JP2017530199A - 置換アミノプリン化合物、その組成物、及びそれによる治療の方法 - Google Patents
置換アミノプリン化合物、その組成物、及びそれによる治療の方法 Download PDFInfo
- Publication number
- JP2017530199A JP2017530199A JP2017538172A JP2017538172A JP2017530199A JP 2017530199 A JP2017530199 A JP 2017530199A JP 2017538172 A JP2017538172 A JP 2017538172A JP 2017538172 A JP2017538172 A JP 2017538172A JP 2017530199 A JP2017530199 A JP 2017530199A
- Authority
- JP
- Japan
- Prior art keywords
- amino
- substituted
- compound
- pyran
- unsubstituted
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- -1 aminopurine compounds Chemical class 0.000 title claims abstract description 215
- 238000000034 method Methods 0.000 title claims abstract description 129
- 239000000203 mixture Chemical class 0.000 title abstract description 243
- 238000011282 treatment Methods 0.000 title description 19
- 150000001875 compounds Chemical class 0.000 claims abstract description 184
- 201000001441 melanoma Diseases 0.000 claims abstract description 30
- 150000003839 salts Chemical class 0.000 claims abstract description 16
- 125000000217 alkyl group Chemical group 0.000 claims description 93
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 45
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 33
- 229910052736 halogen Inorganic materials 0.000 claims description 29
- 125000001424 substituent group Chemical group 0.000 claims description 26
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 25
- 125000003118 aryl group Chemical group 0.000 claims description 24
- 125000000623 heterocyclic group Chemical group 0.000 claims description 20
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 19
- 150000002367 halogens Chemical class 0.000 claims description 19
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 12
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 11
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 10
- 239000003981 vehicle Substances 0.000 claims description 9
- 108091000080 Phosphotransferase Proteins 0.000 claims description 7
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 7
- 102000020233 phosphotransferase Human genes 0.000 claims description 7
- 125000005936 piperidyl group Chemical group 0.000 claims description 7
- 125000004076 pyridyl group Chemical group 0.000 claims description 7
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 6
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 6
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 6
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 6
- 239000003937 drug carrier Substances 0.000 claims description 6
- 125000001072 heteroaryl group Chemical group 0.000 claims description 6
- 230000002401 inhibitory effect Effects 0.000 claims description 6
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 6
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 6
- VYOMWAWIBCGOKB-BJHJDKERSA-N chembl1950291 Chemical compound N1([C@H]2CC[C@H](CC2)C(N)=O)C2=NC(NC(C)C)=NC=C2N=C1NC1=C(F)C=C(F)C=C1F VYOMWAWIBCGOKB-BJHJDKERSA-N 0.000 claims description 5
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 5
- 125000005843 halogen group Chemical group 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 5
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 4
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 4
- 125000001715 oxadiazolyl group Chemical group 0.000 claims description 4
- 125000003551 oxepanyl group Chemical group 0.000 claims description 4
- 125000003566 oxetanyl group Chemical group 0.000 claims description 4
- BUGOPWGPQGYYGR-UHFFFAOYSA-N thiane 1,1-dioxide Chemical compound O=S1(=O)CCCCC1 BUGOPWGPQGYYGR-UHFFFAOYSA-N 0.000 claims description 4
- 102000001253 Protein Kinase Human genes 0.000 claims description 3
- 230000004663 cell proliferation Effects 0.000 claims description 3
- 238000000338 in vitro Methods 0.000 claims description 3
- 108060006633 protein kinase Proteins 0.000 claims description 3
- 125000005916 2-methylpentyl group Chemical group 0.000 claims description 2
- 125000005917 3-methylpentyl group Chemical group 0.000 claims description 2
- QBCBXKOOFXNSLU-AMPCRFMZSA-N NC(=O)[C@@H]1CC[C@@H](CC1)N1C(NC2=CC=C(F)C=C2F)=NC2=CN=C(N[C@H]3CC[C@H](O)CC3)N=C12 Chemical compound NC(=O)[C@@H]1CC[C@@H](CC1)N1C(NC2=CC=C(F)C=C2F)=NC2=CN=C(N[C@H]3CC[C@H](O)CC3)N=C12 QBCBXKOOFXNSLU-AMPCRFMZSA-N 0.000 claims description 2
- 125000002877 alkyl aryl group Chemical group 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- 206010028980 Neoplasm Diseases 0.000 abstract description 21
- 201000011510 cancer Diseases 0.000 abstract description 11
- 239000000126 substance Substances 0.000 abstract description 5
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 213
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 208
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 201
- 239000000243 solution Substances 0.000 description 159
- 238000006243 chemical reaction Methods 0.000 description 149
- PNZXMIKHJXIPEK-UHFFFAOYSA-N cyclohexanecarboxamide Chemical compound NC(=O)C1CCCCC1 PNZXMIKHJXIPEK-UHFFFAOYSA-N 0.000 description 90
- 239000007787 solid Substances 0.000 description 85
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 75
- 239000002904 solvent Substances 0.000 description 75
- 238000000746 purification Methods 0.000 description 73
- 239000011541 reaction mixture Substances 0.000 description 66
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 66
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 58
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 53
- 238000010626 work up procedure Methods 0.000 description 53
- FDKXTQMXEQVLRF-ZHACJKMWSA-N (E)-dacarbazine Chemical compound CN(C)\N=N\c1[nH]cnc1C(N)=O FDKXTQMXEQVLRF-ZHACJKMWSA-N 0.000 description 50
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 48
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 47
- 239000011734 sodium Substances 0.000 description 45
- 239000000706 filtrate Substances 0.000 description 42
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 37
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 36
- 239000012044 organic layer Substances 0.000 description 34
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 32
- NZNMSOFKMUBTKW-UHFFFAOYSA-N cyclohexanecarboxylic acid Chemical compound OC(=O)C1CCCCC1 NZNMSOFKMUBTKW-UHFFFAOYSA-N 0.000 description 32
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 31
- 238000010898 silica gel chromatography Methods 0.000 description 29
- 239000000725 suspension Substances 0.000 description 29
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 27
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 26
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 26
- 239000012043 crude product Substances 0.000 description 25
- 239000003921 oil Substances 0.000 description 25
- 235000019198 oils Nutrition 0.000 description 25
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 24
- 238000003756 stirring Methods 0.000 description 24
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 23
- 229920005989 resin Polymers 0.000 description 22
- 239000011347 resin Substances 0.000 description 22
- 229910052739 hydrogen Inorganic materials 0.000 description 21
- 239000001257 hydrogen Substances 0.000 description 21
- 229910052763 palladium Inorganic materials 0.000 description 21
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 20
- 210000004027 cell Anatomy 0.000 description 20
- 238000004440 column chromatography Methods 0.000 description 19
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 18
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 18
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 18
- 239000000741 silica gel Substances 0.000 description 17
- 229910002027 silica gel Inorganic materials 0.000 description 17
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 15
- 239000012074 organic phase Substances 0.000 description 15
- 239000000047 product Substances 0.000 description 15
- 229920006395 saturated elastomer Polymers 0.000 description 15
- 239000007821 HATU Substances 0.000 description 14
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 14
- 239000010410 layer Substances 0.000 description 13
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 12
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 12
- 239000012267 brine Substances 0.000 description 11
- 239000012230 colorless oil Substances 0.000 description 11
- 208000035475 disorder Diseases 0.000 description 11
- 230000000694 effects Effects 0.000 description 11
- 239000003208 petroleum Substances 0.000 description 11
- 239000003826 tablet Substances 0.000 description 11
- PVTTZZSJLBWJDF-UHFFFAOYSA-N ClC1=C(C(=CC(=C1)Cl)F)N=C=S Chemical compound ClC1=C(C(=CC(=C1)Cl)F)N=C=S PVTTZZSJLBWJDF-UHFFFAOYSA-N 0.000 description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 10
- 241001465754 Metazoa Species 0.000 description 10
- 125000004432 carbon atom Chemical group C* 0.000 description 10
- 230000002829 reductive effect Effects 0.000 description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- 239000008346 aqueous phase Substances 0.000 description 9
- 239000002775 capsule Substances 0.000 description 9
- 238000009472 formulation Methods 0.000 description 9
- 239000012299 nitrogen atmosphere Substances 0.000 description 9
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 9
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- 125000004429 atom Chemical group 0.000 description 8
- 230000037396 body weight Effects 0.000 description 8
- 125000004093 cyano group Chemical group *C#N 0.000 description 8
- 239000003814 drug Substances 0.000 description 8
- LLJSSSLSNWIKDE-UHFFFAOYSA-N 3,5-dichloro-4-isothiocyanatobenzonitrile Chemical compound ClC1=CC(C#N)=CC(Cl)=C1N=C=S LLJSSSLSNWIKDE-UHFFFAOYSA-N 0.000 description 7
- 241000699670 Mus sp. Species 0.000 description 7
- 229920002472 Starch Polymers 0.000 description 7
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 7
- 239000003638 chemical reducing agent Substances 0.000 description 7
- 239000007822 coupling agent Substances 0.000 description 7
- 201000010099 disease Diseases 0.000 description 7
- 239000008107 starch Substances 0.000 description 7
- 235000019698 starch Nutrition 0.000 description 7
- UAIXEOIQIOOYES-DGCLKSJQSA-N (3S,4R)-N-benzyl-3-methyloxan-4-amine Chemical compound C(C1=CC=CC=C1)N[C@H]1[C@@H](COCC1)C UAIXEOIQIOOYES-DGCLKSJQSA-N 0.000 description 6
- WNDSHZVSXJQYSU-UHFFFAOYSA-N 1-chloro-2-fluoro-4-isothiocyanato-3-methylbenzene Chemical compound ClC1=C(C(=C(C=C1)N=C=S)C)F WNDSHZVSXJQYSU-UHFFFAOYSA-N 0.000 description 6
- UQOKRDJILZMZKU-UHFFFAOYSA-N 2-nitropyrimidine Chemical compound [O-][N+](=O)C1=NC=CC=N1 UQOKRDJILZMZKU-UHFFFAOYSA-N 0.000 description 6
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 description 6
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 238000003556 assay Methods 0.000 description 6
- 239000003054 catalyst Substances 0.000 description 6
- VZFUCHSFHOYXIS-UHFFFAOYSA-N cycloheptane carboxylic acid Natural products OC(=O)C1CCCCCC1 VZFUCHSFHOYXIS-UHFFFAOYSA-N 0.000 description 6
- 239000003085 diluting agent Substances 0.000 description 6
- 239000000284 extract Substances 0.000 description 6
- 230000000155 isotopic effect Effects 0.000 description 6
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 6
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- ZWZVWGITAAIFPS-UHFFFAOYSA-N thiophosgene Chemical compound ClC(Cl)=S ZWZVWGITAAIFPS-UHFFFAOYSA-N 0.000 description 6
- AJQFAPDMBFEYRX-VXGBXAGGSA-N (3S,4R)-N-benzyl-3-fluorooxan-4-amine Chemical compound C(C1=CC=CC=C1)N[C@H]1[C@@H](COCC1)F AJQFAPDMBFEYRX-VXGBXAGGSA-N 0.000 description 5
- JYZWPWDEIMDHFF-JBUOLDKXSA-N (3S,4S)-3-fluorooxan-4-amine hydrochloride Chemical compound Cl.N[C@H]1CCOC[C@H]1F JYZWPWDEIMDHFF-JBUOLDKXSA-N 0.000 description 5
