meanings as described above, and R 5 represents a hydroxyl group, an alkoxy group or a hydroxyamino group.
- the oxidizing agent is (+)-(8,8-dichlorocamphorylsulfonyl) oxaziridine, and the optically active form is represented by the formula (4S):
- n, R, R 1 and R 5 have the same meanings as described above.
- the present invention also relates to a method for producing a benzothiazin-3-one compound production intermediate represented by the following [25] to [26], and a production intermediate represented by the following [27]. That is,
- n and R 1 are as defined above, and R 2 ′ is a protecting group for a carboxy group or a formula (6):
- R 3 represents an alkyl group or an aryl group.
- n, R 1 and R 2 ′ are as defined above, and X 2 represents a bromine atom or a trifluoromethyl sulfonyloxy group.
- X 1 represents a halogen atom or a nitro group, and is reacted with a compound represented by R (as defined above) or a salt thereof, Formula (9):
- n, X 1 , R 1 , R 2 ′, and R are as defined above.
- n, R 1 and R 3 are as defined above, and X 5 represents a bromine atom or a hydroxyl group.
- the present invention also relates to a method for producing an optically active polyhydroxycarboxylic acid represented by the following [28] to [30]. That is,
- n and R 1 are as defined above.
- optical resolution is represented by the above formula (10), characterized in that a diastereomer is formed by adding optically active ether triethylamine in an inert solvent to the racemic form of the compound represented by A method for producing an optically active compound of the compound
- optically active ⁇ -tolylethylamine is (1) one ⁇ -tolylethylamine, and the optically active compound represented by the formula (10) is represented by the formula (1 OS):
- n and R 1 are as defined above and in formula (10).
- optically active ⁇ -tolylethylamine is (+) -tolylethylamine
- optically active compound represented by the formula (10) is represented by the formula (1 OR): (10R)
- n and R 1 are as defined above and in the formula (10).
- FIG. 1 shows the results of an evaluation test of oral absorbability using rats. BEST MODE FOR CARRYING OUT THE INVENTION
- examples of the halogen atom for R 1 include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.
- the halogen atom for R 1 preferably represents a fluorine atom or a chlorine atom.
- the alkoxy group for R 1 represents a C 1 to C 4 chain or branched alkoxy group, specifically, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, Examples thereof include a 1-methyl-1-propoxy group, a 1-methyl-2-propoxy group, a 2-methyl-11-propoxy group and a 2-methyl-12-propoxy group.
- the alkoxy group in R 1 preferably represents a methoxy group.
- the haloalkyl group for R 1 represents a straight-chain or branched Haguchialkyl group having 1 to 5 identical or different halogen atoms, and having 1 to 4 carbon atoms. And a 2,2-, 2-trifluoroethyl group or a 2-fluoroethyl group.
- R 1 preferably represents a trifluoromethyl group.
- the haloalkoxy group for R 1 represents a straight-chain or branched haguchialkoxy group having 1 to 5 carbon atoms and having 1 to 5 identical or different halogen atoms.
- R 1 preferably represents a trifluoromethoxy group.
- the alkyl group for R 3 represents a linear or branched alkyl group having 1 to 4 carbon atoms, and specific examples thereof include an isopropyl group and an isobutyl group.
- examples of the aryl group for R 3 include a phenyl group, a 1-naphthyl group, a 2-naphthyl group, and a benzyl group.
- a first aspect of the present invention is a compound represented by the above formula (1) or a pharmaceutically acceptable compound thereof. Related to salt.
- the compound represented by the formula (1) has an asymmetric carbon atom at the 2-position of the benzothiazine skeleton, the formula (1) is a concept including both optical isomers.
- the compound represented by the formula (1) is desirably an optically active compound, and the configuration of the asymmetric carbon atom is preferably S.
- R is a compound related to the configuration of the asymmetric carbon atom. The notation of and S follows the rules of IUPAC organic chemical nomenclature).
- optically active substance (1-)-ethyl 4_ [2- (hydroxyamino) -2-oxoethyl] -2-[3- (4-methoxyphenyl) propyl] -3-oxo-3 , 4-Dihydro-2H-1,4-benzothiazine-6-propoxylate or (I) -4- [2- (hydroxyamino) -2-oxoethyl] -2- [3- (4-methoxyphenyl) ) Propyl] -3-oxo-3,4-dihydro-2H-1,4-benzothiazine-6-carboxylic acid.
- the compound of the present invention represented by the formula (1) can be obtained by a known method such as the method described in WO 00/63197, a method analogous thereto, or a combination of the methods of the present invention as needed. Can be manufactured. The specific manufacturing method is described below. When R represents an ethyl group in the formula (1), it can be produced according to Production Methods 1 to 4. Manufacturing method 1
- n and R 1 are as defined above, X 3 and X 4 independently represent a leaving group, and R 2 ′′ and R 4 independently represent a carboxy-protecting group
- the protecting group for the carboxy group represented by R 2 ′ ′ and R 4 a protecting group widely used by those skilled in the art, which can be removed under the condition that the ethyl ester is not hydrolyzed, is mentioned.
- a protecting group such as a benzyl group, a P-nitrobenzyl group, a p-methoxybenzyl group or a tert-butyl group is preferred.
- the protecting group is described in W; "Protective Group in Organic Synthesis” (3rd edition; written by TW Darline; John Wiley & Sons, Inc. (1999); hereinafter referred to as Green literature). I have.
- examples of the leaving group represented by X 3 and X 4 include a halogen atom such as a bromine atom or an iodine atom, or a sulfonyloxy group.
- examples of the sulfonyloxy group include an alkylsulfonyloxy group such as a haloafurylsulfonyloxy group or a methanesulfonyloxy group such as a trifluoromethanesulfonyloxy group, and an arylsulfonyl group such as a p-toluenesulfonyloxy group.
- X 4 is preferably a bromine atom.
- the protecting group for the carboxy group of the compound of the formula (1-3) (that is, the group represented by R 2 ′′) was converted by the method described in the above “Green Reference” or the like under the condition that the ethyl ester was not hydrolyzed. Can be deprotected.
- R 2 '' is a p-nitrobenzene group
- a metal such as iron or zinc is reacted in the absence of a solvent or in a hydrophilic solvent such as THF in the presence of an acid such as acetic acid or ammonium chloride.
- the compound of the formula (1-4) can be produced.
- N, N'-Dicyclohexylcarposimide (DCC), triethyl-3- (3) is added to the compound of the formula (114) in an inert solvent such as methylene chloride in the presence of a base such as triethylamine.
- the compound of formula (15) can be produced by reacting a dalysin ester with a condensing agent such as' -dimethylaminopropyl) carbodiimide (EDC) or carbonyldiimidazole (CDI).
- EDC -dimethylaminopropyl carbodiimide
- CDI carbonyldiimidazole
- an activator may be added as necessary. Examples of the activator include N-hydroxybenzotriazole (HOBt) and N-hydroxysuccinimide (HOSu).
- the benzothiazin-3-one compound of 1-6 can be produced.
- This step can be carried out, for example, according to the method described in "Bucliwald et al., J. Am. Chem. So, Vol. 119 p 845 1-8458 (1997)".
- Specific examples of the metal catalyst include tris (dibenzylideneacetone) palladium (0), tetrakis (triphenylphosphine) palladium (0), and the like.
- the ligand include 1,1'-bis (diphenylphosphino) phenene (dppf) and tris (o-tolylphosphine). Particularly preferred is dpp f it can.
- the inert solvent used here is not particularly limited, and for example, toluene and the like can be used.
- the inert solvent is used in an amount of 10 to 50 m, preferably 30 to 4 Oml, per 1 g of the raw material.
- the reaction temperature is not particularly limited, but the reaction is usually carried out at 60 to 120 ° C.
- the reaction time can be appropriately adjusted with reference to the disappearance of the raw materials, but is usually 3 hours to 8 hours.
- the compound of the formula (1-7) can be produced by a method appropriately selected according to the kind of the ester of the compound of the formula (116).
- a method appropriately selected according to the kind of the ester of the compound of the formula (116).
- the method described in "Comprehensive Saiichi Gannic Transformations" (RC Lalock, VCH Publications Second Edition, Inc. New York (1999); hereinafter referred to as Lalock literature) may be used.
