CN107106526B - 用于组织自修复和再生的经取代芳族化合物和药物组合物 - Google Patents
用于组织自修复和再生的经取代芳族化合物和药物组合物 Download PDFInfo
- Publication number
- CN107106526B CN107106526B CN201580071284.6A CN201580071284A CN107106526B CN 107106526 B CN107106526 B CN 107106526B CN 201580071284 A CN201580071284 A CN 201580071284A CN 107106526 B CN107106526 B CN 107106526B
- Authority
- CN
- China
- Prior art keywords
- tissue
- compound
- nmr
- pharmaceutically acceptable
- organ
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 238000011069 regeneration method Methods 0.000 title description 23
- 230000008929 regeneration Effects 0.000 title description 21
- 239000008194 pharmaceutical composition Chemical class 0.000 title description 11
- 150000001491 aromatic compounds Chemical class 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 209
- 150000003839 salts Chemical class 0.000 claims abstract description 77
- 210000000056 organ Anatomy 0.000 claims abstract description 71
- 230000017423 tissue regeneration Effects 0.000 claims abstract description 39
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 27
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 7
- 230000004936 stimulating effect Effects 0.000 claims abstract description 6
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 4
- 210000001519 tissue Anatomy 0.000 claims description 91
- 159000000000 sodium salts Chemical group 0.000 claims description 39
- 239000011734 sodium Substances 0.000 claims description 38
- 210000003491 skin Anatomy 0.000 claims description 23
- 125000000217 alkyl group Chemical group 0.000 claims description 14
- 210000001035 gastrointestinal tract Anatomy 0.000 claims description 8
- 210000003205 muscle Anatomy 0.000 claims description 8
- 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 claims description 7
- 210000004185 liver Anatomy 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims description 7
- 229910052708 sodium Inorganic materials 0.000 claims description 7
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 6
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 6
- 239000011575 calcium Substances 0.000 claims description 6
- 229910052791 calcium Inorganic materials 0.000 claims description 6
- 210000004072 lung Anatomy 0.000 claims description 6
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 5
- 239000011777 magnesium Substances 0.000 claims description 5
- 229910052749 magnesium Inorganic materials 0.000 claims description 5
- 210000002784 stomach Anatomy 0.000 claims description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims description 4
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 4
- 125000003342 alkenyl group Chemical group 0.000 claims description 4
- 210000000845 cartilage Anatomy 0.000 claims description 4
- 239000003814 drug Substances 0.000 claims description 4
- 229910052751 metal Inorganic materials 0.000 claims description 4
- 239000002184 metal Substances 0.000 claims description 4
- 229910052700 potassium Inorganic materials 0.000 claims description 4
- 239000011591 potassium Substances 0.000 claims description 4
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 3
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 3
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 3
- 229910052802 copper Inorganic materials 0.000 claims description 3
- 239000010949 copper Substances 0.000 claims description 3
- 229910052742 iron Inorganic materials 0.000 claims description 3
- 229910052744 lithium Inorganic materials 0.000 claims description 3
- WPBNNNQJVZRUHP-UHFFFAOYSA-L manganese(2+);methyl n-[[2-(methoxycarbonylcarbamothioylamino)phenyl]carbamothioyl]carbamate;n-[2-(sulfidocarbothioylamino)ethyl]carbamodithioate Chemical compound [Mn+2].[S-]C(=S)NCCNC([S-])=S.COC(=O)NC(=S)NC1=CC=CC=C1NC(=S)NC(=O)OC WPBNNNQJVZRUHP-UHFFFAOYSA-L 0.000 claims description 3
- 239000011701 zinc Substances 0.000 claims description 3
- 229910052725 zinc Inorganic materials 0.000 claims description 3
- 239000000203 mixture Substances 0.000 abstract description 95
- 238000000034 method Methods 0.000 abstract description 41
- 230000006378 damage Effects 0.000 abstract description 21
- 230000003712 anti-aging effect Effects 0.000 abstract description 10
- 230000001737 promoting effect Effects 0.000 abstract description 7
- 239000003550 marker Substances 0.000 abstract description 5
- 230000008467 tissue growth Effects 0.000 abstract description 3
- 230000029663 wound healing Effects 0.000 abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 183
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 156
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 132
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 91
- 238000005160 1H NMR spectroscopy Methods 0.000 description 82
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 79
- 239000000243 solution Substances 0.000 description 78
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 67
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 59
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 58
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 53
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 52
- 210000004027 cell Anatomy 0.000 description 49
- 238000006243 chemical reaction Methods 0.000 description 48
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 44
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 39
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 39
- 239000012071 phase Substances 0.000 description 31
- 239000007787 solid Substances 0.000 description 31
- 238000000746 purification Methods 0.000 description 30
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 29
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 28
- 238000004704 ultra performance liquid chromatography Methods 0.000 description 28
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 27
- 239000000377 silicon dioxide Substances 0.000 description 27
- 229910052938 sodium sulfate Inorganic materials 0.000 description 27
- 235000011152 sodium sulphate Nutrition 0.000 description 27
- 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 26
- -1 bioavailability Chemical class 0.000 description 26
- 235000019253 formic acid Nutrition 0.000 description 26
- 102000003745 Hepatocyte Growth Factor Human genes 0.000 description 24
- 108090000100 Hepatocyte Growth Factor Proteins 0.000 description 24
- 238000004128 high performance liquid chromatography Methods 0.000 description 24
- 229920006395 saturated elastomer Polymers 0.000 description 23
- 239000002904 solvent Substances 0.000 description 23
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 22
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 22
- 239000011780 sodium chloride Substances 0.000 description 22
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 21
- 239000012043 crude product Substances 0.000 description 21
- 238000004293 19F NMR spectroscopy Methods 0.000 description 20
- 239000011541 reaction mixture Substances 0.000 description 20
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 19
- UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 19
- 230000014509 gene expression Effects 0.000 description 18
- 208000014674 injury Diseases 0.000 description 18
- 208000027418 Wounds and injury Diseases 0.000 description 17
- 238000001914 filtration Methods 0.000 description 17
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 17
- 239000000284 extract Substances 0.000 description 16
- 239000002253 acid Substances 0.000 description 15
- 238000001704 evaporation Methods 0.000 description 14
- 238000001035 drying Methods 0.000 description 13
- 230000008020 evaporation Effects 0.000 description 13
- 238000009472 formulation Methods 0.000 description 13
- 229910052757 nitrogen Inorganic materials 0.000 description 13
- 239000007790 solid phase Chemical group 0.000 description 13
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 12
- 102000004887 Transforming Growth Factor beta Human genes 0.000 description 12
- 108090001012 Transforming Growth Factor beta Proteins 0.000 description 12
- 150000003254 radicals Chemical class 0.000 description 12
- ZRKFYGHZFMAOKI-QMGMOQQFSA-N tgfbeta Chemical compound C([C@H](NC(=O)[C@H](C(C)C)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CCSC)C(C)C)[C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O)C1=CC=C(O)C=C1 ZRKFYGHZFMAOKI-QMGMOQQFSA-N 0.000 description 12
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 11
- 239000002585 base Substances 0.000 description 11
- 239000006071 cream Substances 0.000 description 11
- 230000000694 effects Effects 0.000 description 11
- 239000006210 lotion Substances 0.000 description 11
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 11
- 108010003894 Protein-Lysine 6-Oxidase Proteins 0.000 description 10
- 102100026858 Protein-lysine 6-oxidase Human genes 0.000 description 10
- 239000002502 liposome Substances 0.000 description 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 10
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 10
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 9
- 102100020944 Integrin-linked protein kinase Human genes 0.000 description 9
- 102000005741 Metalloproteases Human genes 0.000 description 9
- 108010006035 Metalloproteases Proteins 0.000 description 9
- 108010022233 Plasminogen Activator Inhibitor 1 Proteins 0.000 description 9
- 102100039418 Plasminogen activator inhibitor 1 Human genes 0.000 description 9
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 9
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 9
- 239000003102 growth factor Substances 0.000 description 9
- 239000001257 hydrogen Substances 0.000 description 9
- 108010059517 integrin-linked kinase Proteins 0.000 description 9
- 150000002632 lipids Chemical class 0.000 description 9
- 239000003921 oil Substances 0.000 description 9
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 9
- 238000011282 treatment Methods 0.000 description 9
- 239000003981 vehicle Substances 0.000 description 9
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 8
- 229910052681 coesite Inorganic materials 0.000 description 8
- 229910052906 cristobalite Inorganic materials 0.000 description 8
- 239000007788 liquid Substances 0.000 description 8
- 239000000463 material Substances 0.000 description 8
- AGJSNMGHAVDLRQ-IWFBPKFRSA-N methyl (2s)-2-[[(2s)-2-[[(2s)-2-[[(2r)-2-amino-3-sulfanylpropanoyl]amino]-3-methylbutanoyl]amino]-3-(4-hydroxy-2,3-dimethylphenyl)propanoyl]amino]-4-methylsulfanylbutanoate Chemical compound SC[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(=O)N[C@@H](CCSC)C(=O)OC)CC1=CC=C(O)C(C)=C1C AGJSNMGHAVDLRQ-IWFBPKFRSA-N 0.000 description 8
- 235000019198 oils Nutrition 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- 235000012239 silicon dioxide Nutrition 0.000 description 8
- 235000017557 sodium bicarbonate Nutrition 0.000 description 8
- 229910052682 stishovite Inorganic materials 0.000 description 8
- 229910052905 tridymite Inorganic materials 0.000 description 8
- 241000282412 Homo Species 0.000 description 7
- 201000010099 disease Diseases 0.000 description 7
- 150000002148 esters Chemical class 0.000 description 7
- 239000000499 gel Substances 0.000 description 7
- 230000008018 melting Effects 0.000 description 7
- 238000002844 melting Methods 0.000 description 7
- 239000003883 ointment base Substances 0.000 description 7
- 239000012074 organic phase Substances 0.000 description 7
- 239000000126 substance Substances 0.000 description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 7
- 102100027995 Collagenase 3 Human genes 0.000 description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- 101000577887 Homo sapiens Collagenase 3 Proteins 0.000 description 6
- FIWILGQIZHDAQG-UHFFFAOYSA-N NC1=C(C(=O)NCC2=CC=C(C=C2)OCC(F)(F)F)C=C(C(=N1)N)N1N=C(N=C1)C1(CC1)C(F)(F)F Chemical compound NC1=C(C(=O)NCC2=CC=C(C=C2)OCC(F)(F)F)C=C(C(=N1)N)N1N=C(N=C1)C1(CC1)C(F)(F)F FIWILGQIZHDAQG-UHFFFAOYSA-N 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
- 108010031429 Tissue Inhibitor of Metalloproteinase-3 Proteins 0.000 description 6
- 102000005406 Tissue Inhibitor of Metalloproteinase-3 Human genes 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- CIUQDSCDWFSTQR-UHFFFAOYSA-N [C]1=CC=CC=C1 Chemical compound [C]1=CC=CC=C1 CIUQDSCDWFSTQR-UHFFFAOYSA-N 0.000 description 6
- 239000004480 active ingredient Substances 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 239000003153 chemical reaction reagent Substances 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 6
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 6
- 238000005984 hydrogenation reaction Methods 0.000 description 6
- 239000000693 micelle Substances 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- 230000002829 reductive effect Effects 0.000 description 6
- 239000000725 suspension Substances 0.000 description 6
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 6
- PAOJMGKYYPHNDO-MDZDMXLPSA-N 2-[(e)-hex-1-enyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Chemical compound CCCC\C=C\B1OC(C)(C)C(C)(C)O1 PAOJMGKYYPHNDO-MDZDMXLPSA-N 0.000 description 5
- 102100026802 72 kDa type IV collagenase Human genes 0.000 description 5
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 5
- 101000627872 Homo sapiens 72 kDa type IV collagenase Proteins 0.000 description 5
- 101001013150 Homo sapiens Interstitial collagenase Proteins 0.000 description 5
- 101000990902 Homo sapiens Matrix metalloproteinase-9 Proteins 0.000 description 5
- 102000000380 Matrix Metalloproteinase 1 Human genes 0.000 description 5
- 102100030412 Matrix metalloproteinase-9 Human genes 0.000 description 5
- 239000004264 Petrolatum Substances 0.000 description 5
- 101150055168 Plat gene Proteins 0.000 description 5
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 5
- 125000004432 carbon atom Chemical group C* 0.000 description 5
- 239000002537 cosmetic Substances 0.000 description 5
- 238000010931 ester hydrolysis Methods 0.000 description 5
- 239000011159 matrix material Substances 0.000 description 5
- 229940066842 petrolatum Drugs 0.000 description 5
- 235000019271 petrolatum Nutrition 0.000 description 5
- 239000000741 silica gel Substances 0.000 description 5
- 229910002027 silica gel Inorganic materials 0.000 description 5
- BMIBJCFFZPYJHF-UHFFFAOYSA-N 2-methoxy-5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine Chemical compound COC1=NC=C(C)C=C1B1OC(C)(C)C(C)(C)O1 BMIBJCFFZPYJHF-UHFFFAOYSA-N 0.000 description 4
- IMIHEZMTQOARIK-CMDGGOBGSA-N 4,4,5,5-tetramethyl-2-[(e)-pent-1-enyl]-1,3,2-dioxaborolane Chemical compound CCC\C=C\B1OC(C)(C)C(C)(C)O1 IMIHEZMTQOARIK-CMDGGOBGSA-N 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- BVBSGGBDFJUSIH-UHFFFAOYSA-N Methyl (2-hydroxyphenyl)acetate Chemical compound COC(=O)CC1=CC=CC=C1O BVBSGGBDFJUSIH-UHFFFAOYSA-N 0.000 description 4
- 102000008847 Serpin Human genes 0.000 description 4
- 108050000761 Serpin Proteins 0.000 description 4
- 238000006069 Suzuki reaction reaction Methods 0.000 description 4
- 239000008346 aqueous phase Substances 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 229910052786 argon Inorganic materials 0.000 description 4
- 230000005779 cell damage Effects 0.000 description 4
- 239000013058 crude material Substances 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 210000003734 kidney Anatomy 0.000 description 4
- ULSSGHADTSRELG-UHFFFAOYSA-N methyl 2-(3-bromophenyl)acetate Chemical compound COC(=O)CC1=CC=CC(Br)=C1 ULSSGHADTSRELG-UHFFFAOYSA-N 0.000 description 4
- 239000004005 microsphere Substances 0.000 description 4
- 210000005036 nerve Anatomy 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 4
- 229920001223 polyethylene glycol Polymers 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 239000000651 prodrug Substances 0.000 description 4
- 229940002612 prodrug Drugs 0.000 description 4
- 230000005855 radiation Effects 0.000 description 4
- 230000008439 repair process Effects 0.000 description 4
- 239000003001 serine protease inhibitor Substances 0.000 description 4
- 230000037380 skin damage Effects 0.000 description 4