- AJQFAPDMBFEYRX-NEPJUHHUSA-N (3s,4s)-n-benzyl-3-fluorooxan-4-amine Chemical compound F[C@@H]1COCC[C@@H]1NCC1=CC=CC=C1 AJQFAPDMBFEYRX-NEPJUHHUSA-N 0.000 description 5
- DSXVZIOQROMOEF-UHFFFAOYSA-N 1,3,5-trichloro-2-isothiocyanatobenzene Chemical compound ClC1=CC(Cl)=C(N=C=S)C(Cl)=C1 DSXVZIOQROMOEF-UHFFFAOYSA-N 0.000 description 5
- GDLOOQFSFHLRKT-UHFFFAOYSA-N 1-methylcyclohexane-1-carboxamide Chemical compound NC(=O)C1(C)CCCCC1 GDLOOQFSFHLRKT-UHFFFAOYSA-N 0.000 description 5
- INUSQTPGSHFGHM-UHFFFAOYSA-N 2,4-dichloro-5-nitropyrimidine Chemical compound [O-][N+](=O)C1=CN=C(Cl)N=C1Cl INUSQTPGSHFGHM-UHFFFAOYSA-N 0.000 description 5
- ZEDOBEHSBNTVKR-UHFFFAOYSA-N 2-chloro-6-fluoro-3-methylaniline Chemical compound CC1=CC=C(F)C(N)=C1Cl ZEDOBEHSBNTVKR-UHFFFAOYSA-N 0.000 description 5
- DRNGLYHKYPNTEA-UHFFFAOYSA-N 4-azaniumylcyclohexane-1-carboxylate Chemical class NC1CCC(C(O)=O)CC1 DRNGLYHKYPNTEA-UHFFFAOYSA-N 0.000 description 5
- OYFCZVXGUPBDPD-UHFFFAOYSA-N 5-chloro-1,3-difluoro-2-isothiocyanatobenzene Chemical compound FC1=CC(Cl)=CC(F)=C1N=C=S OYFCZVXGUPBDPD-UHFFFAOYSA-N 0.000 description 5
- XVMSFILGAMDHEY-UHFFFAOYSA-N 6-(4-aminophenyl)sulfonylpyridin-3-amine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)C1=CC=C(N)C=N1 XVMSFILGAMDHEY-UHFFFAOYSA-N 0.000 description 5
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 5
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 5
- 125000003710 aryl alkyl group Chemical group 0.000 description 5
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 5
- 150000003857 carboxamides Chemical class 0.000 description 5
- 239000001913 cellulose Substances 0.000 description 5
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 5
- 125000005842 heteroatom Chemical group 0.000 description 5
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 5
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 5
- 125000002950 monocyclic group Chemical group 0.000 description 5
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 5
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- 239000003960 organic solvent Substances 0.000 description 5
- KWZSCXIYGVEHOB-UHFFFAOYSA-N oxan-4-amine;hydrochloride Chemical compound [Cl-].[NH3+]C1CCOCC1 KWZSCXIYGVEHOB-UHFFFAOYSA-N 0.000 description 5
- 150000003254 radicals Chemical group 0.000 description 5
- 238000011160 research Methods 0.000 description 5
- 208000024891 symptom Diseases 0.000 description 5
- JYZWPWDEIMDHFF-TYSVMGFPSA-N (3s,4r)-3-fluorooxan-4-amine;hydrochloride Chemical compound Cl.N[C@@H]1CCOC[C@H]1F JYZWPWDEIMDHFF-TYSVMGFPSA-N 0.000 description 4
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 4
- BFDKLCVYBCXRPZ-UHFFFAOYSA-N 2,3-dichloro-1-isothiocyanato-4-methylbenzene Chemical compound ClC1=C(C=CC(=C1Cl)C)N=C=S BFDKLCVYBCXRPZ-UHFFFAOYSA-N 0.000 description 4
- XQQWTOJRRSBQOL-UHFFFAOYSA-N 2-chloro-1-isothiocyanato-3-methylbenzene Chemical compound CC1=CC=CC(N=C=S)=C1Cl XQQWTOJRRSBQOL-UHFFFAOYSA-N 0.000 description 4
- AIBDHZJCYMSHOK-UHFFFAOYSA-N 2-chloro-6-fluoro-4-(trifluoromethyl)aniline Chemical compound NC1=C(F)C=C(C(F)(F)F)C=C1Cl AIBDHZJCYMSHOK-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 4
- 229930195725 Mannitol Natural products 0.000 description 4
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- 235000010443 alginic acid Nutrition 0.000 description 4
- 229920000615 alginic acid Polymers 0.000 description 4
- 150000005005 aminopyrimidines Chemical class 0.000 description 4
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 4
- 239000011230 binding agent Substances 0.000 description 4
- 235000010980 cellulose Nutrition 0.000 description 4
- 229920002678 cellulose Polymers 0.000 description 4
- 238000004587 chromatography analysis Methods 0.000 description 4
- NZNMSOFKMUBTKW-UHFFFAOYSA-M cyclohexanecarboxylate Chemical compound [O-]C(=O)C1CCCCC1 NZNMSOFKMUBTKW-UHFFFAOYSA-M 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 238000001704 evaporation Methods 0.000 description 4
- 230000008020 evaporation Effects 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 125000002883 imidazolyl group Chemical group 0.000 description 4
- 239000000314 lubricant Substances 0.000 description 4
- 239000000594 mannitol Substances 0.000 description 4
- 235000010355 mannitol Nutrition 0.000 description 4
- 229920000609 methyl cellulose Polymers 0.000 description 4
- 235000010981 methylcellulose Nutrition 0.000 description 4
- 239000001923 methylcellulose Substances 0.000 description 4
- 125000002757 morpholinyl group Chemical group 0.000 description 4
- 125000001624 naphthyl group Chemical group 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- 229920001223 polyethylene glycol Polymers 0.000 description 4
- 125000000168 pyrrolyl group Chemical group 0.000 description 4
- 230000009467 reduction Effects 0.000 description 4
- 230000004044 response Effects 0.000 description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
- 229910052938 sodium sulfate Inorganic materials 0.000 description 4
- 235000011152 sodium sulphate Nutrition 0.000 description 4
- 230000004083 survival effect Effects 0.000 description 4
- 125000001544 thienyl group Chemical group 0.000 description 4
- QLOHXGYAULHFOG-SCSAIBSYSA-N (1r)-3,3-difluorocyclopentan-1-amine Chemical compound N[C@@H]1CCC(F)(F)C1 QLOHXGYAULHFOG-SCSAIBSYSA-N 0.000 description 3
- AJQFAPDMBFEYRX-RYUDHWBXSA-N (3R,4S)-N-benzyl-3-fluorooxan-4-amine Chemical compound C(C1=CC=CC=C1)N[C@@H]1[C@H](COCC1)F AJQFAPDMBFEYRX-RYUDHWBXSA-N 0.000 description 3
- KNQUEEOHOGWETD-KGZKBUQUSA-N (3S,4R)-3-methyloxan-4-amine hydrochloride Chemical compound Cl.C[C@@H]1COCC[C@H]1N KNQUEEOHOGWETD-KGZKBUQUSA-N 0.000 description 3
- AJQFAPDMBFEYRX-NWDGAFQWSA-N (3r,4r)-n-benzyl-3-fluorooxan-4-amine Chemical compound F[C@H]1COCC[C@H]1NCC1=CC=CC=C1 AJQFAPDMBFEYRX-NWDGAFQWSA-N 0.000 description 3
- NHAYDXCUCXRAMF-UHFFFAOYSA-N (4-methoxycarbonylcyclohexyl)azanium;chloride Chemical compound Cl.COC(=O)C1CCC(N)CC1 NHAYDXCUCXRAMF-UHFFFAOYSA-N 0.000 description 3
- BKQUSECQDJWGCO-UHFFFAOYSA-N 1,2-dichloro-3-fluoro-4-isothiocyanatobenzene Chemical compound ClC1=C(C(=C(C=C1)N=C=S)F)Cl BKQUSECQDJWGCO-UHFFFAOYSA-N 0.000 description 3
- VSKKBQVSBBTEIX-UHFFFAOYSA-N 1,2-dichloro-4-fluoro-3-isothiocyanatobenzene Chemical compound FC1=CC=C(Cl)C(Cl)=C1N=C=S VSKKBQVSBBTEIX-UHFFFAOYSA-N 0.000 description 3
- VXECLLHFYZBCPZ-UHFFFAOYSA-N 1,5-difluoro-2-isothiocyanato-3-methylbenzene Chemical compound FC1=C(C(=CC(=C1)F)C)N=C=S VXECLLHFYZBCPZ-UHFFFAOYSA-N 0.000 description 3
- NYFRSBXRRABDDY-UHFFFAOYSA-N 1-chloro-2,3-difluoro-4-isothiocyanatobenzene Chemical compound ClC1=C(C(=C(C=C1)N=C=S)F)F NYFRSBXRRABDDY-UHFFFAOYSA-N 0.000 description 3
- FZICMKIORMLMJX-UHFFFAOYSA-N 1-chloro-2,5-difluoro-4-isothiocyanatobenzene Chemical compound FC1=CC(N=C=S)=C(F)C=C1Cl FZICMKIORMLMJX-UHFFFAOYSA-N 0.000 description 3
- SZNMZBGPFVULMW-UHFFFAOYSA-N 1-chloro-3,5-difluoro-2-isothiocyanatobenzene Chemical compound FC1=CC(F)=C(N=C=S)C(Cl)=C1 SZNMZBGPFVULMW-UHFFFAOYSA-N 0.000 description 3
- YSCSNIKDJCJHKZ-UHFFFAOYSA-N 1-chloro-3-fluoro-2-isothiocyanato-5-(trifluoromethyl)benzene Chemical compound ClC1=C(C(=CC(=C1)C(F)(F)F)F)N=C=S YSCSNIKDJCJHKZ-UHFFFAOYSA-N 0.000 description 3
- KCORWPNMYHBTJD-UHFFFAOYSA-N 1-chloro-4,5-difluoro-2-isothiocyanatobenzene Chemical compound ClC1=C(C=C(C(=C1)F)F)N=C=S KCORWPNMYHBTJD-UHFFFAOYSA-N 0.000 description 3
- KYBVVBSDWJJJQE-UHFFFAOYSA-N 1-chloro-5-fluoro-2-isothiocyanato-3-methylbenzene Chemical compound ClC1=C(C(=CC(=C1)F)C)N=C=S KYBVVBSDWJJJQE-UHFFFAOYSA-N 0.000 description 3
- YXVJHZWHPLOEAP-UHFFFAOYSA-N 1-chloro-5-fluoro-2-methyl-4-nitrobenzene Chemical compound CC1=CC([N+]([O-])=O)=C(F)C=C1Cl YXVJHZWHPLOEAP-UHFFFAOYSA-N 0.000 description 3
- ILWINSOSJQCIJY-UHFFFAOYSA-N 1-chloro-5-fluoro-4-isothiocyanato-2-methylbenzene Chemical compound ClC1=C(C=C(C(=C1)F)N=C=S)C ILWINSOSJQCIJY-UHFFFAOYSA-N 0.000 description 3
- DDSBNJVJUCCGNO-UHFFFAOYSA-N 1-methyl-4-oxocyclohexane-1-carbonitrile Chemical compound N#CC1(C)CCC(=O)CC1 DDSBNJVJUCCGNO-UHFFFAOYSA-N 0.000 description 3
- YAPLMJQCTRFXQZ-UHFFFAOYSA-N 2,3-dichloro-4-methylaniline Chemical compound CC1=CC=C(N)C(Cl)=C1Cl YAPLMJQCTRFXQZ-UHFFFAOYSA-N 0.000 description 3
- WBHSLAUXVJCSBO-UHFFFAOYSA-N 2,3-dichloro-6-fluoroaniline Chemical compound NC1=C(F)C=CC(Cl)=C1Cl WBHSLAUXVJCSBO-UHFFFAOYSA-N 0.000 description 3
- HJOXQTBUHQHQRI-UHFFFAOYSA-N 2,3-difluoro-1-isothiocyanato-4-methoxybenzene Chemical compound COC1=CC=C(N=C=S)C(F)=C1F HJOXQTBUHQHQRI-UHFFFAOYSA-N 0.000 description 3
- QSEKKBOHYPZREC-UHFFFAOYSA-N 2,3-difluoro-1-isothiocyanato-4-methylbenzene Chemical compound FC1=C(C=CC(=C1F)C)N=C=S QSEKKBOHYPZREC-UHFFFAOYSA-N 0.000 description 3
- MEETZAMYCFAKKW-UHFFFAOYSA-N 2,3-difluoro-4-methoxyaniline Chemical compound COC1=CC=C(N)C(F)=C1F MEETZAMYCFAKKW-UHFFFAOYSA-N 0.000 description 3
- FJZWQRCPTNOPJK-UHFFFAOYSA-N 2,4-dichloro-6-fluoroaniline Chemical compound NC1=C(F)C=C(Cl)C=C1Cl FJZWQRCPTNOPJK-UHFFFAOYSA-N 0.000 description 3
- LCFIGWMSLXQQKF-UHFFFAOYSA-N 2,4-difluoro-3-isothiocyanatobenzonitrile Chemical compound FC1=C(C#N)C=CC(=C1N=C=S)F LCFIGWMSLXQQKF-UHFFFAOYSA-N 0.000 description 3
- YOUATWOIMFYCAR-UHFFFAOYSA-N 2,4-difluoro-6-methylaniline Chemical compound CC1=CC(F)=CC(F)=C1N YOUATWOIMFYCAR-UHFFFAOYSA-N 0.000 description 3
- 125000004215 2,4-difluorophenyl group Chemical group [H]C1=C([H])C(*)=C(F)C([H])=C1F 0.000 description 3
- CHEYNTPPYKGTBF-UHFFFAOYSA-N 2-chloro-3-fluoro-1-isothiocyanato-4-methylbenzene Chemical compound ClC1=C(C=CC(=C1F)C)N=C=S CHEYNTPPYKGTBF-UHFFFAOYSA-N 0.000 description 3
- SDFKASJXQVVGNG-UHFFFAOYSA-N 2-chloro-3-fluoro-4-methylaniline Chemical compound CC1=CC=C(N)C(Cl)=C1F SDFKASJXQVVGNG-UHFFFAOYSA-N 0.000 description 3
- RQRKMXABSUYQBV-UHFFFAOYSA-N 2-chloro-3-methylaniline Chemical compound CC1=CC=CC(N)=C1Cl RQRKMXABSUYQBV-UHFFFAOYSA-N 0.000 description 3
- PLTNCEGFKZZXEI-UHFFFAOYSA-N 2-chloro-4-fluoro-6-methylaniline Chemical compound CC1=CC(F)=CC(Cl)=C1N PLTNCEGFKZZXEI-UHFFFAOYSA-N 0.000 description 3
- IIUHMNFTPGBLCX-UHFFFAOYSA-N 3,3-difluorocyclopentan-1-amine;hydrochloride Chemical compound Cl.NC1CCC(F)(F)C1 IIUHMNFTPGBLCX-UHFFFAOYSA-N 0.000 description 3
- SWFTUJYWXDZKHF-UHFFFAOYSA-N 3,5-difluoro-4-isothiocyanatobenzonitrile Chemical compound FC=1C=C(C#N)C=C(C=1N=C=S)F SWFTUJYWXDZKHF-UHFFFAOYSA-N 0.000 description 3
- VMQYTWJHVLONIU-UHFFFAOYSA-N 3-amino-2,4-difluorobenzonitrile Chemical compound NC1=C(F)C=CC(C#N)=C1F VMQYTWJHVLONIU-UHFFFAOYSA-N 0.000 description 3
- WSGVSQUXDSPFAI-UHFFFAOYSA-N 3-chloro-1-fluoro-2-isothiocyanato-4-methylbenzene Chemical compound CC1=CC=C(F)C(N=C=S)=C1Cl WSGVSQUXDSPFAI-UHFFFAOYSA-N 0.000 description 3
- SSCHOBJLMMBIML-UHFFFAOYSA-N 3-chloro-4-isothiocyanatobenzonitrile Chemical compound ClC1=CC(C#N)=CC=C1N=C=S SSCHOBJLMMBIML-UHFFFAOYSA-N 0.000 description 3
- MDZUDURBHHTAEX-UHFFFAOYSA-N 3-chloro-5-fluoro-4-isothiocyanatobenzonitrile Chemical compound ClC=1C=C(C#N)C=C(C=1N=C=S)F MDZUDURBHHTAEX-UHFFFAOYSA-N 0.000 description 3
- OJCKPWOBQFQMAA-UHFFFAOYSA-N 3-cyano-2,6-difluorobenzoic acid Chemical compound OC(=O)C1=C(F)C=CC(C#N)=C1F OJCKPWOBQFQMAA-UHFFFAOYSA-N 0.000 description 3
- PGPWMORFOPRGCA-UHFFFAOYSA-N 3-methyloxan-4-one Chemical compound CC1COCCC1=O PGPWMORFOPRGCA-UHFFFAOYSA-N 0.000 description 3
- FBZWVZPRCICVPX-UHFFFAOYSA-N 4,4-dimethoxyoxane Chemical compound COC1(OC)CCOCC1 FBZWVZPRCICVPX-UHFFFAOYSA-N 0.000 description 3
- BWAFIBAPFADXHV-UHFFFAOYSA-N 4-amino-3-chloro-5-fluorobenzonitrile Chemical compound NC1=C(F)C=C(C#N)C=C1Cl BWAFIBAPFADXHV-UHFFFAOYSA-N 0.000 description 3
- ZNAZYPNKGBYYIO-UHFFFAOYSA-N 4-bromo-2,3-dichloro-6-fluoroaniline Chemical compound BrC1=C(C(=C(N)C(=C1)F)Cl)Cl ZNAZYPNKGBYYIO-UHFFFAOYSA-N 0.000 description 3
