WO2023191513A1 - Dérivé d'imidazoline conjugué à un sucre et son utilisation - Google Patents
Dérivé d'imidazoline conjugué à un sucre et son utilisation Download PDFInfo
- Publication number
- WO2023191513A1 WO2023191513A1 PCT/KR2023/004208 KR2023004208W WO2023191513A1 WO 2023191513 A1 WO2023191513 A1 WO 2023191513A1 KR 2023004208 W KR2023004208 W KR 2023004208W WO 2023191513 A1 WO2023191513 A1 WO 2023191513A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- substituted
- compound
- pharmaceutically acceptable
- unsubstituted
- formula
- Prior art date
Links
- 235000000346 sugar Nutrition 0.000 title claims abstract description 33
- 150000002462 imidazolines Chemical class 0.000 title abstract description 8
- 239000000693 micelle Substances 0.000 claims abstract description 60
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 48
- 201000010099 disease Diseases 0.000 claims abstract description 32
- 230000032683 aging Effects 0.000 claims abstract description 16
- 239000004480 active ingredient Substances 0.000 claims abstract description 14
- 230000002265 prevention Effects 0.000 claims abstract description 6
- 230000006907 apoptotic process Effects 0.000 claims abstract description 5
- 150000001875 compounds Chemical class 0.000 claims description 56
- 150000003839 salts Chemical class 0.000 claims description 45
- 210000004027 cell Anatomy 0.000 claims description 37
- -1 imidazoline derivative compound Chemical class 0.000 claims description 33
- 125000003118 aryl group Chemical group 0.000 claims description 19
- 125000004450 alkenylene group Chemical group 0.000 claims description 17
- 125000000217 alkyl group Chemical group 0.000 claims description 17
- 125000004419 alkynylene group Chemical group 0.000 claims description 17
- 125000003342 alkenyl group Chemical group 0.000 claims description 16
- 125000003545 alkoxy group Chemical group 0.000 claims description 16
- 208000035475 disorder Diseases 0.000 claims description 16
- 230000036541 health Effects 0.000 claims description 16
- 238000000034 method Methods 0.000 claims description 16
- 239000008194 pharmaceutical composition Substances 0.000 claims description 16
- 125000002947 alkylene group Chemical group 0.000 claims description 13
- 235000013376 functional food Nutrition 0.000 claims description 13
- 125000000304 alkynyl group Chemical group 0.000 claims description 12
- 125000000732 arylene group Chemical group 0.000 claims description 12
- 208000002780 macular degeneration Diseases 0.000 claims description 8
- 206010028980 Neoplasm Diseases 0.000 claims description 7
- 208000024172 Cardiovascular disease Diseases 0.000 claims description 6
- 201000011510 cancer Diseases 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- 150000002367 halogens Chemical class 0.000 claims description 6
- 230000002757 inflammatory effect Effects 0.000 claims description 6
- 150000002772 monosaccharides Chemical group 0.000 claims description 6
- 150000002016 disaccharides Chemical class 0.000 claims description 5
- 208000027866 inflammatory disease Diseases 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- SHZGCJCMOBCMKK-UHFFFAOYSA-N D-mannomethylose Natural products CC1OC(O)C(O)C(O)C1O SHZGCJCMOBCMKK-UHFFFAOYSA-N 0.000 claims description 4
- SRBFZHDQGSBBOR-IOVATXLUSA-N D-xylopyranose Chemical compound O[C@@H]1COC(O)[C@H](O)[C@H]1O SRBFZHDQGSBBOR-IOVATXLUSA-N 0.000 claims description 4
- PYMYPHUHKUWMLA-UHFFFAOYSA-N arabinose Natural products OCC(O)C(O)C(O)C=O PYMYPHUHKUWMLA-UHFFFAOYSA-N 0.000 claims description 4
- SRBFZHDQGSBBOR-UHFFFAOYSA-N beta-D-Pyranose-Lyxose Natural products OC1COC(O)C(O)C1O SRBFZHDQGSBBOR-UHFFFAOYSA-N 0.000 claims description 4
- RXKJFZQQPQGTFL-UHFFFAOYSA-N dihydroxyacetone Chemical compound OCC(=O)CO RXKJFZQQPQGTFL-UHFFFAOYSA-N 0.000 claims description 4
- 208000030533 eye disease Diseases 0.000 claims description 4
- 230000004438 eyesight Effects 0.000 claims description 4
- 208000023275 Autoimmune disease Diseases 0.000 claims description 3
- WQZGKKKJIJFFOK-WHZQZERISA-N D-aldose Chemical compound OC[C@H]1OC(O)[C@@H](O)[C@@H](O)[C@H]1O WQZGKKKJIJFFOK-WHZQZERISA-N 0.000 claims description 3
- LKDRXBCSQODPBY-JDJSBBGDSA-N D-allulose Chemical compound OCC1(O)OC[C@@H](O)[C@@H](O)[C@H]1O LKDRXBCSQODPBY-JDJSBBGDSA-N 0.000 claims description 3
- 208000019693 Lung disease Diseases 0.000 claims description 3
- 230000006735 deficit Effects 0.000 claims description 3
- 208000016097 disease of metabolism Diseases 0.000 claims description 3
- 208000030159 metabolic disease Diseases 0.000 claims description 3
- 210000003470 mitochondria Anatomy 0.000 claims description 3
- 230000004770 neurodegeneration Effects 0.000 claims description 3
- 208000015122 neurodegenerative disease Diseases 0.000 claims description 3
- 201000008482 osteoarthritis Diseases 0.000 claims description 3
- 208000002177 Cataract Diseases 0.000 claims description 2
- YTBSYETUWUMLBZ-UHFFFAOYSA-N D-Erythrose Natural products OCC(O)C(O)C=O YTBSYETUWUMLBZ-UHFFFAOYSA-N 0.000 claims description 2
- WQZGKKKJIJFFOK-CBPJZXOFSA-N D-Gulose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@H](O)[C@H]1O WQZGKKKJIJFFOK-CBPJZXOFSA-N 0.000 claims description 2
- WQZGKKKJIJFFOK-IVMDWMLBSA-N D-allopyranose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@H](O)[C@@H]1O WQZGKKKJIJFFOK-IVMDWMLBSA-N 0.000 claims description 2
- YTBSYETUWUMLBZ-IUYQGCFVSA-N D-erythrose Chemical compound OC[C@@H](O)[C@@H](O)C=O YTBSYETUWUMLBZ-IUYQGCFVSA-N 0.000 claims description 2
- MNQZXJOMYWMBOU-VKHMYHEASA-N D-glyceraldehyde Chemical compound OC[C@@H](O)C=O MNQZXJOMYWMBOU-VKHMYHEASA-N 0.000 claims description 2
- WQZGKKKJIJFFOK-QTVWNMPRSA-N D-mannopyranose Chemical compound OC[C@H]1OC(O)[C@@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-QTVWNMPRSA-N 0.000 claims description 2
- HMFHBZSHGGEWLO-SOOFDHNKSA-N D-ribofuranose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H]1O HMFHBZSHGGEWLO-SOOFDHNKSA-N 0.000 claims description 2
- ZAQJHHRNXZUBTE-NQXXGFSBSA-N D-ribulose Chemical compound OC[C@@H](O)[C@@H](O)C(=O)CO ZAQJHHRNXZUBTE-NQXXGFSBSA-N 0.000 claims description 2
- ZAQJHHRNXZUBTE-UHFFFAOYSA-N D-threo-2-Pentulose Natural products OCC(O)C(O)C(=O)CO ZAQJHHRNXZUBTE-UHFFFAOYSA-N 0.000 claims description 2
- YTBSYETUWUMLBZ-QWWZWVQMSA-N D-threose Chemical compound OC[C@@H](O)[C@H](O)C=O YTBSYETUWUMLBZ-QWWZWVQMSA-N 0.000 claims description 2
- 206010056474 Erythrosis Diseases 0.000 claims description 2
- 229930091371 Fructose Natural products 0.000 claims description 2
- 239000005715 Fructose Substances 0.000 claims description 2
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 claims description 2
- PNNNRSAQSRJVSB-SLPGGIOYSA-N Fucose Natural products C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)C=O PNNNRSAQSRJVSB-SLPGGIOYSA-N 0.000 claims description 2
- 208000010412 Glaucoma Diseases 0.000 claims 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 claims description 2
- LKDRXBCSQODPBY-AMVSKUEXSA-N L-(-)-Sorbose Chemical compound OCC1(O)OC[C@H](O)[C@@H](O)[C@@H]1O LKDRXBCSQODPBY-AMVSKUEXSA-N 0.000 claims description 2
- WQZGKKKJIJFFOK-VSOAQEOCSA-N L-altropyranose Chemical compound OC[C@@H]1OC(O)[C@H](O)[C@@H](O)[C@H]1O WQZGKKKJIJFFOK-VSOAQEOCSA-N 0.000 claims description 2
- SHZGCJCMOBCMKK-DHVFOXMCSA-N L-fucopyranose Chemical compound C[C@@H]1OC(O)[C@@H](O)[C@H](O)[C@@H]1O SHZGCJCMOBCMKK-DHVFOXMCSA-N 0.000 claims description 2
- SHZGCJCMOBCMKK-JFNONXLTSA-N L-rhamnopyranose Chemical compound C[C@@H]1OC(O)[C@H](O)[C@H](O)[C@H]1O SHZGCJCMOBCMKK-JFNONXLTSA-N 0.000 claims description 2
- PNNNRSAQSRJVSB-UHFFFAOYSA-N L-rhamnose Natural products CC(O)C(O)C(O)C(O)C=O PNNNRSAQSRJVSB-UHFFFAOYSA-N 0.000 claims description 2
- PYMYPHUHKUWMLA-LMVFSUKVSA-N Ribose Natural products OC[C@@H](O)[C@@H](O)[C@@H](O)C=O PYMYPHUHKUWMLA-LMVFSUKVSA-N 0.000 claims description 2
- HMFHBZSHGGEWLO-UHFFFAOYSA-N alpha-D-Furanose-Ribose Natural products OCC1OC(O)C(O)C1O HMFHBZSHGGEWLO-UHFFFAOYSA-N 0.000 claims description 2
- WQZGKKKJIJFFOK-PHYPRBDBSA-N alpha-D-galactose Chemical compound OC[C@H]1O[C@H](O)[C@H](O)[C@@H](O)[C@H]1O WQZGKKKJIJFFOK-PHYPRBDBSA-N 0.000 claims description 2
- SRBFZHDQGSBBOR-STGXQOJASA-N alpha-D-lyxopyranose Chemical compound O[C@@H]1CO[C@H](O)[C@@H](O)[C@H]1O SRBFZHDQGSBBOR-STGXQOJASA-N 0.000 claims description 2
- PYMYPHUHKUWMLA-WDCZJNDASA-N arabinose Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)C=O PYMYPHUHKUWMLA-WDCZJNDASA-N 0.000 claims description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 claims description 2
- 229940120503 dihydroxyacetone Drugs 0.000 claims description 2
- UQPHVQVXLPRNCX-UHFFFAOYSA-N erythrulose Chemical compound OCC(O)C(=O)CO UQPHVQVXLPRNCX-UHFFFAOYSA-N 0.000 claims description 2
- 229930182830 galactose Natural products 0.000 claims description 2
- 239000008103 glucose Substances 0.000 claims description 2
- BJHIKXHVCXFQLS-PQLUHFTBSA-N keto-D-tagatose Chemical compound OC[C@@H](O)[C@H](O)[C@H](O)C(=O)CO BJHIKXHVCXFQLS-PQLUHFTBSA-N 0.000 claims description 2
- 239000008177 pharmaceutical agent Substances 0.000 claims description 2
- 201000010041 presbyopia Diseases 0.000 claims description 2
- 125000002951 idosyl group Chemical class C1([C@@H](O)[C@H](O)[C@@H](O)[C@H](O1)CO)* 0.000 claims 1
- 239000000203 mixture Substances 0.000 abstract description 30
- 239000003814 drug Substances 0.000 abstract description 18
- 229940079593 drug Drugs 0.000 abstract description 16
- 230000000694 effects Effects 0.000 abstract description 10
- 239000000654 additive Substances 0.000 abstract description 8
- 239000004094 surface-active agent Substances 0.000 abstract description 6
- 230000001939 inductive effect Effects 0.000 abstract description 3
- 210000001525 retina Anatomy 0.000 description 27
- 210000001519 tissue Anatomy 0.000 description 25
- 239000000243 solution Substances 0.000 description 21
- 238000010186 staining Methods 0.000 description 21
- 230000002207 retinal effect Effects 0.000 description 20
- 125000005842 heteroatom Chemical group 0.000 description 19
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 16
- 239000002253 acid Substances 0.000 description 16
- 239000012530 fluid Substances 0.000 description 16
- 125000001072 heteroaryl group Chemical group 0.000 description 16
- 229910052757 nitrogen Inorganic materials 0.000 description 15
- 230000002496 gastric effect Effects 0.000 description 14
- 235000013305 food Nutrition 0.000 description 13
- 239000000126 substance Substances 0.000 description 13
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- 229910052760 oxygen Inorganic materials 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 10
- 210000003161 choroid Anatomy 0.000 description 10
- 229910052717 sulfur Inorganic materials 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 238000002296 dynamic light scattering Methods 0.000 description 9
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 9
- 108090000623 proteins and genes Proteins 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 description 8
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 8
- 229960004679 doxorubicin Drugs 0.000 description 8
- 239000004615 ingredient Substances 0.000 description 8
- 239000000546 pharmaceutical excipient Substances 0.000 description 8
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- 238000009739 binding Methods 0.000 description 7
- 150000001721 carbon Chemical group 0.000 description 7
- 229910052799 carbon Inorganic materials 0.000 description 7
- 238000006243 chemical reaction Methods 0.000 description 7
- 235000018102 proteins Nutrition 0.000 description 7
- 102000004169 proteins and genes Human genes 0.000 description 7
- 208000024891 symptom Diseases 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- 102000012199 E3 ubiquitin-protein ligase Mdm2 Human genes 0.000 description 6
- 108050002772 E3 ubiquitin-protein ligase Mdm2 Proteins 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 206010064930 age-related macular degeneration Diseases 0.000 description 6
- 125000001931 aliphatic group Chemical group 0.000 description 6
- 239000002585 base Substances 0.000 description 6
- 125000004432 carbon atom Chemical group C* 0.000 description 6
- 239000000796 flavoring agent Substances 0.000 description 6
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 6
- 210000003786 sclera Anatomy 0.000 description 6
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 6
- 239000003981 vehicle Substances 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- 241000282412 Homo Species 0.000 description 5
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 5
- 125000004104 aryloxy group Chemical group 0.000 description 5
- 238000012790 confirmation Methods 0.000 description 5
- 239000012153 distilled water Substances 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- 235000013373 food additive Nutrition 0.000 description 5
- 239000002778 food additive Substances 0.000 description 5
- 238000009472 formulation Methods 0.000 description 5
- 230000001965 increasing effect Effects 0.000 description 5
- 125000004043 oxo group Chemical group O=* 0.000 description 5
- 125000001424 substituent group Chemical group 0.000 description 5
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 5
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 5
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical compound C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 description 4
- XUMBMVFBXHLACL-UHFFFAOYSA-N Melanin Chemical compound O=C1C(=O)C(C2=CNC3=C(C(C(=O)C4=C32)=O)C)=C2C4=CNC2=C1C XUMBMVFBXHLACL-UHFFFAOYSA-N 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- 241000699666 Mus <mouse, genus> Species 0.000 description 4
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 125000002252 acyl group Chemical group 0.000 description 4
- 125000003368 amide group Chemical group 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 239000011230 binding agent Substances 0.000 description 4
- 230000000975 bioactive effect Effects 0.000 description 4
- 210000000845 cartilage Anatomy 0.000 description 4
- 230000030833 cell death Effects 0.000 description 4
- 239000002131 composite material Substances 0.000 description 4
- 125000004093 cyano group Chemical group *C#N 0.000 description 4
- 125000000753 cycloalkyl group Chemical group 0.000 description 4
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 4
- 239000007884 disintegrant Substances 0.000 description 4
- 238000011156 evaluation Methods 0.000 description 4
- 235000013355 food flavoring agent Nutrition 0.000 description 4
- 239000008187 granular material Substances 0.000 description 4
- 125000005843 halogen group Chemical group 0.000 description 4
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 4
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- IANQTJSKSUMEQM-UHFFFAOYSA-N 1-benzofuran Chemical compound C1=CC=C2OC=CC2=C1 IANQTJSKSUMEQM-UHFFFAOYSA-N 0.000 description 3
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical class C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 3
- 206010029719 Nonspecific reaction Diseases 0.000 description 3
- BDUHCSBCVGXTJM-IZLXSDGUSA-N Nutlin-3 Chemical compound CC(C)OC1=CC(OC)=CC=C1C1=N[C@H](C=2C=CC(Cl)=CC=2)[C@H](C=2C=CC(Cl)=CC=2)N1C(=O)N1CC(=O)NCC1 BDUHCSBCVGXTJM-IZLXSDGUSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 229930012538 Paclitaxel Natural products 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical class N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 3
- 238000003917 TEM image Methods 0.000 description 3
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 3
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 3
- 125000005196 alkyl carbonyloxy group Chemical group 0.000 description 3
