WO2005095464A1 - ヒアルロン酸-メトトレキサート結合体 - Google Patents
ヒアルロン酸-メトトレキサート結合体 Download PDFInfo
- Publication number
- WO2005095464A1 WO2005095464A1 PCT/JP2005/006472 JP2005006472W WO2005095464A1 WO 2005095464 A1 WO2005095464 A1 WO 2005095464A1 JP 2005006472 W JP2005006472 W JP 2005006472W WO 2005095464 A1 WO2005095464 A1 WO 2005095464A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- group
- hyaluronic acid
- mtx
- substituted
- formula
- Prior art date
Links
- 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 title claims abstract description 171
- 229920002674 hyaluronan Polymers 0.000 title claims abstract description 151
- 229960003160 hyaluronic acid Drugs 0.000 title claims abstract description 150
- 229960000485 methotrexate Drugs 0.000 title claims abstract description 38
- -1 methotrexate compound Chemical class 0.000 title abstract description 49
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical group 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 claims abstract description 93
- 108090000765 processed proteins & peptides Proteins 0.000 claims abstract description 62
- 239000003814 drug Substances 0.000 claims abstract description 48
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 41
- 150000001413 amino acids Chemical class 0.000 claims abstract description 39
- 208000012659 Joint disease Diseases 0.000 claims abstract description 25
- 229940124597 therapeutic agent Drugs 0.000 claims abstract description 13
- KXDHJXZQYSOELW-UHFFFAOYSA-N Carbamic acid Chemical group NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 claims abstract 2
- 150000001875 compounds Chemical class 0.000 claims description 87
- 125000000217 alkyl group Chemical group 0.000 claims description 61
- 150000003839 salts Chemical class 0.000 claims description 54
- 125000005647 linker group Chemical group 0.000 claims description 51
- 238000002360 preparation method Methods 0.000 claims description 41
- 238000004519 manufacturing process Methods 0.000 claims description 39
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 25
- 125000003282 alkyl amino group Chemical group 0.000 claims description 19
- 239000000126 substance Substances 0.000 claims description 18
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 15
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 13
- 125000003277 amino group Chemical group 0.000 claims description 13
- 125000003545 alkoxy group Chemical group 0.000 claims description 12
- 125000003118 aryl group Chemical group 0.000 claims description 12
- 229910052757 nitrogen Inorganic materials 0.000 claims description 12
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 11
- 125000002947 alkylene group Chemical group 0.000 claims description 11
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 11
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 10
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 9
- WLLGXSLBOPFWQV-UHFFFAOYSA-N MGK 264 Chemical group C1=CC2CC1C1C2C(=O)N(CC(CC)CCCC)C1=O WLLGXSLBOPFWQV-UHFFFAOYSA-N 0.000 claims description 8
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 8
- 125000003368 amide group Chemical group 0.000 claims description 6
- 125000004391 aryl sulfonyl group Chemical group 0.000 claims description 6
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 6
- 239000004480 active ingredient Substances 0.000 claims description 5
- 125000005263 alkylenediamine group Chemical group 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- WSWCOQWTEOXDQX-MQQKCMAXSA-M (E,E)-sorbate Chemical group C\C=C\C=C\C([O-])=O WSWCOQWTEOXDQX-MQQKCMAXSA-M 0.000 claims description 2
- 125000003107 substituted aryl group Chemical group 0.000 claims description 2
- GYPCWHHQAVLMKO-XXKQIVDLSA-N (7s,9s)-7-[(2r,4s,5s,6s)-4-amino-5-hydroxy-6-methyloxan-2-yl]oxy-6,9,11-trihydroxy-9-[(e)-n-[(1-hydroxy-2,2,6,6-tetramethylpiperidin-4-ylidene)amino]-c-methylcarbonimidoyl]-4-methoxy-8,10-dihydro-7h-tetracene-5,12-dione;hydrochloride Chemical group Cl.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(\C)=N\N=C1CC(C)(C)N(O)C(C)(C)C1)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 GYPCWHHQAVLMKO-XXKQIVDLSA-N 0.000 claims 1
- 125000002843 carboxylic acid group Chemical group 0.000 claims 1
- 238000011282 treatment Methods 0.000 abstract description 10
- 239000002253 acid Substances 0.000 abstract description 8
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 69
- 239000000843 powder Substances 0.000 description 47
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 46
- 238000005160 1H NMR spectroscopy Methods 0.000 description 45
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 45
- 239000000243 solution Substances 0.000 description 38
- 238000000034 method Methods 0.000 description 37
- 239000000203 mixture Substances 0.000 description 36
- 229940079593 drug Drugs 0.000 description 32
- 230000000694 effects Effects 0.000 description 32
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 30
- 239000007864 aqueous solution Substances 0.000 description 30
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 29
- 210000000629 knee joint Anatomy 0.000 description 29
- 201000004595 synovitis Diseases 0.000 description 28
- 229940024606 amino acid Drugs 0.000 description 26
- 235000001014 amino acid Nutrition 0.000 description 25
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 24
- 206010003246 arthritis Diseases 0.000 description 24
- 239000002244 precipitate Substances 0.000 description 23
- 238000006243 chemical reaction Methods 0.000 description 21
- 230000002829 reductive effect Effects 0.000 description 21
- 206010039073 rheumatoid arthritis Diseases 0.000 description 21
- 206010023232 Joint swelling Diseases 0.000 description 19
- 230000002401 inhibitory effect Effects 0.000 description 19
- 210000003127 knee Anatomy 0.000 description 16
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- 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 15
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 15
- 229910052739 hydrogen Inorganic materials 0.000 description 15
- 239000011541 reaction mixture Substances 0.000 description 15
- 208000002193 Pain Diseases 0.000 description 14
- 210000002437 synoviocyte Anatomy 0.000 description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- 125000001424 substituent group Chemical group 0.000 description 13
- 238000012360 testing method Methods 0.000 description 13
- 229910021642 ultra pure water Inorganic materials 0.000 description 13
- 239000012498 ultrapure water Substances 0.000 description 13
- 238000001914 filtration Methods 0.000 description 12
- 238000005481 NMR spectroscopy Methods 0.000 description 11
- 125000004432 carbon atom Chemical group C* 0.000 description 11
- 239000011734 sodium Substances 0.000 description 11
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 10
- 229920002385 Sodium hyaluronate Polymers 0.000 description 10
- 230000009471 action Effects 0.000 description 10
- 238000001816 cooling Methods 0.000 description 10
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 10
- 238000001727 in vivo Methods 0.000 description 10
- 230000006698 induction Effects 0.000 description 10
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 10
- 229940010747 sodium hyaluronate Drugs 0.000 description 10
- 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 10
- 238000003756 stirring Methods 0.000 description 10
- RRONHWAVOYADJL-HNNXBMFYSA-N (2s)-3-phenyl-2-(phenylmethoxycarbonylamino)propanoic acid Chemical compound C([C@@H](C(=O)O)NC(=O)OCC=1C=CC=CC=1)C1=CC=CC=C1 RRONHWAVOYADJL-HNNXBMFYSA-N 0.000 description 9
- HMUNWXXNJPVALC-UHFFFAOYSA-N 1-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)C(CN1CC2=C(CC1)NN=N2)=O HMUNWXXNJPVALC-UHFFFAOYSA-N 0.000 description 9
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 9
- 210000004027 cell Anatomy 0.000 description 9
- 239000011780 sodium chloride Substances 0.000 description 9
- YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-UHFFFAOYSA-N 0.000 description 8
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 8
- 241000700159 Rattus Species 0.000 description 8
- 102100040247 Tumor necrosis factor Human genes 0.000 description 8
- 239000007924 injection Substances 0.000 description 8
- 238000002347 injection Methods 0.000 description 8
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 8
- 238000010898 silica gel chromatography Methods 0.000 description 8
- 238000003786 synthesis reaction Methods 0.000 description 8
- 102000029816 Collagenase Human genes 0.000 description 7
- 108060005980 Collagenase Proteins 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 7
- 230000004663 cell proliferation Effects 0.000 description 7
- 229960002424 collagenase Drugs 0.000 description 7
- 201000010099 disease Diseases 0.000 description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 7
- 230000000857 drug effect Effects 0.000 description 7
- 239000012156 elution solvent Substances 0.000 description 7
- 230000007721 medicinal effect Effects 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- 230000008961 swelling Effects 0.000 description 7
- 210000001258 synovial membrane Anatomy 0.000 description 7
- 229910001868 water Inorganic materials 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 239000012298 atmosphere Substances 0.000 description 6
- 125000004429 atom Chemical group 0.000 description 6
- 239000002585 base Substances 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 239000003054 catalyst Substances 0.000 description 6
- 238000005119 centrifugation Methods 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 6
- 239000001257 hydrogen Substances 0.000 description 6
- 108010077055 methylated bovine serum albumin Proteins 0.000 description 6
- 125000006239 protecting group Chemical group 0.000 description 6
- 239000003981 vehicle Substances 0.000 description 6
- KIUKXJAPPMFGSW-YXBJCWEESA-N (2s,4s,5r,6s)-6-[(2s,3r,5s,6r)-3-acetamido-2-[(3s,4r,5r,6r)-6-[(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]1C(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(O[C@@H]3[C@@H]([C@@H](O)C(O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)C(C(O)=O)O1 KIUKXJAPPMFGSW-YXBJCWEESA-N 0.000 description 5
- 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 5
- 206010061218 Inflammation Diseases 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 5
- 210000000845 cartilage Anatomy 0.000 description 5
- 230000004054 inflammatory process Effects 0.000 description 5
- 230000007246 mechanism Effects 0.000 description 5
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 5
- 239000008363 phosphate buffer Substances 0.000 description 5
- 235000017557 sodium bicarbonate Nutrition 0.000 description 5
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 5
- 150000003431 steroids Chemical class 0.000 description 5
- 125000001425 triazolyl group Chemical group 0.000 description 5
- MZOFCQQQCNRIBI-VMXHOPILSA-N (3s)-4-[[(2s)-1-[[(2s)-1-[[(1s)-1-carboxy-2-hydroxyethyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-[[2-[[(2s)-2,6-diaminohexanoyl]amino]acetyl]amino]-4-oxobutanoic acid Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@@H](N)CCCCN MZOFCQQQCNRIBI-VMXHOPILSA-N 0.000 description 4
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 4
- 208000009386 Experimental Arthritis Diseases 0.000 description 4
- IAJILQKETJEXLJ-UHFFFAOYSA-N Galacturonsaeure Natural products O=CC(O)C(O)C(O)C(O)C(O)=O IAJILQKETJEXLJ-UHFFFAOYSA-N 0.000 description 4
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 4
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 4
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- 208000037039 Monarthritis Diseases 0.000 description 4
- 102000035195 Peptidases Human genes 0.000 description 4
- 108091005804 Peptidases Proteins 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical class CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 4
- 229960003767 alanine Drugs 0.000 description 4
- IAJILQKETJEXLJ-QTBDOELSSA-N aldehydo-D-glucuronic acid Chemical compound O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)C(O)=O IAJILQKETJEXLJ-QTBDOELSSA-N 0.000 description 4
- 150000001412 amines Chemical class 0.000 description 4
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 4
- 230000008859 change Effects 0.000 description 4
- 229940125904 compound 1 Drugs 0.000 description 4
- 239000003480 eluent Substances 0.000 description 4
- 238000005516 engineering process Methods 0.000 description 4
- 229940097043 glucuronic acid Drugs 0.000 description 4
- 125000001072 heteroaryl group Chemical group 0.000 description 4
- 230000002757 inflammatory effect Effects 0.000 description 4
- 229910052740 iodine Inorganic materials 0.000 description 4
- 239000011630 iodine Substances 0.000 description 4
- 238000005259 measurement Methods 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- 201000008482 osteoarthritis Diseases 0.000 description 4
- 159000000000 sodium salts Chemical class 0.000 description 4
- 229910052938 sodium sulfate Inorganic materials 0.000 description 4
- 235000011152 sodium sulphate Nutrition 0.000 description 4
- 208000024891 symptom Diseases 0.000 description 4
- 210000001179 synovial fluid Anatomy 0.000 description 4
- 230000009885 systemic effect Effects 0.000 description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 4
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 3
- GEVGRLPYQJTKKS-UHFFFAOYSA-N 3-(phenylmethoxycarbonylamino)propanoic acid Chemical compound OC(=O)CCNC(=O)OCC1=CC=CC=C1 GEVGRLPYQJTKKS-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
- 102000008186 Collagen Human genes 0.000 description 3
- 108010035532 Collagen Proteins 0.000 description 3
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 3
- 239000004471 Glycine Substances 0.000 description 3
- 101000611183 Homo sapiens Tumor necrosis factor Proteins 0.000 description 3
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 3
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 3
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 3
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 3
- 229910019142 PO4 Inorganic materials 0.000 description 3
- 239000004365 Protease Substances 0.000 description 3
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- 239000000654 additive Substances 0.000 description 3
- 230000032683 aging Effects 0.000 description 3
- 235000004279 alanine Nutrition 0.000 description 3
- 150000001371 alpha-amino acids Chemical class 0.000 description 3
- 235000008206 alpha-amino acids Nutrition 0.000 description 3
- 150000003863 ammonium salts Chemical class 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 229920001436 collagen Polymers 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 229940125782 compound 2 Drugs 0.000 description 3
- 230000007850 degeneration Effects 0.000 description 3
- 239000000839 emulsion Substances 0.000 description 3
- 238000012869 ethanol precipitation Methods 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 150000004676 glycans Chemical class 0.000 description 3
- 229910052736 halogen Inorganic materials 0.000 description 3
- 150000002367 halogens Chemical class 0.000 description 3
- 229910052751 metal Inorganic materials 0.000 description 3
- 239000002184 metal Substances 0.000 description 3
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 3
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 3
- 239000010452 phosphate Substances 0.000 description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 3
- 229920000642 polymer Polymers 0.000 description 3
- 229920001282 polysaccharide Polymers 0.000 description 3
- 239000005017 polysaccharide Substances 0.000 description 3
- 235000019419 proteases Nutrition 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 108020003175 receptors Proteins 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 230000000638 stimulation Effects 0.000 description 3
- 210000005222 synovial tissue Anatomy 0.000 description 3
- 229940126585 therapeutic drug Drugs 0.000 description 3
- 210000001519 tissue Anatomy 0.000 description 3
- 125000004306 triazinyl group Chemical group 0.000 description 3
- ASGMFNBUXDJWJJ-JLCFBVMHSA-N (1R,3R)-3-[[3-bromo-1-[4-(5-methyl-1,3,4-thiadiazol-2-yl)phenyl]pyrazolo[3,4-d]pyrimidin-6-yl]amino]-N,1-dimethylcyclopentane-1-carboxamide Chemical compound BrC1=NN(C2=NC(=NC=C21)N[C@H]1C[C@@](CC1)(C(=O)NC)C)C1=CC=C(C=C1)C=1SC(=NN=1)C ASGMFNBUXDJWJJ-JLCFBVMHSA-N 0.000 description 2
- RRONHWAVOYADJL-OAHLLOKOSA-N (2r)-3-phenyl-2-(phenylmethoxycarbonylamino)propanoic acid Chemical compound C([C@H](C(=O)O)NC(=O)OCC=1C=CC=CC=1)C1=CC=CC=C1 RRONHWAVOYADJL-OAHLLOKOSA-N 0.000 description 2
- JXGVXCZADZNAMJ-NSHDSACASA-N (2s)-1-phenylmethoxycarbonylpyrrolidine-2-carboxylic acid Chemical compound OC(=O)[C@@H]1CCCN1C(=O)OCC1=CC=CC=C1 JXGVXCZADZNAMJ-NSHDSACASA-N 0.000 description 2
- YIWGJFPJRAEKMK-UHFFFAOYSA-N 1-(2H-benzotriazol-5-yl)-3-methyl-8-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carbonyl]-1,3,8-triazaspiro[4.5]decane-2,4-dione Chemical compound CN1C(=O)N(c2ccc3n[nH]nc3c2)C2(CCN(CC2)C(=O)c2cnc(NCc3cccc(OC(F)(F)F)c3)nc2)C1=O YIWGJFPJRAEKMK-UHFFFAOYSA-N 0.000 description 2
- PJUPKRYGDFTMTM-UHFFFAOYSA-N 1-hydroxybenzotriazole;hydrate Chemical compound O.C1=CC=C2N(O)N=NC2=C1 PJUPKRYGDFTMTM-UHFFFAOYSA-N 0.000 description 2
- VZSRBBMJRBPUNF-UHFFFAOYSA-N 2-(2,3-dihydro-1H-inden-2-ylamino)-N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]pyrimidine-5-carboxamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C(=O)NCCC(N1CC2=C(CC1)NN=N2)=O VZSRBBMJRBPUNF-UHFFFAOYSA-N 0.000 description 2
- WEZDRVHTDXTVLT-GJZGRUSLSA-N 2-[[(2s)-2-[[(2s)-2-[(2-aminoacetyl)amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]acetic acid Chemical compound OC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC(=O)CN)CC1=CC=CC=C1 WEZDRVHTDXTVLT-GJZGRUSLSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- 208000006820 Arthralgia Diseases 0.000 description 2
- FTNRWCPWDWRPAV-BZSNNMDCSA-N Asn-Phe-Phe Chemical compound C([C@H](NC(=O)[C@H](CC(N)=O)N)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C1=CC=CC=C1 FTNRWCPWDWRPAV-BZSNNMDCSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- 102100032912 CD44 antigen Human genes 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 2
- QBXVXKRWOVBUDB-GRKNLSHJSA-N ClC=1C(=CC(=C(CN2[C@H](C[C@H](C2)O)C(=O)O)C1)OCC1=CC(=CC=C1)C#N)OCC1=C(C(=CC=C1)C1=CC2=C(OCCO2)C=C1)C Chemical compound ClC=1C(=CC(=C(CN2[C@H](C[C@H](C2)O)C(=O)O)C1)OCC1=CC(=CC=C1)C#N)OCC1=C(C(=CC=C1)C1=CC2=C(OCCO2)C=C1)C QBXVXKRWOVBUDB-GRKNLSHJSA-N 0.000 description 2
- 229940127007 Compound 39 Drugs 0.000 description 2
- DSLZVSRJTYRBFB-LLEIAEIESA-N D-glucaric acid Chemical compound OC(=O)[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O DSLZVSRJTYRBFB-LLEIAEIESA-N 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 108010009504 Gly-Phe-Leu-Gly Proteins 0.000 description 2
- 101000868273 Homo sapiens CD44 antigen Proteins 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 2
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 2
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 description 2
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 2
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 2
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 description 2
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 2
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 2
- 239000004472 Lysine Substances 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 2
- 229910002651 NO3 Inorganic materials 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- GLUBLISJVJFHQS-VIFPVBQESA-N Phe-Gly Chemical compound OC(=O)CNC(=O)[C@@H](N)CC1=CC=CC=C1 GLUBLISJVJFHQS-VIFPVBQESA-N 0.000 description 2
- GKZIWHRNKRBEOH-HOTGVXAUSA-N Phe-Phe Chemical compound C([C@H]([NH3+])C(=O)N[C@@H](CC=1C=CC=CC=1)C([O-])=O)C1=CC=CC=C1 GKZIWHRNKRBEOH-HOTGVXAUSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-L Phosphate ion(2-) Chemical compound OP([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-L 0.000 description 2
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 235000010724 Wisteria floribunda Nutrition 0.000 description 2
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 2
- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 description 2
- YLEIFZAVNWDOBM-ZTNXSLBXSA-N ac1l9hc7 Chemical compound C([C@H]12)C[C@@H](C([C@@H](O)CC3)(C)C)[C@@]43C[C@@]14CC[C@@]1(C)[C@@]2(C)C[C@@H]2O[C@]3(O)[C@H](O)C(C)(C)O[C@@H]3[C@@H](C)[C@H]12 YLEIFZAVNWDOBM-ZTNXSLBXSA-N 0.000 description 2
- PMZXXNPJQYDFJX-UHFFFAOYSA-N acetonitrile;2,2,2-trifluoroacetic acid Chemical compound CC#N.OC(=O)C(F)(F)F PMZXXNPJQYDFJX-UHFFFAOYSA-N 0.000 description 2
- 230000003213 activating effect Effects 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 230000000996 additive effect Effects 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- 125000005157 alkyl carboxy group Chemical group 0.000 description 2
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 2
- 229910052782 aluminium Inorganic materials 0.000 description 2
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 2
- 239000002246 antineoplastic agent Substances 0.000 description 2
- 210000001188 articular cartilage Anatomy 0.000 description 2
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical class NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 2
- UCMIRNVEIXFBKS-UHFFFAOYSA-N beta-alanine Chemical compound NCCC(O)=O UCMIRNVEIXFBKS-UHFFFAOYSA-N 0.000 description 2
- 210000000988 bone and bone Anatomy 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 159000000007 calcium salts Chemical class 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 125000004093 cyano group Chemical group *C#N 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 2
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 2
- 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 description 2
- 230000001747 exhibiting effect Effects 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000005194 fractionation Methods 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 description 2
- 238000002523 gelfiltration Methods 0.000 description 2
- YMAWOPBAYDPSLA-UHFFFAOYSA-N glycylglycine Chemical compound [NH3+]CC(=O)NCC([O-])=O YMAWOPBAYDPSLA-UHFFFAOYSA-N 0.000 description 2
- 125000005842 heteroatom Chemical group 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 2
- 125000002883 imidazolyl group Chemical group 0.000 description 2
- 230000001771 impaired effect Effects 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 125000001041 indolyl group Chemical group 0.000 description 2
- 229910052742 iron Inorganic materials 0.000 description 2
- 210000001503 joint Anatomy 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 2
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 125000002950 monocyclic group Chemical group 0.000 description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 230000001575 pathological effect Effects 0.000 description 2
- 230000007170 pathology Effects 0.000 description 2
- 238000010647 peptide synthesis reaction Methods 0.000 description 2
- 239000003444 phase transfer catalyst Substances 0.000 description 2
- BSCCSDNZEIHXOK-UHFFFAOYSA-N phenyl carbamate Chemical class NC(=O)OC1=CC=CC=C1 BSCCSDNZEIHXOK-UHFFFAOYSA-N 0.000 description 2
- 108010073025 phenylalanylphenylalanine Proteins 0.000 description 2
- OJMIONKXNSYLSR-UHFFFAOYSA-N phosphorous acid Chemical compound OP(O)O OJMIONKXNSYLSR-UHFFFAOYSA-N 0.000 description 2
- 229910052698 phosphorus Inorganic materials 0.000 description 2
- 239000011574 phosphorus Substances 0.000 description 2
- 239000002504 physiological saline solution Substances 0.000 description 2
- 125000003367 polycyclic group Chemical group 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 230000035755 proliferation Effects 0.000 description 2
- 230000001737 promoting effect Effects 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000001488 sodium phosphate Substances 0.000 description 2
- 229910000162 sodium phosphate Inorganic materials 0.000 description 2
- 125000006850 spacer group Chemical group 0.000 description 2
- 238000007619 statistical method Methods 0.000 description 2
- 230000035882 stress Effects 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid group Chemical group C(CCC(=O)O)(=O)O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- 229910021653 sulphate ion Inorganic materials 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 238000012353 t test Methods 0.000 description 2
- XOAAWQZATWQOTB-UHFFFAOYSA-N taurine Chemical compound NCCS(O)(=O)=O XOAAWQZATWQOTB-UHFFFAOYSA-N 0.000 description 2
- AOCSUUGBCMTKJH-UHFFFAOYSA-N tert-butyl n-(2-aminoethyl)carbamate Chemical class CC(C)(C)OC(=O)NCCN AOCSUUGBCMTKJH-UHFFFAOYSA-N 0.000 description 2
- DZLFLBLQUQXARW-UHFFFAOYSA-N tetrabutylammonium Chemical class CCCC[N+](CCCC)(CCCC)CCCC DZLFLBLQUQXARW-UHFFFAOYSA-N 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 2
- 239000011701 zinc Substances 0.000 description 2
- 229910052725 zinc Inorganic materials 0.000 description 2
- OGNSCSPNOLGXSM-UHFFFAOYSA-N (+/-)-DABA Natural products NCCC(N)C(O)=O OGNSCSPNOLGXSM-UHFFFAOYSA-N 0.000 description 1
- UAOUIVVJBYDFKD-XKCDOFEDSA-N (1R,9R,10S,11R,12R,15S,18S,21R)-10,11,21-trihydroxy-8,8-dimethyl-14-methylidene-4-(prop-2-enylamino)-20-oxa-5-thia-3-azahexacyclo[9.7.2.112,15.01,9.02,6.012,18]henicosa-2(6),3-dien-13-one Chemical compound C([C@@H]1[C@@H](O)[C@@]23C(C1=C)=O)C[C@H]2[C@]12C(N=C(NCC=C)S4)=C4CC(C)(C)[C@H]1[C@H](O)[C@]3(O)OC2 UAOUIVVJBYDFKD-XKCDOFEDSA-N 0.000 description 1
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 1
- ABJSOROVZZKJGI-OCYUSGCXSA-N (1r,2r,4r)-2-(4-bromophenyl)-n-[(4-chlorophenyl)-(2-fluoropyridin-4-yl)methyl]-4-morpholin-4-ylcyclohexane-1-carboxamide Chemical compound C1=NC(F)=CC(C(NC(=O)[C@H]2[C@@H](C[C@@H](CC2)N2CCOCC2)C=2C=CC(Br)=CC=2)C=2C=CC(Cl)=CC=2)=C1 ABJSOROVZZKJGI-OCYUSGCXSA-N 0.000 description 1
- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 description 1
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 1
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 1
- IUSARDYWEPUTPN-OZBXUNDUSA-N (2r)-n-[(2s,3r)-4-[[(4s)-6-(2,2-dimethylpropyl)spiro[3,4-dihydropyrano[2,3-b]pyridine-2,1'-cyclobutane]-4-yl]amino]-3-hydroxy-1-[3-(1,3-thiazol-2-yl)phenyl]butan-2-yl]-2-methoxypropanamide Chemical compound C([C@H](NC(=O)[C@@H](C)OC)[C@H](O)CN[C@@H]1C2=CC(CC(C)(C)C)=CN=C2OC2(CCC2)C1)C(C=1)=CC=CC=1C1=NC=CS1 IUSARDYWEPUTPN-OZBXUNDUSA-N 0.000 description 1
- BVAUMRCGVHUWOZ-ZETCQYMHSA-N (2s)-2-(cyclohexylazaniumyl)propanoate Chemical group OC(=O)[C@H](C)NC1CCCCC1 BVAUMRCGVHUWOZ-ZETCQYMHSA-N 0.000 description 1
- LDUWTIUXPVCEQF-LURJTMIESA-N (2s)-2-(cyclopentylamino)propanoic acid Chemical group OC(=O)[C@H](C)NC1CCCC1 LDUWTIUXPVCEQF-LURJTMIESA-N 0.000 description 1
- IYKLZBIWFXPUCS-VIFPVBQESA-N (2s)-2-(naphthalen-1-ylamino)propanoic acid Chemical compound C1=CC=C2C(N[C@@H](C)C(O)=O)=CC=CC2=C1 IYKLZBIWFXPUCS-VIFPVBQESA-N 0.000 description 1
- PVFCXMDXBIEMQG-JTQLQIEISA-N (2s)-2-(phenylmethoxycarbonylamino)pentanedioic acid Chemical compound OC(=O)CC[C@@H](C(O)=O)NC(=O)OCC1=CC=CC=C1 PVFCXMDXBIEMQG-JTQLQIEISA-N 0.000 description 1
- CNMAQBJBWQQZFZ-LURJTMIESA-N (2s)-2-(pyridin-2-ylamino)propanoic acid Chemical compound OC(=O)[C@H](C)NC1=CC=CC=N1 CNMAQBJBWQQZFZ-LURJTMIESA-N 0.000 description 1
- WWTBZEKOSBFBEM-SPWPXUSOSA-N (2s)-2-[[2-benzyl-3-[hydroxy-[(1r)-2-phenyl-1-(phenylmethoxycarbonylamino)ethyl]phosphoryl]propanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound N([C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)O)C(=O)C(CP(O)(=O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1C=CC=CC=1)CC1=CC=CC=C1 WWTBZEKOSBFBEM-SPWPXUSOSA-N 0.000 description 1
- NPDBDJFLKKQMCM-SCSAIBSYSA-N (2s)-2-amino-3,3-dimethylbutanoic acid Chemical compound CC(C)(C)[C@H](N)C(O)=O NPDBDJFLKKQMCM-SCSAIBSYSA-N 0.000 description 1
- WAMWSIDTKSNDCU-ZETCQYMHSA-N (2s)-2-azaniumyl-2-cyclohexylacetate Chemical group OC(=O)[C@@H](N)C1CCCCC1 WAMWSIDTKSNDCU-ZETCQYMHSA-N 0.000 description 1
- MCRMUCXATQAAMN-HNNXBMFYSA-N (2s)-3-(4-hydroxyphenyl)-2-(phenylmethoxycarbonylamino)propanoic acid Chemical compound C([C@@H](C(=O)O)NC(=O)OCC=1C=CC=CC=1)C1=CC=C(O)C=C1 MCRMUCXATQAAMN-HNNXBMFYSA-N 0.000 description 1
- GNIDSOFZAKMQAO-VIFPVBQESA-N (2s)-3-hydroxy-2-(phenylmethoxycarbonylamino)propanoic acid Chemical compound OC[C@@H](C(O)=O)NC(=O)OCC1=CC=CC=C1 GNIDSOFZAKMQAO-VIFPVBQESA-N 0.000 description 1
- CANZBRDGRHNSGZ-NSHDSACASA-N (2s)-3-methyl-2-(phenylmethoxycarbonylamino)butanoic acid Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)OCC1=CC=CC=C1 CANZBRDGRHNSGZ-NSHDSACASA-N 0.000 description 1
- STBLNCCBQMHSRC-BATDWUPUSA-N (2s)-n-[(3s,4s)-5-acetyl-7-cyano-4-methyl-1-[(2-methylnaphthalen-1-yl)methyl]-2-oxo-3,4-dihydro-1,5-benzodiazepin-3-yl]-2-(methylamino)propanamide Chemical compound O=C1[C@@H](NC(=O)[C@H](C)NC)[C@H](C)N(C(C)=O)C2=CC(C#N)=CC=C2N1CC1=C(C)C=CC2=CC=CC=C12 STBLNCCBQMHSRC-BATDWUPUSA-N 0.000 description 1
- JSHXJPFZKBRLFU-JQWIXIFHSA-N (2s,3s)-3-methyl-2-(phenylmethoxycarbonylamino)pentanoic acid Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)OCC1=CC=CC=C1 JSHXJPFZKBRLFU-JQWIXIFHSA-N 0.000 description 1
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 1
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 description 1
- NXLNNXIXOYSCMB-UHFFFAOYSA-N (4-nitrophenyl) carbonochloridate Chemical compound [O-][N+](=O)C1=CC=C(OC(Cl)=O)C=C1 NXLNNXIXOYSCMB-UHFFFAOYSA-N 0.000 description 1
- BGMCTGARFXPQML-NSHDSACASA-N (4s)-5-methoxy-5-oxo-4-(phenylmethoxycarbonylamino)pentanoic acid Chemical compound OC(=O)CC[C@@H](C(=O)OC)NC(=O)OCC1=CC=CC=C1 BGMCTGARFXPQML-NSHDSACASA-N 0.000 description 1
- LZDKZFUFMNSQCJ-UHFFFAOYSA-N 1,2-diethoxyethane Chemical compound CCOCCOCC LZDKZFUFMNSQCJ-UHFFFAOYSA-N 0.000 description 1
- VEAFKIYNHVBNIP-UHFFFAOYSA-N 1,3-Diphenylpropane Chemical compound C=1C=CC=CC=1CCCC1=CC=CC=C1 VEAFKIYNHVBNIP-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- MZBACIJSSOHXQA-UHFFFAOYSA-N 1-(2-ethoxyethoxy)propane Chemical compound CCCOCCOCC MZBACIJSSOHXQA-UHFFFAOYSA-N 0.000 description 1
- KQZLRWGGWXJPOS-NLFPWZOASA-N 1-[(1R)-1-(2,4-dichlorophenyl)ethyl]-6-[(4S,5R)-4-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-5-methylcyclohexen-1-yl]pyrazolo[3,4-b]pyrazine-3-carbonitrile Chemical compound ClC1=C(C=CC(=C1)Cl)[C@@H](C)N1N=C(C=2C1=NC(=CN=2)C1=CC[C@@H]([C@@H](C1)C)N1[C@@H](CCC1)CO)C#N KQZLRWGGWXJPOS-NLFPWZOASA-N 0.000 description 1
- WZZBNLYBHUDSHF-DHLKQENFSA-N 1-[(3s,4s)-4-[8-(2-chloro-4-pyrimidin-2-yloxyphenyl)-7-fluoro-2-methylimidazo[4,5-c]quinolin-1-yl]-3-fluoropiperidin-1-yl]-2-hydroxyethanone Chemical compound CC1=NC2=CN=C3C=C(F)C(C=4C(=CC(OC=5N=CC=CN=5)=CC=4)Cl)=CC3=C2N1[C@H]1CCN(C(=O)CO)C[C@@H]1F WZZBNLYBHUDSHF-DHLKQENFSA-N 0.000 description 1
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 1
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 1
- PZHIWRCQKBBTOW-UHFFFAOYSA-N 1-ethoxybutane Chemical compound CCCCOCC PZHIWRCQKBBTOW-UHFFFAOYSA-N 0.000 description 1
- NVJUHMXYKCUMQA-UHFFFAOYSA-N 1-ethoxypropane Chemical compound CCCOCC NVJUHMXYKCUMQA-UHFFFAOYSA-N 0.000 description 1
- LSIXBBPOJBJQHN-UHFFFAOYSA-N 2,3-Dimethylbicyclo[2.2.1]hept-2-ene Chemical compound C1CC2C(C)=C(C)C1C2 LSIXBBPOJBJQHN-UHFFFAOYSA-N 0.000 description 1
- LDXJRKWFNNFDSA-UHFFFAOYSA-N 2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)-1-[4-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidin-5-yl]piperazin-1-yl]ethanone Chemical compound C1CN(CC2=NNN=C21)CC(=O)N3CCN(CC3)C4=CN=C(N=C4)NCC5=CC(=CC=C5)OC(F)(F)F LDXJRKWFNNFDSA-UHFFFAOYSA-N 0.000 description 1
- XGLVDUUYFKXKPL-UHFFFAOYSA-N 2-(2-methoxyethoxy)-n,n-bis[2-(2-methoxyethoxy)ethyl]ethanamine Chemical compound COCCOCCN(CCOCCOC)CCOCCOC XGLVDUUYFKXKPL-UHFFFAOYSA-N 0.000 description 1
- HXOSZXCKDHGOPE-UHFFFAOYSA-N 2-[(2,4-diaminopteridin-6-yl)methyl-methylamino]benzoic acid Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=CC=C1C(O)=O HXOSZXCKDHGOPE-UHFFFAOYSA-N 0.000 description 1
- HXUVTXPOZRFMOY-NSHDSACASA-N 2-[[(2s)-2-[[2-[(2-aminoacetyl)amino]acetyl]amino]-3-phenylpropanoyl]amino]acetic acid Chemical compound NCC(=O)NCC(=O)N[C@H](C(=O)NCC(O)=O)CC1=CC=CC=C1 HXUVTXPOZRFMOY-NSHDSACASA-N 0.000 description 1
- YSUIQYOGTINQIN-UZFYAQMZSA-N 2-amino-9-[(1S,6R,8R,9S,10R,15R,17R,18R)-8-(6-aminopurin-9-yl)-9,18-difluoro-3,12-dihydroxy-3,12-bis(sulfanylidene)-2,4,7,11,13,16-hexaoxa-3lambda5,12lambda5-diphosphatricyclo[13.2.1.06,10]octadecan-17-yl]-1H-purin-6-one Chemical compound NC1=NC2=C(N=CN2[C@@H]2O[C@@H]3COP(S)(=O)O[C@@H]4[C@@H](COP(S)(=O)O[C@@H]2[C@@H]3F)O[C@H]([C@H]4F)N2C=NC3=C2N=CN=C3N)C(=O)N1 YSUIQYOGTINQIN-UZFYAQMZSA-N 0.000 description 1
- TVTJUIAKQFIXCE-HUKYDQBMSA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynyl-1H-purine-6,8-dione Chemical compound NC=1NC(C=2N(C(N(C=2N=1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C)=O TVTJUIAKQFIXCE-HUKYDQBMSA-N 0.000 description 1
- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 description 1
- HCDMJFOHIXMBOV-UHFFFAOYSA-N 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholin-4-ylmethyl)-4,7-dihydropyrrolo[4,5]pyrido[1,2-d]pyrimidin-2-one Chemical compound C=1C2=C3N(CC)C(=O)N(C=4C(=C(OC)C=C(OC)C=4F)F)CC3=CN=C2NC=1CN1CCOCC1 HCDMJFOHIXMBOV-UHFFFAOYSA-N 0.000 description 1
- QBWKPGNFQQJGFY-QLFBSQMISA-N 3-[(1r)-1-[(2r,6s)-2,6-dimethylmorpholin-4-yl]ethyl]-n-[6-methyl-3-(1h-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]-1,2-thiazol-5-amine Chemical compound N1([C@H](C)C2=NSC(NC=3C4=NC=C(N4C=C(C)N=3)C3=CNN=C3)=C2)C[C@H](C)O[C@H](C)C1 QBWKPGNFQQJGFY-QLFBSQMISA-N 0.000 description 1
- JCEZOHLWDIONSP-UHFFFAOYSA-N 3-[2-[2-(3-aminopropoxy)ethoxy]ethoxy]propan-1-amine Chemical compound NCCCOCCOCCOCCCN JCEZOHLWDIONSP-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- LWCXZSDKANNOAR-UHFFFAOYSA-N 4-[(2,4-diaminopteridin-6-yl)methyl-methylamino]benzoic acid Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(O)=O)C=C1 LWCXZSDKANNOAR-UHFFFAOYSA-N 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
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 102000016284 Aggrecans Human genes 0.000 description 1
- 108010067219 Aggrecans Proteins 0.000 description 1
- SOTXLXCVCZAKFI-FXQIFTODSA-N Ala-Val-Ala Chemical compound C[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C)C(O)=O SOTXLXCVCZAKFI-FXQIFTODSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 206010053555 Arthritis bacterial Diseases 0.000 description 1
- 206010003267 Arthritis reactive Diseases 0.000 description 1
- 206010003274 Arthritis viral Diseases 0.000 description 1
- 208000036487 Arthropathies Diseases 0.000 description 1
- DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 description 1
- 208000020084 Bone disease Diseases 0.000 description 1
- BQXUPNKLZNSUMC-YUQWMIPFSA-N CCN(CCCCCOCC(=O)N[C@H](C(=O)N1C[C@H](O)C[C@H]1C(=O)N[C@@H](C)c1ccc(cc1)-c1scnc1C)C(C)(C)C)CCOc1ccc(cc1)C(=O)c1c(sc2cc(O)ccc12)-c1ccc(O)cc1 Chemical compound CCN(CCCCCOCC(=O)N[C@H](C(=O)N1C[C@H](O)C[C@H]1C(=O)N[C@@H](C)c1ccc(cc1)-c1scnc1C)C(C)(C)C)CCOc1ccc(cc1)C(=O)c1c(sc2cc(O)ccc12)-c1ccc(O)cc1 BQXUPNKLZNSUMC-YUQWMIPFSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 206010061762 Chondropathy Diseases 0.000 description 1
- 229940126657 Compound 17 Drugs 0.000 description 1
- 229940126639 Compound 33 Drugs 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 206010063560 Excessive granulation tissue Diseases 0.000 description 1
- 206010016654 Fibrosis Diseases 0.000 description 1
- 241000722985 Fidia Species 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 208000018522 Gastrointestinal disease Diseases 0.000 description 1
- MZZSCEANQDPJER-ONGXEEELSA-N Gly-Ala-Phe Chemical compound NCC(=O)N[C@@H](C)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 MZZSCEANQDPJER-ONGXEEELSA-N 0.000 description 1
- JBCLFWXMTIKCCB-VIFPVBQESA-N Gly-Phe Chemical compound NCC(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 JBCLFWXMTIKCCB-VIFPVBQESA-N 0.000 description 1
- WMGHDYWNHNLGBV-ONGXEEELSA-N Gly-Phe-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)CN)CC1=CC=CC=C1 WMGHDYWNHNLGBV-ONGXEEELSA-N 0.000 description 1
- FEUPVVCGQLNXNP-IRXDYDNUSA-N Gly-Phe-Phe Chemical compound C([C@H](NC(=O)CN)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C1=CC=CC=C1 FEUPVVCGQLNXNP-IRXDYDNUSA-N 0.000 description 1
- JBCLFWXMTIKCCB-UHFFFAOYSA-N H-Gly-Phe-OH Natural products NCC(=O)NC(C(O)=O)CC1=CC=CC=C1 JBCLFWXMTIKCCB-UHFFFAOYSA-N 0.000 description 1
- HVLSXIKZNLPZJJ-TXZCQADKSA-N HA peptide Chemical group C([C@@H](C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](C)C(O)=O)NC(=O)[C@H]1N(CCC1)C(=O)[C@@H](N)CC=1C=CC(O)=CC=1)C1=CC=C(O)C=C1 HVLSXIKZNLPZJJ-TXZCQADKSA-N 0.000 description 1
- 206010020565 Hyperaemia Diseases 0.000 description 1
- 208000004575 Infectious Arthritis Diseases 0.000 description 1
- 206010023203 Joint destruction Diseases 0.000 description 1
- 206010054106 Joint warmth Diseases 0.000 description 1
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 1
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 1
- LRQKBLKVPFOOQJ-YFKPBYRVSA-N L-norleucine Chemical compound CCCC[C@H]([NH3+])C([O-])=O LRQKBLKVPFOOQJ-YFKPBYRVSA-N 0.000 description 1
- LSPYFSHXDAYVDI-SRVKXCTJSA-N Leu-Ala-Leu Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@H](C(O)=O)CC(C)C LSPYFSHXDAYVDI-SRVKXCTJSA-N 0.000 description 1
- MJWVXZABPOKJJF-ACRUOGEOSA-N Leu-Phe-Phe Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O MJWVXZABPOKJJF-ACRUOGEOSA-N 0.000 description 1
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 1
- 206010067125 Liver injury Diseases 0.000 description 1
- 208000019693 Lung disease Diseases 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 102000055008 Matrilin Proteins Human genes 0.000 description 1
- 108010072582 Matrilin Proteins Proteins 0.000 description 1
- 102000002274 Matrix Metalloproteinases Human genes 0.000 description 1
- 108010000684 Matrix Metalloproteinases Proteins 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-M Methanesulfonate Chemical compound CS([O-])(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 108010088249 Monogen Proteins 0.000 description 1
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 1
- VCUFZILGIRCDQQ-KRWDZBQOSA-N N-[[(5S)-2-oxo-3-(2-oxo-3H-1,3-benzoxazol-6-yl)-1,3-oxazolidin-5-yl]methyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C1O[C@H](CN1C1=CC2=C(NC(O2)=O)C=C1)CNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F VCUFZILGIRCDQQ-KRWDZBQOSA-N 0.000 description 1
- USPFMEKVPDBMCG-LBPRGKRZSA-N N-benzyloxycarbonyl-L-leucine Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)OCC1=CC=CC=C1 USPFMEKVPDBMCG-LBPRGKRZSA-N 0.000 description 1
- CJUMAFVKTCBCJK-UHFFFAOYSA-N N-benzyloxycarbonylglycine Chemical compound OC(=O)CNC(=O)OCC1=CC=CC=C1 CJUMAFVKTCBCJK-UHFFFAOYSA-N 0.000 description 1
- OPFJDXRVMFKJJO-ZHHKINOHSA-N N-{[3-(2-benzamido-4-methyl-1,3-thiazol-5-yl)-pyrazol-5-yl]carbonyl}-G-dR-G-dD-dD-dD-NH2 Chemical compound S1C(C=2NN=C(C=2)C(=O)NCC(=O)N[C@H](CCCN=C(N)N)C(=O)NCC(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(N)=O)=C(C)N=C1NC(=O)C1=CC=CC=C1 OPFJDXRVMFKJJO-ZHHKINOHSA-N 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 241001111421 Pannus Species 0.000 description 1
- 206010034464 Periarthritis Diseases 0.000 description 1
- NAXPHWZXEXNDIW-JTQLQIEISA-N Phe-Gly-Gly Chemical compound OC(=O)CNC(=O)CNC(=O)[C@@H](N)CC1=CC=CC=C1 NAXPHWZXEXNDIW-JTQLQIEISA-N 0.000 description 1
- RFCVXVPWSPOMFJ-STQMWFEESA-N Phe-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@@H](N)CC1=CC=CC=C1 RFCVXVPWSPOMFJ-STQMWFEESA-N 0.000 description 1
- SMFGCTXUBWEPKM-KBPBESRZSA-N Phe-Leu-Gly Chemical compound OC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CC1=CC=CC=C1 SMFGCTXUBWEPKM-KBPBESRZSA-N 0.000 description 1
- IWZRODDWOSIXPZ-IRXDYDNUSA-N Phe-Phe-Gly Chemical compound C([C@H](N)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)NCC(O)=O)C1=CC=CC=C1 IWZRODDWOSIXPZ-IRXDYDNUSA-N 0.000 description 1
- JMCOUWKXLXDERB-WMZOPIPTSA-N Phe-Trp Chemical compound C([C@H](N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(O)=O)C1=CC=CC=C1 JMCOUWKXLXDERB-WMZOPIPTSA-N 0.000 description 1
- FSXRLASFHBWESK-HOTGVXAUSA-N Phe-Tyr Chemical compound C([C@H](N)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(O)=O)C1=CC=CC=C1 FSXRLASFHBWESK-HOTGVXAUSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical class OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 1
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 1
- 206010070834 Sensitisation Diseases 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- PNUZDKCDAWUEGK-CYZMBNFOSA-N Sitafloxacin Chemical compound C([C@H]1N)N(C=2C(=C3C(C(C(C(O)=O)=CN3[C@H]3[C@H](C3)F)=O)=CC=2F)Cl)CC11CC1 PNUZDKCDAWUEGK-CYZMBNFOSA-N 0.000 description 1
- 238000000692 Student's t-test Methods 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 1
- 239000004473 Threonine Substances 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- IMMPMHKLUUZKAZ-WMZOPIPTSA-N Trp-Phe Chemical compound C([C@H](NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)N)C(O)=O)C1=CC=CC=C1 IMMPMHKLUUZKAZ-WMZOPIPTSA-N 0.000 description 1
- CGWAPUBOXJWXMS-HOTGVXAUSA-N Tyr-Phe Chemical compound C([C@H](N)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C1=CC=C(O)C=C1 CGWAPUBOXJWXMS-HOTGVXAUSA-N 0.000 description 1
- LJOOWESTVASNOG-UFJKPHDISA-N [(1s,3r,4ar,7s,8s,8as)-3-hydroxy-8-[2-[(4r)-4-hydroxy-6-oxooxan-2-yl]ethyl]-7-methyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-yl] (2s)-2-methylbutanoate Chemical compound C([C@H]1[C@@H](C)C=C[C@H]2C[C@@H](O)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)CC1C[C@@H](O)CC(=O)O1 LJOOWESTVASNOG-UFJKPHDISA-N 0.000 description 1
- SMNRFWMNPDABKZ-WVALLCKVSA-N [[(2R,3S,4R,5S)-5-(2,6-dioxo-3H-pyridin-3-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [[[(2R,3S,4S,5R,6R)-4-fluoro-3,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-hydroxyphosphoryl]oxy-hydroxyphosphoryl] hydrogen phosphate Chemical compound OC[C@H]1O[C@H](OP(O)(=O)OP(O)(=O)OP(O)(=O)OP(O)(=O)OC[C@H]2O[C@H]([C@H](O)[C@@H]2O)C2C=CC(=O)NC2=O)[C@H](O)[C@@H](F)[C@@H]1O SMNRFWMNPDABKZ-WVALLCKVSA-N 0.000 description 1
- 238000000862 absorption spectrum Methods 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 230000021736 acetylation Effects 0.000 description 1
- 238000006640 acetylation reaction Methods 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 150000001294 alanine derivatives Chemical group 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- SRVFFFJZQVENJC-IHRRRGAJSA-N aloxistatin Chemical compound CCOC(=O)[C@H]1O[C@@H]1C(=O)N[C@@H](CC(C)C)C(=O)NCCC(C)C SRVFFFJZQVENJC-IHRRRGAJSA-N 0.000 description 1
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical class [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000033115 angiogenesis Effects 0.000 description 1
- XJDFBLQCLSBCGQ-UHFFFAOYSA-N anthracene-1-carbaldehyde Chemical group C1=CC=C2C=C3C(C=O)=CC=CC3=CC2=C1 XJDFBLQCLSBCGQ-UHFFFAOYSA-N 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 239000000427 antigen Substances 0.000 description 1
- 108091007433 antigens Proteins 0.000 description 1
- 102000036639 antigens Human genes 0.000 description 1
- 239000002543 antimycotic Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 239000003907 antipyretic analgesic agent Substances 0.000 description 1
- 239000003435 antirheumatic agent Substances 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 125000005418 aryl aryl group Chemical group 0.000 description 1
- 229960001230 asparagine Drugs 0.000 description 1
- 235000009582 asparagine Nutrition 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- XRWSZZJLZRKHHD-WVWIJVSJSA-N asunaprevir Chemical compound O=C([C@@H]1C[C@H](CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)OC1=NC=C(C2=CC=C(Cl)C=C21)OC)N[C@]1(C(=O)NS(=O)(=O)C2CC2)C[C@H]1C=C XRWSZZJLZRKHHD-WVWIJVSJSA-N 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 208000025255 bacterial arthritis Diseases 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 125000003354 benzotriazolyl group Chemical group N1N=NC2=C1C=CC=C2* 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- KGNDCEVUMONOKF-UGPLYTSKSA-N benzyl n-[(2r)-1-[(2s,4r)-2-[[(2s)-6-amino-1-(1,3-benzoxazol-2-yl)-1,1-dihydroxyhexan-2-yl]carbamoyl]-4-[(4-methylphenyl)methoxy]pyrrolidin-1-yl]-1-oxo-4-phenylbutan-2-yl]carbamate Chemical compound C1=CC(C)=CC=C1CO[C@H]1CN(C(=O)[C@@H](CCC=2C=CC=CC=2)NC(=O)OCC=2C=CC=CC=2)[C@H](C(=O)N[C@@H](CCCCN)C(O)(O)C=2OC3=CC=CC=C3N=2)C1 KGNDCEVUMONOKF-UGPLYTSKSA-N 0.000 description 1
- 229940000635 beta-alanine Drugs 0.000 description 1
- 150000001576 beta-amino acids Chemical class 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 229920001222 biopolymer Polymers 0.000 description 1
- 125000006267 biphenyl group Chemical group 0.000 description 1
- 125000006367 bivalent amino carbonyl group Chemical group [H]N([*:1])C([*:2])=O 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004744 butyloxycarbonyl group Chemical group 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 230000001364 causal effect Effects 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 125000000068 chlorophenyl group Chemical group 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 230000009850 completed effect Effects 0.000 description 1
- 229940125773 compound 10 Drugs 0.000 description 1
- 229940125797 compound 12 Drugs 0.000 description 1
- 229940126543 compound 14 Drugs 0.000 description 1
- 229940125758 compound 15 Drugs 0.000 description 1
- 229940126142 compound 16 Drugs 0.000 description 1
- 229940125810 compound 20 Drugs 0.000 description 1
- 229940126086 compound 21 Drugs 0.000 description 1
- 229940126208 compound 22 Drugs 0.000 description 1
- 229940125833 compound 23 Drugs 0.000 description 1
- 229940125961 compound 24 Drugs 0.000 description 1
- 229940125846 compound 25 Drugs 0.000 description 1
- 229940125851 compound 27 Drugs 0.000 description 1
- 229940127204 compound 29 Drugs 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 229940125877 compound 31 Drugs 0.000 description 1
- 229940125878 compound 36 Drugs 0.000 description 1
- 229940125807 compound 37 Drugs 0.000 description 1
- 229940127573 compound 38 Drugs 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 238000004132 cross linking Methods 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- YPHMISFOHDHNIV-FSZOTQKASA-N cycloheximide Chemical compound C1[C@@H](C)C[C@H](C)C(=O)[C@@H]1[C@H](O)CC1CC(=O)NC(=O)C1 YPHMISFOHDHNIV-FSZOTQKASA-N 0.000 description 1
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 1
- 235000018417 cysteine Nutrition 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000006866 deterioration Effects 0.000 description 1
- 238000002405 diagnostic procedure Methods 0.000 description 1
- 125000004663 dialkyl amino group Chemical group 0.000 description 1
- 150000004985 diamines Chemical class 0.000 description 1
- 208000010643 digestive system disease Diseases 0.000 description 1
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 1
- FSXRLASFHBWESK-UHFFFAOYSA-N dipeptide phenylalanyl-tyrosine Natural products C=1C=C(O)C=CC=1CC(C(O)=O)NC(=O)C(N)CC1=CC=CC=C1 FSXRLASFHBWESK-UHFFFAOYSA-N 0.000 description 1
- 150000002016 disaccharides Chemical class 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- JMLPVHXESHXUSV-UHFFFAOYSA-N dodecane-1,1-diamine Chemical compound CCCCCCCCCCCC(N)N JMLPVHXESHXUSV-UHFFFAOYSA-N 0.000 description 1
- JRBPAEWTRLWTQC-UHFFFAOYSA-N dodecylamine Chemical compound CCCCCCCCCCCCN JRBPAEWTRLWTQC-UHFFFAOYSA-N 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 description 1
- 230000003090 exacerbative effect Effects 0.000 description 1
- 230000004761 fibrosis Effects 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 125000001207 fluorophenyl group Chemical group 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 229960003692 gamma aminobutyric acid Drugs 0.000 description 1
- 208000018685 gastrointestinal system disease Diseases 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 229960002989 glutamic acid Drugs 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- 229960002449 glycine Drugs 0.000 description 1
- 150000002332 glycine derivatives Chemical group 0.000 description 1
- 108010075431 glycyl-alanyl-phenylalanine Proteins 0.000 description 1
- 108010081551 glycylphenylalanine Proteins 0.000 description 1
- 210000001126 granulation tissue Anatomy 0.000 description 1
- 230000009036 growth inhibition Effects 0.000 description 1
- JAXFJECJQZDFJS-XHEPKHHKSA-N gtpl8555 Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)N[C@H](B1O[C@@]2(C)[C@H]3C[C@H](C3(C)C)C[C@H]2O1)CCC1=CC=C(F)C=C1 JAXFJECJQZDFJS-XHEPKHHKSA-N 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 208000018706 hematopoietic system disease Diseases 0.000 description 1
- 231100000234 hepatic damage Toxicity 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- 208000026278 immune system disease Diseases 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 125000003406 indolizinyl group Chemical group C=1(C=CN2C=CC=CC12)* 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 229910017053 inorganic salt Inorganic materials 0.000 description 1
- 150000002505 iron Chemical class 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 description 1
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 description 1
- 229960000310 isoleucine Drugs 0.000 description 1
- 238000006317 isomerization reaction Methods 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000005956 isoquinolyl group Chemical group 0.000 description 1
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 229960003136 leucine Drugs 0.000 description 1
- 230000008818 liver damage Effects 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 238000005461 lubrication Methods 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 125000005439 maleimidyl group Chemical group C1(C=CC(N1*)=O)=O 0.000 description 1
- 150000002696 manganese Chemical class 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 229930182817 methionine Natural products 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 230000004899 motility Effects 0.000 description 1
- QJITUZDKRABEGK-UHFFFAOYSA-N n'-propylmethanediimine;hydrochloride Chemical compound Cl.CCCN=C=N QJITUZDKRABEGK-UHFFFAOYSA-N 0.000 description 1
- QAPTWHXHEYAIKG-RCOXNQKVSA-N n-[(1r,2s,5r)-5-(tert-butylamino)-2-[(3s)-2-oxo-3-[[6-(trifluoromethyl)quinazolin-4-yl]amino]pyrrolidin-1-yl]cyclohexyl]acetamide Chemical compound CC(=O)N[C@@H]1C[C@H](NC(C)(C)C)CC[C@@H]1N1C(=O)[C@@H](NC=2C3=CC(=CC=C3N=CN=2)C(F)(F)F)CC1 QAPTWHXHEYAIKG-RCOXNQKVSA-N 0.000 description 1
- SFMJNHNUOVADRW-UHFFFAOYSA-N n-[5-[9-[4-(methanesulfonamido)phenyl]-2-oxobenzo[h][1,6]naphthyridin-1-yl]-2-methylphenyl]prop-2-enamide Chemical compound C1=C(NC(=O)C=C)C(C)=CC=C1N1C(=O)C=CC2=C1C1=CC(C=3C=CC(NS(C)(=O)=O)=CC=3)=CC=C1N=C2 SFMJNHNUOVADRW-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000003506 n-propoxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- 125000004888 n-propyl amino group Chemical group [H]N(*)C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000004593 naphthyridinyl group Chemical group N1=C(C=CC2=CC=CN=C12)* 0.000 description 1
- 208000015122 neurodegenerative disease Diseases 0.000 description 1
- 210000004498 neuroglial cell Anatomy 0.000 description 1
- 125000006501 nitrophenyl group Chemical group 0.000 description 1
- JFNLZVQOOSMTJK-UHFFFAOYSA-N norbornene Chemical compound C1C2CCC1C=C2 JFNLZVQOOSMTJK-UHFFFAOYSA-N 0.000 description 1
- JFNLZVQOOSMTJK-KNVOCYPGSA-N norbornene Chemical compound C1[C@@H]2CC[C@H]1C=C2 JFNLZVQOOSMTJK-KNVOCYPGSA-N 0.000 description 1
- 125000003518 norbornenyl group Chemical group C12(C=CC(CC1)C2)* 0.000 description 1
- PIDFDZJZLOTZTM-KHVQSSSXSA-N ombitasvir Chemical compound COC(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@H]1C(=O)NC1=CC=C([C@H]2N([C@@H](CC2)C=2C=CC(NC(=O)[C@H]3N(CCC3)C(=O)[C@@H](NC(=O)OC)C(C)C)=CC=2)C=2C=CC(=CC=2)C(C)(C)C)C=C1 PIDFDZJZLOTZTM-KHVQSSSXSA-N 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 125000004043 oxo group Chemical group O=* 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 230000000242 pagocytic effect Effects 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 230000036285 pathological change Effects 0.000 description 1
- 231100000915 pathological change Toxicity 0.000 description 1
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- 230000002688 persistence Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- AHWALFGBDFAJAI-UHFFFAOYSA-N phenyl carbonochloridate Chemical compound ClC(=O)OC1=CC=CC=C1 AHWALFGBDFAJAI-UHFFFAOYSA-N 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 108010070409 phenylalanyl-glycyl-glycine Proteins 0.000 description 1
- 108010084525 phenylalanyl-phenylalanyl-glycine Proteins 0.000 description 1
- 108010073101 phenylalanylleucine Proteins 0.000 description 1
- 108010083476 phenylalanyltryptophan Proteins 0.000 description 1
- 125000005543 phthalimide group Chemical group 0.000 description 1
- 230000000379 polymerizing effect Effects 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 229960002429 proline Drugs 0.000 description 1
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 125000004742 propyloxycarbonyl group Chemical group 0.000 description 1
- 229940024999 proteolytic enzymes for treatment of wounds and ulcers Drugs 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- KIDHWZJUCRJVML-UHFFFAOYSA-N putrescine Chemical group NCCCCN KIDHWZJUCRJVML-UHFFFAOYSA-N 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000005495 pyridazyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 208000002574 reactive arthritis Diseases 0.000 description 1
- 230000007017 scission Effects 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
- 125000003548 sec-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000035807 sensation Effects 0.000 description 1
- 235000019615 sensations Nutrition 0.000 description 1
- 230000008313 sensitization Effects 0.000 description 1
- 229960001153 serine Drugs 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- KZNICNPSHKQLFF-UHFFFAOYSA-N succinimide Chemical group O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 description 1
- IIACRCGMVDHOTQ-UHFFFAOYSA-N sulfamic acid Chemical class NS(O)(=O)=O IIACRCGMVDHOTQ-UHFFFAOYSA-N 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 239000002344 surface layer Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 229940036220 synvisc Drugs 0.000 description 1
- 238000007910 systemic administration Methods 0.000 description 1
- 238000009121 systemic therapy Methods 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 150000003892 tartrate salts Chemical class 0.000 description 1
- 229960003080 taurine Drugs 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- VENKBTRFJOWPPW-UHFFFAOYSA-N tert-butyl n-[3-[2-(3-aminopropoxy)ethoxy]propyl]carbamate Chemical compound CC(C)(C)OC(=O)NCCCOCCOCCCN VENKBTRFJOWPPW-UHFFFAOYSA-N 0.000 description 1
- WHHYAYNALHPDGJ-UHFFFAOYSA-N tert-butyl n-[3-[2-[2-(3-aminopropoxy)ethoxy]ethoxy]propyl]carbamate Chemical compound CC(C)(C)OC(=O)NCCCOCCOCCOCCCN WHHYAYNALHPDGJ-UHFFFAOYSA-N 0.000 description 1
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- 230000036962 time dependent Effects 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 125000005147 toluenesulfonyl group Chemical group C=1(C(=CC=CC1)S(=O)(=O)*)C 0.000 description 1
- FRXCPDXZCDMUGX-UHFFFAOYSA-N tridecane-1,1-diamine Chemical compound CCCCCCCCCCCCC(N)N FRXCPDXZCDMUGX-UHFFFAOYSA-N 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-O triethanolammonium Chemical class OCC[NH+](CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-O 0.000 description 1
- ZMANZCXQSJIPKH-UHFFFAOYSA-O triethylammonium ion Chemical compound CC[NH+](CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-O 0.000 description 1
- 229960004441 tyrosine Drugs 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- 238000011870 unpaired t-test Methods 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
- C08L5/00—Compositions of polysaccharides or of their derivatives not provided for in groups C08L1/00 or C08L3/00
- C08L5/08—Chitin; Chondroitin sulfate; Hyaluronic acid; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
- A61K47/61—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule the organic macromolecular compound being a polysaccharide or a derivative thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
- A61K47/65—Peptidic linkers, binders or spacers, e.g. peptidic enzyme-labile linkers
-
- 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
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- 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]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D475/00—Heterocyclic compounds containing pteridine ring systems
- C07D475/06—Heterocyclic compounds containing pteridine ring systems with a nitrogen atom directly attached in position 4
- C07D475/08—Heterocyclic compounds containing pteridine ring systems with a nitrogen atom directly attached in position 4 with a nitrogen atom directly attached in position 2
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
- C08B37/006—Heteroglycans, i.e. polysaccharides having more than one sugar residue in the main chain in either alternating or less regular sequence; Gellans; Succinoglycans; Arabinogalactans; Tragacanth or gum tragacanth or traganth from Astragalus; Gum Karaya from Sterculia urens; Gum Ghatti from Anogeissus latifolia; Derivatives thereof
- C08B37/0063—Glycosaminoglycans or mucopolysaccharides, e.g. keratan sulfate; Derivatives thereof, e.g. fucoidan
- C08B37/0072—Hyaluronic acid, i.e. HA or hyaluronan; Derivatives thereof, e.g. crosslinked hyaluronic acid (hylan) or hyaluronates
Definitions
- the present invention relates to a hyaluronic acid-methotrexate conjugate and a pharmaceutical use thereof.
- OA Osteoarthritis
- OA is a type of degenerative disease that develops based on aging.
- the number of patients is steadily increasing. Still, sufficient diagnostic and therapeutic methods have not been established.
- the first pathological change that occurs in OA is the degeneration and wear of articular cartilage, which is the mechanical stress caused by aging, which has become the bow I metal. This change progresses at a very slow rate and gradually evolves into pain.
- HA is an in vivo polysaccharide composed of repeating units of N-acetyldarcosamine and glucuronic acid. As a main component of synovial fluid, it works to maintain the viscoelasticity, load absorption and lubrication of synovial fluid. In the cartilage matrix, it binds to cartilage proteodalican to form a polymer called aggrecan, and plays a central role in maintaining water retention and viscoelasticity.
- HA having a molecular weight of about 600,000 daltons or more and a crosslinked product thereof into a knee joint removes OA pain, and thus HA preparations are widely used as one of the treatments for OA.
- a high-molecular-weight HA preparation (trade name: Svenyl (registered trademark), manufactured and sold by Chugai Pharmaceutical Co., Ltd.) that is close to the molecular weight of HA in normal synovial fluid is available in Japan.
- ⁇ Application is also approved for pain relief in knees associated with gussets (hereinafter also referred to as RA).
- the molecular weight of HA is correlated with the potency of the drug, and it is said that the high molecular weight type HA has a longer lasting, stronger, and more medicinal effect than the low molecular weight type HA! .
- HA preparations relieve pain by returning the viscosity and elasticity of joint fluid impaired in the pathology of OA (or rheumatoid arthritis (RA)) to normal.
- RA rheumatoid arthritis
- the HA formulation added from the outside disappears within a few days from the synovial fluid, the effect lasts for a long period of time. It has also been suggested that it may be working in pain relief.
- One of such mechanisms is an inhibitory effect on OA synovitis described below.
- OA synovitis is not only a major cause of pain and inflammatory symptoms such as joint swelling and hot sensation, but also promotes joint destruction through the production of proteolytic enzymes, cytokins and radicals. It is considered a major exacerbating factor in the development of the disease.
- OA synovitis has no significant proliferative changes as seen in RA, but is common to RA synovitis, such as synovial cell proliferation, angiogenesis and hyperemia, subsynovial edema and fibrosis. Many aspects have been observed. Thus, control of OA synovitis is important from the standpoint of more efficiently removing the pain and inflammation of OA and preventing the development of pathological conditions.
- drugs that control synovitis include modified antirheumatic drugs used in the treatment of RA.
- a group of drugs called drugs (hereinafter also referred to as DMARDs) is well known.
- drugs hereinafter also referred to as MTX
- MTX methotrexate
- MTX is a drug that has advantages such as excellent efficacy and a relatively short time to onset of action.
- MTX is only approved for systemic administration. (At present, only capsules are approved as a therapeutic agent for RA in Japan. Overseas, tablets and injections are approved.
- the synovium is a tissue in which HA easily accumulates.
- Synovial cells also have a mechanism to incorporate HA into cells via HA receptors such as CD44. Therefore, it is thought that HA may be a carrier for accumulating drugs in the synovium. So far, several technologies using HA as a drug carrier in vivo have been reported. However, there are almost no examples of application to technology related to the creation of a drug delivery system (hereinafter, also referred to as DDS) for the treatment of joint diseases, typically MTX, especially for the control of synovitis. Not known.
- DDS drug delivery system
- Patent Document 1 Japanese Patent Application Laid-Open No. 5-39306
- Patent Document 2 International Publication W094Z19376). These are all related to the DDS technology of an anticancer drug that has been shown to migrate to cancer tissues.
- MTX is used for the purpose of an anticancer agent.
- the binding rate of MTX is high (6.4-19% in the examples) to enhance its anticancer effect, and HA has a low molecular weight (100,000 daltons in the example).
- HA has a low molecular weight (100,000 daltons in the example).
- the peptide chain is bonded to the hydroxyl group of HA by an isourea bond, the stability in an aqueous solution is low.
- Patent Document 2 discloses a sputter such as a butyleneamine group (-CHNH-) and an otathyleneamine group (-CHNH-).
- conjugate of HA and a drug bound via 488 816 ser there is disclosed a conjugate of HA and a drug bound via 488 816 ser.
- the conjugate is described as exhibiting a drug effect in a state in which the drug remains bound, assuming an extracellular drug effect.
- the binding between the drug and HA via the spacer is relatively strong, so that the conjugate cannot exert its efficacy unless the conjugate power is released like MTX! is there.
- the patent document is directed to a conjugate using a matrix meta-oral proteinase inhibitor (hereinafter, also referred to as MMP I) as a drug, and the disclosed examples also relate to a conjugate of MMPI. Only things.
- MMP I matrix meta-oral proteinase inhibitor
- the conjugate using MTX as a drug is not specifically disclosed at all, and its usefulness as a medicament is not included in any description.
- Patent Document 3 In International Publication WO02Z44218 (Patent Document 3), norbornene is used by using a spacer in which a more specific group (norbornene) is bonded to a 13-amino-4,7,10-trioxatelide group.
- HA-drug conjugates formed by the formation of a rubamate bond between OH and the hydroxyl group of HA.
- the conjugate also assumes an extracellular drug effect as in Patent Document 2, and the drug effect is exhibited in a state where the drug remains bound. Therefore, if the binding strength is not released, it cannot exert its medicinal effect, and it is difficult to adapt to drugs such as MTX. is there.
- Patent Document 3 is directed to a conjugate using MMPI as a drug, and there is no suggestion about a conjugate using MTX as a drug!
- the present inventors have found that in the method of synthesizing an HA-drug conjugate, which is known as prior art, the molecular weight of HA is greatly reduced during the synthesis process, and the medicinal properties of HA are impaired. Check them out! Conventional methods for the synthesis of HA-drug conjugates use general organic synthesis reaction conditions and post-treatment conditions, but further improvements are needed to prepare high-molecular-weight HA-drug conjugates It is.
- HA-drug conjugates used as pharmaceuticals particularly high-molecular-weight HA-drug conjugates suitable for the treatment of joint diseases, formulations using the same, and methods for synthesizing the conjugates have been known. There was no.
- Patent Document 1 JP-5 - No. 39306
- Patent document 2 International publication WO99Z59603 pamphlet
- Patent document 3 International publication WO02Z44218 pamphlet
- the problem to be solved by the invention is to provide a hyaluronic acid-methotrexate conjugate useful as a therapeutic drug for joint diseases.
- methotrexate is bound to a hydroxyl group of hyaluronic acid via a linker containing a peptide chain, and the linker is linked to the hyaluronic acid, hyaluronic acid derivative or a salt thereof.
- linker is linked to the hyaluronic acid, hyaluronic acid derivative or a salt thereof.
- methotrexate is bound to a hydroxyl group of hyaluronic acid via a linker containing a peptide chain having 1 to 8 amino acids.
- a hyaluronic acid-methotrexate conjugate wherein the linker and the hyaluronic acid, the hyaluronic acid derivative or a salt thereof form a sorbate group and are bound to each other.
- the linker is a peptide chain with 1-8 amino acid strengths, and may have 1-5 oxygen atoms inserted and Z or carboxyl group or C alkoxycarbo- C alkylenediamine optionally substituted with
- the methotrexate bound to the linker has the formula (I), (II), (III) or (IV):
- R and R each independently represent a hydroxyl group, an amino group, a C alkoxy group, a C
- L is the linker binding position
- hyaluronic acid-methotrexate conjugate as described above, represented by:
- a linker containing a peptide chain and methotrexate bound to the linker are represented by the formula ( ⁇ ) or ( ⁇ ′):
- R and R are each independently a hydroxyl group, an amino group, a C alkoxy group, a C
- Q is a peptide chain consisting of 1 to 8 amino acids together with the NH to be bound
- each residue of the amino acid contained in the peptide chain is independently a C alkyl group
- 1-6 1-6 1-6 A group consisting of a sulfonyl group and a substituted! /, May! /, C arylsulfonyl group
- Each amide bond in the peptide chain which may be substituted or protected by one or more groups selected from the group consisting of one or more c alkyl groups and Z or c
- a carbonyl group may be substituted on the nitrogen atom by a carbonyl group, and each carboxy group contained in the residue may be independently an amide group optionally substituted by 1 or 2 C alkyl groups.
- R and R are each independently a hydrogen atom or a C alkyl group
- Q may have 1-5 oxygen atoms inserted and
- [HA] indicates the position of a hydroxyl group in hyaluronic acid, a hyaluronic acid derivative, or a salt thereof, and a linker is bonded to the hyaluronic acid, a hyaluronic acid derivative, or a salt thereof at this position by a hydroxyl group.
- the oxygen atom “-0-0” in “-0-0 [118]” represents an oxygen atom derived from a hydroxyl group at any position in hyaluronic acid, a hyaluronic acid derivative, or a salt thereof. This is the linker to be used. ]
- a pharmaceutical composition containing the above-mentioned hyaluronic acid-methotrexate conjugate as an active ingredient, and a therapeutic agent for joint disease.
- R and R each independently represent a hydroxyl group, an amino group, a C alkoxy group, a C
- L is the formula ( ⁇ ')
- each residue of the amino acid contained in the peptide chain is independently a C alkyl group
- 1-6 1-6 1-6 A group consisting of a sulfonyl group and a substituted! /, May! /, C arylsulfonyl group
- the peptide chain which may be substituted or protected by one or more groups selected from Each included amide bond is independently one or more c alkyl groups and
- the carbonyl group may be substituted on the nitrogen atom by a carbonyl group, and each carboxy group contained in the residue may be independently an amide group optionally substituted by 1 or 2 C alkyl groups.
- R and R are each independently a hydrogen atom or C alkyl
- R represents a C alkyl group, a carboximide group, an optionally substituted heteroaryl group
- Q may have 1-5 oxygen atoms inserted and Z or carboxyl group
- the compound of formula (Va) or (Vb) or a salt thereof is reacted with hyaluronic acid, a hyaluronic acid derivative, or a salt thereof, and the hyaluronic acid is reacted.
- Producing the above-mentioned hyaluronic acid-methotrexate conjugate, comprising the step of bonding the compound of formula (Va) or (Vb) or a salt thereof with a hydroxyl group at the position of the hydroxyl group of the acid, hyaluronic acid derivative or salt thereof A method is also provided.
- the hyaluronic acid-methotrexate conjugate (HA-MTX conjugate) of the present invention is a novel compound (hereinafter, in the HA-MTX conjugate, HA is a hyaluronic acid derivative, a salt thereof, or a salt of hyaluronic acid) May be present).
- HA hyaluronic acid
- methotrexer HMTX MTX is bound to the hydroxyl group of HA via a linker containing a peptide chain, and the linker and the HA are linked to each other.
- an HA-MTX conjugate that retains the pain-reducing action of HA and also has the synovitis-reducing action of MTX. That is, it is considered that the HA-MTX conjugate of the present invention accumulates in the synovium, is taken into synovial cells, and expresses the medicinal effect of MTX in the cells.
- the HA-MTX conjugate of the present invention when administered into a joint of an OA or RA patient, for example, into a joint of a knee, a shoulder, or an elbow, like a conventional HA preparation, a pain relieving action based on the properties of HA is achieved.
- a pain relieving action based on the properties of HA is achieved.
- synovial tissue while accumulating in synovial tissue, it is gradually taken into synovial cells, By dissociating MTX, the synovitis inhibitory action is continuously exhibited.
- the dose of MTX can be significantly reduced as compared with oral administration, and systemic side effects that are a problem with oral administration can be reduced.
- both the HA preparation and the MTX can exhibit pharmacological effects with different mechanisms of action, and thus synergistic drug effects can be expected.
- HA-MTX conjugate of the present invention HA itself exhibits a medicinal effect and also acts as a carrier for localizing MTX.
- the HA-MTX conjugate of the present invention can safely exhibit the synovitis-inhibiting effect of MTX only in the administered joint, while having the aspect of HA as a joint injection. Nina !, an excellent remedy for joint diseases is provided.
- the hyaluronic acid-methotrexate conjugate (HA-MTX conjugate) of the present invention has methotrexate bound to the hydroxyl group of hyaluronic acid via a linker containing a peptide chain. It is linked with hyaluronic acid to form a hydroxyl group.
- the hydroxyl group is one NRCOO—group (R is, for example, represented as R in the formula (X).
- the bond by a forcebamate bond or a forcebamate group means a bond through a forcebamate group.
- a state in which an arbitrary hydroxyl group in hyaluronic acid, a hyaluronic acid derivative, or a salt thereof is bonded to the linker via a power rubamate group is referred to as “1-NRCO—O— [HA] ”,“ One NHCO—0— [HA] ”or“ MTX— (linker containing peptide chain) —O— [HA] ”, where“ —O— [HA] ”
- the oxygen atom “-0-” represented therein is an oxygen atom derived from a hydroxyl group at any position in hyaluronic acid, a hyaluronic acid derivative, or a salt thereof.
- hyaluronic acid is generally referred to as hyaluronic acid, and is a polymer containing, as a repeating unit, a substance such as glucuronic acid and N-acetyldarcosamine.
- a substance such as glucuronic acid and N-acetyldarcosamine.
- a polysaccharide There is no particular limitation as long as it is a polysaccharide.
- it is a polymer of glucuronic acid, N-acetyldarcosamine and a disaccharide having an average molecular weight of 50,000 to 10,000,000 daltons.
- the salt of hyaluronic acid is not particularly limited, and includes, for example, sodium salt, potassium salt, calcium salt, aluminum salt, zinc salt, iron salt, ammonium salt, tetrabutylammonium salt and the like. .
- Specific examples of hyaluronic acid and its salts, and mixtures thereof For example, trade name Smony (registered trademark: manufacture and sale Chugai Pharmaceutical Co., Ltd.); trade name Altz (registered trademark: manufacture Seikagaku Corporation, sales Kaken Pharmaceutical Co., Ltd.); trade name Opegan (registered trademark: manufacture biochemistry) Industrial Co., Ltd., and sales Santen Pharmaceutical Co., Ltd.).
- the “hyaluronic acid derivative” means a substance having an HA skeleton derived from HA.
- the hyaluronic acid derivative include, but are not limited to, a substance in which one or more carboxyl groups in HA are esterified! (For example, benzyl esterified HA (trade name: Hyaff (registered trademark), Fidia Advanced Biopolymers)), a substance obtained by crosslinking HA with formaldehyde and further polymerizing (for example, Synvisc (registered trademark), Biomatrix)), acetylation in which one or more hydroxyl groups in HA are acetylated HA, and the like.
- the HA-MTX conjugate of the present invention expresses the pain relieving action of HA, and therefore has the same molecular weight size and viscoelasticity as HA as a HA-MTX conjugate, which has been confirmed to have a clinical pain relieving action. Is preferable. Considering that the molecular weight increases, the viscoelasticity increases and handling becomes difficult, and considering the effect of HA as a carrier in vivo, the molecular weight of the HA-MTX conjugate is specifically 600,000-600. The molecular weight of the HA-MTX conjugate is more preferably 800,000-6,000,000 daltons The molecular weight of the HA-MTX conjugate is more preferably 1,000,000-5,000,000 daltons Especially preferred,.
- the molecular weight of the raw material HA and the molecular weight of the HA-MTX conjugate are measured by a method of calculating a viscosity average molecular weight from an intrinsic viscosity.
- the conversion from the intrinsic viscosity ([7?]) To the viscosity average molecular weight (Mw) can be calculated using the following equation.
- the peptide chain in the linker containing the peptide chain of the present invention is composed of amino acids.
- the amino acids include glycine, alanine, serine, proline, quinoline, phosphorus, threonine, cysteine, leucine, isoleucine, asparagine, aspartic acid, lysine, glutamine, glutamic acid, methionine, histidine, hueralanine, arginine, tyrosine, tripline.
- ⁇ -amino acids such as tofuan, ⁇ -amino acids with alkyl side chains (eg, norparin, norleucine, t-leucine, etc.), and alanine substituted with a cycloalkyl group Or glycine (eg, cyclopentylalanine, cyclohexylalanine, cyclohexylglycine, etc.), or alanine or glycine substituted with an aryl group (eg, pyridylalanine, chelylalanine, naphthylalanine, substituted phenolylalanine, phenolic)
- ⁇ -amino acids such as ⁇ -alanine
- ⁇ -amino acids such as ⁇ -aminobutyric acid
- aminosulfonic acids such as taurine.
- amino acids in the linker peptide of the present invention include those in which the residues are appropriately substituted or protected.
- a functional group on the residue can be protected using a protecting group.
- Protecting groups used for this purpose are well known in the art, some examples of which are described in other paragraphs herein.
- the method for introducing each substituent and protecting group, particularly the protecting group may be any of those well known in the art!
- the linker may be composed of only amino acids, or may contain a portion derived from a compound other than amino acids in or at the peptide chain.
- a linker in which a diamino compound such as alkylenediamine or oxaalkylenediamine or a dicarboxylic acid conjugate such as succinic acid is bonded to the inside or terminal of a peptide chain is also included in the linker.
- a compound other than an amino acid is contained in or at the terminal of the peptide chain, and the linker binds to the carboxyl group of ⁇ and the hydroxyl group of hyaluronic acid, a compound such as alkylene diamine or oxaalkylene diamine is used.
- a novel diamino compound be present at the end of the peptide chain. It is particularly preferred that 4,7,10 trioxa-1,13 tridecanediamine be present at the end of the peptide chain.
- the amino acid constituting the peptide chain is not particularly limited. However, from the viewpoint of affinity for protease, a terminal which binds to MTX of a linker containing a peptide chain having a preferred amino acid must be a single amino acid. Is preferred.
- the number of amino acids constituting the peptide chain is not particularly limited, but is typically 1 to 8, preferably 1 to 6, and particularly preferably 1 to 4.
- Each residue of amino acids constituting the peptide chain can be appropriately substituted or protected independently by one or more groups.
- groups include C alkyl groups, C alkylcarbo-
- C alkoxycarbonyl group for example, methoxycarbonyl group, ethoxycarbonyl
- a hole group an ethanesulfol group, and (n- or i-) propanesulfol group
- a substituted or unsubstituted Carylsulfol group for example, a benzenesulfol group, (o- ,
- the residue may be converted to an amide group.
- the residue contains a nitrogen-containing heterocyclic ring such as an indole ring or an imidazole ring
- the nitrogen atoms on the ring are each independently a carbon atom.
- the nitrogen atom contained therein is also a C alkyl group.
- the one used can also be selected.
- a thiol group is included in the residue, it may be protected with a C alkyl or C alkylcarbonyl group.
- the amide bond or peptide bond contained in the nitrogen chain also has a C alkyl group on its nitrogen atom.
- the amino acid sequence constituting the peptide chain is not particularly limited !, but examples include the following.
- an amino acid sequence containing the recognition site and Z or a cleavage site may be used.
- Peptide chain with one amino acid Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, His ⁇ lie ⁇ Leu ⁇ Lys ⁇ Met ⁇ Phe ⁇ Pro, Ser ⁇ Thr ⁇ Trp ⁇ Tyr ⁇ Val ,Such.
- P he ⁇ Tyr, Ile, Glu Preferably, P he ⁇ Tyr, Ile, Glu.
- Peptide chain consisting of two amino acids: PhePhe, PheGly, PheLeu, TyrPhe, TrpPhe, PheTrp, PheTyr, GlyPhe, GlyGly, and the like.
- PhePhe, PheGly G PhePhe, PheGly G
- Peptide chain consisting of three amino acids: PheGlyGly, PheLeuGly, PhePheGly, AsnPhePhe, GlyPhePhe, LeuPhePhe, LeuAlaLeu, AlaValAla, GlyAlaPhe, GlyPheAla, GlylleAla, GlyllePal, GlyllePal, GlylleAhe, Ly Preferably, AsnPhePhe.
- Peptide chain consisting of 4 amino acids: GlyPheLeuGly, GlyPhePheLeu, GlyPhePhe Ala, GlyPheTyrAla, GlyPheGlyPhe ⁇ GlyPheGlyGly, GlyGlyPheGly, GlyGlyPheTyr, GlyGlyGuA, GlyGly, Aly Preferably, GlyPheLeuGly 0
- the linker in the present invention may have, for example, the structure represented by the above formula (X), in which case Q is bonded to -NH together with 1 to 8 From amino acids
- Q is the force to insert 1 to 5 oxygen atoms or
- Q include a 1,2-diyl group and a 1,3-diphenyl propane
- the HA-MTX conjugate of the present invention is a compound in which MTX is bound to a hydroxyl group of HA via a linker containing a peptide chain, and the linker and the hyaluronic acid are bound by a forcebamate bond.
- Any connection mode may be used. That is, a linker containing a peptide chain is
- the linker containing a peptide chain is preferably bonded to the carboxyl group at the ⁇ -position of ⁇ and the carboxyl group at the ⁇ or ⁇ to form the linker. Is more preferably combined with the carboxyl group at the a position of ⁇ . /.
- a linker containing a peptide chain and a particularly preferable binding mode thereof include a diamino compound at the end of the peptide chain in which the linker containing the peptide chain is a amino acid.
- the N-terminus of the peptide chain is bonded to the ⁇ -position carboxyl group of MTX by an acid amide bond, and the C-terminus of the peptide chain is linked via a diamino compound to the hydroxyl group and the olebamate group.
- methotrexate ( ⁇ ) portion in the hyaluronic acid-methotrexate conjugate of the present invention may be prodruged by a known method in addition to modification with a linker.
- a C alkyl group has 1 carbon atom.
- C alkylcarbonyl is a straight or branched chain having 1 to 6 carbon atoms.
- alkyl carboxy group for example, an acetyl group, a propioyl group, a 2-methylpropioyl group, a 2,2-dimethylpropioyl group, etc. Includes what you have.
- C alkoxy is a straight-chain or branched alcohol having 1 to 6 carbon atoms.
- xy group includes those having an alkyl group as defined above, such as a methoxy group, an ethoxy group and an n-propoxy group, as an alkyl moiety.
- C alkylamino is a straight-chain or branched chain having 1 to 6 carbon atoms.
- alkylamino group includes those having an alkyl group as defined above, such as a methylamino group, an ethylamino group, an n-propylamino group, as an alkyl moiety.
- di C alkylamino is a straight-chain or branched-chain having 1 to 6 carbon atoms.
- Dialkylamino group including those having an alkyl moiety which has the same or different alkyl group as defined above, such as a dimethylamino group, an ethylmethylamino group, a methylamino group, and an ethyl n-propylamino group. It is.
- C alkylene is a straight-chain or branched alkyl having 2 to 20 carbon atoms.
- kylene group includes, for example, an ethylene group, a propylene group, a butylene group, an otaylene group, a decalene group and the like.
- a C alkoxycarboyl group is a straight or branched chain having 1 to 6 carbon atoms.
- chain alkoxycarbyl group includes, for example, those having an alkyl group as defined above, such as a methoxycarbyl group, an ethoxycarbonyl group, an n -propoxycarbyl group, as an alkyl moiety.
- a C alkylsulfonyl group is a straight or branched chain having 1 to 6 carbon atoms.
- alkyl moiety has an alkyl group as defined above, such as a methanesulfol group, an ethanesulfol group or an n-propanesulfol group.
- the carboximide group may be cyclic or linear. May be substituted with a plurality of substituents.
- the carboximide group is bonded to the ⁇ atom at the ⁇ atom.
- Specific examples of the carboximide group include, for example, a succinimide group, a phthalimide group, a 5-norbornene 2,3 carboximide group, a maleimide group, and a daltarimide group.
- the aryl group means an aryl group having 6 to 18 carbon atoms which may be substituted with one or more substituents, and may be monocyclic or polycyclic.
- the substituent includes a C alkyl group as defined above; a C alkoxy group as defined above;
- Halogens such as nitrogen, chlorine, bromine and iodine; nitro groups; c alkoxycarbo as defined above
- Specific examples of the aryl group include a phenyl group, a nitrophenyl group, a fluorophenyl group, a chlorophenyl group, a naphthyl group, and an anthral group.
- a Caryl sulfol group is substituted with one or more substituents.
- the substituent includes a C alkyl group as defined above; a C alkoxy group as defined above; fluorine, chlorine, and odor.
- Halogen such as iodine and iodine; nitro group; C alkoxycarbonyl group as defined above; acyl
- Caryl sulfol groups include benzenesulfo-
- heteroaryl group means a group containing a 5- or 6-membered aromatic ring having one or more heteroatoms in the ring, and may be 1 or It may be substituted with a plurality of substituents. Heteroatoms include nitrogen, oxygen, and sulfur. The substituents include the substituents and oxo groups described above for the aryl group.
- Heteroaryl groups include pyridyl, pyrazil, pyrimidinyl, pyridazyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, triazinyl, tetrazolyl, oxazolyl, indolizinyl, indolyl, isoindolyl, indazolyl, purinyl, quinolizyl, isoquinolyl, quinolyl, Includes tarazinyl, naphthyridinyl, quinoxalinyl, oxaziazolyl, thiazolyl, thiadiazolyl, benzimidazolyl.
- the triazolyl group may be any isomer and may be substituted with one or more substituents.
- the triazolyl group is preferably bonded to a ⁇ atom by a ⁇ atom.
- Specific examples of the triazolyl group include, for example, a benzotriazolyl group, a 7-azabenzotriazolyl group, and the like.
- the triazyl group may be any isomer and may be substituted with one or more substituents.
- the triazyl group is preferably bonded to a ⁇ atom by a ⁇ atom.
- Specific examples of the triazinyl group include, for example, a 3,4 dihydro-14-oxo 1,2,3 benzotriazyl group.
- acylation in the present specification includes C alkylcarbonylation
- benzoyl group is C alkyl, halogen atom, C alkoxy, etc.
- the binding ratio of ⁇ ⁇ ⁇ ⁇ in the ⁇ - ⁇ conjugate of the present invention is preferably within a range in which a medicinal effect is exhibited and side effects are reduced.
- the bond ratio of ⁇ in the present specification is represented by the following formula:
- [0082] is calculated.
- a value calculated based on an ultraviolet absorption spectrum is used as the bond ratio of ⁇ .
- the binding ratio of ⁇ is not particularly limited, but is preferably 0.5% or more, and more preferably 1.0% or more, from the viewpoint of exhibiting a drug effect.
- the binding rate is preferably less than 10% in order to localize the action of ⁇ to the administration site and reduce the systemic side effects of ⁇ .
- the binding rate of ⁇ is 0.5%. More preferably, it is more preferably less than 4.5%, more preferably more than 1.0% and less than 4.5%.
- the present ⁇ - ⁇ conjugate is preferably a pharmaceutically acceptable salt in consideration of its use, which can also exist as a salt, and its use.
- Pharmaceutically acceptable salts of the HA-MTX conjugate include non-toxic base addition salts commonly used in the art, for example, alkali metal salts, alkaline earth metal salts, or ammonium salts. Contains salt. Such base addition salts include sodium, potassium, calcium, aluminum, zinc, iron, magnesium, ammonium, trimethylammonium, triethylammonium, piberidium. Powers including, but not limited to, gum salt, morpholium salt, pyrrolidium salt, benzylammonium salt, diethanolammonium salt, triethanolammonium salt, tetrabutylammonium salt, etc.
- the pharmaceutically acceptable salts of the HA-MTX conjugate also include non-toxic inorganic or organic acid addition salts commonly used in the art.
- acid addition salts include hydrochloride, hydrobromide, hydroiodide, hydrofluoride, sulphate, sulphate, phosphate, hydrogen phosphate, phosphorus Dihydrogen acid, nitrate, phosphite, formate, acetate, trifluoroacetate, benzoate, succinate, saccharate, fumarate, maleate, lactate, citrate, tartaric acid Salts, dalconate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate, but are not limited thereto.
- the HA-MTX conjugate of the present invention can be obtained by binding HA, a linker containing a peptide chain, and MTX in an appropriate order.
- a route for introducing MTX after constructing a linker containing an HA-peptide chain there are a route for introducing MTX after constructing a linker containing an HA-peptide chain, and a route for constructing a linker containing an MTX-peptide chain and then introducing the linker into HA.
- R and R each independently represent a hydroxyl group, an amino group, a C alkoxy group, a C
- L is the formula ( ⁇ ')
- each residue of the amino acid contained in the peptide chain is independently a C alkyl group
- 1-6 1-6 1-6 A group consisting of a sulfonyl group and a substituted! /, May! /, C arylsulfonyl group
- Each amide bond in the peptide chain which may be substituted or protected by one or more groups selected from one or more, is independently one or more c alkyl groups and
- the carbonyl group may be substituted on the nitrogen atom by a carbonyl group, and each carboxy group contained in the residue may be independently an amide group optionally substituted by 1 or 2 C alkyl groups.
- R and R are each independently a hydrogen atom or C alkyl
- R is a hydrogen atom, a C alkyl group, a carboximide group, an optionally substituted
- Q is an alkylene, wherein the alkylene has 1 to 5 oxygen atoms inserted.
- heteroaryl group and aryl group used in R may be substituted with one or more substituents.
- substituents include, but are not limited to, any of those already exemplified in relation to the aryl group, for example, a C alkyl group as previously defined;
- Halogen such as nitrogen, chlorine, bromine and iodine; and -toro.
- R is preferably a C alkyl group or an optionally substituted aryl group.
- the active substance may be isolated and used, or may be generated in-situ and reacted with force. Further, the isolated active form can be provided in the form of a salt acceptable for organic synthesis. Such salts may be any of the acid or base addition salts already exemplified in connection with the HA-MTX conjugate.
- active form salts include hydrochloride, hydrobromide, hydroiodide, hydrofluoride, sulfate, hydrogen sulfate, phosphate, hydrogen phosphate, dihydrogen phosphate Salt, nitrate, phosphite, formate, acetate, trifluoroacetate, benzoate, succinate, saccharate, fumarate, maleate, lactate, citrate, tartrate, dalcone Acid, methanesulphonate, ethanesulphonate, benzenesulphonate, p-toluenesulphonate and pamoate; sodium, potassium, calcium, aluminum, zinc, iron, magnesium, ammonium Salt, trimethylammonium salt, triethylammonium salt, piberidinium salt, morpholium salt, pyrrolidi-pam salt, benzylammonium salt, diethanolammonium salt, triethanolamine Mode - ⁇ unsalted, Tetorabu Chi
- the reaction can be carried out at a temperature of 20 ° C. to 50 ° C. for several minutes to several days using a generally used solvent and, if necessary, a reaction promoting additive.
- Examples of the solvent include water, N, N dimethylformamide, N, N dimethylacetamide, dimethyl sulfoxide, tetrahydrofuran, dioxane, methanol, ethanol, dichloromethane, and chloroform. These solvents may be used alone or in combination.
- Examples of the reaction promoting additive include a phase transfer catalyst and a base.
- Examples of the phase transfer catalyst include various halogenated quaternary ammonium salts such as cetylpyridyl-dimethyl chloride, tetrabutylammonium-dimethylbromide, cetyltrimethylammonium-dimethylbromide, and benzylcetyldimethylammonium-dimethyl chloride. ⁇ Muchloride is preferred.
- Examples of the base include triethylamine, tributylamine, N-methylmorpholine, N, N-diisopropylethylamine, tris [2- (2-methoxyethoxy) ethyl] amine, and the like, with triptylamine being preferred. These additives may be used alone or in combination.
- a functional group such as an amino acid side chain, for example, a hydroxyl group, a carboxyl group, or an amino group, a protecting group widely used in ordinary organic synthesis can be used, if necessary.
- the reaction temperature is not particularly limited as long as a medicinal HA-MTX conjugate is obtained, but is typically -10 ° C or higher, preferably 0 ° C or higher, and 40 ° C or lower. Preferably it is 30 ° C or lower.
- the reaction time is not particularly limited, but is 1 hour or more from the viewpoint of performing a uniform reaction, and is economically 24 hours or less, preferably 12 hours or less.
- joint disease specifically refers to articular cartilage defect, osteoarthritis (including primary having no apparent cause and secondary having a causal disease), shoulder Refers to diseases such as periarthritis, rheumatoid arthritis, reactive arthritis, viral arthritis, pyogenic arthritis, tuberculous arthritis, and neuroarthritis. Knee joint pain).
- agent for treating joint disease includes a drug used for the prevention of the disease used alone for the treatment of the joint disease, and a drug used for suppressing the progression of the disease state (preventing deterioration and maintaining the status quo). Include.
- the HA-MTX conjugate of the present invention is obtained by adding an effective amount of a pharmaceutically acceptable carrier, excipient, disintegrant, lubricant, binder, flavor, coloring agent and the like to an effective amount thereof. It can be used as a product.
- the pharmaceutical composition containing the HA-MTX conjugate of the present invention as an active ingredient is preferably used as a therapeutic drug for joint diseases, and among them, it is particularly preferable to be used as a preparation for local administration to joints.
- the HA-MTX conjugate of the present invention is formulated as a therapeutic agent for joint disease, it is not particularly limited.
- the HA-MTX conjugate is dissolved in physiological saline or phosphate physiological saline or the like to a desired concentration, and the mixture is injected. It can be formulated as a formulation.
- the solution may be adjusted to a desired pH by adding an acid or a base.
- the solution is adjusted to a desired salt concentration by adding a monovalent metal salt such as a sodium salt and a potassium salt, and an inorganic salt such as a divalent metal salt such as a magnesium salt, a calcium salt, and a manganese salt. Is also good.
- the HA-MTX conjugate of the present invention may be distributed in a form in which it is pre-filled in a syringe such as a disposable syringe.
- a syringe such as a disposable syringe.
- the HA-MTX conjugate of the present invention is 0.01% to 10%.
- a solution having a solution concentration of 0.1% to 2.0% w / v, preferably 0.5% to 1.5% w / v, 1 to 3 mL per patient may be administered.
- the dose may be appropriately increased or decreased depending on the instructions of a doctor, the target patient, the type and severity of the disease, the molecular weight of the HA-MTX conjugate, and the like, as appropriate.
- the HA-MTX conjugate of the present invention reduces synovitis not seen in HA when administered intraarticularly to an arthritis model in which a pathological condition develops in the knee joint. Is expressed.
- FIG. 1 shows the time course of knee joint swelling measured in each test substance-administered group and control group (HA and vehicle) when an mBS A solution was administered into the knee joint. Is shown.
- FIG. 2 shows the AUC for the graph of each test substance administration group and control group in FIG.
- Fig. 3 shows the time course of the knee joint width in a collagen arthritis model.
- the left figure shows the right knee joint (administration site) measured immediately after the induction of collagen arthritis in the group to which the compound of Example 3-7 or the control drug (HA or Vehicle) was administered only into the right knee joint.
- the time course of the width is shown.
- the right figure shows the time course of the left knee joint width, which is the non-administration site.
- the graph shows the standard error of the mean.
- FIG. 4 shows the results of measuring knee swelling in a collagenase-induced arthritis (OA) model.
- the left figure shows the time course of knee swelling measured from immediately after the induction of arthritis to 27 days after the administration of the compound of Example 3-7 or the control drug (HA or vehicle), and the right figure shows the time course. Indicates AUC.
- N-carbobenzoxy-L-phen-l-alanine (Cbz Phe: 7.16 g, 25.4 mmol)
- Nt-butoxycarbo-lu-ethylenediamine hydrochloride (5.00 g, 25.4 mmol)
- 1-hydroxybenzo Triazole hydrate (HOBT: 4.28 g, 28. Ommol)
- N-methylmorpholine NMM: 3.07 mL, 28. Ommol
- NMM 3.07 mL, 28. Ommol
- DMF dimethylformamide
- EDC 1-ethyl 3 — (3 Dimethylaminopropyl) carposimid hydrochloride
- the compound lb (11.lg, 18.9 mg) was dissolved in 800 mL of methanol, 50 mL of DMF and 500 mL of THF, 1.00 g of 10% palladium on carbon was added, and the mixture was stirred at room temperature under a hydrogen atmosphere for 1 day. After filtering off the catalyst from the reaction mixture, the reaction mixture was concentrated under reduced pressure.
- N-Carbobenzoxy-L-phen-alanine (Cbz Phe: 852 mg, 2.85 mmol) and N-t-butoxycarbonyl-4,7,10 trioxa-1,13 tridecanediamine (76 Omg, 2.37 mmol) and 1-hydroxybenzotriazole hydrate (HOBT: 363 mg, 2.37 mmol) were dissolved in 6 mL of dimethylformamide (DMF), and the mixture was stirred under ice-cooling and stirred with 1-ethyl-3- (3-dimethylamino).
- DMF dimethylformamide
- EDC 1-ethyl-3- (3-dimethylamino
- the compound 2c (514 mg, 0.576 mmol) was suspended in 30 mL of methanol, 100 mg of 10% palladium on carbon was added, and the mixture was stirred at room temperature under a hydrogen atmosphere for 1.5 hours. After filtering off the catalyst from the reaction mixture, the reaction mixture was concentrated under reduced pressure. This residue, 4- [N- (2,4-diamino-6-pteridyl-methyl) -N-methylamino] benzoic acid: 281 mg, 0.864 mmol) and HOBT (132 mg, 0.864 mmol) were dissolved in 5 mL of DMF.
- Trioxa 13— [N— [N— [N— [4 — [[(2,4 diamino-16 pteridyl) methyl] methylamino] benzoyl] —a— (O 5-ethyl Glutamyl)] Fer-Fara-L] Fuer-Fala-Lamino] Tride-Lamine: MTX (Et) -a-PhePhe-N HC HO NH (Compound 2,)
- a yellow powder was prepared in the same manner as in Example 1-1, except that Nt-butoxycarbol-l, 5-pentadiamine was used instead of Nt-butoxycarbol-l, 2-ethylenediamine. 148 mg of the title compound was obtained.
- Example 12 Title of yellow powder was prepared in the same manner as in Example 1-2 except that N-carbobenzoxyglycine was used in place of N-carbobenzoxy L-phenylalanine in the step of (a). 528 mg of the compound were obtained.
- N-t-butoxycarbol-4,7,10-trioxa--1,13 instead of tridecanediamine, N-t-butoxycarbonyl-4,9-dioxa-1 Using 12 dodecanediamine, 300 mg of the title compound was obtained as a yellow powder.
- N-t-butoxycarbol-4,7,10-trioxa--1,13 instead of tridecandamine, N-t-butoxycarbonyl-4,7-dioxa-1 Using 10 decanedamine, 300 mg of the title compound was obtained as a yellow powder.
- Example 1-2 The title of a yellow powder was obtained in the same manner as in Example 12 except that N-carbobenzoxy L-proline was used in place of N-carbobenzoxy L-phenalanine in the step (a). 382 mg of the compound were obtained.
- Example 1-2 A yellow powder was prepared in the same manner as in Example 1-2, except that N-carbobenzoxy ⁇ -alanine was used in place of N-carbobenzoxy L-phenalanine in the step (a). 180 mg of the title compound were obtained.
- Example 11 A yellow powder of the title compound was obtained in the same manner as in Example 1-1, except that N-carbobenzoxy- ⁇ -alanine was used in place of N-carbobenzoxy L-phenalanine in the step of (a). 194 mg were obtained.
- Example 1-2 Except that the step of (b) was omitted, 496 mg of the title compound as yellow powder was obtained in the same manner as in Example 1-2.
- N-t-butoxycarbonyl-4,7,10-trioxa-1,13-substituted N-t-butoxycarbonyl-1,2-ethylenediamine was used in place of tridecandamine. This gave 320 mg of the title compound as a yellow powder.
- Example 117 By a method similar to that in Example 117, 133 mg of the title compound was obtained as a yellow powder using N-carbobenzoxy L-tyrosine in place of N-carbobenzoxy L-phenylalanine.
- Example 117 In the same manner as in Example 117, 416 mg of the title compound was obtained as a yellow powder by using N-carbobenzoxy L-serine instead of N-carbobenzoxy L-phenalanine.
- Example 117 By a method similar to that in Example 117, 590 mg of the title compound was obtained as a yellow powder by using N-carbobenzoxy L-valine instead of N-carbobenzoxy L-phenalanine.
- N-carbobenzoxy L-histamine was used in place of N-carbobenzoxy L-phenalanine V, to give the title compound as a yellow powder, 81 mg.
- Example 1-5 the title of a yellow powder was obtained using ⁇ -carbobenzoxy-L-glutamic acid- ⁇ -methylester instead of N-carbobenzoxy-L-glutamic acid- ⁇ -methyl ester. 80 mg of the compound were obtained.
- Example 1-17 In the same manner as in Example 1-17, 480 mg of the title compound was obtained as a yellow powder by using ⁇ -carbobenzoxy-L-glutamic acid- ⁇ -methyl ester instead of N-carbobenzoxy-L-glutamic acid- ⁇ -methyl ester. Obtained.
- Example 1-20 the title compound was obtained as a yellow powder by using ⁇ -carbobenzoxy-L-glutamic acid- ⁇ methyl ester instead of N-carbobenzoxy-L-glutamic acid- ⁇ -methyl ester. 438 mg were obtained.
- Example 1 In the same manner as in Example 30, N-carbobenzoxy L-phenylalanine Using N-carbobenzoxy D-phenylalanine instead, 85 mg of the title compound was obtained as a yellow powder.
- Example 1-2 In the same manner as in Example 1-2, the peptide chain was extended according to a usual peptide synthesis method to obtain 145 mg of the title compound as a yellow powder.
- Example 2-1 the compounds of Examples 1-1 to 1-8, 1-10 to 1-17, and 1-19 to 1-38 can be respectively converted to phenyl carbamates. It was possible.
- Example 2-6 In the same manner as in Example 2-2 above, it was possible to convert the compounds of Examples 1-1 to 1-38 to p-to-mouth phenol carbamates, respectively.
- the precipitate was dissolved in ultrapure water (60 mL), 1N aqueous sodium hydroxide solution (7.5 mL) was added, and the mixture was stirred at 5 ° C for 2 hours. The solution was neutralized by adding 1N hydrochloric acid (7.5 mL), and sodium chloride (2.25 g) was added. Then, ethanol (150 mL) was added dropwise to perform ethanol precipitation. Was separated by centrifugation.
- the precipitate was dissolved in ultrapure water (lOOmL), and a solution prepared by dissolving sodium salt (6g) in ultrapure water (lOOmL) was added thereto. Then, ethanol (400 mL) was added dropwise to the filtrate aseptically to precipitate ethanol, and the precipitate was collected by filtration and dried in vacuo.
- the molecular weight determined by gel filtration using hyaluronic acid as a standard substance was about 2.44 million. . Further, the binding ratio of MTX in the obtained conjugate was 1.0% as calculated by measuring ultraviolet absorption (259 nm).
- Example 3-1 In the same manner as in Example 3-1, hyaluronic acid sodium salt (200 mg, molecular weight: about 2.5 million) and MTX- ⁇ -PhePhe-NHCHONHCO-O-C obtained in Example 2-1
- the molecular weight determined by the same method as in 3-1 is about 2.48 million, and the binding rate of MTX is 1.8%.
- Example 3-1 hyaluronic acid sodium salt (200 mg, molecular weight: about 2.2 million) and MTX- ⁇ -PhePhe—NHC H O NHCO—O—C obtained in Example 2-2
- Example 3-1 hyaluronic acid sodium salt (200 mg, molecular weight: about 2.2 million) and MTX- ⁇ -PhePhe—NHC H O NHCO—O—C obtained in Example 2-2
- the molecular weight determined by the same method as in Example 3-1 was about 2.16 million, and the binding ratio of MTX was 2.0%.
- Example 3-1 hyaluronic acid sodium salt (200 mg, molecular weight: about 2.2 million) and MTX- ⁇ -PhePhe—NHC H O NHCO—O—C obtained in Example 2-2
- the molecular weight determined by the same method as in Example 3-1 was about 2.11 million, and the binding ratio of MTX was 1.6%.
- the precipitate was dissolved in ultrapure water (35 mL), and 1N aqueous sodium hydroxide solution (5 mL) was added thereto, followed by stirring at 5 ° C for 1 hour.
- the solution was neutralized by adding 1N hydrochloric acid (5 mL), and a solution of sodium chloride (1.17 g) dissolved in ultrapure water (5 mL) was added. Then, ethanol (100 mL) was added. Ethanol was precipitated by dropping, and the precipitate was separated by centrifugation.
- the precipitate was dissolved in ultrapure water (50 mL), a solution of sodium chloride (3 g) dissolved in ultrapure water (50 mL) was added, and then a 0.45 m filter (Sterivex HV) was added. : Millipore), ethanol (200 mL) was added dropwise to the filtrate aseptically to precipitate ethanol, and the precipitate was collected by filtration and dried in vacuo.
- Example 2-1 sodium hyaluronate (500 mg, molecular weight: about 2.3 million) and MTX- ⁇ -PhePhe-NHCHONHCO-O-C obtained in Example 2-1 were used.
- the molecular weight determined by the same method as in 3-6 was about 2.1 million, and the binding ratio of MTX was 2.0%.
- Example 2-1 sodium hyaluronate (500 mg, molecular weight: about 2.3 million) and MTX- ⁇ -PhePhe-NHCHONHCO-O-C obtained in Example 2-1 were used.
- the molecular weight determined by the same method as in 3-6 was about 2.13 million, and the binding ratio of MTX was 2.5%.
- Example 2-1 sodium hyaluronate (500 mg, molecular weight: about 2.3 million) and MTX- ⁇ -PhePhe-NHCHONHCO-O-C obtained in Example 2-1 were used.
- the molecular weight determined by the same method as in 3-6 was about 2.32 million, and the binding ratio of MTX was 2.6%.
- Example 2-1 sodium hyaluronate (500 mg, molecular weight: about 2.3 million) and MTX- ⁇ -PhePhe-NHCHONHCO-O-C obtained in Example 2-1 were used.
- the molecular weight determined by the same method as in 3-6 was about 2.05 million, and the binding ratio of MTX was 3.8%.
- Example 2-1 sodium hyaluronate (100 mg, molecular weight: about 860,000) and MTX— ⁇ —PhePhe—NHC H O NHCO—O—CH obtained in Example 2-1 were used.
- Example 2-1 sodium hyaluronate (100 mg, molecular weight: about 860,000) and MTX— ⁇ —PhePhe—NHC H O NHCO—O—CH obtained in Example 2-1 were used.
- Example 2-1 sodium hyaluronate (100 mg, molecular weight: about 350,000) and MTX— ⁇ —PhePhe—NHC H O NHCO—O—C H obtained in Example 2-1
- HA-MTX conjugate (0.004 mmol) to give an aqueous solution of the title HA-MTX conjugate.
- the molecular weight determined by the same method as in Example 36 was about 350,000, and the binding ratio of MTX was 1.1%.
- Example 2-3 sodium hyaluronate (100 mg, molecular weight: about 2.3 million) and MTX- ⁇ -PheGly-NHC H O NHCO—O—C obtained in Example 2-3
- the viscoelasticity of the conjugate of Example 3 and the viscoelasticity of hyaluronic acid as a control were It was measured at 37 ° C with a mold stress-controlled rheometer (Carri-Med) using a cone having a diameter of 4 cm.
- HA- ⁇ conjugate of the present invention Using human synovial cells (HFLS), the effect of the HA- ⁇ conjugate of the present invention on the enhancement of cell proliferation induced by TNF- ⁇ was examined.
- the main focus of rheumatoid arthritis (RA) is the synovial tissue.
- RA rheumatoid arthritis
- One of its features is that synovial cells abnormally proliferate to form granulation tissue (pannus) and destroy cartilage and bone of joints. It is known. Secondary synovitis is also seen in osteoarthritis (OA).
- synovitis causes inflammatory symptoms such as joint swelling, pain and warmth that are characteristic of knee OA ( Edited by Nobuyuki Takasaka et al., "Bone and Joint Diseases" 2003, Asakura Shoten). Therefore, a compound that inhibits the proliferation of synovial cells enhanced by TNF- ⁇ , which is an inflammatory site power-in, can be used as a drug for suppressing or treating the progression of RA and OA.
- HFLS is composed of human synovial cells from RA patients (HFLS-RA, CA404-05, Lot No .: 1493) and human synovial cells from OA patients 03 ⁇ 41 ⁇ -08, Ji400-05, 1 ⁇ No .: 1442) was purchased from CELL APPLICATIONS INS.
- HFLS was seeded on a 96-well plate (Falcon) at 5000 cells Zwell, and cultured in an Iscove's modified Dulbecco s medium (IMDM) medium containing 5% FBS and lx Antibiotic-antimycotic (uIB and O) for 3 hours. After cell attachment, TNF-a (final concentration lOngZ mL) and HA-MTX conjugate at each concentration were added and cultured for 5 days.
- IMDM Iscove's modified Dulbecco s medium
- uIB and O Antibiotic-antimycotic
- the radioactivity of each test substance measured in each experiment was calculated as a relative value (% of control) using the radioactivity of the group cultured without adding the test substance as a control.
- the MTX concentration of the HA-MTX conjugate is 2.49x10 " 3 mol / L (lg / 401 / L: 401 is the molecular weight of N-acetyldarcosamine + glucuronic acid) per 1 mgZmL of hyaluronic acid Therefore, the value was calculated by multiplying this value by the binding ratio of MTX. (MTX coupling ratio of 1% HA -.
- MTX conjugate Img / mL MTX concentration 2.49x10- 5 molZL and the) obtained using the value 4 parameter logistic method (analysis software GraphPad Prism 3.02 Contact and 4.02), the cell growth inhibitory activity (IC value) was calculated.
- Table 2 shows the IC values of the HA-MTX conjugate in HFLS-RA and those in HFLS-OA.
- Table 3 shows the IC values of the HA-MTX conjugate.
- S-RA has an effect of suppressing the increase in cell proliferation.
- the in vivo synovitis inhibitory effect of the HA-MTX conjugate of the present invention was evaluated by the knee methyl swelling inhibitory effect of a rat methylated bovine serum albumin (mBSA) -induced monoarthritis model.
- mBSA rat methylated bovine serum albumin
- the mBSA-induced monoarthritis model used in this experiment is widely used as an antigen-induced arthritis model and is known to induce synovitis (Sven E. Andersson, et al. The Journal of From Rheumatology (1998) 25: 9, 1772-7), the inhibitory effect on joint swelling in vivo observed in this model can be considered to be a synovitis inhibitory effect.
- Compounds that suppress synovitis in vivo are useful as therapeutics for joint diseases associated with synovitis (such as RA and OA).
- the animals used were LEWZCrj rats (Charles Japan's Riva-1, 6 weeks old, male). Twenty-one and fourteen days before the induction of arthritis, 0.5 mL of an emulsion prepared with 2 mgZmL of mBSA (Calbiochem) aqueous solution and an equal amount of Freund's complete adjuvant (Difco) was subcutaneously administered to the flank of rats. Arthritis was induced by injecting 50 L of a 2 mg ZmL aqueous solution of mBSA into the right knee joint. The left knee joint was untreated and served as a control for each individual. The test substance (sterile water solution) and the control drug, hyaluronic acid, were administered 50 L intra-articularly to the right knee joint 7 days and 1 day before and 7 days after induction of arthritis.
- mBSA Calbiochem
- Freund's complete adjuvant Freund's complete adjuvant
- the knee joint swelling was measured by measuring the width of both knee joints with a vernier caliper, and the difference between the left and right sides (right knee diameter, left knee diameter) was defined as knee joint swelling.
- the width of the knee joint is measured twice a week from immediately before the induction of arthritis to two weeks later, and the change over time is used to determine the AUC (Area Under the Curve; also referred to as the area under the curve. The area under the objective curve is shown.)
- the average value and standard deviation of AUC were calculated for each measurement, and a t-test was performed between the test substance-administered group and the HA-administered group, and a significant difference was judged to be significant when the risk factor was less than 5%. .
- Statistical analysis used SAS version 6.12 or 8.02 (SAS Institute Japan). For the AUC of each test substance, the relative value (% of control) of each test substance was calculated using the HA administration group as a control.
- Table 4 shows the results of examining the effect of each HA-MTX conjugate of the present invention by the above method. [0230] [Table 4]
- HA-MTX conjugate of the present invention In order to verify the usefulness of the HA-MTX conjugate of the present invention according to the method of Experimental Example 3, 1) the administration group of the HA-MTX conjugate (sterile aqueous solution) prepared in Example 3-10, 2) HA—Group administered with a solution containing the same amount of MTX as the MTX contained in the MTX conjugate, and 3) a mixture of the same amount of MTX and hyaluronic acid (HA) (HA + MTX) contained in the conjugate ) Were compared for their joint swelling inhibitory effects. HA and Veicle (2 mM phosphate buffer, 0.9% NaCl) were used as controls.
- the HA-MTX conjugate of the present invention was obtained in vitro, which is not observed in HA.
- TNF- ⁇ stimulation has been shown to have an inhibitory effect on human synovial cell proliferation and an effect of reducing synovitis in vivo (in a model of developing arthritis).
- MTX alone or a mixture of HA and MTX did not show a sufficient synovitis-mitigating effect, whereas the HA-MTX conjugate had a strong synovitis-mitigating effect. It became clear that it exerted.
- the in vivo synovitis inhibitory effect of the HA-MTX conjugate was evaluated using a rat collagen arthritis model (Kane et al., “Joint Surgery” (1998), Vol. 17, No. 2), which is widely used as a model for rheumatoid arthritis (RA). , 111-21).
- the compound of the present invention that suppresses inflammation in this model is useful for treating autoantigen-induced immune diseases represented by RA.
- DAZSlc rats Japan SLC, Inc., 11 weeks old, female were used as animals.
- Dissolve E-type collagen (collagen technology workshop) in a 0.1 mol / mL aqueous solution of OlmolZL acetic acid and add an equal amount of Freund's incomplete adjuvant (Difco) to the emulsion.
- Difco Freund's incomplete adjuvant
- a total of 0.4 mL of this emulsion was applied to the skin at the back of the rat at a total of 0.4 mL / force to induce arthritis.
- test substance sterile aqueous solution
- control agents hyaluronic acid (HA) and Vehicle (2 mM phosphate buffer, 0.9% NaCl)
- HA hyaluronic acid
- Vehicle 2 mM phosphate buffer, 0.9% NaCl
- FIG. 3 shows the results of examining the effect of the HA-MTX conjugate of the present invention by the above method.
- the HA-MTX conjugate of the present invention was found to be more active than the HA-administered group.
- the width of swollen joints was significantly suppressed by the induction of monogen arthritis, and the change over time in the joint widths was almost at the same level as in the normal group. This effect was observed only at the site where the HA-MTX conjugate was administered (right knee), and was not observed at the site where no HA-MTX conjugate was administered (left knee).
- the present compound can exert an action limited to the administration site.
- Collagenase-induced OA model is a model in which collagen in cartilage tissue is directly digested by injecting aqueous collagenase solution into the joint to induce inflammation in the joint.
- This model shows histopathological changes similar to human OA pathology, such as articular cartilage degeneration and synovitis, and is useful for evaluating therapeutic agents for OA (Takanori K. et al., Osteoarthritis and Cartilage (1998) 6, 177-86). Therefore, the compound that suppresses the inflammation of the present model is useful as a therapeutic agent for OA.
- the animals used were SDZCrj rats (Charles' Riva Japan, 6 weeks old, male). 1.5 ⁇ L Collagenase (SIGMA) solution (50 ⁇ L) was administered into the right knee joint cavity to induce arthritis. The left knee joint was left untreated to serve as a control for each individual.
- the test substance of Example 3-7 sterile aqueous solution
- the control drugs hyaluronic acid (HA) and Vehicle (2 mM phosphate buffer, 0.9% NaCl) were administered weekly from 7 and 1 days before the induction of arthritis. In each case, 50 L was administered into the right knee joint.
- the knee joint swelling was measured by measuring the width of both knee joints with a vernier caliper, and calculating the difference between the left and right sides (right knee diameter, left knee diameter) as knee joint swelling. From just before the induction of arthritis to 20 days after the induction of arthritis, the width of the knee joint was measured approximately twice a week, and the AUC of the graph showing the time course was calculated. The average value and standard error of AUC were calculated for each measurement, and an unpaired t-test was performed between the test substance-administered group and the HA-administered group. When the risk factor was less than 5%, it was determined that there was a significant difference.
- FIG. 4 shows the results of examining the effect of the HA-MTX conjugate of the present invention by the above method.
- the left figure in FIG. 4 shows the time-dependent changes in typical joint swelling of the HA-MTX conjugate, and the AUC obtained therefrom is shown in the right figure in FIG. [0243]
- the HA-MTX conjugate of the present invention can safely exhibit the synovitis-inhibiting effect of MTX only in the administered joint, while having the aspect of HA as a joint injection. (4) An excellent therapeutic agent for joint disease having an effect is provided.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- Polymers & Plastics (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Molecular Biology (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Materials Engineering (AREA)
- Biochemistry (AREA)
- Biomedical Technology (AREA)
- Physical Education & Sports Medicine (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Immunology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Polysaccharides And Polysaccharide Derivatives (AREA)
Abstract
Description
Claims
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP05727780A EP1739097A4 (en) | 2004-04-02 | 2005-04-01 | HYALURONIC ACID / METHOTREXATE COMPOUND |
JP2006511841A JP5001645B2 (ja) | 2004-04-02 | 2005-04-01 | ヒアルロン酸−メトトレキサート結合体 |
US11/547,158 US7807675B2 (en) | 2004-04-02 | 2005-04-01 | Hyaluronic acid-methotrexate conjugate |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2004-110423 | 2004-04-02 | ||
JP2004110423 | 2004-04-02 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2005095464A1 true WO2005095464A1 (ja) | 2005-10-13 |
Family
ID=35063729
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/JP2005/006472 WO2005095464A1 (ja) | 2004-04-02 | 2005-04-01 | ヒアルロン酸-メトトレキサート結合体 |
Country Status (5)
Country | Link |
---|---|
US (1) | US7807675B2 (ja) |
EP (1) | EP1739097A4 (ja) |
JP (1) | JP5001645B2 (ja) |
TW (1) | TW200536861A (ja) |
WO (1) | WO2005095464A1 (ja) |
Cited By (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2007063538A1 (en) * | 2005-11-30 | 2007-06-07 | Can-Fite Biopharma Ltd. | Use of a3 adenosine receptor agonist in osteoarthritis treatment |
WO2010053140A1 (ja) | 2008-11-05 | 2010-05-14 | 国立大学法人 東京医科歯科大学 | ヒアルロン酸誘導体、およびその医薬組成物 |
JP2012510535A (ja) * | 2008-11-28 | 2012-05-10 | ユニヴァーシタ’デグリ ステュディ ディ パレルモ | ヒアルロン酸官能基化誘導体の製造方法及びそのヒドロゲル形成 |
US8557986B2 (en) * | 2006-05-01 | 2013-10-15 | Seikagaku Corporation | Method of producing polysaccharide derivatives |
WO2014038641A1 (ja) | 2012-09-05 | 2014-03-13 | 中外製薬株式会社 | アミノ酸およびステリル基が導入されたヒアルロン酸誘導体 |
JP2019059951A (ja) * | 2013-07-10 | 2019-04-18 | 生化学工業株式会社 | グリコサミノグリカン誘導体及びその製造方法 |
WO2019098393A1 (ja) | 2017-11-15 | 2019-05-23 | 中外製薬株式会社 | ポリエチレングリコールにより修飾されたヒアルロン酸誘導体 |
JP2021528138A (ja) * | 2018-06-15 | 2021-10-21 | クロマ−ファーマ ゲゼルシャフト エム.ベー.ハー. | 架橋ポリマーを含むヒドロゲル組成物 |
Families Citing this family (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR101234476B1 (ko) * | 2004-03-05 | 2013-02-18 | 덴끼 가가꾸 고교 가부시키가이샤 | 히알루론산/메토트렉세이트 화합물 |
DE102006035083A1 (de) * | 2006-07-28 | 2008-01-31 | medac Gesellschaft für klinische Spezialgeräte mbH | Proteinbindende Methotrexat-Derivate und diese enthaltende Arzneimittel |
AU2014218512B2 (en) * | 2013-02-20 | 2017-09-28 | The University Of Queensland | Conjugate compound and uses of same |
ES2835499T3 (es) * | 2014-07-30 | 2021-06-22 | Massachusetts Eye & Ear Infirmary | Metotrexato para la vitreorretinopatía proliferativa |
CN104497167B (zh) * | 2014-11-24 | 2017-05-17 | 山东省药学科学院 | 透明质酸衍生物及其治疗药物 |
US20210386863A1 (en) * | 2018-10-24 | 2021-12-16 | Phi Biomed Inc. | Drug conjugate prepared using aldehyde group at end of hyaluronic acid |
CN111821470B (zh) * | 2020-09-01 | 2022-08-12 | 中南大学 | 包载甲氨蝶呤的铁-鞣酸配合物及其制备方法与应用 |
PL243573B1 (pl) * | 2021-06-11 | 2023-09-11 | Univ Medyczny Im Piastow Slaskich We Wroclawiu | Koniugat metotreksatu i glukozy do zastosowania w zapobieganiu lub leczeniu chorób autoimmunologicznych |
CN116270423B (zh) * | 2023-01-12 | 2024-01-16 | 南方医科大学珠江医院 | 一种装载甲氨蝶呤的透明质酸水凝胶及其制备方法和应用 |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS6440499A (en) * | 1987-08-06 | 1989-02-10 | Teijin Ltd | Folic acid-analog derivative and production thereof |
JPH0539306A (ja) * | 1990-12-14 | 1993-02-19 | D D S Kenkyusho:Kk | ヒアルロン酸およびコンドロイチン誘導体 |
JPH0680705A (ja) * | 1992-09-02 | 1994-03-22 | D D S Kenkyusho:Kk | ヘパリン誘導体 |
JPH0885703A (ja) * | 1994-09-16 | 1996-04-02 | D D S Kenkyusho:Kk | 臓器移行性を有する多糖誘導体および薬物担体 |
JPH09188705A (ja) * | 1995-11-07 | 1997-07-22 | Seikagaku Kogyo Co Ltd | グリコサミノグリカン誘導体およびその製造法 |
JPH11222425A (ja) * | 1997-10-27 | 1999-08-17 | Ss Pharmaceut Co Ltd | 関節疾患治療用関節内投与製剤 |
Family Cites Families (15)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA1188988A (en) * | 1981-07-02 | 1985-06-18 | Alan G. Walton | Chondroitin drug complexes |
US5554386A (en) * | 1986-07-03 | 1996-09-10 | Advanced Magnetics, Inc. | Delivery of therapeutic agents to receptors using polysaccharides |
JP3357362B2 (ja) * | 1990-12-19 | 2002-12-16 | アドバンスド・マグネティクス・インク | 多糖類を用いる治療薬のターゲティング |
US5902795A (en) * | 1992-06-16 | 1999-05-11 | Trustees Of Tufts College | Oligosaccharides reactive with hyaluronan-binding protein and their methods of use |
WO1994013327A1 (en) * | 1992-12-15 | 1994-06-23 | The Wellcome Foundation Limited | Immunoreactive reagents employing dihydrofolate reductase |
ATE195324T1 (de) | 1993-02-26 | 2000-08-15 | Drug Delivery System Inst Ltd | Polysaccharidderivat und wirkstoffträger |
US6322815B1 (en) * | 1994-07-22 | 2001-11-27 | W. Mark Saltzman | Multipart drug delivery system |
TW577758B (en) | 1997-10-27 | 2004-03-01 | Ssp Co Ltd | Intra-articular preparation for the treatment of arthropathy |
CA2332802A1 (en) | 1998-05-20 | 1999-11-25 | Chugai Seiyaku Kabushiki Kaisha | Conjugate of therapeutic agent for joint disease and hyaluronic acid |
AU772074B2 (en) * | 1999-04-28 | 2004-04-08 | Vectramed, Inc. | Enzymatically activated polymeric drug conjugates |
US6749865B2 (en) * | 2000-02-15 | 2004-06-15 | Genzyme Corporation | Modification of biopolymers for improved drug delivery |
IT1318403B1 (it) * | 2000-03-17 | 2003-08-25 | Cooperativa Ct Ricerche Poly T | Esteri polisaccaridici di n-derivati di acido glutammico. |
US7034127B2 (en) * | 2002-07-02 | 2006-04-25 | Genzyme Corporation | Hydrophilic biopolymer-drug conjugates, their preparation and use |
AU2003284885A1 (en) * | 2002-10-21 | 2004-05-13 | Kensey Nash Corporation | Device and methods for sequential, regional delivery of multiple cytotoxic agents |
CA2609069A1 (en) * | 2005-05-18 | 2006-11-23 | Eurand Pharmaceuticals Limited | Antiproliferative conjugates comprising hyaluronic acid and n-derivatives of glutamic acid |
-
2005
- 2005-04-01 US US11/547,158 patent/US7807675B2/en not_active Expired - Fee Related
- 2005-04-01 WO PCT/JP2005/006472 patent/WO2005095464A1/ja active Application Filing
- 2005-04-01 JP JP2006511841A patent/JP5001645B2/ja not_active Expired - Fee Related
- 2005-04-01 TW TW094110506A patent/TW200536861A/zh unknown
- 2005-04-01 EP EP05727780A patent/EP1739097A4/en not_active Withdrawn
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS6440499A (en) * | 1987-08-06 | 1989-02-10 | Teijin Ltd | Folic acid-analog derivative and production thereof |
JPH0539306A (ja) * | 1990-12-14 | 1993-02-19 | D D S Kenkyusho:Kk | ヒアルロン酸およびコンドロイチン誘導体 |
JPH0680705A (ja) * | 1992-09-02 | 1994-03-22 | D D S Kenkyusho:Kk | ヘパリン誘導体 |
JPH0885703A (ja) * | 1994-09-16 | 1996-04-02 | D D S Kenkyusho:Kk | 臓器移行性を有する多糖誘導体および薬物担体 |
JPH09188705A (ja) * | 1995-11-07 | 1997-07-22 | Seikagaku Kogyo Co Ltd | グリコサミノグリカン誘導体およびその製造法 |
JPH11222425A (ja) * | 1997-10-27 | 1999-08-17 | Ss Pharmaceut Co Ltd | 関節疾患治療用関節内投与製剤 |
Non-Patent Citations (2)
Title |
---|
ROSOWSKY A. ET AL: "Methotrexate analogs. 22. Synthesis, Dihydrofolate Reductase Affinity, Cytotoxicity, and in Vivo Antitumor Activity of Some Putative Degradation Products of Methotrexate-Poly(L-lysine)Conjugates.", JOURNAL OF MEDICINAL CHEMISTRY., vol. 27, no. 7, 1984, pages 888 - 893, XP002989867 * |
See also references of EP1739097A4 * |
Cited By (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2007063538A1 (en) * | 2005-11-30 | 2007-06-07 | Can-Fite Biopharma Ltd. | Use of a3 adenosine receptor agonist in osteoarthritis treatment |
AU2006321165B2 (en) * | 2005-11-30 | 2010-04-22 | Can-Fite Biopharma Ltd. | Use of A3 adenosine receptor agonist in osteoarthritis treatment |
US10265337B2 (en) | 2005-11-30 | 2019-04-23 | Can-Fite Biopharma Ltd. | Use of A3 adenosine receptor agonist in osteoarthritis treatment |
US8557986B2 (en) * | 2006-05-01 | 2013-10-15 | Seikagaku Corporation | Method of producing polysaccharide derivatives |
WO2010053140A1 (ja) | 2008-11-05 | 2010-05-14 | 国立大学法人 東京医科歯科大学 | ヒアルロン酸誘導体、およびその医薬組成物 |
JP2012510535A (ja) * | 2008-11-28 | 2012-05-10 | ユニヴァーシタ’デグリ ステュディ ディ パレルモ | ヒアルロン酸官能基化誘導体の製造方法及びそのヒドロゲル形成 |
WO2014038641A1 (ja) | 2012-09-05 | 2014-03-13 | 中外製薬株式会社 | アミノ酸およびステリル基が導入されたヒアルロン酸誘導体 |
JP2019059951A (ja) * | 2013-07-10 | 2019-04-18 | 生化学工業株式会社 | グリコサミノグリカン誘導体及びその製造方法 |
WO2019098393A1 (ja) | 2017-11-15 | 2019-05-23 | 中外製薬株式会社 | ポリエチレングリコールにより修飾されたヒアルロン酸誘導体 |
JP2021528138A (ja) * | 2018-06-15 | 2021-10-21 | クロマ−ファーマ ゲゼルシャフト エム.ベー.ハー. | 架橋ポリマーを含むヒドロゲル組成物 |
Also Published As
Publication number | Publication date |
---|---|
EP1739097A4 (en) | 2010-12-08 |
US20090093414A1 (en) | 2009-04-09 |
TW200536861A (en) | 2005-11-16 |
EP1739097A1 (en) | 2007-01-03 |
JPWO2005095464A1 (ja) | 2008-02-21 |
JP5001645B2 (ja) | 2012-08-15 |
US7807675B2 (en) | 2010-10-05 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
WO2005095464A1 (ja) | ヒアルロン酸-メトトレキサート結合体 | |
JP4927536B2 (ja) | ヒアルロン酸−メトトレキサート結合体 | |
EP2682409B1 (en) | Derivative of hyaluronic acid modified with amino-carboxylic acid | |
JP5856069B2 (ja) | 新規なシチジン系代謝拮抗剤の高分子誘導体 | |
US20090311182A1 (en) | Macromolecular Delivery Systems for Non-Invasive Imaging, Evaluation and Treatment of Arthritis and Other Inflammatory Diseases | |
JPWO2006095775A1 (ja) | 水溶性ヒアルロン酸修飾物とglp−1アナログの結合体 | |
JP4467888B2 (ja) | アロエ−エモジン誘導体と腫瘍性病理学の治療におけるその使用 | |
ES2906599T3 (es) | Acido hialurónico funcionalizado o un derivado del mismo en el tratamiento de estados inflamatorios | |
JPH08502519A (ja) | 生物学的に活性な化合物 | |
JP6851977B2 (ja) | マクロライド系免疫抑制剤の高分子誘導体 | |
WO2017119272A1 (ja) | マクロライド系免疫抑制剤の高分子誘導体 | |
WO2015002078A1 (ja) | ボロン酸化合物の新規製剤 | |
WO2020254606A1 (en) | Conjugates of heteroaromatic nitrogen-comprising compounds | |
PT98783A (pt) | Processo para a preparacao de um polimero contendo acido poliaspartico apropriado para inibir a nefrotoxicidade do aminoglicosido | |
CA3015459A1 (en) | Pharmaceutical preparation containing camptothecin-based polymeric derivative |
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): BW GH 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 |
|
DPEN | Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed from 20040101) | ||
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: 2006511841 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: 2005727780 Country of ref document: EP |
|
WWP | Wipo information: published in national office |
Ref document number: 2005727780 Country of ref document: EP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 11547158 Country of ref document: US |