- 239000001632 sodium acetate Substances 0.000 description 4
- 235000017281 sodium acetate Nutrition 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 239000004094 surface-active agent Substances 0.000 description 4
- 230000000451 tissue damage Effects 0.000 description 4
- VIGJPLLOGSYVQF-UHFFFAOYSA-N 1,3-dibromo-5-(bromomethyl)-2-fluorobenzene Chemical compound FC1=C(Br)C=C(CBr)C=C1Br VIGJPLLOGSYVQF-UHFFFAOYSA-N 0.000 description 3
- QSSXJPIWXQTSIX-UHFFFAOYSA-N 1-bromo-2-methylbenzene Chemical compound CC1=CC=CC=C1Br QSSXJPIWXQTSIX-UHFFFAOYSA-N 0.000 description 3
- FAYROYTZAOJDRM-UHFFFAOYSA-N 2-(2-fluoro-3,5-dipentylphenyl)acetic acid Chemical compound FC1=C(C=C(C=C1CCCCC)CCCCC)CC(=O)O FAYROYTZAOJDRM-UHFFFAOYSA-N 0.000 description 3
- NYYKLRQNNOBRQG-UHFFFAOYSA-N 2-(2-hydroxy-3,5-dipentylphenyl)acetic acid Chemical compound CCCCCC1=CC(CCCCC)=C(O)C(CC(O)=O)=C1 NYYKLRQNNOBRQG-UHFFFAOYSA-N 0.000 description 3
- CGMDQKKIJZHZGH-UHFFFAOYSA-N 2-(2-hydroxy-3-pentylphenyl)acetic acid Chemical compound CCCCCC1=CC=CC(CC(O)=O)=C1O CGMDQKKIJZHZGH-UHFFFAOYSA-N 0.000 description 3
- VQGJRNOEWGDKKW-UHFFFAOYSA-N 2-(3-pentylphenyl)propanoic acid Chemical compound CCCCCC1=CC=CC(C(C)C(O)=O)=C1 VQGJRNOEWGDKKW-UHFFFAOYSA-N 0.000 description 3
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 3
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- IVDFJHOHABJVEH-UHFFFAOYSA-N HOCMe2CMe2OH Natural products CC(C)(O)C(C)(C)O IVDFJHOHABJVEH-UHFFFAOYSA-N 0.000 description 3
- 241000124008 Mammalia Species 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 3
- 239000002202 Polyethylene glycol Substances 0.000 description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- SYKWJOZHNDPWIM-SNAWJCMRSA-N [(e)-pent-1-enyl]boronic acid Chemical compound CCC\C=C\B(O)O SYKWJOZHNDPWIM-SNAWJCMRSA-N 0.000 description 3
- 239000013543 active substance Substances 0.000 description 3
- 125000001931 aliphatic group Chemical group 0.000 description 3
- 125000000129 anionic group Chemical group 0.000 description 3
- 238000003556 assay Methods 0.000 description 3
- 210000000988 bone and bone Anatomy 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- 125000002091 cationic group Chemical group 0.000 description 3
- 208000037887 cell injury Diseases 0.000 description 3
- KXZJHVJKXJLBKO-UHFFFAOYSA-N chembl1408157 Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=CC=1C1=CC=C(O)C=C1 KXZJHVJKXJLBKO-UHFFFAOYSA-N 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- 239000003995 emulsifying agent Substances 0.000 description 3
- 239000000839 emulsion Substances 0.000 description 3
- 210000002216 heart Anatomy 0.000 description 3
- 150000002430 hydrocarbons Chemical group 0.000 description 3
- 238000012606 in vitro cell culture Methods 0.000 description 3
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 3
- 108020004999 messenger RNA Proteins 0.000 description 3
- BXWNKGSJHAJOGX-UHFFFAOYSA-N n-hexadecyl alcohol Natural products CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 3
- 230000001537 neural effect Effects 0.000 description 3
- MWUXSHHQAYIFBG-UHFFFAOYSA-N nitrogen oxide Inorganic materials O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 3
- 239000002674 ointment Substances 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- PEGQOIGYZLJMIB-UHFFFAOYSA-N setogepram Chemical compound CCCCCC1=CC=CC(CC(O)=O)=C1 PEGQOIGYZLJMIB-UHFFFAOYSA-N 0.000 description 3
- 230000009759 skin aging Effects 0.000 description 3
- 239000002002 slurry Substances 0.000 description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 description 3
- 239000012312 sodium hydride Substances 0.000 description 3
- 229910000104 sodium hydride Inorganic materials 0.000 description 3
- 210000000952 spleen Anatomy 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 239000008096 xylene Substances 0.000 description 3
- DKHGNVSVCGHFDB-UHFFFAOYSA-N (2-fluoro-3,5-dipentylphenyl)methyl methanesulfonate Chemical compound CS(=O)(=O)OCC1=C(C(=CC(=C1)CCCCC)CCCCC)F DKHGNVSVCGHFDB-UHFFFAOYSA-N 0.000 description 2
- CCVYRRGZDBSHFU-UHFFFAOYSA-N (2-hydroxyphenyl)acetic acid Chemical compound OC(=O)CC1=CC=CC=C1O CCVYRRGZDBSHFU-UHFFFAOYSA-N 0.000 description 2
- FMCAFXHLMUOIGG-JTJHWIPRSA-N (2s)-2-[[(2r)-2-[[(2s)-2-[[(2r)-2-formamido-3-sulfanylpropanoyl]amino]-3-methylbutanoyl]amino]-3-(4-hydroxy-2,5-dimethylphenyl)propanoyl]amino]-4-methylsulfanylbutanoic acid Chemical compound O=CN[C@@H](CS)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(=O)N[C@@H](CCSC)C(O)=O)CC1=CC(C)=C(O)C=C1C FMCAFXHLMUOIGG-JTJHWIPRSA-N 0.000 description 2
- KQWBQTOZXPPFIY-UHFFFAOYSA-N (3-bromo-5-fluorophenyl)methanol Chemical compound OCC1=CC(F)=CC(Br)=C1 KQWBQTOZXPPFIY-UHFFFAOYSA-N 0.000 description 2
- SNKAWJBJQDLSFF-NVKMUCNASA-N 1,2-dioleoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/CCCCCCCC SNKAWJBJQDLSFF-NVKMUCNASA-N 0.000 description 2
- DAUWIPUGOIFZNF-UHFFFAOYSA-N 1-bromo-3-(bromomethyl)-5-fluorobenzene Chemical compound FC1=CC(Br)=CC(CBr)=C1 DAUWIPUGOIFZNF-UHFFFAOYSA-N 0.000 description 2
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 2
- LDGWQMRUWMSZIU-LQDDAWAPSA-M 2,3-bis[(z)-octadec-9-enoxy]propyl-trimethylazanium;chloride Chemical compound [Cl-].CCCCCCCC\C=C/CCCCCCCCOCC(C[N+](C)(C)C)OCCCCCCCC\C=C/CCCCCCCC LDGWQMRUWMSZIU-LQDDAWAPSA-M 0.000 description 2
- DBUQQJYXOUNYAT-UHFFFAOYSA-N 2-(2-benzyl-5-pentylphenyl)acetic acid Chemical compound C(C1=CC=CC=C1)C1=C(C=C(C=C1)CCCCC)CC(=O)O DBUQQJYXOUNYAT-UHFFFAOYSA-N 0.000 description 2
- OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 2
- FYDRDZZLDUQWAN-UHFFFAOYSA-N 2-(2-fluoro-3,5-dipentylphenyl)acetonitrile Chemical compound FC1=C(C=C(C=C1CCCCC)CCCCC)CC#N FYDRDZZLDUQWAN-UHFFFAOYSA-N 0.000 description 2
- PMAHTUAKLYOXGN-UHFFFAOYSA-N 2-(3,5-dibromo-2-hydroxyphenyl)acetic acid Chemical compound OC(=O)CC1=CC(Br)=CC(Br)=C1O PMAHTUAKLYOXGN-UHFFFAOYSA-N 0.000 description 2
- PZUUZXMFJVRIKM-UHFFFAOYSA-N 2-(3,5-dibromo-2-hydroxyphenyl)acetonitrile Chemical compound OC1=C(Br)C=C(Br)C=C1CC#N PZUUZXMFJVRIKM-UHFFFAOYSA-N 0.000 description 2
- WZHLZXHHXUHDDU-UHFFFAOYSA-N 2-(3,5-dibromo-4-hydroxyphenyl)acetic acid Chemical compound OC(=O)CC1=CC(Br)=C(O)C(Br)=C1 WZHLZXHHXUHDDU-UHFFFAOYSA-N 0.000 description 2
- UOOUQBZAJMGBNV-UHFFFAOYSA-N 2-(3-fluoro-5-pentylphenyl)acetic acid Chemical compound CCCCCC1=CC(F)=CC(CC(O)=O)=C1 UOOUQBZAJMGBNV-UHFFFAOYSA-N 0.000 description 2
- KMKJNRBXOKZAHT-UHFFFAOYSA-N 2-oxo-2-(3-pentylphenyl)acetic acid Chemical compound CCCCCC1=CC=CC(C(=O)C(O)=O)=C1 KMKJNRBXOKZAHT-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- QULYKKATZBMKKF-UHFFFAOYSA-N C(CCCC)C=1C=CC(=C(C=1)CC(=O)OC)OS(=O)(=O)C(F)(F)F Chemical compound C(CCCC)C=1C=CC(=C(C=1)CC(=O)OC)OS(=O)(=O)C(F)(F)F QULYKKATZBMKKF-UHFFFAOYSA-N 0.000 description 2
- DRSHXJFUUPIBHX-UHFFFAOYSA-N COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 Chemical compound COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 DRSHXJFUUPIBHX-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- 206010021245 Idiopathic thrombocytopenic purpura Diseases 0.000 description 2
- 208000022559 Inflammatory bowel disease Diseases 0.000 description 2
- 208000029549 Muscle injury Diseases 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 2
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 2
- 208000028389 Nerve injury Diseases 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- 239000004698 Polyethylene Substances 0.000 description 2
- 239000008156 Ringer's lactate solution Substances 0.000 description 2
- 229920002125 Sokalan® Polymers 0.000 description 2
- 208000031981 Thrombocytopenic Idiopathic Purpura Diseases 0.000 description 2
- DSNRWDQKZIEDDB-GCMPNPAFSA-N [(2r)-3-[2,3-dihydroxypropoxy(hydroxy)phosphoryl]oxy-2-[(z)-octadec-9-enoyl]oxypropyl] (z)-octadec-9-enoate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@H](COP(O)(=O)OCC(O)CO)OC(=O)CCCCCCC\C=C/CCCCCCCC DSNRWDQKZIEDDB-GCMPNPAFSA-N 0.000 description 2
- 238000005299 abrasion Methods 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 229940022663 acetate Drugs 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 239000008186 active pharmaceutical agent Substances 0.000 description 2
- 230000001154 acute effect Effects 0.000 description 2
- 230000032683 aging Effects 0.000 description 2
- 239000012298 atmosphere Substances 0.000 description 2
- 201000003710 autoimmune thrombocytopenic purpura Diseases 0.000 description 2
- QUKGYYKBILRGFE-UHFFFAOYSA-N benzyl acetate Chemical compound CC(=O)OCC1=CC=CC=C1 QUKGYYKBILRGFE-UHFFFAOYSA-N 0.000 description 2
- SESFRYSPDFLNCH-UHFFFAOYSA-N benzyl benzoate Chemical compound C=1C=CC=CC=1C(=O)OCC1=CC=CC=C1 SESFRYSPDFLNCH-UHFFFAOYSA-N 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 210000004204 blood vessel Anatomy 0.000 description 2
- 210000000481 breast Anatomy 0.000 description 2
- 239000012267 brine Substances 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 229960000541 cetyl alcohol Drugs 0.000 description 2
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- IWPBRSJMNUCZAJ-UHFFFAOYSA-N diethyl 2-(3-bromophenyl)-2-methylpropanedioate Chemical compound CCOC(=O)C(C)(C(=O)OCC)C1=CC=CC(Br)=C1 IWPBRSJMNUCZAJ-UHFFFAOYSA-N 0.000 description 2
- 230000001079 digestive effect Effects 0.000 description 2
- MWRBNPKJOOWZPW-CLFAGFIQSA-N dioleoyl phosphatidylethanolamine Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC(COP(O)(=O)OCCN)OC(=O)CCCCCCC\C=C/CCCCCCCC MWRBNPKJOOWZPW-CLFAGFIQSA-N 0.000 description 2
- 208000035475 disorder Diseases 0.000 description 2
- 239000002270 dispersing agent Substances 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 230000006353 environmental stress Effects 0.000 description 2
- 210000002919 epithelial cell Anatomy 0.000 description 2
- 210000002950 fibroblast Anatomy 0.000 description 2
- 238000003818 flash chromatography Methods 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- WVDDGKGOMKODPV-UHFFFAOYSA-N hydroxymethyl benzene Natural products OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 230000002757 inflammatory effect Effects 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 229940090044 injection Drugs 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000002198 insoluble material Substances 0.000 description 2
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 2
- 210000000936 intestine Anatomy 0.000 description 2
- 239000002085 irritant Substances 0.000 description 2
- 231100000021 irritant Toxicity 0.000 description 2
- 239000007951 isotonicity adjuster Substances 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 230000000670 limiting effect Effects 0.000 description 2
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 2
- 229920002521 macromolecule Polymers 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- 235000019341 magnesium sulphate Nutrition 0.000 description 2
- KFRPYXLEHUASEB-UHFFFAOYSA-N methyl 2-(2-hydroxy-3,5-dipentylphenyl)acetate Chemical compound CCCCCC1=CC(CCCCC)=C(O)C(CC(=O)OC)=C1 KFRPYXLEHUASEB-UHFFFAOYSA-N 0.000 description 2
- KVQQLVAXFDBSNO-UHFFFAOYSA-N methyl 2-(2-hydroxy-3-pentylphenyl)acetate Chemical compound CCCCCC1=CC=CC(CC(=O)OC)=C1O KVQQLVAXFDBSNO-UHFFFAOYSA-N 0.000 description 2
- GQTRQUTUAGDWDI-UHFFFAOYSA-N methyl 2-(2-pent-1-en-3-yloxyphenyl)acetate Chemical compound CCC(C=C)OC1=CC=CC=C1CC(=O)OC GQTRQUTUAGDWDI-UHFFFAOYSA-N 0.000 description 2
- XDOIIYQCWBRFOY-UHFFFAOYSA-N methyl 2-(3,5-dibromo-2-hydroxyphenyl)acetate Chemical compound COC(=O)CC1=CC(Br)=CC(Br)=C1O XDOIIYQCWBRFOY-UHFFFAOYSA-N 0.000 description 2
- XUQJUGORGAHUBL-UHFFFAOYSA-N methyl 2-(3-pentylphenyl)acetate Chemical compound CCCCCC1=CC=CC(CC(=O)OC)=C1 XUQJUGORGAHUBL-UHFFFAOYSA-N 0.000 description 2
- MNMDQOXBKNSROF-UHFFFAOYSA-N methyl 2-amino-3,5-dipentylbenzoate Chemical compound NC1=C(C(=O)OC)C=C(C=C1CCCCC)CCCCC MNMDQOXBKNSROF-UHFFFAOYSA-N 0.000 description 2
- JJQABIQQXVXZKF-UHFFFAOYSA-N methyl 2-fluoro-3,5-dipentylbenzoate Chemical compound FC1=C(C(=O)OC)C=C(C=C1CCCCC)CCCCC JJQABIQQXVXZKF-UHFFFAOYSA-N 0.000 description 2
- 229920000609 methyl cellulose Polymers 0.000 description 2
- 150000004702 methyl esters Chemical class 0.000 description 2
- 239000001923 methylcellulose Substances 0.000 description 2
- 235000010981 methylcellulose Nutrition 0.000 description 2
- 210000000214 mouth Anatomy 0.000 description 2
- 230000008764 nerve damage Effects 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 230000008816 organ damage Effects 0.000 description 2
- 230000005305 organ development Effects 0.000 description 2
- 230000002611 ovarian Effects 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- 238000007911 parenteral administration Methods 0.000 description 2
- 210000000578 peripheral nerve Anatomy 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 description 2
- SIOXPEMLGUPBBT-UHFFFAOYSA-N picolinic acid Chemical compound OC(=O)C1=CC=CC=N1 SIOXPEMLGUPBBT-UHFFFAOYSA-N 0.000 description 2
- 229920000573 polyethylene Polymers 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- 229920005862 polyol Polymers 0.000 description 2
- 150000003077 polyols Chemical class 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 230000002035 prolonged effect Effects 0.000 description 2
- 210000002307 prostate Anatomy 0.000 description 2
- 238000003753 real-time PCR Methods 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 230000001172 regenerating effect Effects 0.000 description 2
- 210000002345 respiratory system Anatomy 0.000 description 2
- 238000012552 review Methods 0.000 description 2
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 230000000638 stimulation Effects 0.000 description 2
- 239000000375 suspending agent Substances 0.000 description 2
- 238000013268 sustained release Methods 0.000 description 2
- 239000012730 sustained-release form Substances 0.000 description 2
- 201000000596 systemic lupus erythematosus Diseases 0.000 description 2
- HJUGFYREWKUQJT-UHFFFAOYSA-N tetrabromomethane Chemical compound BrC(Br)(Br)Br HJUGFYREWKUQJT-UHFFFAOYSA-N 0.000 description 2
- 231100000827 tissue damage Toxicity 0.000 description 2
- 230000000699 topical effect Effects 0.000 description 2
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- 235000015112 vegetable and seed oil Nutrition 0.000 description 2
- 239000008158 vegetable oil Substances 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- FMCAFXHLMUOIGG-IWFBPKFRSA-N (2s)-2-[[(2s)-2-[[(2s)-2-[[(2r)-2-formamido-3-sulfanylpropanoyl]amino]-3-methylbutanoyl]amino]-3-(4-hydroxy-2,5-dimethylphenyl)propanoyl]amino]-4-methylsulfanylbutanoic acid Chemical compound O=CN[C@@H](CS)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(=O)N[C@@H](CCSC)C(O)=O)CC1=CC(C)=C(O)C=C1C FMCAFXHLMUOIGG-IWFBPKFRSA-N 0.000 description 1
- KAKVFSYQVNHFBS-UHFFFAOYSA-N (5-hydroxycyclopenten-1-yl)-phenylmethanone Chemical compound OC1CCC=C1C(=O)C1=CC=CC=C1 KAKVFSYQVNHFBS-UHFFFAOYSA-N 0.000 description 1
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 1
- SRXPLJYKMAEZKI-UHFFFAOYSA-N 1,3-dibromo-2-fluoro-5-methylbenzene Chemical compound CC1=CC(Br)=C(F)C(Br)=C1 SRXPLJYKMAEZKI-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- VHVMXWZXFBOANQ-UHFFFAOYSA-N 1-Penten-3-ol Chemical compound CCC(O)C=C VHVMXWZXFBOANQ-UHFFFAOYSA-N 0.000 description 1
- CTPUUDQIXKUAMO-UHFFFAOYSA-N 1-bromo-3-iodobenzene Chemical compound BrC1=CC=CC(I)=C1 CTPUUDQIXKUAMO-UHFFFAOYSA-N 0.000 description 1
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 1
- FDLFMPKQBNPIER-UHFFFAOYSA-N 1-methyl-3-(3-methylphenoxy)benzene Chemical compound CC1=CC=CC(OC=2C=C(C)C=CC=2)=C1 FDLFMPKQBNPIER-UHFFFAOYSA-N 0.000 description 1
- IBXNCJKFFQIKKY-UHFFFAOYSA-N 1-pentyne Chemical compound CCCC#C IBXNCJKFFQIKKY-UHFFFAOYSA-N 0.000 description 1
- SMWFVJSDGOWFBM-UHFFFAOYSA-N 18-hydroxyoctadecyl hydrogen sulfate Chemical compound OCCCCCCCCCCCCCCCCCCOS(O)(=O)=O SMWFVJSDGOWFBM-UHFFFAOYSA-N 0.000 description 1
- LTMRRSWNXVJMBA-UHFFFAOYSA-L 2,2-diethylpropanedioate Chemical compound CCC(CC)(C([O-])=O)C([O-])=O LTMRRSWNXVJMBA-UHFFFAOYSA-L 0.000 description 1
- ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 2,3-dimethylbutane Chemical group CC(C)C(C)C ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 0.000 description 1