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 239000003963 antioxidant agent Substances 0.000 description 3
- 235000006708 antioxidants Nutrition 0.000 description 3
- 125000003435 aroyl group Chemical group 0.000 description 3
- 125000005126 aryl alkyl carbonyl amino group Chemical group 0.000 description 3
- 125000002102 aryl alkyloxo group Chemical group 0.000 description 3
- 125000005100 aryl amino carbonyl group Chemical group 0.000 description 3
- 125000004658 aryl carbonyl amino group Chemical group 0.000 description 3
- 102000005936 beta-Galactosidase Human genes 0.000 description 3
- 108010005774 beta-Galactosidase Proteins 0.000 description 3
- 230000000903 blocking effect Effects 0.000 description 3
- BTANRVKWQNVYAZ-UHFFFAOYSA-N butan-2-ol Chemical compound CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 210000000170 cell membrane Anatomy 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 125000000392 cycloalkenyl group Chemical group 0.000 description 3
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 description 3
- 125000005167 cycloalkylaminocarbonyl group Chemical group 0.000 description 3
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
- 238000011049 filling Methods 0.000 description 3
- 235000011187 glycerol Nutrition 0.000 description 3
- 239000007902 hard capsule Substances 0.000 description 3
- 125000004404 heteroalkyl group Chemical group 0.000 description 3
- 125000005222 heteroarylaminocarbonyl group Chemical group 0.000 description 3
- 125000005224 heteroarylcarbonylamino group Chemical group 0.000 description 3
- 125000005553 heteroaryloxy group Chemical group 0.000 description 3
- 230000002209 hydrophobic effect Effects 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 238000012758 nuclear staining Methods 0.000 description 3
- 229960001592 paclitaxel Drugs 0.000 description 3
- 230000035699 permeability Effects 0.000 description 3
- 230000000144 pharmacologic effect Effects 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- XSCHRSMBECNVNS-UHFFFAOYSA-N quinoxaline Chemical compound N1=CC=NC2=CC=CC=C21 XSCHRSMBECNVNS-UHFFFAOYSA-N 0.000 description 3
- 125000006413 ring segment Chemical group 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- NVBFHJWHLNUMCV-UHFFFAOYSA-N sulfamide Chemical compound NS(N)(=O)=O NVBFHJWHLNUMCV-UHFFFAOYSA-N 0.000 description 3
- 125000004434 sulfur atom Chemical group 0.000 description 3
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 3
- 125000003396 thiol group Chemical group [H]S* 0.000 description 3
- 238000004627 transmission electron microscopy Methods 0.000 description 3
- GHOKWGTUZJEAQD-ZETCQYMHSA-N (D)-(+)-Pantothenic acid Chemical compound OCC(C)(C)[C@@H](O)C(=O)NCCC(O)=O GHOKWGTUZJEAQD-ZETCQYMHSA-N 0.000 description 2
- NWGPLYYBECWONP-UHFFFAOYSA-N (carbamoylamino) hydrogen sulfate Chemical compound NC(=O)NOS(O)(=O)=O NWGPLYYBECWONP-UHFFFAOYSA-N 0.000 description 2
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical group NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-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
- 206010003694 Atrophy Diseases 0.000 description 2
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 2
- 201000004569 Blindness Diseases 0.000 description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 2
- 238000011746 C57BL/6J (JAX™ mouse strain) Methods 0.000 description 2
- 238000011814 C57BL/6N mouse Methods 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 206010009944 Colon cancer Diseases 0.000 description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
- 201000004624 Dermatitis Diseases 0.000 description 2
- 206010048768 Dermatosis Diseases 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 206010019280 Heart failures Diseases 0.000 description 2
- 206010020751 Hypersensitivity Diseases 0.000 description 2
- 206010061218 Inflammation Diseases 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 206010025323 Lymphomas Diseases 0.000 description 2
- 206010025421 Macule Diseases 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical group CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- 206010028851 Necrosis Diseases 0.000 description 2
- 208000002193 Pain Diseases 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 2
- 208000015634 Rectal Neoplasms Diseases 0.000 description 2
- 208000000453 Skin Neoplasms Diseases 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 2
- 208000000208 Wet Macular Degeneration Diseases 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 2
- 125000004171 alkoxy aryl group Chemical group 0.000 description 2
- 125000004457 alkyl amino carbonyl group Chemical group 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 description 2
- 210000002159 anterior chamber Anatomy 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 229940111121 antirheumatic drug quinolines Drugs 0.000 description 2
- 125000003710 aryl alkyl group Chemical group 0.000 description 2
- 230000037444 atrophy Effects 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- AFYNADDZULBEJA-UHFFFAOYSA-N bicinchoninic acid Chemical compound C1=CC=CC2=NC(C=3C=C(C4=CC=CC=C4N=3)C(=O)O)=CC(C(O)=O)=C21 AFYNADDZULBEJA-UHFFFAOYSA-N 0.000 description 2
- 125000002619 bicyclic group Chemical group 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 239000004305 biphenyl Substances 0.000 description 2
- 235000010290 biphenyl Nutrition 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 2
- 235000021466 carotenoid Nutrition 0.000 description 2
- 150000001747 carotenoids Chemical class 0.000 description 2
- 238000010609 cell counting kit-8 assay Methods 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 208000029742 colonic neoplasm Diseases 0.000 description 2
- 239000003086 colorant Substances 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 235000009508 confectionery Nutrition 0.000 description 2
- 230000034994 death Effects 0.000 description 2
- 238000000502 dialysis Methods 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 235000019634 flavors Nutrition 0.000 description 2
- 238000002875 fluorescence polarization Methods 0.000 description 2
- 235000015203 fruit juice Nutrition 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 125000004474 heteroalkylene group Chemical group 0.000 description 2
- 125000000623 heterocyclic group Chemical group 0.000 description 2
- 125000004366 heterocycloalkenyl group Chemical group 0.000 description 2
- 125000005885 heterocycloalkylalkyl group Chemical group 0.000 description 2
- 125000006588 heterocycloalkylene group Chemical group 0.000 description 2
- 125000002636 imidazolinyl group Chemical group 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 230000004054 inflammatory process Effects 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 230000000968 intestinal effect Effects 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 2
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 2
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 125000002950 monocyclic group Chemical group 0.000 description 2
- 125000002757 morpholinyl group Chemical group 0.000 description 2
- TXXHDPDFNKHHGW-UHFFFAOYSA-N muconic acid Chemical compound OC(=O)C=CC=CC(O)=O TXXHDPDFNKHHGW-UHFFFAOYSA-N 0.000 description 2
- 239000002105 nanoparticle Substances 0.000 description 2
- 125000001624 naphthyl group Chemical group 0.000 description 2
- 230000017074 necrotic cell death Effects 0.000 description 2
- 235000015097 nutrients Nutrition 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 235000005985 organic acids Nutrition 0.000 description 2
- 239000005416 organic matter Substances 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 229940083254 peripheral vasodilators imidazoline derivative Drugs 0.000 description 2
- LFSXCDWNBUNEEM-UHFFFAOYSA-N phthalazine Chemical compound C1=NN=CC2=CC=CC=C21 LFSXCDWNBUNEEM-UHFFFAOYSA-N 0.000 description 2
- XNGIFLGASWRNHJ-UHFFFAOYSA-N phthalic acid Chemical compound OC(=O)C1=CC=CC=C1C(O)=O XNGIFLGASWRNHJ-UHFFFAOYSA-N 0.000 description 2
- 230000001766 physiological effect Effects 0.000 description 2
- 239000000049 pigment Substances 0.000 description 2
- 125000004193 piperazinyl group Chemical group 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical compound CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 description 2
- 239000008213 purified water Substances 0.000 description 2
- LXNHXLLTXMVWPM-UHFFFAOYSA-N pyridoxine Chemical compound CC1=NC=C(CO)C(CO)=C1O LXNHXLLTXMVWPM-UHFFFAOYSA-N 0.000 description 2
- 206010038038 rectal cancer Diseases 0.000 description 2
- 201000001275 rectum cancer Diseases 0.000 description 2
- 210000000844 retinal pigment epithelial cell Anatomy 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 230000009758 senescence Effects 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- 201000000849 skin cancer Diseases 0.000 description 2
- 208000017520 skin disease Diseases 0.000 description 2
- 210000000813 small intestine Anatomy 0.000 description 2
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000012192 staining solution Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 150000008163 sugars Chemical class 0.000 description 2
- 125000006296 sulfonyl amino group Chemical group [H]N(*)S(*)(=O)=O 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- 150000003536 tetrazoles Chemical class 0.000 description 2
- 229940124597 therapeutic agent Drugs 0.000 description 2
- 229930192474 thiophene Natural products 0.000 description 2
- 210000001578 tight junction Anatomy 0.000 description 2
- 230000000451 tissue damage Effects 0.000 description 2
- 231100000827 tissue damage Toxicity 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 150000003852 triazoles Chemical class 0.000 description 2
- 229940086542 triethylamine Drugs 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- 125000005289 uranyl group Chemical group 0.000 description 2
- 230000035899 viability Effects 0.000 description 2
- 230000004393 visual impairment Effects 0.000 description 2
- 229930003231 vitamin Natural products 0.000 description 2
- 235000013343 vitamin Nutrition 0.000 description 2
- 239000011782 vitamin Substances 0.000 description 2
- 229940088594 vitamin Drugs 0.000 description 2
- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 description 1
- CYAYKKUWALRRPA-UHFFFAOYSA-N (3,4,5-triacetyloxy-6-bromooxan-2-yl)methyl acetate Chemical compound CC(=O)OCC1OC(Br)C(OC(C)=O)C(OC(C)=O)C1OC(C)=O CYAYKKUWALRRPA-UHFFFAOYSA-N 0.000 description 1
- JYEUMXHLPRZUAT-UHFFFAOYSA-N 1,2,3-triazine Chemical compound C1=CN=NN=C1 JYEUMXHLPRZUAT-UHFFFAOYSA-N 0.000 description 1
- 150000003919 1,2,3-triazines Chemical class 0.000 description 1
- 150000003920 1,2,4-triazines Chemical class 0.000 description 1
- JIHQDMXYYFUGFV-UHFFFAOYSA-N 1,3,5-triazine Chemical compound C1=NC=NC=N1 JIHQDMXYYFUGFV-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- TUSDEZXZIZRFGC-UHFFFAOYSA-N 1-O-galloyl-3,6-(R)-HHDP-beta-D-glucose Natural products OC1C(O2)COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC1C(O)C2OC(=O)C1=CC(O)=C(O)C(O)=C1 TUSDEZXZIZRFGC-UHFFFAOYSA-N 0.000 description 1
- IYDMGGPKSVWQRT-IHLOFXLRSA-N 1-[4-[(4r,5s)-4,5-bis(4-chlorophenyl)-2-(4-methoxy-2-propan-2-yloxyphenyl)-4,5-dihydroimidazole-1-carbonyl]piperazin-1-yl]ethanone Chemical compound CC(C)OC1=CC(OC)=CC=C1C1=N[C@H](C=2C=CC(Cl)=CC=2)[C@H](C=2C=CC(Cl)=CC=2)N1C(=O)N1CCN(C(C)=O)CC1 IYDMGGPKSVWQRT-IHLOFXLRSA-N 0.000 description 1
- OWEGMIWEEQEYGQ-UHFFFAOYSA-N 100676-05-9 Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC2C(OC(O)C(O)C2O)CO)O1 OWEGMIWEEQEYGQ-UHFFFAOYSA-N 0.000 description 1
- FPIPGXGPPPQFEQ-UHFFFAOYSA-N 13-cis retinol Natural products OCC=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-UHFFFAOYSA-N 0.000 description 1
- KJUGUADJHNHALS-UHFFFAOYSA-N 1H-tetrazole Substances C=1N=NNN=1 KJUGUADJHNHALS-UHFFFAOYSA-N 0.000 description 1
- ZEPAXLPHESYSJU-UHFFFAOYSA-N 2,3,4,5,6,7,8-heptahydroxyoctanal Chemical compound OCC(O)C(O)C(O)C(O)C(O)C(O)C=O ZEPAXLPHESYSJU-UHFFFAOYSA-N 0.000 description 1
- YMRIDJQAEZFTSC-UHFFFAOYSA-N 2,3-dihydro-1h-tetrazole Chemical compound N1NC=NN1 YMRIDJQAEZFTSC-UHFFFAOYSA-N 0.000 description 1
- GVNVAWHJIKLAGL-UHFFFAOYSA-N 2-(cyclohexen-1-yl)cyclohexan-1-one Chemical compound O=C1CCCCC1C1=CCCCC1 GVNVAWHJIKLAGL-UHFFFAOYSA-N 0.000 description 1
- 125000004974 2-butenyl group Chemical group C(C=CC)* 0.000 description 1
- IKCLCGXPQILATA-UHFFFAOYSA-N 2-chlorobenzoic acid Chemical compound OC(=O)C1=CC=CC=C1Cl IKCLCGXPQILATA-UHFFFAOYSA-N 0.000 description 1
- 125000006040 2-hexenyl group Chemical group 0.000 description 1
- XWKFPIODWVPXLX-UHFFFAOYSA-N 2-methyl-5-methylpyridine Natural products CC1=CC=C(C)N=C1 XWKFPIODWVPXLX-UHFFFAOYSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 1
- VHMICKWLTGFITH-UHFFFAOYSA-N 2H-isoindole Chemical compound C1=CC=CC2=CNC=C21 VHMICKWLTGFITH-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- UOQHWNPVNXSDDO-UHFFFAOYSA-N 3-bromoimidazo[1,2-a]pyridine-6-carbonitrile Chemical compound C1=CC(C#N)=CN2C(Br)=CN=C21 UOQHWNPVNXSDDO-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- BDUHCSBCVGXTJM-WUFINQPMSA-N 4-[[(4S,5R)-4,5-bis(4-chlorophenyl)-2-(4-methoxy-2-propan-2-yloxyphenyl)-4,5-dihydroimidazol-1-yl]-oxomethyl]-2-piperazinone Chemical compound CC(C)OC1=CC(OC)=CC=C1C1=N[C@@H](C=2C=CC(Cl)=CC=2)[C@@H](C=2C=CC(Cl)=CC=2)N1C(=O)N1CC(=O)NCC1 BDUHCSBCVGXTJM-WUFINQPMSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 208000024893 Acute lymphoblastic leukemia Diseases 0.000 description 1
- 208000014697 Acute lymphocytic leukaemia Diseases 0.000 description 1
- 208000031261 Acute myeloid leukaemia Diseases 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- 206010061424 Anal cancer Diseases 0.000 description 1
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- 208000007860 Anus Neoplasms Diseases 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- ROFVEXUMMXZLPA-UHFFFAOYSA-N Bipyridyl Chemical compound N1=CC=CC=C1C1=CC=CC=N1 ROFVEXUMMXZLPA-UHFFFAOYSA-N 0.000 description 1
- 206010005003 Bladder cancer Diseases 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-N Carbamic acid Chemical group NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 1
- 206010007559 Cardiac failure congestive Diseases 0.000 description 1
- 208000031229 Cardiomyopathies Diseases 0.000 description 1
- 206010048610 Cardiotoxicity Diseases 0.000 description 1
- QRYRORQUOLYVBU-VBKZILBWSA-N Carnosic acid Natural products CC([C@@H]1CC2)(C)CCC[C@]1(C(O)=O)C1=C2C=C(C(C)C)C(O)=C1O QRYRORQUOLYVBU-VBKZILBWSA-N 0.000 description 1
- 108010087806 Carnosine Proteins 0.000 description 1
- 208000014882 Carotid artery disease Diseases 0.000 description 1
- 206010008342 Cervix carcinoma Diseases 0.000 description 1
- GHOKWGTUZJEAQD-UHFFFAOYSA-N Chick antidermatitis factor Natural products OCC(C)(C)C(O)C(=O)NCCC(O)=O GHOKWGTUZJEAQD-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 1
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 description 1
- 101150065749 Churc1 gene Proteins 0.000 description 1
- 208000034656 Contusions Diseases 0.000 description 1
- 206010011091 Coronary artery thrombosis Diseases 0.000 description 1
- 244000124209 Crocus sativus Species 0.000 description 1
- 235000015655 Crocus sativus Nutrition 0.000 description 1
- 229930153442 Curcuminoid Natural products 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- 201000003883 Cystic fibrosis Diseases 0.000 description 1
- GUBGYTABKSRVRQ-CUHNMECISA-N D-Cellobiose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-CUHNMECISA-N 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
- AUNGANRZJHBGPY-UHFFFAOYSA-N D-Lyxoflavin Natural products OCC(O)C(O)C(O)CN1C=2C=C(C)C(C)=CC=2N=C2C1=NC(=O)NC2=O AUNGANRZJHBGPY-UHFFFAOYSA-N 0.000 description 1