- UEVLRVBHLWKNEN-UHFFFAOYSA-N 4-bromo-2,3-difluoroaniline Chemical compound NC1=CC=C(Br)C(F)=C1F UEVLRVBHLWKNEN-UHFFFAOYSA-N 0.000 description 3
- SKJMNEFZWYBTHT-UHFFFAOYSA-N 4-bromo-5-chloro-2-fluoroaniline Chemical compound NC1=CC(Cl)=C(Br)C=C1F SKJMNEFZWYBTHT-UHFFFAOYSA-N 0.000 description 3
- KOYRUTVRISCZSB-UHFFFAOYSA-N 4-bromo-6-chloro-2,3-difluoroaniline Chemical compound BrC1=C(C(=C(N)C(=C1)Cl)F)F KOYRUTVRISCZSB-UHFFFAOYSA-N 0.000 description 3
- KLAJZEMLYSDWNR-UHFFFAOYSA-N 4-chloro-2,3-difluoroaniline Chemical compound NC1=CC=C(Cl)C(F)=C1F KLAJZEMLYSDWNR-UHFFFAOYSA-N 0.000 description 3
- PYRVOUSDQGBZRG-UHFFFAOYSA-N 4-chloro-2,5-difluoroaniline Chemical compound NC1=CC(F)=C(Cl)C=C1F PYRVOUSDQGBZRG-UHFFFAOYSA-N 0.000 description 3
- AMZYGCDRRKZPRM-UHFFFAOYSA-N 4-chloro-2-fluoro-3-methylaniline Chemical compound CC1=C(F)C(N)=CC=C1Cl AMZYGCDRRKZPRM-UHFFFAOYSA-N 0.000 description 3
- KENAMMSVUHVEOL-UHFFFAOYSA-N 4-chloro-2-fluoro-5-methylaniline Chemical compound CC1=CC(N)=C(F)C=C1Cl KENAMMSVUHVEOL-UHFFFAOYSA-N 0.000 description 3
- JOVNAPZGYWRKSE-UHFFFAOYSA-N 4-chloro-2-fluoro-6-methylaniline Chemical compound CC1=CC(Cl)=CC(F)=C1N JOVNAPZGYWRKSE-UHFFFAOYSA-N 0.000 description 3
- TZSBJDYIRNTFJG-UHFFFAOYSA-N 4-chloro-3-fluoro-2-methylaniline Chemical compound CC1=C(N)C=CC(Cl)=C1F TZSBJDYIRNTFJG-UHFFFAOYSA-N 0.000 description 3
- FSMHNRHLQAABPS-UHFFFAOYSA-N 4-methoxy-3,6-dihydro-2h-pyran Chemical compound COC1=CCOCC1 FSMHNRHLQAABPS-UHFFFAOYSA-N 0.000 description 3
- DZGNULCWFCXXPO-UHFFFAOYSA-N 5-chloro-1-fluoro-2-isothiocyanato-3-methylbenzene Chemical compound ClC=1C=C(C(=C(C=1)F)N=C=S)C DZGNULCWFCXXPO-UHFFFAOYSA-N 0.000 description 3
- WBLYPLRDZHWMPV-UHFFFAOYSA-N 6-chloro-2,3-difluoroaniline Chemical compound NC1=C(Cl)C=CC(F)=C1F WBLYPLRDZHWMPV-UHFFFAOYSA-N 0.000 description 3
- 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 3
- 229910021554 Chromium(II) chloride Inorganic materials 0.000 description 3
- JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 3
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 3
- 102000000588 Interleukin-2 Human genes 0.000 description 3
- 108010002350 Interleukin-2 Proteins 0.000 description 3
- 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 3
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 description 3
- 239000002202 Polyethylene glycol Substances 0.000 description 3
- 229930006000 Sucrose Natural products 0.000 description 3
- 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 3
- ZMZDMBWJUHKJPS-UHFFFAOYSA-M Thiocyanate anion Chemical compound [S-]C#N ZMZDMBWJUHKJPS-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- SORGEQQSQGNZFI-UHFFFAOYSA-N [azido(phenoxy)phosphoryl]oxybenzene Chemical compound C=1C=CC=CC=1OP(=O)(N=[N+]=[N-])OC1=CC=CC=C1 SORGEQQSQGNZFI-UHFFFAOYSA-N 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 125000004442 acylamino group Chemical group 0.000 description 3
- 150000001299 aldehydes Chemical class 0.000 description 3
- 125000004183 alkoxy alkyl group Chemical group 0.000 description 3
- 125000003545 alkoxy group Chemical group 0.000 description 3
- 125000005262 alkoxyamine group Chemical group 0.000 description 3
- 150000001409 amidines Chemical class 0.000 description 3
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 3
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 3
- 125000003354 benzotriazolyl group Chemical group N1N=NC2=C1C=CC=C2* 0.000 description 3
- 125000001246 bromo group Chemical group Br* 0.000 description 3
- 239000001506 calcium phosphate Substances 0.000 description 3
- 235000011010 calcium phosphates Nutrition 0.000 description 3
- 239000004202 carbamide Substances 0.000 description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 3
- 150000007942 carboxylates Chemical class 0.000 description 3
- 238000004296 chiral HPLC Methods 0.000 description 3
- XBWRJSSJWDOUSJ-UHFFFAOYSA-L chromium(ii) chloride Chemical compound Cl[Cr]Cl XBWRJSSJWDOUSJ-UHFFFAOYSA-L 0.000 description 3
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 description 3
- 238000004090 dissolution Methods 0.000 description 3
- 150000002081 enamines Chemical class 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- UXXWGBLTOSRBAY-UHFFFAOYSA-N ethyl 1,4-dioxaspiro[4.5]decane-8-carboxylate Chemical compound C1CC(C(=O)OCC)CCC21OCCO2 UXXWGBLTOSRBAY-UHFFFAOYSA-N 0.000 description 3
- GYDKHYAZKCAMAS-UHFFFAOYSA-N ethyl 1-methyl-4-oxocyclohexane-1-carboxylate Chemical compound CCOC(=O)C1(C)CCC(=O)CC1 GYDKHYAZKCAMAS-UHFFFAOYSA-N 0.000 description 3
- NFHQFOMQLVEACK-UHFFFAOYSA-N ethyl 4-amino-1-methylcyclohexane-1-carboxylate hydrochloride Chemical compound Cl.CCOC(=O)C1(C)CCC(N)CC1 NFHQFOMQLVEACK-UHFFFAOYSA-N 0.000 description 3
- UTSNQRPECDOZEY-UHFFFAOYSA-N ethyl 4-hydroxyimino-1-methylcyclohexane-1-carboxylate Chemical compound ON=C1CCC(CC1)(C(=O)OCC)C UTSNQRPECDOZEY-UHFFFAOYSA-N 0.000 description 3
- VFWAGFFGWYTECB-UHFFFAOYSA-N ethyl 8-methyl-1,4-dioxaspiro[4.5]decane-8-carboxylate Chemical compound C1CC(C(=O)OCC)(C)CCC21OCCO2 VFWAGFFGWYTECB-UHFFFAOYSA-N 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
- 125000001153 fluoro group Chemical group F* 0.000 description 3
- 125000002541 furyl group Chemical group 0.000 description 3
- 125000004415 heterocyclylalkyl group Chemical group 0.000 description 3
- 150000007857 hydrazones Chemical class 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- 125000002632 imidazolidinyl group Chemical group 0.000 description 3
- 150000003949 imides Chemical class 0.000 description 3
- 150000002466 imines Chemical class 0.000 description 3
- 125000001041 indolyl group Chemical group 0.000 description 3
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 3
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 3
- 125000000842 isoxazolyl group Chemical group 0.000 description 3
- 150000002576 ketones Chemical class 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 231100000252 nontoxic Toxicity 0.000 description 3
- 230000003000 nontoxic effect Effects 0.000 description 3
- 125000002971 oxazolyl group Chemical group 0.000 description 3
- 150000002923 oximes Chemical class 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- 239000008188 pellet Substances 0.000 description 3
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 description 3
- 125000004193 piperazinyl group Chemical group 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 238000002953 preparative HPLC Methods 0.000 description 3
- 230000002265 prevention Effects 0.000 description 3
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 3
- 125000003373 pyrazinyl group Chemical group 0.000 description 3
- 125000003226 pyrazolyl group Chemical group 0.000 description 3
- 125000002098 pyridazinyl group Chemical group 0.000 description 3
- 125000000714 pyrimidinyl group Chemical group 0.000 description 3
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 3
- 125000006413 ring segment Chemical group 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 239000005720 sucrose Substances 0.000 description 3
- 235000000346 sugar Nutrition 0.000 description 3
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 3
- 150000003457 sulfones Chemical class 0.000 description 3
- 239000000829 suppository Substances 0.000 description 3
- 239000000454 talc Substances 0.000 description 3
- 229910052623 talc Inorganic materials 0.000 description 3
- 235000012222 talc Nutrition 0.000 description 3
- HYGQGFJZMPAANY-UHFFFAOYSA-N tert-butyl N-(3-cyano-2,6-difluorophenyl)carbamate Chemical compound C(#N)C=1C(=C(C(=CC=1)F)NC(OC(C)(C)C)=O)F HYGQGFJZMPAANY-UHFFFAOYSA-N 0.000 description 3
- SCXQXMBCRMLPGO-UHFFFAOYSA-N tert-butyl n-(3,3-difluorocyclopentyl)carbamate Chemical compound CC(C)(C)OC(=O)NC1CCC(F)(F)C1 SCXQXMBCRMLPGO-UHFFFAOYSA-N 0.000 description 3
- HILAGAFOXBPCFN-UHFFFAOYSA-N tert-butyl n-(4-carbamoylcyclohexyl)carbamate Chemical compound CC(C)(C)OC(=O)NC1CCC(C(N)=O)CC1 HILAGAFOXBPCFN-UHFFFAOYSA-N 0.000 description 3
- 125000003831 tetrazolyl group Chemical group 0.000 description 3
- 125000000335 thiazolyl group Chemical group 0.000 description 3
- 238000004809 thin layer chromatography Methods 0.000 description 3
- 150000003568 thioethers Chemical class 0.000 description 3
- 150000003585 thioureas Chemical class 0.000 description 3
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 3
- 125000001425 triazolyl group Chemical group 0.000 description 3
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 3
- GPXBXXGIAQBQNI-UHFFFAOYSA-N vemurafenib Chemical compound CCCS(=O)(=O)NC1=CC=C(F)C(C(=O)C=2C3=CC(=CN=C3NC=2)C=2C=CC(Cl)=CC=2)=C1F GPXBXXGIAQBQNI-UHFFFAOYSA-N 0.000 description 3
- 239000001993 wax Substances 0.000 description 3
- JYZWPWDEIMDHFF-UYXJWNHNSA-N (3r,4r)-3-fluorooxan-4-amine;hydrochloride Chemical compound Cl.N[C@@H]1CCOC[C@@H]1F JYZWPWDEIMDHFF-UYXJWNHNSA-N 0.000 description 2
- JYZWPWDEIMDHFF-FHAQVOQBSA-N (3r,4s)-3-fluorooxan-4-amine;hydrochloride Chemical compound Cl.N[C@H]1CCOC[C@@H]1F JYZWPWDEIMDHFF-FHAQVOQBSA-N 0.000 description 2
- 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
- JPISVBDECFJHDB-UHFFFAOYSA-N 1,3,5-trifluoro-2-isothiocyanatobenzene Chemical compound FC1=CC(F)=C(N=C=S)C(F)=C1 JPISVBDECFJHDB-UHFFFAOYSA-N 0.000 description 2
- NQPJDJVGBDHCAD-UHFFFAOYSA-N 1,3-diazinan-2-one Chemical compound OC1=NCCCN1 NQPJDJVGBDHCAD-UHFFFAOYSA-N 0.000 description 2
- VKRKCBWIVLSRBJ-UHFFFAOYSA-N 1,4-dioxaspiro[4.5]decan-8-one Chemical compound C1CC(=O)CCC21OCCO2 VKRKCBWIVLSRBJ-UHFFFAOYSA-N 0.000 description 2
- WZWQNWWFCHNJON-UHFFFAOYSA-N 1,4-dioxaspiro[4.5]decane-8-carbonitrile Chemical compound C1CC(C#N)CCC21OCCO2 WZWQNWWFCHNJON-UHFFFAOYSA-N 0.000 description 2
- OPGCZAMPLLZADO-UHFFFAOYSA-N 2,4-difluoro-6-(methylsulfanylmethyl)aniline Chemical compound FC1=C(N)C(=CC(=C1)F)CSC OPGCZAMPLLZADO-UHFFFAOYSA-N 0.000 description 2
- HMIDTEOXZYESNP-UHFFFAOYSA-N 2-N-(oxan-4-yl)pyrimidine-2,5-diamine Chemical compound N1=CC(N)=CN=C1NC1CCOCC1 HMIDTEOXZYESNP-UHFFFAOYSA-N 0.000 description 2
- VCNCNVOMGXWTBZ-UHFFFAOYSA-N 2-chloro-6-fluoro-3-methylbenzoic acid Chemical compound CC1=CC=C(F)C(C(O)=O)=C1Cl VCNCNVOMGXWTBZ-UHFFFAOYSA-N 0.000 description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 2
- REUFKTIIFWODQS-UHFFFAOYSA-N 3-azidocyclopentan-1-one Chemical compound [N-]=[N+]=NC1CCC(=O)C1 REUFKTIIFWODQS-UHFFFAOYSA-N 0.000 description 2
- QORMSHMHGGKSSD-UHFFFAOYSA-N 3-fluorooxan-4-one Chemical compound FC1COCCC1=O QORMSHMHGGKSSD-UHFFFAOYSA-N 0.000 description 2
- HKLHUWBDESDDQX-HRDQMINSSA-N 4-[8-(2,4-dichloro-6-fluoroanilino)-2-[[(1R)-3,3-difluorocyclopentyl]amino]purin-9-yl]cyclohexane-1-carboxamide Chemical compound NC(=O)C1CCC(CC1)N1C(NC2=C(Cl)C=C(Cl)C=C2F)=NC2=CN=C(N[C@@H]3CCC(F)(F)C3)N=C12 HKLHUWBDESDDQX-HRDQMINSSA-N 0.000 description 2
- HVBSAKJJOYLTQU-UHFFFAOYSA-N 4-aminobenzenesulfonic acid Chemical compound NC1=CC=C(S(O)(=O)=O)C=C1 HVBSAKJJOYLTQU-UHFFFAOYSA-N 0.000 description 2
- 125000001417 5'-guanylyl group Chemical group C=12N=C(N([H])[H])N([H])C(=O)C=1N=C([H])N2[C@@]1([H])[C@@](O[H])([H])[C@@](O[H])([H])[C@](C(OP(=O)(O[H])[*])([H])[H])([H])O1 0.000 description 2
- VKKXEIQIGGPMHT-UHFFFAOYSA-N 7h-purine-2,8-diamine Chemical class NC1=NC=C2NC(N)=NC2=N1 VKKXEIQIGGPMHT-UHFFFAOYSA-N 0.000 description 2
- 244000215068 Acacia senegal Species 0.000 description 2
- ZKHQWZAMYRWXGA-KQYNXXCUSA-N Adenosine triphosphate Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)[C@@H](O)[C@H]1O ZKHQWZAMYRWXGA-KQYNXXCUSA-N 0.000 description 2