- OUCUYVFUWKNILM-IPZCTEOASA-N 2,3-dimethylbutane-2,3-diol;[(e)-hex-1-enyl]boronic acid Chemical compound CC(C)(O)C(C)(C)O.CCCC\C=C\B(O)O OUCUYVFUWKNILM-IPZCTEOASA-N 0.000 description 1
- SPUZPJKEJXIRSF-UHFFFAOYSA-N 2,4-dibromo-6-(bromomethyl)phenol Chemical compound OC1=C(Br)C=C(Br)C=C1CBr SPUZPJKEJXIRSF-UHFFFAOYSA-N 0.000 description 1
- XWKXEBCVMWOIQP-UHFFFAOYSA-N 2-(2-benzyl-3,5-dipentylphenyl)acetic acid Chemical compound C(C1=CC=CC=C1)C1=C(C=C(C=C1CCCCC)CCCCC)CC(=O)O XWKXEBCVMWOIQP-UHFFFAOYSA-N 0.000 description 1
- UVLYZXAZFBJMQP-UHFFFAOYSA-N 2-(2-fluoro-3-pentylphenyl)acetic acid Chemical compound CCCCCC1=CC=CC(CC(O)=O)=C1F UVLYZXAZFBJMQP-UHFFFAOYSA-N 0.000 description 1
- CGMDQKKIJZHZGH-UHFFFAOYSA-M 2-(2-hydroxy-3-pentylphenyl)acetate Chemical compound CCCCCC1=CC=CC(CC([O-])=O)=C1O CGMDQKKIJZHZGH-UHFFFAOYSA-M 0.000 description 1
- MPJBVCSKJFHRMK-UHFFFAOYSA-N 2-(2-hydroxy-5-pentylphenyl)acetic acid Chemical compound CCCCCC1=CC=C(O)C(CC(O)=O)=C1 MPJBVCSKJFHRMK-UHFFFAOYSA-N 0.000 description 1
- MXEUSWZBXYCKCM-UHFFFAOYSA-N 2-(3,5-dihexyl-2-hydroxyphenyl)acetic acid Chemical compound CCCCCCC1=CC(CCCCCC)=C(O)C(CC(O)=O)=C1 MXEUSWZBXYCKCM-UHFFFAOYSA-N 0.000 description 1
- XSWUWPVGSZQANY-UHFFFAOYSA-N 2-(3,5-dihexyl-4-hydroxyphenyl)acetic acid Chemical compound CCCCCCC1=CC(CC(O)=O)=CC(CCCCCC)=C1O XSWUWPVGSZQANY-UHFFFAOYSA-N 0.000 description 1
- ZKRZLLWCJPYOCK-UHFFFAOYSA-N 2-(3,5-dihexylphenyl)acetic acid Chemical compound CCCCCCC1=CC(CCCCCC)=CC(CC(O)=O)=C1 ZKRZLLWCJPYOCK-UHFFFAOYSA-N 0.000 description 1
- XBCZJMLISJZMEK-UHFFFAOYSA-N 2-(3,5-dipentylphenyl)-2-methylpropanoic acid Chemical compound C(CCCC)C=1C=C(C=C(C=1)CCCCC)C(C(=O)O)(C)C XBCZJMLISJZMEK-UHFFFAOYSA-N 0.000 description 1
- XXFGIJYSXNXNAU-UHFFFAOYSA-N 2-(3-bromo-4-fluorophenyl)acetic acid Chemical compound OC(=O)CC1=CC=C(F)C(Br)=C1 XXFGIJYSXNXNAU-UHFFFAOYSA-N 0.000 description 1
- KYNNBXCGXUOREX-UHFFFAOYSA-N 2-(3-bromophenyl)acetic acid Chemical compound OC(=O)CC1=CC=CC(Br)=C1 KYNNBXCGXUOREX-UHFFFAOYSA-N 0.000 description 1
- XQMHGFVMOHMVSU-UHFFFAOYSA-N 2-(3-hexylphenyl)acetic acid Chemical compound CCCCCCC1=CC=CC(CC(O)=O)=C1 XQMHGFVMOHMVSU-UHFFFAOYSA-N 0.000 description 1
- CGIVCQYEGSEUEH-UHFFFAOYSA-N 2-(3-hydroxy-5-pentylphenyl)acetic acid Chemical compound CCCCCC1=CC(O)=CC(CC(O)=O)=C1 CGIVCQYEGSEUEH-UHFFFAOYSA-N 0.000 description 1
- OLKONWWYPKOGQO-UHFFFAOYSA-N 2-(4-fluoro-3,5-dihexylphenyl)acetic acid Chemical compound CCCCCCC1=CC(CC(O)=O)=CC(CCCCCC)=C1F OLKONWWYPKOGQO-UHFFFAOYSA-N 0.000 description 1
- YLZCRHXGJUPONH-UHFFFAOYSA-N 2-(4-fluoro-3,5-dipentylphenyl)acetic acid Chemical compound CCCCCC1=CC(CC(O)=O)=CC(CCCCC)=C1F YLZCRHXGJUPONH-UHFFFAOYSA-N 0.000 description 1
- OUSRCJYVHBEUDU-UHFFFAOYSA-N 2-(4-fluoro-3-pentylphenyl)acetic acid Chemical compound CCCCCC1=CC(CC(O)=O)=CC=C1F OUSRCJYVHBEUDU-UHFFFAOYSA-N 0.000 description 1
- FOIZRLGQKPGLNB-UHFFFAOYSA-N 2-(4-hydroxy-3,5-dipentylphenyl)acetic acid Chemical compound CCCCCC1=CC(CC(O)=O)=CC(CCCCC)=C1O FOIZRLGQKPGLNB-UHFFFAOYSA-N 0.000 description 1
- MOVTZAQTBFNXKK-UHFFFAOYSA-N 2-(4-hydroxy-3-pentylphenyl)acetic acid Chemical compound CCCCCC1=CC(CC(O)=O)=CC=C1O MOVTZAQTBFNXKK-UHFFFAOYSA-N 0.000 description 1
- SKGHTMGJWQZJEI-UHFFFAOYSA-N 2-(5-bromo-2-hydroxyphenyl)acetic acid Chemical compound OC(=O)CC1=CC(Br)=CC=C1O SKGHTMGJWQZJEI-UHFFFAOYSA-N 0.000 description 1
- OBTZDIRUQWFRFZ-UHFFFAOYSA-N 2-(5-methylfuran-2-yl)-n-(4-methylphenyl)quinoline-4-carboxamide Chemical compound O1C(C)=CC=C1C1=CC(C(=O)NC=2C=CC(C)=CC=2)=C(C=CC=C2)C2=N1 OBTZDIRUQWFRFZ-UHFFFAOYSA-N 0.000 description 1
- PFZQMBOZQBXZBT-WGDLNXRISA-N 2-[3,5-bis[(E)-hex-1-enyl]phenyl]acetic acid Chemical compound C(=C\CCCC)/C=1C=C(C=C(C=1)\C=C\CCCC)CC(=O)O PFZQMBOZQBXZBT-WGDLNXRISA-N 0.000 description 1
- APINNHOSONNDKI-GQCTYLIASA-N 2-[3-[(e)-pent-1-enyl]phenyl]acetic acid Chemical compound CCC\C=C\C1=CC=CC(CC(O)=O)=C1 APINNHOSONNDKI-GQCTYLIASA-N 0.000 description 1
- DRXCEHHRSZTPRP-UHFFFAOYSA-N 2-fluoro-2-(3-pentylphenyl)acetic acid Chemical compound CCCCCC1=CC=CC(C(F)C(O)=O)=C1 DRXCEHHRSZTPRP-UHFFFAOYSA-N 0.000 description 1
- DRQYCDXCZZRBJW-UHFFFAOYSA-N 2-methyl-2-(3-pentylphenyl)propanoic acid Chemical compound CCCCCC1=CC=CC(C(C)(C)C(O)=O)=C1 DRQYCDXCZZRBJW-UHFFFAOYSA-N 0.000 description 1
- CXIISRLRZRAKST-UHFFFAOYSA-N 29‐(4‐nonylphenoxy)‐3,6,9,12,15,18,21,24,27‐ nonaoxanonacosan‐1‐ol Chemical compound CCCCCCCCCC1=CC=C(OCCOCCOCCOCCOCCOCCOCCOCCOCCOCCO)C=C1 CXIISRLRZRAKST-UHFFFAOYSA-N 0.000 description 1
- AMKWPMUHANVQSZ-UHFFFAOYSA-N 3-(3,5-dibromophenyl)propanoic acid Chemical compound OC(=O)CCC1=CC(Br)=CC(Br)=C1 AMKWPMUHANVQSZ-UHFFFAOYSA-N 0.000 description 1
- CBEDYSJCQAVZKP-UHFFFAOYSA-N 3-(3-butylphenyl)propanoic acid Chemical compound CCCCC1=CC=CC(CCC(O)=O)=C1 CBEDYSJCQAVZKP-UHFFFAOYSA-N 0.000 description 1
- LHGCGRRANBCAOL-UHFFFAOYSA-N 3-(3-pentylphenyl)propanoic acid Chemical compound CCCCCC1=CC=CC(CCC(O)=O)=C1 LHGCGRRANBCAOL-UHFFFAOYSA-N 0.000 description 1
- UVKURTLVTLRSSM-UHFFFAOYSA-N 3-bromo-2-fluorobenzoic acid Chemical compound OC(=O)C1=CC=CC(Br)=C1F UVKURTLVTLRSSM-UHFFFAOYSA-N 0.000 description 1
- KLSLJMGWUPAQGZ-UHFFFAOYSA-N 3-bromo-5-fluorobenzoic acid Chemical compound OC(=O)C1=CC(F)=CC(Br)=C1 KLSLJMGWUPAQGZ-UHFFFAOYSA-N 0.000 description 1
- HIQIXEFWDLTDED-UHFFFAOYSA-N 4-hydroxy-1-piperidin-4-ylpyrrolidin-2-one Chemical compound O=C1CC(O)CN1C1CCNCC1 HIQIXEFWDLTDED-UHFFFAOYSA-N 0.000 description 1
- IQRBNRFCRAJXJF-UHFFFAOYSA-N 9-benzyl-9-borabicyclo[3.3.1]nonane Chemical compound C1CCC2CCCC1B2CC1=CC=CC=C1 IQRBNRFCRAJXJF-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- 102100022712 Alpha-1-antitrypsin Human genes 0.000 description 1
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 description 1
- 229910000013 Ammonium bicarbonate Inorganic materials 0.000 description 1
- 206010002556 Ankylosing Spondylitis Diseases 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 206010007710 Cartilage injury Diseases 0.000 description 1
- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 1
- 208000011231 Crohn disease Diseases 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 102000016911 Deoxyribonucleases Human genes 0.000 description 1
- 108010053770 Deoxyribonucleases Proteins 0.000 description 1
- 201000004624 Dermatitis Diseases 0.000 description 1
- 206010013786 Dry skin Diseases 0.000 description 1
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- 108700039887 Essential Genes Proteins 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 206010016654 Fibrosis Diseases 0.000 description 1
- 206010018364 Glomerulonephritis Diseases 0.000 description 1
- 102100031181 Glyceraldehyde-3-phosphate dehydrogenase Human genes 0.000 description 1
- JZNWSCPGTDBMEW-UHFFFAOYSA-N Glycerophosphorylethanolamin Natural products NCCOP(O)(=O)OCC(O)CO JZNWSCPGTDBMEW-UHFFFAOYSA-N 0.000 description 1
- 206010072579 Granulomatosis with polyangiitis Diseases 0.000 description 1
- 101150022655 HGF gene Proteins 0.000 description 1
- 208000032672 Histiocytosis haematophagic Diseases 0.000 description 1
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 1
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 102100023915 Insulin Human genes 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- 206010059176 Juvenile idiopathic arthritis Diseases 0.000 description 1
- 239000004166 Lanolin Substances 0.000 description 1
- 208000004987 Macrophage activation syndrome Diseases 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 1
- 206010050031 Muscle strain Diseases 0.000 description 1
- 201000002481 Myositis Diseases 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 239000004677 Nylon Substances 0.000 description 1
- FJPJPAYHDKVQLI-RCKHEGBHSA-N OC(C)(C)C(C)(C)O.C(=C\CCC)/B(O)O Chemical compound OC(C)(C)C(C)(C)O.C(=C\CCC)/B(O)O FJPJPAYHDKVQLI-RCKHEGBHSA-N 0.000 description 1
- 101150108126 PLAU gene Proteins 0.000 description 1
- 101150003085 Pdcl gene Proteins 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 208000010886 Peripheral nerve injury Diseases 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 239000004372 Polyvinyl alcohol Substances 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- 201000001263 Psoriatic Arthritis Diseases 0.000 description 1
- 208000036824 Psoriatic arthropathy Diseases 0.000 description 1
- 238000002123 RNA extraction Methods 0.000 description 1
- 208000033464 Reiter syndrome Diseases 0.000 description 1
- 206010039710 Scleroderma Diseases 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 238000003477 Sonogashira cross-coupling reaction Methods 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 206010042496 Sunburn Diseases 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 102000046299 Transforming Growth Factor beta1 Human genes 0.000 description 1
- 101800002279 Transforming growth factor beta-1 Proteins 0.000 description 1
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 1
- 206010046851 Uveitis Diseases 0.000 description 1
- 206010047115 Vasculitis Diseases 0.000 description 1
- HJHITTCYGWZKHG-JXMROGBWSA-N [(e)-pent-1-enyl] benzoate Chemical compound CCC\C=C\OC(=O)C1=CC=CC=C1 HJHITTCYGWZKHG-JXMROGBWSA-N 0.000 description 1
- 239000002250 absorbent Substances 0.000 description 1
- 230000002745 absorbent Effects 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- CSCPPACGZOOCGX-WFGJKAKNSA-N acetone d6 Chemical compound [2H]C([2H])([2H])C(=O)C([2H])([2H])[2H] CSCPPACGZOOCGX-WFGJKAKNSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000012042 active reagent Substances 0.000 description 1
- 231100000569 acute exposure Toxicity 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 230000002152 alkylating effect Effects 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 108010050122 alpha 1-Antitrypsin Proteins 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 235000012538 ammonium bicarbonate Nutrition 0.000 description 1
- 239000001099 ammonium carbonate Substances 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 1
- 239000002280 amphoteric surfactant Substances 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000019552 anatomical structure morphogenesis Effects 0.000 description 1
- 229940031955 anhydrous lanolin Drugs 0.000 description 1
- 239000003945 anionic surfactant Substances 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000001166 anti-perspirative effect Effects 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 239000003213 antiperspirant Substances 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 230000009118 appropriate response Effects 0.000 description 1
- 239000008135 aqueous vehicle Substances 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- 150000001499 aryl bromides Chemical class 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 239000000305 astragalus gummifer gum Substances 0.000 description 1
- 238000011914 asymmetric synthesis Methods 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- 230000003376 axonal effect Effects 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 150000007962 benzene acetonitriles Chemical class 0.000 description 1
- IZALUMVGBVKPJD-UHFFFAOYSA-N benzene-1,3-dicarbaldehyde Chemical compound O=CC1=CC=CC(C=O)=C1 IZALUMVGBVKPJD-UHFFFAOYSA-N 0.000 description 1
- 229940007550 benzyl acetate Drugs 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- 229960002903 benzyl benzoate Drugs 0.000 description 1
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 1
- 229920000249 biocompatible polymer Polymers 0.000 description 1
- 210000005068 bladder tissue Anatomy 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 230000010072 bone remodeling Effects 0.000 description 1
- UWTDFICHZKXYAC-UHFFFAOYSA-N boron;oxolane Chemical compound [B].C1CCOC1 UWTDFICHZKXYAC-UHFFFAOYSA-N 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 238000010804 cDNA synthesis Methods 0.000 description 1
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- BPKIGYQJPYCAOW-FFJTTWKXSA-I calcium;potassium;disodium;(2s)-2-hydroxypropanoate;dichloride;dihydroxide;hydrate Chemical compound O.[OH-].[OH-].[Na+].[Na+].[Cl-].[Cl-].[K+].[Ca+2].C[C@H](O)C([O-])=O BPKIGYQJPYCAOW-FFJTTWKXSA-I 0.000 description 1
- BMLSTPRTEKLIPM-UHFFFAOYSA-I calcium;potassium;disodium;hydrogen carbonate;dichloride;dihydroxide;hydrate Chemical compound O.[OH-].[OH-].[Na+].[Na+].[Cl-].[Cl-].[K+].[Ca+2].OC([O-])=O BMLSTPRTEKLIPM-UHFFFAOYSA-I 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 229960001631 carbomer Drugs 0.000 description 1
- 235000011089 carbon dioxide Nutrition 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical group 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000003093 cationic surfactant Substances 0.000 description 1
- 230000010094 cellular senescence Effects 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 239000013043 chemical agent Substances 0.000 description 1
- 150000005829 chemical entities Chemical class 0.000 description 1
- 239000012069 chiral reagent Substances 0.000 description 1
- 229960004926 chlorobutanol Drugs 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 238000004040 coloring Methods 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 1
- 239000002285 corn oil Substances 0.000 description 1
- 235000005687 corn oil Nutrition 0.000 description 1
- 235000012343 cottonseed oil Nutrition 0.000 description 1
- 239000002385 cottonseed oil Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000005520 cutting process Methods 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 238000007405 data analysis Methods 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- PLMFYJJFUUUCRZ-UHFFFAOYSA-M decyltrimethylammonium bromide Chemical compound [Br-].CCCCCCCCCC[N+](C)(C)C PLMFYJJFUUUCRZ-UHFFFAOYSA-M 0.000 description 1
- 230000001934 delay Effects 0.000 description 1
- 230000002939 deleterious effect Effects 0.000 description 1
- 238000004925 denaturation Methods 0.000 description 1
- 230000036425 denaturation Effects 0.000 description 1
- 239000002781 deodorant agent Substances 0.000 description 1
- 230000002951 depilatory effect Effects 0.000 description 1
- 239000008356 dextrose and sodium chloride injection Substances 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- UGMCXQCYOVCMTB-UHFFFAOYSA-K dihydroxy(stearato)aluminium Chemical compound CCCCCCCCCCCCCCCCCC(=O)O[Al](O)O UGMCXQCYOVCMTB-UHFFFAOYSA-K 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 239000002612 dispersion medium Substances 0.000 description 1
- TWFQJFPTTMIETC-UHFFFAOYSA-N dodecan-1-amine;hydron;chloride Chemical compound [Cl-].CCCCCCCCCCCC[NH3+] TWFQJFPTTMIETC-UHFFFAOYSA-N 0.000 description 1
- XJWSAJYUBXQQDR-UHFFFAOYSA-M dodecyltrimethylammonium bromide Chemical compound [Br-].CCCCCCCCCCCC[N+](C)(C)C XJWSAJYUBXQQDR-UHFFFAOYSA-M 0.000 description 1
- 239000006196 drop Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000000890 drug combination Substances 0.000 description 1
- 230000037336 dry skin Effects 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 230000002500 effect on skin Effects 0.000 description 1
- 239000008393 encapsulating agent Substances 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 239000003344 environmental pollutant Substances 0.000 description 1
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 1
- CAERSDJFKGMKLY-UHFFFAOYSA-N ethyl 2-(3-bromophenyl)acetate Chemical compound CCOC(=O)CC1=CC=CC(Br)=C1 CAERSDJFKGMKLY-UHFFFAOYSA-N 0.000 description 1
- ILFCNHNHURVLGC-UHFFFAOYSA-N ethyl 2-(3-pent-1-ynylphenyl)acetate Chemical compound CCCC#CC1=CC=CC(CC(=O)OCC)=C1 ILFCNHNHURVLGC-UHFFFAOYSA-N 0.000 description 1
- BHDCDLFTKBHSHR-UHFFFAOYSA-N ethyl 2-(3-pentylphenyl)acetate Chemical compound CCCCCC1=CC=CC(CC(=O)OCC)=C1 BHDCDLFTKBHSHR-UHFFFAOYSA-N 0.000 description 1
- RDPCREHDURVCFH-UHFFFAOYSA-N ethyl 2-fluoro-2-(3-pentylphenyl)acetate Chemical compound CCCCCC1=CC=CC(C(F)C(=O)OCC)=C1 RDPCREHDURVCFH-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 1
- 229940093471 ethyl oleate Drugs 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 238000004299 exfoliation Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000003925 fat Substances 0.000 description 1