- Lalock literature a tert-butyl group
- an acid such as acetic acid or hydrochloric acid
- a scavenger such as dimethyl sulfide, anisol or water as necessary
- an aproton such as methylene chloride
- Lewis acid such as boron trichloride can be used in a neutral solvent, if necessary, in the presence of a sulfide compound such as dimethyl sulfide.
- a hydrogen addition reaction can be performed on the compound of the formula (1_6) in an inert solvent such as ethanol in the presence of a catalyst such as palladium-carbon.
- R 4 is a p-nitrobenzyl group
- the reduction reaction can be carried out in the same manner as in the case where R 4 is a benzyl group, or in acetic acid in the presence of zinc or iron.
- hydroxylamine or a hydroxylamine derivative is reacted to obtain a compound of the formula (1-8) in which R in formula (1) represents an ethyl group.
- R in formula (1) represents an ethyl group.
- Examples of a method for activating a carboxy group include an amide bond formation reaction widely used by those skilled in the art. For example, the method is described in “Lalock literature” or “Basic and experimental experiments on peptide synthesis” (Nobuo Izumiya) Authors, Maruzen, 1985).
- the compound of (17) can be prepared by acid chloride method using pivaloyl chloride, etc., mixed acid anhydride method using alkyl chloroformate, etc., active ester method such as penfluorofluorophenyl ester, etc. After activating the carboxyl group, it is reacted with hydroxylamine or a hydroxylamine derivative.
- a compound of formula (17) is treated with isobutyl chloroformate in an inert solvent such as THF in the presence of a base such as N-methylmorpholine, and then reacted with a reagent such as O-trimethylsilylhydroxylamine.
- an acid such as dilute hydrochloric acid
- the compound represented by the formula (11-1), which is an intermediate for producing the compound represented by the formula (1), is novel in itself.
- the compound represented by the formula (111) can be produced, for example, by the following method.
- n, R 1 , R 2 and X 3 are as defined above.
- the compound of (1-1) can be produced.
- the compound of the formula (1-1) can be produced by reacting carbon tetrabromide and triphenylphosphine with the compound of the formula (1-19). . Further, it can also be produced by reacting a compound of the formula (1-9) with thionyl bromide or phosphorus tribromide. Further, when X 3 represents a bromine atom, the compound of the formula (111) can also be produced by the following method.
- n, R 1 , and R 2 ′′ are as defined above.
- the compound of the formula (1-10) can be prepared by adding an aqueous acid solution such as aqueous hydrogen chloride, aqueous hydrogen bromide, or sulfuric acid, an organic acid solvent such as acetic acid, or the organic acid solvent and toluene or dioxane Or sodium nitrite in a mixed solution with an inert organic solvent such as THF or the like, and then treat this with an aqueous solution of potassium bromide, sodium bromide, lithium bromide, etc. Can lead to the compound of the formula (1-1 1).
- the compound of the formula (1-112) can be converted into a compound of the formula (1-112) by esterifying the compound of the formula (1-11) according to a method known to those skilled in the art. This method is described in WO 00/63197, Synthesis, 583 (1999), or Tetrahedron Letters, 28, 1993 (1987).
- the compound of the formula (1-1) can also be produced by using a known method described in Tetrahedron Asymmetry, 6, 1919 (1995).
- the compound of the formula (111) is a known compound and can be prepared by a method known to those skilled in the art. Specifically, it can be synthesized by the method described in Tetrahedron, 58, 6117 (2002).
- the compound of the formula (119) can be produced by a known method or a method described in Examples of the present specification.
- the method for producing the optically active compound of the compound of the formula (1-9) will be described in detail in Production Method 6 or 7 described below.
- the compound of the above formula (116) can also be produced according to the following production method 2. Manufacturing method 2
- n, R 1 , R 2 ′′, R 4 and X 3 are as defined above.
- a halogen atom such as a bromine atom or an iodine atom
- a sulfonyloxy group such as a trifluoromethanesulfonyloxy group or a methanesulfonyloxy group
- the formula (2-2) By reacting the compound of the formula (111) with the compound of the formula (2_1) in an inert solvent such as THF in the presence of a suitable base such as N-methylmorpholine and triethylamine, the formula (2-2) ) Can be produced.
- a cyclization reaction is carried out by reacting the compound of the formula (2-2) with iron or zinc in the presence of acetic acid or ammonium chloride in the absence of a solvent or a solvent such as toluene, and the compound of the formula (2-3) Compounds can be prepared.
- the protecting group for the carboxy group represented by R 2 ′′ a protecting group widely used by those skilled in the art can be mentioned, and specific examples include a methyl group, an ethyl group, and a P-nitrobenzyl group. Are preferred.
- the compound of the formula (2-3) and the compound of the formula (2-4) are combined with a compound such as dimethylformamide. 8
- the compound of the formula (16) can be produced by reacting in an active solvent in the presence of a base such as cesium carbonate or carbonated carbonate or sodium hydride.
- the compound of the formula (118) can be converted to the compound of the formula (118) by the method described in the above Production Method 1.
- a compound of the formula (3-3) corresponding to a case where R represents a hydrogen atom can be produced according to the following production method 3.
- R 1 R 4 and n have the same meanings as described above, and R 7 represents a protecting group for a carboxy group.
- R 4 of the compound represented by the formula (3-1) is selectively removed, and the compound represented by the formula (3-2) is obtained by a method similar to the step 2 or the step 5 in the above-mentioned production method 1.
- the combination of the protecting groups of R 4 and R 7 may be any combination in which the conditions under which R 7 is not simultaneously removed when R 4 is removed can be selected.
- the compound of the formula (3-1) can be produced in the same manner as in production method 1.
- the compound represented by the formula (3-3) can be produced, for example, when R 7 is an alkyl group such as an ethyl group.
- the hydrolysis can be carried out in an alcoholic solvent such as ethanol using an aqueous solution of alcohol.
- the alkaline aqueous solution include an aqueous solution of lithium hydroxide, an aqueous solution of potassium hydroxide, an aqueous solution of sodium hydroxide, an aqueous solution of cesium hydroxide, and an aqueous solution of barium hydroxide.
- An aqueous solution or an aqueous sodium hydroxide solution may be used.
- racemization proceeds under the above-mentioned conditions such as hydrolysis with an alkaline aqueous solution,
- the optical purity of the compound represented by the formula (3-3) may be greatly reduced.
- a method of avoiding the progress of racemization for example, a method of adding a 1% to 50% alkaline aqueous solution in a 5 mM to 5 M tetrahydrofuran solvent at a low temperature can be mentioned.
- the reaction temperature is from -25 ° C to 15 ° C, preferably from -20 to 5 ° C, and more preferably from -15 ° C to -5.
- an aqueous hydroxide aqueous solution or an aqueous sodium hydroxide solution is used as the alkaline aqueous solution to be used.
- the equivalent of the metal salt to be added is 1 to 10 equivalents, preferably 2 to 5 equivalents, and more preferably 2 to 3 equivalents.
- the compound represented by the formula (3-2) is hydrolyzed by a hydrolase known to those skilled in the art such as lipase or esterase to convert the compound represented by the formula (3-3) into a compound represented by the formula (3-3) — It can also be produced while maintaining the optical purity of the compound of 2).
- Intermediate in Production Method 1 Compound of formula (13), Intermediate in Production Method 2: Compound of Formula (2-2), or Intermediate in Production Method 6 described below:
- Formula (5- The production intermediate such as the compound 7) can be produced according to the following production method 4.
- the method for producing the compound represented by the formula (9) according to Production method 4 is also within the scope of the present invention.
- the compound of the formula (5) as a starting material can be produced by the above-mentioned production methods and the methods described in the examples of the present specification.
- n preferably represents 3 or 4.
- the compound represented by the formula (7) can be produced from the compound represented by the formula (5) by the following method.
- n, R 1 , R 2 ′, and X 2 have the same meanings as described above.
- the compound of the formula (5) is converted into an inert solvent in the presence of a base represented by an organic amine such as triethylamine and N-methylmorpholine.
- the compound of the formula (7) can be produced by reacting with trifluoromethanesulfonic anhydride, which is a trifluoromethanesulfonylation reagent.
- the base can be used usually in an amount of 1.0 mol to 1.2 mol per 1 mol of the raw material.