- ZKHQWZAMYRWXGA-UHFFFAOYSA-N Adenosine triphosphate Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(=O)OP(O)(=O)OP(O)(O)=O)C(O)C1O ZKHQWZAMYRWXGA-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-OUBTZVSYSA-N Ammonia-15N Chemical compound [15NH3] QGZKDVFQNNGYKY-OUBTZVSYSA-N 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- 0 CC(C)(CC1)CCC1Nc1nc(N*)ncc1N Chemical compound CC(C)(CC1)CCC1Nc1nc(N*)ncc1N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- OKTJSMMVPCPJKN-OUBTZVSYSA-N Carbon-13 Chemical compound [13C] OKTJSMMVPCPJKN-OUBTZVSYSA-N 0.000 description 2
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 2
- BZKFMUIJRXWWQK-UHFFFAOYSA-N Cyclopentenone Chemical compound O=C1CCC=C1 BZKFMUIJRXWWQK-UHFFFAOYSA-N 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
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- 229930091371 Fructose Natural products 0.000 description 2
- 239000005715 Fructose Substances 0.000 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 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- IAJILQKETJEXLJ-UHFFFAOYSA-N Galacturonsaeure Natural products O=CC(O)C(O)C(O)C(O)C(O)=O IAJILQKETJEXLJ-UHFFFAOYSA-N 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- 229920000084 Gum arabic Polymers 0.000 description 2
- 101000652482 Homo sapiens TBC1 domain family member 8 Proteins 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 102000043136 MAP kinase family Human genes 0.000 description 2
- 108091054455 MAP kinase family Proteins 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- 206010027480 Metastatic malignant melanoma Diseases 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 150000001204 N-oxides Chemical class 0.000 description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 2
- 239000007868 Raney catalyst Substances 0.000 description 2
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 2
- 229910000564 Raney nickel Inorganic materials 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 235000021355 Stearic acid Nutrition 0.000 description 2
- 102100030302 TBC1 domain family member 8 Human genes 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 2
- 235000010489 acacia gum Nutrition 0.000 description 2
- 239000000205 acacia gum Substances 0.000 description 2
- 229960001456 adenosine triphosphate Drugs 0.000 description 2
- 239000000783 alginic acid Substances 0.000 description 2
- 229960001126 alginic acid Drugs 0.000 description 2
- 150000004781 alginic acids Chemical class 0.000 description 2
- 125000003282 alkyl amino group Chemical group 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- RWZYAGGXGHYGMB-UHFFFAOYSA-N anthranilic acid Chemical compound NC1=CC=CC=C1C(O)=O RWZYAGGXGHYGMB-UHFFFAOYSA-N 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 125000005602 azabenzimidazolyl group Chemical group 0.000 description 2
- 125000005334 azaindolyl group Chemical group N1N=C(C2=CC=CC=C12)* 0.000 description 2
- 125000003725 azepanyl group Chemical group 0.000 description 2
- 125000002393 azetidinyl group Chemical group 0.000 description 2
- 150000001540 azides Chemical class 0.000 description 2
- 125000004069 aziridinyl group Chemical group 0.000 description 2
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 2
- 125000004603 benzisoxazolyl group Chemical group O1N=C(C2=C1C=CC=C2)* 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 125000005874 benzothiadiazolyl group Chemical group 0.000 description 2
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 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 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 229910000389 calcium phosphate Inorganic materials 0.000 description 2
- 125000002837 carbocyclic group Chemical group 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 2
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 239000007910 chewable tablet Substances 0.000 description 2
- 229940110456 cocoa butter Drugs 0.000 description 2
- 235000019868 cocoa butter Nutrition 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 208000035250 cutaneous malignant susceptibility to 1 melanoma Diseases 0.000 description 2
- 208000030381 cutaneous melanoma Diseases 0.000 description 2
- XLJMAIOERFSOGZ-UHFFFAOYSA-M cyanate group Chemical group [O-]C#N XLJMAIOERFSOGZ-UHFFFAOYSA-M 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- 229960003901 dacarbazine Drugs 0.000 description 2
- 229910052805 deuterium Inorganic materials 0.000 description 2
- CSJLBAMHHLJAAS-UHFFFAOYSA-N diethylaminosulfur trifluoride Chemical compound CCN(CC)S(F)(F)F CSJLBAMHHLJAAS-UHFFFAOYSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- 239000007884 disintegrant Substances 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 125000005883 dithianyl group Chemical group 0.000 description 2
- 238000011049 filling Methods 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- ZMZDMBWJUHKJPS-UHFFFAOYSA-N hydrogen thiocyanate Natural products SC#N ZMZDMBWJUHKJPS-UHFFFAOYSA-N 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 125000002636 imidazolinyl group Chemical group 0.000 description 2
- 125000005945 imidazopyridyl group Chemical group 0.000 description 2
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 2
- 238000011081 inoculation Methods 0.000 description 2
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 2
- 239000012948 isocyanate Substances 0.000 description 2
- 150000002513 isocyanates Chemical class 0.000 description 2
- 150000002540 isothiocyanates Chemical group 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000004020 luminiscence type Methods 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 2
- 239000011976 maleic acid Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 210000002752 melanocyte Anatomy 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 208000021039 metastatic melanoma Diseases 0.000 description 2
- 229940098779 methanesulfonic acid Drugs 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 2
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 235000005985 organic acids Nutrition 0.000 description 2
- JMJRYTGVHCAYCT-UHFFFAOYSA-N oxan-4-one Chemical compound O=C1CCOCC1 JMJRYTGVHCAYCT-UHFFFAOYSA-N 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 230000037361 pathway Effects 0.000 description 2
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 2
- 208000024335 physical disease Diseases 0.000 description 2
- 125000003367 polycyclic group Chemical group 0.000 description 2
- 239000013641 positive control Substances 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 238000012746 preparative thin layer chromatography Methods 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 238000004393 prognosis Methods 0.000 description 2
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 2
- 125000003072 pyrazolidinyl group Chemical group 0.000 description 2
- 125000006085 pyrrolopyridyl group Chemical group 0.000 description 2
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 2
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 208000002491 severe combined immunodeficiency Diseases 0.000 description 2
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 2
- 241000894007 species Species 0.000 description 2
- 239000008117 stearic acid Substances 0.000 description 2
- 229940124530 sulfonamide Drugs 0.000 description 2
- 150000003456 sulfonamides Chemical class 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 2
- 239000002511 suppository base Substances 0.000 description 2
- 238000013268 sustained release Methods 0.000 description 2
- 239000012730 sustained-release form Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- CLOXAWYNXXEWBT-UHFFFAOYSA-N tert-butyl n-(3-oxocyclopentyl)carbamate Chemical compound CC(C)(C)OC(=O)NC1CCC(=O)C1 CLOXAWYNXXEWBT-UHFFFAOYSA-N 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 description 2
- 125000003507 tetrahydrothiofenyl group Chemical group 0.000 description 2
- 125000004632 tetrahydrothiopyranyl group Chemical group S1C(CCCC1)* 0.000 description 2
- 229940124597 therapeutic agent Drugs 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 125000001984 thiazolidinyl group Chemical group 0.000 description 2
- 125000002813 thiocarbonyl group Chemical group *C(*)=S 0.000 description 2
- 150000003573 thiols Chemical class 0.000 description 2
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 229960003862 vemurafenib Drugs 0.000 description 2
- 229920002554 vinyl polymer Polymers 0.000 description 2
- NOOLISFMXDJSKH-UTLUCORTSA-N (+)-Neomenthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@@H]1O NOOLISFMXDJSKH-UTLUCORTSA-N 0.000 description 1
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- UAIXEOIQIOOYES-AAEUAGOBSA-N (3R,4S)-N-benzyl-3-methyloxan-4-amine Chemical compound C(C1=CC=CC=C1)N[C@@H]1[C@H](COCC1)C UAIXEOIQIOOYES-AAEUAGOBSA-N 0.000 description 1
- BKMMTJMQCTUHRP-VKHMYHEASA-N (S)-2-aminopropan-1-ol Chemical compound C[C@H](N)CO BKMMTJMQCTUHRP-VKHMYHEASA-N 0.000 description 1
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- JRZGPXSSNPTNMA-UHFFFAOYSA-N 1,2,3,4-tetrahydronaphthalen-1-amine Chemical compound C1=CC=C2C(N)CCCC2=C1 JRZGPXSSNPTNMA-UHFFFAOYSA-N 0.000 description 1
- LCGFVWKNXLRFIF-UHFFFAOYSA-N 1,2,3,4-tetrahydronaphthalen-2-amine Chemical compound C1=CC=C2CC(N)CCC2=C1 LCGFVWKNXLRFIF-UHFFFAOYSA-N 0.000 description 1
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 1
- ASTXSJBUNUUSTN-UHFFFAOYSA-N 1,3-dichloro-5-fluoro-2-isothiocyanatobenzene Chemical compound FC1=CC(Cl)=C(N=C=S)C(Cl)=C1 ASTXSJBUNUUSTN-UHFFFAOYSA-N 0.000 description 1
- DBSXNGIBAKYMSS-UHFFFAOYSA-N 1,3-difluoro-2-isothiocyanatobenzene Chemical compound FC1=CC=CC(F)=C1N=C=S DBSXNGIBAKYMSS-UHFFFAOYSA-N 0.000 description 1
- ZXOFAHRGRROAQR-UHFFFAOYSA-N 1-(isocyanomethylsulfonyl)-2-methylbenzene Chemical compound CC1=CC=CC=C1S(=O)(=O)C[N+]#[C-] ZXOFAHRGRROAQR-UHFFFAOYSA-N 0.000 description 1
- OFQRRFRIDGZHSC-UHFFFAOYSA-N 1-chloro-2,3-difluoro-4-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=C(Cl)C(F)=C1F OFQRRFRIDGZHSC-UHFFFAOYSA-N 0.000 description 1
- HBGYPLNIBDKWIK-UHFFFAOYSA-N 1-chloro-2,5-difluoro-4-nitrobenzene Chemical compound [O-][N+](=O)C1=CC(F)=C(Cl)C=C1F HBGYPLNIBDKWIK-UHFFFAOYSA-N 0.000 description 1
- YONIWCRCAZXTQP-UHFFFAOYSA-N 1-chloro-3,4-difluoro-2-isothiocyanatobenzene Chemical compound ClC1=C(C(=C(C=C1)F)F)N=C=S YONIWCRCAZXTQP-UHFFFAOYSA-N 0.000 description 1
- ZXEZATIRZLJXFU-UHFFFAOYSA-N 1-chloro-3-isothiocyanato-2-methylbenzene Chemical compound CC1=C(Cl)C=CC=C1N=C=S ZXEZATIRZLJXFU-UHFFFAOYSA-N 0.000 description 1
- NFIUJHJMCQQYDL-UHFFFAOYSA-N 1-fluoro-4-isothiocyanatobenzene Chemical compound FC1=CC=C(N=C=S)C=C1 NFIUJHJMCQQYDL-UHFFFAOYSA-N 0.000 description 1
- 125000006432 1-methyl cyclopropyl group Chemical group [H]C([H])([H])C1(*)C([H])([H])C1([H])[H] 0.000 description 1
- REHQLKUNRPCYEW-UHFFFAOYSA-M 1-methylcyclohexane-1-carboxylate Chemical compound [O-]C(=O)C1(C)CCCCC1 REHQLKUNRPCYEW-UHFFFAOYSA-M 0.000 description 1
- KDXIYOKCZFOFOR-UHFFFAOYSA-N 2,3-difluoro-1-methoxy-4-nitrobenzene Chemical compound COC1=CC=C([N+]([O-])=O)C(F)=C1F KDXIYOKCZFOFOR-UHFFFAOYSA-N 0.000 description 1
- HMDHQYKNBZEFTH-UHFFFAOYSA-N 2,3-difluoro-4-methylaniline Chemical compound CC1=CC=C(N)C(F)=C1F HMDHQYKNBZEFTH-UHFFFAOYSA-N 0.000 description 1
- YCCQGFYAVUTQFK-UHFFFAOYSA-N 2,3-difluoroaniline Chemical compound NC1=CC=CC(F)=C1F YCCQGFYAVUTQFK-UHFFFAOYSA-N 0.000 description 1
- CEPCPXLLFXPZGW-UHFFFAOYSA-N 2,4-difluoroaniline Chemical compound NC1=CC=C(F)C=C1F CEPCPXLLFXPZGW-UHFFFAOYSA-N 0.000 description 1
- LJFDXXUKKMEQKE-UHFFFAOYSA-N 2,4-difluorobenzonitrile Chemical compound FC1=CC=C(C#N)C(F)=C1 LJFDXXUKKMEQKE-UHFFFAOYSA-N 0.000 description 1
- XTSGZXRUCAWXKY-UHFFFAOYSA-N 2-chloro-1-methyl-3-nitrobenzene Chemical compound CC1=CC=CC([N+]([O-])=O)=C1Cl XTSGZXRUCAWXKY-UHFFFAOYSA-N 0.000 description 1
- ZNDPHOPPLHZBMV-UHFFFAOYSA-N 2-chloro-4,5-difluoroaniline Chemical compound NC1=CC(F)=C(F)C=C1Cl ZNDPHOPPLHZBMV-UHFFFAOYSA-N 0.000 description 1
- WFZUBZAEFXETBF-UHFFFAOYSA-N 2-fluoro-3-methylaniline Chemical compound CC1=CC=CC(N)=C1F WFZUBZAEFXETBF-UHFFFAOYSA-N 0.000 description 1
- ARHDUOQIXLGANT-UHFFFAOYSA-N 2-fluoro-4-(trifluoromethyl)aniline Chemical compound NC1=CC=C(C(F)(F)F)C=C1F ARHDUOQIXLGANT-UHFFFAOYSA-N 0.000 description 1
- QZUXMXZNVAJNSE-UHFFFAOYSA-N 2-fluoro-5-methylaniline Chemical compound CC1=CC=C(F)C(N)=C1 QZUXMXZNVAJNSE-UHFFFAOYSA-N 0.000 description 1
- CMVJYZNBMRJICR-UHFFFAOYSA-N 2-fluoro-6-methylaniline Chemical compound CC1=CC=CC(F)=C1N CMVJYZNBMRJICR-UHFFFAOYSA-N 0.000 description 1
- FTZQXOJYPFINKJ-UHFFFAOYSA-N 2-fluoroaniline Chemical compound NC1=CC=CC=C1F FTZQXOJYPFINKJ-UHFFFAOYSA-N 0.000 description 1
- SMNDYUVBFMFKNZ-UHFFFAOYSA-N 2-furoic acid Chemical compound OC(=O)C1=CC=CO1 SMNDYUVBFMFKNZ-UHFFFAOYSA-N 0.000 description 1
- WLJVXDMOQOGPHL-PPJXEINESA-N 2-phenylacetic acid Chemical compound O[14C](=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-PPJXEINESA-N 0.000 description 1
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- SOXWRSSBCLIMRE-UHFFFAOYSA-N 2h-pyran-4-ylazanium;chloride Chemical compound Cl.NC1=CCOC=C1 SOXWRSSBCLIMRE-UHFFFAOYSA-N 0.000 description 1
- ZPTBUEKFZSYXBD-UHFFFAOYSA-N 3,4-dichloro-2-fluoroaniline Chemical compound NC1=CC=C(Cl)C(Cl)=C1F ZPTBUEKFZSYXBD-UHFFFAOYSA-N 0.000 description 1
- RQKFYFNZSHWXAW-UHFFFAOYSA-N 3-chloro-p-toluidine Chemical compound CC1=CC=C(N)C=C1Cl RQKFYFNZSHWXAW-UHFFFAOYSA-N 0.000 description 1
- SLDLVGFPFFLYBM-UHFFFAOYSA-N 3-fluoro-2-methyl-aniline Chemical compound CC1=C(N)C=CC=C1F SLDLVGFPFFLYBM-UHFFFAOYSA-N 0.000 description 1
- MGRHBBRSAFPBIN-UHFFFAOYSA-N 3-fluoro-4-methylaniline Chemical compound CC1=CC=C(N)C=C1F MGRHBBRSAFPBIN-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
- GGFXAVVXKLICCO-UHFFFAOYSA-N 4-[(2-chloro-5-nitropyrimidin-4-yl)amino]cyclohexane-1-carboxamide Chemical compound NC(=O)C1CCC(CC1)NC1=C(C=NC(Cl)=N1)[N+]([O-])=O GGFXAVVXKLICCO-UHFFFAOYSA-N 0.000 description 1
- KXMRDHPZQHAXML-UHFFFAOYSA-N 4-[(2-methylpropan-2-yl)oxycarbonylamino]cyclohexane-1-carboxylic acid Chemical compound CC(C)(C)OC(=O)NC1CCC(C(O)=O)CC1 KXMRDHPZQHAXML-UHFFFAOYSA-N 0.000 description 1
- BGLJCKPSSJKDJH-UHFFFAOYSA-N 4-amino-1-methylcyclohexane-1-carboxamide Chemical compound NC(=O)C1(C)CCC(N)CC1 BGLJCKPSSJKDJH-UHFFFAOYSA-N 0.000 description 1
- COFNCCWGWXFACE-UHFFFAOYSA-N 4-amino-3,5-dichlorobenzonitrile Chemical compound NC1=C(Cl)C=C(C#N)C=C1Cl COFNCCWGWXFACE-UHFFFAOYSA-N 0.000 description 1
- KVHGANXAAWNSFM-UHFFFAOYSA-N 4-amino-3,5-difluorobenzonitrile Chemical compound NC1=C(F)C=C(C#N)C=C1F KVHGANXAAWNSFM-UHFFFAOYSA-N 0.000 description 1
- OREVCMGFYSUYPX-UHFFFAOYSA-N 4-amino-3-chlorobenzonitrile Chemical compound NC1=CC=C(C#N)C=C1Cl OREVCMGFYSUYPX-UHFFFAOYSA-N 0.000 description 1
- RLMBRRQWBTWGMB-UHFFFAOYSA-N 4-amino-3-fluorobenzonitrile Chemical compound NC1=CC=C(C#N)C=C1F RLMBRRQWBTWGMB-UHFFFAOYSA-N 0.000 description 1
- IPNQNRNCZHLKTP-UHFFFAOYSA-N 4-aminocyclohexane-1-carboxamide;hydrochloride Chemical compound Cl.NC1CCC(C(N)=O)CC1 IPNQNRNCZHLKTP-UHFFFAOYSA-N 0.000 description 1
- AKDPHEYBBWDWCM-UHFFFAOYSA-N 4-chloro-2,6-difluoroaniline Chemical compound NC1=C(F)C=C(Cl)C=C1F AKDPHEYBBWDWCM-UHFFFAOYSA-N 0.000 description 1
- KMHLGVTVACLEJE-UHFFFAOYSA-N 4-fluoro-2-methylaniline Chemical compound CC1=CC(F)=CC=C1N KMHLGVTVACLEJE-UHFFFAOYSA-N 0.000 description 1
- JCYROOANFKVAIB-UHFFFAOYSA-N 5-chloro-2-fluoroaniline Chemical compound NC1=CC(Cl)=CC=C1F JCYROOANFKVAIB-UHFFFAOYSA-N 0.000 description 1
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- 229940125431 BRAF inhibitor Drugs 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- IEFANFNAUYZPFS-UHFFFAOYSA-N C1COCCC1NC2=NC=C3C(=N2)N=C(N3)NC4=C(C=C(C=C4F)F)F Chemical compound C1COCCC1NC2=NC=C3C(=N2)N=C(N3)NC4=C(C=C(C=C4F)F)F IEFANFNAUYZPFS-UHFFFAOYSA-N 0.000 description 1
- FCUTXIBNHBLEGB-UHFFFAOYSA-N C1COCCC1NC2=NC=C3C(=N2)N=C(N3)NC4=CC=C(C=C4)F Chemical compound C1COCCC1NC2=NC=C3C(=N2)N=C(N3)NC4=CC=C(C=C4)F FCUTXIBNHBLEGB-UHFFFAOYSA-N 0.000 description 1
- JGLMVXWAHNTPRF-CMDGGOBGSA-N CCN1N=C(C)C=C1C(=O)NC1=NC2=CC(=CC(OC)=C2N1C\C=C\CN1C(NC(=O)C2=CC(C)=NN2CC)=NC2=CC(=CC(OCCCN3CCOCC3)=C12)C(N)=O)C(N)=O Chemical compound CCN1N=C(C)C=C1C(=O)NC1=NC2=CC(=CC(OC)=C2N1C\C=C\CN1C(NC(=O)C2=CC(C)=NN2CC)=NC2=CC(=CC(OCCCN3CCOCC3)=C12)C(N)=O)C(N)=O JGLMVXWAHNTPRF-CMDGGOBGSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- OKTJSMMVPCPJKN-NJFSPNSNSA-N Carbon-14 Chemical compound [14C] OKTJSMMVPCPJKN-NJFSPNSNSA-N 0.000 description 1
- 241000700199 Cavia porcellus Species 0.000 description 1
- 238000003734 CellTiter-Glo Luminescent Cell Viability Assay Methods 0.000 description 1
- 241000282693 Cercopithecidae Species 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
- 241000207199 Citrus Species 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-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
- NOOLISFMXDJSKH-UHFFFAOYSA-N DL-menthol Natural products CC(C)C1CCC(C)CC1O NOOLISFMXDJSKH-UHFFFAOYSA-N 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
- 206010059866 Drug resistance Diseases 0.000 description 1
- 241000283073 Equus caballus Species 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 241000287828 Gallus gallus Species 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
- 239000004471 Glycine Substances 0.000 description 1
- 229920002907 Guar gum Polymers 0.000 description 1
- 241000282412 Homo Species 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
- 206010061218 Inflammation Diseases 0.000 description 1
- PIWKPBJCKXDKJR-UHFFFAOYSA-N Isoflurane Chemical compound FC(F)OC(Cl)C(F)(F)F PIWKPBJCKXDKJR-UHFFFAOYSA-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
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 239000012448 Lithium borohydride Substances 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- HSHXDCVZWHOWCS-UHFFFAOYSA-N N'-hexadecylthiophene-2-carbohydrazide Chemical compound CCCCCCCCCCCCCCCCNNC(=O)c1cccs1 HSHXDCVZWHOWCS-UHFFFAOYSA-N 0.000 description 1
- 125000000815 N-oxide group Chemical group 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 235000019502 Orange oil Nutrition 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 241000009328 Perro Species 0.000 description 1
- 241000286209 Phasianidae Species 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 239000006146 Roswell Park Memorial Institute medium Substances 0.000 description 1
- 238000011579 SCID mouse model Methods 0.000 description 1
- 208000000453 Skin Neoplasms Diseases 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- NINIDFKCEFEMDL-AKLPVKDBSA-N Sulfur-35 Chemical compound [35S] NINIDFKCEFEMDL-AKLPVKDBSA-N 0.000 description 1
- 241000282898 Sus scrofa 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
- YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- PNDPGZBMCMUPRI-XXSWNUTMSA-N [125I][125I] Chemical compound [125I][125I] PNDPGZBMCMUPRI-XXSWNUTMSA-N 0.000 description 1
- 238000010306 acid treatment Methods 0.000 description 1
- 125000000641 acridinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3C=C12)* 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 description 1
- 238000011374 additional therapy Methods 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 125000005426 adeninyl group Chemical group N1=C(N=C2N=CNC2=C1N)* 0.000 description 1
- GFFGJBXGBJISGV-UHFFFAOYSA-N adenyl group Chemical group N1=CN=C2N=CNC2=C1N GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 235000010419 agar Nutrition 0.000 description 1
- IAJILQKETJEXLJ-RSJOWCBRSA-N aldehydo-D-galacturonic acid Chemical compound O=C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)C(O)=O IAJILQKETJEXLJ-RSJOWCBRSA-N 0.000 description 1
- IAJILQKETJEXLJ-QTBDOELSSA-N aldehydo-D-glucuronic acid Chemical compound O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)C(O)=O IAJILQKETJEXLJ-QTBDOELSSA-N 0.000 description 1
- 229940072056 alginate Drugs 0.000 description 1
- 150000003973 alkyl amines Chemical group 0.000 description 1
- 125000005907 alkyl ester group Chemical group 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- CEGOLXSVJUTHNZ-UHFFFAOYSA-K aluminium tristearate Chemical compound [Al+3].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CEGOLXSVJUTHNZ-UHFFFAOYSA-K 0.000 description 1
- 229940063655 aluminum stearate Drugs 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 150000005018 aminopurines Chemical class 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 125000005428 anthryl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C3C(*)=C([H])C([H])=C([H])C3=C([H])C2=C1[H] 0.000 description 1
- 230000001028 anti-proliverative effect Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 235000015197 apple juice Nutrition 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 125000002102 aryl alkyloxo group Chemical group 0.000 description 1
- 125000004104 aryloxy group Chemical group 0.000 description 1
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 239000000440 bentonite Substances 0.000 description 1
- 229910000278 bentonite Inorganic materials 0.000 description 1
- 235000012216 bentonite Nutrition 0.000 description 1
- SVPXDRXYRYOSEX-UHFFFAOYSA-N bentoquatam Chemical compound O.O=[Si]=O.O=[Al]O[Al]=O SVPXDRXYRYOSEX-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
- 125000005605 benzo group Chemical group 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 125000005872 benzooxazolyl group Chemical group 0.000 description 1
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 1
- CUXWKMAACKAECM-UHFFFAOYSA-N benzyl n-(3,3-difluorocyclopentyl)carbamate Chemical compound C1C(F)(F)CCC1NC(=O)OCC1=CC=CC=C1 CUXWKMAACKAECM-UHFFFAOYSA-N 0.000 description 1
- 125000002619 bicyclic group Chemical group 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 101150048834 braF gene Proteins 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
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 235000010216 calcium carbonate Nutrition 0.000 description 1
- FNAQSUUGMSOBHW-UHFFFAOYSA-H calcium citrate Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O FNAQSUUGMSOBHW-UHFFFAOYSA-H 0.000 description 1
- 239000001354 calcium citrate Substances 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Inorganic materials [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 1
- 230000000711 cancerogenic effect Effects 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 150000001722 carbon compounds Chemical class 0.000 description 1
- 229910002091 carbon monoxide Inorganic materials 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 231100000504 carcinogenesis Toxicity 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000003729 cation exchange resin Substances 0.000 description 1
- 238000000423 cell based assay Methods 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 230000003833 cell viability Effects 0.000 description 1
- 238000012054 celltiter-glo Methods 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 229940068682 chewable tablet Drugs 0.000 description 1
- 125000000068 chlorophenyl group Chemical group 0.000 description 1
- VDANGULDQQJODZ-UHFFFAOYSA-N chloroprocaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1Cl VDANGULDQQJODZ-UHFFFAOYSA-N 0.000 description 1
- 229960002023 chloroprocaine Drugs 0.000 description 1
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 1
- 229960001231 choline Drugs 0.000 description 1
- 125000000259 cinnolinyl group Chemical group N1=NC(=CC2=CC=CC=C12)* 0.000 description 1
- 235000020971 citrus fruits Nutrition 0.000 description 1
- 239000004927 clay Substances 0.000 description 1
- 230000006552 constitutive activation Effects 0.000 description 1
- 239000012050 conventional carrier Substances 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 125000006165 cyclic alkyl group Chemical group 0.000 description 1
- 125000004367 cycloalkylaryl group Chemical group 0.000 description 1
- 125000003678 cyclohexadienyl group Chemical group C1(=CC=CCC1)* 0.000 description 1
- HPXRVTGHNJAIIH-UHFFFAOYSA-N cyclohexanol Chemical compound OC1CCCCC1 HPXRVTGHNJAIIH-UHFFFAOYSA-N 0.000 description 1
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 description 1
- PAFZNILMFXTMIY-UHFFFAOYSA-N cyclohexylamine Chemical group NC1CCCCC1 PAFZNILMFXTMIY-UHFFFAOYSA-N 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 239000000032 diagnostic agent Substances 0.000 description 1
- 229940039227 diagnostic agent Drugs 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 229940043237 diethanolamine Drugs 0.000 description 1
- 125000005433 dihydrobenzodioxinyl group Chemical group O1C(COC2=C1C=CC=C2)* 0.000 description 1
- 125000000723 dihydrobenzofuranyl group Chemical group O1C(CC2=C1C=CC=C2)* 0.000 description 1
- 125000001070 dihydroindolyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 description 1
- 125000004925 dihydropyridyl group Chemical group N1(CC=CC=C1)* 0.000 description 1
- 229940043279 diisopropylamine Drugs 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 125000000597 dioxinyl group Chemical group 0.000 description 1
- 238000007907 direct compression Methods 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 238000007908 dry granulation Methods 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 210000002615 epidermis Anatomy 0.000 description 1
- ZXYAWONOWHSQRU-UHFFFAOYSA-N ethyl 4-oxocyclohexanecarboxylate Chemical compound CCOC(=O)C1CCC(=O)CC1 ZXYAWONOWHSQRU-UHFFFAOYSA-N 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 125000006437 ethyl cyclopropyl group Chemical group 0.000 description 1
- 229940012017 ethylenediamine Drugs 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 235000013312 flour Nutrition 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 235000011389 fruit/vegetable juice Nutrition 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000000174 gluconic acid Substances 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 235000001727 glucose Nutrition 0.000 description 1
- 229940097043 glucuronic acid Drugs 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 235000010417 guar gum Nutrition 0.000 description 1
- 239000000665 guar gum Substances 0.000 description 1
- 229960002154 guar gum Drugs 0.000 description 1
- 229920000591 gum Polymers 0.000 description 1
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 1
- 125000005844 heterocyclyloxy group Chemical group 0.000 description 1
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 229960000443 hydrochloric acid Drugs 0.000 description 1
- 239000008172 hydrogenated vegetable oil Substances 0.000 description 1
- 239000001341 hydroxy propyl starch Substances 0.000 description 1
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 1
- 229920003063 hydroxymethyl cellulose Polymers 0.000 description 1
- 229940031574 hydroxymethyl cellulose Drugs 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- 235000013828 hydroxypropyl starch Nutrition 0.000 description 1
- 239000012216 imaging agent Substances 0.000 description 1
- GVONPBONFIJAHJ-UHFFFAOYSA-N imidazolidin-4-one Chemical compound O=C1CNCN1 GVONPBONFIJAHJ-UHFFFAOYSA-N 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000011503 in vivo imaging Methods 0.000 description 1
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 description 1
- 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 description 1
- 125000003406 indolizinyl group Chemical group C=1(C=CN2C=CC=CC12)* 0.000 description 1
- 230000004054 inflammatory process Effects 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
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 229940044173 iodine-125 Drugs 0.000 description 1
- 229960005386 ipilimumab Drugs 0.000 description 1
- 229940045996 isethionic acid Drugs 0.000 description 1
- IQPQWNKOIGAROB-UHFFFAOYSA-N isocyanate group Chemical group [N-]=C=O IQPQWNKOIGAROB-UHFFFAOYSA-N 0.000 description 1
- 229960002725 isoflurane Drugs 0.000 description 1
- 125000004594 isoindolinyl group Chemical group C1(NCC2=CC=CC=C12)* 0.000 description 1
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- GRHBQAYDJPGGLF-UHFFFAOYSA-N isothiocyanic acid Chemical compound N=C=S GRHBQAYDJPGGLF-UHFFFAOYSA-N 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 229960000448 lactic acid Drugs 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 1
- 230000004904 long-term response Effects 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 210000003141 lower extremity Anatomy 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229940098895 maleic acid Drugs 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 229940099690 malic acid Drugs 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 235000012054 meals Nutrition 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 229960003194 meglumine Drugs 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 229940041616 menthol Drugs 0.000 description 1
- 125000006431 methyl cyclopropyl group Chemical group 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 229960002216 methylparaben Drugs 0.000 description 1
- 239000003094 microcapsule Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- ACYBVNYNIZTUIL-UHFFFAOYSA-N n'-benzylethane-1,2-diamine Chemical compound NCCNCC1=CC=CC=C1 ACYBVNYNIZTUIL-UHFFFAOYSA-N 0.000 description 1
- VJPHAMJNGICSLT-UHFFFAOYSA-N n-methylcyclohexanecarboxamide Chemical compound CNC(=O)C1CCCCC1 VJPHAMJNGICSLT-UHFFFAOYSA-N 0.000 description 1
- 125000004593 naphthyridinyl group Chemical group N1=C(C=CC2=CC=CN=C12)* 0.000 description 1
- CMWTZPSULFXXJA-VIFPVBQESA-N naproxen Chemical group C1=C([C@H](C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-VIFPVBQESA-N 0.000 description 1
- 229920003052 natural elastomer Polymers 0.000 description 1
- 229920001194 natural rubber Polymers 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 230000010309 neoplastic transformation Effects 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 238000010899 nucleation Methods 0.000 description 1
- KPTCZURLWZSRKB-UHFFFAOYSA-N o-prop-2-enylhydroxylamine Chemical group NOCC=C KPTCZURLWZSRKB-UHFFFAOYSA-N 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 235000015205 orange juice Nutrition 0.000 description 1
- 239000010502 orange oil Substances 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- AHVQYHFYQWKUKB-UHFFFAOYSA-N oxan-4-amine Chemical compound NC1CCOCC1 AHVQYHFYQWKUKB-UHFFFAOYSA-N 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
- 239000011713 pantothenic acid Substances 0.000 description 1
- 229940055726 pantothenic acid Drugs 0.000 description 1
- 235000019161 pantothenic acid Nutrition 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
- 239000003182 parenteral nutrition solution Substances 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 239000002304 perfume Substances 0.000 description 1
- 235000019271 petrolatum Nutrition 0.000 description 1
- 229960004838 phosphoric acid Drugs 0.000 description 1
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 239000002952 polymeric resin Substances 0.000 description 1
- 229920006316 polyvinylpyrrolidine Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 229920003124 powdered cellulose Polymers 0.000 description 1
- 235000019814 powdered cellulose Nutrition 0.000 description 1
- 239000012254 powdered material Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 229940095574 propionic acid Drugs 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 229960003415 propylparaben Drugs 0.000 description 1
- 239000003223 protective agent Substances 0.000 description 1
- 238000000159 protein binding assay Methods 0.000 description 1
- 125000001042 pteridinyl group Chemical group N1=C(N=CC2=NC=CN=C12)* 0.000 description 1
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- 150000003217 pyrazoles Chemical class 0.000 description 1
- 125000002755 pyrazolinyl group Chemical group 0.000 description 1
- 125000001422 pyrrolinyl group Chemical group 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
- 230000002285 radioactive effect Effects 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 239000000565 sealant Substances 0.000 description 1
- 239000012363 selectfluor Substances 0.000 description 1
- 238000013207 serial dilution Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 201000000849 skin cancer Diseases 0.000 description 1
- 201000003708 skin melanoma Diseases 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 229960003885 sodium benzoate Drugs 0.000 description 1
- 229940001607 sodium bisulfite Drugs 0.000 description 1
- 229910001467 sodium calcium phosphate Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 235000010268 sodium methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 125000005346 substituted cycloalkyl group Chemical group 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 229950000244 sulfanilic acid Drugs 0.000 description 1
- 125000005420 sulfonamido group Chemical group S(=O)(=O)(N*)* 0.000 description 1
- 125000006296 sulfonyl amino group Chemical group [H]N(*)S(*)(=O)=O 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 229920003051 synthetic elastomer Polymers 0.000 description 1
- 229920003002 synthetic resin Polymers 0.000 description 1
- 239000005061 synthetic rubber Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 230000009897 systematic effect Effects 0.000 description 1
- 239000007916 tablet composition Substances 0.000 description 1
- 239000007885 tablet disintegrant Substances 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 238000003419 tautomerization reaction Methods 0.000 description 1
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 1
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000005888 tetrahydroindolyl group Chemical group 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- ZVQXQPNJHRNGID-UHFFFAOYSA-N tetramethylsuccinonitrile Chemical compound N#CC(C)(C)C(C)(C)C#N ZVQXQPNJHRNGID-UHFFFAOYSA-N 0.000 description 1
- 125000004305 thiazinyl group Chemical group S1NC(=CC=C1)* 0.000 description 1
- 125000002769 thiazolinyl group Chemical group 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 235000013337 tricalcium citrate Nutrition 0.000 description 1
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 230000004222 uncontrolled growth Effects 0.000 description 1
- 125000004417 unsaturated alkyl group Chemical group 0.000 description 1
- 231100000747 viability assay Toxicity 0.000 description 1
- 238000003026 viability measurement method Methods 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- NLVXSWCKKBEXTG-UHFFFAOYSA-N vinylsulfonic acid Chemical compound OS(=O)(=O)C=C NLVXSWCKKBEXTG-UHFFFAOYSA-N 0.000 description 1
- 238000005550 wet granulation Methods 0.000 description 1
- 239000003871 white petrolatum Substances 0.000 description 1
- 239000002023 wood Substances 0.000 description 1
- 229940034727 zelboraf Drugs 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
- A61K31/52—Purines, e.g. adenine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- 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
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/50—Three nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
- C07D473/32—Nitrogen atom
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
特定のアミノプリン化合物、有効量のそのような化合物を含む組成物、及びそれを必要とする対象に有効量のそのようなアミノプリン化合物化合物を投与することを含む、癌、例えば、メラノーマを治療又は予防する方法が本明細書に提供される。
メラノーマは、色素産生細胞(メラノサイト)の制御されない成長を特徴とする癌である。悪性メラノーマはメラノサイトの腫瘍性形質転換から発生するが、それは、表皮の基底層及び眼に圧倒的に存在する(Spagnolo Fらの文献(Archives of Dermatology Research, 2012, 304: 177-184);Hurst E Aらの文献(Archives of Dermatology Research, 2003, 139: 1067-1073))。悪性メラノーマは、最も攻撃的な形態の皮膚癌である。2014年に、皮膚のメラノーマの76,100の新症例があると推定されており、推定で9,710人がこの疾病で死亡するだろう(SEER Stat Fact Sheets: Melanoma of the Skin, Surveillance Epidemiology and End Results Program, 2014年6月2日にhttp://seer.cancer.gov/statfacts/html/melan.htmlにアクセスされた)。
以下の式(I)を有する化合物:
(定義)
「アルキル」基は、1〜10個の炭素原子、典型的には、1〜8個の炭素、又はいくつかの実施態様においては、1〜6個、1〜4個、若しくは2〜6個の炭素原子を有する、飽和した、部分的に飽和した、又は不飽和の直鎖又は分岐状非環式炭化水素である。代表的なアルキル基としては、-メチル、-エチル、-n-プロピル、-n-ブチル、-n-ペンチル、及び-n-ヘキシルが挙げられ;一方、飽和分岐アルキルとしては、-イソプロピル、-sec-ブチル、-イソブチル、-tert-ブチル、-イソペンチル、-ネオペンチル、tert-ペンチル、-2-メチルペンチル、-3-メチルペンチル、-4-メチルペンチル、-2,3-ジメチルブチルなどが挙げられる。不飽和アルキル基の例としては、特に、ビニル、アリル、-CH=CH(CH3)、-CH=C(CH3)2、-C(CH3)=CH2、-C(CH3)=CH(CH3)、-C(CH2CH3)=CH2、-C≡CH、-C≡C(CH3)、-C≡C(CH2CH3)、-CH2C≡CH、-CH2C≡C(CH3)、及び-CH2C≡C(CH2CH3)が挙げられるが、これらに限定されない。アルキル基は、置換されていても、置換されていなくてもよい。本明細書に記載のアルキル基が「置換されている」と言われるとき、それらは、本明細書に開示される例示的な化合物及び実施態様に見られるもの、並びにハロゲン(クロロ、ヨード、ブロモ、若しくはフルオロ);アルキル;ヒドロキシル;アルコキシ;アルコキシアルキル;アミノ;アルキルアミノ;カルボキシ;ニトロ;シアノ;チオール;チオエーテル;イミン;イミド;アミジン;グアニジン;エナミン;アミノカルボニル;アシルアミノ;ホスホネート;ホスフィン;チオカルボニル;スルフィニル;スルホン;スルホンアミド;ケトン;アルデヒド;エステル;ウレア;ウレタン;オキシム;ヒドロキシルアミン;アルコキシアミン;アリールオキシアミン、アラルコキシアミン;N-オキシド;ヒドラジン;ヒドラジド;ヒドラゾン;アジド;イソシアネート;イソチオシアネート;シアネート;チオシアネート;B(OH)2、又はO(アルキル)アミノカルボニルのような、任意の置換基(単数)又は置換基(複数)で置換されていてもよい。
以下の式(I)を有する化合物:
(式中、
R1は、置換若しくは非置換のC1-8アルキル、置換若しくは非置換のシクロアルキル、置換若しくは非置換のシクロアルキルアルキル、又は置換若しくは非置換の非芳香族ヘテロシクリルであり;
R2は、H又は置換若しくは非置換のC1-3アルキルであり;
R3は、1つ以上のハロゲンにより置換され、置換又は非置換のC1-3アルキル、CN、及び-OR'から独立に選択される1つ以上の置換基により任意にさらに置換されたフェニルであり(式中、各R'は、独立に、置換又は非置換のC1-3アルキルである);
但し、該化合物が、4-[2-[(1-メチルエチル)アミノ]-8-[(2,4,6-トリフルオロフェニル)アミノ]-9H-プリン-9-イル]-シス-シクロヘキサンカルボキサミド
(式中、
各R1aは、独立に、F、OH、OCH3、SO2CH3、又はメチルであり;
R1bは、H又はCH3であり;
且つ、aは0〜4である)。
(式中、各R1cは、独立に、F、OH、メチル、又はCH2OHであり;
且つ、cは0〜3である)。
(式中、
各Halは、独立に、ハロゲンであり;
各R8は、独立に、置換又は非置換のC1-3アルキル、CN、又はOR'であり;
各R'は、独立に、置換又は非置換のC1-3アルキルであり;
mは、1〜3であり;
且つ、pは、0〜2である)。
アミノプリン化合物は、従来の有機合成及び市販の出発物質を利用して合成できる。限定ではなく例として、式(I)のアミノプリン化合物は、米国特許第7,723,340号及び米国特許第8,158,635号に記載の通り、又は以下に示されるスキーム1に略述される通り、並びに本明細書に述べられる実施例にある通り製造できる。当業者であれば、説明的なスキーム及び実施例に述べられる手順を改変して所望の生成物に到達する方法を知っているだろうことに留意されたい。
(式中、R1は、置換若しくは非置換のC1-8アルキル、置換若しくは非置換のシクロアルキル、置換若しくは非置換のシクロアルキルアルキル、又は置換若しくは非置換の非芳香族ヘテロシクリルであり;
R2は、H又は置換若しくは非置換のC1-3アルキルであり;
R3は、1つ以上のハロゲンにより置換されており、置換又は非置換のC1-3アルキル、CN、及び-OR'から選択される1つ以上の置換基により任意にさらに置換されているフェニルである(式中、各R'は、独立に、置換又は非置換のC1-3アルキルである))。
(式中、
R1は、置換若しくは非置換のC1-8アルキル、置換若しくは非置換のシクロアルキル、置換若しくは非置換のシクロアルキルアルキル、又は置換若しくは非置換の非芳香族ヘテロシクリルであり;
R2は、H又は置換若しくは非置換のC1-3アルキルであり;
R3は、1つ以上のハロゲンにより置換されており、置換又は非置換のC1-3アルキル、CN、及び-OR'から選択される1つ以上の置換基により任意にさらに置換されているフェニルである(式中、各R'は、独立に、置換又は非置換のC1-3アルキルである))。
(式中、R1は、置換若しくは非置換のC1-8アルキル、置換若しくは非置換のシクロアルキル、置換若しくは非置換のシクロアルキルアルキル、又は置換若しくは非置換の非芳香族ヘテロシクリルであり;
R2は、H又は置換若しくは非置換のC1-3アルキルであり;
R3は、1つ以上のハロゲンにより置換されており、置換又は非置換のC1-3アルキル、CN、及び-OR'から選択される1つ以上の置換基により任意にさらに置換されているフェニルであり(式中、各R'は、独立に、置換又は非置換のC1-3アルキルである);且つ
Pは樹脂である)。
アミノプリン化合物は、動物又はヒトの病態を治療、予防、又は改善する医薬として有用である。したがって、本明細書に提供されるものは、本明細書に提供される全方法に利用できる。特に、本明細書に提供されるアミノプリン化合物は、メラノーマの治療又は予防に使用するためのものである。本明細書に提供される方法は、有効量の1種以上のアミノプリン化合物(複数可)のそれを必要とする対象への投与を含む。
アミノプリン化合物は、経口的、局所的、又は非経口的に、カプセル剤、マイクロカプセル剤、錠剤、顆粒剤、散剤、トローチ剤、丸剤、坐剤、注射剤、懸濁剤、シロップ剤、パッチ剤、クリーム剤、ローション剤、軟膏剤、ゲル剤、スプレー剤、液剤、及び乳剤などの従来の製剤形態で、対象に投与することができる。好適な製剤は、従来の有機又は無機添加物、例えば、賦形剤(例えば、スクロース、デンプン、マンニトール、ソルビトール、ラクトース、グルコース、セルロース、タルク、リン酸カルシウム、又は炭酸カルシウム)、結合剤(例えば、セルロース、メチルセルロース、ヒドロキシメチルセルロース、ポリプロピルピロリドン、ポリビニルピロリドン、ゼラチン、アラビアゴム、ポリエチレングリコール、スクロース、又はデンプン)、崩壊剤(例えば、デンプン、カルボキシメチルセルロース、ヒドロキシプロピルデンプン、低置換ヒドロキシプロピルセルロース、炭酸水素ナトリウム、リン酸カルシウム、又はクエン酸カルシウム)、滑沢剤(例えば、ステアリン酸マグネシウム、軽質無水ケイ酸、タルク、又はラウリル硫酸ナトリウム)、香味剤(例えば、クエン酸、メントール、グリシン、又はオレンジパウダー)、防腐剤(例えば、安息香酸ナトリウム、重亜硫酸ナトリウム、メチルパラベン、又はプロピルパラベン)、安定化剤(例えば、クエン酸、クエン酸ナトリウム、又は酢酸)、懸濁化剤(例えば、メチルセルロース、ポリビニルピロリクロン(pyrroliclone)、又はステアリン酸アルミニウム)、分散剤(例えば、ヒドロキシプロピルメチルセルロース)、希釈剤(例えば、水)、及びベースワックス(例えば、カカオバター、白色ワセリン、又はポリエチレングリコール)を用いて、一般に利用される方法によって製造することができる。医薬組成物中のアミノプリン化合物の有効量は、所望の効果を発揮するであろうレベル;例えば、経口投与と非経口投与の両方についての単位投薬量で対象の体重1kg当たり約0.005mgから対象の体重1kg当たり約10mgであり得る。
(実施例1.(1s,4s)-4-(8-((4-クロロ-2,6-ジフルオロフェニル)アミノ)-2-((テトラヒドロ-2H-ピラン-4-イル)アミノ)-9H-プリン-9-イル)シクロヘキサン-1-カルボキサミド)
(細胞アッセイ)
アミノプリン化合物の成長阻害作用の決定。Lox-IMVIメラノーマ細胞株(入手源:NCI-DCTD、カタログ番号0507283)をRPMI+10% FBS中で維持し、試験した。細胞株の播種密度を最適化して、384-ウェルプレートにおけるアッセイの直線性を確実にした。
y=(A+((B-A)/(1+((C/x)^D))))
式中
A=YMin
B=YMax
C=EC50
D=ヒル勾配
IC50は、Y=DMSO対照の50%である場合の化合物濃度である
Y=蛍光単位
(異種移植片モデル)。異種移植片モデル試験のために、ヒトメラノーマ癌細胞株を、SCID(重症複合型免疫不全症)マウスに注射した。癌細胞株を、インビトロで培養して増殖させた。精密に決定された数の細胞をマウスに注射することにより、担癌動物を発生させた。動物の接種後に、腫瘍を、無作為化の前に特定の大きさまで成長させた。所定の大きさの範囲である異種移植片腫瘍を有するマウスを共に集め、種々の治療群に無作為化した。典型的な有効性試験設計は、種々の用量段階の1種以上の化合物を坦癌マウスに投与することを含む。さらに、基準化学療法剤(陽性対照)及び陰性対照を同様に投与し、維持した。腫瘍測定値及び体重を、試験の期間にわたり測定した。
表1中の化合物のそれぞれを、アッセイの1つ以上で試験し、その中で活性を有することが見出されたが、細胞系アッセイにおいて全ての化合物が10μM未満のIC50を有し、いくつかの化合物は1μMを超えるIC50を(活性レベルA)、いくつかの化合物は500nMから1μMのIC50を(活性レベルB)、いくつかの化合物を250nMから500nMのIC50を(活性レベルC)、及び他の化合物は250nM未満のIC50を(活性レベルD)有する。
Claims (47)
- 式(I)の化合物:
(式中、
R1は、置換若しくは非置換のC1-8アルキル、置換若しくは非置換のシクロアルキル、置換若しくは非置換のシクロアルキルアルキル、又は置換若しくは非置換の非芳香族ヘテロシクリルであり;
R2は、H又は置換若しくは非置換のC1-3アルキルであり;
R3は、1つ以上のハロゲンにより置換され、置換又は非置換のC1-3アルキル、CN、及び-OR'から独立に選択される1つ以上の置換基により任意にさらに置換されたフェニルであり(式中、各R'は、独立に、置換又は非置換のC1-3アルキルである);
但し、該化合物が
4-[2-[(1-メチルエチル)アミノ]-8-[(2,4,6-トリフルオロフェニル)アミノ]-9H-プリン-9-イル]-シス-シクロヘキサンカルボキサミド、又は
4-[8-[(2,4-ジフルオロフェニル)アミノ]-2-[(トランス-4-ヒドロキシシクロヘキシル)アミノ]-9H-プリン-9-イル]-シス-シクロヘキサンカルボキサミド
でないことを条件とする)。 - R1が置換又は非置換のC1-8アルキルである、請求項1記載の化合物。
- R1が、置換若しくは非置換のメチル、エチル、n-プロピル、イソプロピル、n-ブチル、sec-ブチル、イソブチル、tert-ブチル、n-ペンチル、2-メチルペンチル、3-メチルペンチル、イソペンチル、又はネオペンチルである、請求項2記載の化合物。
- R1が、ハロゲン及びORから独立に選択される1つ以上の置換基により置換されており、各Rが、独立に、H又は置換若しくは非置換のC1-3アルキルである、請求項2記載の化合物。
- R1が、F、OH、及びOCH3から独立に選択される1つ以上の置換基により置換されている、請求項2記載の化合物。
- R1が、エチル、イソプロピル、イソブチル、tert-ブチル、CH2CH2F、CH2CHF2、CH2CF3、CH2CH(CH3)OH、CH2CH(CH3)OCH3、CH(CH3)CH2OH、CH(CH3)CH2OCH3、CH2C(F2)CH2OH、CH2C(F2)CH2OCH3、CH(CF3)CH2OH、CH(CF3)CH2OCH3、CH(CH2OH)CH2CH3、CH(CH2OCH3)CH2CH3、CH2C(CH3)2CH2OH、又はCH2C(CH3)2CH2OCH3である、請求項2記載の化合物。
- R1が、イソプロピル、イソブチル、tert-ブチル、CH2CF3、CH2CH(CH3)OH、CH(CH3)CH2OH、CH(CH3)CH2OCH3、CH2C(F2)CH2OH、CH(CF3)CH2OH、CH(CH2OH)CH2CH3、又はCH2C(CH3)2CH2OHである、請求項2記載の化合物。
- R1が、置換又は非置換のシクロアルキルである、請求項1記載の化合物。
- R1が、置換若しくは非置換のシクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル、又はシクロヘプチルである、請求項8記載の化合物。
- R1が、ハロゲン、OR、SO2R'、置換又は非置換のC1-3アルキル、及び置換又は非置換のヘテロシクリルから独立に選択される1つ以上の置換基により置換されており、各Rが、独立に、H又は置換若しくは非置換のC1-3アルキルであり、各R'が、独立に、置換又は非置換のC1-3アルキルである、請求項8記載の化合物。
- R1が、F、OH、OCH3、SO2CH3、メチル、及び置換又は非置換の5員ヘテロシクリルから独立に選択される1つ以上の置換基により置換されている、請求項8記載の化合物。
- 前記5員ヘテロシクリル(heterocylyl)が、ピロリジンジオニル、又はオキサジアゾリルである、請求項11記載の化合物。
- R1が、F、OH、OCH3、SO2CH3、メチル、ピロリジンジオニル、及びオキサジアゾリルから独立に選択される1つ以上の置換基により任意に置換されているシクロブチル、シクロペンチル、シクロヘキシル、又はシクロヘプチルである、請求項8記載の化合物。
- R1が、置換又は非置換のシクロアルキルアルキルである、請求項1記載の化合物。
- R1が、置換又は非置換の(C1-3アルキル)-(C1-8シクロアルキル)である、請求項14記載の化合物。
- R1が、置換若しくは非置換のCH2-シクロプロピル、CH2-シクロブチル、CH2-シクロペンチル、CH2-シクロヘキシル、又はCH2-シクロヘプチルである、請求項14記載の化合物。
- R1が、(C1-3アルキル)OR又はORから独立に選択される1つ以上の置換基により置換されており、各Rが、独立に、H又は置換若しくは非置換のC1-3アルキルである、請求項14記載の化合物。
- R1が、1つ以上のCH2OH又はOHにより任意に置換されているCH2-シクロプロピル、CH2-シクロブチル、CH2-シクロペンチル、又はCH2-シクロヘキシルである、請求項14記載の化合物。
- R1が、置換又は非置換の非芳香族ヘテロシクリルである、請求項1記載の化合物。
- R1が、置換若しくは非置換のオキセタニル、テトラヒドロフラニル、テトラヒドロピラニル、テトラヒドロ-チオピランジオキシド、ピペリジル、オキセパニル、又はオキサスピロヘプチルである、請求項19記載の化合物。
- R1が、ハロゲン、OR、SO2R4、C(=O)R5、C(=O)OR6、C(=O)NRR7、置換又は非置換のC1-3アルキル、置換又は非置換のアリール、置換又は非置換のヘテロアリール、置換又は非置換の又はアルキルアリールから独立に選択される1つ以上の置換基により置換されており(式中、各Rは、独立に、H又は置換若しくは非置換のC1-3アルキルである);R4が、置換若しくは非置換のC1-3アルキル、又は置換若しくは非置換のアリールであり;R5が、置換又は非置換のC1-3アルキルであり;R6が、置換又は非置換のC1-6アルキルであり;且つ、R7が、置換若しくは非置換のC1-3アルキル、又は置換若しくは非置換のアリールである、請求項19記載の化合物。
- R1が、F、OH、SO2CH3、SO2-トシル、C(=O)CH3、C(=O)OCH3、C(=O)O-tert-ブチル、C(=O)O-イソプロピル、C(=O)NHCH3、C(=O)NH-フェニル、メチル、エチル、イソプロピル、CH2OH、フェニル、ピリジル、又はベンジルから独立に選択される1つ以上の置換基により任意に置換されているオキセタニル、テトラヒドロフラニル、テトラヒドロピラニル、テトラヒドロ-チオピランジオキシド、ピペリジル、オキセパニル、又はオキサスピロヘプチルである、請求項19記載の化合物。
- R2がHである、請求項1記載の化合物。
- R2がCH3である、請求項1記載の化合物。
- R3が、オルト-ハロゲン置換フェニルである、請求項1記載の化合物。
- R3が、パラ-ハロゲン置換フェニルである、請求項1記載の化合物。
- R3が、パラ-CN置換フェニルである、請求項1記載の化合物。
- R3が、オルト、オルト-ジハロゲン置換フェニルである、請求項1記載の化合物。
- R3が、オルト、パラ-ジハロゲン置換フェニルである、請求項1記載の化合物。
- R3が、2,4,6-トリハロゲン置換フェニルである、請求項1記載の化合物。
- R3が、オルト-ハロゲン、パラ-CN置換フェニルである、請求項1記載の化合物。
- 各Halが、独立に、Cl又はFである、請求項32記載の化合物。
- 各R8が、独立に、CH3、CF3、CN、又はOCH3である、請求項32記載の化合物。
- mが2又は3である、請求項32記載の化合物。
- pが0又は1である、請求項32記載の化合物。
- 各Halが、独立に、F又はClである、請求項37記載の化合物。
- 前記化合物が、表1、並びにその医薬として許容し得る塩、互変異性体、立体異性体、エナンチオマー、及びアイソトポログから選択される、請求項1記載の化合物。
- 10μMの濃度の前記化合物が、メラノーマ細胞増殖を、少なくとも約50%阻害する、請求項1記載の化合物。
- 有効量の請求項1又は請求項39記載の化合物及び医薬として許容し得る担体、賦形剤又はビヒクルを含む医薬組成物。
- キナーゼを発現している細胞中の該キナーゼを阻害する方法であって、該細胞を、有効量の請求項1又は請求項39記載の化合物と接触させることを含む方法。
- キナーゼを発現している細胞中の該キナーゼを阻害するインビトロ方法であって、該細胞を、有効量の請求項1又は請求項39記載の化合物と接触させることを含む方法。
- キナーゼを発現している細胞中の該キナーゼを阻害するエクスビボ方法であって、該細胞を、有効量の請求項1又は請求項39記載の化合物と接触させることを含む方法。
- キナーゼを発現している細胞中の該キナーゼを阻害する方法であって、該細胞を、有効量の前記化合物と接触させることを含む方法に使用するための請求項1〜39のいずれか一項記載の化合物。
- メラノーマの治療又は予防の方法であって、それを必要とする対象に、有効量の請求項1又は請求項39記載の化合物を投与することを含む方法。
- メラノーマの治療又は予防の方法であって、それを必要とする対象に、有効量の前記化合物を投与することを含む方法に使用するための、請求項1〜39のいずれか一項記載の化合物。
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2019182133A JP6987823B2 (ja) | 2014-10-06 | 2019-10-02 | 置換アミノプリン化合物、その組成物、及びそれによる治療の方法 |
JP2021195105A JP7196270B2 (ja) | 2014-10-06 | 2021-12-01 | 置換アミノプリン化合物、その組成物、及びそれによる治療の方法 |
JP2022199122A JP2023027269A (ja) | 2014-10-06 | 2022-12-14 | 置換アミノプリン化合物、その組成物、及びそれによる治療の方法 |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201462060339P | 2014-10-06 | 2014-10-06 | |
US62/060,339 | 2014-10-06 | ||
PCT/US2015/053941 WO2016057370A1 (en) | 2014-10-06 | 2015-10-05 | Substituted aminopurine compounds, compositions thereof, and methods of treatment therewith |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2019182133A Division JP6987823B2 (ja) | 2014-10-06 | 2019-10-02 | 置換アミノプリン化合物、その組成物、及びそれによる治療の方法 |
Publications (3)
Publication Number | Publication Date |
---|---|
JP2017530199A true JP2017530199A (ja) | 2017-10-12 |
JP2017530199A5 JP2017530199A5 (ja) | 2018-11-15 |
JP6884701B2 JP6884701B2 (ja) | 2021-06-09 |
Family
ID=55632334
Family Applications (4)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2017538172A Active JP6884701B2 (ja) | 2014-10-06 | 2015-10-05 | 置換アミノプリン化合物、その組成物、及びそれによる治療の方法 |
JP2019182133A Active JP6987823B2 (ja) | 2014-10-06 | 2019-10-02 | 置換アミノプリン化合物、その組成物、及びそれによる治療の方法 |
JP2021195105A Active JP7196270B2 (ja) | 2014-10-06 | 2021-12-01 | 置換アミノプリン化合物、その組成物、及びそれによる治療の方法 |
JP2022199122A Pending JP2023027269A (ja) | 2014-10-06 | 2022-12-14 | 置換アミノプリン化合物、その組成物、及びそれによる治療の方法 |
Family Applications After (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2019182133A Active JP6987823B2 (ja) | 2014-10-06 | 2019-10-02 | 置換アミノプリン化合物、その組成物、及びそれによる治療の方法 |
JP2021195105A Active JP7196270B2 (ja) | 2014-10-06 | 2021-12-01 | 置換アミノプリン化合物、その組成物、及びそれによる治療の方法 |
JP2022199122A Pending JP2023027269A (ja) | 2014-10-06 | 2022-12-14 | 置換アミノプリン化合物、その組成物、及びそれによる治療の方法 |
Country Status (28)
Country | Link |
---|---|
US (8) | US9512124B2 (ja) |
EP (2) | EP3204386B1 (ja) |
JP (4) | JP6884701B2 (ja) |
KR (2) | KR102504849B1 (ja) |
CN (2) | CN107001372B (ja) |
AR (1) | AR102171A1 (ja) |
AU (2) | AU2015328414B2 (ja) |
CA (1) | CA2963639C (ja) |
CL (1) | CL2017000820A1 (ja) |
CO (1) | CO2017003838A2 (ja) |
CY (1) | CY1124173T1 (ja) |
DK (1) | DK3204386T3 (ja) |
EA (1) | EA201790779A1 (ja) |
EC (1) | ECSP17026210A (ja) |
ES (1) | ES2871142T3 (ja) |
HR (1) | HRP20210656T1 (ja) |
HU (1) | HUE054694T2 (ja) |
IL (2) | IL251566B (ja) |
LT (1) | LT3204386T (ja) |
MX (2) | MX2017004600A (ja) |
NZ (2) | NZ767954A (ja) |
PL (1) | PL3204386T3 (ja) |
PT (1) | PT3204386T (ja) |
RS (1) | RS61884B1 (ja) |
SG (2) | SG11201702759XA (ja) |
SI (1) | SI3204386T1 (ja) |
TW (1) | TW201629063A (ja) |
WO (1) | WO2016057370A1 (ja) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2019515889A (ja) * | 2016-04-01 | 2019-06-13 | シグナル ファーマシューティカルズ,エルエルシー | (1s,4s)−4−(2−(((3s,4r)−3−フルオロテトラヒドロ−2h−ピラン−4−イル)アミノ)−8−((2,4,6−トリクロロフェニル)アミノ)−9h−プリン−9−イル)−1−メチルクロロヘキサン−1−カルボキサミドの固体形態及びその使用方法 |
Families Citing this family (15)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA2963639C (en) * | 2014-10-06 | 2023-07-04 | Signal Pharmaceuticals, Llc | Substituted aminopurine compounds, compositions thereof, and methods of treatment therewith |
ES2882954T3 (es) | 2014-12-16 | 2021-12-03 | Signal Pharm Llc | Usos médicos que comprenden métodos para la medición de la inhibición de la quinasa c-Jun N-terminal en la piel |
US20180022710A1 (en) | 2015-01-29 | 2018-01-25 | Signal Pharmaceuticals, Llc | Isotopologues of 2-(tert-butylamino)-4-((1r,3r,4r)-3-hydroxy-4-methylcyclohexylamino)-pyrimidine-5-carboxamide |
MX2017011433A (es) | 2015-03-18 | 2017-11-10 | Bristol Myers Squibb Co | Compuestos heterociclicos triciclicos utiles como inhibidores del factor de necrosis tumoral (tnf). |
KR102654709B1 (ko) | 2015-03-18 | 2024-04-03 | 브리스톨-마이어스 스큅 컴퍼니 | 치환된 트리시클릭 헤테로시클릭 화합물 |
CN107567450B (zh) | 2015-03-18 | 2020-03-13 | 百时美施贵宝公司 | 用作tnf抑制剂的杂环化合物 |
CA3208587A1 (en) | 2015-07-24 | 2017-02-02 | Celgene Corporation | Methods of synthesis of (1r,2r,5r)-5-amino-2-methylcyclohexanol hydrochloride and intermediates useful therein |
BR112018001980A2 (pt) | 2015-08-03 | 2018-09-18 | Bristol Myers Squibb Co | compostos cíclicos úteis como moduladores de tnf alfa |
EA039392B1 (ru) | 2016-04-01 | 2022-01-21 | СИГНАЛ ФАРМАСЬЮТИКАЛЗ, ЭлЭлСи | Способ лечения рака с применением замещенного аминопуринового соединения |
JP6949057B2 (ja) * | 2016-06-02 | 2021-10-13 | セルジーン コーポレイション | 動物及びヒトの抗トリパノソーマならびに抗リーシュマニア薬 |
CN109563095B (zh) * | 2016-06-02 | 2021-10-29 | 细胞基因公司 | 动物和人抗疟剂 |
WO2019070827A1 (en) | 2017-10-04 | 2019-04-11 | Celgene Corporation | PROCESSES FOR THE PREPARATION OF CIS-4 [2 - {(3S, 4R) -3-FLUOROOXAN-4-YL] AMINO) -8- (2,4,6-TRICHLOROANILINO) -9H-PURIN-9-YL] -1 -MÉTHYLCYCLOHEXANE-1-carboxamide |
BR112020006599B1 (pt) | 2017-10-04 | 2024-02-20 | Celgene Corporation | Cápsulas compreendendo cis-4-[2-{[(3s,4r)-3-fluoro-oxan-4-il]amino}-8-(2,4,6-tricl oroanilino)-9h-purin-9-il]-1-metilciclohexano-1-carb oxamida |
CN115916747A (zh) * | 2020-07-01 | 2023-04-04 | 四川海思科制药有限公司 | 一种并环杂环衍生物及其在医药上的应用 |
CN114478326B (zh) * | 2022-01-21 | 2023-10-03 | 安徽宁亿泰科技有限公司 | 一种苯嘧磺草胺关键中间体的合成方法 |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2008526989A (ja) * | 2005-01-13 | 2008-07-24 | シグナル ファーマシューティカルズ,エルエルシー | ハロアリール置換アミノプリン、その組成物、およびそれによる治療の方法 |
Family Cites Families (17)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
IL99699A (en) | 1990-10-10 | 2002-04-21 | Autoimmune Inc | Drug with the option of oral, intra-intestinal, or inhaled dosing for suppression of autoimmune response associated with type I diabetes |
FI109088B (fi) | 1997-09-19 | 2002-05-31 | Leiras Oy | Tabletti ja menetelmä sen valmistamiseksi |
CZ27399A3 (cs) * | 1999-01-26 | 2000-08-16 | Ústav Experimentální Botaniky Av Čr | Substituované dusíkaté heterocyklické deriváty, způsob jejich přípravy, tyto deriváty pro použití jako léčiva, farmaceutická kompozice a kombinovaný farmaceutický přípravek tyto deriváty obsahující a použití těchto derivátů pro výrobu léčiv |
US7672705B2 (en) * | 2004-07-19 | 2010-03-02 | Resonant Medical, Inc. | Weighted surface-to-surface mapping |
US7521446B2 (en) | 2005-01-13 | 2009-04-21 | Signal Pharmaceuticals, Llc | Haloaryl substituted aminopurines, compositions thereof, and methods of treatment therewith |
US7759342B2 (en) | 2005-01-13 | 2010-07-20 | Signal Pharmaceuticals, Llc | Methods of treatment and prevention using haloaryl substituted aminopurines |
US20090215744A1 (en) | 2005-11-18 | 2009-08-27 | Astrazeneca Ab | Solid Formulations |
TWI398252B (zh) | 2006-05-26 | 2013-06-11 | Novartis Ag | 吡咯并嘧啶化合物及其用途 |
AU2007318132B2 (en) | 2006-10-27 | 2012-11-08 | Signal Pharmaceuticals, Llc | Solid forms comprising 4-[9-(tetrahydro-furan-3-yl)-8-(2,4,6-trifluoro-phenylamino)-9H-purin-2-ylamino]-cyclohexan-1-ol, compositions thereof, and use therewith |
WO2009130342A1 (es) | 2008-04-23 | 2009-10-29 | Farmasierra Manufacturing, S.L. | Formulación farmacéutica mejorada a base de ibuprofeno y codeína |
WO2011071491A1 (en) | 2009-12-09 | 2011-06-16 | Signal Pharmaceuticals, Llc | Isotopologues of 4-[9-(tetrahydro-furan-3-yl)-8-(2, 4, 6- trifluoro-phenylamino)-9h-purin-2-ylamino]-cyclohexan-1-ol |
US8680076B2 (en) * | 2010-10-25 | 2014-03-25 | Signal Pharmaceuticals, Llc | Methods of treatment, improvement and prevention using haloaryl substituted aminopurines |
US8603527B2 (en) | 2010-10-25 | 2013-12-10 | Signal Pharmaceuticals, Llc | Pharmaceutical formulations of a substituted diaminopurine |
WO2014172616A2 (en) | 2013-04-18 | 2014-10-23 | President And Fellows Of Harvard College | Methods, compositions and kits for promoting motor neuron survival and treating and diagnosing neurodegenerative disorders |
GB201321737D0 (en) | 2013-12-09 | 2014-01-22 | Ucb Pharma Sa | Therapeutic Agents |
CA2963639C (en) * | 2014-10-06 | 2023-07-04 | Signal Pharmaceuticals, Llc | Substituted aminopurine compounds, compositions thereof, and methods of treatment therewith |
CN109819649B (zh) | 2016-04-01 | 2023-02-28 | 西格诺药品有限公司 | 氨基嘌呤化合物的固体形式及其使用方法 |
-
2015
- 2015-10-05 CA CA2963639A patent/CA2963639C/en active Active
- 2015-10-05 LT LTEP15848476.6T patent/LT3204386T/lt unknown
- 2015-10-05 ES ES15848476T patent/ES2871142T3/es active Active
- 2015-10-05 HU HUE15848476A patent/HUE054694T2/hu unknown
- 2015-10-05 DK DK15848476.6T patent/DK3204386T3/da active
- 2015-10-05 RS RS20210632A patent/RS61884B1/sr unknown
- 2015-10-05 KR KR1020177010551A patent/KR102504849B1/ko active IP Right Grant
- 2015-10-05 CN CN201580065272.2A patent/CN107001372B/zh active Active
- 2015-10-05 TW TW104132732A patent/TW201629063A/zh unknown
- 2015-10-05 US US14/874,513 patent/US9512124B2/en active Active
- 2015-10-05 AR ARP150103202A patent/AR102171A1/es not_active Application Discontinuation
- 2015-10-05 PL PL15848476T patent/PL3204386T3/pl unknown
- 2015-10-05 EP EP15848476.6A patent/EP3204386B1/en active Active
- 2015-10-05 SG SG11201702759XA patent/SG11201702759XA/en unknown
- 2015-10-05 NZ NZ767954A patent/NZ767954A/en unknown
- 2015-10-05 SI SI201531584T patent/SI3204386T1/sl unknown
- 2015-10-05 KR KR1020237006598A patent/KR20230035424A/ko active Application Filing
- 2015-10-05 NZ NZ730753A patent/NZ730753A/en unknown
- 2015-10-05 SG SG10202009598VA patent/SG10202009598VA/en unknown
- 2015-10-05 WO PCT/US2015/053941 patent/WO2016057370A1/en active Application Filing
- 2015-10-05 PT PT158484766T patent/PT3204386T/pt unknown
- 2015-10-05 MX MX2017004600A patent/MX2017004600A/es unknown
- 2015-10-05 CN CN202110381676.XA patent/CN113248506A/zh active Pending
- 2015-10-05 JP JP2017538172A patent/JP6884701B2/ja active Active
- 2015-10-05 AU AU2015328414A patent/AU2015328414B2/en active Active
- 2015-10-05 EP EP20214685.8A patent/EP3822274B1/en active Active
- 2015-10-05 EA EA201790779A patent/EA201790779A1/ru unknown
-
2016
- 2016-10-27 US US15/335,619 patent/US9737541B2/en active Active
-
2017
- 2017-04-04 IL IL251566A patent/IL251566B/en active IP Right Grant
- 2017-04-04 CL CL2017000820A patent/CL2017000820A1/es unknown
- 2017-04-06 MX MX2021014531A patent/MX2021014531A/es unknown
- 2017-04-20 CO CONC2017/0003838A patent/CO2017003838A2/es unknown
- 2017-04-27 EC ECIEPI201726210A patent/ECSP17026210A/es unknown
- 2017-07-05 US US15/641,383 patent/US10149849B2/en active Active
-
2018
- 2018-10-24 US US16/169,414 patent/US10398700B2/en active Active
-
2019
- 2019-07-17 US US16/514,749 patent/US10646493B2/en active Active
- 2019-10-02 JP JP2019182133A patent/JP6987823B2/ja active Active
-
2020
- 2020-02-28 AU AU2020201486A patent/AU2020201486B2/en active Active
- 2020-04-13 US US16/846,503 patent/US10940152B2/en active Active
- 2020-09-01 IL IL277069A patent/IL277069B/en unknown
-
2021
- 2021-01-12 US US17/147,127 patent/US11590139B2/en active Active
- 2021-04-26 HR HRP20210656TT patent/HRP20210656T1/hr unknown
- 2021-05-24 CY CY20211100444T patent/CY1124173T1/el unknown
- 2021-12-01 JP JP2021195105A patent/JP7196270B2/ja active Active
-
2022
- 2022-12-14 JP JP2022199122A patent/JP2023027269A/ja active Pending
-
2023
- 2023-01-11 US US18/095,670 patent/US20230158035A1/en active Pending
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2008526989A (ja) * | 2005-01-13 | 2008-07-24 | シグナル ファーマシューティカルズ,エルエルシー | ハロアリール置換アミノプリン、その組成物、およびそれによる治療の方法 |
Non-Patent Citations (1)
Title |
---|
X. CEHN ET AL., NEOPLASMA, vol. 61,5, JPN7018004326, 16 July 2014 (2014-07-16), pages 514 - 522, ISSN: 0004047056 * |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2019515889A (ja) * | 2016-04-01 | 2019-06-13 | シグナル ファーマシューティカルズ,エルエルシー | (1s,4s)−4−(2−(((3s,4r)−3−フルオロテトラヒドロ−2h−ピラン−4−イル)アミノ)−8−((2,4,6−トリクロロフェニル)アミノ)−9h−プリン−9−イル)−1−メチルクロロヘキサン−1−カルボキサミドの固体形態及びその使用方法 |
JP6995058B2 (ja) | 2016-04-01 | 2022-02-21 | シグナル ファーマシューティカルズ,エルエルシー | (1s,4s)-4-(2-(((3s,4r)-3-フルオロテトラヒドロ-2h-ピラン-4-イル)アミノ)-8-((2,4,6-トリクロロフェニル)アミノ)-9h-プリン-9-イル)-1-メチルクロロヘキサン-1-カルボキサミドの固体形態及びその使用方法 |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP7196270B2 (ja) | 置換アミノプリン化合物、その組成物、及びそれによる治療の方法 | |
US9783505B2 (en) | Substituted diaminopyrimidyl compounds, compositions thereof, and methods of treatment therewith | |
US10420772B2 (en) | Animal and human anti-trypanosomonal and anti-leishmania agents | |
BR112017006998B1 (pt) | Composto de aminopurina substituído, composição farmacêutica compreendendo o mesmo, uso e método para preparar o referido composto e métodos in vitro e ex vivo de inibição de quinase |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20180928 |
|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20180928 |
|
A871 | Explanation of circumstances concerning accelerated examination |
Free format text: JAPANESE INTERMEDIATE CODE: A871 Effective date: 20180928 |
|
A975 | Report on accelerated examination |
Free format text: JAPANESE INTERMEDIATE CODE: A971005 Effective date: 20181220 |
|
A977 | Report on retrieval |
Free format text: JAPANESE INTERMEDIATE CODE: A971007 Effective date: 20181220 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20190108 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A821 Effective date: 20190405 |
|
A02 | Decision of refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A02 Effective date: 20190604 |
|
C60 | Trial request (containing other claim documents, opposition documents) |
Free format text: JAPANESE INTERMEDIATE CODE: C60 Effective date: 20191002 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A821 Effective date: 20191003 |
|
C22 | Notice of designation (change) of administrative judge |
Free format text: JAPANESE INTERMEDIATE CODE: C22 Effective date: 20200602 |
|
C27C | Written answer of applicant after an oral proceeding |
Free format text: JAPANESE INTERMEDIATE CODE: C2721 Effective date: 20200714 |
|
C13 | Notice of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: C13 Effective date: 20200825 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20201124 |
|
C22 | Notice of designation (change) of administrative judge |
Free format text: JAPANESE INTERMEDIATE CODE: C22 Effective date: 20201201 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20201209 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A821 Effective date: 20201210 |
|
C23 | Notice of termination of proceedings |
Free format text: JAPANESE INTERMEDIATE CODE: C23 Effective date: 20210309 |
|
C03 | Trial/appeal decision taken |
Free format text: JAPANESE INTERMEDIATE CODE: C03 Effective date: 20210413 |
|
C30A | Notification sent |
Free format text: JAPANESE INTERMEDIATE CODE: C3012 Effective date: 20210413 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20210512 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 6884701 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |