RU2259997C2 - Ингибиторы фарнезилтрансферазы - Google Patents

Info

Publication number

RU2259997C2

RU2259997C2 RU2002119405/04A RU2002119405A RU2259997C2 RU 2259997 C2 RU2259997 C2 RU 2259997C2 RU 2002119405/04 A RU2002119405/04 A RU 2002119405/04A RU 2002119405 A RU2002119405 A RU 2002119405A RU 2259997 C2 RU2259997 C2 RU 2259997C2

Authority

RU

Russia

Prior art keywords

compound

formula

groups

amino

compounds

Prior art date

1999-12-22

Links

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• 239000003528 protein farnesyltransferase inhibitor Substances 0.000 title description 4
• 150000001875 compounds Chemical class 0.000 claims abstract description 186
• -1 N-methyltetrahydropyridyl Chemical group 0.000 claims abstract description 72
• 206010028980 Neoplasm Diseases 0.000 claims abstract description 19
• 150000003839 salts Chemical class 0.000 claims abstract description 16
• 238000011282 treatment Methods 0.000 claims abstract description 16
• PAMIQIKDUOTOBW-UHFFFAOYSA-N 1-methylpiperidine Chemical compound CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 claims abstract description 14
• 201000011510 cancer Diseases 0.000 claims abstract description 14
• 239000003814 drug Substances 0.000 claims abstract description 14
• 229910052717 sulfur Inorganic materials 0.000 claims abstract description 11
• 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 8
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 7
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims abstract description 6
• 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims abstract description 4
• 125000004076 pyridyl group Chemical group 0.000 claims abstract description 4
• 125000006239 protecting group Chemical group 0.000 claims description 22
• 238000006243 chemical reaction Methods 0.000 claims description 20
• 239000001257 hydrogen Substances 0.000 claims description 14
• 229910052739 hydrogen Inorganic materials 0.000 claims description 14
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 12
• 230000006126 farnesylation Effects 0.000 claims description 12
• 229910052736 halogen Inorganic materials 0.000 claims description 9
• 150000002367 halogens Chemical class 0.000 claims description 9
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 8
• PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 7
• RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical group C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 7
• 239000011737 fluorine Substances 0.000 claims description 7
• 229910052731 fluorine Inorganic materials 0.000 claims description 7
• 230000001404 mediated effect Effects 0.000 claims description 7
• 229910052799 carbon Inorganic materials 0.000 claims description 6
• 239000003085 diluting agent Substances 0.000 claims description 6
• 238000004519 manufacturing process Methods 0.000 claims description 6
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 6
• 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 5
• 239000002243 precursor Substances 0.000 claims description 4
• 150000001412 amines Chemical class 0.000 claims description 2
• 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 2
• 150000002431 hydrogen Chemical class 0.000 claims description 2
• PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical class [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 claims description 2
• 150000001721 carbon Chemical group 0.000 claims 2
• 125000003396 thiol group Chemical group [H]S* 0.000 claims 1
• 239000003112 inhibitor Substances 0.000 abstract description 8
• 102000004190 Enzymes Human genes 0.000 abstract description 5
• 108090000790 Enzymes Proteins 0.000 abstract description 5
• 108090000623 proteins and genes Proteins 0.000 abstract description 5
• 102000004357 Transferases Human genes 0.000 abstract description 4
• 108090000992 Transferases Proteins 0.000 abstract description 4
• 230000000694 effects Effects 0.000 abstract description 4
• 125000004030 farnesyl group Chemical group [H]C([*])([H])C([H])=C(C([H])([H])[H])C([H])([H])C([H])([H])C([H])=C(C([H])([H])[H])C([H])([H])C([H])([H])C([H])=C(C([H])([H])[H])C([H])([H])[H] 0.000 abstract description 4
• 239000000126 substance Substances 0.000 abstract description 4
• 125000005843 halogen group Chemical group 0.000 abstract description 3
• 102000004169 proteins and genes Human genes 0.000 abstract description 3
• 102000007317 Farnesyltranstransferase Human genes 0.000 abstract description 2
• 108010007508 Farnesyltranstransferase Proteins 0.000 abstract description 2
• 125000004434 sulfur atom Chemical group 0.000 abstract description 2
• 125000004435 hydrogen atom Chemical group [H]* 0.000 abstract 4
• 230000007721 medicinal effect Effects 0.000 abstract 1
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 62
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 36
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 33
• 238000000034 method Methods 0.000 description 27
• 239000000203 mixture Substances 0.000 description 25
• 239000000243 solution Substances 0.000 description 24
• 210000004027 cell Anatomy 0.000 description 23
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 20
• 238000005160 1H NMR spectroscopy Methods 0.000 description 19
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 19
• 125000000217 alkyl group Chemical group 0.000 description 19
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 18
• 102000016914 ras Proteins Human genes 0.000 description 18
• 108010014186 ras Proteins Proteins 0.000 description 18
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
• AFABGHUZZDYHJO-UHFFFAOYSA-N 2-Methylpentane Chemical compound CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 description 14
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 14
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 13
• 239000007787 solid Substances 0.000 description 13
• LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 12
• 150000002148 esters Chemical class 0.000 description 12
• 239000000047 product Substances 0.000 description 12
• 239000002253 acid Substances 0.000 description 11
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 10
• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 10
• 239000002904 solvent Substances 0.000 description 10
• 239000000725 suspension Substances 0.000 description 10
• AQRLNPVMDITEJU-UHFFFAOYSA-N triethylsilane Chemical compound CC[SiH](CC)CC AQRLNPVMDITEJU-UHFFFAOYSA-N 0.000 description 10
• 239000000443 aerosol Substances 0.000 description 9
• 125000003118 aryl group Chemical group 0.000 description 9
• RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 description 9
• 239000000543 intermediate Substances 0.000 description 9
• 239000000843 powder Substances 0.000 description 9
• 239000003826 tablet Substances 0.000 description 9
• SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 8
• 125000000623 heterocyclic group Chemical group 0.000 description 8
• HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 8
• 229910052757 nitrogen Inorganic materials 0.000 description 8
• 239000000546 pharmaceutical excipient Substances 0.000 description 8
• 229940002612 prodrug Drugs 0.000 description 8
• 239000000651 prodrug Substances 0.000 description 8
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
• VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 7
• 239000004480 active ingredient Substances 0.000 description 7
• 239000002585 base Substances 0.000 description 7
• 125000004432 carbon atom Chemical group C* 0.000 description 7
• 239000003795 chemical substances by application Substances 0.000 description 7
• 239000012895 dilution Substances 0.000 description 7
• 238000010790 dilution Methods 0.000 description 7
• 201000010099 disease Diseases 0.000 description 7
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 7
• CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 description 7
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
• CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 6
• 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 6
• 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 6
• 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 6
• DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
• 239000003054 catalyst Substances 0.000 description 6
• 235000003599 food sweetener Nutrition 0.000 description 6
• 239000003102 growth factor Substances 0.000 description 6
• RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 6
• 239000008101 lactose Substances 0.000 description 6
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 6
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
• 239000003960 organic solvent Substances 0.000 description 6
• 239000003755 preservative agent Substances 0.000 description 6
• 239000000377 silicon dioxide Substances 0.000 description 6
• 239000000600 sorbitol Substances 0.000 description 6
• 235000010356 sorbitol Nutrition 0.000 description 6
• 239000000375 suspending agent Substances 0.000 description 6
• 239000003765 sweetening agent Substances 0.000 description 6
• KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 5
• 102000004142 Trypsin Human genes 0.000 description 5
• 108090000631 Trypsin Proteins 0.000 description 5
• 125000003545 alkoxy group Chemical group 0.000 description 5
• 239000000460 chlorine Substances 0.000 description 5
• KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Natural products OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 5
• 238000007796 conventional method Methods 0.000 description 5
• PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical compound FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 description 5
• 239000000796 flavoring agent Substances 0.000 description 5
• 238000005984 hydrogenation reaction Methods 0.000 description 5
• 239000003921 oil Substances 0.000 description 5
• 235000019198 oils Nutrition 0.000 description 5
• 238000002360 preparation method Methods 0.000 description 5
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
• 239000012588 trypsin Substances 0.000 description 5
• VWFJDQUYCIWHTN-YFVJMOTDSA-N 2-trans,6-trans-farnesyl diphosphate Chemical compound CC(C)=CCC\C(C)=C\CC\C(C)=C\CO[P@](O)(=O)OP(O)(O)=O VWFJDQUYCIWHTN-YFVJMOTDSA-N 0.000 description 4
• VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 4
• 239000004338 Dichlorodifluoromethane Substances 0.000 description 4
• 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 4
• IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 4
• XKMLYUALXHKNFT-UUOKFMHZSA-N Guanosine-5'-triphosphate Chemical compound C1=2NC(N)=NC(=O)C=2N=CN1[C@@H]1O[C@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)[C@@H](O)[C@H]1O XKMLYUALXHKNFT-UUOKFMHZSA-N 0.000 description 4
• 239000012981 Hank's balanced salt solution Substances 0.000 description 4
• 241001465754 Metazoa Species 0.000 description 4
• KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
• NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 4
• KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 4
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
• SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 4
• CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
• DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 4
• 125000004453 alkoxycarbonyl group Chemical group 0.000 description 4
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 4
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 4
• 238000010511 deprotection reaction Methods 0.000 description 4
• 235000019404 dichlorodifluoromethane Nutrition 0.000 description 4
• 229940088598 enzyme Drugs 0.000 description 4
• 229960003180 glutathione Drugs 0.000 description 4
• 125000005842 heteroatom Chemical group 0.000 description 4
• 125000004356 hydroxy functional group Chemical group O* 0.000 description 4
• AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 4
• 235000019359 magnesium stearate Nutrition 0.000 description 4
• 230000036961 partial effect Effects 0.000 description 4
• 108700042226 ras Genes Proteins 0.000 description 4
• 239000011541 reaction mixture Substances 0.000 description 4
• 239000007858 starting material Substances 0.000 description 4
• ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 4
• 238000012360 testing method Methods 0.000 description 4
• 229940029284 trichlorofluoromethane Drugs 0.000 description 4
• 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
• 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 4
• 0 *N(*)C(C(C1)N(*)CC1O)=O Chemical compound *N(*)C(C(C1)N(*)CC1O)=O 0.000 description 3
• DDMOUSALMHHKOS-UHFFFAOYSA-N 1,2-dichloro-1,1,2,2-tetrafluoroethane Chemical compound FC(F)(Cl)C(F)(F)Cl DDMOUSALMHHKOS-UHFFFAOYSA-N 0.000 description 3
• YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-UHFFFAOYSA-N 0.000 description 3
• 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 3
• 229960000549 4-dimethylaminophenol Drugs 0.000 description 3
• CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
• ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
• 229920002785 Croscarmellose sodium Polymers 0.000 description 3
• QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 3
• VWFJDQUYCIWHTN-UHFFFAOYSA-N Farnesyl pyrophosphate Natural products CC(C)=CCCC(C)=CCCC(C)=CCOP(O)(=O)OP(O)(O)=O VWFJDQUYCIWHTN-UHFFFAOYSA-N 0.000 description 3
• 241000282412 Homo Species 0.000 description 3
• YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical group C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 3
• FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 3
• 238000005481 NMR spectroscopy Methods 0.000 description 3
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
• 150000001299 aldehydes Chemical class 0.000 description 3
• 125000004849 alkoxymethyl group Chemical group 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
• 239000007900 aqueous suspension Substances 0.000 description 3
• 125000005104 aryl silyl group Chemical group 0.000 description 3
• 229960005070 ascorbic acid Drugs 0.000 description 3
• 235000010323 ascorbic acid Nutrition 0.000 description 3
• 239000011668 ascorbic acid Substances 0.000 description 3
• 230000037396 body weight Effects 0.000 description 3
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• 238000005119 centrifugation Methods 0.000 description 3
• 230000008859 change Effects 0.000 description 3
• 239000003638 chemical reducing agent Substances 0.000 description 3
• 229910052801 chlorine Inorganic materials 0.000 description 3
• 239000003086 colorant Substances 0.000 description 3
• 238000009833 condensation Methods 0.000 description 3
• 230000005494 condensation Effects 0.000 description 3
• 229960001681 croscarmellose sodium Drugs 0.000 description 3
• 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 3
• 229940087091 dichlorotetrafluoroethane Drugs 0.000 description 3
• 235000014113 dietary fatty acids Nutrition 0.000 description 3
• 239000002552 dosage form Substances 0.000 description 3
• 239000000839 emulsion Substances 0.000 description 3
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
• 239000000194 fatty acid Substances 0.000 description 3
• 229930195729 fatty acid Natural products 0.000 description 3
• 150000004665 fatty acids Chemical class 0.000 description 3
• 235000019634 flavors Nutrition 0.000 description 3
• 239000006260 foam Substances 0.000 description 3
• ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 3
• NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 3
• 230000002401 inhibitory effect Effects 0.000 description 3
• 238000002347 injection Methods 0.000 description 3
• 239000007924 injection Substances 0.000 description 3
• 239000000644 isotonic solution Substances 0.000 description 3
• 229940057995 liquid paraffin Drugs 0.000 description 3
• 239000012280 lithium aluminium hydride Substances 0.000 description 3
• 238000002844 melting Methods 0.000 description 3
• 230000008018 melting Effects 0.000 description 3
• 229910052751 metal Inorganic materials 0.000 description 3
• 239000002184 metal Substances 0.000 description 3
• 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 3
• 230000003020 moisturizing effect Effects 0.000 description 3
• 239000002674 ointment Substances 0.000 description 3
• 239000004006 olive oil Substances 0.000 description 3
• 235000008390 olive oil Nutrition 0.000 description 3
• 229910052760 oxygen Inorganic materials 0.000 description 3
• 239000002245 particle Substances 0.000 description 3
• 230000000069 prophylactic effect Effects 0.000 description 3
• 239000011734 sodium Substances 0.000 description 3
• 238000003786 synthesis reaction Methods 0.000 description 3
• 230000001225 therapeutic effect Effects 0.000 description 3
• 230000000699 topical effect Effects 0.000 description 3
• 125000004665 trialkylsilyl group Chemical group 0.000 description 3
• CSRZQMIRAZTJOY-UHFFFAOYSA-N trimethylsilyl iodide Substances C[Si](C)(C)I CSRZQMIRAZTJOY-UHFFFAOYSA-N 0.000 description 3
• 239000008215 water for injection Substances 0.000 description 3
• PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 2
• ZORQXIQZAOLNGE-UHFFFAOYSA-N 1,1-difluorocyclohexane Chemical compound FC1(F)CCCCC1 ZORQXIQZAOLNGE-UHFFFAOYSA-N 0.000 description 2
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