- 150000002191 fatty alcohols Chemical class 0.000 description 1
- 230000004761 fibrosis Effects 0.000 description 1
- 230000003176 fibrotic effect Effects 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 235000019264 food flavour enhancer Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 210000000232 gallbladder Anatomy 0.000 description 1
- 238000001030 gas--liquid chromatography Methods 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 239000003349 gelling agent Substances 0.000 description 1
- 238000001415 gene therapy Methods 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 229940093181 glucose injection Drugs 0.000 description 1
- 108020004445 glyceraldehyde-3-phosphate dehydrogenase Proteins 0.000 description 1
- 229940075507 glyceryl monostearate Drugs 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 239000008266 hair spray Substances 0.000 description 1
- 239000008240 homogeneous mixture Substances 0.000 description 1
- 239000003906 humectant Substances 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 229920001477 hydrophilic polymer Polymers 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 229920003132 hydroxypropyl methylcellulose phthalate Polymers 0.000 description 1
- 229940031704 hydroxypropyl methylcellulose phthalate Drugs 0.000 description 1
- 150000003949 imides Chemical class 0.000 description 1
- 230000003116 impacting effect Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 239000012678 infectious agent Substances 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000003999 initiator Substances 0.000 description 1
- 239000007972 injectable composition Substances 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 229940074928 isopropyl myristate Drugs 0.000 description 1
- 201000002215 juvenile rheumatoid arthritis Diseases 0.000 description 1
- 210000002510 keratinocyte Anatomy 0.000 description 1
- 125000000468 ketone group Chemical group 0.000 description 1
- 229940039717 lanolin Drugs 0.000 description 1
- 235000019388 lanolin Nutrition 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 210000003041 ligament Anatomy 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 239000012669 liquid formulation Substances 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 229910003002 lithium salt Inorganic materials 0.000 description 1
- 159000000002 lithium salts Chemical class 0.000 description 1
- 210000005228 liver tissue Anatomy 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- GCXBCPZHYKTEHI-UHFFFAOYSA-N methyl (2E)-2-diazo-2-(3-pentylphenyl)acetate Chemical compound [N+](=[N-])=C(C(=O)OC)C1=CC(=CC=C1)CCCCC GCXBCPZHYKTEHI-UHFFFAOYSA-N 0.000 description 1
- AGJSNMGHAVDLRQ-HUUJSLGLSA-N methyl (2s)-2-[[(2r)-2-[[(2s)-2-[[(2r)-2-amino-3-sulfanylpropanoyl]amino]-3-methylbutanoyl]amino]-3-(4-hydroxy-2,3-dimethylphenyl)propanoyl]amino]-4-methylsulfanylbutanoate Chemical compound SC[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(=O)N[C@@H](CCSC)C(=O)OC)CC1=CC=C(O)C(C)=C1C AGJSNMGHAVDLRQ-HUUJSLGLSA-N 0.000 description 1
- PURZNDMCBOHOBG-UHFFFAOYSA-N methyl 2-(3,5-dibromo-2-phenylmethoxyphenyl)acetate Chemical compound COC(=O)CC1=CC(Br)=CC(Br)=C1OCC1=CC=CC=C1 PURZNDMCBOHOBG-UHFFFAOYSA-N 0.000 description 1
- OZMVMMGUHPFAND-UHFFFAOYSA-N methyl 2-(3-bromo-4-fluorophenyl)acetate Chemical compound COC(=O)CC1=CC=C(F)C(Br)=C1 OZMVMMGUHPFAND-UHFFFAOYSA-N 0.000 description 1
- ONQUOYZYFBDHIJ-UHFFFAOYSA-N methyl 2-(5-bromo-2-phenylmethoxyphenyl)acetate Chemical compound COC(=O)CC1=CC(Br)=CC=C1OCC1=CC=CC=C1 ONQUOYZYFBDHIJ-UHFFFAOYSA-N 0.000 description 1
- NTNUDYROPUKXNA-UHFFFAOYSA-N methyl 2-(triphenyl-$l^{5}-phosphanylidene)acetate Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)(=CC(=O)OC)C1=CC=CC=C1 NTNUDYROPUKXNA-UHFFFAOYSA-N 0.000 description 1
- UECYGKYEZZZRIJ-SNAWJCMRSA-N methyl 2-[2-hydroxy-3-[(e)-pent-2-enyl]phenyl]acetate Chemical compound CC\C=C\CC1=CC=CC(CC(=O)OC)=C1O UECYGKYEZZZRIJ-SNAWJCMRSA-N 0.000 description 1
- NGXVMFCGYYHEGC-UHFFFAOYSA-N methyl 2-amino-3,5-dibromobenzoate Chemical compound COC(=O)C1=CC(Br)=CC(Br)=C1N NGXVMFCGYYHEGC-UHFFFAOYSA-N 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000003020 moisturizing effect Effects 0.000 description 1
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- 210000002200 mouth mucosa Anatomy 0.000 description 1
- 210000004877 mucosa Anatomy 0.000 description 1
- 201000006417 multiple sclerosis Diseases 0.000 description 1
- NTMHWRHEGDRTPD-UHFFFAOYSA-N n-(4-azidosulfonylphenyl)acetamide Chemical compound CC(=O)NC1=CC=C(S(=O)(=O)N=[N+]=[N-])C=C1 NTMHWRHEGDRTPD-UHFFFAOYSA-N 0.000 description 1
- GOQYKNQRPGWPLP-UHFFFAOYSA-N n-heptadecyl alcohol Natural products CCCCCCCCCCCCCCCCCO GOQYKNQRPGWPLP-UHFFFAOYSA-N 0.000 description 1
- 210000002850 nasal mucosa Anatomy 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 230000004766 neurogenesis Effects 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 231100000344 non-irritating Toxicity 0.000 description 1
- 239000002687 nonaqueous vehicle Substances 0.000 description 1
- 239000002736 nonionic surfactant Substances 0.000 description 1
- 229940073555 nonoxynol-10 Drugs 0.000 description 1
- 229940073554 nonoxynol-30 Drugs 0.000 description 1
- 238000010606 normalization Methods 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 229920001778 nylon Polymers 0.000 description 1
- 239000007764 o/w emulsion Substances 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- LXNAVEXFUKBNMK-UHFFFAOYSA-N palladium(II) acetate Substances [Pd].CC(O)=O.CC(O)=O LXNAVEXFUKBNMK-UHFFFAOYSA-N 0.000 description 1
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 1
- 125000000913 palmityl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 210000004923 pancreatic tissue Anatomy 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 230000003239 periodontal effect Effects 0.000 description 1
- 210000001428 peripheral nervous system Anatomy 0.000 description 1
- 208000033808 peripheral neuropathy Diseases 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000003209 petroleum derivative Substances 0.000 description 1
- 229960003742 phenol Drugs 0.000 description 1
- WTJKGGKOPKCXLL-RRHRGVEJSA-N phosphatidylcholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCC=CCCCCCCCC WTJKGGKOPKCXLL-RRHRGVEJSA-N 0.000 description 1
- 150000008104 phosphatidylethanolamines Chemical class 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- XYFCBTPGUUZFHI-UHFFFAOYSA-O phosphonium Chemical compound [PH4+] XYFCBTPGUUZFHI-UHFFFAOYSA-O 0.000 description 1
- 231100000719 pollutant Toxicity 0.000 description 1
- 229920000058 polyacrylate Polymers 0.000 description 1
- 229920000098 polyolefin Polymers 0.000 description 1
- 229920002503 polyoxyethylene-polyoxypropylene Polymers 0.000 description 1
- 229920001451 polypropylene glycol Polymers 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- LJCNRYVRMXRIQR-OLXYHTOASA-L potassium sodium L-tartrate Chemical compound [Na+].[K+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O LJCNRYVRMXRIQR-OLXYHTOASA-L 0.000 description 1
- 229940074439 potassium sodium tartrate Drugs 0.000 description 1
- HDMGAZBPFLDBCX-UHFFFAOYSA-M potassium;sulfooxy sulfate Chemical compound [K+].OS(=O)(=O)OOS([O-])(=O)=O HDMGAZBPFLDBCX-UHFFFAOYSA-M 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 210000005234 proximal tubule cell Anatomy 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 208000002574 reactive arthritis Diseases 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 210000005084 renal tissue Anatomy 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000004007 reversed phase HPLC Methods 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 239000008299 semisolid dosage form Substances 0.000 description 1
- 230000037307 sensitive skin Effects 0.000 description 1
- 230000001235 sensitizing effect Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 239000002453 shampoo Substances 0.000 description 1
- 230000035939 shock Effects 0.000 description 1
- 210000001626 skin fibroblast Anatomy 0.000 description 1
- 230000000391 smoking effect Effects 0.000 description 1
- 239000000344 soap Substances 0.000 description 1
- QWIJVXQSVJUYSO-UHFFFAOYSA-M sodium 2-(2-fluoro-3,5-dipentylphenyl)acetate Chemical compound FC1=C(C=C(C=C1CCCCC)CCCCC)CC(=O)[O-].[Na+] QWIJVXQSVJUYSO-UHFFFAOYSA-M 0.000 description 1
- RHVBEXZEZHFKLE-UHFFFAOYSA-M sodium 2-(2-hydroxy-3,5-dipentylphenyl)acetate Chemical compound [Na+].CCCCCC1=CC(CCCCC)=C(O)C(CC([O-])=O)=C1 RHVBEXZEZHFKLE-UHFFFAOYSA-M 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000008354 sodium chloride injection Substances 0.000 description 1
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- 235000011006 sodium potassium tartrate Nutrition 0.000 description 1
- 239000004324 sodium propionate Substances 0.000 description 1
- JXKPEJDQGNYQSM-UHFFFAOYSA-M sodium propionate Chemical compound [Na+].CCC([O-])=O JXKPEJDQGNYQSM-UHFFFAOYSA-M 0.000 description 1
- 235000010334 sodium propionate Nutrition 0.000 description 1
- 229960003212 sodium propionate Drugs 0.000 description 1
- QBAPYNYWZFKXQY-UHFFFAOYSA-M sodium;2-oxo-2-(3-pentylphenyl)acetate Chemical compound [Na+].CCCCCC1=CC=CC(C(=O)C([O-])=O)=C1 QBAPYNYWZFKXQY-UHFFFAOYSA-M 0.000 description 1
- AIMUHNZKNFEZSN-UHFFFAOYSA-M sodium;decane-1-sulfonate Chemical compound [Na+].CCCCCCCCCCS([O-])(=O)=O AIMUHNZKNFEZSN-UHFFFAOYSA-M 0.000 description 1
- DAJSVUQLFFJUSX-UHFFFAOYSA-M sodium;dodecane-1-sulfonate Chemical compound [Na+].CCCCCCCCCCCCS([O-])(=O)=O DAJSVUQLFFJUSX-UHFFFAOYSA-M 0.000 description 1
- HRQDCDQDOPSGBR-UHFFFAOYSA-M sodium;octane-1-sulfonate Chemical compound [Na+].CCCCCCCCS([O-])(=O)=O HRQDCDQDOPSGBR-UHFFFAOYSA-M 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- VNFWTIYUKDMAOP-UHFFFAOYSA-N sphos Chemical group COC1=CC=CC(OC)=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 VNFWTIYUKDMAOP-UHFFFAOYSA-N 0.000 description 1
- 210000000278 spinal cord Anatomy 0.000 description 1
- 208000020431 spinal cord injury Diseases 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 229960004274 stearic acid Drugs 0.000 description 1
- 210000000434 stratum corneum Anatomy 0.000 description 1
- 230000035882 stress Effects 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 230000000475 sunscreen effect Effects 0.000 description 1
- 239000000516 sunscreening agent Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 210000002435 tendon Anatomy 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- UQCWXKSHRQJGPH-UHFFFAOYSA-M tetrabutylazanium;fluoride;hydrate Chemical compound O.[F-].CCCC[N+](CCCC)(CCCC)CCCC UQCWXKSHRQJGPH-UHFFFAOYSA-M 0.000 description 1
- 150000003536 tetrazoles Chemical group 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
- 229940033663 thimerosal Drugs 0.000 description 1
- 208000037816 tissue injury Diseases 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 239000012049 topical pharmaceutical composition Substances 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical class OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- CEYYIKYYFSTQRU-UHFFFAOYSA-M trimethyl(tetradecyl)azanium;chloride Chemical compound [Cl-].CCCCCCCCCCCCCC[N+](C)(C)C CEYYIKYYFSTQRU-UHFFFAOYSA-M 0.000 description 1
- XMQSELBBYSAURN-UHFFFAOYSA-M triphenyl(propyl)phosphanium;bromide Chemical compound [Br-].C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(CCC)C1=CC=CC=C1 XMQSELBBYSAURN-UHFFFAOYSA-M 0.000 description 1
- 229910000404 tripotassium phosphate Inorganic materials 0.000 description 1
- 235000019798 tripotassium phosphate Nutrition 0.000 description 1
- 210000004926 tubular epithelial cell Anatomy 0.000 description 1
- 239000007762 w/o emulsion Substances 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 239000008136 water-miscible vehicle Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
- 235000010493 xanthan gum Nutrition 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- 229940082509 xanthan gum Drugs 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
-
- 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
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/19—Cosmetics or similar toiletry preparations characterised by the composition containing inorganic ingredients
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
- A61K8/36—Carboxylic acids; Salts or anhydrides thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
- A61K8/36—Carboxylic acids; Salts or anhydrides thereof
- A61K8/365—Hydroxycarboxylic acids; Ketocarboxylic acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
- A61K8/37—Esters of carboxylic acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q19/00—Preparations for care of the skin
- A61Q19/08—Anti-ageing preparations
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
- C07C57/30—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
- C07C57/30—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing six-membered aromatic rings
- C07C57/32—Phenylacetic acid
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
- C07C57/52—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing halogen
- C07C57/58—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing halogen containing six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/40—Unsaturated compounds
- C07C59/42—Unsaturated compounds containing hydroxy or O-metal groups
- C07C59/52—Unsaturated compounds containing hydroxy or O-metal groups a hydroxy or O-metal group being bound to a carbon atom of a six-membered aromatic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/40—Unsaturated compounds
- C07C59/76—Unsaturated compounds containing keto groups
- C07C59/84—Unsaturated compounds containing keto groups containing six membered aromatic rings
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Birds (AREA)
- Emergency Medicine (AREA)
- Dermatology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Physical Education & Sports Medicine (AREA)
- Gerontology & Geriatric Medicine (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Rheumatology (AREA)
- Inorganic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本文描述了式I化合物,或其药学上可接受的盐,或其组合,以及其用途。此类用途包括促进器官的组织自修复或组织再生;刺激产生组织生长;调节(例如增加)组织修复标记物的水平;治疗器官、组织或细胞中的物理损伤;促进伤口愈合;以及抗老化应用。还描述了相应组合物、方法和用途。对于式I,其中A为C5烷基、C6烷基、C5烯基、C6烯基、C(O)‑(CH2)n‑CH3或CH(OH)‑(CH2)n‑CH3,其中n为3或4;R1为H、F或OH;R2为H、F、OH、C5烷基、C6烷基、C5烯基、C6烯基、C(O)‑(CH2)n‑CH3或CH(OH)‑(CH2)n‑CH3,其中n为3或4;R3为H、F、OH或CH2Ph;R4为H、F或OH;Q为1)(CH2)C(O)OH,其中m为1或2,2)CH(CH3)C(O)OH,3)C(CH3)2C(O)OH,4)CH(F)‑C(O)OH,5)CF2‑C(O)OH或6)C(O)‑C(O)OH。
Description
技术领域
本发明涉及医学领域。本发明的特定方面涉及用于损伤器官的组织自修复和/或组织再生、用于刺激产生组织生长和/或用于调节组织自修复标记物和/或组织再生标记物诸如金属蛋白酶和生长因子的表达的化合物、药物组合物及其用途。
发明背景
组织再生涉及已知标记物诸如金属蛋白酶和生长因子,包括但不限于HGF(肝细胞生长因子)、LOX(赖氨酰氧化酶)、MMP1、MMP2、MMP9、MMP13、PLAT(tPA)、PLAU(uPA)、SerpinA1(AAT)、Serpin E1(PAI-1)、TIMP3、ILK(整合素连接激酶)。
HGF在组织修复和再生中的作用充分描述于以下科学综述中:The discovery ofHepatocyte Growth factor(HGF)and its significance for cell biology,lifesciences and clinical medicine,Nakamura和Mizuno,Proc.Jpn.Acad.Ser B86(2010)。此综述文章描述HGF在肝脏、肾脏、心脏和肺中的组织再生中的作用。另外,HGF为皮肤、胃、肠道、肌肉和软骨损伤之后自修复所需的,且还参与器官发育(包括有丝分裂发生、运动发生和形态发生的器官发生)。HGF还因其对再生酶(金属蛋白酶)的调节并且因抑制凋亡而与损伤组织的再生有关。此外,新近报导表明HGF具有抗炎作用且减缓细胞衰老。因此,HGF基因治疗或增加HGF表达和分泌的化合物可为心血管疾病中的抗老化治疗(Nakagami,Morishita,2009)。HGF还已知加速伤口愈合(Li等人,BioMed Research International,第2013卷(2013),文章ID 470418。
再生酶(包括金属蛋白酶)在损伤器官的修复和再生中还非常重要。
近期出版物(由Radtke等人在2014年整形外科会议(Plastic surgery meeting2014)上所呈现的标题为Single treatment With Alpha-1antitrypsin Enhances NerveRegeneration After Peripheral Nerve Injury的摘要)已证实AAT改进周围神经再生。AAT应用至急性轴突切断术模型中与类似对照动物相比引起显著改进的轴突再生和髓鞘再生。此外,在急性周围神经病变后直接注射AAT之后观测到组织改进而且观测到功能改进。其结果表明递送至损伤周围神经中的AAT参与神经修复。
皮肤老化为一种对皮肤的进行性变化负有责任的复杂现象。皮肤老化起因于两种过程:(1)固有过程,其对应于随时间老化;和(2)非固有过程,其主要起因于暴露环境应力的有害作用。遗传、UV曝露、气候因素(恶劣/风/冷/暖)、污染(化学、自由基、污染物、氮氧化物、金属)、饮酒或吸烟为皮肤老化中所涉及的因素。
暴露于刺激物损害角质层的屏障功能且降低其保护皮肤不受环境应力(例如紫外线照射、感染剂等)影响的能力。重复和长期暴露于环境刺激物使得皮肤蛋白质变性、脂质薄层瓦解、保护性细胞间脂质移除、天然润湿因子损失和细胞间内聚力减小。这些损伤还对负责角质细胞剥离的酶的功能损失负有责任。在暴露于污染、冷、太阳、风、低湿度或化学试剂的情况下,这些问题加重。刺激物为如果暴露充足时间且以充足浓度暴露,则能够产生细胞损伤的任何试剂。损伤的严重程度取决于暴露于这些刺激因素的类型和强度。还存在使人易于因外部因素而造成皮肤损伤的内在因素。这些因素包括具有活性皮肤病,诸如湿疹、遗传性干燥皮肤病状、先前皮肤病史、敏感性皮肤和/或超龄。
需要新颖化合物和药剂来刺激损伤器官中的组织自修复和组织再生。