- ZZZCUOFIHGPKAK-UHFFFAOYSA-N D-erythro-ascorbic acid Natural products OCC1OC(=O)C(O)=C1O ZZZCUOFIHGPKAK-UHFFFAOYSA-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
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 1
- 108020004414 DNA Proteins 0.000 description 1
- 206010011878 Deafness Diseases 0.000 description 1
- 206010012289 Dementia Diseases 0.000 description 1
- 206010012438 Dermatitis atopic Diseases 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 206010012688 Diabetic retinal oedema Diseases 0.000 description 1
- 206010056340 Diabetic ulcer Diseases 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- 206010014561 Emphysema Diseases 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- 208000000461 Esophageal Neoplasms Diseases 0.000 description 1
- 208000010201 Exanthema Diseases 0.000 description 1
- 239000001263 FEMA 3042 Substances 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 206010016654 Fibrosis Diseases 0.000 description 1
- 239000004606 Fillers/Extenders Substances 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 102000002464 Galactosidases Human genes 0.000 description 1
- 108010093031 Galactosidases Proteins 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 208000008069 Geographic Atrophy Diseases 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 208000032843 Hemorrhage Diseases 0.000 description 1
- 208000023105 Huntington disease Diseases 0.000 description 1
- 208000035150 Hypercholesterolemia Diseases 0.000 description 1
- 208000031226 Hyperlipidaemia Diseases 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 208000022559 Inflammatory bowel disease Diseases 0.000 description 1
- 208000003618 Intervertebral Disc Displacement Diseases 0.000 description 1
- 206010050296 Intervertebral disc protrusion Diseases 0.000 description 1
- 201000008450 Intracranial aneurysm Diseases 0.000 description 1
- 208000008839 Kidney Neoplasms Diseases 0.000 description 1
- 208000003947 Knee Osteoarthritis Diseases 0.000 description 1
- 206010023509 Kyphosis Diseases 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 208000001344 Macular Edema Diseases 0.000 description 1
- 206010025415 Macular oedema Diseases 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-PICCSMPSSA-N Maltose Natural products O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-PICCSMPSSA-N 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 206010027145 Melanocytic naevus Diseases 0.000 description 1
- 208000001145 Metabolic Syndrome Diseases 0.000 description 1
- 208000003430 Mitral Valve Prolapse Diseases 0.000 description 1
- TXXHDPDFNKHHGW-CCAGOZQPSA-N Muconic acid Natural products OC(=O)\C=C/C=C\C(O)=O TXXHDPDFNKHHGW-CCAGOZQPSA-N 0.000 description 1
- 208000034578 Multiple myelomas Diseases 0.000 description 1
- 206010049565 Muscle fatigue Diseases 0.000 description 1
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 description 1
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 description 1
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 1
- CQOVPNPJLQNMDC-UHFFFAOYSA-N N-beta-alanyl-L-histidine Natural products NCCC(=O)NC(C(O)=O)CC1=CN=CN1 CQOVPNPJLQNMDC-UHFFFAOYSA-N 0.000 description 1
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 description 1
- AFBPFSWMIHJQDM-UHFFFAOYSA-N N-methylaniline Chemical compound CNC1=CC=CC=C1 AFBPFSWMIHJQDM-UHFFFAOYSA-N 0.000 description 1
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
- 150000001204 N-oxides Chemical class 0.000 description 1
- 206010029350 Neurotoxicity Diseases 0.000 description 1
- 206010058105 Neutrophilic dermatosis Diseases 0.000 description 1
- 208000007256 Nevus Diseases 0.000 description 1
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 208000008589 Obesity Diseases 0.000 description 1
- 206010030155 Oesophageal carcinoma Diseases 0.000 description 1
- 206010031023 Oral submucosal fibrosis Diseases 0.000 description 1
- 208000001132 Osteoporosis Diseases 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 1
- 239000002033 PVDF binder Substances 0.000 description 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 1
- 108010019160 Pancreatin Proteins 0.000 description 1
- 108010067035 Pancrelipase Proteins 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 229920002230 Pectic acid Polymers 0.000 description 1
- 206010034277 Pemphigoid Diseases 0.000 description 1
- 241000721454 Pemphigus Species 0.000 description 1
- LRBQNJMCXXYXIU-PPKXGCFTSA-N Penta-digallate-beta-D-glucose Natural products OC1=C(O)C(O)=CC(C(=O)OC=2C(=C(O)C=C(C=2)C(=O)OC[C@@H]2[C@H]([C@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)O2)OC(=O)C=2C=C(OC(=O)C=3C=C(O)C(O)=C(O)C=3)C(O)=C(O)C=2)O)=C1 LRBQNJMCXXYXIU-PPKXGCFTSA-N 0.000 description 1
- 102000057297 Pepsin A Human genes 0.000 description 1
- 108090000284 Pepsin A Proteins 0.000 description 1
- 208000018262 Peripheral vascular disease Diseases 0.000 description 1
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 description 1
- 206010051246 Photodermatosis Diseases 0.000 description 1
- 206010034972 Photosensitivity reaction Diseases 0.000 description 1
- 206010035226 Plasma cell myeloma Diseases 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 102100038239 Protein Churchill Human genes 0.000 description 1
- 208000003251 Pruritus Diseases 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- 208000001647 Renal Insufficiency Diseases 0.000 description 1
- 206010038389 Renal cancer Diseases 0.000 description 1
- 208000002367 Retinal Perforations Diseases 0.000 description 1
- AUNGANRZJHBGPY-SCRDCRAPSA-N Riboflavin Chemical compound OC[C@@H](O)[C@@H](O)[C@@H](O)CN1C=2C=C(C)C(C)=CC=2N=C2C1=NC(=O)NC2=O AUNGANRZJHBGPY-SCRDCRAPSA-N 0.000 description 1
- BUGBHKTXTAQXES-UHFFFAOYSA-N Selenium Chemical compound [Se] BUGBHKTXTAQXES-UHFFFAOYSA-N 0.000 description 1
- 108010087230 Sincalide Proteins 0.000 description 1
- 206010072170 Skin wound Diseases 0.000 description 1
- 206010040954 Skin wrinkling Diseases 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 208000005718 Stomach Neoplasms Diseases 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 206010043189 Telangiectasia Diseases 0.000 description 1
- 244000269722 Thea sinensis Species 0.000 description 1
- 244000299461 Theobroma cacao Species 0.000 description 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
- 208000024770 Thyroid neoplasm Diseases 0.000 description 1
- 206010044221 Toxic encephalopathy Diseases 0.000 description 1
- HDTRYLNUVZCQOY-WSWWMNSNSA-N Trehalose Natural products O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-WSWWMNSNSA-N 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- 206010046431 Urethral cancer Diseases 0.000 description 1
- 206010046458 Urethral neoplasms Diseases 0.000 description 1
- LEHOTFFKMJEONL-UHFFFAOYSA-N Uric Acid Chemical compound N1C(=O)NC(=O)C2=C1NC(=O)N2 LEHOTFFKMJEONL-UHFFFAOYSA-N 0.000 description 1
- TVWHNULVHGKJHS-UHFFFAOYSA-N Uric acid Natural products N1C(=O)NC(=O)C2NC(=O)NC21 TVWHNULVHGKJHS-UHFFFAOYSA-N 0.000 description 1
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 1
- 208000024780 Urticaria Diseases 0.000 description 1
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 1
- 206010047571 Visual impairment Diseases 0.000 description 1
- FPIPGXGPPPQFEQ-BOOMUCAASA-N Vitamin A Natural products OC/C=C(/C)\C=C\C=C(\C)/C=C/C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-BOOMUCAASA-N 0.000 description 1
- 229930003451 Vitamin B1 Natural products 0.000 description 1
- 229930003779 Vitamin B12 Natural products 0.000 description 1
- 229930003471 Vitamin B2 Natural products 0.000 description 1
- 229930003537 Vitamin B3 Natural products 0.000 description 1
- 229930003761 Vitamin B9 Natural products 0.000 description 1
- 229930003268 Vitamin C Natural products 0.000 description 1
- 229930003427 Vitamin E Natural products 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- PVRYEWOXWGDQHA-URLMMPGGSA-N [(4s,5r)-4,5-bis(4-bromophenyl)-2-(2-ethoxy-4-methoxyphenyl)-4,5-dihydroimidazol-1-yl]-[4-(2-hydroxyethyl)piperazin-1-yl]methanone Chemical compound CCOC1=CC(OC)=CC=C1C1=N[C@@H](C=2C=CC(Br)=CC=2)[C@@H](C=2C=CC(Br)=CC=2)N1C(=O)N1CCN(CCO)CC1 PVRYEWOXWGDQHA-URLMMPGGSA-N 0.000 description 1
- 206010000059 abdominal discomfort Diseases 0.000 description 1
- 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 235000013334 alcoholic beverage Nutrition 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 125000004183 alkoxy alkyl group Chemical group 0.000 description 1
- 125000005082 alkoxyalkenyl group Chemical group 0.000 description 1
- 125000005078 alkoxycarbonylalkyl group Chemical group 0.000 description 1
- 125000003806 alkyl carbonyl amino group Chemical group 0.000 description 1
- 125000005197 alkyl carbonyloxy alkyl group Chemical group 0.000 description 1
- 125000005233 alkylalcohol group Chemical group 0.000 description 1
- FPIPGXGPPPQFEQ-OVSJKPMPSA-N all-trans-retinol Chemical compound OC\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-OVSJKPMPSA-N 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 125000005021 aminoalkenyl group Chemical group 0.000 description 1
- 125000004103 aminoalkyl group Chemical group 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 235000010208 anthocyanin Nutrition 0.000 description 1
- 239000004410 anthocyanin Substances 0.000 description 1
- 229930002877 anthocyanin Natural products 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 201000011165 anus cancer Diseases 0.000 description 1
- 208000007474 aortic aneurysm Diseases 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 230000006793 arrhythmia Effects 0.000 description 1
- 206010003119 arrhythmia Diseases 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 239000012131 assay buffer Substances 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 201000008937 atopic dermatitis Diseases 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- JUHORIMYRDESRB-UHFFFAOYSA-N benzathine Chemical compound C=1C=CC=CC=1CNCCNCC1=CC=CC=C1 JUHORIMYRDESRB-UHFFFAOYSA-N 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QUYVBRFLSA-N beta-maltose Chemical compound OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O GUBGYTABKSRVRQ-QUYVBRFLSA-N 0.000 description 1
- 235000013361 beverage Nutrition 0.000 description 1
- 125000005841 biaryl group Chemical group 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 235000008429 bread Nutrition 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 201000009267 bronchiectasis Diseases 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000000480 butynyl group Chemical group [*]C#CC([H])([H])C([H])([H])[H] 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 239000007963 capsule composition Substances 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 235000014171 carbonated beverage Nutrition 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 125000004181 carboxyalkyl group Chemical group 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 230000009787 cardiac fibrosis Effects 0.000 description 1
- 231100000259 cardiotoxicity Toxicity 0.000 description 1
- CQOVPNPJLQNMDC-ZETCQYMHSA-N carnosine Chemical compound [NH3+]CCC(=O)N[C@H](C([O-])=O)CC1=CNC=N1 CQOVPNPJLQNMDC-ZETCQYMHSA-N 0.000 description 1
- 229940044199 carnosine Drugs 0.000 description 1
- 210000003321 cartilage cell Anatomy 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 235000019438 castor oil Nutrition 0.000 description 1
- YCIMNLLNPGFGHC-UHFFFAOYSA-N catechol Chemical compound OC1=CC=CC=C1O YCIMNLLNPGFGHC-UHFFFAOYSA-N 0.000 description 1
- 230000022534 cell killing Effects 0.000 description 1
- 210000002421 cell wall Anatomy 0.000 description 1
- 201000010881 cervical cancer Diseases 0.000 description 1
- 150000008280 chlorinated hydrocarbons Chemical class 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 235000019219 chocolate Nutrition 0.000 description 1
- 150000001854 cinnolines Chemical class 0.000 description 1
- 208000019425 cirrhosis of liver Diseases 0.000 description 1
- AGVAZMGAQJOSFJ-WZHZPDAFSA-M cobalt(2+);[(2r,3s,4r,5s)-5-(5,6-dimethylbenzimidazol-1-yl)-4-hydroxy-2-(hydroxymethyl)oxolan-3-yl] [(2r)-1-[3-[(1r,2r,3r,4z,7s,9z,12s,13s,14z,17s,18s,19r)-2,13,18-tris(2-amino-2-oxoethyl)-7,12,17-tris(3-amino-3-oxopropyl)-3,5,8,8,13,15,18,19-octamethyl-2 Chemical compound [Co+2].N#[C-].[N-]([C@@H]1[C@H](CC(N)=O)[C@@]2(C)CCC(=O)NC[C@@H](C)OP(O)(=O)O[C@H]3[C@H]([C@H](O[C@@H]3CO)N3C4=CC(C)=C(C)C=C4N=C3)O)\C2=C(C)/C([C@H](C\2(C)C)CCC(N)=O)=N/C/2=C\C([C@H]([C@@]/2(CC(N)=O)C)CCC(N)=O)=N\C\2=C(C)/C2=N[C@]1(C)[C@@](C)(CC(N)=O)[C@@H]2CCC(N)=O AGVAZMGAQJOSFJ-WZHZPDAFSA-M 0.000 description 1
- 208000010877 cognitive disease Diseases 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- 238000000748 compression moulding Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 208000029078 coronary artery disease Diseases 0.000 description 1
- 208000002528 coronary thrombosis Diseases 0.000 description 1
- 150000001907 coumarones Chemical class 0.000 description 1
- 125000004966 cyanoalkyl group Chemical group 0.000 description 1
- 125000005724 cycloalkenylene group Chemical group 0.000 description 1
- 125000000000 cycloalkoxy group Chemical group 0.000 description 1
- 125000005169 cycloalkylcarbonylamino group Chemical group 0.000 description 1
- 125000002993 cycloalkylene group Chemical group 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- HCAJEUSONLESMK-UHFFFAOYSA-N cyclohexylsulfamic acid Chemical compound OS(=O)(=O)NC1CCCCC1 HCAJEUSONLESMK-UHFFFAOYSA-N 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 235000013365 dairy product Nutrition 0.000 description 1
- 230000007850 degeneration Effects 0.000 description 1
- 230000001934 delay Effects 0.000 description 1
- 230000035614 depigmentation Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 201000011190 diabetic macular edema Diseases 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 229940043279 diisopropylamine Drugs 0.000 description 1
- XXBDWLFCJWSEKW-UHFFFAOYSA-N dimethylbenzylamine Chemical compound CN(C)CC1=CC=CC=C1 XXBDWLFCJWSEKW-UHFFFAOYSA-N 0.000 description 1
- WEHWNAOGRSTTBQ-UHFFFAOYSA-N dipropylamine Chemical compound CCCNCCC WEHWNAOGRSTTBQ-UHFFFAOYSA-N 0.000 description 1
- 208000037765 diseases and disorders Diseases 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 229930004069 diterpene Natural products 0.000 description 1
- 150000004141 diterpene derivatives Chemical class 0.000 description 1
- 208000002173 dizziness Diseases 0.000 description 1
- 229960003668 docetaxel Drugs 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000012137 double-staining Methods 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 208000011325 dry age related macular degeneration Diseases 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 239000003792 electrolyte Substances 0.000 description 1
- 238000001962 electrophoresis Methods 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 206010014665 endocarditis Diseases 0.000 description 1
- 230000002327 eosinophilic effect Effects 0.000 description 1
- 210000000981 epithelium Anatomy 0.000 description 1
- 201000004101 esophageal cancer Diseases 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 201000005884 exanthem Diseases 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 210000000416 exudates and transudate Anatomy 0.000 description 1
- 230000004761 fibrosis Effects 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000000834 fixative Substances 0.000 description 1
- 229930003935 flavonoid Natural products 0.000 description 1
- 150000002215 flavonoids Chemical class 0.000 description 1
- 235000017173 flavonoids Nutrition 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 description 1
- 230000037406 food intake Effects 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 150000002240 furans Chemical class 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- LRBQNJMCXXYXIU-QWKBTXIPSA-N gallotannic acid Chemical compound OC1=C(O)C(O)=CC(C(=O)OC=2C(=C(O)C=C(C=2)C(=O)OC[C@H]2[C@@H]([C@@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)O2)OC(=O)C=2C=C(OC(=O)C=3C=C(O)C(O)=C(O)C=3)C(O)=C(O)C=2)O)=C1 LRBQNJMCXXYXIU-QWKBTXIPSA-N 0.000 description 1
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 description 1
- 206010017758 gastric cancer Diseases 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 238000012812 general test Methods 0.000 description 1
- 239000000174 gluconic acid Substances 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 125000000262 haloalkenyl group Chemical group 0.000 description 1
- 125000001188 haloalkyl group Chemical group 0.000 description 1
- 201000010536 head and neck cancer Diseases 0.000 description 1
- 208000014829 head and neck neoplasm Diseases 0.000 description 1
- 230000008821 health effect Effects 0.000 description 1
- 230000003862 health status Effects 0.000 description 1
- 230000010370 hearing loss Effects 0.000 description 1
- 231100000888 hearing loss Toxicity 0.000 description 1
- 208000016354 hearing loss disease Diseases 0.000 description 1
- 201000005787 hematologic cancer Diseases 0.000 description 1
- 230000002489 hematologic effect Effects 0.000 description 1
- 208000024200 hematopoietic and lymphoid system neoplasm Diseases 0.000 description 1
- 150000002386 heptoses Chemical class 0.000 description 1
- 125000005114 heteroarylalkoxy group Chemical group 0.000 description 1
- 125000005549 heteroarylene group Chemical group 0.000 description 1
- 150000002402 hexoses Chemical class 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 125000005020 hydroxyalkenyl group Chemical group 0.000 description 1
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 1
- 208000000069 hyperpigmentation Diseases 0.000 description 1
- 230000003810 hyperpigmentation Effects 0.000 description 1
- 230000009610 hypersensitivity Effects 0.000 description 1
- 235000015243 ice cream Nutrition 0.000 description 1
- 150000002454 idoses Chemical class 0.000 description 1
- 150000002460 imidazoles Chemical class 0.000 description 1
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 1
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 1
- 150000002475 indoles Chemical class 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 229940045996 isethionic acid Drugs 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 150000002518 isoindoles Chemical class 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 1
- 150000002537 isoquinolines Chemical class 0.000 description 1
- ZLTPDFXIESTBQG-UHFFFAOYSA-N isothiazole Chemical compound C=1C=NSC=1 ZLTPDFXIESTBQG-UHFFFAOYSA-N 0.000 description 1
- 150000003854 isothiazoles Chemical class 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 201000010982 kidney cancer Diseases 0.000 description 1
- 208000017169 kidney disease Diseases 0.000 description 1
- 201000006370 kidney failure Diseases 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 229940099563 lactobionic acid Drugs 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- JCQLYHFGKNRPGE-FCVZTGTOSA-N lactulose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 JCQLYHFGKNRPGE-FCVZTGTOSA-N 0.000 description 1
- 229960000511 lactulose Drugs 0.000 description 1
- PFCRQPBOOFTZGQ-UHFFFAOYSA-N lactulose keto form Natural products OCC(=O)C(O)C(C(O)CO)OC1OC(CO)C(O)C(O)C1O PFCRQPBOOFTZGQ-UHFFFAOYSA-N 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 230000003859 lipid peroxidation Effects 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 239000006193 liquid solution Substances 0.000 description 1
- 229910003002 lithium salt Inorganic materials 0.000 description 1
- 159000000002 lithium salts Chemical class 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 230000004199 lung function Effects 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 206010025135 lupus erythematosus Diseases 0.000 description 1
- KBPHJBAIARWVSC-RGZFRNHPSA-N lutein Chemical compound C([C@H](O)CC=1C)C(C)(C)C=1\C=C\C(\C)=C\C=C\C(\C)=C\C=C\C=C(/C)\C=C\C=C(/C)\C=C\[C@H]1C(C)=C[C@H](O)CC1(C)C KBPHJBAIARWVSC-RGZFRNHPSA-N 0.000 description 1
- 229960005375 lutein Drugs 0.000 description 1
- 208000029233 macular holes Diseases 0.000 description 1
- 201000010230 macular retinal edema Diseases 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 235000013372 meat Nutrition 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- LRMHVVPPGGOAJQ-UHFFFAOYSA-N methyl nitrate Chemical compound CO[N+]([O-])=O LRMHVVPPGGOAJQ-UHFFFAOYSA-N 0.000 description 1
- 239000004530 micro-emulsion Substances 0.000 description 1
- 208000027061 mild cognitive impairment Diseases 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 210000002161 motor neuron Anatomy 0.000 description 1
- 238000000465 moulding Methods 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- LNOPIUAQISRISI-UHFFFAOYSA-N n'-hydroxy-2-propan-2-ylsulfonylethanimidamide Chemical compound CC(C)S(=O)(=O)CC(N)=NO LNOPIUAQISRISI-UHFFFAOYSA-N 0.000 description 1
- 125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- RIWRFSMVIUAEBX-UHFFFAOYSA-N n-methyl-1-phenylmethanamine Chemical compound CNCC1=CC=CC=C1 RIWRFSMVIUAEBX-UHFFFAOYSA-N 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000002159 nanocrystal Substances 0.000 description 1
- 230000006764 neuronal dysfunction Effects 0.000 description 1
- 230000007823 neuropathy Effects 0.000 description 1
- 201000001119 neuropathy Diseases 0.000 description 1
- 230000007135 neurotoxicity Effects 0.000 description 1
- 231100000228 neurotoxicity Toxicity 0.000 description 1
- 229960003512 nicotinic acid Drugs 0.000 description 1
- DFPAKSUCGFBDDF-UHFFFAOYSA-N nicotinic acid amide Natural products NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 239000012457 nonaqueous media Substances 0.000 description 1
- 235000012149 noodles Nutrition 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
- 235000020824 obesity Nutrition 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
- 239000006186 oral dosage form Substances 0.000 description 1
- 208000005207 oral submucous fibrosis Diseases 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 230000002611 ovarian Effects 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 150000002916 oxazoles Chemical class 0.000 description 1
- 125000005254 oxyacyl group Chemical group 0.000 description 1
- 229940118537 p53 inhibitor Drugs 0.000 description 1
- 235000019629 palatability Nutrition 0.000 description 1
- WLJNZVDCPSBLRP-UHFFFAOYSA-N pamoic acid Chemical compound C1=CC=C2C(CC=3C4=CC=CC=C4C=C(C=3O)C(=O)O)=C(O)C(C(O)=O)=CC2=C1 WLJNZVDCPSBLRP-UHFFFAOYSA-N 0.000 description 1
- 201000002528 pancreatic cancer Diseases 0.000 description 1
- 208000008443 pancreatic carcinoma Diseases 0.000 description 1
- 229940055695 pancreatin Drugs 0.000 description 1
- 229940055726 pantothenic acid Drugs 0.000 description 1
- 235000019161 pantothenic acid Nutrition 0.000 description 1
- 239000011713 pantothenic acid Substances 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000006201 parenteral dosage form Substances 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- LCLHHZYHLXDRQG-ZNKJPWOQSA-N pectic acid Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)O[C@H](C(O)=O)[C@@H]1OC1[C@H](O)[C@@H](O)[C@@H](OC2[C@@H]([C@@H](O)[C@@H](O)[C@H](O2)C(O)=O)O)[C@@H](C(O)=O)O1 LCLHHZYHLXDRQG-ZNKJPWOQSA-N 0.000 description 1
- 230000006320 pegylation Effects 0.000 description 1
- 235000019371 penicillin G benzathine Nutrition 0.000 description 1
- 150000002972 pentoses Chemical class 0.000 description 1
- 125000004115 pentoxy group Chemical group [*]OC([H])([H])C([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 229940111202 pepsin Drugs 0.000 description 1
- 208000033808 peripheral neuropathy Diseases 0.000 description 1
- 230000005043 peripheral vision Effects 0.000 description 1
- 125000005496 phosphonium group Chemical group 0.000 description 1
- 235000011007 phosphoric acid Nutrition 0.000 description 1
- 230000008845 photoaging Effects 0.000 description 1
- 210000000608 photoreceptor cell Anatomy 0.000 description 1
- 230000036211 photosensitivity Effects 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 239000004014 plasticizer Substances 0.000 description 1
- 239000002574 poison Substances 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 239000010318 polygalacturonic acid Substances 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 150000004804 polysaccharides Chemical class 0.000 description 1
- 229920000915 polyvinyl chloride Polymers 0.000 description 1
- 239000004800 polyvinyl chloride Substances 0.000 description 1
- 229920002981 polyvinylidene fluoride Polymers 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 229930008679 prenylflavonoid Natural products 0.000 description 1
- 150000007951 prenylflavonoids Chemical class 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 235000019260 propionic acid Nutrition 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
- 238000002731 protein assay Methods 0.000 description 1
- 208000005069 pulmonary fibrosis Diseases 0.000 description 1
- 150000003217 pyrazoles Chemical class 0.000 description 1
- XMYLDITUFLHWLR-UHFFFAOYSA-N pyrene Chemical compound C1=CC=C2C=CC3=CC=CC4=CC=C1C2=C43.C1=CC=C2C=CC3=CC=CC4=CC=C1C2=C43 XMYLDITUFLHWLR-UHFFFAOYSA-N 0.000 description 1
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 1
- 150000004892 pyridazines Chemical class 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- RADKZDMFGJYCBB-UHFFFAOYSA-N pyridoxal hydrochloride Natural products CC1=NC=C(CO)C(C=O)=C1O RADKZDMFGJYCBB-UHFFFAOYSA-N 0.000 description 1
- 150000003230 pyrimidines Chemical class 0.000 description 1
- 125000001453 quaternary ammonium group Chemical group 0.000 description 1
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 description 1
- 150000003246 quinazolines Chemical class 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 150000003248 quinolines Chemical class 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 206010037844 rash Diseases 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 210000003583 retinal pigment epithelium Anatomy 0.000 description 1
- 150000004492 retinoid derivatives Chemical class 0.000 description 1
- 229960002477 riboflavin Drugs 0.000 description 1
- 239000004248 saffron Substances 0.000 description 1
- 235000013974 saffron Nutrition 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 208000001076 sarcopenia Diseases 0.000 description 1
- 235000013580 sausages Nutrition 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000011669 selenium Substances 0.000 description 1
- 229910052711 selenium Inorganic materials 0.000 description 1
- 235000011649 selenium Nutrition 0.000 description 1
- 230000001953 sensory effect Effects 0.000 description 1
- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 1
- 235000011888 snacks Nutrition 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000014347 soups Nutrition 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 150000003436 stilbenoids Chemical class 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- 208000003265 stomatitis Diseases 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 125000005017 substituted alkenyl group Chemical group 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- 125000005346 substituted cycloalkyl group Chemical group 0.000 description 1
- 150000005846 sugar alcohols Chemical class 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 238000007910 systemic administration Methods 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000015523 tannic acid Nutrition 0.000 description 1
- 229920002258 tannic acid Polymers 0.000 description 1
- 229940033123 tannic acid Drugs 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000013616 tea Nutrition 0.000 description 1
- 208000009056 telangiectasis Diseases 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000003538 tetroses Chemical class 0.000 description 1
- 229960003495 thiamine Drugs 0.000 description 1
- DPJRMOMPQZCRJU-UHFFFAOYSA-M thiamine hydrochloride Chemical compound Cl.[Cl-].CC1=C(CCO)SC=[N+]1CC1=CN=C(C)N=C1N DPJRMOMPQZCRJU-UHFFFAOYSA-M 0.000 description 1
- 150000003557 thiazoles Chemical class 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 150000003577 thiophenes Chemical class 0.000 description 1
- 201000002510 thyroid cancer Diseases 0.000 description 1
- KBPHJBAIARWVSC-XQIHNALSSA-N trans-lutein Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C1=C(C)CC(O)CC1(C)C)C=CC=C(/C)C=CC2C(=CC(O)CC2(C)C)C KBPHJBAIARWVSC-XQIHNALSSA-N 0.000 description 1
- 125000006168 tricyclic group Chemical group 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- RKBCYCFRFCNLTO-UHFFFAOYSA-N triisopropylamine Chemical compound CC(C)N(C(C)C)C(C)C RKBCYCFRFCNLTO-UHFFFAOYSA-N 0.000 description 1
- 150000003641 trioses Chemical class 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- 150000004043 trisaccharides Chemical class 0.000 description 1
- 229940116269 uric acid Drugs 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- 229960005486 vaccine Drugs 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 208000029257 vision disease Diseases 0.000 description 1
- 235000019155 vitamin A Nutrition 0.000 description 1
- 239000011719 vitamin A Substances 0.000 description 1
- 235000010374 vitamin B1 Nutrition 0.000 description 1
- 239000011691 vitamin B1 Substances 0.000 description 1
- 235000019163 vitamin B12 Nutrition 0.000 description 1
- 239000011715 vitamin B12 Substances 0.000 description 1
- 235000019164 vitamin B2 Nutrition 0.000 description 1
- 239000011716 vitamin B2 Substances 0.000 description 1
- 235000019160 vitamin B3 Nutrition 0.000 description 1
- 239000011708 vitamin B3 Substances 0.000 description 1
- 235000019158 vitamin B6 Nutrition 0.000 description 1
- 239000011726 vitamin B6 Substances 0.000 description 1
- 235000019159 vitamin B9 Nutrition 0.000 description 1
- 239000011727 vitamin B9 Substances 0.000 description 1
- 235000019154 vitamin C Nutrition 0.000 description 1
- 239000011718 vitamin C Substances 0.000 description 1
- 235000019165 vitamin E Nutrition 0.000 description 1
- 239000011709 vitamin E Substances 0.000 description 1
- 229940046009 vitamin E Drugs 0.000 description 1
- 229940045997 vitamin a Drugs 0.000 description 1
- 229940011671 vitamin b6 Drugs 0.000 description 1
- 150000003722 vitamin derivatives Chemical class 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 230000029663 wound healing Effects 0.000 description 1
- 230000037303 wrinkles Effects 0.000 description 1
- FJHBOVDFOQMZRV-XQIHNALSSA-N xanthophyll Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C1=C(C)CC(O)CC1(C)C)C=CC=C(/C)C=CC2C=C(C)C(O)CC2(C)C FJHBOVDFOQMZRV-XQIHNALSSA-N 0.000 description 1
- 235000008210 xanthophylls Nutrition 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 235000016804 zinc Nutrition 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/7056—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing five-membered rings with nitrogen as a ring hetero atom
-
- 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/26—Acyclic or carbocyclic radicals, substituted by hetero rings
Definitions
- poorly soluble drugs for example, imidazoline derivative compounds
- These poorly soluble drugs cause severe pain to patients even when administered in a curable amount, and cannot be administered in large amounts due to excessive side effects.
- additional substances must be added to resolve the poor solubility, but many cases have been reported in which use is restricted due to the toxicity of the added substances.
- Cremorphor EL is a mixture of polyoxyethylated castor oil and absolute ethanol.
- Cremorphor EL is a mixture of polyoxyethylated castor oil and absolute ethanol.
- the present inventors dramatically improved the solubility by combining an imidazoline derivative compound and a sugar, so that it can be effectively used to remove senescent cells without the use of additional additives, and can be used to remove nanocrystals in an aqueous solution without the use of surfactants. It was confirmed that particle micelles could be produced, and the present invention was completed.
- One aspect is to provide a composition comprising a compound represented by Formula 1:
- Another aspect is to provide micelles containing the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof.
- Another aspect is to provide a pharmaceutical composition for preventing or treating aging-related diseases, which includes the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
- Another aspect is to provide a health functional food for preventing or improving aging-related diseases containing the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
- Another aspect is to provide a method for preventing or treating aging-related diseases, comprising administering an effective amount of the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof to a subject in need thereof.
- Another aspect is to provide a method for improving aging comprising administering an effective amount of the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof to a subject in need thereof.
- Another aspect is to provide a use of the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof for use in the manufacture of a pharmaceutical agent for preventing or treating age-related diseases.
- Another aspect is to provide a use of the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof for use in health functional foods for preventing or treating age-related diseases.
- composition comprising a compound represented by Formula 1:
- R 1 to R 2 are each independently H, substituted or unsubstituted alkyl of C 1 to C 10 , substituted or unsubstituted alkenyl of C 2 to C 10 , or substituted C 2 to C 10 or unsubstituted alkynyl, substituted or unsubstituted alkoxy of C 1 to C 10 , or substituted or unsubstituted aryl;
- R 3 is sugar or a derivative thereof;
- R 4 is substituted or unsubstituted alkylene of C 1 to C 10 , substituted or unsubstituted alkenylene of C 2 to C 10 , substituted or unsubstituted alkynylene of C 2 to C 10 , or substituted or unsubstituted alkynylene.
- X 1 and X 2 are each independently halogen.
- substituted refers to one or more substituents, such as hydroxy group, alkyl group, alkoxy group, mercapto group, cycloalkyl group, substituted cycloalkyl group, heterocyclic group, substituted heterocyclic group, aryl.
- aryl group substituted aryl group, heteroaryl group, substituted heteroaryl group, aryloxy group, substituted aryloxy group, halogen group, trifluoromethyl group, cyano group, nitro group, oxo group, amino group, amido group, aldehyde It means substituted with a group, acyl group, oxyacyl group, carboxyl group, carbamate group, sulfonyl group, sulfonamide, sulfuryl group, etc.
- alkyl refers to a saturated aliphatic hydrocarbon group containing 1 to 10 carbon atoms, such as 1 to 8, 1 to 6, or 1 to 4 carbon atoms, and the alkyl group is straight chain or Or it may be branched. Additionally, the alkyl includes cycloalkyl, heteroalkyl, and heterocycloalkyl. Examples include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-heptyl, or 2-ethylhexyl.
- the alkyl may have one or more substituents, such as halo, phospho, cycloaliphatic (e.g., cycloalkyl or cycloalkenyl), heterocycloaliphatic (e.g., heterocycloalkyl or heterocycloalkenyl), aryl.
- substituents such as halo, phospho, cycloaliphatic (e.g., cycloalkyl or cycloalkenyl), heterocycloaliphatic (e.g., heterocycloalkyl or heterocycloalkenyl), aryl.
- heteroaryl alkoxy, aroyl, heteroaroyl, acyl (e.g., (aliphatic)carbonyl, (cycloaliphatic)carbonyl, or (heterocycloaliphatic)carbonyl), nitro, cyano, amido ( For example, (cycloalkylalkyl)carbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl)carbonylamino, (heterocycloalkylalkyl)carbonylamino, heteroarylcarbonylamino, hetero aralkylcarbonylamino alkylaminocarbonyl, cycloalkylaminocarbonyl, heterocycloalkylaminocarbonyl, arylaminocarbonyl, or heteroarylaminocarbonyl), amino (e.g., aliphatic amino, cycloaliphatic amino, or heterocycloaliphatic amino), sulfon
- Substituted alkyl may be carboxyalkyl (e.g.
- HOOC-alkyl alkoxycarbonylalkyl or alkylcarbonyloxyalkyl
- cyanoalkyl hydroxyalkyl, alkoxyalkyl, asylalkyl, aralkyl, (alkoxyaryl)alkyl, (sulfonylamino)alkyl (such as (alkyl-SO 2 -amino)alkyl), aminoalkyl, amidoalkyl, (cycloaliphatic)alkyl, haloalkyl, amine cation, quaternary ammonium or quaternary phosphonium.
- heteroalkyl refers to alkyl consisting of a carbon atom and one or more heteroatoms selected from the group consisting of O, N, and S.
- the nitrogen and sulfur atoms can optionally be oxidized, and the heteroatoms O, N and/or S can be placed at any internal position of the heteroalkyl group.
- alkenyl refers to an aliphatic carbon group containing 2 to 10, for example, 2 to 8, 2 to 6, or 2 to 4 carbon atoms and one or more double bonds. Similar to alkyl groups, alkenyl groups can be straight chain or branched. Additionally, the alkenyl includes cycloalkenyl, heteroalkenyl, and cycloheteroalkenyl. The alkenyl may be, for example, allyl, isoprenyl, 2-butenyl, or 2-hexenyl, but is not limited thereto.
- the alkenyl may have one or more substituents, such as halo, phospho, cycloaliphatic (e.g., cycloalkyl or cycloalkenyl), heterocycloaliphatic (e.g., heterocycloalkyl or heterocycloalkenyl), Aryl, heteroaryl, alkoxy, aroyl, heteroaroyl, acyl (e.g., (aliphatic)carbonyl, (cycloaliphatic)carbonyl, or (heterocycloaliphatic)carbonyl), nitro, cyano, amido (For example, (cycloalkylalkyl)carbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl)carbonylamino, (heterocycloalkylalkyl)carbonylamino, heteroarylcarbonylamino, Heteroaralkylcarbonylamino alkylaminocarbonyl
- Substituted alkenyls include cyanoalkenyl, alkoxyalkenyl, acylalkenyl, hydroxyalkenyl, aralkenyl, (alkoxyaryl)alkenyl, (sulfonylamino)alkenyl (e.g., (alkyl-SO 2 -amino) alkenyl), aminoalkenyl, amidoalkenyl, (cycloaliphatic)alkenyl, or haloalkenyl.
- heteroalkenyl refers to alkenyl consisting of a carbon atom and one or more heteroatoms selected from the group consisting of O, N, and S.
- the nitrogen and sulfur atoms can optionally be oxidized, and the heteroatoms O, N and/or S can be placed at any internal position of the heteroalkenyl group.
- alkynyl refers to an aliphatic carbon group containing 2 to 10 carbon atoms, such as 2 to 8, 2 to 6, or 2 to 4 carbon atoms, and having at least one triple bond; , the alkynyl group may be straight chain or branched.
- the alkynyl includes cycloalkynyl, heteroalkynyl, and cycloheteroalkynyl.
- the alkynyl group can be propargyl or butynyl.
- Alkynyl may have one or more substituents, such as aroyl, heteroaroyl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, nitro, carboxy, cyano, halo, hydride.
- substituents such as aroyl, heteroaroyl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, nitro, carboxy, cyano, halo, hydride.
- aliphatic sulfinyl SO 2 -, aliphatic amino-SO 2 -, or cycloaliphatic-SO 2 -), amido (e.g. aminocarbonyl, alkylaminocarbonyl, alkylcarbonylamino, cycloalkylaminocarbonyl, heterocycloalkyl Aminocarbonyl, cycloalkylcarbonylamino, arylaminocarbonyl, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl)carbonylamino, (cycloalkylalkyl)carbonylamino, heteroaralkylcarbonylamino , heteroarylcarbonylamino or heteroarylaminocarbonyl), urea, thiourea, sulfamoyl, sulfamide, alkoxycarbonyl, alkylcarbonyloxy, cycloaliphatic, heterocycloaliphatic, ary
- heteroalkynyl refers to alkynyl consisting of a carbon atom and one or more heteroatoms selected from the group consisting of O, N, and S.
- the nitrogen and sulfur atoms can optionally be oxidized, and the heteroatoms O, N and/or S can be placed at any internal position of the heteroalkynyl group.
- alkoxy refers to a group in which the hydrogen atom of hydroxyl is replaced with the alkyl, alkenyl, or alkynyl.
- the alkoxy may be a C 1 to C 10 alkoxy such as methoxy, ethoxy, propoxy, butoxy, and pentoxy.
- aryl refers to an aromatic ring system containing 6 to 16 ring atoms, and includes heteroaryl.
- the aryl group may be a monocyclic, bicyclic or tricyclic group, or may be connected by a bond to form a biaryl group.
- the aryl group may be phenyl, naphthyl, or biphenyl.
- the aryl group may include an alkylene linkage to form an arylalkyl group, such as a benzyl group.
- the aryl group may have 6 to 12 ring members, such as phenyl, naphthyl, or biphenyl, and the aryl may be substituted or unsubstituted.
- heteroaryl refers to a monocyclic, fused bicyclic or tricyclic aromatic ring assembly containing 5 to 16 ring atoms, where 1 to 5 of the atoms constituting the ring are Heteroatoms may be for example N, O or S.
- the heteroatoms may be oxidized and examples include, but are not limited to, N-oxide, -S(O)-, and -S(O) 2 -.
- Heteroaryl groups can have any number of ring atoms, for example 3 to 6, 4 to 6, 5 to 6, 3 to 8, 4 to 8, 5 to 8, 6 to 8, 3 to 9, 3 to 10, It may contain 3 to 11, or 3 to 12 ring members.
- the heteroaryl group has 5 to 8 ring members and 1 to 4 heteroatoms, or 5 to 8 ring members and 1 to 3 heteroatoms, or 5 to 6 ring members and 1 to 4 heteroatoms. It may have heteroatoms, or 5 to 6 ring members and 1 to 3 heteroatoms.
- the heteroaryl group is pyrrole, pyridine, imidazole, pyrazole, triazole, tetrazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4-, and 1,3, 5-isomer), thiophene, furan, thiazole, isothiazole, oxazole and isoxazole.
- the heteroaryl group can also be fused to an aromatic ring system, such as a phenyl ring, to form benzopyrroles such as indole and isoindole, benzopyridines such as quinoline and isoquinoline, benzopyrazine, benzopyrimidine, benzopyridazine such as phthalazine and cinine. Including, but not limited to, noline, benzothiophene, and benzofuran. Additionally, the heteroaryl group may include a heteroaryl ring linked by a bond, for example, bipyridine, and the heteroaryl group may be substituted or unsubstituted.
- the heteroaryl group may be connected through any position on the ring.
- pyrrole includes 1-, 2-, and 3-pyrrole; Pyridines include 2-, 3-, and 4-pyridines; Imidazoles include 1-, 2-, 4-, and 5-imidazole; Pyrazoles include 1-, 3-, 4- and 5-pyrazoles; Triazoles include 1-, 4-, and 5-triazoles; Tetrazoles include 1- and 5-tetrazole; Pyrimidines include 2-, 4-, 5-, and 6-pyrimidines; Pyridazines include 3- and 4-pyridazine; 1,2,3-triazines include 4- and 5-triazines; 1,2,4-triazines include 3-, 5- and 6-triazines; 1,3,5-triazine includes 2-triazine; Thiophenes include 2- and 3-thiophene; Furans include 2- and 3-furans; Thiazoles include 2-, 4-, and 5-thiazoles; Isothiazoles include 3-, 4-, and 5-isothiazoles; Oxazoles
- sucrose refers to a common compound/composition (CH 2 O) n or a derivative thereof, including monosaccharides, disaccharides, trisaccharides, polysaccharides, sugar alcohols, reducing sugars, non-reducing sugars, etc. .
- the sugar may be a monosaccharide or a disaccharide.
- the monosaccharide may be triose, tetrose, pentose, hexose, heptose, octose, or nonose.
- the monosaccharides include galactose, glucose, fructose, mannose, allose, altrose, gulose, and talose ( talose, psicose, sorbose, tagatose, idose, rhamnose, xylose, arabinose, fucose , glyceraldehyde, erythrose, threose, ribose, lyxose, dihydroxyacetone, erythrulose and ribulose. ) may be any one or more selected from the group consisting of
- the disaccharide may be sucrose, lactulose, lactose, maltose, trehalose, or cellobiose.
- sugar derivative refers to a sugar in which one or more hydroxyl groups of the sugar have been modified with different substituents.
- the sugar derivative may be one in which the hydroxyl group of the sugar is replaced with an alkoxy group.
- the sugar derivative may be a compound represented by the following formula (2):
- R 4 is substituted or unsubstituted alkylene of C 1 to C 10 , substituted or unsubstituted alkenylene of C 2 to C 10 , substituted or unsubstituted alkenylene of C 2 to C 10 It may be substituted alkynylene, or substituted or unsubstituted arylene.
- the sugar derivative may be a compound represented by the following formula (3):
- R 4 is substituted or unsubstituted alkylene of C 1 to C 10 , substituted or unsubstituted alkenylene of C 2 to C 10 , substituted or unsubstituted alkenylene of C 2 to C 10 It may be substituted alkynylene, or substituted or unsubstituted arylene.
- the sugar derivative may be a compound represented by the following formula (4):
- R 4 is substituted or unsubstituted alkylene of C 1 to C 10 , substituted or unsubstituted alkenylene of C 2 to C 10 , substituted or unsubstituted alkenylene of C 2 to C 10 It may be substituted alkynylene, or substituted or unsubstituted arylene.
- the sugar derivative may be a compound represented by the following formula (5):
- R 4 is substituted or unsubstituted alkylene of C 1 to C 10 , substituted or unsubstituted alkenylene of C 2 to C 10 , substituted or unsubstituted alkenylene of C 2 to C 10 It may be substituted alkynylene, or substituted or unsubstituted arylene.
- the sugar derivative may be a compound represented by the following formula (6):
- R 4 is substituted or unsubstituted alkylene of C 1 to C 10 , substituted or unsubstituted alkenylene of C 2 to C 10 , substituted or unsubstituted alkenylene of C 2 to C 10 It may be substituted alkynylene, or substituted or unsubstituted arylene.
- alkylene refers to a divalent radical derived from an alkane, and may be, for example, -CH 2 CH 2 CH 2 CH 2 -.
- the alkylene includes cycloalkylene, heteroalkylene, and heterocycloalkylene.
- the heteroalkylene or heterocycloalkylene may include a carbon atom and one or more heteroatoms selected from the group consisting of O, N, and S.
- the alkenylene includes cycloalkenylene, heteroalkenylene, and heterocycloylkylene.
- the heteroalkenylene or heterocycloalkenylene may include a carbon atom and one or more heteroatoms selected from the group consisting of O, N, and S.
- alkynylene refers to a functional group having at least one carbon-carbon triple bond, for example, -CH 2 -C ⁇ C-CH 2 -CH 2 -.
- the alkynylene includes cycloalkynylene, heteroalkynylene, and heterocycloalkynylene.
- the heteroalkynylene or heterocycloalkynylene may include a carbon atom and one or more heteroatoms selected from the group consisting of O, N, and S.
- arylene generally refers to a divalent aromatic group having 6 to 14 carbon atoms.
- the arylene includes heteroarylene.
- the heteroalkynylene or heterocycloalkynylene may include a carbon atom and one or more heteroatoms selected from the group consisting of O, N, and S.
- R 6 is H, hydroxy, C 1 -C 6 alkyl, -NH 2 , amino substituted with C 1 -C 6 alkyl, C 1 -C 6 alkyl which may be substituted with hydroxy, and C 1 -C 6 alkyl which may be substituted with NH 2
- R 5 may be selected from -N(CH 3 )CH 3 , -NHCH 2 CH 2 NH 2 , -NH 2 , morpholinyl and piperazinyl.
- halogen means fluorine, chlorine, bromine, or iodine.
- the term “pharmaceutically acceptable” means that it is physiologically acceptable and does not usually cause gastrointestinal upset, allergic reactions such as dizziness, or similar reactions when administered to humans.
- the term “pharmaceutically acceptable salt” refers to a salt according to one aspect of the present invention that is pharmaceutically acceptable and has the desired pharmacological activity of the parent compound.
- Salts of the parent compound can be synthesized from the parent compound containing a basic or acidic moiety by conventional chemical methods. Generally, these salts are prepared by reacting the free acid form of these compounds with a stoichiometric amount of an appropriate base, such as sodium, calcium, magnesium, or potassium, or by reacting the free base form of these compounds with a stoichiometric amount of an appropriate acid. It can be manufactured by: These reactions are typically carried out in water or in organic solvents or mixtures of the two.
- non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile may be used.
- the pharmaceutically acceptable salt includes both addition salts of acids or bases and their stereochemical isomeric forms, and may be, for example, addition salts of organic acids or inorganic acids.
- the salt includes any salt that maintains the activity of the parent compound in the subject of administration and does not cause undesirable effects, and is not particularly limited.
- salts include inorganic and organic salts, such as acetic acid, nitric acid, aspartic acid, sulfonic acid, sulfuric acid, maleic acid, glutamic acid, formic acid, succinic acid, phosphoric acid, phthalic acid, tannic acid, tartaric acid, and hydrobromic acid. , propionic acid, benzenesulfonic acid, benzoic acid, stearic acid, lactic acid, bicarboxylic acid, bisulfuric acid, bitartaric acid, oxalic acid, butyric acid, calcium idete, carbonic acid, chlorobenzoic acid, citric acid, idetic acid, toluene.
- acetic acid such as acetic acid, nitric acid, aspartic acid, sulfonic acid, sulfuric acid, maleic acid, glutamic acid, formic acid, succinic acid, phosphoric acid, phthalic acid, tannic acid, tartaric acid,
- Sulfonic acid fumaric acid, gluceptic acid, esilinic acid, pamoic acid, gluconic acid, methylnitric acid, malonic acid, hydrochloric acid, hydroiodoic acid, hydroxynaphtholic acid, isethionic acid, lactobionic acid, bay.
- the salts include salts of alkali and alkaline earth metals such as ammonium salts, lithium salts, sodium salts, potassium salts, magnesium salts and calcium salts, for example, benzathine, N-methyl-D-glucamine, hydrochloric acid salts, etc. It includes salts with organic bases such as labamine salts, and salts with amino acids such as arginine and lysine. Additionally, the salt form may be converted to the free form by treatment with a suitable base or acid.
- alkali and alkaline earth metals such as ammonium salts, lithium salts, sodium salts, potassium salts, magnesium salts and calcium salts, for example, benzathine, N-methyl-D-glucamine, hydrochloric acid salts, etc. It includes salts with organic bases such as labamine salts, and salts with amino acids such as arginine and lysine. Additionally, the salt form may be converted to the free form by treatment with a suitable base or acid.
- the imidazoline derivative compound represented by Formula 1 may be a compound selected from the group consisting of Formulas 7 to 10 below, or a pharmaceutically acceptable salt thereof.
- the compound represented by Formula 1 may be an imidazoline derivative or a pharmaceutically acceptable salt thereof; And it may be obtained by combining sugar or a derivative thereof.
- the imidazoline derivative may be one selected from the group consisting of Nutlin-1, Nutlin-2, or Nutlin-3, and the Nutlin-3 may be Nutlin-3a or Nutlin-3b, but is not limited thereto. .
- the bond may be an imidazoline derivative or a pharmaceutically acceptable salt thereof;
- the sugar or its derivative can be combined by reacting in the presence of a base and a solvent for 5 to 20 hours, for example, 10 to 20 hours, 15 to 20 hours, 15 to 19 hours, or 15 to 18 hours.
- the reaction can be performed at room temperature, and those skilled in the art can appropriately change the reaction time depending on the temperature.
- the base is NaH, lithium diisopropylamide (LDA), 4-dimethylaminopyridine (DMAP), triethylamine (TEA), pyridine, ammonia, methylamine, ethylamine, propyl Amine, isopropylamine, dimethylamine, diethylamine, dipropylamine, diisopropylamine, trimethylamine, tripropylamine, triisopropylamine, aniline, methylaniline, dimethylaniline, pyridine, azazulolidine, benzyl It may be an amine, methylbenzylamine, dimethylbenzylamine, 2,6-lutidine, morpholine, piperidine, piperazine, proton-sponge, ammonium hydroxide, triethanolamine, ethanolamine, or trismile.
- LDA lithium diisopropylamide
- DMAP 4-dimethylaminopyridine
- TAA triethylamine
- pyridine ammoni
- the solvent is dimethylacetamide (DMAc), dichloromethane (DCM), tetrahydrofuran (THF), dimethylformamide (DMF), acetonitrile (ACN), DMAP, water, Acetic acid, acetone, dioxane, benzene, 1-butanol, 2-butanol, tert-butyl alcohol, carbon tetrachloride, chloroform, cyclohexane, hexane, diethyl ether, dimethyl sulfoxide (DMSO), ethanol, ethyl acetate, It may be ethylene glycol, glycerin, heptane, pentane, pyridine, toluene, hydrochloric acid, and triethyl amine.
- DMAc dimethylacetamide
- DCM dichloromethane
- THF tetrahydrofuran
- DMF dimethylformamide
- ACN acetonitrile
- Another aspect provides micelles containing a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof:
- R 1 to R 2 are each independently H, substituted or unsubstituted alkyl of C 1 to C 10 , substituted or unsubstituted alkenyl of C 2 to C 10 , or substituted C 2 to C 10 or unsubstituted alkynyl, substituted or unsubstituted alkoxy of C 1 to C 10 , or substituted or unsubstituted aryl;
- R 3 is sugar or a derivative thereof;
- R 4 is substituted or unsubstituted alkylene of C 1 to C 10 , substituted or unsubstituted alkenylene of C 2 to C 10 , substituted or unsubstituted alkynylene of C 2 to C 10 , or substituted or unsubstituted alkynylene.
- X 1 and X 2 are each independently halogen.
- the compound represented by Formula 1 is as described above.
- the term “micelle” refers to an aggregate of amphiphilic molecules having an inner core and an outer surface in an aqueous medium, wherein most of the amphiphilic molecules have their hydrophobic portion forming the core and the hydrophilic portion forming the core. It is oriented to form an outer surface.
- the micelle according to the present invention is oriented so that the drug forms the hydrophobic part to form the core, and the hydrophilic peptide forms the hydrophilic part to form the outer surface.
- the micelles can be prepared in an aqueous solution without using a surfactant.
- the micelles are prepared by dissolving the compound represented by Formula 1 in an organic solvent such as fluorinated alcohol, dimethylformamide, dimethyl sulfoxide, chlorinated hydrocarbon, hydrocarbon or alkyl alcohol, and then dissolving the compound represented by Formula 1 at 10°C to 30°C, for example 15°C.
- the micelles may be prepared by stirring at °C to 30°C, 15°C to 25°C, or room temperature, and then performing artificial dialysis.
- the artificial dialysis may be performed for 1 to 5 days, for example, 1 to 4 days or 2 to 3 days.
- the size of the micelles may be 50 nm to 200 nm.
- it may be 50 nm to 200 nm, 50 nm to 150 nm, or 50 nm to 100 nm.
- the zeta potential of the micelle may be -10 mv to -40 mv.
- it may be -10 mv to -30 mv or -20 mv to -30 mv.
- Another aspect provides a pharmaceutical composition for preventing or treating aging-related diseases, comprising the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof:
- R 1 to R 2 are each independently H, substituted or unsubstituted alkyl of C 1 to C 10 , substituted or unsubstituted alkenyl of C 2 to C 10 , or substituted C 2 to C 10 or unsubstituted alkynyl, substituted or unsubstituted alkoxy of C 1 to C 10 , or substituted or unsubstituted aryl;
- R 3 is sugar or a derivative thereof;
- R 4 is substituted or unsubstituted alkylene of C 1 to C 10 , substituted or unsubstituted alkenylene of C 2 to C 10 , substituted or unsubstituted alkynylene of C 2 to C 10 , or substituted or unsubstituted alkynylene.
- X 1 and X 2 are each independently halogen.
- the compound represented by Formula 1 is as described above.
- the compound of the composition may selectively induce apoptosis in mitochondria within senescent cells by overexpressing p53 and p21 compared to normal cells.
- Apoptosis is a form of cell death controlled by genes, and is distinguished from necrosis, which is cell death caused by stimuli such as burns, bruises, or poisons, as necrosis or pathological death of cells. This refers to the death of cells, which begins with cells shrinking, then gaps are created between adjacent cells, and within the cells, DNA is regularly cut and fragmented.
- the age-related diseases include cancer, cardiovascular disease or disorder in the elderly, inflammatory or autoimmune disease or disorder in the elderly, neurodegenerative disease in the elderly, metabolic disease in the elderly, pulmonary disease in the elderly, eye disease or disorder in the elderly, age-related disorders in the elderly, and dermatology in the elderly. It may be one or more selected from the group consisting of adverse diseases or disorders.
- the cancer may be hematological cancer or solid cancer.
- the blood cancer is selected from the group consisting of Acute Myeloid Leukemia, Acute Lymphoblastic Leukemia, Chronic Myelogenous Leukemia, Multiple Myeloma, and Lymphoma. However, it is not limited to this.
- the solid cancers include breast cancer, colon cancer, head and neck cancer, lung cancer, stomach cancer, skin cancer, colon cancer, prostate cancer, bladder cancer, kidney cancer, rectal cancer, thyroid cancer, liver cancer, cervical cancer, skin cancer, rectal cancer, anal cancer, urethral cancer, ovarian cancer, and esophageal cancer. and pancreatic cancer, but is not limited thereto.
- the elderly cardiovascular disease or disorder is atherosclerosis, angina pectoris, arrhythmia, cardiomyopathy, congestive heart failure, coronary artery disease, carotid artery disease, endocarditis, coronary thrombosis, myocardial infarction, hypertension, aortic aneurysm, heart failure. It may be dysfunction, hypercholesterolemia, hyperlipidemia, mitral valve prolapse, peripheral vascular disease, cardiac load resistance, cardiac fibrosis, cerebral aneurysm, and stroke.
- the geriatric inflammatory or autoimmune disease or disorder may be osteoarthritis, osteoporosis, oral mucositis, inflammatory bowel disease, kyphosis, and intervertebral disc herniation.
- the geriatric neurodegenerative disease may be Alzheimer's disease, Parkinson's disease, Huntington's disease, dementia, mild cognitive impairment, and motor neuron dysfunction.
- the metabolic disease in the elderly may be diabetes, diabetic ulcer, metabolic syndrome, and obesity.
- the elderly lung disease may be pulmonary fibrosis, chronic obstructive pulmonary disease, asthma, cystic fibrosis, emphysema, bronchiectasis, and age-related loss of lung function.
- the elderly eye disease may be macular degeneration, glaucoma, cataract, presbyopia, and vision impairment.
- acula is the name of the central part of the retina, which is responsible for central vision in contrast to peripheral vision.
- Macular degeneration includes age-related macular degeneration, diabetic macular edema, cystic macular edema, macular hole, and macular telangiectasia.
- age-related macular degeneration refers to progressive or multifactorial degeneration or atrophy of the retina, retinal pigment epithelium, choriocapillaris, etc. in adults in their 50s or older. It is a disease in which photoreceptor cells in the macular area are lost with aging, resulting in visual impairment.
- the macular degeneration includes dry macular degeneration and wet macular degeneration.
- Dry age-related macular degeneration which accounts for the majority of age-related macular degeneration, refers to lesions such as drusen, pigmentary abnormality, or atrophy of the retinal epithelium in the retina. It does not usually cause severe vision loss, but it can develop into a wet form.
- Wet age-related macular degeneration is a condition in which choroidal new blood vessels grow under the retina, causing exudate and hemorrhage in the macula, affecting central vision and, in severe cases, blindness.
- the age-related disorder may be kidney disease, renal failure, weakness, hearing loss, muscle fatigue, skin condition, skin wound healing, liver fibrosis, pancreatic fibrosis, oral submucosal fibrosis, and sarcopenia.
- the dermatological diseases include eczema, psoriasis, hyperpigmentation, nevus, rash, atopic dermatitis, urticaria, diseases and disorders related to photosensitivity or photoaging, wrinkles; pruritus; sensory impairment; eczematous rash; Eosinophilic dermatosis; reactive neutrophilic dermatosis; pemphigus; pemphigoid; immunobullous dermatosis; Fibrohistiocytic proliferation of the skin; Cutaneous lymphoma; and cutaneous lupus.
- prevention refers to partially or completely delaying or preventing the onset or recurrence of a disease, disorder, or its secondary symptoms, preventing the acquisition or re-acquisition of a disease or disorder, or preventing the development or recurrence of a disease or disorder.
- a general term for reducing the risk of acquisition. The prevention refers to any action that suppresses or delays the occurrence of inflammation or inflammation-related diseases, disorders, or symptoms by administering the composition according to the present invention.
- treatment refers to any action that improves or beneficially changes a disease, disorder, or its accompanying symptoms.
- the term “therapeutic agent” or “pharmaceutical composition” refers to a molecule or compound that imparts some beneficial effect upon administration to a subject. Beneficial effects include enabling diagnostic decisions; Improvement of a disease, symptom, disorder or condition; Reducing or preventing the onset of a disease, symptom, disorder or condition; and generally includes responding to a disease, symptom, disorder or condition.
- the composition may further include antioxidants, and the antioxidants include nicotinamide, anthocyanin, benzenediol abiethane diterpene, carnosine, carotenoid, xanthophyll, and carotenoids in saffron, cur Cuminoid, cyclopentenone prostaglandin, flavonoid, prenylflavonoid, retinoid, stilbenoid, uric acid, vitamin A, vitamin B1, vitamin B2, vitamin B3, vitamin B6, vitamin B9, vitamin B12, vitamin C, vitamin E, selenium , zinc, inhibitors and scavengers of lipid peroxidation and its by-products, tirilazade, and analogs, derivatives, salts, and combinations thereof.
- the antioxidants include nicotinamide, anthocyanin, benzenediol abiethane diterpene, carnosine, carotenoid, xanthophyll, and carotenoids in s
- composition may additionally contain a pharmaceutically effective amount of a bioactive ingredient or may contain one or more pharmaceutically acceptable carriers, excipients, or diluents.
- the pharmaceutically effective amount refers to an amount sufficient to exhibit the desired physiological or pharmacological activity when the bioactive ingredient is administered to animals or humans.
- the pharmaceutically effective amount may vary appropriately depending on the age, weight, health status, gender, administration route, and treatment period of the administration subject.
- the “biologically active ingredient” is a substance that can induce a desired biological or pharmacological effect by promoting or inhibiting physiological functions in the body of animals or humans, and is a chemical or biological substance or compound suitable for administration to animals or humans. It means (1) has a preventive effect on organic matter by preventing unwanted biological effects, such as preventing infection, and (2) alleviates conditions caused by disease, for example, alleviating pain or infection as a result of disease. , (3) can play a role in alleviating, reducing or completely eliminating disease from organic matter. Additionally, “the bioactive ingredient” may be used interchangeably with the term “therapeutic agent.”
- the bioactive ingredient may be selected from the group consisting of proteins, anticancer agents, anti-inflammatory painkillers, antibiotics, antibacterial agents, hormones, genes, and vaccines, but is not limited thereto.
- the pharmaceutical composition may be formulated using diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, and surfactants by methods known in the art, and such formulations may be oral or parenteral administration formulations.
- diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, and surfactants by methods known in the art, and such formulations may be oral or parenteral administration formulations.
- the oral dosage form may be granules, powder, solution, tablet, capsule, dry syrup, or a combination thereof, and the parenteral dosage form may be an injection, but is not limited thereto.
- the administration may be performed by methods known in the art. Administration may be administered directly to the subject by any means, such as, for example, intravenous, intramuscular, oral, transdermal, mucosal, intranasal, intratracheal or subcutaneous administration. You can. The administration may be administered systemically or locally.
- the subject may include, but is not limited to, mammals, such as humans, cattle, horses, pigs, dogs, sheep, goats, or cats.
- the subject may be an individual in need of improvement in conditions related to aging.
- the therapeutically effective dosage of the pharmaceutical composition is 0.01 to 1000 mg per kg of body weight per day, for example, 0.1 to 500 mg or 0.1 to 300 mg, and can be administered in one to several divided doses.
- the therapeutically effective dosage or therapeutically effective amount may vary depending on the formulation method, administration method, administration time, and/or administration route of the pharmaceutical composition.
- the type and degree of reaction to be achieved by administration of the composition, type of subject to be administered, age, weight, general health condition, symptoms or degree of disease, gender, diet, excretion, simultaneous or different effects on the subject It may vary depending on various factors, including drugs and other composition components used together, and similar factors well known in the pharmaceutical field, and a person skilled in the art can easily determine the effective dosage for the desired treatment. and can be prescribed.
- Another aspect provides a health functional food for preventing or improving aging-related diseases containing the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient:
- R 1 to R 2 are each independently H, substituted or unsubstituted alkyl of C 1 to C 10 , substituted or unsubstituted alkenyl of C 2 to C 10 , or substituted C 2 to C 10 or unsubstituted alkynyl, substituted or unsubstituted alkoxy of C 1 to C 10 , or substituted or unsubstituted aryl;
- R 3 is sugar or a derivative thereof;
- R 4 is substituted or unsubstituted alkylene of C 1 to C 10 , substituted or unsubstituted alkenylene of C 2 to C 10 , substituted or unsubstituted alkynylene of C 2 to C 10 , or substituted or unsubstituted alkynylene.
- X 1 and X 2 are each independently halogen.
- the compound represented by Formula 1 is as described above.
- the health functional food may further include the antioxidants described above.
- health functional food refers to food manufactured and processed using raw materials or ingredients with functionality useful to the human body in accordance with Act No. 6727 on Health Functional Food, and nutrients for the structure and function of the human body. It means ingestion for the purpose of controlling health or obtaining useful health effects such as physiological effects.
- the composition of the present invention when using the composition of the present invention as a food additive, the composition can be added as is or used with other foods or ingredients, and can be used appropriately according to conventional methods.
- the mixing amount of the active ingredient can be appropriately determined depending on the purpose of use.
- food additives usually refer to small amounts intentionally added to food for the purpose of improving appearance, flavor, texture or storage, and improve the quality of food, improving preservation or palatability as well as nutritional value and It means using it for the purpose of increasing the practical value of food.
- this may be a substance used by adding, mixing, infiltrating, or using other methods in manufacturing, processing, or preserving food.
- Examples of foods to which the composition of the present invention can be added include meat, sausages, breads, chocolates, candies, snacks, confectionery, ramen, other noodles, gums, dairy products including ice cream, various soups, beverages, tea, There are drinks, alcoholic beverages, vitamin complexes, etc., and can include all foods in the conventional sense, and include foods used as feed for animals.
- the health functional food of the present invention may contain common food additives, and its suitability as a food additive is determined in accordance with the general provisions and general test methods of the food additive code approved by the Food and Drug Administration, unless otherwise specified. Judgment is made according to specifications and standards.
- the food composition of the present invention contains various nutrients, vitamins, electrolytes, flavors, colorants, pectic acid and its salts, alginic acid and its salts, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, and alcohol.
- it may contain pulp for the production of natural fruit juice, fruit juice drinks, and vegetable drinks.
- the food can be manufactured in dosage forms such as tablets, granules, powders, capsules, liquid solutions, and pills according to known manufacturing methods.
- dosage forms such as tablets, granules, powders, capsules, liquid solutions, and pills according to known manufacturing methods.
- other ingredients such as tablets, granules, powders, capsules, liquid solutions, and pills.
- various common flavoring agents or natural carbohydrates may be included as additional ingredients.
- the health functional food in tablet form is prepared by granulating a mixture of the compound of Formula 1, which is the active ingredient of the present invention, with excipients, binders, disintegrants and other additives in a conventional manner, and then adding a lubricant. etc. can be put into compression molding, or the mixture can be directly compression molded.
- the health functional food in the form of tablets may contain flavoring agents, etc., if necessary.
- the granule formulation can be prepared into granules by mixing the compound of Formula 1, which is the active ingredient of the present invention, with excipients, binders, disintegrants, etc., using a known method, and if necessary, flavoring agents and flavoring agents. It may contain etc.
- hard capsules can be prepared by filling a regular hard capsule with a mixture of the compound of Formula 1, which is the active ingredient of the present invention, with additives such as excipients
- soft capsules can be prepared by filling a regular hard capsule with a mixture of the compound of Formula 1, which is the active ingredient of the present invention, with additives such as excipients. It can be prepared by filling a mixture of additives such as excipients into a capsule base such as gelatin, and may contain plasticizers such as glycerin or sorbitol, colorants, and preservatives, if necessary.
- the ring formulation can be prepared by molding a mixture of the compound of Formula 1, which is the active ingredient of the present invention, and excipients, binders, disintegrants, etc., by a known method, and if necessary, can be added with sucrose or other skin-care agents. It can be peeled off, or the surface can be coated with a substance such as starch or talc.
- the solubility of imidazoline derivatives is improved without the use of additives such as surfactants, and the drug can be effectively used to prevent, improve, or treat diseases.
- additives such as surfactants
- the micelles there is an effect of improving drug-induced side effects by improving the selectivity of the drug for cells or tissues that require drug treatment.
- Figure 1 is an image showing the degree of redispersion of N201-gal micelles in the aqueous solution prepared in Example 2.
- Figure 2 is a graph confirming the critical micelle concentration (CMC) concentration of N201-gal micelles by comparing I 335 /I 332 values at each concentration.
- CMC critical micelle concentration
- Figure 3 is a TEM image of N201-gal micelles.
- Figure 4 is a graph showing the DLS results of N201-gal micelles.
- Figure 5 is a graph showing the DLS results of N201-gal micelles in artificial gastrointestinal fluid (SGF-SIF solution).
- Figure 6 is a graph comparing the HLPC intensity results of N201-gal micelles in artificial gastrointestinal fluid (SGF-SIF solution) over time.
- Figure 7 is an image showing the chemical structures of N101, N201, and N201-gal.
- Figure 8 is an image showing a plot of the binding ratio to MDM2 according to the concentration of N101, N201, and N201-gal in logarithmic values.
- Figure 9 is an image showing the protein electrophoresis results of SnC-ARPE19 cells treated with N101, N201, and N201-gal.
- Figure 10 is a graph comparing the viability of cells treated with N201 and N201-gal.
- Figure 11 is an image of the medium in which senescent cells isolated from 3D cartilage tissue were treated with 50 uM and 100 uM of N101, N201, and N201-gal drugs.
- Figure 12 is an image comparing the staining results of SA- ⁇ -gal in retinal tissue when N201-gal was orally administered.
- Figure 13 is a graph comparing the relative value of the intensity of images quantifying the staining results of SA- ⁇ -gal in retinal tissue when N201-gal was orally administered.
- Figure 14 is an image comparing the staining results of p16 protein in retinal tissue when N201-gal was orally administered.
- Figure 15 is an image comparing the staining results of p21 protein in retinal tissue when N201-gal was orally administered.
- Figure 16 is a graph comparing and analyzing the number of p16 protein and double-stained nuclei in percentage compared to the total number of nuclei in retinal tissue when N201-gal was orally administered.
- Figure 17 is a graph comparing and analyzing the number of p21 protein and double-stained nuclei in percentage compared to the total number of nuclei in retinal tissue when N201-gal was orally administered.
- Figure 18 is an image comparing Mito-sox staining results in retinal tissue when N201-gal was orally administered.
- Figure 19 is a graph comparing the relative value of the intensity of images quantifying the staining results of Mito-sox in retinal tissue when N201-gal was orally administered.
- Figure 20 is an image comparing the staining results of retinal cell walls in retinal tissue when N201-gal was orally administered.
- Figure 21 is a graph comparing the relative value of the intensity of images quantifying the area comprised by tight junctions of retinal pigment epithelial cells in retinal tissue when N201-gal is orally administered.
- Figure 22 is an image comparing the staining results of p21 protein in retinal tissue when N201-gal was administered intravitreally.
- Figure 23 is a graph comparing and analyzing the number of p21 protein and double-stained nuclei in percentage compared to the total number of nuclei in retinal tissue when N201-gal was administered intravitreally.
- N201-gal conjugate was prepared in which a sugar was bound to an imidazoline derivative.
- the nutlin derivative (N201, 200 mg, 0.42 mmol) was incubated with AcGal-Br ((2S, 3R, 4R, 5S, 6S)- in the presence of DMAP (281.2 mg, 2.21 mmol)/DCM solution for 16 hours at room temperature.
- DMAP 281.2 mg, 2.21 mmol
- 2-(acetoxymethyl)-6-bromotetrahydro-2H-pyran-3,4,5-triyl triacetate) 340.8 mg, 0.87 mmol.
- 2 ml of ammonia solution was added to the reaction and stirred for 1 hour. Then, N201-gal was separated through silica column chromatography.
- N201-gal was made into a methanol solution (10 mM, 1 ml), diluted with 50 ml purified water, and freeze-dried for 3 days.
- the parent compound N201 was able to produce micelle-type nanoparticles with amphiphilic properties, and the results are shown in Figure 1.
- Figure 1 is an image showing the degree of redispersion of N201-gal micelles in the aqueous solution prepared in Example 2.
- N201-gal micelles freeze-dried as above were again made into a 1 mM solution, then diluted to concentrations of 0.2, 0.5, 2, 3, 5, 10, 20, 30, 100, 200, and 300 uM and added with 1 mM pyrene ( pyrene) is added dropwise. After stirring it overnight, the FL value was measured. The results are shown in Figure 2.
- Figure 2 is a graph confirming the critical micelle concentration (CMC) concentration of N201-gal micelles by comparing I 335 /I 332 values at each concentration.
- CMC critical micelle concentration
- N301-gal conjugate was prepared in which a sugar was bound to an imidazoline derivative.
- the nutlin derivative (N301, 200 mg, 0.42 mmol) was incubated with AcGal-NO2((2S,3R,4R,5S,6R)- in the presence of DMAP (431.4 mg, 2.21 mmol)/DCM solution for 16 hours at room temperature.
- DMAP 431.4 mg, 2.21 mmol
- 1 ml of 1 M sodium tert-butoxide in THF was added and reacted for 10 minutes. Then, N301-gal was separated through silica column chromatography.
- the N201-gal micelles prepared in Example 2 above were dispersed in 100 uM purified water to prepare a solution.
- TEM images were taken by taking 8 ⁇ l of the solution, drying it on a TEM grid for about a day, performing uranyl staining, and removing the remaining uranyl staining solution after 5 minutes in the dark.
- the results are shown in Figure 3.
- the DLS Number measurement value was measured by taking 0.7 ml of the above solution, placing it in a DLS tube, and storing it at room temperature for 7 days. The results are shown in Figure 4.
- Figure 3 is a TEM image of N201-gal micelles.
- N201-gal micelles were observed using TEM, it was confirmed that N201-gal micelle aggregates were formed with a particle size of 40 to 60 nm.
- Figure 4 is a graph showing the DLS results of N201-gal micelles.
- N201-gal micelles were observed with DLS, the average size of N201-gal micelles was confirmed to be 50 to 80 nm, and it was confirmed that the micelles remained stable for 7 days in a dispersed state.
- N201-gal micelles prepared in Example 2 was confirmed in artificial gastrointestinal fluid (SGF-SIF solution).
- simulated gastric fluid SGF
- simulated intestinal fluid SIF
- For artificial gastrointestinal fluid dissolve 2.0 g of NaCl and 3.2 g of pepsin (hog stomach, Fluka 77163) in 500 ml of distilled water, add 7.0 ml of HCl (30%), make 1000 ml with distilled water, and adjust the pH to 1.2 with 1N HCl. Adjusted.
- For the artificial small intestine solution dissolve 6.8 g of KH 2 PO 4 in 250 ml of distilled water, add 190 ml of 0.2 N NaOH and 400 ml of distilled water, then add 10 g of pancreatin (porcine pancrease, Sigma P-1500), and then add 0.2 N NaOH. After adjusting the pH to 7.5, the solution was adjusted to 1,000 ml with distilled water.
- the following experiment was performed to confirm whether N201-gal micelles remained stably dispersed in artificial gastrointestinal fluid (SGF-SIF solution).
- the SGF condition was dissolved in 100 uM of artificial gastrointestinal fluid as above.
- the SGF-SIF conditions were dissolved at 1 mM in artificial gastrointestinal fluid (SGF) as above, and then changed to 100 uM artificial small intestinal fluid (SIF) as above 1 hour later. Afterwards, 0.7 ml of solution was taken from each and placed in a DLS tube and measured by number. The results are shown in Figure 5.
- the average size of N201-gal micelles in artificial gastrointestinal fluid was confirmed to be 40 to 50 nm, and the average size of N201-gal micelles in artificial gastrointestinal fluid (SGF-SIF solution) was It was confirmed that the size was 40 to 80 nm, and it was confirmed that the micelles remained stably dispersed even in artificial gastrointestinal fluid under acidic conditions.
- FP Fluorescence polarization
- ARPE19/ SnC -ARPE19 8 Total protein concentration was measured using the bicinchoninic acid (BCA) protein assay kit (PIERCE) according to the manufacturer's instructions. 20 ug of protein was heat denatured at 95°C for 10 minutes, resolved on a TGX SDS-PAGE gel, and blotted with a 0.45 ⁇ m PVDF membrane. Primary antibodies include anti-p53 (sc-126), anti-p21 (sc-817), anti-MDM2 (ab259265), anti-p16 (A0262), anti-HMGB1 (ab18256) and anti-GAPDH (sc-32233). ) was used, and then incubated with an appropriate secondary antibody. Protein concentration was measured by detection with SuperSignal West Pico plus ECL (# 34580, Pierce), and the results are shown in Figure 9. For reference, the chemical structures of nutlin derivatives N101, N201, and N201-gal are shown in Figure 7.
- N201-gal micelles prepared in Example 2 The ability of N201-gal micelles prepared in Example 2 to kill senescent cells was compared and analyzed with N201.
- ARPE19/SnC-ARPE19 8X10 5 /60mm cells were treated with N201 in DMSO (dimethyl sulfoxide) solution for 24 hours. After 24 hours, 10 ⁇ l CCK-8 solution (CK04, Cell counting kit-8) and 90 ⁇ l culture medium were added to the well, and cultured for 3 hours at 37°C in a humidified incubator with 5% CO2. The viability of the cells was measured using an ELISA reader (450 nm), and the comparison results are shown in Figure 10.
- N201 was confirmed to have lower toxicity in normal cells and selectively remove senescent cells due to the attachment of the sugar group.
- N201-gal micelles prepared in Example 2 The senescent cell killing ability of N201-gal micelles prepared in Example 2 was compared and analyzed with N201 in 3D cartilage tissue.
- Cartilage cells were isolated from cartilage tissue removed from patients undergoing knee osteoarthritis surgery, and the cells were distributed in a circular 96 well plate at a number of 4x105 cells. Using a centrifuge, centrifuge at 150 g for 10 minutes to allow the cells to clump together. The plate was placed in a CO 2 incubator at 37°C and cultured for a week while changing the medium every two days. Senescent cells were treated with 50 uM and 100 uM N101, N201, and N201-gal drugs for 4 days, and senescent cells were stained using Senescence ⁇ -Galactosidase Staining Kit (#9860). The results are shown in Figure 11.
- N201-gal removed senescent cells to the same level as N101 and N201.
- Example 2 When the N201-gal micelle prepared in Example 2 was orally administered, it was confirmed that senescent cells in the retina were removed in vivo.
- doxorubicin a senescent cell inducing substance
- Dox doxorubicin
- a small hole was made in the limbus using a 30-gauge sterile needle (BD Science, San Jose, USA).
- a blunt 35-gauge Hamilton microsyringe (Hamilton Company, NV, USA) was then slowly inserted through the hole.
- 1 uL of 100 ng/ ⁇ l Dox was injected under the retina of C57BL/6N or C57BL/6J mice, respectively.
- N201-gal was administered orally at doses of 10, 25, 50, and 100 mg/kg once a day for 7 days using a gastric tube.
- the mouse was anesthetized with CO 2 gas, and the eyes were immediately removed.
- the anterior chamber eye was dissected in cold PBS.
- RPE/choroid/sclera complex tissue or sectioned retina was immediately stained with SA- ⁇ galactosidase (SA- ⁇ -gal) staining kit (BioVision, # K320, California, They were fixed for 20 min at room temperature with the fixative provided with the SA- ⁇ -gal staining kit (USA) and stained with the staining solution mix provided with the SA- ⁇ -gal staining kit according to the manufacturer's protocol. After SA- ⁇ -gal staining overnight at 37°C, the dark melanin pigment in the RPE/choroid was bleached, revealing SA- ⁇ -gal staining masked by melanin pigment in these tissues.
- SA- ⁇ galactosidase SA- ⁇ galactosidase
- the RPE/choroid/sclera composite tissue was immersed in 30% H 2 O 2 , incubated in a 55 °C heat block for 45 min, then rinsed with PBS, and micro-dissected under a light microscope (Olympus SZ51). It was held flat with pointed forceps and a surgical blade (World Precision Instruments, Florida, USA). Images of stained RPE/choroid flat mounts or sectioned retinas were taken using an inverted microscope (Leica Microsystems #DMi1, Wetzlar, Germany), and the results are shown in Figure 12.
- the RPE/choroid/sclera composite tissue or sectioned retina was immediately fixed at room temperature for 20 minutes. Primary antibody staining, secondary antibody staining, and nuclear staining were performed while increasing cell membrane permeability and blocking non-specific reactions. Images of the stained nuclei were taken using a confocal microscope (40X, 60X), and the results are shown in Figures 14 and 15 .
- the RPE/choroid/sclera composite tissue or the sliced retina was fixed at room temperature for 20 minutes.
- Primary antibody staining, secondary antibody staining, and nuclear staining were performed while increasing cell membrane permeability and blocking non-specific reactions. Images of the stained nuclei were taken using a confocal microscope (40X, 60X), and the results are shown in Figure 20 .
- Example 2 When the N201-gal micelles prepared in Example 2 were administered into the vitreous cavity, it was confirmed that senescent cells in the retina were removed in vivo.
- doxorubicin a senescent cell inducing substance
- Dox doxorubicin
- a small hole was made in the limbus using a 30-gauge sterile needle (BD Science, San Jose, USA).
- a blunt 35-gauge Hamilton microsyringe (Hamilton Company, NV, USA) was then slowly inserted through the hole.
- 1 uL of 100 ng/ ⁇ l Dox was injected under the retina of C57BL/6N or C57BL/6J mice, respectively, to induce senescence in retinal tissue.
- 1 ul of N201-gal was administered into the vitreous cavity at concentrations of 50, 100, and 200 ng/ul on the 3rd day.
- the mouse was anesthetized with CO 2 gas and the eyes were immediately removed.
- the anterior chamber eye was dissected in cold PBS.
- the RPE/choroid/sclera composite tissue or sectioned retina was immediately fixed at room temperature for 20 minutes. Primary antibody staining, secondary antibody staining, and nuclear staining were performed while increasing cell membrane permeability and blocking non-specific reactions. Images of the stained nuclei were taken using a confocal microscope (40X, 60X), and the results are shown in Figure 23.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Molecular Biology (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Biochemistry (AREA)
- Dispersion Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Biotechnology (AREA)
- Genetics & Genomics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
La présente invention concerne une composition comprenant un dérivé d'imidazoline et un sucre en tant que principes actifs. Selon la composition et une micelle selon un aspect, la solubilité du dérivé d'imidazoline peut être améliorée sans utiliser d'additifs tels qu'un tensioactif, et ainsi, il y a un effet d'utiliser de manière efficace un médicament dans la prévention, le soulagement ou le traitement de maladies. De plus, dans le cas de l'utilisation de la micelle, il existe un effet d'atténuation des effets secondaires dus à un médicament par amélioration de la sélectivité du médicament pour des cellules ou des tissus nécessitant un traitement médicamenteux. En particulier, l'induction spécifique de l'apoptose de cellules sénescentes permet d'utiliser la micelle de manière efficace dans la prévention ou le traitement de maladies liées au vieillissement.
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
KR10-2022-0039191 | 2022-03-29 | ||
KR20220039191 | 2022-03-29 | ||
KR10-2023-0041078 | 2023-03-29 | ||
KR1020230041078A KR20230141604A (ko) | 2022-03-29 | 2023-03-29 | 당 결합된 이미다졸린 유도체 및 이의 용도 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2023191513A1 true WO2023191513A1 (fr) | 2023-10-05 |
Family
ID=88203123
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/KR2023/004208 WO2023191513A1 (fr) | 2022-03-29 | 2023-03-29 | Dérivé d'imidazoline conjugué à un sucre et son utilisation |
Country Status (1)
Country | Link |
---|---|
WO (1) | WO2023191513A1 (fr) |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5292669A (en) * | 1989-10-17 | 1994-03-08 | Boehringer Mannheim Gmbh | Agents for the detection of substrates with hydrolase activity |
KR20040068277A (ko) * | 2001-12-18 | 2004-07-30 | 에프. 호프만-라 로슈 아게 | 시스-2,4,5-트리페닐-이미다졸린 및 종양 치료에서의 그의용도 |
KR20130139512A (ko) * | 2012-06-13 | 2013-12-23 | 가톨릭대학교 산학협력단 | Mdm2 억제제를 유효성분으로 포함하는 노화 억제용 조성물 |
KR20160117519A (ko) * | 2014-01-28 | 2016-10-10 | 버크 인스티튜트 포 리서치 온 에이징 | 노화 세포를 사멸시키고 노화 관련 질환 및 장애를 치료하기 위한 방법 및 조성물 |
-
2023
- 2023-03-29 WO PCT/KR2023/004208 patent/WO2023191513A1/fr unknown
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5292669A (en) * | 1989-10-17 | 1994-03-08 | Boehringer Mannheim Gmbh | Agents for the detection of substrates with hydrolase activity |
KR20040068277A (ko) * | 2001-12-18 | 2004-07-30 | 에프. 호프만-라 로슈 아게 | 시스-2,4,5-트리페닐-이미다졸린 및 종양 치료에서의 그의용도 |
KR20130139512A (ko) * | 2012-06-13 | 2013-12-23 | 가톨릭대학교 산학협력단 | Mdm2 억제제를 유효성분으로 포함하는 노화 억제용 조성물 |
KR20160117519A (ko) * | 2014-01-28 | 2016-10-10 | 버크 인스티튜트 포 리서치 온 에이징 | 노화 세포를 사멸시키고 노화 관련 질환 및 장애를 치료하기 위한 방법 및 조성물 |
Non-Patent Citations (1)
Title |
---|
V. S. TAILE, K. M. HATZADE, P. K. GAIDHANE, V. N. INGLE: "Synthesis and biological evaluation of novel 2-(4-O-β-D-glucosidoxyphenyl)-4,5-disubstituted imidazoles", JOURNAL OF HETEROCYCLIC CHEMISTRY, ¬HETEROCORPORATION|, vol. 47, no. 4, 17 July 2010 (2010-07-17), pages 903 - 907, XP055094097, ISSN: 0022152X, DOI: 10.1002/jhet.433 * |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
DE60314013T2 (de) | 2-(1h-indazol-6-ylamino)- benzamid-verbindungen als protein kinase inhibitoren und deren verwendung zur behandlung von ophthalmischen krankheiten | |
WO2014171801A1 (fr) | Dérivé d'amidopyridinol ou sel pharmaceutiquement acceptable correspondant et composition pharmaceutique le comprenant comme constituant actif | |
WO2011159137A2 (fr) | Nouvelle thio-urée ou nouveau dérivé d'urée, procédé permettant leur préparation, et composition pharmaceutique destinée à prévenir ou à traiter le sida, les contenant en tant que principe actif | |
WO2019098699A1 (fr) | Composition destinée à prévenir ou à traiter des maladies neurodégénératives, contenant un composé à base de diterpène | |
WO2023191513A1 (fr) | Dérivé d'imidazoline conjugué à un sucre et son utilisation | |
WO2016080796A2 (fr) | Composition pharmaceutique contenant un composé sesquiterpénique et utilisable en vue de la prévention ou du traitement de maladies à médiation par stat3, et son utilisation | |
WO2022225108A1 (fr) | Composition permettant de prévenir ou de traiter des maladies provoquées par un dysfonctionnement mitochondrial, contenant un composé dérivé d'isoquinoléine en tant que principe actif | |
CA2879054C (fr) | Derives d'imidazopyridine utiles dans le traitement du diabete | |
WO2012134187A2 (fr) | Composition pharmaceutique pour la prévention ou le traitement de la dégénérescence maculaire | |
WO2016111523A2 (fr) | Antagoniste de hnf4-a et utilisation associée | |
WO2020055129A1 (fr) | Composition de traitement ou de prévention du cancer comprenant un dérivé de verbénone | |
WO2023277584A1 (fr) | Composition pour éliminer les cellules sénescentes comprenant un composé sélénié en tant que principe actif | |
WO2023048453A1 (fr) | Nanoparticules comprenant des dimères de médicament et leur utilisation | |
KR20230141604A (ko) | 당 결합된 이미다졸린 유도체 및 이의 용도 | |
WO2021020820A1 (fr) | Composition pharmaceutique comprenant de l'udénafil | |
WO2018105998A1 (fr) | Composition destinée à la prévention et au traitement de l'infertilité masculine, comprenant un composé dérivé de flavonoïdes en tant que principe actif, et son utilisation | |
WO2021054510A1 (fr) | Composition destinée à prévenir et à traiter le cancer du sein contenant de la sélénopsammapline a en tant que principe actif | |
WO2018105999A1 (fr) | Composition pour la prévention et le traitement de l'infertilité masculine, contenant un composé dérivé d'iridoïde en tant qu'ingrédient actif et utilisation de celle-ci | |
WO2020027534A1 (fr) | Composition comprenant de la punicalagine permettant d'inhiber l'activité de par2 | |
WO2019231262A1 (fr) | Nouveau composé dérivé de biphényle et son utilisation | |
WO2020130696A1 (fr) | Composition comprenant un composé inhibant le cyp4a utilisé comme principe actif pour la prévention ou le traitement de maladies métaboliques | |
WO2023182606A1 (fr) | Nouveau composé induisant l'expression du gène anti-vieillissement klotho | |
WO2022234888A1 (fr) | Composition pharmaceutique pour le traitement de la dégénérescence maculaire, contenant un composé dérivé de l'imidazoline en tant que principe actif | |
WO2020080641A1 (fr) | Composition pour la prévention et le traitement de maladies liées à l'ampk, comprenant un extrait de gynostemma longipes vk1 ou un composé isolé à partir de celui-ci en tant qu'ingrédient actif | |
WO2018217009A1 (fr) | Composition pour prévenir ou traiter des maladies liées aux muscles, contenant un extrait d'angelica keiskei ou un composé isolé à partir de celui-ci, et son utilisation |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 23781366 Country of ref document: EP Kind code of ref document: A1 |