- R 2 ′ is preferably an alkoxy group having 1 to 6 carbon atoms, 4-nitrobenzyloxy group or 2,2,2-trichloroethoxy group, and the alkoxy group is preferably a carbon atom.
- An alkoxy group of the number 2 or 3 is exemplified.
- the inert solvent is not particularly limited, but preferably, acetonitrile, methylene chloride, THF and the like can be used. A more preferred inert solvent is acetonitrile.
- the inert solvent can be used in an amount of 3 m1 to 5 m1 per 1 g of the raw material.
- the reaction temperature is not particularly limited, but the reaction is usually carried out at -30 to -5 "C.
- the reaction time can be appropriately adjusted based on the disappearance of the raw materials, but is usually 0.5 to 2 hours.
- X 2 is a bromine atom
- the method described in the aforementioned production method 1 The compound of the formula (7) can be produced by a method such as using phenylphosphine and carbon tetrabromide as a brominating agent.
- X 2 is a bromine atom
- a hydrogen atom on the ⁇ -carbon atom of a known compound of the formula (411) (see Helvetica Chimica Acta, 40, 1812 (1957)) Can be converted into silyl enol ether using a base such as LD LD and a silylating agent such as trimethylsilyl sulfide, and then brominated with a brominating agent such as N-bromosuccinimide (Tetrahedron Asymmetry, 6, 1919 (1995)).
- a base such as LD LD and a silylating agent such as trimethylsilyl sulfide
- n, R 1 , R 2 ′, and X 2 have the same meanings as described above.
- the compound of formula (9) can be produced by condensing the compound of formula (7) and the compound of formula (8) in an inert solvent in the presence of a base.
- n, R 1 , R 2 ′, R, X 1 and X 2 are as defined above.
- the inert solvent is not particularly limited, but preferably includes acetonitrile, methylene chloride, or THF, and more preferably includes THF.
- the product obtained in the step 1, that is, the compound of the formula (7) may be subjected to the step 2 in the same system without isolation, and the compound of the formula (5)
- the compound of the formula (7) is an optically active compound, when DMF diacetonitrile is used, racemization occurs partially, but by using THF, the compound of the formula (9) having high optical purity can be obtained without racemization. It was found that the compound of the formula (1) could be produced in good yield.
- the inert solvent can be used in an amount of 2 m1 to 10 m1 per 1 g of the raw material.
- salt Examples of the group include organic amines such as N-methylmorpholine and triethylamine.
- the base is usually used in an amount of 1.0 mol to 1.2 mol per 1 mol of the raw material.
- the compound of the formula (8) can be used usually in an amount of 1.0 mol to 1.2 mol per 1 mol of the raw material.
- the reaction temperature is not particularly limited, but the reaction is usually carried out at a temperature of 150 to 5 ° C, preferably at a temperature of 120 to 0 ° C.
- the reaction time can be appropriately adjusted based on the disappearance of the raw materials, but is usually 0.5 to 2 hours.
- the compound of the formula (8) can be produced by a method known to those skilled in the art, and specific examples include the methods described in Examples of the present specification.
- the compound represented by the formula (2) and the compound represented by the formula (3), which are intermediates for producing the compound represented by the formula (1), are themselves novel compounds.
- n, R 1 and R 2 are as defined above.
- n and R 1 have the same meanings as in formula (1), and R 10 is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, a 4-nitrobenzyl group, or a 2,2,2-trichloroethyl group. Represents.
- R 1 in the formulas (2) and (3) preferably represents a methoxy group.
- examples of the alkyl group having 2 to 3 carbon atoms for R 2 include an ethyl group, a propyl group, and an isopropyl group.
- the alkyl group having 1 to 6 carbon atoms at R 1 ° may be a straight-chain alkyl group. Or a branched alkyl group, specifically, methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 1,1-dimethylethyl, pentyl, hexyl And the like.
- R 10 represents an alkyl group having 1 to 3 carbon atoms, more preferably a methyl group or an ethyl group.
- the compounds of the formulas (2) and (3) are compounds having one asymmetric carbon atom, and the present invention includes both optically active mixtures (racemic forms) and optically active forms.
- the optically active form of the compound can be produced by the method described below, and the compound can be used to produce an optically active compound represented by the formula (1) and a production intermediate thereof.
- the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof may be a solvate, and the solvent in the solvate is, for example, an alcohol such as methanol, ethanol, propanol, or isopropanol. , Ketones such as acetone, ethers such as tetrahydrofuran or dioxane, and water.
- the amount of solvent per compound molecule represented by the formula (1) is not particularly limited, but includes, for example, 0 to 3 molecules, specifically, 1/2, 1, 2, or 3 molecules of solvent. Solvents are mentioned.
- the compound represented by the formula (1) and a production intermediate for producing the compound can be purified by a method known to those skilled in the art.
- it can be purified by various column chromatography such as normal phase or reverse phase silica gel, ion exchange resin or molecular sieve, high performance liquid chromatography (HPLC), or recrystallization.
- the recrystallization solvent include alcohol solvents such as methanol, ethanol or 2-propanol, non-protonic solvents such as dimethylformamide or dimethyl sulfoxide, ether solvents such as dimethyl ether, and ethyl acetate.
- Ester solvents aromatic hydrocarbon solvents such as toluene, ketone solvents such as acetone, hydrocarbon solvents such as hexane, halogenated hydrocarbon solvents such as chloroform and dichloroethane, or mixed solvents thereof And the like.
- the compound represented by the formula (1) can be converted into a pharmaceutically acceptable salt as described below.
- Pharmaceutically acceptable salts include base addition salts.
- Examples of the base addition salt include inorganic base salts such as sodium salt, potassium salt, cesium salt, and ammonium salt.
- organic base salts such as medalmine salt, trishydroxymethylamino methane salt, triethylamine salt and lysine salt.
- the compound represented by the formula (1) is a compound having one asymmetric carbon atom, and the present invention includes both a mixture of the optically active substances (racemic form) and an optically active substance.
- the compound represented by the formula (1) or a production intermediate thereof is a racemate, the compound is separated into an optically active substance by a method described later in the present specification, and an optically active substance is produced according to the production method 13 described above. Body can be manufactured.
- the optically active form of the compound of the formula (1) can be produced by using an optically active form of a production intermediate represented by the formula (1-1) described later.
- the compound of the formula (1) and the optically active isomer thereof can be produced by the production methods described in the following production method 58. That is, the method of producing the compound of the formula (1) described in Production Method 58, a pharmaceutically acceptable salt thereof, and an optically active isomer of the production intermediate thereof are also within the scope of the present invention.
- the intermediate for the production of the compound of the formula (1) represented by the formula (4) can be optically resolved by the following production method 5.
- n RR 1 and R 5 are as defined above.
- the alkoxy group for R 5 is not particularly limited as long as it is an alkoxy group used as a protecting group for a carboxy group, and specific examples include a tert-butoxy group and a benzyloxy group.
- a compound represented by the formula (4) [corresponding to a compound represented by the formula (1) or an intermediate thereof.
- the oxidizing agent used here is the water-modified Slmrpless reagent described in Tetrahedron Asymmetry, 8, 13, 2109-2114 (1997), that is, (+) — or (I) — diisopropyl tartrate, tetraisopropoxy. Titanium, t-butyl hydroperoxide, a mixture of a small amount of water and molecular sieves (4A), or a ⁇ -sulfonyloxaziridine reagent described in J. Org. Chem., 57, 7274 (1992). No. '
- optically active oxidizing agent examples include (+)-(8,8-dichlorocamphoryl sulfonyl) oxaziridine [(+)-(8, 8-dichlorocamphorylsulfonyl) oxazi lidine).
- the formula ( The S-form of the compound of the formula (1) represented by 4S) can be selectively obtained.
- (1)-(8,8-dichlorocanphorylsulfonyl) oxaziridine (1)-(8,8-dichloroca immediately horylsuliony Doxazilidine) as an oxidizing agent, it is represented by the formula (4R).
- the R-form of the compound of the formula (1) can be selectively obtained.
- R represents an ethyl group and R 5 represents an NHOH group or an O-tert-butyl group, it can be optically resolved in a high yield by treating with 2 equivalents of an optically active oxidizing agent in methylene chloride.
- R represents a hydrogen atom and R 5 represents an NHOH group
- treatment with 5 equivalents of an optically active oxidizing agent in ethyl acetate makes it possible to obtain a good optical resolution.
- the inert solvent used here is not particularly limited, and for example, acetonitrile, methylene chloride, ethyl acetate and the like can be used.
- the amount of the inert solvent is not particularly limited as long as the raw materials are dissolved.
- the reaction temperature is not particularly limited, but the reaction is usually performed at 0 ° C to 3O.
- the reaction time can be appropriately adjusted based on the rate of disappearance of the raw materials, but is usually 1 hour to 10 days.
- the compound represented by the formula (4-2R) or the formula (4-2S) obtained by the above-mentioned production method 4 can be converted to a compound of the formula (4) by reduction using titanium tetraoxide. You can play it. This reaction is described in Synlett, 2000, 10, 1437-1438. Further, an optically active isomer of the compound of the formula (1):
- the compound of the formula (5-5) can be produced by the following production method 6.
- n represents R 1 and R 2 ′′ as defined above, and R 8 represents an isopropyl group, an isobutyl group, a phenyl group, a 1-naphthyl group, a 2-naphthyl group or a benzyl group; 9 represents a bromine atom or a hydroxyl group.
- step 1 of the above reaction scheme the compound of the formula (5-1) and the compound of the formula (5-2) are condensed by a method known to those skilled in the art to give a compound of the formula (5-3) can do. That is, the compound of formula (5-1) can be treated with oxalyl chloride to convert it to acid chloride, and then reacted with the compound of formula (5-2) (commercially available). This is described in Tetrahedron Lett., 38, 3853 (1997).
- step 2 the compound of the formula (5-4) can be obtained by treating the compound of the formula (5_3) with an oxidizing agent or a brominating agent in an inert solvent.
- the Davis reagent can be used in the presence of a strong base in an inert solvent.
- R 8 represents a phenyl group.
- the strong base used here includes sodium hexamethyldisilazide and the like.
- THF or the like can be used as the inert solvent.
- the amount of the inert solvent is not particularly limited as long as the raw material is dissolved. For example, 5 to 40 ml can be used for the raw material lg.
- the reaction temperature is not particularly limited, but the reaction is usually carried out at -78 to 0, preferably at -78.
- reaction time can be appropriately adjusted based on the disappearance of the raw materials, but is usually 1 hour to 5 hours.
- R 9 is a bromine atom in the formula (5-3)
- the compound is treated with dibutylporone triflate and diisopropylethylamine in an inert solvent, and then N is added as a brominating agent.
- N is added as a brominating agent.
- - can be brominated using promosuccinimide.
- R 8 represents a benzyl group or an isopropyl group.
- the inert solvent used here is not particularly limited, and for example, methylene chloride or the like can be used.
- the amount of the inert solvent is not particularly limited as long as the raw material is dissolved. For example, 10 ml to 50 ml can be used per 1 g of the raw material.
- the reaction temperature is not particularly limited, the reaction is usually carried out at -78 to 0, preferably at -78 ° C.
- the reaction time can be appropriately adjusted with reference to disappearance of the raw materials, but is usually 1 hour to 5 hours.
- step 3 the compound of formula (5-5) can be obtained by treating the compound of formula (5-4) with a metal alkoxide.
- a metal alkoxide for example, when R 2 ′′ is a methyl group, sodium methoxide or potassium methoxide in methanol can be used.
- n, R 1 and R 8 are as defined above.
- Step 4 and Step 5 can be carried out in the same manner as Step 1 and Step 2 in the above-mentioned Production Method 2.
- the optically active form of the compound represented by the formula (2) can be produced by the following production method 7 (see Tetrahedron Lett., 39, 5501 (1998)). Manufacturing method 7
- the (S) form of the formula (10S) can be produced by treating the compound of the formula (6-1) with (+)-diisopinocampheylpolyancide, 1) By treating with diisopinocampheylpanolchloride, the compound of formula (10R)
- the body can be manufactured.
- the compound of formula (1OR) or formula (10S) can be converted to an optically active compound represented by formula (2R) or formula (2S) by esterification by a known method. Further, an optically active form of -hydroxycarboxylic acid, which is an intermediate for producing the compound represented by the formula (2), can be produced by the following production method 8.
- n and R 1 are as defined above.
- n preferably represents 3 or 4.
- the compound of the formula (10) as a starting material can be produced by a known method or a method described in Examples in the present specification.
- the compound of the formula (10) is reacted with (a) ⁇ -tolylethylamine in an inert solvent to give the compound of the formula (10S).
- the compound of formula (10S) can be produced by isolating the mono-tolyleethylamine salt as a diastereomer salt and treating the diastereomer salt with an acid in a usual manner.
- the compound of formula (10) is reacted with '(+) —— tolylethylamine in an inert solvent to convert the (1) mono- ⁇ -tolylethylamine salt of the compound of formula (10R).
- the compound of the formula (10R) can be produced by treating the diastereomer salt with an acid in a usual manner.
- optical resolution of the compound represented by the formula (10) can be performed by the following steps:
- Step 1 a step of dissolving the compound represented by the formula (10) and an optically active mono-tolyleethylamine in an inert solvent
- Step 2 a step of precipitating a diastereomer salt crystal represented by the formula (11S) or (11R), and
- Step 3 A step of isolating the crystals obtained in (Step 2).
- the inert solvent used in (Step 1) is not particularly limited as long as it can dissolve the compound represented by the formula (10), and specifically, acetone, hydrated acetone, acetonitrile, tetrahydrofuran ( Examples thereof include alcohols such as THF), 1,4-dioxane, ethyl acetate, toluene, and ethanol, and preferably, acetone or hydrated acetone.
- the inert solvent can be used in an amount of 5 to 10 ml per 1 g of the raw material.
- the amount of the optically active —tolylethylamine used is in the range of about 0.8 to about 1.5 equivalents, preferably 1 equivalent, relative to the substrate.
- the temperature include a range from room temperature to the boiling point of the inert solvent.
- the reaction is usually performed at 40 ° C to 70 ° C. In order to improve the optical purity, it is desirable to raise the temperature once to near the boiling point of the solvent.
- the reaction time can be appropriately adjusted with reference to dissolution of all the raw materials, but is usually 0.5 to 2 hours.
- the method of precipitating the crystals of the ⁇ -tolyleluamine salt represented by the formula (11S) or (11R) is not particularly limited, and a method known to those skilled in the art can be used.
- the crystals can be precipitated by allowing the solution to stand still.
- the salt thus precipitated can be cooled if necessary before being collected by filtration to improve the yield.
- the solvent may be appropriately distilled off at normal pressure or under reduced pressure, at room temperature or under heating.
- step (3) the formed crystals are separated by filtration and, if necessary, the crystals are placed in an inert solvent (for example, alcohol solvents such as methanol, ethanol, 2-propanol, ether solvents such as dimethyl ether, ethyl acetate, etc.).
- an inert solvent for example, alcohol solvents such as methanol, ethanol, 2-propanol, ether solvents such as dimethyl ether, ethyl acetate, etc.
- an ester solvent an aromatic hydrocarbon solvent such as toluene, an acetonitrile, etc., and a mixed solvent thereof, and a high purity ethyl acetate represented by the formula (11S) or (11R). Luamine salts can also be obtained.
- high purity means that the purity is usually 90% ee or more, preferably 95% ee or more, and more preferably 98% ee or more.
- the ⁇ -tolyletylamine salt represented by the formula (11S) or the formula (11R) can be converted to a compound represented by the formula (10S) by using an acid such as hydrochloric acid, phosphoric acid or sulfuric acid, if necessary. Alternatively, it can lead to an optically active carboxylic acid compound represented by the formula (10R).
- an organic solvent such as ethyl acetate
- extracting with a 0.1 to 2N aqueous hydrochloric acid solution it can.
- the compound represented by the formula (10) includes not only the complete racemic form (0% ee) in which the (+) form and the (1) form are present in a 1: 1 ratio but also those having a certain degree of optical purity. It is.
- an optically active substance of the compound of the formula (10) is produced by the method described in the above-mentioned production method 7, and an optically active substance having higher optical purity can be obtained by using the method of the present invention.
- the optical purity of the intermediate optically active substance can be further improved by a method known to those skilled in the art.
- the optically active substance can be separated by purification using a fractional recrystallization method for forming a salt with an optically active base, a chromatography method using an optically active column, or the like.
- the fractional recrystallization method include: in an inert solvent (eg, an alcohol-based solvent such as methanol, ethanol, or 2-propanol; an ether-based solvent such as dimethyl ether; an ester-based solvent such as ethyl acetate; Hydrogen-based solvents, acetonitrile, or a mixture thereof; optically active bases (eg, organic amines such as hyphenethylamine, -tolyletylamine, quinine, quinidine, cinchonidine, cinchonine, or strychnine) And a method of forming a salt.
- an inert solvent eg, an alcohol-based solvent such as methanol, ethanol, or 2-propanol
- an ether-based solvent such as
- the temperature at which the salt is formed includes a range from room temperature to the boiling point of the solvent. In order to improve the optical purity, it is desirable to raise the temperature once to near the boiling point of the solvent. Before the precipitated salt is collected by filtration, the salt can be cooled if necessary to improve the yield.
- the amount of the optically active acid or amine used is generally in the range of about 0.5 to about 2.0 equivalents, preferably about 1 equivalent, relative to the substrate. If necessary, crystallize in an inert solvent (for example, alcohol solvents such as methanol, ethanol, and 2-propanol; ether solvents such as getyl ether; ester solvents such as ethyl acetate; and aromatic hydrocarbon solvents such as toluene. , Acetonitrile and the like and a mixed solvent thereof) to obtain a high-purity optically active salt. If necessary, the obtained salt can be treated with an acid or a base in a usual manner to obtain a free form.
- optically active column used in the chromatography method those commonly used by those skilled in the art can be used.
- CHIRALCEL registered trademark
- CHI RA LCELAS-RH manufactured by Daicel Chemical Industries, Ltd.
- a method of optically resolving the compound of the formula (1) including the compounds of the formulas (118) and (3-3).
- the optically active isomers of the compound of the formula (1) of the present invention the optically active isomer having the S-configuration has a higher activity.
- Specific compounds include the compounds described in Example 7 and Example 14 and the like.
- the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof can be administered orally or parenterally, systemically or locally, when used as a medicament.
- examples of the administration form include capsules, tablets, powders, cachets, liquids and the like.
- the dosage form can be, for example, injection, transdermal, nasal, rectal or the like.
- examples of the injection include a sterile solution or suspension.
- transdermal agents include creams, ointments, lotions, patches, and matrixes.
- Rectal preparations include suppositories, enemas (solution injection) and the like.
- Nasal preparations include azoles and nasal drops.
- specific administration methods include intra-articular administration, transdermal administration and the like.
- the compound of the formula (1) or a pharmaceutically acceptable salt thereof can be used as a pharmaceutical composition together with pharmaceutically acceptable excipients and additives commonly used by those skilled in the art.
- Pharmaceutically acceptable excipients and additives include carriers, binders, flavors, buffers, thickeners, coloring agents, stabilizers, emulsifiers, dispersants, suspending agents, preservatives, etc. Can be
- Pharmaceutically acceptable carriers include, for example, magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low melting wax. And cocoa butter.
- Capsules can be formulated by incorporating a compound of the present invention together with a pharmaceutically acceptable carrier.
- the benzothiazin-3-one compound of the present invention or a pharmaceutically acceptable salt thereof can be mixed with a pharmaceutically acceptable excipient or placed in a capsule without an excipient.
- Cassiers can be produced in a similar manner.
- Solutions for injection include solutions, suspensions, emulsions and the like.
- an aqueous solution, a water-propylene glycol solution and the like can be mentioned.
- the solution can also be prepared in the form of a solution of polyethylene glycol or / and propylene glycol, which may contain water.
- Liquid preparations suitable for oral administration can be prepared by adding the compound of the present invention to water and adding a coloring agent, a flavor, a stabilizing agent, a sweetening agent, a solubilizing agent, a thickening agent and the like as necessary.
- Liquid preparations suitable for buccal administration can also be prepared by adding the benzothiazin-3-one compound of the present invention or a pharmaceutically acceptable salt thereof to water together with a dispersing agent to make it viscous.
- a dispersing agent examples include pharmaceutically acceptable natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and known suspending agents.
- Examples of the agent for topical administration include the above liquid preparations, creams, aerosols, sprays, powders, mouthwashes, ointments and the like.
- the above-mentioned topical preparation can be produced by mixing the benzothiazin-3-one derivative of the present invention or a salt thereof with a pharmaceutically acceptable diluent and carrier commonly used.
- Ointments and creams are obtained, for example, by formulating an aqueous or oily base with a thickener and a Z or gelling agent.
- Examples of the base include water, liquid paraffin, vegetable oils (eg, pine nut oil, castor oil) and the like.
- Examples of the thickener include soft paraffin, aluminum stearate, setostearyl alcohol, propylene glycol, polyethylene glycol, lanolin, hydrogenated lanolin, honey, and the like.
- Lotions can be prepared by adding one or more pharmaceutically acceptable stabilizers, suspending agents, emulsifiers, diffusing agents, thickeners, coloring agents, fragrances, etc. to an aqueous or oily base. Wear.
- the powder is formulated with a pharmaceutically acceptable powder base.
- the base include sugar, lactose, starch and the like.
- Drops may be formulated with an aqueous or non-aqueous base and one or more pharmaceutically acceptable diffusing, suspending, or dissolving agents.
- the topical preparation may contain, if necessary, a preservative such as methyl hydroxybenzoate, propyl hydroxybenzoate, cresol closole, benzalkonidum chloride, and a bacterial growth inhibitor.
- a preservative such as methyl hydroxybenzoate, propyl hydroxybenzoate, cresol closole, benzalkonidum chloride, and a bacterial growth inhibitor.
- Liquid preparations, sprays or powdered preparations containing the benzothiazin-3-one derivative or a salt thereof of the present invention as an active ingredient can also be administered nasally.
- a compound represented by the formula (1) wherein R is an ethyl group and a pharmaceutically acceptable salt thereof are: a prodrug that exhibits excellent oral absorption and is converted into a highly active form by being metabolized in vivo It is characterized by acting as. That is, HOO
- n and R 1 are as defined above.
- the compound represented by the formula (1-8) is metabolized in vivo by an enzyme and converted into a metabolite represented by the formula (3-3).
- the compound represented by the formula (3-3) exhibits excellent MMP inhibitory activity in vivo,
- the compound represented by the formula (18) or a pharmaceutically acceptable salt thereof is preferably administered orally as a systemically administered agent or parenterally as a locally administered agent. You.
- the compound represented by the formula (3-3) or a pharmaceutically acceptable salt thereof is preferably administered parenterally.
- the dose and frequency of administration of the compound represented by the formula (1) (compound of the formula (118) or the formula (3-3)) or a pharmaceutically acceptable salt thereof are as follows: symptoms, age, Depending on body weight, administration form, etc., when administered orally, the dose is usually about 1 to about 100 mg / day, preferably about 5 to about 30 mg / day for adults. It can be administered once or in several divided doses. When administered as an injection, the dosage is usually about 0.1 to about 300 mg / day, preferably about 1 to about 100 mg / day for adults, divided into one or several doses. Can be administered.
- the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof includes cartilage degenerative diseases such as osteoarthritis or rheumatoid arthritis, cancer, inflammatory diseases, COPD (chronic obstructive pulmonary disease), It can be used as a therapeutic or preventive agent for diseases such as asthma, multiple sclerosis, dermatitis, spondylopathy, periodontal disease, wound, muscle pain, ulcer, stenosis, eating disorder, and sepsis.
- the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof is particularly preferably useful as a therapeutic agent for cartilage degenerative disease, and exhibits an excellent effect as a therapeutic agent for osteoarthritis.
- the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof when used as a therapeutic agent for a specific disease, it can be used in combination with various therapeutic agents for the disease.
- the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof includes a TNFa inhibitor (including an anti-TNF antibody), methotrexate, leflunomide, hydroxycloquinone, d — Penicillamine, nonsteroidal anti-inflammatory drugs (diclofenac, naproxen, flurbiprofen, ibuprofen, etc.), cyclooxygenase inhibitors 2 (meloxicam, celecoxib, etc.), salicylic acids (aspirin, etc.), steroids (corticosteroids) ), Immunosuppressants (cycloporin, tacrolimus, etc.), hyaluronic acid (hyalgan, symbics, etc.), etc.
- TNFa inhibitor including an anti-TNF antibody
- methotrexate including an anti
- cancer In the case of cancer, it can be used in combination with various anticancer agents (eg, angiostin, adriamycin, cis bratin, taxol, etc.).
- anticancer agents eg, angiostin, adriamycin, cis bratin, taxol, etc.
- room temperature or ambient temperature represents 15 ° C to 30 ° C. All non-aqueous reactions were performed under a nitrogen atmosphere. Concentration under reduced pressure means that a rotary evaporator was used.
- the obtained target compound can be used, if necessary, for example, by recrystallization, reprecipitation, or a method usually used for separation and purification of organic compounds, for example, silica gel, alumina, magnesium-silica gel-based florisil.
- Adsorption force ram chromatography using such a carrier Sephadex LH-20 (Pharmacia), Amberlite XAD-11 (Rohm & Haas), Diaion HP-20 (Mitsubishi Chemical Co., Ltd.) using a synthetic adsorbent such as partition column chromatography using a carrier, using ion exchange chromatography, or normal and reverse phases using silica gel or lower alkylated silica gel.
- the column chromatography method (preferably high performance liquid chromatography) is appropriately combined and eluted with a suitable eluent. Connexion can be separated and purified.
- NMR data is reported in ppm ( ⁇ ) and is relative to the lock signal of the diuterium from the sample solvent.
- Commercial reagents were used without further purification.
- CDC 1 3 heavy black port Holm, DM.SO- d 6 is a heavy dimethyl sulfoxide.
- Commercial reagents were used without further purification.
- the abbreviations used for NMR-data are as follows: s: Single let
- the oil layer was dehydrated with anhydrous sodium sulfate and concentrated under reduced pressure.
- reaction solution was poured into a saturated aqueous solution of sodium hydrogencarbonate, extracted with ethyl acetate, and the organic layer was washed with a saturated aqueous solution of ammonium chloride and saturated saline, and then dried over anhydrous sodium sulfate.
- the desiccant was removed by filtration, the solvent was distilled off under reduced pressure, and the residue was recrystallized with a mixed solvent of ethyl acetate and diisopropyl ether to obtain (1) ethyl 4- (2-hydroxyamino).
- Example 7 The compound described in Example 7 (0.51 g) was added to a solution prepared by adding N-methyldalcamine to a 0.1 M aqueous solution of sodium dihydrogen phosphate to pH 8.0, and the mixture was stirred at 40 ° C. Stirred. Porcine liver esterase (250 mg) was added, and the mixture was stirred at 40 for 8 hours and at room temperature for 4 days. After filtration, potassium hydrogen sulfate (13. Og) was added to the filtrate, and the mixture was extracted with ethyl acetate. The oil layer was washed with a 5% aqueous solution of potassium hydrogen sulfate and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
- 4- (4-Methoxyphenyl) 4-oxoptanoic acid (40 g) is added (insoluble) to a mixed solvent of acetic acid (100 ml) and THF (100 ml), and 10% palladium-butane (50% —wet) is added. (4 g) was added, and the mixture was stirred under a hydrogen atmosphere (0.4 MPa) for 9 hours. The catalyst was removed by filtration through celite, toluene was added, and the solvent was distilled off under reduced pressure to obtain 4_ (4-methoxyphenyl) butanoic acid quantitatively.
- the optical purity analysis conditions are as follows.
- Ethyl 3-promo-4-mercaptobenzenecarboxyimidate (3.00 g) was dissolved in ethanol (100 ml), water was added with O (10 ml), and concentrated sulfuric acid (1 Oml) was added dropwise. ⁇ ⁇ Stirring was performed. Zinc (lg) is added to the reaction system, and the mixture is stirred at room temperature for 2 hours to derive a monomer. Then, after removing the zinc powder by celite filtration, the ethanol is distilled off under reduced pressure, extracted with ethyl acetate, and the organic layer is washed with water (x4). The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain pale yellow solid ethyl 3-bromo-4-mercaptobenzoate (2.58 g).
- the optical purity analysis conditions are as follows.
- Zinc (3.73 g) and ammonium chloride (3.69 g) were added to water (34.5 ml), and the compound of Reference Example 7 (6.89 g, 99% e.e.) was treated with THF. (30 ml) The solution was added dropwise under ice cooling. After completion of the dropwise addition, the temperature was raised to room temperature, and the mixture was stirred for 6 hours. Ethyl acetate and water were added to the reaction solution, and the mixture was filtered through celite. The organic layer was washed with 1N aqueous hydrochloric acid and saturated brine, and dried over anhydrous sodium sulfate.
- Example 1 The compound described in Step B (62 mg) was dissolved in methylene chloride (2.5 ml), and (1)-(8,8-dichlorocamphonylsulfonyl) oxaziridine (37 mg) was added thereto. For 10 days. The reaction mixture was poured into saturated saline and extracted with ethyl acetate. The organic layer was collected, dried over anhydrous magnesium sulfate, and concentrated in an evaporator overnight.
- Example 14 The compound described in Example 14 (25% 90% e.e.) was obtained in the same manner as in Reference Example 14 using oxaziridine and ethyl acetate as the solvent. Optical purity was determined by the method described in Example 14.
- Jetyl 4,4'-dithiopis (3-nitrobenzoate) (0.64 g) was dissolved in tetrahydrofuran (10 ml), and dithiothreitol (0.24 g) and N-methylmorpholine (0.21 ml) were dissolved at room temperature. added.
- optical purity analysis conditions are as follows.
- optical purity analysis conditions are as follows.
- UV Detection wavelength
- Methyl (2R) -2-hydroxy-5- (4-methoxyphenyl) pentanoate (10 g, 98% ee) synthesized in Reference Example 27 was dissolved in acetonitrile (50 ml), and anhydrous trifluoromethane was added under ice cooling.
- Lomethanesulfonic acid (9 ml) and triethylamine (6.5 ml) were sequentially added, and the mixture was stirred at the same temperature for 1 hour.
- a saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate.
- Acetic acid 50 ml was added to the reduced iron (8.2 g), and a solution of the compound of Reference Example 30 in toluene (50 ml, insoluble matter was Kiriyama Filtration) was added at 90 ° C. The mixture was stirred at the same temperature for 5 hours, cooled to room temperature, and filtered through celite. The filtrate was poured into 1N aqueous hydrochloric acid (200 ml). Ethyl acetate (100 ml) was added, and after extraction, the organic layer was washed with a saturated saline solution and subjected to anhydrous sodium sulfate 1.
- ethyl 4-chloro-1--3-benzobenzoate (1.00 g) was suspended in ethanol (10 ml), and NaSH nH20 (ca 70 wt%, 0.34 g) was cooled on ice. After 30 minutes, the temperature was changed to a 20 ° C water bath, and the mixture was stirred for 1 hour. After concentrating the ethanol to half the volume, water was added, extracted with toluene, and the organic phase was concentrated under reduced pressure to obtain ethyl 4-thio-3-nitrobenzoate (l.O Og).
- dibutyl 4,4'-dithiobis (3-ditrobenzoate) (22.8 g) was suspended in ethanol (151 ml), and sodium borohydride (4.79 g) was added little by little under ice cooling. Stirred for 1 hour. After adding 1N aqueous hydrochloric acid (554 ml) to the reaction mixture under ice-cooling, the mixture was extracted with toluene (228 m 1 ⁇ 2). After washing the organic layer with water (114 ml), the solvent was distilled off under reduced pressure to quantitatively obtain ethyl needle 4-thio-3-nitrobenzoate as yellow needle crystals.
- bioavailability (bioavailability; BA) when the compound of Example 7 was orally administered was 18.4%, and when the compound of Example 14 was orally administered (bioavailability: 2.7%). %), It was confirmed to be a prodrug with superior oral absorption.
- MMP-13 is based on a known human MMP-13 gene base sequence (J. Biol. Chem., 269 (24), 16766-16773 (1994)) and is genetically engineered (human chondrocyte cDN ⁇ library). 1 'as the material, Primer 1'-
- the measurement of the inhibitory activity against human MMP-13 was carried out according to the method of C. G. Knigh et al.
- MCA L-aralanyl-L-arginineamide
- Dimethylsulfoxide solution was diluted with Atsushi buffer to make 80 M, and 25 1 of the substrate solution was added thereto, and the fluorescence (ex. 320 nm, em. 405 nm) was measured with a fluorescence plate reader. After reaction at 37 ° C. for 12 hours, fluorescence was measured with a fluorescent plate reader to measure the remaining enzyme activity.
- the MMP-13 inhibitory activity of the compound of Example 14 was 44 nM in terms of IC 50 value. Test example 3
- the test compound was administered orally with l OmlZkg (solvent 5% methylcellulose) 6 times for Z weeks and 3 weeks.After weighing, the right hind limb tibia was collected and fixed with 10% neutral buffered formalin. . Paraffin specimens were prepared as tissue specimens. First, after embedding in paraffin, the slices were sliced to a thickness of 6 m and stained with Safranin ⁇ Z First Darline. Tissue specimens were prepared at the position of 3 bandages from the front where, after formalin fixation and macroscopically observed, severe degeneration occurred.
- the cartilage site inside the tibia was divided into nine sites as shown in the figure below, and proteodalican was used for each site.
- the decrease in staining was scored blindly. The highest score of the position is set to 1 and quantified by the rate of decrease in staining (Example: If staining deteriorates in 1/4 site, score 25), and the total of 9 sites is scored for that sample (0-9) ).
- the average value of each group was calculated, and the degree of cartilage degeneration of each compound was calculated by the following formula, with the degree of cartilage degeneration in the disease state control group as 100%.
- Inhibition rate (%) 1-(mean score value of medication group / score value of control group)
- the compound of Example 7 showed a cartilage degeneration inhibition rate of 52% at 50 mg / kg, and it was confirmed that the compound of the present invention had an excellent pharmacological action on osteoarthritis.
- the present invention it has become possible to provide a novel benzothiazine-13-one conjugate which is useful as an active ingredient of a drug. That is, since the compound of the present invention exhibits good oral absorption properties and gives a compound that is metabolized in vivo and exhibits excellent matrix metaoral protease inhibitory activity, it can be used in cartilage such as osteoarthritis and rheumatoid arthritis. It is useful as a therapeutic, prophylactic or anti-inflammatory agent for degenerative diseases and metastasis of cancer cells. Further, it has become possible to produce a 2-thiocarboxylic acid derivative or an optically active 2-hydroxycarboxylic acid, which is a production intermediate for producing the benzothiazin-3-one compound in good yield. Sequence listing free text
- SEQ ID NO: 3 Synthetic peptide
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Physics & Mathematics (AREA)
- Physical Education & Sports Medicine (AREA)
- Optics & Photonics (AREA)
- General Physics & Mathematics (AREA)
- Vascular Medicine (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Heart & Thoracic Surgery (AREA)
- Pulmonology (AREA)
- Rheumatology (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Communicable Diseases (AREA)
- Immunology (AREA)
- Pain & Pain Management (AREA)
- Oncology (AREA)
- Nutrition Science (AREA)
- Obesity (AREA)
- Cardiology (AREA)
- Diabetes (AREA)
- Dermatology (AREA)
- Neurosurgery (AREA)
- Child & Adolescent Psychology (AREA)
- Urology & Nephrology (AREA)
- Hematology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
Claims
Priority Applications (7)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2006510553A JP4856537B2 (ja) | 2004-03-02 | 2005-02-28 | ベンゾチアジン−3−オン化合物及びその製造中間体 |
EP05720093A EP1726587B1 (en) | 2004-03-02 | 2005-02-28 | Benzothiazin-3-one compound and intermediate therefor |
US10/598,516 US7598240B2 (en) | 2004-03-02 | 2005-02-28 | Benzothiazin-3-one compound and intermediate therefor |
AT05720093T ATE479668T1 (de) | 2004-03-02 | 2005-02-28 | Benzothiazin-3-one verbindung und zwischenprodukt dafür |
DE602005023279T DE602005023279D1 (de) | 2004-03-02 | 2005-02-28 | Benzothiazin-3-one verbindung und zwischenprodukt dafür |
CA002560664A CA2560664A1 (en) | 2004-03-02 | 2005-02-28 | Benzothiazin-3-one compound and intermediate therefor |
US12/547,574 US7879843B2 (en) | 2004-03-02 | 2009-08-26 | Benzothiazin-3-one compound and intermediate therefor |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2004-057808 | 2004-03-02 | ||
JP2004057808 | 2004-03-02 |
Related Child Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US10/598,516 A-371-Of-International US7598240B2 (en) | 2004-03-02 | 2005-02-28 | Benzothiazin-3-one compound and intermediate therefor |
US12/547,574 Division US7879843B2 (en) | 2004-03-02 | 2009-08-26 | Benzothiazin-3-one compound and intermediate therefor |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2005082872A1 true WO2005082872A1 (ja) | 2005-09-09 |
Family
ID=34909060
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/JP2005/003821 WO2005082872A1 (ja) | 2004-03-02 | 2005-02-28 | ベンゾチアジン-3-オン化合物及びその製造中間体 |
Country Status (9)
Country | Link |
---|---|
US (2) | US7598240B2 (ja) |
EP (1) | EP1726587B1 (ja) |
JP (1) | JP4856537B2 (ja) |
AT (1) | ATE479668T1 (ja) |
CA (1) | CA2560664A1 (ja) |
DE (1) | DE602005023279D1 (ja) |
ES (1) | ES2351605T3 (ja) |
TW (1) | TW200538132A (ja) |
WO (1) | WO2005082872A1 (ja) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2007045793A (ja) * | 2005-08-12 | 2007-02-22 | Sumitomo Chemical Co Ltd | α−チオエステル化合物の製造方法およびその製造中間体 |
WO2008093737A1 (ja) | 2007-01-31 | 2008-08-07 | Dainippon Sumitomo Pharma Co., Ltd. | アミド誘導体 |
WO2010150840A1 (ja) | 2009-06-24 | 2010-12-29 | 大日本住友製薬株式会社 | N-置換-環状アミノ誘導体 |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20140081017A1 (en) * | 2012-09-14 | 2014-03-20 | Methylgene Inc. | Histone Deacetylase Inhibitors for Enhancing Activity of Antifungal Agents |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2002128769A (ja) * | 2000-10-17 | 2002-05-09 | Sumitomo Pharmaceut Co Ltd | ベンゾチアジン−3−オン誘導体 |
JP2002542238A (ja) * | 1999-04-19 | 2002-12-10 | 住友製薬株式会社 | ヒドロキサム酸誘導体 |
WO2003055851A1 (fr) * | 2001-12-27 | 2003-07-10 | Sumitomo Pharmaceuticals Company, Limited | Derives d'acide hydroxamique et inhibiteur des mmp contenant ces derniers en tant que substance active |
WO2004014389A1 (en) * | 2002-08-13 | 2004-02-19 | Warner-Lambert Company Llc | 3,4-dihydroquinolin-2-one, 5,6-fused oxazin-3-one, and 5,6-fused thiazin-3-one derivatives as matrix metalloproteinase inhibitors |
Family Cites Families (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB1268194A (en) | 1968-03-18 | 1972-03-22 | Ici Ltd | Pyridine derivatives and their manufacture |
US3910904A (en) | 1974-08-12 | 1975-10-07 | Monsanto Co | 2-Substituted methylene-3,4-dihydro-3-oxo-2H-1,4-benzothiazine-4-acetic acid and esters thereof |
US3923709A (en) | 1974-08-30 | 1975-12-02 | Monsanto Co | 3,4-Dihydro-3-oxo-2H-1,4-benzothiazines and benzoxazines |
US4584300A (en) | 1983-02-07 | 1986-04-22 | Santen Pharmaceutical Co., Ltd. | Platelet anti-aggregative- and calcium antagonistic -1,4-benzothiazin-3-one derivatives, compositions, and methods of use therefor |
IE58312B1 (en) | 1984-05-18 | 1993-09-08 | Union Pharma Scient Appl | Heterocyclic derivatives, processes for their preparation and drugs in which they are present, which are useful especially as aldose reductase inhibitors |
AU602641B2 (en) | 1986-04-17 | 1990-10-18 | Senju Pharmaceutical Co., Ltd. | Thiolactam-N-acetic acid derivatives, their production and use |
WO1994005647A1 (en) | 1992-08-31 | 1994-03-17 | Santen Pharmaceutical Co., Ltd. | 3-oxo-1,4-benzothiazine derivative |
KR960022486A (ko) | 1994-12-29 | 1996-07-18 | 김준웅 | 신규 티아졸리딘-4-온 유도체 |
JPH1084987A (ja) | 1996-09-18 | 1998-04-07 | Takeda Chem Ind Ltd | 光学活性化合物の製造法 |
JP3899147B2 (ja) | 1996-10-24 | 2007-03-28 | 武田薬品工業株式会社 | 光学活性化合物の製造法 |
JP2000309575A (ja) | 1999-04-27 | 2000-11-07 | Takeda Chem Ind Ltd | 新規ヒダントイン誘導体およびその製造法 |
US6713477B1 (en) | 2000-04-19 | 2004-03-30 | Sumitomo Pharmaceuticals Company, Limited | Hydroxamic acid derivatives |
JP2002037761A (ja) | 2000-07-24 | 2002-02-06 | Takeda Chem Ind Ltd | α−ヒドロキシカルボン酸化合物の製造法 |
JP4856408B2 (ja) * | 2005-08-12 | 2012-01-18 | 大日本住友製薬株式会社 | α−チオエステル化合物の製造方法およびその製造中間体 |
-
2005
- 2005-02-28 DE DE602005023279T patent/DE602005023279D1/de active Active
- 2005-02-28 ES ES05720093T patent/ES2351605T3/es active Active
- 2005-02-28 US US10/598,516 patent/US7598240B2/en not_active Expired - Fee Related
- 2005-02-28 AT AT05720093T patent/ATE479668T1/de not_active IP Right Cessation
- 2005-02-28 EP EP05720093A patent/EP1726587B1/en not_active Not-in-force
- 2005-02-28 CA CA002560664A patent/CA2560664A1/en not_active Abandoned
- 2005-02-28 WO PCT/JP2005/003821 patent/WO2005082872A1/ja active Application Filing
- 2005-02-28 JP JP2006510553A patent/JP4856537B2/ja not_active Expired - Fee Related
- 2005-03-02 TW TW094106274A patent/TW200538132A/zh not_active IP Right Cessation
-
2009
- 2009-08-26 US US12/547,574 patent/US7879843B2/en not_active Expired - Fee Related
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2002542238A (ja) * | 1999-04-19 | 2002-12-10 | 住友製薬株式会社 | ヒドロキサム酸誘導体 |
JP2002128769A (ja) * | 2000-10-17 | 2002-05-09 | Sumitomo Pharmaceut Co Ltd | ベンゾチアジン−3−オン誘導体 |
WO2003055851A1 (fr) * | 2001-12-27 | 2003-07-10 | Sumitomo Pharmaceuticals Company, Limited | Derives d'acide hydroxamique et inhibiteur des mmp contenant ces derniers en tant que substance active |
WO2004014389A1 (en) * | 2002-08-13 | 2004-02-19 | Warner-Lambert Company Llc | 3,4-dihydroquinolin-2-one, 5,6-fused oxazin-3-one, and 5,6-fused thiazin-3-one derivatives as matrix metalloproteinase inhibitors |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2007045793A (ja) * | 2005-08-12 | 2007-02-22 | Sumitomo Chemical Co Ltd | α−チオエステル化合物の製造方法およびその製造中間体 |
WO2008093737A1 (ja) | 2007-01-31 | 2008-08-07 | Dainippon Sumitomo Pharma Co., Ltd. | アミド誘導体 |
WO2010150840A1 (ja) | 2009-06-24 | 2010-12-29 | 大日本住友製薬株式会社 | N-置換-環状アミノ誘導体 |
Also Published As
Publication number | Publication date |
---|---|
EP1726587B1 (en) | 2010-09-01 |
EP1726587A1 (en) | 2006-11-29 |
DE602005023279D1 (de) | 2010-10-14 |
TW200538132A (en) | 2005-12-01 |
JP4856537B2 (ja) | 2012-01-18 |
US20100009976A1 (en) | 2010-01-14 |
US20080058321A1 (en) | 2008-03-06 |
US7598240B2 (en) | 2009-10-06 |
ES2351605T3 (es) | 2011-02-08 |
CA2560664A1 (en) | 2005-09-09 |
TWI367097B (ja) | 2012-07-01 |
EP1726587A4 (en) | 2008-07-09 |
JPWO2005082872A1 (ja) | 2008-01-17 |
US7879843B2 (en) | 2011-02-01 |
ATE479668T1 (de) | 2010-09-15 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CA2700274C (en) | Quinone derivatives, pharmaceutical compositions, and uses thereof | |
JP3569550B2 (ja) | 縮合二環式環含有化合物およびその製造法 | |
AU773445B2 (en) | Substituted phenylpropanoic acid derivatives as agonists to human peroxisome proliferator-activated receptor (PPAR) alpha | |
JPH11509519A (ja) | 非ステロイド系抗炎症剤誘導毒性を予防する組成物および方法 | |
JPH09503222A (ja) | サイトカイン産生阻害剤としてのヒドロキサム酸誘導体 | |
WO2002059077A1 (fr) | Derivés aminoéthanol | |
WO2004022551A1 (ja) | フランまたはチオフェン誘導体およびその医薬用途 | |
BG107889A (bg) | Тетралонови производни като антитуморни средства | |
JP2010248209A (ja) | ニトロソ化およびニトロシル化された非ステロイド抗炎症性化合物、組成物および使用方法 | |
CZ285476B6 (cs) | Heterocyklické aromatické oxazolové sloučeniny, jejich oximové, ketonové, ketomethylenové, esterové a amidové sloučeniny a farmaceutické přípravky, inhibitory cyklooxygenasy a protizánětlivá činidla obsahující tyto oxazolové sloučeniny | |
IL146851A (en) | 5 - Aryl 2 - Pyrozelin converted to 1 - (4 - Sulfamilril) - 3 as cycloxyginase inhibitors - 2 | |
WO1998012210A1 (en) | 4-substituted-3-(2-amino-2-cycloalkyl methyl)-acetamido azetidin-2-one derivatives as cysteine proteinase regulators | |
JP2000502710A (ja) | 置換n―[(アミノイミノメチル又はアミノメチル)フェニル]プロピルアミド | |
EP0950046B1 (en) | 3,4-disubstituted azetidin-2-one derivatives useful as cysteine proteinase regulators | |
JP2018526448A (ja) | 一酸化窒素を放出可能なプロドラッグ分子 | |
JPH10511084A (ja) | ポリアリールカルバモイルアザ及びカルバモイルアルカン二酸 | |
WO2005082872A1 (ja) | ベンゾチアジン-3-オン化合物及びその製造中間体 | |
JPH10503779A (ja) | フェノキシフェニル酢酸誘導体 | |
WO2008044729A1 (en) | Carboxylic acid derivative | |
JP2002515428A (ja) | プロテアーゼ阻害剤 | |
JP4313678B2 (ja) | ヒドロキサム酸誘導体およびそれを有効成分とするmmp阻害剤 | |
JP2002212177A (ja) | 脂質代謝改善剤 | |
JP2006028104A (ja) | ヒストンデアセチラーゼ阻害剤 | |
JP2001163862A (ja) | テトラヒドロピリダジン誘導体 | |
AU737584B2 (en) | Compositions and methods to prevent toxicity induced by nonsteroidal antiinflammatory drugs |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AK | Designated states |
Kind code of ref document: A1 Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BW BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NA NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SM SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW |
|
AL | Designated countries for regional patents |
Kind code of ref document: A1 Designated state(s): GM KE LS MW MZ NA SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LT LU MC NL PL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG |
|
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
WWE | Wipo information: entry into national phase |
Ref document number: 2006510553 Country of ref document: JP |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
WWW | Wipo information: withdrawn in national office |
Country of ref document: DE |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2560664 Country of ref document: CA |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2005720093 Country of ref document: EP |
|
WWP | Wipo information: published in national office |
Ref document number: 2005720093 Country of ref document: EP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 10598516 Country of ref document: US |
|
WWP | Wipo information: published in national office |
Ref document number: 10598516 Country of ref document: US |