发明概要
本发明的总体方面涉及如本文所定义的根据式I的化合物和其药学上可接受的盐的医药用途。
本发明的特定方面涉及化合物和组合物用于损伤器官的组织自修复和/或组织再生和/或用于调节组织自修复标记物和/或组织再生标记物诸如金属蛋白酶和生长因子(包括但不限于HGF、LOX(赖氨酰氧化酶)、MMP1、MMP2、MMP9、MMP13、PLAT(tPA)、PLAU(uPA)、Serpin A1(AAT)、Serpin E1(PAI-1)、TIMP3和ILK(整合素连接激酶))的表达的用途。
一种用于有需要的受试者中的器官的组织自修复或组织再生的方法,其包括向有需要的受试者施用由式I表示的化合物或其药学上可接受的盐的步骤:
根据另一方面,本发明涉及一种用于有需要的受试者中的器官的组织自修复或组织再生的方法,其包括向所述受试者施用如本文所定义的由式I表示的化合物或其药学上可接受的盐。在一个实施方案中,本发明涉及一种用于有需要的受试者中的器官的组织自修复的方法,其包括向所述受试者施用如本文所定义的由式I表示的化合物或其药学上可接受的盐。在一个实施方案中,本发明涉及一种用于有需要的受试者中的器官的组织重建的方法,其包括向所述受试者施用如本文所定义的由式I表示的化合物或其药学上可接受的盐。在一个实施方案中,本发明涉及一种用于有需要的受试者中的器官的组织再生的方法,其包括向所述受试者施用如本文所定义的由式I表示的化合物或其药学上可接受的盐。
根据另一方面,本发明涉及一种用于用如本文所定义的由式I表示的化合物或其药学上可接受的盐刺激产生组织生长的方法。
根据另一方面,本发明涉及一种用于用如本文所定义的由式I表示的化合物或其药学上可接受的盐刺激组织自修复标记物和/或组织再生标记物的表达的方法。更具体地,这些标记物包括但不限于金属蛋白酶、生长因子、肝细胞生长因子(HGF)、LOX(赖氨酰氧化酶)、MMP1、MMP2、MMP9、MMP13、PLAT(tPA)、PLAU(uPA)、Serpin A1(AAT)、Serpin E1(PAI-1)、TIMP3和ILK(整合素连接激酶)。
根据另一方面,本发明涉及一种用于增加器官中的HGF水平的方法,其包括向所述器官施用如本文所定义的由式I表示的化合物或其药学上可接受的盐的步骤。所述器官包括但不限于肾脏、心脏、肝脏、肺、皮肤、胃、肠道、肌肉和软骨。
根据另一方面,本发明涉及一种用于增加器官中的AAT水平的方法,其包括向所述器官施用如本文所定义的由式I表示的化合物或其药学上可接受的盐的步骤。
根据以下描述、权利要求书和本文的概述,本领域技术人员将显而易知本发明的其它方面。
附图简述
图1为化合物I关于增加肝细胞生长因子(HGF,一种参与组织自修复和再生的生长因子)的mRNA表达的作用的说明。
图2为化合物I关于调节在损伤纤维母细胞(NHDF)中表达的参与组织自修复和再生的再生标记物的作用的说明。
图3为化合物I关于调节在损伤上皮细胞(HK-2)中表达的参与组织自修复和再生的再生标记物的作用的说明。
图4证实化合物I可增加参与神经产生的Serpin A1(AAT)的mRNA表达。
图5为在存在化合物I的情况下所观测到的器官功能(GFR)增加且指示损伤肾脏的组织再生的代表图。
发明详述
本发明公开了式I化合物、其药学上可接受的盐、包含它们的组合物及其用途。本发明的各个实施方案包括:
本发明的化合物
根据一个方面,本发明涉及由式I表示的化合物或其药学上可接受的盐的医药用途:
式I
其中
A为C5烷基、C6烷基、C5烯基、C6烯基、C(O)-(CH2)n-CH3或CH(OH)-(CH2)n-CH3,其中n为3或4;或为C5烷基、C5烯基、C(O)-(CH2)n-CH3或CH(OH)-(CH2)n-CH3,其中n为3;或为C6烷基、C6烯基、C(O)-(CH2)n-CH3或CH(OH)-(CH2)n-CH3,其中n为4;
R1为H、F或OH;或为H或OH;
R2为H、F、OH、C5烷基、C6烷基、C5烯基、C6烯基、C(O)-(CH2)n-CH3或CH(OH)-(CH2)n-CH3,其中n为3或4;或为C5烷基、C5烯基、C(O)-(CH2)n-CH3或CH(OH)-(CH2)n-CH3,其中n为3;或为C6烷基、C6烯基、C(O)-(CH2)n-CH3或CH(OH)-(CH2)n-CH3,其中n为4
R3为H、F、OH或CH2Ph;或为H、F或OH;或为H或OH;
R4为H、F或OH;或为H或OH;
Q为
1)(CH2)mC(O)OH,其中m为1或2,
2)CH(CH3)C(O)OH,
3)C(CH3)2C(O)OH,
4)CH(F)-C(O)OH,
5)CF2-C(O)OH,或
6)C(O)-C(O)OH。
根据一个特定实施方案,A为C5烷基或C6烷基。优选地,C5烷基为直链C5烷基。
根据一个特定实施方案,R1为H或OH。
根据一个特定实施方案,R2为H、F、OH、C5烷基或C6烷基。
根据一个特定实施方案,R3为H或OH。
根据一个特定实施方案,R4为H或OH。
根据一个特定实施方案,Q为:
1)(CH2)mC(O)OH,其中m为1或2,
2)CH(F)-C(O)OH,
3)CF2-C(O)OH,或
4)C(O)-C(O)OH。
根据一个特定实施方案,Q为(CH2)mC(O)OH,其中m为1或2。
根据另一个实施方案,化合物具有式I,其中A为C5烷基或C6烷基;R1为H、F或OH;R2为H、F、OH、C5烷基或C6烷基;R3为H、OH或CH2Ph;R4为H、F或OH;且Q为(CH2)mC(O)OH,其中m为1或2。
根据另一个实施方案,化合物具有式I;其中A为C5烷基;R1为H;R2为H或C5烷基;R3为H;R4为H;且Q为(CH2)mC(O)OH,其中m为1。
如本文所用,术语“烷基”旨在包括具有呈线性排列的指定数目的碳原子的直链饱和脂族烃基,和具有呈非线性排列的指定数目的碳原子的分枝链饱和脂族烃基。
如本文所用,术语“环烷基”旨在包括具有呈环状排列的指定数目的碳原子的环状链饱和脂族烃基。
如本文所用,术语“烯基”旨在意谓具有指定数目的碳原子的不饱和直链烃基,且其中至少两个碳原子通过双键彼此键结,且其中具有E或Z区域选择性及其组合。
式I化合物的实例包括但不限于下文列于表1中的化合物I至XXXIII及其酸形式。
表1:代表性式I化合物及其酸形式
盐
如本文所用,术语“药学上可接受的盐”旨在意谓碱加成盐。药学上可接受的盐的实例还描述于例如Berge等人,“Pharmaceutical Salts”,J.Pharm.Sci.66,1-19(1977)中。药学上可接受的盐可通过常规化学方法自含有酸性部分的母体试剂合成。一般而言,此类盐是通过使这些试剂的游离酸形式与化学计量量的适当碱在水中或在有机溶剂中或在两者的混合物中反应来制备。盐可在最终分离或纯化试剂期间或通过分开地使呈游离酸形式的纯化的本发明化合物与所需相应碱反应且分离由此形成的盐而原位制备。
式I化合物的药学上可接受的盐可选自由以下各项的碱加成盐组成的组:钠、钾、钙、镁、锂、铵、锰、锌、铁或铜。在优选实施方案中,根据本发明的化合物的药学上可接受的盐可为钠、钾、钙、镁或锂盐。更优选地,药学上可接受的盐为钠盐。
本文所公开的式I化合物可呈任何形式,包括任何酸、盐或其它离子和非离子形式。举例而言,如果在本文中化合物显示为酸,则还包括化合物的盐形式。同样地,如果化合物显示为盐,则还包括酸形式。
前药
在某些实施方案中,本文所公开的式I化合物(其中所述化合物以游离羧酸形式存在)还可包括其所有药学上可接受的盐、诸如四唑的等排等效物和前药形式。后者的实例包括在乙醇或胺(包括氨基酸)与由式I定义的游离酸反应后获得的药学上可接受的酯或酰胺。
手性
本文所公开的式I化合物、其药学上可接受的盐或其前药可含有一个或多个不对称中心、手性轴和手性平面,且因此可产生对映异构体、非对映异构体和其它立体异构形式,且可用诸如(R)-或(S)-的绝对立体化学来定义。本发明旨在包括所有此类可能的异构体以及其外消旋和光学纯形式。光学活性(+)和(-)、(R)-和(S)-异构体可使用手性合成单体或手性试剂来制备,或使用诸如反相HPLC的常规技术进行拆分。可制备外消旋混合物且此后分离成个别光学异构体,或者这些光学异构体可通过手性合成来制备。对映异构体可通过本领域技术人员已知的方法进行拆分,例如通过形成非对映异构盐,然后可将非对映异构盐通过结晶、气-液或液相色谱、一种对映异构体与对映异构体特异性试剂的选择性反应来加以分离。本领域技术人员还将了解,在所需对映异构体通过分离技术转化成另一化学实体的情况下,然后需要额外的步骤来形成所需对映异构形式。或者,特定对映异构体可通过使用光学活性试剂、底物、催化剂或溶剂进行不对称合成或通过由不对称转换将一种对映异构体转化成另一种对映异构体来进行合成。
本文所公开的某些式I化合物或其药学上可接受的盐可以两性离子形式存在,且本发明包括使用这些化合物的两性离子形式及其混合物。
水合物
此外,本文所公开的式I化合物或其药学上可接受的盐还可以水合物和无水形式存在。本文包括使用本文所描述的式I化合物或其药学上可接受的盐中任一种的水合物,其可以单水合物形式或以多水合物形式存在。
制备方法
一般而言,所有本文所公开的所有式I化合物或其药学上可接受的盐均可通过任何常规方法使用可容易获得和/或常规可制备的起始物质、试剂和常规合成程序来制备。特别受关注的是Hundertmark,T.;Littke,A.F.;Buchwald,S.L.;Fu,G.C.Org.Lett.12,1729-1731(2000)的工作。
下文的例示部分提供用于合成化合物I-XXXIII的通用方案和特定但非限制性实施例。
药学用途
本文所公开的式I化合物或其药学上可接受的盐(或包含其的组合物)适用于:损伤器官、组织或细胞的组织自修复和/或组织再生、刺激在体外细胞培养物中产生新的细胞和/或调节组织自修复标记物和/或组织再生标记物(诸如金属蛋白酶和生长因子)的表达。根据一个实施方案,本文所公开的式I化合物或其药学上可接受的盐适用于抗老化治疗。在一个实施方案中,所述治疗优选包括施用本文所公开的式I化合物或其药学上可接受的盐或其组合或包含治疗有效量的一种或多种本文所公开的式I化合物或其药学上可接受的盐的药物组合物。本文所用的表述“组织自修复”和“组织再生”还可指抗老化治疗中所涉及的过程。已发现根据本文所公开的式I的代表性化合物刺激已知与抗老化、组织再生和组织自修复相关的标记物的表达,且刺激产生新的细胞。
在一个实施方案中,损伤器官、组织或细胞不为因炎性相关疾病而损伤的器官、组织或细胞。在一个实施方案中,损伤器官、组织或细胞不为因癌症而损伤的器官、组织或细胞。
在一个实施方案中,器官、组织或细胞损伤是起因于物理损伤(即在急性暴露于对器官、组织或细胞产生一些形式的损害/损伤的外部试剂或应力之后),例如因物理外伤/伤损(例如割、咬、冲撞、撕、刺入、穿孔、灼伤(热或化学)、冷冻、辐射、电击、身体用力过度)或手术而损伤的器官、组织或细胞。如本文所用的物理损伤排除由以下原因引起的器官、组织或细胞损害(即其中器官、组织或细胞损害的主要原因为):基础疾病,例如炎性或自体免疫疾病,诸如炎性肠道疾病、肾小球性肾炎、血管炎、银屑病性关节炎、系统性红斑狼疮(SLE)、特发性血小板减少性紫癜(ITP)、银屑病、克罗恩氏病(Crohn's disease)、炎性肠道疾病、强直性脊柱炎、肖格伦氏综合征(Sjogren's syndrome)、斯蒂尔氏病(Still's disease)(巨噬细胞活化综合征)、葡萄膜炎、硬皮病、肌炎、赖特尔氏综合征(Reiter’s syndrome)和韦格纳氏综合征(Wegener’s syndrome)。然而,本文所公开的式I化合物或其药学上可接受的盐(或包含其的组合物)可用于促进组织自修复和/或组织再生以治疗由初始物理损伤引起的继发性组织损害/损伤,例如由在初始物理损伤之后可产生的炎症引起的继发性组织损害/损伤。
因此,在另一方面中,本发明提供一种用于治疗器官、组织或细胞中的物理损伤(例如用于促进损伤器官、组织或细胞的自修复和/或组织再生)的方法,所述方法包括使器官、组织或细胞与有效量的本文所公开的式I化合物或其药学上可接受的盐(或包含其的组合物)接触。
在另一方面中,本发明提供本文所公开的式I化合物或其药学上可接受的盐(或包含其的组合物)的用途,其用于治疗器官、组织或细胞中的物理损伤(例如用于促进损伤器官、组织或细胞的自修复和/或组织再生)。在另一方面中,本发明提供本文所公开的式I化合物或其药学上可接受的盐(或包含其的组合物),其用于治疗器官、组织或细胞中的物理损伤(例如用于促进损伤器官、组织或细胞的自修复和/或组织再生)。
在一个实施方案中,(物理)损伤器官、组织或细胞不为肾脏或肾脏组织。在另一个实施方案中,(物理)损伤器官、组织或细胞不为骨骼或骨骼组织。在一个实施方案中,(物理)损伤器官、组织或细胞为皮肤、肌肉、肌腱、韧带、肝脏、心脏、胰腺、消化道/胃肠道(例如口腔、食管、胃、肠道)的器官/组织、胆囊、肝脏、呼吸道(例如肺)的器官、脊髓、脾脏、乳房、眼组织、血管、牙周组织、粘膜(例如口腔粘膜、鼻粘膜)和/或软骨。
在一个实施方案中,本文所公开的式I化合物或其药学上可接受的盐(或包含其的组合物)是紧急使用/施用,即在损伤之后不久使用/施用。在一个实施方案中,本文所公开的式I化合物或其药学上可接受的盐(或包含其的组合物)是为了在损伤器官、组织或细胞中发生纤维化之前(例如在发生纤维化疾病之前)促进组织自修复和/或组织再生而使用/施用。
在一个实施方案中,本文所公开的式I化合物或其药学上可接受的盐(或包含其的组合物)适用于促进伤口愈合。
在另一个实施方案中,损伤器官、组织或细胞为神经系统(例如神经组织)的器官、组织或细胞,例如中枢神经系统或周围神经系统的器官、组织或细胞。在一个实施方案中,本文所公开的式I化合物或其药学上可接受的盐(或包含其的组合物)适用于在神经损伤(例如脊髓损伤、周围神经损伤或与多发性硬化相关的神经损伤)之后的组织自修复和/或组织再生。
在一个实施方案中,本文所公开的式I化合物或其药学上可接受的盐(或包含其的组合物)适用于在皮肤中例如在皮肤割伤、刺入、擦伤或灼伤之后的组织自修复和/或组织再生。
在一个实施方案中,损伤器官、组织或细胞为呼吸系统(例如肺)的器官、组织或细胞。
在一个实施方案中,损伤器官、组织或细胞为肝脏或肝脏组织。
在一个实施方案中,损伤器官、组织或细胞为膀胱或膀胱组织。
在一个实施方案中,损伤器官、组织或细胞为卵巢或卵巢组织。
在一个实施方案中,损伤器官、组织或细胞为前列腺或前列腺组织。
在一个实施方案中,损伤器官、组织或细胞为脾或脾组织。
在一个实施方案中,损伤器官、组织或细胞为乳腺或乳腺组织。
在一个实施方案中,损伤器官、组织或细胞为肌肉,例如因肌肉拉伤、肌肉撕裂和/或任何其它类型的物理肌肉损伤而损伤的肌肉。
在一个实施方案中,损伤器官、组织或细胞为血管(例如动脉)。
在一个实施方案中,损伤器官、组织或细胞为消化道/胃肠道(例如口腔、食管、胃、肠道)的器官/组织。
在特定实施方案中,本文所描述的方法和用途并非用于骨骼重建和/或胰岛再生。在一个特定实施方案中,组织不为骨骼。在一个实施方案中,组织不为胰腺组织。
本发明人已证实本文所公开的代表性式I化合物或其药学上可接受的盐(或包含其的组合物)使刺激受试者中损伤器官的组织自修复和组织再生的标记物增加。在一个实施方案中,本文所描述的式I化合物发挥组织再生活性。
在另一方面中,本发明涉及一种化妆品组合物,其包含本文所公开的式I化合物或其药学上可接受的盐(或包含其的组合物)。在另一方面中,本发明涉及一种皮肤护理组合物,其包含本文所公开的式I化合物或其药学上可接受的盐(或包含其的组合物)。在另一方面中,本发明涉及一种抗老化皮肤护理组合物,其包含本文所公开的式I化合物或其药学上可接受的盐(或包含其的组合物)。
在另一方面中,本发明涉及以上所提及的用于抗老化皮肤护理的式I化合物或其药学上可接受的盐(或包含其的组合物)。在另一个实施方案中,以上所提及的式I化合物或包含其的组合物是用于在与老化相关的皮肤损害之后刺激皮肤修复和/或再生。在另一个实施方案中,以上所提及的化合物或组合物是用于在皮肤损害或损伤之后刺激皮肤修复和/或再生。在一个实施方案中,皮肤损害或损伤是起因于曝露于UV照射,例如曝露于太阳(例如日灼)。
在一个实施方案中,本文所公开的方法和用途还包括确定受试者是否具有损伤器官、组织或细胞且需要用以上所提及的式I化合物或其药学上可接受的盐(或包含其的组合物)进行治疗以促进损伤器官、组织或细胞中的组织自修复和/或组织再生。所述方法可包括确定在来自受试者的样品(诸如器官、组织或细胞样品)中,一种或多种组织自修复和/或组织再生标记物诸如金属蛋白酶和生长因子(包括但不限于HGF、LOX(赖氨酰氧化酶)、MMP1、MMP2、MMP9、MMP13、PLAT(tPA)、PLAU(uPA)、Serpin A1(AAT)、Serpin E1(PAI-1)、TIMP3和ILK(整合素连接激酶))的水平降低,和使所述器官、组织或细胞与有效量的本文所公开的式I化合物或其药学上可接受的盐(或包含其的组合物)接触。
术语“受试者”包括需要如本文所公开的治疗的活生物体,例如其中器官受到损伤者。术语“受试者”包括诸如哺乳动物或鸟的动物。优选地,受试者为哺乳动物,包括但不限于人、马、狗和猫。在一些实施方案中,哺乳动物不为小鼠。更优选地,受试者为人。
药物组合物和制剂
在一个实施方案中,本文所描述的式I化合物或其药学上可接受的盐包含于包含治疗有效量的所述化合物或其药学上可接受的盐的药物组合物中。如上文所指示,药物组合物可适用于:损伤器官的组织自修复和/或组织再生,刺激在体外细胞培养物中产生新的细胞和/或调节组织自修复标记物和/或组织再生标记物(诸如金属蛋白酶和生长因子)的表达。
如本文所用,术语“治疗有效量”意谓化合物在向受试者施用以治疗或预防特定病症、疾病或病状,或发挥生物效应(例如用于刺激损伤器官的组织自修复和/或组织再生,刺激在体外细胞培养物中产生新的细胞和/或调节(增加)组织自修复标记物和/或组织再生标记物的表达)时,足以实现所述病症、疾病或病状的此类治疗或预防或发挥生物效应的量。剂量和治疗有效量可例如视包括以下的多种因素而不同:所使用特定试剂的活性、受试者的年龄、体重、总体健康、性别和膳食、投药时间、投药途径、排泄速率和任何药物组合,如果适用,从业者需要化合物对受试者具有的效应、化合物的性质(例如生物利用度、稳定性、效能、毒性等)和受试者遭受的特定病症。此外,治疗有效量可视以下而定:受试者的血液参数(例如钙水平、脂质概况、胰岛素水平、血糖)、疾病状态的严重程度、器官功能或基础疾病或并发症。此类适当剂量可使用包括本文所描述的分析的任何可用分析来确定。当向人施用本文所公开的式I化合物或其药学上可接受的盐中的一者或多者时,医师可例如首先开出相对低剂量,随后增加剂量直至获得适当反应。所要施用的剂量将最终由健康照护专家决定。然而,一般而言,设想本文所公开的式I化合物或其药学上可接受的盐的剂量可在于人中每天约1至约50mg/kg范围内。在所选实施方案中,所述范围可在于人中每天1至30mg/kg之间。在所选实施方案中,所述范围可在于人中每天1至20mg/kg之间。在所选实施方案中,所述范围可在于人中每天5至18mg/kg之间。在所选实施方案中,所述范围可在于人中每天1至18mg/kg之间。
如本文所用,术语“药物组合物”是指存在至少一种如本文所定义的根据式I的化合物或其药学上可接受的盐和至少一种药学上可接受的载体、稀释剂、媒介物或赋形剂。如本文所用,术语“药学上可接受的载体”、“药学上可接受的稀释剂”或“药学上可接受的赋形剂”旨在意谓但不限于任何助剂、载体、赋形剂、助流剂、甜味剂、稀释剂、防腐剂、染料/染色剂、增味剂、表面活性剂、润湿剂、分散剂、悬浮剂、稳定剂、等张剂、溶剂、乳化剂或囊封试剂,诸如脂质体、环糊精、囊封聚合递送系统或聚乙二醇基质,其可为在受试者、优选人中使用可接受的。其优选指由联邦政府或州政府的管理机构批准或可批准或列于美国药典或其它普遍认可用于动物且更具体地用于人的药典中的化合物或组合物。药学上可接受的媒介物可为含有例如水、乙醇、多元醇(例如甘油、丙二醇和液体聚乙二醇)、其适合的混合物和植物油的溶剂或分散介质。药学上可接受的媒介物的其它实例包括但不限于:注射用水USP;水性媒介物,诸如但不限于氯化钠注射液、林格氏注射液、葡萄糖注射液、右旋糖和氯化钠注射液和乳酸盐林格氏注射液;水可混溶媒介物,诸如但不限于乙醇、聚乙二醇和聚丙二醇;和非水性媒介物,诸如但不限于玉米油、棉籽油、花生油、芝麻油、油酸乙酯、肉豆蔻酸异丙酯和苯甲酸苯甲酯。对微生物的作用的预防可通过添加抗细菌和抗真菌剂(例如对羟基苯甲酸酯、氯丁醇、苯酚、抗坏血酸、硫柳汞及其类似物)来达成。在许多情况下,在组合物中包括等张剂,例如糖、氯化钠或多元醇,诸如甘露糖醇和山梨糖醇。可注射组合物的延长吸收可通过在组合物中包括一种延迟吸收的试剂(例如单硬脂酸铝或明胶)来产生。
本发明的组合物可包括一种或多种如本文所定义的式I化合物或其药学上可接受的衍生物、盐、前药、类似物、异构体或对映异构体。可制备活性化合物的制剂,从而提供呈适合用于肠道、粘膜(包括口腔、舌下、眼部、鼻内、肺部和直肠)、肠胃外(包括肌肉内、真皮内、皮下和静脉内)或局部(包括软膏、乳膏、洗剂或滴剂)施用的形式的药物组合物。在适当的情况下,制剂可能宜以离散剂量单元形式存在,且可通过医药配制技术中熟知的方法中的任一种来制备。所有方法均包括根据需要将活性医药成分与液体载体或精细粉碎的固体载体或两者汇集在一起的步骤。在适当时,可修改以上所描述的制剂,从而提供活性医药成分的持续释放。本领域熟知的持续释放制剂包括使用快速注射、连续输注、生物相容聚合物或脂质体。
以上所提及的化合物或组合物可配制成表面可适用的化妆品组合物(例如局部制剂)。此类表面可适用组合物的非限制性实例包括皮肤护理乳膏、清洁霜、软膏、皮肤护理洗剂、皮肤护理凝胶、皮肤护理泡沫、防晒护理组合物、遮光皮肤护理物、卸妆乳膏、卸妆洗剂、粉底霜、液体粉底、沐浴和淋浴制剂、除臭组合物、止汗组合物、剃须产品组合物、剃须后凝胶或洗剂、美容组合物、脱毛乳膏、肥皂组合物、洗手剂组合物、清洁棒、婴儿护理物、头发护理物、洗发香波、卷发洗剂、治疗洗剂、发乳、毛胶、着色组合物、重建组合物、永久性组合物或适合用于局部化妆品方案中的任何其它组合物。此类组合物可还包含一种或多种药妆可接受的媒介物。
如医药和药妆制剂技术中熟知的乳膏为水包油或油包水的粘性液体或半固体乳液。乳膏基质为水可洗涤的,且含有油相、乳化剂和水相。油相(也称为“内部”相)通常包含矿脂和脂肪醇,诸如鲸蜡醇或硬脂醇。水相的体积通常(不过未必)超过油相,且通常含有保湿剂。乳膏制剂中的乳化剂通常为非离子型、阴离子型、阳离子型或两性表面活性剂。
洗剂为要施加至皮肤表面而不会有摩擦的制剂,且典型地为液体或半液体制剂,其中包括活性剂的固体粒子存在于水或乙醇基质中。洗剂通常为固体的悬浮液,且优选出于本发明目的包含水包油型液体油性乳液。洗剂为用于治疗大身体面积的优选制剂,因为流动性更大的组合物易于施加。洗剂中的不溶性物质通常需要为精细粉碎的。洗剂将典型地含有用于产生适合用于定位且保持活性剂与皮肤接触的更佳分散体以及化合物的悬浮剂,例如甲基纤维素、羧甲基-纤维素钠或其类似物。
溶液为通过将将一种或多种化学物质(溶质)溶解于液体中使得溶解物质的分子分散于溶剂分子之间而制备的均匀混合物。溶液可含有其它药妆可接受的化学品以缓冲、稳定或保存溶质。用于制备溶液的溶剂的常见实例为乙醇、水、丙二醇或任何其它药妆可接受的媒介物。
凝胶为半固体、悬浮液型系统。单相凝胶含有实质上均匀地分布于载体液体中的有机大分子,所述载体液体典型地为水溶液,而且优选含有乙醇和任选地存在的油。“有机大分子”(即凝胶剂)为交联丙烯酸聚合物,诸如“卡波姆”家族的聚合物,例如在商业上可以CarbopolTM获得的羧基聚烯烃。其它实例为亲水聚合物,诸如聚氧化乙烯、聚氧乙烯-聚氧丙烯共聚物和聚乙烯醇;纤维素聚合物,诸如羟丙基纤维素、羟乙基纤维素、羟丙基甲基纤维素、羟丙基甲基纤维素邻苯二甲酸酯和甲基纤维素;树胶,诸如黄蓍胶和黄原胶;海藻酸钠;和明胶。为制备均匀凝胶,可添加诸如乙醇或甘油的分散剂,或可通过研磨、机械混合或搅拌分散凝胶剂,或其组合。
软膏为典型地基于矿脂或其它石油衍生物的半固体制剂。如本领域技术人员将了解,要使用的特定软膏基质为将提供许多所需特征(例如润滑性或其类似物)的软膏基质。与其它载体或媒介物一样,软膏基质应为惰性、稳定、无刺激且不致敏的。如Remington:TheScience and Practice of Pharmacy,第19版(Easton,Pa.:Mack Publishing Co.,1995)第1399-1404页所述,且软膏基质可划分为四种类别:油脂性基质;可乳化基质;乳剂基质;和水溶性基质。油性软膏基质包括例如植物油、获自动物的脂肪和获自石油的半固体烃类。可乳化软膏基质(也称为吸收性软膏基质)几乎不含水且包括例如羟基硬脂精硫酸酯、无水羊毛脂和亲水性矿脂。乳剂软膏基质为油包水(W/O)乳液或水包油(O/W)乳液,且包括例如十六烷醇、单硬脂酸甘油酯、羊毛脂和硬脂酸。优选水溶性软膏基质是自具有不同分子量的聚乙二醇制备;关于其它信息再次参见Remington:The Science and Practice ofPharmacy。
糊剂为活性剂悬浮于适合的基质中的半固体剂型。视基质的性质而定,将糊剂划分为脂肪糊剂或由单相水性凝胶制成的糊剂。脂肪糊剂中的基质通常为矿脂或亲水性矿脂等。由单相水溶液凝胶制成的糊剂通常并有羧甲基纤维素或其类似物作为基质。
制剂还可用脂质体、胶束和微球制备。脂质体为具有包含双层脂质的脂质壁的微观囊泡,且在本发明上下文中,囊封抗老化制剂的一种或多种组分。本文的脂质体制剂包括阳离子(带正电荷)、阴离子(带负电荷)和中性制剂。阳离子脂质体可容易地获得。举例而言,N[1-2,3-二油烯基氧基)丙基]-N,N,N-三乙基铵(DOTMA)脂质体可以商标名LipofectinTM(GIBCO BRL,Grand Island,N.Y.)获得。类似地,阴离子和中性脂质体同样可容易地获得,例如来自Avanti Polar Lipids(Birmingham,Ala.),或可使用可容易地获得的物质容易地制备。此类物质包括磷脂酰胆碱、胆固醇、磷脂酰乙醇胺、二油酰基磷脂酰胆碱(DOPC)、二油酰基磷脂酰甘油(DOPG)和二油酰基磷脂酰乙醇胺(DOPE)等。这些物质还可以适当比率与DOTMA混合。用于使用这些材料制备脂质体的方法为本领域中熟知的。
胶束在本领域中已知包含表面活性剂分子,所述等表面活性剂分子经布置使得其极性头部基团形成外部球形壳体,同时疏水性烃链朝向球形的中心取向,从而形成核心。胶束形成于含有足够高浓度的表面活性剂以使得胶束自然地产生的水溶液中。适合用于形成胶束的表面活性剂包括但不限于月桂酸钾、辛烷磺酸钠、癸烷磺酸钠、十二烷磺酸钠、月桂基硫酸钠、多库酯钠、癸基三甲基溴化铵、十二烷基三甲基溴化铵、十四烷基三甲基溴化铵、十四烷基三甲基氯化铵、十二烷基氯化铵、聚乙二醇-8十二烷基醚、聚乙二醇-12十二烷基醚、壬苯醇醚10和壬苯醇醚30。
类似地,可将微球并入本发明制剂。像脂质体和胶束一样,微球基本上囊封本发明制剂的一种或多种组分。其通常不过未必由脂质、优选带电荷脂质(诸如磷脂)形成。脂质微球的制备为本领域中熟知的且描述于相关文本和文献中。
试剂盒
本文所公开的式I化合物或其药学上可接受的盐可经包装作为试剂盒的部分,所述试剂盒任选地包括一容器(例如包装、箱、小瓶等)。试剂盒可在商业上根据本文所描述的方法使用,且可包括在本文所公开的方法中的使用说明。其它试剂盒组分可包括酸、碱、缓冲剂、无机盐、溶剂、抗氧化剂、防腐剂或金属螯合剂。其它试剂盒组分是以纯组合物形式或以并有一种或多种其它试剂盒组分的水性或有机溶液的形式存在。任何或所有试剂盒组分均任选地还包含缓冲液。
本文所公开的式I化合物或其药学上可接受的盐可能或可能不同时或通过相同投药途径向患者施用。因此,本发明的方法涵盖试剂盒,在由医学从业者使用时其可使得向患者施用适当量的两种或更多种活性成分简化。
本发明的典型试剂盒包含至少一种如本文所定义的式I化合物或其药学上可接受的盐的单位剂型,和至少一种其它活性成分的单位剂型。可与本发明的化合物结合使用的其它活性成分的实例包括但不限于在上文指出可与如本文所定义的式I化合物或其药学上可接受的盐组合使用的药物中的任一种。
本发明的试剂盒可还包含可用于施用一种或多种活性成分的药学上可接受的媒介物。举例而言,如果活性成分是以必须复原以便肠胃外施用的固体形式提供,则试剂盒可包含密封容器或适合的媒介物,其中活性成分可溶解以形成不含粒子的适合用于肠胃外施用的无菌溶液。药学上可接受的媒介物的实例提供于上文中。
实施例
以下实施例进一步说明对本发明的实践,但不旨在对其进行限制。
实施例1:用于制备某些代表性化合物的实验程序
所有HPLC色谱图和质谱均记录于HP 1100 LC-MS AgilentTM仪器上,使用分析型C18柱(250×4.6mm,5微米),使用经5min 15-99%CH3CN-H2O的梯度,以0.01%TFA作为洗脱剂,且流速为2mL/min。
化合物I:使用改进型薗头反应程序(Sonogashira procedure)合成(3-戊基苯基)乙酸的钠盐
步骤1
在室温下向3-溴苯基乙酸(5.02g、23.33mmol)于乙醇(100mL)中的溶液/悬浮液中添加浓硫酸(1mL)。然后将无色固体在80℃下搅拌隔夜。将溶液在减压下浓缩。将残余物用乙酸乙酯(25mL)、水(25mL)稀释,且将两个层分离。将水层用乙酸乙酯(2×25mL)和盐水(20mL)萃取。将合并的有机层用NaHCO3饱和溶液(2×25mL)、盐水(25mL)洗涤且经硫酸钠干燥。在溶液过滤之后,将其蒸发至干燥。此举得到浅黄色油状物(5.4g,95%)。1H-NMR(400MHz,CDCl3):δ1.26(t,J=4.7Hz,3H),3.57(s,2H),4.15(Q,J=7.0和14.3Hz,2H),7.17-7.26(m,2H),7.38-7.44(m,1H),7.44(d,J=1.56Hz,1H)。
步骤2
在密封管中将(3-溴苯基)乙酸乙酯(0.3g,1.24mmol)与水合氟化四丁铵(0.97g,3.72mmol)的混合物用PdCl2(PPh3)2(26mg,0.037mmol;3摩尔%)和1-戊炔(367μL,3.72mmol)处理。将管在80℃下加热2h。将混合物用水处理,且用二乙醚萃取。将有机萃取物经硫酸钠干燥,过滤且在真空中蒸发,得到粗产物。在BiotageTM25M柱(二氧化硅)上纯化,用乙酸乙酯/己烷0:1至2:98洗脱,得到呈淡黄色油状的(3-(戊炔-1-基)苯基)乙酸乙酯(0.23g,79%)。
步骤3
在氮气氛围下向含[3-[戊炔-1-基]苯基]-乙酸乙酯(0.23g,0.98mmol)的乙醇(5mL)中添加碳载Pd(10%,25mg,10%w/w)。将混合物在氢气氛围下在室温下剧烈搅拌隔夜。将溶液过滤且将钯/碳用乙醇(20mL)洗涤。将滤液用硅胶浓缩。将粗产物通过快速色谱法使用10%己烷/乙酸乙酯的混合物加以纯化。获得透明油状物(0.21g,90%)。
步骤4
在0℃下向酯(0.2g,0.9mmol)于四氢呋喃(5mL)、甲醇(1.5mL)和水(1.5mL)中的溶液中添加氢氧化锂(0.09g,3.6mmol)。将反应混合物在室温下搅拌隔夜。将不溶物质过滤且将滤液在减压下浓缩。然后将残余物用2M HCl处理且用乙酸乙酯萃取。将有机相经硫酸钠干燥且在减压下蒸发。使用乙酸乙酯/己烷(0:10至4:6)作为洗脱剂,将粗物质在40LBiotage柱(二氧化硅)上纯化。此举得到呈白色胶状固体的纯(3-戊基苯基)乙酸(0.19g,99%)。1H NMR(400MHz,CD3OD):δ0.90(t,J=7.0Hz,3H),1.28-1.38(m,4H),1.61(qt,J=7.6Hz,15.0Hz,2H),2.58(t,J=7.6Hz,2H),3.56(s,2H),7.07(m,3H),7.20(m,1H);LRMS(ESI):m/z 207(MH+);HPLC:4min。
步骤5
向酸(0.19g,0.82mmol)于乙醇(4mL)和水(1mL)中的搅拌溶液中添加碳酸氢钠(0.07g,0.82mmol)。将反应混合物在室温下搅拌隔夜。蒸发溶剂且将白色胶状固体溶解于水中且将溶液冻干。此举得到呈白色固体的纯的(3-戊基苯基)乙酸的钠盐(0.17g,92%)。熔点110-112℃;1H NMR(400MHz,CD3OD):δ0.89(t,J=6.8Hz,3H),1.28-1.37(m,4H),1.60(qt,J=7.4Hz,15.0Hz,2H),2.56(t,J=7.6Hz,2H),3.43(s,2H),6.96(m,1H),7.12(m,3H);LRMS(ESI):m/z 207((MH+);HPLC:4min。
化合物II:3-(3-戊基苯基)丙酸的钠盐
以上化合物是以3-氧代-3-溴苯基丙酸乙酯为起始物质如化合物I一般进行制备。在氢气压力下在乙醇中使用钯/碳同时将酮基和双键还原。白色固体;1H NMR(400MHz,CDCl3):δ7.14-7.10(m,1H),7.04-7.00(m,2H),6.95-6.93(m,1H),2.88-2.84(m,2H),2.55(t,J=7.4Hz,2H),2.44-2.40(m,2H),1.63-1.55(m,2H),1.35-1.28(m,4H),0.90(m,3H);13CNMR(101MHz,CD3OD):δ179.3,141.2,140.8,126.7,126.4,124.0,123.8,38.6,34.2,31.2,29.9,29.8,20.9,11.7;LRMS(ESI):m/z 203(MH+-CO-NaOH);HPLC:4.5min。
化合物III:3-(3-丁基苯基)丙酸的钠盐
步骤1
在圆底烧瓶(250mL)中称取异酞醛(1.0g,7.5mmol),继之以二氯甲烷(100mL)。在室温下在压力平衡下经由分液漏斗添加含(三苯基-亚正膦基)乙酸甲酯(2.7g,8.2mmol)的二氯甲烷(25mL)。将反应物在室温下搅拌隔夜。将混合物经小硅胶垫过滤,且用二氯甲烷(150mL)洗涤。然后将溶剂在减压下蒸发且未进一步纯化即将粗产物用于下一步骤。
步骤2
在氮气下,将溴化丙基三苯基鏻(3.2g,8.2mmol)置放于圆底烧瓶中,且添加无水THF(5mL)。将烧瓶在冰/丙酮(-10℃)浴中冷却,且缓慢添加正丁基锂(2.5M己烷溶液,3.28mL,8.2mmol)。搅拌30分钟,混合物变为深色的。在氮气下将含来自先前步骤的粗反应混合物的无水THF(5mL)置放于冰/丙酮(-10℃)浴中。在-10℃下将鏻溶液缓慢添加至醛溶液中,且将反应混合物缓慢升温至室温且搅拌4h。添加饱和氯化铵溶液(10mL)且将有机层用乙酸乙酯萃取(3次)。将有机层经无水硫酸钠干燥、过滤且添加硅胶以获得防潮包装。将化合物用SP1(乙酸乙酯/己烷)纯化。此举得到预期产物(8.8g,54%)。1H NMR(400MHz,CDCl3):δ7.70-7.65(m,1H),7.45-7.24(m,4.5H),6.45-6.28(m,2.5H),5.70-5.67(m,0.5H),3.78(m,3H),2.34-2.20(m,2H),1.10-1.03(m,3H)。
步骤3
将溶解于乙酸乙酯(10mL)中的不饱和酯(140mg,0.65mmol)置放于圆底烧瓶(25mL)中。向此溶液中添加10%活性炭载钯Pd/C(10mg)。将烧瓶用隔板加盖,且在顶部置放氢气囊。将烧瓶用氢气吹扫三次,且将反应物在室温下搅拌隔夜。然后将固体经CeliteTM过滤。添加硅胶且制备防潮包装。通过快速色谱法使用0-20%乙酸乙酯/己烷纯化,得到所需产物(124mg,87%)。LRMS(ESI):m/z 221(MH+);HPLC:5.0min。
步骤4
依次将该酯(124mg,0.56mmol)与甲醇(4mL)和氢氧化锂(118mg,2.8mmol)置放于圆瓶烧瓶中。添加水(1mL)且将反应物在搅拌下在50℃下加热17h。将反应物转移至分液漏斗中,用HCl(1M)酸化至pH值较低于4,且用乙酸乙酯萃取(3次)。将有机层经无水硫酸钠干燥,过滤且蒸发。将粗物质通过HPLC/水纯化。此举得到白色固体(80mg,70%)。1H NMR(400MHz,CD3OD):δ7.16-7.12(m,1H),7.01-6.96(m,3H),2.88-2.84(m,2H),2.57-2.53(m,4H),1.60-1.52(m,2H),1.37-1.28(m,2H),0.91(t,3H,J=7.3Hz);LRMS(ESI):m/z 205(M-H);HPLC:4.2min。
步骤5
依次将该酸(80mg,0.39mmol)与NaHCO3(33mg,0.39mmol)和水(8mL)置放于烧瓶(20mL)中。向混合物中添加乙腈(3mL)且将反应物超音处理,加热且搅拌直至几乎所有固体呈溶液状态。将溶液经尼龙过滤器过滤。通过将小瓶浸没于干冰/丙酮浴中来将水固化,且冻干隔夜。此举得到呈白色固体的所需产物。1H NMR(400MHz,CD3OD):δ7.14-7.10(m,1H),7.04-6.93(m,3H),2.88-2.84(m,2H),2.57-2.54(m,2H),2.44-2.40(m,4H),1.61-1.53(m,2H),1.39-1.30(m,2H),0.93(t,3H,J=7.3Hz);13C NMR(101MHZ,CD3OD):δ142.7,142.4,128.2,128.0,125.6,125.4,125.3,40.1,35.5,33.9,32.7,22.2,13.1;LRMS(ESI):m/z251.0(m,MNa+),229.0(w,MH+),189.2(100%,酰阳离子[M–Na++2H+-H2O]);HPLC:4.1min。
化合物IV:E-(3-戊-1-烯基-苯基)乙酸的钠盐。
以上化合物是以E-(3-戊-1-烯基-苯基)乙酸甲酯为起始物质如化合物I一般进行制备。后者是通过使3-溴苯基乙酸甲酯与反-1-戊烯基硼酸频哪醇酯在铃木(Suzuki)条件下反应来进行制备。白色固体;1H NMR(400MHz,CD3OD):δ=7.32(s,1H),7.11-7.18(m,3H),6.35(d,J=15.7Hz,1H),6.20-6.27(m,1H),3.44(s,2H),2.19(m,2H),1.45-1.54(m,2H),0.96(t,J=7.4,3H);13C NMR(101MHz,CD3OD):δ=179.26,138.25,137.92,130.32,130.04,128.06,127.59,126.60,123.52,45.21,35.06,22.52,12.89;LRMS(ESI):m/z 205(MH+);HPLC:4.1min。
化合物V:2-(3-(己-1-烯基]苯基)乙酸的钠盐。
以上化合物是如下制备:如化合物VII一般进行2-(3-溴苯基)乙酸甲酯与(E)-己-1-烯基硼酸频哪醇酯的铃木偶合;随后如化合物I一般进行酯水解和钠盐形成。白色固体:1H NMR(400MHz,CD3OD):δ7.33(s,1H),7.12-7.19(m,3H),6.35(d,J=15.8Hz,1H),6.20(dt,J=15.8,6.8Hz,1H),3.46(s,2H),2.17-2.22(m,2H),1.33-1.49(m,4H),0.93(t,J=7.2Hz,3H);13C NMR(101MHz,CD3OD):δ179.35,138.27,137.95,130.27,130.16,128.10,127.61,126.64,123.56,45.24,32.66,31.67,22.16,13.22;LRMS(ESI):m/z 263.1(100%,M+Na+);HPLC:4.4min。
化合物VI:2-(3-己基苯基)乙酸的钠盐
以上化合物是如下制备:如化合物VII一般进行2-(3-溴苯基)乙酸甲酯与(E)-己-1-烯基硼酸频哪醇酯的铃木偶合;随后如化合物I一般进行加氢、酯水解和钠盐形成。白色固体;1H NMR(400MHz,D2O):δ7.14(dd,J=7.8,7.6Hz,1H),7.01(s,1H),7.00(d,J=7.8Hz,1H),6.96(d,J=7.6Hz,1H),3.34(s,2H),2.46(d,J=7.5Hz,2H),1.41-1.48(m,2H),1.10-1.18(m,6H),0.70(t,J=6.8Hz,3H);13C NMR(101MHz,D2O):δ181.23,143.98,137.46,129.47,128.73,126.63,126.48,44.58,35.14,31.12,30.94,28.23,22.13,13.53;LRMS(ESI):m/z 265(100%,M+Na+);HPLC:4.6min。
化合物VII:3-羟基-5-戊基苯基乙酸的钠盐
步骤1
将[3,5-二羟苯基]乙酸甲酯(2.1g,11.5mmol)于丙酮(100mL)中的溶液用碳酸钾(2.4g,17.4mmol)、碘化钾(383mg,2.31mmol)和溴甲苯(1.5mL,12.7mmol)处理,且将混合物在室温下搅拌隔夜。将反应物用水稀释且用二氯甲烷萃取(3次)。将合并的有机萃取物经硫酸钠干燥且在真空中蒸发。将粗物质在BiotageTM40M柱(二氧化硅)上纯化,用40%乙酸乙酯/己烷洗脱,得到[3-苯甲基氧基-5-羟苯基]乙酸甲酯(1.0g,33%)。1H NMR(400MHz,CDCl3):δ7.32-7.42(m,5H),6.48(d,J=1.4Hz,1H),6.38-6.39(m,2H),4.99(s,2H),3.69(s,3H),3.53(s,2H)。
步骤2
将0℃下的二甲苯醚(1.04g,3.8mmol)于二氯甲烷(15mL)中的溶液用N-苯基-双(三氟磺酰基)酰亚胺(1.40g,3.9mmol)处理,且然后缓慢添加三乙胺(0.6mL,4.1mmol)。将反应物在0℃下搅拌1h,且然后在室温下搅拌1h。将反应混合物用水稀释,且然后用二乙醚萃取(2次)。将合并的有机萃取物用1M氢氧化钠水溶液、水(2次)和饱和氯化钠水溶液洗涤,然后经硫酸钠干燥,过滤且在真空中蒸发,得到粗产物。在BiotageTM40M柱(二氧化硅)上纯化,用25%乙酸乙酯/己烷洗脱,得到[3-苯甲基氧基-5-三氟甲磺酰氧基苯基]乙酸甲酯(1.2g,79%)。1H NMR(400MHz,CDCl3):δ7.36-7.46(m,5H),6.98(s,1H),6.97(s,1H),6.84(s,1H),5.06(s,2H),3.72(s,3H),3.63(s,2H)。
步骤3
将E-1-戊烯-1-基硼酸频哪醇酯(0.8g,3.9mmol)于二甲氧基乙烷(5mL)中的溶液用三氟甲磺酸酯(1.2g,3.0mmol)于二甲氧基乙烷(5mL)中的溶液处理。将溶液用零价钯(0.7g,0.6mmol)和2M碳酸钠水溶液(1.3mL,2.6mmol)处理。然后将混合物在90℃下加热3天。将反应物冷却至室温且经CeliteTM过滤。将滤液在真空中蒸发,且将粗物质在BiotageTM25M柱(二氧化硅)上纯化,用5%乙酸乙酯/己烷洗脱,得到[3-苯甲基氧基-5-[戊-1-烯基]苯基]乙酸甲酯(0.4g,40%)。1H NMR(400MHz,CDCl3):δ7.36-7.47(m,5H),6.90-6.92(m,2H),6.79(dd,J=2.0,2.0Hz,1H),6.35(d,J=15.9Hz,1H),6.24(dt,J=15.9,6.8Hz,1H),5.07(s,2H),3.70(s,3H),3.59(s,2H),2.20(td,J=7.4,6.8Hz,2H),1.51(dt,J=7.4Hz,2H),0.98(t,J=7.4Hz,3H)。
步骤4
将链烯(0.4g,1.2mmol)于乙醇(13mL)中的溶液用1%碳载钯(40mg)处理。将混合物在室温下在1大气压氢气下搅拌隔夜。将反应物过滤,在真空中蒸发,且在BiotageTM25S柱(二氧化硅)上纯化,用15%乙酸乙酯/己烷洗脱,得到[3-羟基-5-戊基苯基]乙酸甲酯(0.3g,93%)。1H NMR(400MHz,CDCl3):δ6.64(s,1H),6.58-6.60(m,2H),3.70(s,3H),3.55(s,2H),2.51(t,J=7.7Hz,2H),1.55-1.59(m,2H),1.28-1.34(m,4H),0.88(t,J=7.0Hz,3H)。
步骤5
将该酯(0.3g,1.3mmol)于乙醇(12mL)中的溶液用水(3mL)和氢氧化锂(155mg,6.4mmol)处理,且将混合物在室温下剧烈搅拌隔夜。将反应混合物用水(100mL)稀释;用二氯甲烷洗涤;然后用1M盐酸水溶液酸化至pH 1且用二氯甲烷萃取(3次)。将合并的有机萃取物经硫酸钠干燥(0.3g,95%)。此物质未进一步纯化即使用。1H NMR(400MHz,CDCl3):δ6.66(s,1H),6.58-6.59(m,2H),3.55(s,2H),2.52(t,J=7.7Hz,2H),1.55-1.59(m,2H)。
步骤6
将该酸(0.27g,1.23mmol)于乙醇(6mL)和水(6mL)中的溶液用碳酸氢钠(0.1g,1.2mmol)处理,且将反应物在室温下搅拌数小时。将溶剂真空浓缩,且将溶液用水稀释,过滤(0.2μm)且冻干,得到呈白色固体的[3-羟基-5-戊基苯基]乙酸钠(0.3g,95%)。熔点63-66℃;1H NMR(400MHz,CD3OD):δ6.63(s,1H),6.58(s,1H),6.42(s,1H),3.36(s,2H),2.48(t,J=7.6Hz,2H),1.55-1.62(m,2H),1.26-1.38(m,4H),0.89(t,J=6.8Hz,3H);13C NMR(101MHz,CD3OD):δ177.79,155.31,142.36,137.62,119.08,111.66,111.18,43.70,34.17,29.95,29.56,20.87,11.64;LRMS(ESI):m/z 445.2(2M-2Na++3H+),m/z 223(M-Na++2H+);HPLC:3.5min。
化合物VIII:2-(4-羟基-3-戊基苯基)乙酸的钠盐
以上化合物是如下制备:如实施例VII一般进行2-(4-(苄氧基)-3-溴苯基)乙酸苯甲酯与(E)-戊-1-烯基硼酸频哪醇酯的铃木偶合;随后加氢。白色固体;熔点192-195℃;1HNMR(400MHz,CD3OD):δ7.01(d,J=2.3Hz,1H),6.93(dd,J=8.2,2.3Hz,1H),6.64(d,J=8.2Hz,1H),3.35(s,2H),2.53(t,J=7.7Hz,2H),1.54-1.61(m,2H),1.30-1.37(m,4H),0.90(t,J=7.2Hz,3H);13C NMR(101MHz,CD3OD):δ180.25,153.20,130.54,128.80,128.76,127.10,114.49,44.45,31.84,30.10,29.73,22.52,13.31;LRMS(ESI):m/z 245.2(55%,MH+),177.4(100%,M–CO2Na);HPLC:1.9min。
化合物IX:2-(2-羟基-3-戊基苯基)乙酸的钠盐
步骤1
将2-(2-羟苯基)乙酸(3.00g,19.7mmol)于甲醇(40mL)中的溶液用硫酸(0.95mL,17.8mmol)处理且将反应物在室温下搅拌18小时。将反应混合物用乙酸乙酯(250mL)稀释,且将溶液用水(2×150mL)且用饱和氯化钠水溶液(150mL)洗涤;经硫酸钠干燥;过滤且在真空中蒸发,得到粗产物。自热己烷中再结晶,得到2-(2-羟苯基)乙酸甲酯(2.83g,87%)。1HNMR(400MHz,CDCl3):δ7.20(ddd,J=7.7,7.4,1.8Hz,1H),7.09-7.11(m,1H),6.94(dd,J=8.0,1.2Hz,1H),6.88(ddd,J=7.4,7.4,1.2Hz,1H),3.75(s,3H),3.69(s,2H)。
步骤2
将2-(2-羟苯基)乙酸甲酯(1.00g,6.0mmol)、三苯基膦(2.37g,9.0mmol)和戊-1-烯-3-醇(0.78g,9.0mmol)于四氢呋喃(30mL)中的溶液在氮气下冷却至0℃,且历时10分钟逐滴添加氮杂二甲酸二异丙酯(1.86mL;9.0mL)。然后将反应物加热至60℃持续21.5小时。将溶剂在真空中蒸发且将残余物用5%乙酸乙酯/己烷萃取。将萃取物过滤且在真空中蒸发,得到粗产物。在BiotageTMSP1系统(120g二氧化硅柱)上纯化,用0-3%乙酸乙酯/己烷洗脱,得到2-(2-(戊-1-烯-3-基氧基)苯基)乙酸甲酯(0.39g,28%)。1H NMR(400MHz,CDCl3):δ7.21-7.26(m,1H),7.20(d,J=7.6Hz,1H),6.91(ddd,J=7.4,7.4,1.0Hz,1H),6.87(d,J=8.0Hz,1H),5.84(ddd,J=17.4,10.7,6.0Hz,1H),5.26(d,J=17.4Hz,1H),5.22(d,J=10.7Hz,1H),4.63(dt,J=6.0,6.0Hz,2H),3.70(s,3H),3.68(s,2H),1.71-1.87(m,2H),1.02(t,J=7.5Hz,3H);13C NMR(101MHz,CDCl3):δ172.58,.156.28,137.75,131.19,128.50,123.87,120.52,116.66,113.18,79.76,52.00,36.61,28.71,9.62。
步骤3
将2-(2-(戊-1-烯-3-基氧基)苯基)乙酸甲酯(0.24g,1.0mmol)于N-甲基-2-吡咯烷酮(1.0mL)中的溶液在Biotage引发器中在180℃下用微波辐射照射30分钟,然后持续15分钟。将溶液用乙酸乙酯(25mL)稀释,然后用水(4×25mL)且用饱和氯化钠水溶液(25mL)洗涤;经硫酸钠干燥;过滤且在真空中蒸发,得到粗产物。在BiotageTMSP1系统(40g二氧化硅柱)上纯化,用0-7%乙酸乙酯/己烷洗脱,得到(E)-2-(2-羟基-3-(戊-2-烯基)苯基)乙酸甲酯(0.89g,37%)。1H NMR(400MHz,CDCl3):δ7.09(s,1H),7.08(dd,J=7.4,1.6Hz,1H),7.01(dd,J=7.6,1.6Hz,1H),6.85(dd,J=7.6,7.4Hz,1H),5.59-5.70(m,2H),3.75(s,3H),3.69(s,2H),3.41(d,J=4.7Hz,2H),2.04-2.11(m,2H),1.01(t,J=7.4Hz,3H);13C NMR(101MHz,CDCl3):δ174.31,153.53,134.44,129.86,129.32,128.62,127.13,121.08,120.82,52.79,37.59,34.17,25.77,13.97。
步骤4
将(E)-2-(2-羟基-3-(戊-2-烯基)苯基)乙酸甲酯(0.14g,0.6mmol)如化合物I,步骤3一般进行氢化,但使用甲醇作为溶剂,得到2-(2-羟基-3-戊基苯基)乙酸甲酯(0.11g,76%)。1H NMR(400MHz,CDCl3):δ7.57(s,1H),7.11(dd,J=7.4,1.6Hz,1H),6.96(dd,J=7.4,1.6Hz,1H),6.84(dd,J=7.4,7.4Hz,1H),3.76(s,3H),3.70(s,2H),2.68(t,J=7.8Hz,2H),1.61-1.67(m,2H),1.36-1.43(m,4H),0.93(t,J=7.0Hz,3H);13C NMR(101MHz,CDCl3):δ175.01,153.48,131.75,129.98,128.75,120.74,120.60,53.01,38.30,32.10,30.50,29.91,22.87,14.34。
步骤5
将2-(2-羟基-3-戊基苯基)乙酸甲酯(0.11g,0.5mmol)如化合物I,步骤4一般进行水解,使用乙腈/水(4:1)作为溶剂,得到2-(2-羟基-3-戊基苯基)乙酸(0.57g,57%)。1HNMR(400MHz,CDCl3):δ8.70(br s,1H),7.09(dd,J=7.6,1.6Hz,1H),6.98(dd,J=7.4,1.6Hz,1H),6.84(dd,J=7.6,7.4Hz,1H),3.68(s,2H),2.62(t,J=7.8Hz,2H),1.57-1.65(m,2H),1.31-1.40(m,4H),0.91(t,J=7.0Hz,3H);13C NMR(101MHz,CDCl3):δ179.89,152.79,130.92,130.04,128.98,121.08,120.24,37.74,32.02,30.34,29.78,22.80,14.30。
步骤6
将2-(2-羟基-3-戊基苯基)乙酸(22mg,0.098mmol)如化合物I,步骤5一般转化为钠盐,得到2-(2-羟基-3-戊基苯基)乙酸钠(24mg,98%)。1H NMR(400MHz,CD3OD):δ6.91(dd,J=7.5,1.6Hz,1H),6.87(dd,J=7.5,1.6Hz,1H),6.66(dd,J=7.5,7.5Hz,1H),3.49(s,2H),2.59(t,J=7.7Hz,2H),1.55-1.62(m,2H),1.28-1.38(m,4H),0.90(t,J=7.0Hz,3H);13C NMR(101MHz,CD3OD):δ180.26,154.27,130.75,128.21,127.90,124.24,119.23,42.91,31.83,30.21,29.82,22.51,13.29;LRMS(ESI负):m/z 220.8(100%,M–Na+);UPLC(系统A):5.0min。UPLC系统A:移动相A=10mM甲酸铵水溶液;移动相B=乙腈;固相=HSS T3柱;梯度=经10分钟5-100%B/A。
化合物X:2-(3-氟-5-戊基苯基)乙酸的钠盐
步骤1
将3-溴-5-氟苯甲酸(2.74g,12.5mmol)于四氢呋喃(6mL)中的溶液在0℃下在氮气下用硼烷-四氢呋喃复合物(1M,15mL,15mmol)以小份进行处理历时12min,且然后将反应物在0℃下搅拌70分钟,且在室温下搅拌22h。通过添加甲醇(10mL)中止反应,且将甲醇混合物在室温下搅拌3h,且然后在真空中蒸发,同时自甲醇中然后自乙酸乙酯共蒸发,得到粗产物。将物质溶解于乙酸乙酯(200mL)中,且将溶液用0.5M氢氧化钠水溶液(200mL)且用饱和氯化钠水溶液(100mL)洗涤;然后经硫酸钠干燥;过滤且在真空中蒸发,得到3-溴-5-氟苯甲醇(1.79g,67%)。1H NMR(400MHz,CDCl3):δ7.29(s,1H),7.15(ddd,JHF=8.2Hz,JHH=2.2,1.8Hz,1H),7.00-7.02和7.02-7.04(dm,JHF=9.2Hz,JHH=未解析,1H),4.66(s,2H),2.04(br s,1H);19F NMR(377MHz,CDCl3):δ-111.05(dd,JHF=9.3,8.0Hz,1F);13C NMR(101MHz,CDCl3):δ162.87(d,JCF=250.6Hz),145.42(d,JCF=6.9Hz),125.45(d,JCF=3.1Hz),122.69(d,JCF=9.2Hz),118.01(d,JCF=24.6Hz),112.51(d,JCF=21.5Hz),63.60(d,JCF=2.3Hz)。
步骤2
将3-溴-5-氟苯甲醇(1.79g,8.39mmol)和三苯基膦(3.65g,10.10mmol)于二氯甲烷(45mL)中的溶液用四溴化碳(3.34g,10.10mmol)以小份进行处理历时10min,且然后将反应物在室温下搅拌隔夜。将溶剂在真空中蒸发,且将残余物用二乙醚(50mL)处理。将所得白色浆料在室温下搅拌,且然后经CeliteTM过滤。将残余物用二乙醚(2×50mL)洗涤,且将合并的滤液和洗涤液在真空中蒸发得到粗产物。在二氧化硅垫上纯化,用2%乙酸乙酯/己烷洗脱,得到3-溴-5-氟苯甲基溴化物(2.21g,98%)。1H NMR(400MHz,CDCl3):δ7.33(s,1H),7.18(ddd,JHF=8.2Hz,JHH=2.0,2.0Hz,1H),7.05(ddd,JHF=9.0Hz,JHH=1.8,1.6Hz,1H),4.38(s,2H);19F NMR(377MHz,CDCl3):δ-110.19至-110.14(m,1F);13C NMR(101MHz,CDCl3):δ162.67(d,JCF=252.1Hz),141.61(d,JCF=8.5Hz),128.17(d,JCF=3.1Hz),122.94(d,JCF=10.0Hz),119.39(d,JCF=24.6Hz),115.34(d,JCF=22.3Hz),31.31(d,JCF=2.3Hz)。
步骤3
将氰化钠(0.38g,7.73mmol)于水(0.35mL)中的悬浮液用3-溴-5-氟苯甲基溴化物(1.38g,5.15mmol)于二甲基甲酰胺(2.6mL)中的溶液处理,且将反应物在密封管中在75℃下加热3h。将反应物冷却至室温且分配于乙酸乙酯(50mL)与2.5%w/v碳酸氢钠水溶液(100mL)之间。将水相用另一部分乙酸乙酯(50mL)萃取;且将合并的萃取物用水(2×50mL)且用饱和氯化钠水溶液(50mL)洗涤;经硫酸钠干燥;过滤且在真空中蒸发,得到粗产物。在BiotageTM40iM柱(二氧化硅)上纯化,用10%乙酸乙酯/己烷洗脱,得到2-[3-溴-5-氟苯基]乙腈(0.64g,58%)。1H NMR(400MHz,CDCl3):δ7.26-7.28(m,1H),7.17-7.19&7.19-7.21(dm,JHF=8.0Hz,JHH=未解析,1H),6.98-7.00&7.00-7.02(dm,JHF=8.8Hz,JHH=未解析,1H),3.73(s,2H);19F NMR(377MHz,CDCl3):δ-109.46(dd,JHF=8.0,8.0Hz,1F);13C NMR(101MHz,CDCl3):δ162.90(d,JCF=252.1Hz),133.95(d,JCF=8.5Hz),127.24(d,JCF=3.8Hz),123.53(d,JCF=10.0Hz),119.22(d,JCF=23.8Hz),117.00,114.50(d,JCF=23.1Hz),23.30(d,JCF=1.5Hz)。
步骤4
将芳基溴(0.55g,2.58mmol)和(E)-1-戊烯-1-基硼酸频哪醇酯(0.61g,3.13mmol)于二甲氧基乙烷(13mL)中的溶液用碳酸钠(0.55g,5.17mmol)于水(3mL)中的溶液处理。将溶液用氮气脱氧,且用四(三苯基膦)钯(0.15g,0.13mmol;5摩尔%)处理。然后将混合物在密封管中在90℃下加热17h。将反应物冷却至室温且分配于乙酸乙酯(50mL)与1M盐酸水溶液(50mL)之间。将有机相用饱和氯化钠水溶液(30mL)洗涤;经硫酸钠干燥;过滤且在真空中蒸发,得到粗产物。在BiotageTM40iM柱(二氧化硅)上纯化,用(3%)乙酸乙酯/己烷洗脱,得到(E)-2-[3-氟-5-[戊-1-烯基]苯基]乙腈(0.43g,82%)。1H NMR(400MHz,CDCl3):δ7.04(s,1H),6.97(ddd,JHF=9.8Hz,JHH=2.0,1.5Hz,1H),6.82-6.85(m,1H),6.31(d,J=15.8Hz,1H),6.25(ddd,J=15.8,5.9,0Hz,1H),3.68(s,2H),2.18(td,J=7.2,5.4Hz,2H),1.49(qt,J=7.4,7.4Hz,2H),0.95(t,J=7.4Hz,3H);19F NMR(377MHz,CDCl3):δ-112.93(dd,JHF=10.6,9.3Hz,1F);13C NMR(101MHz,CDCl3):δ163.43(d,JCF=246.0Hz),141.44(d,JCF=8.5Hz),133.99,132.37(d,JCF=8.5Hz),128.42(d,JCF=2.3Hz),121.60(d,JCF=3.1Hz),117.66,113.40(d,JCF=23.1Hz),112.21(d,JCF=22.3Hz),35.22,23.49(d,JCF=2.3Hz),22.51,13.94。
步骤5
将苯基乙腈衍生物(0.43g,2.10mmol)于甲醇(42mL)中的溶液用氢氧化钠水溶液(5M;21mL,105mmol)处理,且将混合物在密封管中在75℃下加热4.5h。将反应混合物冷却至室温,且用6M盐酸水溶液(21mL)中止反应;在室温下搅拌10min;然后用乙酸乙酯(2×75mL)萃取。将有机萃取物用饱和氯化钠水溶液(75mL)洗涤;经硫酸钠干燥;过滤且在真空中蒸发,得到粗产物。在BiotageTM40iM柱(二氧化硅)上纯化,用70%乙酸乙酯/己烷洗脱,得到所需产物的甲酯(0.09g,18%),和约95%纯(E)-2-[3-氟-5-[戊-1-烯基]苯基]乙酸(0.22g,48%)。1H NMR(400MHz,CDCl3):δ11.17(br s,1H),7.02(s,1H),6.98(ddd,JHF=9.8Hz,JHH=2.0,1.8Hz,1H),6.85(ddd,JHF=9.0Hz,JHH=1.8,1.6Hz,1H),6.33(d,J=15.8Hz,1H),6.25(dt,J=15.8,6.4Hz,1H),3.62(s,2H),2.17-2.22(m,2H),1.51(qt,J=7.4,7.4Hz,2H),0.96(t,J=7.4Hz,3H);19F NMR(377MHz,CDCl3):δ-114.10(dd,JHF=9.3,9.3Hz,1F)。
步骤6
将部分纯化的酸(0.28g,1.26mmol)于丙酮(5mL)中的溶液用碳酸钾(0.26g,1.90mmol)、碘化钾(0.04g,0.25mmol)和溴甲苯(0.18mL,1.5mmol)进行处理,且将反应物在室温下搅拌18h。将反应混合物分配于乙酸乙酯(25mL)与1M盐酸水溶液(25mL)之间。然后将有机相用饱和氯化钠水溶液(25mL)洗涤;经硫酸钠干燥;过滤且在真空中蒸发,得到粗产物。在BiotageTM40iM柱(二氧化硅)上纯化,用5%乙酸乙酯/己烷洗脱,得到(E)-2-[3-氟-5-[戊-1-烯基]苯基]乙酸苯甲酯(0.3g,75%)。1H NMR(400MHz,CDCl3):δ7.32-7.40(m,5H),7.03(s,1H),6.97(ddd,JHF=10.0Hz,JHH=2.3,1.5Hz,1H),6.86(ddd,JHF=9.0Hz,JHH=2.0,1.7Hz,1H),6.33(d,J=15.8Hz,1H),6.23(dt,J=15.8,6.5Hz,1H),5.16(s,2H),3.64(s,2H),2.17-2.23(m,2H),1.52(qt,J=7.4,7.4Hz,2H),0.97(t,J=7.4Hz,3H);19F NMR(377MHz,CDCl3):δ-114.34(dd,JHF=9.3,9.3Hz,1F);13C NMR(101MHz,CDCl3):δ171.08,163.32(d,JCF=244.4Hz),140.65(d,JCF=7.7Hz),136.17(d,JCF=8.5Hz),135.93,133.05,128.95(d,JCF=3.1Hz),128.84,128.52(d,JCF=9.2Hz),128.48,123.09(d,JCF=2.3Hz),114.78(d,JCF=22.3Hz),111.46(d,JCF=22.3Hz),67.04,41.26(d,JCF=1.5Hz),35.27,22.63,14.00。
步骤7
将该苯甲酯(0.16g,0.50mmol)于乙酸乙酯(2mL)中的溶液用碳载钯(1%w/w Pd;15mg)处理。将混合物用氢气脱气,且在1大气压的氢气下在室温下搅拌隔夜。将反应物过滤,且在真空中蒸发,得到2-[3-氟-5-戊基苯基]-乙酸(0.11g,97%)。1H NMR(400MHz,CDCl3):δ11.47(br s,1H),6.89(s,1H),6.81-6.86(m,2H),3.62(s,2H),2.60(t,J=7.8Hz,2H),1.58-1.66(m,2H),1.28-1.41(m,4H),0.92(t,J=6.8Hz,3H);19F NMR(377MHz,CDCl3):δ-114.34(dd,JHF=9.3,9.3Hz,1F);13C NMR(101MHz,CDCl3):δ178.15,163.08(d,JCF=246.0Hz),145.02(d,JCF=7.7Hz),135.04(d,JCF=8.5Hz),125.49(d,JCF=2.3Hz),114.49(d,JCF=20.8Hz),113.83(d,JCF=22.3Hz),41.01(d,JCF=1.5Hz),35.87(d,JCF=1.5Hz),31.67,31.03,22.74,14.24。
步骤8
将该酸(0.11g,0.49mmol)于乙醇(3mL)中的溶液用碳酸氢钠(0.041g,0.49mmol)于水(0.75mL)中的溶液处理,且将反应物在室温下搅拌17h。在真空中蒸发乙醇,且将残余水性浆用水(10mL)稀释,过滤(0.2μm)且冻干,得到呈白色固体的2-[3-氟-5-戊基苯基]乙酸钠(0.12g,99%)。熔点120-123℃;1H NMR(400MHz,CD3OD):δ6.94(s,1H),6.87(ddd,JHF=9.8Hz,JHH=2.0,2.0Hz,1H),6.70(ddd,JHF=10.0Hz,JHH=2.0,2.0Hz,1H),3.45(s,2H),2.56(t,J=7.7Hz,2H),1.58-1.63(m,2H),1.26-1.39(m,4H),0.90(t,J=7.0Hz,3H);19FNMR(377MHz,CD3OD):δ-117.54(dd,JHF=10.0,10.0Hz,1F);13C NMR(101MHz,CD3OD):δ178.66,163.04(d,JCF=242.9Hz),145.07(d,JCF=7.7Hz),140.42(d,JCF=8.5Hz),125.03(d,JCF=2.3Hz),112.99(d,JCF=22.3Hz),112.30(d,JCF=20.8Hz),44.96,35.53(d,JCF=1.5Hz),31.46,31.00,22.45,13.30;HPLC:1.2min。
化合物XI:2-(2-氟-3-戊基苯基)乙酸的钠盐
以上化合物是以3-溴-2-氟苯甲酸为起始物质如化合物X一般进行制备。白色固体;1H NMR(400MHz,CD3OD):δ7.13(ddd,JHF=7.0Hz,JHH=7.4,1.9Hz,2H),7.03(ddd,JHF=7.0Hz,JHH=7.4,1.9Hz,1H),6.97(dd,JHH=7.4,7.4Hz,1H),3.51(d,JHF=1.4Hz,2H),2.61(t,J=7.6Hz,2H),1.56-1.63(m,2H),1.28-1.40(m,4H),0.90(t,J=6.9Hz,3H);13C NMR(101MHz,CD3OD):δ178.21,159.70(d,JCF=242.9Hz),129.07(d,JCF=4.6Hz),128.88,128.43(d,JCF=5.4Hz),125.02(d,JCF=17.7Hz),123.31(d,JCF=4.6Hz),37.89(d,JCF=3.8Hz),31.55,29.98,28.91(d,JCF=3.1Hz),22.41,13.26;19F NMR(377MHz,CD3OD):δ-126.09至-126.05(m,1F);LRMS(ESI):m/z 220.0(M–CO2Na+乙腈),179.4(M–CO2Na);HPLC:1.2min。
化合物XII:2-(4-氟-3-戊基苯基)乙酸的钠盐
以上化合物是自2-(3-溴-4-氟苯基)乙酸甲酯如下进行制备:如化合物VII一般进行铃木偶合;随后如化合物I一般进行加氢、酯水解和盐形成。起始酯是通过使2-(3-溴-4-氟苯基)乙酸与甲醇在硫酸存在下进行反应来制备。白色固体;1H NMR(400MHz,CD3OD):δ7.16(dd,JHF=7.4Hz,JHH=2.3Hz,2H),7.08(ddd,JHF=5.0Hz,JHH=8.3,2.3Hz,1H),6.88(dd,JHF=10.1Hz,JHH=8.3Hz,1H),3.40(s,2H),2.59(t,J=7.7Hz,2H),1.55-1.63(m,2H),1.28-1.40(m,4H),0.90(t,J=7.0Hz,3H);13C NMR(101MHz,CD3OD):δ179.12,159.88(d,JCF=240.6Hz),133.88(d,JCF=3.8Hz),131.26(d,JCF=4.6Hz),128.78(d,JCF=16.1Hz),127.96(d,JCF=8.5Hz),114.26(d,JCF=23.1Hz),44.38,31.51,30.00,28.76(d,JCF=1.5Hz),22.36,13.18;19F NMR(377MHz,CD3OD):δ-126.45至-126.40(m,1F);LRMS(ESI):m/z225.2(M–Na++2H+);HPLC:1.9min。
化合物XIII:(RS)-2-氟-2-(3-戊基苯基)乙酸的钠盐
以上化合物是自2-氟-2-(3-戊基苯基)乙酸乙酯如化合物I一般进行制备。酯是通过使2-(3-戊基苯基)乙酸乙酯与二异丙基氨基锂和N-氟苯磺酰亚胺在-78℃下在四氢呋喃中进行反应来制备。白色固体;1H NMR(400MHz,CD3OD):δ7.34(s,1H),7.30(dd,J=7.6,1.4Hz,1H),7.24(dd,J=7.6,7.6Hz,1H),7.13(dd,J=7.4,1.0Hz,1H),5.53(d,JHF=51.3Hz,1H),2.60(t,J=7.7Hz,2H),1.59-1.65(m,2H),1.27-1.39(m,4H),0.76(t,J=6.9Hz,3H);13C NMR(101MHz,CD3OD):δ173.73(d,JCF=23.9Hz),141.34,136.37(d,JCF=20.0Hz),126.79(d,JCF=2.3Hz),126.40,125.41(d,JCF=5.4Hz),122.84(d,JCF=5.4Hz),90.34(d,JCF=183.4Hz),34.13,29.91,29.65,20.85,11.64;19F NMR(377MHz,CD3OD):δ-168.83(d,JHF=51.7Hz,1F);LRMS(ESI负):m/z 223.0(100%,M–Na+);HPLC:4.1min。
化合物XIV:2-[3,5-二戊基苯基]乙酸钠
步骤1
在0℃下在氮气下,将2-[3,5-二羟苯基]乙酸甲酯(1.00g,5.49mmol)和N-苯基-双(三氟甲基磺酰基)酰亚胺(4.31g,12.1mmol)于二氯甲烷(20mL)中的悬浮液用三乙胺(1.68mL,12.1mmol)处理。形成透明溶液。然后将反应物在氮气下在0℃下搅拌2h,且在室温下搅拌21h。将反应物用乙酸乙酯(100mL)稀释,且将溶液用0.5M氢氧化钠水溶液(2×100mL)且用饱和氯化钠水溶液(75mL)洗涤,然后经硫酸钠干燥;过滤且在真空中蒸发,得到粗产物。在BiotageTM40iM柱(二氧化硅)上纯化,用乙酸乙酯/己烷0:1至1:9洗脱,得到呈淡色油状物的2-[3,5-双(三氟甲基磺酰氧基)苯基]乙酸甲酯(2.23g,91%)。1H NMR(400MHz,CDCl3):δ7.32(d,J=2.2Hz,2H),7.18(dd,J=2.2,2.2Hz,1H),3.72(s,5H);19F NMR(377MHz,CDCl3):δ-73.20(s,3F);13C NMR(101MHz,CDCl3):δ170.05,149.48,139.01,122.95,118.87(q,JCF=320.5Hz),114.42,52.62,40.29。
步骤2
将双(三氟甲磺酸)芳基酯(2.23g,4.99mmol)和(E)-1-戊烯-1-基硼酸频哪醇酯(2.45g,12.5mmol)于1,2-二甲氧基乙烷(25mL)中的溶液用碳酸钠(1.59g,15.0mmol)于水(8mL)中的溶液处理。将溶液用氮气脱氧,且然后用四(三苯基膦)钯(0.58g,0.50mmol)处理。将混合物在密封管中在90℃下加热17h。将反应物冷却至室温且分配于乙酸乙酯(200mL)与1M盐酸水溶液(150mL)之间。将有机相用5%碳酸氢钠水溶液(150mL)且用饱和氯化钠水溶液(150mL)洗涤;然后经硫酸钠干燥;过滤且在真空中蒸发,得到粗产物。在BiotageTM40iL柱(二氧化硅)上纯化,用乙酸乙酯/己烷0:1至3:97洗脱,得到呈与过量(E)-1-戊烯-1-基硼酸频哪醇酯的不可分离10:4混合物形式的2-[3,5-二[(E)-1-戊-1-烯基]苯基]乙酸甲酯(1.12g,61%)。1H NMR(400MHz,CDCl3):δ7.21(s,1H),7.10(d,J=1.3Hz,2H),6.34(d,J=15.8Hz,1H),6.22(dd,J=15.8,6.7Hz,1H),3.65(s,3H),3.55(s,2H),2.18(tdd,J=6.8,6.8,1.0Hz,2H),1.49(qt,J=7.4,7.2Hz,2H),0.96(t,J=7.4Hz,3H);13C NMR(101MHz,CDCl3):δ172.04,138.59,134.47,131.34,129.97,125.57,122.75,52.07,41.32,35.39,22.77,13.97。
步骤3
将不饱和化合物(1.12g,78.5%w/w,3.07mmol)于乙酸乙酯(1mL)和甲醇(1mL)中的溶液用碳载钯(10%w/w Pd;0.12g)处理。将混合物用氢气脱气,且在1大气压氢气下在室温下搅拌22h。将反应物过滤,且在真空中蒸发,得到呈与苯基硼酸频哪醇酯的不可分离10:4混合物形式的2-[3,5-二戊基苯基]乙酸甲酯(0.86g,76%)。1H NMR(400MHz,CDCl3):δ6.93(s,3H),3.70(s,3H),3.59(s,2H),2.58(t,J=7.9Hz,2H),1.58-1.66(m,2H),1.32-1.38(m,4H),0.91(t,J=6.8Hz,3H)。
步骤4
将甲酯(0.86g,79%w/w,2.34mmol)于乙腈(24mL)中的溶液用氢氧化锂(0.28g,11.7mmol)于水(6mL)中的溶液处理,且将反应物在室温下搅拌22h。将反应用1M盐酸水溶液(55mL)中止,且然后用乙酸乙酯(100mL)萃取。将有机萃取物用饱和氯化钠水溶液(50mL)洗涤;然后经硫酸钠干燥;过滤且在真空中蒸发,得到粗产物。在SiliaSep二氧化硅柱上纯化,用乙酸乙酯/己烷0:1至1:4洗脱,得到呈无色油状的2-[3,5-二戊基]苯基]乙酸(0.55g,84%)。1H NMR(400MHz,CDCl3):δ6.99(s,3H),3.65(s,2H),2.63(t,J=7.8Hz,2H),1.64-71(m,2H),1.36-1.44(m,4H),0.97(t,J=6.9Hz,3H);13C NMR(101MHz,CDCl3):δ178.96,143.55,133.21,127.93,127.06,41.47,36.13,31.94,31.47,22.86,14.34。
步骤5
将该酸(0.48g,1.75mmol)于乙醇(12mL)中的溶液用碳酸氢钠(0.15g,1.75mmol)于水(3mL)中的溶液处理,且将反应物在室温下搅拌3天。在真空中蒸发乙醇,且将残余水性浆用水(50mL)稀释,过滤(PES,0.2μm)且冻干,得到呈白色固体的2-[3,5-二戊基苯基]乙酸钠(0.52g,定量)。熔点225-230℃;1H NMR(400MHz,CD3OD+D2O):δ6.92(s,2H),6.76(s,1H),3.41(s,2H),2.50(t,J=7.5Hz,2H),1.52-1.59(m,2H),1.23-1.33(m,4H),0.85(t,J=6.9Hz,3H);13C NMR(101MHz,CD3OD+D2O):δ179.99,142.66,137.63,126.66,126.16,45.11,35.61,31.36,31.19,22.41,13.47;LRMS(ESI):m/z 277.5(w,[M–Na++2H+]),231.1(100%,因失去羧基而产生的鎓离子);HPLC:3.0min。
化合物XV:2-(3,5-二己基苯基)乙酸的钠盐
以上化合物是自(E)-己-1-烯基硼酸频哪醇酯如化合物XIV一般进行制备。白色固体;1H NMR(400MHz,CD3OD):δ6.96(s,2H),6.79(s,1H),3.43(s,2H),2.54(d,J=7.7Hz,4H),1.55-1.63(m,4H),1.28-1.36(m,12H),0.89(t,J=6.8Hz,6H);13C NMR(101MHz,CD3OD):δ179.68,142.38,137.82,126.55,126.07,45.30,35.87,31.83,31.67,29.02,22.61,13.42;LRMS(ESI):m/z 322.0(100%,M-Na++H++NH4+)和259.0(35%,M–CO2Na);UPLC(系统A):8.9min。UPLC系统A:移动相A=10mM碳酸氢铵水溶液;移动相B=乙腈;固相=HSS T3柱;梯度=经10分钟5-100%B/A。
化合物XVI:2-(2-羟基-3,5-二戊基苯基)乙酸的钠盐
步骤1
将2,4-二溴-6-(溴甲基)苯酚(3.5g,10.0mmol)于乙腈(17mL)中的溶液用氰化钠(2.5g,50.0mmol)的溶液处理,且将反应物在100℃下在回流下加热1h。将反应混合物冷却至室温且倾入水(100mL)中。用1M盐酸水溶液将pH值自10调节至8,且将混合物用乙酸乙酯(3×250mL)萃取。将合并的萃取物用1M盐酸水溶液(250mL)且用饱和氯化钠水溶液(250mL)洗涤;经硫酸钠干燥;过滤且在真空中蒸发,得到粗产物。用丙酮萃取;过滤;且在真空中蒸发,得到2-(3,5-二溴-2-羟苯基)乙腈(2.6g,90%)。1H NMR(400MHz,d6-丙酮):δ8.75(brs,1H),7.69(d,J=2.3Hz,1H),7.54(d,J=2.3Hz,1H),3.92(s,2H);13C NMR(101MHz,d6-丙酮):δ151.31,134.51,131.92,122.80,117.43,111.89,111.53,18.70。
步骤2
将2-(3,5-二溴-2-羟苯基)乙腈(2.6g,9.0mmol)用硫酸(2.5mL)、乙酸(2.5mL)和水(2.5mL)的混合物处理,且将反应物在125℃下在回流下加热2h。将反应混合物冷却至室温且倾入冰(50mL)与水(50mL)的混合物中,且然后搅拌直至冰已溶解为止。将混合物用乙酸乙酯(250mL)萃取;且然后将萃取物用水(100mL)且用饱和氯化钠水溶液(100mL)洗涤;经硫酸钠干燥;过滤且在真空中蒸发,得到粗2-(3,5-二溴-2-羟苯基)乙酸(3.1g)。此物质未进一步纯化或表征即直接用于下一步骤。
步骤3
将粗2-(3,5-二溴-2-羟苯基)乙酸(3.1g,9.0mmol)于甲醇(17mL)中的溶液用硫酸(0.43mL,8.1mmol)处理,且将反应物在周围温度下搅拌16h。在真空中蒸发甲醇,且将残余物溶解于乙酸乙酯(270mL)中。将溶液用水(2×200mL)且用饱和氯化钠水溶液(130mL)洗涤;经硫酸钠干燥;过滤且在真空中蒸发,得到粗产物。在BiotageTMSP1系统(120g二氧化硅柱)上纯化,用0-20%乙酸乙酯/己烷洗脱,得到2-(3,5-二溴-2-羟苯基)乙酸甲酯(1.4g,49%)。1H NMR(400MHz,CDCl3):δ7.52(d,J=2.2Hz,1H),7.23(d,J=2.2Hz,1H),6.42(br s,1H),3.72(s,3H),3.65(s,2H);13C NMR(101MHz,CDCl3):δ172.06,150.60,133.74,133.50,123.94,112.62,111.77,52.78,36.61。
步骤4
将2-(3,5-二溴-2-羟苯基)乙酸甲酯(0.5g,1.54mmol)于丙酮(5mL)中的溶液用碳酸钾(0.26g,1.86mmol)、碘化钾(0.05g,0.32mmol)和溴甲苯(0.20mL,1.7mmol)处理,且将反应物在室温下搅拌1h。在真空中蒸发丙酮,且将残余物分配于乙酸乙酯(50mL)与1M盐酸水溶液(50mL)之间。将有机相用饱和氯化钠水溶液(50mL)洗涤;经硫酸钠干燥;过滤且在真空中蒸发,得到粗产物。在BiotageTMSP1系统(40g二氧化硅柱)上纯化,用0-10%乙酸乙酯/己烷洗脱,得到2-(2-(苄氧基)-3,5-二溴苯基)乙酸甲酯(0.6g,95%)。1H NMR(400MHz,CDCl3):δ7.67(d,J=2.4Hz,1H),7.48-7.51(m,2H),7.37(d,J=2.4Hz,1H),7.34-7.43(m,3H),4.99(s,2H),3.66(s,3H),3.60(s,2H);13C NMR(101MHz,CDCl3):δ171.26,153.79,136.56,135.38,133.57,132.04,128.82,128.64,128.52,118.69,117.56,75.53,52.50,35.86。
步骤5
如化合物I,步骤2一般使2-(2-(苄氧基)-3,5-二溴苯基)乙酸甲酯(0.3g,0.73mmol)与(E)-戊-1-烯基硼酸频哪醇酯(0.4g,1.79mmol)偶合,得到2-(2-(苄氧基)-3,5-二((E)-戊-1-烯基)苯基)乙酸甲酯(0.21mg,72%)。1H NMR(400MHz,CDCl3):δ7.50(d,J=7.2Hz,2H),7.44(dd,J=7.2,7.2Hz,2H),7.43(d,J=2.1Hz,1H),7.38(dd,J=7.2,7.2Hz,1H),7.18(d,J=2.1Hz,1H),6.72(d,J=15.8Hz,1H),6.39(d,J=15.8Hz,1H),6.32(dt,J=15.8,7.0Hz,1H),6.22(dt,J=15.8,6.8Hz,1H),4.87(s,2H),3.69(s,3H),3.67(s,2H),2.20-2.29(m,4H),1.50-1.60(m,4H),1.01(t,J=7.3Hz,3H),1.00(t,J=7.4Hz,3H);13CNMR(101MHz,CDCl3):δ172.49,153.59,137.58,134.35,132.91,131.91,130.84,129.53,128.78,128.32,128.30,128.24,127.26,125.21,123.89,75.89,52.21,35.94,35.74,35.42,22.87,22.77,14.07,14.06。
步骤6
如化合物I,步骤3一般将2-(2-(苄氧基)-3,5-二((E)-戊-1-烯基)苯基)乙酸甲酯(0.2g,0.53mmol)氢化,得到2-(2-羟基-3,5-二戊基苯基)乙酸甲酯(0.12g,73%)。1H NMR(400MHz,CDCl3):δ7.37(s,1H),6.92(d,J=2.1Hz,2H),6.77(d,J=2.1Hz,1H),3.76(s,3H),3.67(s,2H),2.65(t,J=7.8Hz,2H),2.51(t,J=7.8Hz,2H),1.58-1.66(m,4H),1.31-1.41(m,8H),0.93(t,J=7.0Hz,3H),0.92(t,J=6.9Hz,3H);13C NMR(101MHz,CDCl3):δ175.01,151.27,135.14,131.48,129.92,128.52,120.30,52.95,38.35,35.34,32.15,31.86,31.74,30.61,30.03,22.87,22.83,14.34,14.31。
步骤7
如化合物I,步骤4一般将2-(2-羟基-3,5-二戊基苯基)乙酸甲酯(0.2g,0.53mmol)水解,得到混合有内酯化物质的粗产物。将一小部分在BiotageTMSP1系统(120g二氧化硅柱)上纯化,用0-100%乙酸乙酯/己烷洗脱,得到2-(2-羟基-3,5-二戊基苯基)乙酸(13.5mg)。1H NMR(400MHz,CDCl3):δ10.5(br s,1H),6.89(d,J=2.2Hz,1H),6.78(d,J=2.2Hz,1H),6.32(br s,1H),3.66(s,2H),2.58(t,J=7.9Hz,2H),2.48(t,J=7.8Hz,2H),1.52-1.63(m,4H),1.26-1.37(m,8H),0.90(t,J=7.0Hz,3H),0.88(t,J=6.8Hz,3H)。
步骤8
如化合物I,步骤5一般将2-(2-羟基-3,5-二戊基苯基)乙酸(13.5mg,0.046mmol)转化为钠盐,得到2-(2-羟基-3,5-二戊基苯基)乙酸钠(11mg,77%)。1H NMR(400MHz,CD3OD):δ6.72(d,J=2.0Hz,1H),6.69(d,J=2.0Hz,1H),3.46(s,2H),2.56(t,J=7.6Hz,2H),2.44(t,J=7.6Hz,2H),1.50-1.61(m,4H),1.25-1.37(m,8H),0.90(t,J=6.8Hz,3H),0.88(t,J=7.0Hz,3H);13C NMR(101MHz,CD3OD):δ180.33,151.94,133.47,130.37,128.21,127.81,123.99,42.90,34.97,31.81,31.60,31.40,30.25,29.88,22.51,22.45,13.29,13.24;LRMS(ESI负):m/z 291.2(100%,M–Na+);UPLC(系统B):7.7min。UPLC系统B:移动相A=0.1%甲酸水溶液;移动相B=0.1%甲酸/乙腈;固相=HSS T3柱;梯度=经10分钟5-100%B/A。
化合物XVII:2-(3,5-二己基-2-羟苯基)乙酸的钠盐
以上化合物是使用(E)-己-1-烯基硼酸频哪醇酯如化合物XVI一般进行制备。1HNMR(400MHz,CD3OD):δ6.72(d,J=2.0Hz,1H),6.69(d,J=2.0Hz,1H),3.46(s,2H),2.56(t,J=7.6Hz,2H),2.44(t,J=7.5Hz,2H),1.50-1.60(m,4H),1.27-1.37(m,12H),0.89(t,J=6.6Hz,3H),0.88(t,J=6.80Hz,3H);LRMS(ESI负):m/z 319(100%,M–Na+);UPLC(系统B):8.7min。ULC系统B:移动相A=0.1%甲酸水溶液;移动相B=0.1%甲酸/乙腈;固相=HSS T3柱;梯度=经10分钟5-100%B/A。
化合物XVIII:2-(4-羟基-3,5-二戊基苯基)乙酸的钠盐
以上化合物是自2-(3,5-二溴-4-羟苯基)乙酸如化合物XVI一般进行制备。1H NMR(400MHz,CD3OD):δ6.87(s,2H),3.33(s,2H),2.55(t,J=7.7Hz,4H),1.53-1.61(m,4H),1.31-1.37(m,8H),0.90(t,J=7.0Hz,6H);LRMS(ESI负):m/z 291.1(100%,M–Na+);UPLC(系统B):6.8min。UPLC系统B:移动相A=0.1%甲酸水溶液;移动相B=0.1%甲酸/乙腈;固相=HSS T3柱;梯度=经10分钟5-100%B/A。
化合物XIX:2-(3,5-二己基-4-羟苯基)乙酸的钠盐
以上化合物是自2-(3,5-二溴-4-羟苯基)乙酸和(E)-己-1-烯基硼酸频哪醇酯如化合物XVI一般进行制备。1H NMR(400MHz,CD3OD):δ6.72(d,J=2.0Hz,1H),6.69(d,J=2.0Hz,1H),3.46(s,2H),2.56(t,J=7.6Hz,2H),2.44(t,J=7.5Hz,2H),1.50-1.60(m,4H),1.27-1.37(m,12H),0.89(t,J=6.6Hz,3H),0.88(t,J=6.8Hz,3H);LRMS(ESI负):m/z319.1(100%,M–Na+);UPLC(系统B):7.6min。UPLC系统B:移动相A=0.1%甲酸水溶液;移动相B=0.1%甲酸/乙腈;固相=HSS T3柱;梯度=经10分钟5-100%B/A。
化合物XX:2-(4-氟-3,5-二己基苯基)乙酸的钠盐
以上化合物是以3,5-二溴-4-氟苯甲基溴化物和(E)-己-1-烯基硼酸频哪醇酯为起始物质如化合物XVI一般进行制备。3,5-二溴-4-氟苯甲基溴化物是通过在80℃下于乙腈中用N-溴丁二酰亚胺和偶氮二异丁腈将3,5-二溴-4-氟代甲苯溴化来进行制备。1H NMR(400MHz,CD3OD):δ6.98(d,JHF=7.0Hz,2H),3.38(s,2H),2.57(t,J=7.7Hz,4H),1.54-1.61(m,4H),1.28-1.37(m,12H),0.89(t,J=6.7Hz,6H);19F NMR(377MHz,CD3OD):δ-132.17(d,JHF=6.6Hz,1F);13C NMR(101MHz,CD3OD):δ179.44,158.11(d,JCF=239.8Hz),133.26(d,JCF=3.8Hz),128.73(d,JCF=5.4Hz),128.56(d,JCF=16.9Hz),44.52,31.69,30.35(d,JCF=1.5Hz),28.98,28.97(d,JCF=3.1Hz),22.51,13.29;LRMS(ESI负):m/z321.0(100%,M–Na+);UPLC(系统B):9.2min。UPLC系统B:移动相A=0.1%甲酸水溶液;移动相B=0.1%甲酸/乙腈;固相=HSS T3柱;梯度=经10分钟5-100%B/A。
化合物XXI:2-(4-氟-3,5-二戊基苯基)乙酸的钠盐
以上化合物是以3,5-二溴-4-氟苯甲基溴化物为起始物质如化合物XVI一般进行制备。1H NMR(400MHz,CD3OD):δ6.98(d,JHF=6.8Hz,2H),3.37(s,2H),2.57(t,J=7.6Hz,4H),1.54-1.62(m,4H),1.28-1.37(m,8H),0.90(t,J=7.0Hz,6H);19F NMR(377MHz,CD3OD):δ-132.34(d,JHF=6.6Hz,1F);13C NMR(101MHz,CD3OD):δ179.41,158.10(d,JCF=239.8Hz),133.26(d,JCF=3.8Hz),128.72(d,JCF=4.6Hz),128.56(d,JCF=16.9Hz),44.51,31.54,30.07,28.92(d,JCF=3.1Hz),22.38,13.22;LRMS(ESI负):m/z 293.0(100%,M–Na+);UPLC(系统B):8.4min。UPLC系统B:移动相A=0.1%甲酸水溶液;移动相B=0.1%甲酸/乙腈;固相=HSS T3柱;梯度=经10分钟5-100%B/A。
化合物XXII:2-(2-苯甲基-3,5-二戊基苯基)乙酸的钠盐
标题化合物是自2-(2-苯甲基-3,5-二((E)-戊-1-烯基)苯基)乙酸甲酯如化合物XIV一般进行制备。自按比例增加的化合物XIV中分离后者作为副产物(1.1%产率)。1H NMR(400MHz,CD3OD):δ7.17(dd,J=7.3,7.3Hz,2H),7.09(dd,J=7.3,7.3Hz,1H),6.97-6.99(m,3H),6.86(d,J=1.8Hz,1H),4.13(s,2H),3.40(s,2H),2.55(t,J=7.7Hz,2H),2.49(t,J=7.8Hz,2H),1.59-1.67(m,2H),1.31-1.45(m,6H),1.21-1.26(m,4H),0.91(t,J=7.0Hz,3H),0.82(t,J=7.0Hz,3H);13C NMR(101MHz,CD3OD):δ179.48,141.46,141.24,140.47,137.46,133.70,128.36,128.05,127.86,127.75,125.42,43.25,35.54,33.90,33.61,31.86,31.65,31.25,30.96,22.49,22.40,13.31,13.23;LRMS(ESI负):m/z 365.0(20%,M–Na+),321.1(100%,M–CO2Na);UPLC(系统B):9min。(UPLC系统B:移动相A=0.1%甲酸水溶液;移动相B=0.1%甲酸/乙腈;固相=HSS T3;梯度=经10分钟5-100%B/A。)
化合物XXIII:2-[3,5-二[(E)-戊-1-烯基]苯基]乙酸钠
标题化合物是使用与化合物XIV相同的程序进行制备,但省略加氢步骤。熔点226-30℃;1H NMR(400MHz,CD3OD):δ7.18(d,J=1.2Hz,2H),7.11(d,J=1.2Hz,1H),6.34(d,J=15.9Hz,2H),2.23(dt,J=15.9,6.7Hz,2H),3.44(s,2H),2.14-2.19(m,4H),1.49(tq,J=7.4,7.4Hz,4H),0.95(t,J=7.3Hz,6H);13C NMR(101MHz,CD3OD):δ179.41,138.34,138.06,130.30,130.16,125.26,121.60,45.24,35.10,22.55&12.98;LRMS(负模式):m/z 271(w,[M–Na+]),227.2(100%,[M–Na+–CO2]);UPLC:8min。(UPLC;条件溶剂A=0.1%甲酸/水;溶剂B=0.1%甲酸/乙腈;梯度:在0.7mL/min下经10分钟5-100%B/A。)
化合物XXIV:3-[3,5-二戊基苯基]丙酸钠
标题化合物是以3-[3,5-二溴苯基]丙酸为起始物质使用与化合物XIV相同的程序进行制备。熔点211-217℃;1H NMR(400MHz,CDCl3):δ6.73(s,1H),6.68(s,2H),2.73-2.77(m,2H),2.42-2.46(m,2H),2.38(t,J=7.8Hz,4H),1.43-1.51(m,4H),1.19-1.28(m,8H),0.83(t,J=6.9Hz,6H);13C NMR(101MHz,CDCl3):δ182.55,142.93,141.85,125.96,125.77,39.80,36.13,32.77,31.99,31.47,22.79&14.27;LRMS(负模式):m/z 289.4(100%,[M–Na+]);UPLC:9min。(UPLC:条件溶剂A=0.1%甲酸/水,溶剂B=0.1%甲酸/乙腈,梯度:在0.7mL/min下经10min 5-100%B/A。
化合物XXV:2-甲基-2-(3-戊基苯基)丙酸的钠盐
标题化合物是自2-[3-溴苯基]乙酸甲酯如化合物XIV一般进行制备,同时具有用氢化钠和碘甲烷将2-[3-戊基苯基]乙酸甲酯烷基化的额外步骤;且其中酯水解步骤的温度升至50℃。米白色固体:1H NMR(400MHz,D2O):δ7.11(dd,J=7.7,7.7Hz,1H),7.07(s,1H),7.02(d,J=7.6Hz,1H),6.95(d,J=7.4Hz,1H),2.44(t,J=7.7Hz,2H),1.43(tt,J=7.4,7.4Hz,2H),1.28(s,6H),1.09-1.17(m,4H),0.68(t,J=7.0Hz,3H);13C NMR(101MHz,D2O):δ186.51,148.17,143.67,128.48,126.27,126.24,123.26,48.67,35.33,30.90,30.77,27.20,22.01,13.46;LRMS(ESI+ve):m/z 189.1(100%,MH+-CO2Na);HPLC:5min(经5min15-99%乙腈/水(于两种溶剂中的三氟乙酸)。
化合物XXVI:(RS)-2-(3-戊基苯基)丙酸的钠盐
步骤1
将碘化铜(I)(17mg,0.09mmol)、2-吡啶甲酸(22mg,0.18mmol)和碳酸铯(1.7g,5.30mmol)的混合物在氩气下用无水1,4-二噁烷(3ml)、丙二酸二乙酯(0.54ml,3.5mmol)和1-溴-3-碘苯(0.23ml,1.77mmol)处理。然后将反应物在氩气下在70℃下加热15h。将粗反应混合物蒸发至硅胶上且在SiliaSep SiO2柱上纯化,用乙酸乙酯/己烷(0-12%)洗脱,得到2-[3-溴苯基]丙二酸二乙酯(0.34g,64%)。1H NMR(400MHz,CDCl3):δ7.30-7.47(m,3H),7.20-7.26(m,1H),4.16-4.24(m,4H),3.36(s,1H),1.23-1.29(m,6H)。
步骤2
将氢化钠(60%w/w;0.53g,13.3mmol)于无水THF(16ml)中的悬浮液在氩气下冷却至0℃,且用2-[3-溴苯基]丙二酸二乙酯(3.0g,9.52mmol)于无水THF(20ml)中的溶液处理。将反应混合物在0℃下搅拌30min,且然后用碘甲烷(0.8ml,13.3mmol)逐滴处理。然后将反应混合物升温至室温,且在室温下在氩气下搅拌隔夜。用饱和氯化铵水溶液(100ml)中止反应,且将混合物用乙酸乙酯(3×100ml)萃取。将合并的有机萃取物干燥(硫酸镁)且在真空中蒸发,得到粗化合物。在SiliaSep SiO2柱上纯化,用乙酸乙酯/己烷(0-5%)洗脱,得到2-[3-溴苯基]-2-甲基丙二酸二乙酯(2.6g,82%)。1H NMR(400MHz,CDCl3):δ7.52(ddd,J=1.9,1.9,0.4Hz,1H),7.43(ddd,J=7.9,1.9,1.0Hz,1H),7.31(ddd,J=8.0,1.9,1.0Hz,1H),7.20(ddd,J=7.9,7.9,0.4Hz,1H),4.21-4.26(m,4H),1.84(s,3H),1.26(t,J=7.2Hz,6H)。
步骤3
使用在化合物X,步骤4中所描述的方法使2-[3-溴苯基]-2-甲基丙二酸二乙酯(2.6g,7.8mmol)与(E)-1-戊烯-1-基硼酸频哪醇酯(2.1g,10.9mmol)偶合,得到(E)-2-甲基-2-[3-[戊-1-烯基]苯基]丙二酸二乙酯(1.7g,68%)。1H NMR(400MHz,CDCl3):δ7.24-7.32(m,3H),7.21(ddd,J=7.1,1.9,1.9Hz,1H),6.37(d,J=15.9Hz,1H),6.20(dt,J=15.9,6.9Hz,1H),4.21-4.26(m,4H),2.15-2.21(m,2H),1.87(s,3H),1.49(tt,J=7.3,7.3Hz,2H),1.26(t,J=7.2Hz,6H),0.95(t,J=7.4Hz,3H)。
步骤4
使用在化合物I,步骤3中所描述的方法将(E)-2-甲基-2-[3-[戊-1-烯基]苯基]丙二酸二乙酯(1.4g,4.27mmol)氢化,得到2-甲基-2-[3-戊基苯基]丙二酸二乙酯(1.2g,91%)。1H NMR(400MHz,CDCl3):δ7.24(dd,J=7.3,7.3Hz,1H),7.16(d,J=7.3Hz,1H),7.15(s,1H),7.10(d,J=7.6Hz,1H),4.20-4.25(m,4H),2.59(t,J=7.9Hz,2H),1.85(s,3H),1.49(tt,J=7.6,7.6Hz,2H),1.28-1.34(m,4H),1.25(t,J=7.0Hz,6H),0.88(t,J=7.0Hz,3H)。
步骤5
将2-甲基-2-[3-戊基苯基]丙二酸二乙酯(1.1g,3.5mmol)于乙腈(9ml)、甲醇(3ml)和水(3ml)中的溶液用氢氧化锂(1.3g,52.8mmol)处理,且将混合物在50℃下加热48h。将反应混合物在真空中浓缩,用水(10ml)稀释,且然后用二氯甲烷(15ml)洗涤。然后将水相的pH值用1M盐酸水溶液调节至pH 4,且将混合物用二氯甲烷(3×25ml)萃取。将合并的有机萃取物干燥(硫酸镁)且在真空中蒸发,得到粗化合物。在SiliaSep SiO2柱上纯化,用乙酸乙酯/己烷(0-20%)洗脱,得到(RS)-2-[3-戊基苯基]丙酸(0.4g,52%)。1H NMR(400MHz,CD3OD):δ7.20(dd,J=7.6,7.6Hz,1H),7.03-7.12(m,3H),3.66(q,J=7.1Hz,1H),2.58(t,J=7.8Hz,2H),1.60(tt,J=7.6,7.6Hz,2H),1.42(d,J=7.1Hz,3H),1.27-1.38(m,4H),0.90(t,J=7.1Hz,3H)。
步骤6
使用在化合物I,步骤5中所描述的方法将(RS)-2-[3-戊基苯基]丙酸(0.4g,1.8mmol)转化为钠盐,得到(RS)-2-[3-戊基苯基]丙酸钠(0.44g,定量)。1H NMR(400MHz,CD3OD):δ7.19(s,1H),7.14-7.17(m,1H),7.13(dd,J=7.5,7.5Hz,1H),6.95(d,J=6.9Hz,1H),3.54(q,J=7.1Hz,1H),2.56(t,J=7.8Hz,2H),1.60(tt,J=7.5,7.5Hz,2H),1.39(d,J=7.2Hz,3H),1.29-1.35(m,4H),0.90(t,J=7.0Hz,3H);13C NMR(101MHz,CD3OD):δ182.18,144.23,142.49,127.76,127.55,125.82,124.73,49.17,35.85,31.54,31.33,22.43,18.95,13.22;HPLC:5min(经5min 15-99%乙腈/水(于两种溶剂中的三氟乙酸)。
化合物XXVII:2-(2-羟基-5-戊基苯基)乙酸的钠盐
以上化合物是使用2-[2-(苄氧基)-5-溴苯基]乙酸甲酯(以2个步骤自2-[5-溴-2-羟苯基]乙酸制备)以与化合物VII,步骤3-6相同的方式制备。白色固体:1H NMR(400MHz,CD3OD):δ6.82-6.88(m,2H),6.69(d,J=8.6Hz,1H),3.47(s,2H),2.47(t,J=7.7Hz,2H),1.51-1.59(m,2H),1.24-1.36(m,4H),0.89(t,J=7.0Hz,3H);13C NMR(101MHz,CD3OD):δ180.04,154.04,134.05,130.25,127.36,124.15,116.57,42.50,34.90,31.59,31.42,22.44,13.23;LRMS(ESI-ve):m/z 221.1(100%,M-Na+),177.1(m,M-Na+-CO2);HPLC:2min(梯度使用在经5min 70-99%乙腈/水和于两种溶剂中的三氟乙酸)。
化合物XXVIII:2-氧代-2-[3-戊基苯基]乙酸的钠盐
步骤1:
i)将2-[3-戊基苯基]乙酸甲酯(0.5g,2.0mmol)于乙腈(15ml)中的溶液在氮气下用1,8-二氮杂双环[5.4.0]十一-7-烯(0.22ml,1.5mmol)处理,且将反应物在室温下搅拌15min。将反应物冷却至0℃,且缓慢添加4-乙酰胺基苯磺酰基叠氮化物(0.6g,2.4mmol)。然后将反应物升温至室温,且在氮气下搅拌22.5h。
ii)将2-重氮基-2-[3-戊基苯基]乙酸甲酯中间物的此溶液用甲苯(15ml)、丙酮(11ml)和水(15ml)稀释,且然后用碳酸氢钠(6.4g,75.7mmol)处理。缓慢添加过硫酸氢钾(12.1g,19.7mmol),且然后将反应混合物在室温下剧烈搅拌25min。将反应物用水(30ml)稀释,且然后用乙酸乙酯(3×30ml)萃取。将合并的萃取物用饱和氯化钠水溶液(30ml)洗涤,经硫酸钠干燥,且在真空中蒸发,得到粗产物。用二氯甲烷萃取且在SiliaSep SiO2柱上纯化,用乙酸乙酯/己烷(0-2%)洗脱,得到2-氧代-2-[3-戊基苯基]乙酸甲酯(0.13g,30%)。1H NMR(400MHz,CDCl3):δ7.79-7.82(m,2H),7.47(d,J=7.6Hz,1H),7.66(dd,J=7.6,7.6Hz,1H),3.97(s,3H),2.66(d,J=7.8Hz,2H),1.58-1.64(m,2H),1.27-1.35(m,4H),0.88(t,J=6.9Hz,3H);13C NMR(101MHz,CDCl3):δ186.61,164.48,144.17,135.53,132.61,129.88,129.01,127.97,52.96,35.87,31.58,31.18,22.70,14.22。
步骤2
如化合物IX,步骤5中所描述将2-氧代-2-[3-戊基苯基]乙酸甲酯(64mg,0.8mmol)水解,得到2-氧代-2-[3-戊基苯基]乙酸(60mg,定量)。1H NMR(400MHz,CDCl3):δ10.32(brs,1H),7.98(d,J=7.4Hz,1H),7.96(s,1H),7.43(d,J=7.5Hz,1H),7.36(dd,J=7.4,7.4Hz,1H),),2.60(d,J=7.7Hz,2H),1.52-1.59(m,2H),1.20-1.29(m,4H),0.81(t,J=6.8Hz,3H);13C NMR(101MHz,CDCl3):δ185.51,164.18,144.28,136.10,132.04,130.81,129.12,128.85,35.90,31.59,31.19,22.71,14.23。
步骤3
使用在化合物I,步骤5中所描述的方法将2-氧代-2-[3-戊基苯基]乙酸(57mg,0.3mmol)转化为钠盐,得到2-氧代-2-[3-戊基苯基]乙酸钠(51mg,95%)。1H NMR(400M Hz,CD3OD):δ7.79-7.81(m,2H),7.45(ddd,J=7.6,1.5,1.5Hz,1H),7.41(ddd,J=7.8,7.8,1.0Hz,1H),2.67(t,J=7.6Hz,2H),1.64(tt,J=7.5,7.5Hz,2H),1.28-1.39(m,4H),0.90(t,J=7.1Hz,3H);13C NMR(101MHz,CD3OD):δ196.19,172.77,143.54,133.89,133.76,129.34,128.47,127.03,35.45,31.32,31.06,22.38,13.20;LRMS(ESI-ve):m/z 219.1(100%,M–Na+);HPLC:3.3min(梯度使用经5min 15-99%乙腈/水和于两种溶剂中的三氟乙酸)。
化合物XXIX:(E)-2-[2-氟-5-[戊-1-烯基]苯基]乙酸的钠盐
以上化合物是自2-[2-氟-5-溴苯基]乙酸甲酯如化合物XIV一般进行制备,且省略加氢步骤。白色固体;1H NMR(400MHz,CD3OD):δ7.32(dd,JHF=7.4Hz,JHH=2.1Hz,1H),7.15-7.18(m,1H),6.92(dd,JHF=9.4Hz,JHH=8.8Hz,1H),6.33(d,J=15.8Hz,1H),6.16(dd,J=15.8,7.0Hz,1H),2.16(td,J=7.1,7.1Hz,2H),1.48(tt,J=7.3,7.3Hz,2H),0.95(t,J=7.3Hz,3H);19F NMR(377MHz,CD3OD):δ-122.74至-122.26(m,1F),13C NMR(101MHz,CD3OD):δ177.91,160.51(d,JCF=243.6Hz),134.08(d,JCF=3.8Hz),129.87(d,JCF=1.5Hz),129.23,128.94(d,JCF=4.6Hz),125.09-125.26(m,2C),114.63(d,JCF=22.3Hz),37.75(d,JCF=1.5Hz),35.00,22.50,12.87;LRMS(ESI-ve):m/z 176.9(100%,M–Na+–CO2);HPLC:6min(UPLC梯度:移动相A=0.1%甲酸/水;移动相B=0.1%甲酸/乙腈;固相=HSS T3;梯度=经10min 5-100%B/A)。
化合物XXX:2-[2-苯甲基-5-戊基苯基]乙酸的钠盐
步骤1
将化合物XXVII(2.4g,10.0mmol)以与化合物IX,步骤1相同的方式酯化,得到2-[2-羟基-5-戊基苯基]乙酸甲酯(2.3g,96%)。1H NMR(400MHz,CDCl3):δ7.24(br s,1H),6.98(dd,J=8.2,2.3Hz,1H),6.90(d,J=2.3Hz,1H),6.83(d,J=8.2Hz,1H),3.73(s,3H),3.65(s,2H),2.50(t,J=7.9Hz,2H),1.52-1.60(m,2H),1.25-1.36(m,4H),0.86-0.90(m,3H)。
步骤2
如化合物VII,步骤2中所描述将2-[2-羟基-5-戊基苯基]乙酸甲酯(2.3g,9.6mmol)转化为三氟甲烷磺酸酯衍生物,得到2-[5-戊基-2-(三氟甲基磺酰氧基)苯基]乙酸甲酯(3.4g,97%)。1H NMR(400MHz,CDCl3):δ7.20(d,J=8.6Hz,1H),7.18(d,J=2.4Hz,1H),7.16(dd,J=8.6,2.4Hz,1H),3.72(s,3H),3.71(s,2H),2.60(t,J=7.8Hz,2H),1.56-1.64(m,2H),1.27-1.37(m,4H),0.89(t,J=6.9Hz,3H);19F NMR(377MHz,CDCl3):δ-73.92(s,3F);13C NMR(101MHz,CDCl3):δ170.59,146.25,143.76,132.42,129.30,126.95,121.31,118.76(q,JCF=319.8Hz),52.38,35.70,35.40,31.62,31.08,22.66,14.10。
步骤3
将氮气冲洗的压力容器连续地装入磷酸三钾(5.4g,25.3mmol);乙酸钯(II)(74mg,0.33mmol);2-二环己基膦基-2’,6’-二甲氧基-1,1’-联苯(0.14g,0.33mmol);2-[5-戊基-2-(三氟甲基磺酰氧基)苯基]乙酸甲酯(3.1g,8.3mmol)于无水四氢呋喃(20ml)中的溶液和9-苯甲基-9-硼双环[3.3.1]壬烷于四氢呋喃(34ml,17mmol)中的0.5M溶液。然后将容器密封,且将反应物在60℃下加热。在17h之后,将反应混合物冷却至室温且分配于乙酸乙酯(300ml)与0.5M氢氧化钠水溶液(250ml)之间。将有机相用饱和氯化钠水溶液(200ml)洗涤,经硫酸钠干燥,过滤且在真空中蒸发,得到粗化合物。在SiliaSep SiO2柱上纯化,用乙酸乙酯/己烷(0-2%)洗脱,得到2-[2-苯甲基-5-戊基苯基]乙酸甲酯(2.5g,96%)。1HNMR(400MHz,CDCl3):δ7.29(dd,J=7.4,7.0Hz,2H),7.21(dd,J=7.4,7.0Hz,1H),7.13-7.15(m,2H),7.08-7.09(m,3H),4.04(s,2H),3.63(s,3H),3.60(s,2H),2.61(t,J=7.8Hz,2H),1.61-1.68(m,2H),1.34-1.39(m,4H),0.93(t,J=7.1Hz,3H);13C NMR(101MHz,CDCl3):δ172.29,141.66,140.65,136.61,132.84,131.21,130.87,129.03,128.67,127.83,126.28,52.19,39.01,39.00,35.73,31.89,31.40,22.84,14.35。
步骤4
如化合物IX,步骤5中所描述将2-[2-苯甲基-5-戊基苯基]乙酸甲酯(2.9g,9.3mmol)水解,得到2-[2-苯甲基-5-戊基苯基]乙酸(2.48g,90%)。1H NMR(400MHz,CDCl3):δ7.26(dd,J=7.3,7.3Hz,2H),7.16(dd,J=7.5,7.5Hz,1H),7.10-7.13(m,2H),7.05-7.07(m,3H),4.01(s,2H),3.58(s,2H),2.58(t,J=7.8Hz,2H),1.57-1.65(m,2H),1.30-1.37(m,4H),0.90(t,J=7.0Hz,3H);13C NMR(101MHz,CDCl3):δ178.67,141.80,140.51,136.84,132.20,131.37,130.95,129.08,128.75,128.13,136.39,39.07,38.98,35.74,31.93,31.41,22.87,14.38。
步骤5
使用在化合物I,步骤5中所描述的方法将2-[2-苯甲基-5-戊基苯基]乙酸(2.5g,8.4mmol)转化为钠盐,得到2-[2-苯甲基-5-戊基苯基]乙酸钠(2.5g,93%)。1H NMR(400MHz,CD3OD):δ7.22(dd,J=8.4,7.4Hz,2H),7.09-7.15(m,3H),6.92-6.93(m,3H),4.03(s,2H),3.47(s,2H),2.55(t,J=7.8Hz,2H),1.57-1.65(m,2H),1.28-1.38(m,4H),0.90(t,J=7.0Hz,3H);13C NMR(101MHz,CD3OD):δ179.25,141.25,140.60,136.90,136.48,130.45,129.78,128.83,128.13,126.13,125.64,42.70,38.49,35.49,31.64,31.32,22.51,13.35;LRMS(ESI-ve):m/z295.2(40%,M–Na+),251.2(100%,M–Na+–CO2);HPLC:5.0min(梯度使用经5min 70-99%MeCN/水和于两种溶剂中的三氟乙酸)。
化合物XXXI:2-(3,5-二((E)-己-1-烯基)苯基)乙酸的钠盐
以与化合物II相同的方式制备标题化合物,但省略加氢步骤。米白色固体:1H NMR(400MHz,CD3OD):δ7.17(d,J=1.1Hz,2H),7.10(s,1H),6.33(d,J=15.8Hz,2H),6.22(dt,J=15.8,6.7Hz,2H),3.44(s,2H),2.16-2.21(m,4H),1.34-1.46(m,8H),0.93(t,J=7.3Hz,6H);13C NMR(101MHz,CD3OD):δ179.44,138.34,138.07,130.37,130.13,125.27,121.60,45.26,32.70,31.67,22.19,13.27;LRMS(ESI负模式):m/z 299.2(m,M-Na+)和255.2(100%,M–Na+–CO2);UPLC:8.7min.(UPLC条件:溶剂A=0.1%甲酸/水;移动相B=0.1%甲酸/乙腈;固相=HSS T3;梯度=经10min 5-100%B/A)
化合物XXXII:2-(2-氟-3,5-二戊基苯基)乙酸的钠盐
步骤1:
使用关于化合物I所描述的方法使2-氨基-3,5-二溴苯甲酸甲酯(10.0g,32.4mmol)与(E)-1-戊烯-1-基硼酸频哪醇酯(15.2g,77.7)偶合,得到2-氨基-3,5-二[(E)-戊-1-烯基]苯甲酸甲酯(6.00g,64%)。1H NMR(400MHz,CDCl3):δ7.76(d,J=2.2Hz,1H),7.37(d,J=2.2Hz,1H),6.35(d,J=15.4Hz,1H),6.26(d,J=15.8Hz,1H),6.08(dt,J=15.6,7.0Hz,1H),6.06(dt,J=15.8,7.0Hz,1H),5.5-6.5(br s,2H),3.87(s.3H),2.19-2.25(m,2H),2.13-2.18(m,2H),1.43-1.56(m,8H),0.97(t,J=7.3Hz,3H),0.94(t,J=7.3Hz,3H)。
步骤2:
如关于化合物I所描述将2-氨基-3,5-[(E)-戊-1-烯基]苯甲酸甲酯(5.7g,19.9mmol)氢化,得到2-氨基-3,5-二戊基苯甲酸甲酯(5.50g,95%)。1H NMR(400MHz,CDCl3):δ7.50(d,J=2.2Hz,1H),6.95(d,J=2.2Hz,1H),5.5-6.1(br s,2H),3.79(s.3H),2.40(t,J=7.2Hz,4H),1.45-1.58(m,4H),1.20-1.32(m,8H),0.84(t,J=7.2Hz,3H),0.82(t,J=7.1Hz,3H)。
步骤3:
将2-氨基-3,5-二戊基苯甲酸甲酯(4.5g,15.4mmol)用四氟硼酸水溶液(5.5M,3.7ml,20mmol)和盐酸水溶液(8.5M,3.3ml,28mmol)处理。将混合物冷却至0℃,且然后历时2分钟用亚硝酸钠(2.1M,8.8ml,18.5mmol)水溶液逐滴处理。在0℃下60分钟之后,将反应混合物用二甲苯(30ml)萃取。将二甲苯萃取物经硫酸钠干燥,且然后历时55分钟自60℃加热至120℃。过滤且在真空中蒸发二甲苯,得到粗化合物,将其在SiliaSep SiO2柱上纯化,用乙酸乙酯/己烷(0-5%)洗脱,得到2-氟-3,5-二戊基苯甲酸甲酯(3.1g,69%)。1H NMR(400MHz,CDCl3):δ7.50(dd,JHF=6.5Hz,JHH=2.4Hz,1H),7.15(dd,JHF=6.5Hz,JHH=2.4Hz,1H),3.91(s.3H),2.62(td,JHH=7.7Hz,JHF=1.2Hz,2H),2.56(t,J=7.7Hz,2H),1.55-1.63(m,4H),1.26-1.37(m,8H),0.89(t,J=7.0Hz,6H);19F NMR(377MHz,CDCl3):δ-121.31(dd,JHF=6.6,6.6Hz,1F)。
步骤4:
将2-氟-3,5-二戊基苯甲酸甲酯(3.1g,10.6mmol)于无水四氢呋喃(60ml)中的溶液冷却至-78℃,且用氢化铝锂(0.5g,13.8mmol)缓慢处理。将反应混合物在-78℃下搅拌25分钟,然后在0℃下搅拌30分钟。通过添加乙酸乙酯中止反应。将混合物用酒石酸钾钠水溶液(1M,100ml)且用饱和氯化钠水溶液(100ml)洗涤;且然后经硫酸钠干燥,过滤且在真空中蒸发,得到粗化合物。在SiliaSep SiO2柱上纯化,用乙酸乙酯/己烷(3-20%)洗脱,得到2-氟-3,5-二戊基苯甲醇(1.8g,65%)。1H NMR(400MHz,CDCl3):δ7.02(dd,JHF=6.8Hz,JHH=2.3Hz,1H),6.92(dd,JHF=7.1Hz,JHH=2.4Hz,1H),4.71(s.2H),2.59(td,JHH=7.6Hz,JHF=1.2Hz,2H),2.54(t,J=7.8Hz,2H),1.73(s,1H),1.54-1.62(m,4H),1.25-1.36(m,8H),0.894(t,J=7.0Hz,3H),0.890(t,J=7.1Hz,3H);19F NMR(377MHz,CDCl3):δ-131.25(dd,JHF=6.7,6.6Hz,1F);13C NMR(101MHz,CDCl3):δ157.41(d,JCF=242.9Hz),138.48(d,JCF=4.3Hz),130.07(d,JCF=5.4Hz),129.33(d,JCF=16.2Hz),127.33(d,JCF=15.6Hz),126.67(d,JCF=4.6Hz),59.84(d,JCF=5.4Hz),35.50,31.86,31.77,31.62,30.21,29.21(d,JCF=2.4Hz),22.80,22.74,14.28(2C)。
步骤5:
将2-氟-3,5-二戊基苯甲醇(1.4g,5.3mmol)于无水二氯甲烷(35ml)中的溶液冷却至0℃,且历时10分钟用甲磺酰氯(0.5ml,5.8mmol)逐滴处理。将反应物在0℃下搅拌20分钟,且然后通过添加冰冷水(35ml)中止反应。将有机相用盐酸水溶液(1M,35ml)、饱和碳酸氢钠水溶液(35ml)和饱和氯化钠水溶液(35ml)洗涤;且然后经硫酸钠干燥,过滤且在真空中蒸发,得到粗甲烷磺酸2-氟-3,5-二戊基苯甲酯(1.7g,93%)。此物质未纯化即用于下一步骤。1H NMR(400MHz,CDCl3):δ7.02-7.05(m,2H),5.26(d,JHF=1.0Hz,2H),2.98(s.3H),2.52-2.63(m,2H),2.54(t,J=7.8Hz,2H),1.54-1.62(m,4H),1.27-1.37(m,8H),0.892(t,J=7.0Hz,3H),0.888(t,J=7.0Hz,3H)。
步骤6:
用6M盐酸水溶液将氰化钠(0.4g,7.4mmol)于水(5ml)中的溶液的pH值调节至pH10。然后添加甲烷磺酸2-氟-3,5-二戊基苯甲酯(1.7g,4.9mmol)于乙腈(25ml)中的溶液,且将反应物在60℃下加热2h。将反应混合物在真空中浓缩至15ml,且用乙酸乙酯(100ml)萃取。将有机萃取物用水(100ml)且用饱和氯化钠水溶液(100ml)洗涤;且然后经硫酸钠干燥,过滤且在真空中蒸发,得到粗化合物。在SiliaSep SiO2柱上纯化,用乙酸乙酯/己烷(1-10%)洗脱,得到2-[2-氟-3,5-二戊基苯基]乙腈(0.7g,55%)。1H NMR(400MHz,CDCl3):δ7.04(dd,JHF=6.9Hz,JHH=2.2Hz,1H),6.96(dd,JHF=7.1Hz,JHH=2.2Hz,1H),3.72(s.2H),2.59(td,JHH=7.7Hz,JHF=0.9Hz,2H),2.55(t,J=7.8Hz,2H),1.54-1.62(m,4H),1.27-1.37(m,8H),0.90(t,J=7.0Hz,6H);19F NMR(377MHz,CDCl3):δ-131.25(ddd,JHF=7.0,7.0,0.8Hz,1F);13C NMR(101MHz,CDCl3):δ157.02(d,JCF=244.5Hz),139.16(d,JCF=4.7Hz),130.84(d,JCF=4.6Hz),129.93(d,JCF=16.1Hz),126.97(d,JCF=3.1Hz),117.52,116.79(d,JCF=16.2Hz),35.38,31.74,31.66,31.54,30.06,29.16(d,JCF=2.4Hz),22.74,22.68,17.90(d,JCF=6.1Hz),14.26,14.23。
步骤7:
将2-[2-氟-3,5-二戊基苯基]乙腈(0.7g,2.7mmol)、乙酸(4ml)和水(4ml)的混合物用浓硫酸(4ml)逐滴处理;且然后将混合物在125℃下加热3.5h。将反应物冷却至室温且然后通过添加冰(40ml)中止反应。将混合物用乙酸乙酯(40ml)萃取,且然后将有机萃取物用饱和氯化钠水溶液(40ml)洗涤;经硫酸钠干燥,过滤且在真空中蒸发,得到2-[2-氟-3,5-二戊基苯基]乙酸(537mg,67%)。1H NMR(400MHz,CDCl3):δ6.84(dd,JHF=7.0Hz,JHH=2.3Hz,1H),6.80(dd,JHF=6.8Hz,JHH=2.2Hz,1H),3.59(d,JHF=1.2Hz,2H),2.52(t,J=7.5Hz,2H),2.45(t,J=7.8Hz,2H),1.46-1.55(m,4H),1.20-1.30(m,8H),0.80-0.84(m,6H)。
步骤8:
如关于化合物I所描述将2-[2-氟-3,5-二戊基苯基]乙酸(537mg,1.8mmol)转化为钠盐,得到呈淡棕色粘性固体的2-[2-氟-3,5-二戊基苯基]乙酸钠(465mg,81%):1H NMR(400MHz,CD3OD):δ6.94(dd,JHF=6.9Hz,JHH=2.2Hz,1H),6.83(dd,JHF=7.0Hz,JHH=2.3Hz,1H),3.48(d,JHF=1.1Hz,2H),2.58(t,J=7.6Hz,2H),2.51(t,J=7.6Hz,2H),1.54-1.62(m,4H),1.28-1.38(m,8H),0.90(t,J=7.0Hz,3H),0.89(t,J=7.0Hz,3H);19F NMR(377MHz,CD3OD):δ-130.71(dd,JHF=6.6,6.6Hz,1F);13C NMR(101MHz,CD3OD):δ178.31,157.95(d,JCF=240.6Hz),137.64(d,JCF=3.8Hz),128.72(d,JCF=4.6Hz),128.42(d,JCF=17.7Hz),128.21(d,JCF=5.4Hz),124.50(d,JCF=17.7Hz),37.94(d,JCF=3.1Hz),35.05,31.52,31.45,31.37,30.00,28.96(d,JCF=2.3Hz),22.43,22.38,13.23,13.21;LRMS(ESI负模式):m/z 293(w,M-Na+)和249.1(100%,M–Na+–CO2);UPLC:8.4min(UPLC条件:移动相A=0.1%甲酸/水;移动相B=0.1%甲酸/乙腈;固相=HSS T3;梯度=经10min5-100%B/A。
化合物XXXIII:2-(3,5-二戊基苯基)-2-甲基丙酸的钠盐
以上化合物是以与化合物I相同的方式制备,同时具有用氢化钠和碘甲烷将2-[3,5-二戊基苯基]乙酸甲酯中间物烷基化的额外步骤;且其中酯水解步骤的温度升至100℃。米白色固体:1H NMR(400MHz,CD3OD):δ7.04(d,J=1.3Hz,2H),6.76(s,1H),2.54(t,J=7.7Hz,4H),1.55-1.63(m,4H),1.46(s,6H),1.27-1.38(m,8H),0.90(t,J=7.0Hz,6H);13CNMR(101MHz,CD3OD):δ184.58,148.51,141.98,125.57,123.46,36.02,48.26,31.59,31.42,27.57,22.47,13.29;LRMS(ESI负模式):m/z 303.1(100%,M-Na+);UPLC:8.9min(UPLC条件:移动相A=0.1%甲酸/水;移动相B=0.1%甲酸/乙腈;固相=HSS T3;梯度=经10min 5-100%B/A)。
实施例2:代表性式I化合物对在组织自修复、再生和抗老化中肝细胞生长因子(HGF)的表达的影响。
进行实验以确定化合物对肝细胞生长因子在来自成人供体的体外正常人皮肤纤维母细胞(NHDF)(Clonetics#CC-2511)中的表达的影响。使NHDF在DMEM/F12+0.5%FBS中饥饿隔夜,且用rhTGF-β1(10ng/ml)和化合物I(500μM)处理24h或不处理。用试剂盒分离RNA,包括柱上DNA酶消化步骤。使用RT2第一链试剂盒(#330401)进行cDNA合成(每次反应0.5μg RNA)。如RT2测定器PCR测定手册中所描述在AB-7900HT实时循环器上进行实时PCR。使用ΔΔCt方法在RT2测定器PCR数组数据分析网门户网站上分析实时PCR数据。所有Ct值>35或未扩增者变成截止值为35。用于归一化的看家基因为GAPDH和RPLP0。对照组为TGF-β1处理的细胞。
图1中所示,化合物I使与组织修复、再生和抗老化相关的生长因子HGF的表达增加。下表2表明TGF-β1使NHDF细胞(未处理)中的HGF表达降低,其在本文所公开的代表性式I化合物(化合物#)的情况下得以校正或有所增加。
表2
细胞 | 化合物浓度(μM) | HGF相对定量 |
Untreated | - | 7.23 |
TGF-β1 | - | 1.00 |
TGF-β1+化合物I | 500 | 4.23 |
TGF-β1+化合物XVIII | 25 | 1.40 |
TGF-β1+化合物XXXIII | 6 | 1.54 |
TGF-β1+化合物XXXII | 10 | 1.73 |
TGF-β1+化合物IV | 500 | 3.80 |
TGF-β1+化合物III | 500 | 2.41 |
TGF-β1+化合物II | 250 | 1.37 |
TGF-β1+化合物XII | 500 | 2.47 |
TGF-β1+化合物V | 100 | 2.73 |
TGF-β1+化合物VI | 100 | 2.77 |
TGF-β1+化合物XIII | 500 | 1.71 |
TGF-β1+化合物VII | 500 | 2.66 |
TGF-β1+化合物VIII | 500 | 1.44 |
TGF-β1+化合物XI | 250 | 3.38 |
TGF-β1+化合物X | 250 | 3.06 |
进行实验以确定化合物对再生标记物的表达的影响。此实验是使用在单次、多次或持续损伤之后参与组织再生的NHDF(正常人皮肤纤维母细胞)和人上皮细胞(肾小管上皮细胞,HK-2)来进行。损伤是通过使细胞与TGF-β1一起孵育来模拟。NHDF是如先前所描述进行使用,且使HK-2人上皮近端小管细胞(ATCC#CRL-2190)在DMEM/F12+0.2%FBS中饥饿隔夜且用rhTGF-β1(10ng/ml)和化合物I(500μM)处理24h或不处理。结果表明化合物I使再生标记物的表达水平在正常控制水平,从而指示损伤细胞的自修复机制。在NHDF中(图2),LOX、MMP13、PLAU(uPA)、serpin E1、TIMP3和ILK全部以正常水平表达,另外在HK-2细胞中(图3),LOX、MMP1、MMP2、MMP9、MMP13、TIMP3和PLAT(tPA)还全部以接近于在健康细胞中观测到的正常水平的水平表达。
实施例3:化合物I对AAT的内源性产生和神经组织的再生的影响。
如以上所提及,AAT可诱导神经再生。通过关于NHDF的qPCR-面板分析(实施例2中所描述的方法),化合物I已展示使在损伤细胞中AAT mRNA表达增加的能力(图4),表明化合物I可增加神经再生或其它损伤组织。化合物I代表本文所公开的式I化合物。因此,本文所公开的式I化合物可经由在损伤位点产生内源性AAT而增加神经再生。
***
本文中包括标题供参考且用于帮助定位某些部分。这些标题不旨在限制其中所描述概念的范围,且这些概念可在整个说明书通篇中的其它部分中具有适用性。因此,本发明不旨在限于本文所示的实施方案,而是与符合本文所公开的原理和新颖特征的最宽范围相一致。
除非上下文另外明确规定,否则单数形式“一个/种(a/an)”和“所述”包括相应复数参考物。
除非另外指出,否则本说明书和权利要求书中所用的所有表示成分的量、反应条件浓度、性质等的数字应理解为在所有情况下由术语“约”修饰。最低限度地,各数值参数至少应根据具有所报告有效数字的数字且通过应用一般舍入技术来理解。因此,除非指示为相反,否则本说明书和所附权利要求书中所阐述的数值参数为近似值,其可视设法获得的性质而变化。尽管阐述实施方案的广泛范围的数值范围和参数为近似值,但特定实施例中所阐述的数值为尽可能精确报告的。然而,任何数值固有地含有因实验、测试量测、统计分析和此类因素而产生的某些误差。
应了解,本文所描述的实施例和实施方案仅用于说明性目的,且将向本领域技术人员建议对其作出的各种修改或变化,且其应包括在本发明和随附权利要求书的范围内。
Claims (21)
1.由式I表示的化合物或其药学上可接受的盐或其组合在制备用于刺激有需要的受试者的损伤器官或组织中的组织自修复或组织再生的药剂中的用途,其中所述器官或组织为肝脏、肺、皮肤、胃、肠道、肌肉或软骨:
其中
A为C5烷基、C6烷基、C5烯基、或C6烯基;
R1为H、F或OH;
R2为H、F、OH、C5烷基、C6烷基、C5烯基、或C6烯基;
R3为H、F、OH或CH2Ph;
R4为H、F或OH;
Q为
1)(CH2)mC(O)OH,其中m为1或2,
2)CH(CH3)C(O)OH,
3)C(CH3)2C(O)OH,
4)CH(F)-C(O)OH,
5)CF2-C(O)OH,或
6)C(O)-C(O)OH。
2.如权利要求1所述的用途,其中A为C5烷基或C6烷基。
3.如权利要求1或2中任一项所述的用途,其中R2为H、F、OH、C5烷基或C6烷基。
4.如权利要求1所述的用途,其中R3为H、OH或CH2Ph。
5.如权利要求1所述的用途,其中Q为(CH2)mC(O)OH,其中m为1或2。
6.如权利要求1所述的用途,其中A为C5烷基或C6烷基;R1为H、F或OH;R2为H、F、OH、C5烷基或C6烷基;R3为H、OH或CH2Ph;R4为H、F或OH;且Q为(CH2)mC(O)OH,其中m为1或2。
7.如权利要求1所述的用途,其中A为C5烷基;R1为H;R2为H或C5烷基;R3为H;R4为H;且Q为(CH2)mC(O)OH,其中m为1。
11.如权利要求1所述的用途,其中所述药学上可接受的盐为包含选自由钠、钾、钙、镁、锂、铵、锰、锌、铁或铜组成的组的金属抗衡离子的碱加成盐。
12.如权利要求8所述的用途,其中所述药学上可接受的盐为包含选自由钠、钾、钙、镁、锂、铵、锰、锌、铁或铜组成的组的金属抗衡离子的碱加成盐。
13.如权利要求11所述的用途,其中所述药学上可接受的盐为钠盐。
14.如权利要求12所述的用途,其中所述药学上可接受的盐为钠盐。
15.如权利要求1所述的用途,其中所述损伤器官或组织为皮肤。
16.如权利要求1所述的用途,其中所述损伤器官或组织为肝脏。
17.如权利要求1所述的用途,其中所述损伤器官或组织为肺。
18.如权利要求1所述的用途,其中所述损伤器官或组织为胃。
19.如权利要求1所述的用途,其中所述损伤器官或组织为肠道。
20.如权利要求1所述的用途,其中所述损伤器官或组织为肌肉。
21.如权利要求1所述的用途,其中所述损伤器官或组织为软骨。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201462078704P | 2014-11-12 | 2014-11-12 | |
US62/078704 | 2014-11-12 | ||
PCT/CA2015/000572 WO2016074068A1 (en) | 2014-11-12 | 2015-11-12 | Substituted aromatic compounds and pharmaceutical compositions for tissue self-repair and regeneration |
Publications (2)
Publication Number | Publication Date |
---|---|
CN107106526A CN107106526A (zh) | 2017-08-29 |
CN107106526B true CN107106526B (zh) | 2021-05-28 |
Family
ID=55953490
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201580071284.6A Active CN107106526B (zh) | 2014-11-12 | 2015-11-12 | 用于组织自修复和再生的经取代芳族化合物和药物组合物 |
Country Status (19)
Country | Link |
---|---|
US (3) | US10391073B2 (zh) |
EP (1) | EP3217968A4 (zh) |
JP (1) | JP6720169B2 (zh) |
KR (1) | KR20170072352A (zh) |
CN (1) | CN107106526B (zh) |
AR (1) | AR102634A1 (zh) |
AU (2) | AU2015345943B2 (zh) |
BR (1) | BR112017009899A2 (zh) |
CA (1) | CA2967499C (zh) |
IL (1) | IL252221B (zh) |
MX (1) | MX2017006281A (zh) |
MY (1) | MY187515A (zh) |
PH (1) | PH12017500856A1 (zh) |
RU (1) | RU2728782C2 (zh) |
SG (1) | SG11201703741TA (zh) |
TW (1) | TWI723967B (zh) |
UY (1) | UY36399A (zh) |
WO (1) | WO2016074068A1 (zh) |
ZA (1) | ZA201703579B (zh) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
TWI689489B (zh) * | 2013-03-15 | 2020-04-01 | 英商邊緣生物科技有限公司 | 用於治療肺纖維化、肝纖維化、皮膚纖維化及心臟纖維化之經取代之芳族化合物 |
AU2015345943B2 (en) * | 2014-11-12 | 2020-03-19 | Liminal Biosciences Limited | Substituted aromatic compounds and pharmaceutical compositions for tissue self-repair and regeneration |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102421742A (zh) * | 2009-05-04 | 2012-04-18 | 普罗米蒂克生物科学公司 | 3-戊基苯乙酸的盐及其药物用途 |
CN102438975A (zh) * | 2009-05-04 | 2012-05-02 | 普罗米蒂克生物科学公司 | 取代的芳香化合物及其药物用途 |
CN103347509A (zh) * | 2010-10-27 | 2013-10-09 | 普罗米蒂克生物科学公司 | 用于治疗癌症的化合物和组合物 |
WO2014138906A1 (en) * | 2013-03-15 | 2014-09-18 | Prometic Biosciences Inc. | Substituted aromatic compounds and related method for the treatment of fibrosis |
Family Cites Families (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
RU2289417C1 (ru) * | 2005-04-15 | 2006-12-20 | Равиль Шамилевич Мирхайдаров | Способ биологического омоложения кожи |
EP1953222A1 (en) * | 2007-01-24 | 2008-08-06 | Boehringer Ingelheim Pharma GmbH & Co. KG | Improvement of cell growth |
ES2351005B1 (es) * | 2009-07-10 | 2011-11-18 | Consejo Superior De Investigaciones Científicas (Csic) | Uso de anhidrasa carbónica ii para la elaboración de un medicamento. |
MX348253B (es) * | 2010-10-27 | 2017-05-31 | Prometic Pharma Smt Ltd | Compuestos de carboxilato de fenilcetona y sus usos farmaceuticos. |
JP5388233B2 (ja) * | 2011-01-19 | 2014-01-15 | 富士ソフト株式会社 | 再生軟骨の軟骨特性を評価する方法 |
JP2014522879A (ja) * | 2011-08-10 | 2014-09-08 | ディグナ ビオテク、エセ エレ | 腎疾患の治療のためのカルジオトロフィン−1の使用 |
TWI689489B (zh) | 2013-03-15 | 2020-04-01 | 英商邊緣生物科技有限公司 | 用於治療肺纖維化、肝纖維化、皮膚纖維化及心臟纖維化之經取代之芳族化合物 |
CN106999458B (zh) * | 2014-10-10 | 2021-04-13 | 普罗米蒂克医药Smt有限公司 | 用于预防和治疗糖尿病的经取代芳族化合物和药物组合物 |
CA2963354A1 (en) * | 2014-10-10 | 2016-04-14 | Prometic Biosciences Inc. | Substituted aromatic compounds and pharmaceutical compositions for the prevention and treatment of osteoporosis |
AU2015345943B2 (en) * | 2014-11-12 | 2020-03-19 | Liminal Biosciences Limited | Substituted aromatic compounds and pharmaceutical compositions for tissue self-repair and regeneration |
-
2015
- 2015-11-12 AU AU2015345943A patent/AU2015345943B2/en not_active Ceased
- 2015-11-12 RU RU2017120401A patent/RU2728782C2/ru active
- 2015-11-12 KR KR1020177015741A patent/KR20170072352A/ko not_active Application Discontinuation
- 2015-11-12 BR BR112017009899A patent/BR112017009899A2/pt active Search and Examination
- 2015-11-12 WO PCT/CA2015/000572 patent/WO2016074068A1/en active Application Filing
- 2015-11-12 JP JP2017525587A patent/JP6720169B2/ja not_active Expired - Fee Related
- 2015-11-12 US US15/526,405 patent/US10391073B2/en not_active Expired - Fee Related
- 2015-11-12 UY UY0001036399A patent/UY36399A/es unknown
- 2015-11-12 AR ARP150103693A patent/AR102634A1/es unknown
- 2015-11-12 SG SG11201703741TA patent/SG11201703741TA/en unknown
- 2015-11-12 CN CN201580071284.6A patent/CN107106526B/zh active Active
- 2015-11-12 CA CA2967499A patent/CA2967499C/en active Active
- 2015-11-12 MY MYPI2017000688A patent/MY187515A/en unknown
- 2015-11-12 MX MX2017006281A patent/MX2017006281A/es unknown
- 2015-11-12 TW TW104137375A patent/TWI723967B/zh not_active IP Right Cessation
- 2015-11-12 EP EP15859768.2A patent/EP3217968A4/en not_active Withdrawn
-
2017
- 2017-05-08 PH PH12017500856A patent/PH12017500856A1/en unknown
- 2017-05-10 IL IL252221A patent/IL252221B/en unknown
- 2017-05-24 ZA ZA2017/03579A patent/ZA201703579B/en unknown
-
2019
- 2019-07-12 US US16/510,581 patent/US10869849B2/en active Active
-
2020
- 2020-06-19 AU AU2020204112A patent/AU2020204112B2/en not_active Ceased
- 2020-12-03 US US17/111,146 patent/US20210085626A1/en not_active Abandoned
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102421742A (zh) * | 2009-05-04 | 2012-04-18 | 普罗米蒂克生物科学公司 | 3-戊基苯乙酸的盐及其药物用途 |
CN102438975A (zh) * | 2009-05-04 | 2012-05-02 | 普罗米蒂克生物科学公司 | 取代的芳香化合物及其药物用途 |
CN103347509A (zh) * | 2010-10-27 | 2013-10-09 | 普罗米蒂克生物科学公司 | 用于治疗癌症的化合物和组合物 |
WO2014138906A1 (en) * | 2013-03-15 | 2014-09-18 | Prometic Biosciences Inc. | Substituted aromatic compounds and related method for the treatment of fibrosis |
Non-Patent Citations (2)
Title |
---|
抑制心肌纤维化促进心肌再生治疗慢性心血管疾病;米粟;《生理科学进展》;20101117;第41卷(第5期);第355页右栏第9-11行,第357页右栏第1-2行 * |
米粟.抑制心肌纤维化促进心肌再生治疗慢性心血管疾病.《生理科学进展》.2010,第41卷(第5期),第352-358页. * |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP1753708B1 (en) | Novel sirtuin activating compounds and methods for making the same | |
DE69923573T2 (de) | Vitamin d-analoga | |
JP3591763B2 (ja) | レゾルシノール誘導体を含む組成物 | |
CN1137087C (zh) | 用作光化学疗法中的光致敏剂的5-氨基酮戊酸的酯 | |
TWI634888B (zh) | 治療帕金森疾病的新穎高穿透性藥物和醫藥組合物 | |
EP0557404B1 (fr) | UTILISATION ANTIVIRALE DE COMPOSE 2,6-DI-t-BUTYLPHENOL SUBSTITUE EN POSITION 4, NOTAMMENT VIS-A-VIS DES VIRUS DE L'HERPES ET DES PAPILLOMAVIRUS | |
AU2020204112B2 (en) | Substituted aromatic compounds and pharmaceutical compositions for tissue self-repair and regeneration | |
Dong et al. | Asymmetric synthesis and biological evaluation of Danshensu derivatives as anti-myocardial ischemia drug candidates | |
TWI699200B (zh) | 用於預防及治療骨質疏鬆症之經取代之芳族化合物及醫藥組合物 | |
TWI322151B (zh) | ||
JP5722312B2 (ja) | ベンジリデンマロネート類 | |
JP4268872B2 (ja) | 3,4,5−トリメトキシフェニル系のエステル化合物及びこれを含有する美白化粧料組成物 | |
CN101434557A (zh) | 神经酰胺的短链2-羟基羧酸系的衍生物 | |
JP7073384B2 (ja) | 化合物及び使用方法 | |
JP4541699B2 (ja) | カルボキシレート−ゲート−ニトロキシド(cgn)化合物および組成物ならびにその使用方法 | |
JP3276375B2 (ja) | シクロヘキサンジオール誘導体 | |
KR101461625B1 (ko) | 16-히드록시헥사데카노익 피토스핑고신을 유효성분으로 포함하는 피부장벽 손상의 개선 또는 치료, 또는 피부장벽 기능의 개선 또는 강화용 조성물 | |
CN110621654B (zh) | Trpv1调节剂化合物 | |
JP3955585B2 (ja) | 落屑剤としての(ジヒドロ)ジャスモン酸誘導体の使用 | |
JPH0967225A (ja) | 皮膚外用剤 | |
JP2022105049A (ja) | 3-ヒドロキシシクロペンチル酢酸から誘導される新規化合物の合成方法 | |
Siggins et al. | Myelographic Agents. I. Iodobenzoates | |
JPH0987127A (ja) | 美白剤及びこれを含有する皮膚外用剤 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant |