EA016445B1 - ИНГИБИТОРЫ p70 S6 КИНАЗЫ - Google Patents
ИНГИБИТОРЫ p70 S6 КИНАЗЫ Download PDFInfo
- Publication number
- EA016445B1 EA016445B1 EA200971051A EA200971051A EA016445B1 EA 016445 B1 EA016445 B1 EA 016445B1 EA 200971051 A EA200971051 A EA 200971051A EA 200971051 A EA200971051 A EA 200971051A EA 016445 B1 EA016445 B1 EA 016445B1
- Authority
- EA
- Eurasian Patent Office
- Prior art keywords
- imidazol
- piperidine
- mmol
- compound
- fluoro
- Prior art date
Links
- 229940043355 kinase inhibitor Drugs 0.000 title abstract description 7
- 239000003757 phosphotransferase inhibitor Substances 0.000 title abstract description 7
- 108010013238 70-kDa Ribosomal Protein S6 Kinases Proteins 0.000 title abstract 2
- 238000000034 method Methods 0.000 claims abstract description 35
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 18
- 150000001875 compounds Chemical class 0.000 claims description 221
- -1 4-fluoro-3-trifluoromethylphenyl Chemical group 0.000 claims description 127
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 77
- 150000003839 salts Chemical class 0.000 claims description 68
- RWTNPBWLLIMQHL-UHFFFAOYSA-N fexofenadine Chemical compound C1=CC(C(C)(C(O)=O)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 RWTNPBWLLIMQHL-UHFFFAOYSA-N 0.000 claims description 61
- 125000001424 substituent group Chemical group 0.000 claims description 40
- 241000124008 Mammalia Species 0.000 claims description 32
- 229910052736 halogen Inorganic materials 0.000 claims description 30
- 150000002367 halogens Chemical class 0.000 claims description 30
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 19
- 239000003814 drug Substances 0.000 claims description 18
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 17
- 238000004519 manufacturing process Methods 0.000 claims description 15
- 239000003085 diluting agent Substances 0.000 claims description 14
- 230000002401 inhibitory effect Effects 0.000 claims description 14
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 14
- 230000033115 angiogenesis Effects 0.000 claims description 13
- 239000003937 drug carrier Substances 0.000 claims description 13
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 13
- 229910052739 hydrogen Inorganic materials 0.000 claims description 9
- 208000029742 colonic neoplasm Diseases 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 7
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 1
- 150000002431 hydrogen Chemical class 0.000 claims 1
- 230000008520 organization Effects 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 136
- 230000015572 biosynthetic process Effects 0.000 description 113
- 238000003786 synthesis reaction Methods 0.000 description 110
- 239000000203 mixture Substances 0.000 description 73
- 239000007787 solid Substances 0.000 description 72
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 70
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Natural products CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 68
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 68
- 239000000243 solution Substances 0.000 description 60
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 59
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 59
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Natural products CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 57
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 53
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 44
- 239000011541 reaction mixture Substances 0.000 description 42
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 40
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 36
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical class Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 34
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 34
- 238000006243 chemical reaction Methods 0.000 description 33
- 229920006395 saturated elastomer Polymers 0.000 description 33
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 32
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 31
- 239000002244 precipitate Substances 0.000 description 31
- 239000002904 solvent Substances 0.000 description 30
- 239000000725 suspension Substances 0.000 description 29
- IDXKTTNFXPPXJY-UHFFFAOYSA-N pyrimidin-1-ium;chloride Chemical compound Cl.C1=CN=CN=C1 IDXKTTNFXPPXJY-UHFFFAOYSA-N 0.000 description 28
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 27
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 27
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 27
- 239000012044 organic layer Substances 0.000 description 27
- 239000011780 sodium chloride Substances 0.000 description 26
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 24
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 24
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 23
- 230000002829 reductive effect Effects 0.000 description 23
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 21
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 20
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 18
- 239000000741 silica gel Substances 0.000 description 18
- 229910002027 silica gel Inorganic materials 0.000 description 18
- 238000003756 stirring Methods 0.000 description 18
- 235000008504 concentrate Nutrition 0.000 description 16
- 239000012141 concentrate Substances 0.000 description 16
- 239000000047 product Substances 0.000 description 16
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 15
- 238000001914 filtration Methods 0.000 description 15
- DNUTZBZXLPWRJG-UHFFFAOYSA-M piperidine-1-carboxylate Chemical compound [O-]C(=O)N1CCCCC1 DNUTZBZXLPWRJG-UHFFFAOYSA-M 0.000 description 15
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 14
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 14
- 210000004027 cell Anatomy 0.000 description 12
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 12
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 12
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Substances C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 12
- 238000004809 thin layer chromatography Methods 0.000 description 12
- 239000000460 chlorine Substances 0.000 description 11
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 10
- 239000010410 layer Substances 0.000 description 10
- 238000010898 silica gel chromatography Methods 0.000 description 10
- 108091000080 Phosphotransferase Proteins 0.000 description 9
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 9
- 239000000706 filtrate Substances 0.000 description 9
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 9
- 102000020233 phosphotransferase Human genes 0.000 description 9
- 206010028980 Neoplasm Diseases 0.000 description 8
- 150000001409 amidines Chemical class 0.000 description 8
- 125000004528 pyrimidin-5-yl group Chemical group N1=CN=CC(=C1)* 0.000 description 8
- DRGCXLJWMQGVJA-UHFFFAOYSA-N pyrimidine;dihydrochloride Chemical compound Cl.Cl.C1=CN=CN=C1 DRGCXLJWMQGVJA-UHFFFAOYSA-N 0.000 description 8
- RQCNHUCCQJMSRG-UHFFFAOYSA-N tert-butyl piperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCCCC1 RQCNHUCCQJMSRG-UHFFFAOYSA-N 0.000 description 8
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 7
- LRHPLDYGYMQRHN-UHFFFAOYSA-N Butanol Natural products CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 7
- 238000001816 cooling Methods 0.000 description 7
- 239000013058 crude material Substances 0.000 description 7
- 229910052757 nitrogen Inorganic materials 0.000 description 7
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 7
- 238000002360 preparation method Methods 0.000 description 7
- NOGILORWSQYUJQ-UHFFFAOYSA-N tert-butyl 4-[[2-oxo-2-[3-(trifluoromethyl)phenyl]ethyl]carbamoyl]piperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1C(=O)NCC(=O)C1=CC=CC(C(F)(F)F)=C1 NOGILORWSQYUJQ-UHFFFAOYSA-N 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- ROLMZTIHUMKEAI-UHFFFAOYSA-N 4,5-difluoro-2-hydroxybenzonitrile Chemical compound OC1=CC(F)=C(F)C=C1C#N ROLMZTIHUMKEAI-UHFFFAOYSA-N 0.000 description 6
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 6
- 239000005695 Ammonium acetate Substances 0.000 description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 6
- 229940043376 ammonium acetate Drugs 0.000 description 6
- 235000019257 ammonium acetate Nutrition 0.000 description 6
- 239000002585 base Substances 0.000 description 6
- 125000003037 imidazol-2-yl group Chemical group [H]N1C([*])=NC([H])=C1[H] 0.000 description 6
- 230000005764 inhibitory process Effects 0.000 description 6
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- 125000006239 protecting group Chemical group 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- 239000003826 tablet Substances 0.000 description 6
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 6
- PAQZWJGSJMLPMG-UHFFFAOYSA-N 2,4,6-tripropyl-1,3,5,2$l^{5},4$l^{5},6$l^{5}-trioxatriphosphinane 2,4,6-trioxide Chemical compound CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1 PAQZWJGSJMLPMG-UHFFFAOYSA-N 0.000 description 5
- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 description 5
- 201000010915 Glioblastoma multiforme Diseases 0.000 description 5
- 206010033128 Ovarian cancer Diseases 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 238000004458 analytical method Methods 0.000 description 5
- 239000002775 capsule Substances 0.000 description 5
- 238000004587 chromatography analysis Methods 0.000 description 5
- 201000010897 colon adenocarcinoma Diseases 0.000 description 5
- 239000013078 crystal Substances 0.000 description 5
- 238000004821 distillation Methods 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 208000005017 glioblastoma Diseases 0.000 description 5
- VKYKSIONXSXAKP-UHFFFAOYSA-N hexamethylenetetramine Chemical compound C1N(C2)CN3CN1CN2C3 VKYKSIONXSXAKP-UHFFFAOYSA-N 0.000 description 5
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 5
- 239000003921 oil Substances 0.000 description 5
- 235000019198 oils Nutrition 0.000 description 5
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 5
- 235000017557 sodium bicarbonate Nutrition 0.000 description 5
- DLLYEBNXXOZNAR-UHFFFAOYSA-N tert-butyl 4-[5-[4-fluoro-3-(trifluoromethyl)phenyl]-1h-imidazol-2-yl]piperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1C1=NC(C=2C=C(C(F)=CC=2)C(F)(F)F)=CN1 DLLYEBNXXOZNAR-UHFFFAOYSA-N 0.000 description 5
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Substances [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 5
- DNUTZBZXLPWRJG-UHFFFAOYSA-N 1-Piperidine carboxylic acid Chemical compound OC(=O)N1CCCCC1 DNUTZBZXLPWRJG-UHFFFAOYSA-N 0.000 description 4
- JWOHBPPVVDQMKB-UHFFFAOYSA-N 1-[(2-methylpropan-2-yl)oxycarbonyl]piperidine-4-carboxylic acid Chemical compound CC(C)(C)OC(=O)N1CCC(C(O)=O)CC1 JWOHBPPVVDQMKB-UHFFFAOYSA-N 0.000 description 4
- KCIOUOSMPVZWDY-UHFFFAOYSA-N 1-benzyl-4-[5-(3-chloro-4-fluorophenyl)-1h-imidazol-2-yl]piperidine Chemical compound C1=C(Cl)C(F)=CC=C1C1=CN=C(C2CCN(CC=3C=CC=CC=3)CC2)N1 KCIOUOSMPVZWDY-UHFFFAOYSA-N 0.000 description 4
- XJPZKYIHCLDXST-UHFFFAOYSA-N 4,6-dichloropyrimidine Chemical compound ClC1=CC(Cl)=NC=N1 XJPZKYIHCLDXST-UHFFFAOYSA-N 0.000 description 4
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 4
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 4
- 206010060862 Prostate cancer Diseases 0.000 description 4
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 4
- WGLPBDUCMAPZCE-UHFFFAOYSA-N Trioxochromium Chemical compound O=[Cr](=O)=O WGLPBDUCMAPZCE-UHFFFAOYSA-N 0.000 description 4
- 201000008275 breast carcinoma Diseases 0.000 description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 4
- 229910052794 bromium Inorganic materials 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
- 238000004440 column chromatography Methods 0.000 description 4
- 238000005859 coupling reaction Methods 0.000 description 4
- 208000021045 exocrine pancreatic carcinoma Diseases 0.000 description 4
- 239000006260 foam Substances 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 4
- 208000032839 leukemia Diseases 0.000 description 4
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 4
- 208000008443 pancreatic carcinoma Diseases 0.000 description 4
- YBYRMVIVWMBXKQ-UHFFFAOYSA-N phenylmethanesulfonyl fluoride Chemical compound FS(=O)(=O)CC1=CC=CC=C1 YBYRMVIVWMBXKQ-UHFFFAOYSA-N 0.000 description 4
- 230000005855 radiation Effects 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- OVTAORBMYQLVOL-UHFFFAOYSA-N tert-butyl 4-[4-[4-fluoro-3-(trifluoromethyl)phenyl]-1-methylimidazol-2-yl]piperidine-1-carboxylate Chemical compound CN1C=C(C=2C=C(C(F)=CC=2)C(F)(F)F)N=C1C1CCN(C(=O)OC(C)(C)C)CC1 OVTAORBMYQLVOL-UHFFFAOYSA-N 0.000 description 4
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 4
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 3
- LNFALWVPKGGUOM-UHFFFAOYSA-N 1-benzyl-4-[4-(3-chloro-4-fluorophenyl)-1-ethylimidazol-2-yl]piperidine Chemical compound CCN1C=C(C=2C=C(Cl)C(F)=CC=2)N=C1C(CC1)CCN1CC1=CC=CC=C1 LNFALWVPKGGUOM-UHFFFAOYSA-N 0.000 description 3
- HFWQQMZSDODLGZ-UHFFFAOYSA-N 1-benzylpiperidine-4-carboximidamide;dihydrochloride Chemical compound Cl.Cl.C1CC(C(=N)N)CCN1CC1=CC=CC=C1 HFWQQMZSDODLGZ-UHFFFAOYSA-N 0.000 description 3
- HEPPSEJUYWXQJV-UHFFFAOYSA-N 2-amino-1-[3-(trifluoromethyl)phenyl]ethanone;hydrochloride Chemical compound Cl.NCC(=O)C1=CC=CC(C(F)(F)F)=C1 HEPPSEJUYWXQJV-UHFFFAOYSA-N 0.000 description 3
- YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical compound CC(C)COC(Cl)=O YOETUEMZNOLGDB-UHFFFAOYSA-N 0.000 description 3
- 125000006275 3-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C([H])C(*)=C1[H] 0.000 description 3
- ROGYJTCGEPAVSF-UHFFFAOYSA-N 4-[5-[3-(trifluoromethyl)phenyl]-1h-imidazol-2-yl]piperidine Chemical compound FC(F)(F)C1=CC=CC(C=2N=C(NC=2)C2CCNCC2)=C1 ROGYJTCGEPAVSF-UHFFFAOYSA-N 0.000 description 3
- FFDMUBXYXJRXIA-UHFFFAOYSA-N 4-[5-[4-fluoro-3-(trifluoromethyl)phenyl]-1h-imidazol-2-yl]piperidine;hydrochloride Chemical compound Cl.C1=C(C(F)(F)F)C(F)=CC=C1C1=CNC(C2CCNCC2)=N1 FFDMUBXYXJRXIA-UHFFFAOYSA-N 0.000 description 3
- 206010006187 Breast cancer Diseases 0.000 description 3
- 208000026310 Breast neoplasm Diseases 0.000 description 3
- 206010009944 Colon cancer Diseases 0.000 description 3
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 3
- 238000002441 X-ray diffraction Methods 0.000 description 3
- 229910021529 ammonia Inorganic materials 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 239000012300 argon atmosphere Substances 0.000 description 3
- 239000012298 atmosphere Substances 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000012230 colorless oil Substances 0.000 description 3
- 125000000753 cycloalkyl group Chemical group 0.000 description 3
- IJGVPIQKQDHSKH-UHFFFAOYSA-N cyclopropyl-(4,6-dichloropyrimidin-5-yl)methanol Chemical compound ClC=1N=CN=C(Cl)C=1C(O)C1CC1 IJGVPIQKQDHSKH-UHFFFAOYSA-N 0.000 description 3
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 230000008020 evaporation Effects 0.000 description 3
- 239000012458 free base Substances 0.000 description 3
- 235000010299 hexamethylene tetramine Nutrition 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- 229960004011 methenamine Drugs 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 description 3
- OHEDMAIVEXQCOZ-UHFFFAOYSA-N piperidine;dihydrochloride Chemical compound Cl.Cl.C1CCNCC1 OHEDMAIVEXQCOZ-UHFFFAOYSA-N 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- TVDSBUOJIPERQY-UHFFFAOYSA-N prop-2-yn-1-ol Chemical compound OCC#C TVDSBUOJIPERQY-UHFFFAOYSA-N 0.000 description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 description 3
- 239000012312 sodium hydride Substances 0.000 description 3
- 229910000104 sodium hydride Inorganic materials 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- YGWJTAUDJMYMKA-UHFFFAOYSA-N tert-butyl 4-[1-methyl-4-[3-(trifluoromethyl)phenyl]imidazol-2-yl]piperidine-1-carboxylate Chemical compound CN1C=C(C=2C=C(C=CC=2)C(F)(F)F)N=C1C1CCN(C(=O)OC(C)(C)C)CC1 YGWJTAUDJMYMKA-UHFFFAOYSA-N 0.000 description 3
- HXZJTMNTYSDUCE-UHFFFAOYSA-N tert-butyl 4-[5-[3-(trifluoromethyl)phenyl]-1h-imidazol-2-yl]piperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1C1=NC(C=2C=C(C=CC=2)C(F)(F)F)=CN1 HXZJTMNTYSDUCE-UHFFFAOYSA-N 0.000 description 3
- ZDZXZKQTFNUKKG-UHFFFAOYSA-N tert-butyl 4-carbamimidoylpiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(C(N)=N)CC1 ZDZXZKQTFNUKKG-UHFFFAOYSA-N 0.000 description 3
- 238000004448 titration Methods 0.000 description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- GOLDWWUEWZOTQH-UHFFFAOYSA-N 1-benzyl-4-[5-(4-fluorophenyl)-1h-imidazol-2-yl]piperidine Chemical compound C1=CC(F)=CC=C1C1=CNC(C2CCN(CC=3C=CC=CC=3)CC2)=N1 GOLDWWUEWZOTQH-UHFFFAOYSA-N 0.000 description 2
- CKJUFUGVCGDYHH-UHFFFAOYSA-N 1-benzylpiperidine-4-carbonitrile Chemical compound C1CC(C#N)CCN1CC1=CC=CC=C1 CKJUFUGVCGDYHH-UHFFFAOYSA-N 0.000 description 2
- 125000004215 2,4-difluorophenyl group Chemical group [H]C1=C([H])C(*)=C(F)C([H])=C1F 0.000 description 2
- DIJAADONAGMAJP-UHFFFAOYSA-N 2-amino-1-[4-fluoro-3-(trifluoromethyl)phenyl]propan-1-one Chemical compound CC(N)C(=O)C1=CC=C(F)C(C(F)(F)F)=C1 DIJAADONAGMAJP-UHFFFAOYSA-N 0.000 description 2
- TZIYNLSEBAYCBZ-UHFFFAOYSA-N 2-bromo-1-[3-(trifluoromethyl)phenyl]ethanone Chemical compound FC(F)(F)C1=CC=CC(C(=O)CBr)=C1 TZIYNLSEBAYCBZ-UHFFFAOYSA-N 0.000 description 2
- 125000004189 3,4-dichlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(Cl)C([H])=C1* 0.000 description 2
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 2
- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 description 2
- XQSJHQXYQAUDFC-UHFFFAOYSA-N 4,6-dichloropyrimidine-5-carbaldehyde Chemical compound ClC1=NC=NC(Cl)=C1C=O XQSJHQXYQAUDFC-UHFFFAOYSA-N 0.000 description 2
- UEKMRIMFRALCBN-UHFFFAOYSA-N 4-(5-phenyl-1h-imidazol-2-yl)piperidine;hydrochloride Chemical compound Cl.C1CNCCC1C1=NC(C=2C=CC=CC=2)=CN1 UEKMRIMFRALCBN-UHFFFAOYSA-N 0.000 description 2
- QPFXUEVSBFKNJV-UHFFFAOYSA-N 4-[4-[4-fluoro-3-(trifluoromethyl)phenyl]-1-methylimidazol-2-yl]piperidine Chemical compound CN1C=C(C=2C=C(C(F)=CC=2)C(F)(F)F)N=C1C1CCNCC1 QPFXUEVSBFKNJV-UHFFFAOYSA-N 0.000 description 2
- WTVCUMRIYJVHKS-UHFFFAOYSA-N 4-[4-[4-fluoro-3-(trifluoromethyl)phenyl]-1-methylimidazol-2-yl]piperidine;dihydrochloride Chemical compound Cl.Cl.CN1C=C(C=2C=C(C(F)=CC=2)C(F)(F)F)N=C1C1CCNCC1 WTVCUMRIYJVHKS-UHFFFAOYSA-N 0.000 description 2
- NMOOOWPUNMXJRZ-UHFFFAOYSA-N 4-[5-[3-fluoro-4-(trifluoromethyl)phenyl]-1h-imidazol-2-yl]piperidine;hydrochloride Chemical compound Cl.C1=C(C(F)(F)F)C(F)=CC(C=2N=C(NC=2)C2CCNCC2)=C1 NMOOOWPUNMXJRZ-UHFFFAOYSA-N 0.000 description 2
- RIDQZQZJZJBQMM-UHFFFAOYSA-N 4-[5-[4-fluoro-3-(trifluoromethyl)phenyl]-1h-imidazol-2-yl]piperidine Chemical compound C1=C(C(F)(F)F)C(F)=CC=C1C1=CNC(C2CCNCC2)=N1 RIDQZQZJZJBQMM-UHFFFAOYSA-N 0.000 description 2
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 2
- CYJRNFFLTBEQSQ-UHFFFAOYSA-N 8-(3-methyl-1-benzothiophen-5-yl)-N-(4-methylsulfonylpyridin-3-yl)quinoxalin-6-amine Chemical compound CS(=O)(=O)C1=C(C=NC=C1)NC=1C=C2N=CC=NC2=C(C=1)C=1C=CC2=C(C(=CS2)C)C=1 CYJRNFFLTBEQSQ-UHFFFAOYSA-N 0.000 description 2
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- UVEHGGBEAVAEJI-UHFFFAOYSA-N Cc1ccc(cc1)S(O)(=O)=O.NCC(=O)c1cccc(c1)C(F)(F)F Chemical compound Cc1ccc(cc1)S(O)(=O)=O.NCC(=O)c1cccc(c1)C(F)(F)F UVEHGGBEAVAEJI-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 229910016523 CuKa Inorganic materials 0.000 description 2
- 102000008130 Cyclic AMP-Dependent Protein Kinases Human genes 0.000 description 2
- 108010049894 Cyclic AMP-Dependent Protein Kinases Proteins 0.000 description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- 241000699660 Mus musculus Species 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 2
- 102000003923 Protein Kinase C Human genes 0.000 description 2
- 108090000315 Protein Kinase C Proteins 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical class [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- FKMJXALNHKIDOD-LBPRGKRZSA-N TAMe Chemical compound NC(=N)NCCC[C@@H](C(=O)OC)NS(=O)(=O)C1=CC=C(C)C=C1 FKMJXALNHKIDOD-LBPRGKRZSA-N 0.000 description 2
- MWAREVYCFWUDTM-UHFFFAOYSA-N [2-[4-fluoro-3-(trifluoromethyl)phenyl]-2-oxoethyl]azanium;chloride Chemical compound Cl.NCC(=O)C1=CC=C(F)C(C(F)(F)F)=C1 MWAREVYCFWUDTM-UHFFFAOYSA-N 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 125000000304 alkynyl group Chemical group 0.000 description 2
- OFCNXPDARWKPPY-UHFFFAOYSA-N allopurinol Chemical compound OC1=NC=NC2=C1C=NN2 OFCNXPDARWKPPY-UHFFFAOYSA-N 0.000 description 2
- 229960003459 allopurinol Drugs 0.000 description 2
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 2
- 235000019270 ammonium chloride Nutrition 0.000 description 2
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 2
- DHCLVCXQIBBOPH-UHFFFAOYSA-N beta-glycerol phosphate Natural products OCC(CO)OP(O)(O)=O DHCLVCXQIBBOPH-UHFFFAOYSA-N 0.000 description 2
- GHRQXJHBXKYCLZ-UHFFFAOYSA-L beta-glycerolphosphate Chemical compound [Na+].[Na+].CC(CO)OOP([O-])([O-])=O GHRQXJHBXKYCLZ-UHFFFAOYSA-L 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 229910002091 carbon monoxide Inorganic materials 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- QOPVNWQGBQYBBP-UHFFFAOYSA-N chloroethyl chloroformate Chemical compound CC(Cl)OC(Cl)=O QOPVNWQGBQYBBP-UHFFFAOYSA-N 0.000 description 2
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 description 2
- 239000011248 coating agent Substances 0.000 description 2
- 239000003086 colorant Substances 0.000 description 2
- 239000010779 crude oil Substances 0.000 description 2
- JMYVMOUINOAAPA-UHFFFAOYSA-N cyclopropanecarbaldehyde Chemical compound O=CC1CC1 JMYVMOUINOAAPA-UHFFFAOYSA-N 0.000 description 2
- AQEFLFZSWDEAIP-UHFFFAOYSA-N di-tert-butyl ether Chemical compound CC(C)(C)OC(C)(C)C AQEFLFZSWDEAIP-UHFFFAOYSA-N 0.000 description 2
- 239000012954 diazonium Substances 0.000 description 2
- 238000002050 diffraction method Methods 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 231100000673 dose–response relationship Toxicity 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 238000003818 flash chromatography Methods 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 235000013355 food flavoring agent Nutrition 0.000 description 2
- 235000003599 food sweetener Nutrition 0.000 description 2
- 239000004312 hexamethylene tetramine Substances 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 238000002513 implantation Methods 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 229910052745 lead Inorganic materials 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000006166 lysate Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 238000004949 mass spectrometry Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 208000030159 metabolic disease Diseases 0.000 description 2
- OSWPMRLSEDHDFF-UHFFFAOYSA-N methyl salicylate Chemical compound COC(=O)C1=CC=CC=C1O OSWPMRLSEDHDFF-UHFFFAOYSA-N 0.000 description 2
- 239000008108 microcrystalline cellulose Substances 0.000 description 2
- 229940016286 microcrystalline cellulose Drugs 0.000 description 2
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 2
- WDKQNCOJYGKYPL-UHFFFAOYSA-N n'-hydroxypiperidine-1-carboximidamide Chemical compound ON=C(N)N1CCCCC1 WDKQNCOJYGKYPL-UHFFFAOYSA-N 0.000 description 2
- 239000012299 nitrogen atmosphere Substances 0.000 description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 238000011580 nude mouse model Methods 0.000 description 2
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 2
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 2
- LIGACIXOYTUXAW-UHFFFAOYSA-N phenacyl bromide Chemical compound BrCC(=O)C1=CC=CC=C1 LIGACIXOYTUXAW-UHFFFAOYSA-N 0.000 description 2
- 230000026731 phosphorylation Effects 0.000 description 2
- 238000006366 phosphorylation reaction Methods 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- NVPICXQHSYQKGM-UHFFFAOYSA-N piperidine-1-carbonitrile Chemical compound N#CN1CCCCC1 NVPICXQHSYQKGM-UHFFFAOYSA-N 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- 238000013207 serial dilution Methods 0.000 description 2
- 239000010802 sludge Substances 0.000 description 2
- DAEPDZWVDSPTHF-UHFFFAOYSA-M sodium pyruvate Chemical compound [Na+].CC(=O)C([O-])=O DAEPDZWVDSPTHF-UHFFFAOYSA-M 0.000 description 2
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 229960004793 sucrose Drugs 0.000 description 2
- 239000003765 sweetening agent Substances 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- LVGHAXNNRRKPIJ-UHFFFAOYSA-N tert-butyl 1-[[2-[4-fluoro-3-(trifluoromethyl)phenyl]-2-oxoethyl]carbamoyl]piperidine-4-carboxylate Chemical compound C1CC(C(=O)OC(C)(C)C)CCN1C(=O)NCC(=O)C1=CC=C(F)C(C(F)(F)F)=C1 LVGHAXNNRRKPIJ-UHFFFAOYSA-N 0.000 description 2
- QJMZCTXXDQBKAB-UHFFFAOYSA-N tert-butyl 4-[[2-[4-fluoro-3-(trifluoromethyl)phenyl]-2-oxoethyl]carbamoyl]piperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1C(=O)NCC(=O)C1=CC=C(F)C(C(F)(F)F)=C1 QJMZCTXXDQBKAB-UHFFFAOYSA-N 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- 210000001541 thymus gland Anatomy 0.000 description 2
- CWMFRHBXRUITQE-UHFFFAOYSA-N trimethylsilylacetylene Chemical group C[Si](C)(C)C#C CWMFRHBXRUITQE-UHFFFAOYSA-N 0.000 description 2
- 230000004614 tumor growth Effects 0.000 description 2
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 description 1
- VHPCRQZVRSYZNF-UHFFFAOYSA-N 1-(4,6-dichloropyrimidin-5-yl)ethanol Chemical compound CC(O)C1=C(Cl)N=CN=C1Cl VHPCRQZVRSYZNF-UHFFFAOYSA-N 0.000 description 1
- AMOPGZSOKQKCHT-UHFFFAOYSA-N 1-(4,6-dichloropyrimidin-5-yl)ethanone Chemical compound CC(=O)C1=C(Cl)N=CN=C1Cl AMOPGZSOKQKCHT-UHFFFAOYSA-N 0.000 description 1
- FVBJBAHHSONBOC-UHFFFAOYSA-N 1-(4,6-dichloropyrimidin-5-yl)propan-1-ol Chemical compound CCC(O)C1=C(Cl)N=CN=C1Cl FVBJBAHHSONBOC-UHFFFAOYSA-N 0.000 description 1
- BUVRFQPDAORILD-UHFFFAOYSA-N 1-(4,6-dichloropyrimidin-5-yl)propan-1-one Chemical compound CCC(=O)C1=C(Cl)N=CN=C1Cl BUVRFQPDAORILD-UHFFFAOYSA-N 0.000 description 1
- SCKAMDGXXQFMFY-UHFFFAOYSA-N 1-[2-fluoro-5-(trifluoromethyl)phenyl]propan-1-one Chemical compound CCC(=O)C1=CC(C(F)(F)F)=CC=C1F SCKAMDGXXQFMFY-UHFFFAOYSA-N 0.000 description 1
- ABXGMGUHGLQMAW-UHFFFAOYSA-N 1-[3-(trifluoromethyl)phenyl]ethanone Chemical compound CC(=O)C1=CC=CC(C(F)(F)F)=C1 ABXGMGUHGLQMAW-UHFFFAOYSA-N 0.000 description 1
- UWOZLJXODNPKOQ-UHFFFAOYSA-N 1-[5-[4-fluoro-3-(trifluoromethyl)phenyl]-1h-imidazol-2-yl]piperazine Chemical compound C1=C(C(F)(F)F)C(F)=CC=C1C1=CN=C(N2CCNCC2)N1 UWOZLJXODNPKOQ-UHFFFAOYSA-N 0.000 description 1
- MTVDVKFOEKYQKM-UHFFFAOYSA-N 1-[[2-[4-fluoro-3-(trifluoromethyl)phenyl]-2-oxoethyl]carbamoyl]piperidine-4-carboxylic acid Chemical compound C1CC(C(=O)O)CCN1C(=O)NCC(=O)C1=CC=C(F)C(C(F)(F)F)=C1 MTVDVKFOEKYQKM-UHFFFAOYSA-N 0.000 description 1
- ADCDQTBERXMVBN-UHFFFAOYSA-N 1-benzyl-4-[4-(3,4-difluorophenyl)-1-methylimidazol-2-yl]piperidine Chemical compound CN1C=C(C=2C=C(F)C(F)=CC=2)N=C1C(CC1)CCN1CC1=CC=CC=C1 ADCDQTBERXMVBN-UHFFFAOYSA-N 0.000 description 1
- CLIXGFQSVKBMGK-UHFFFAOYSA-N 1-benzyl-4-[4-(3-chloro-4-fluorophenyl)-1-methylimidazol-2-yl]piperidine Chemical compound CN1C=C(C=2C=C(Cl)C(F)=CC=2)N=C1C(CC1)CCN1CC1=CC=CC=C1 CLIXGFQSVKBMGK-UHFFFAOYSA-N 0.000 description 1
- OZWPYPVYRFPDJF-UHFFFAOYSA-N 1-benzyl-4-[4-(3-chloro-4-fluorophenyl)-1-propan-2-ylimidazol-2-yl]piperidine Chemical compound CC(C)N1C=C(C=2C=C(Cl)C(F)=CC=2)N=C1C(CC1)CCN1CC1=CC=CC=C1 OZWPYPVYRFPDJF-UHFFFAOYSA-N 0.000 description 1
- BYEOFNPDPILBQK-UHFFFAOYSA-N 1-benzylpiperidine-4-carbonitrile;hydrochloride Chemical compound Cl.C1CC(C#N)CCN1CC1=CC=CC=C1 BYEOFNPDPILBQK-UHFFFAOYSA-N 0.000 description 1
- WOGOXEPEEXSPAF-UHFFFAOYSA-N 1h-imidazole;piperidine Chemical compound C1=CNC=N1.C1CCNCC1 WOGOXEPEEXSPAF-UHFFFAOYSA-N 0.000 description 1
- 125000004201 2,4-dichlorophenyl group Chemical group [H]C1=C([H])C(*)=C(Cl)C([H])=C1Cl 0.000 description 1
- BPXKZEMBEZGUAH-UHFFFAOYSA-N 2-(chloromethoxy)ethyl-trimethylsilane Chemical compound C[Si](C)(C)CCOCCl BPXKZEMBEZGUAH-UHFFFAOYSA-N 0.000 description 1
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- OEGINEPXTRKDOK-UHFFFAOYSA-N 2-amino-1-(3-chloro-4-fluorophenyl)propan-1-one Chemical compound CC(N)C(=O)C1=CC=C(F)C(Cl)=C1 OEGINEPXTRKDOK-UHFFFAOYSA-N 0.000 description 1
- UZPHXBYKYSZQCZ-UHFFFAOYSA-N 2-amino-1-(3-fluorophenyl)propan-1-one Chemical compound CC(N)C(=O)C1=CC=CC(F)=C1 UZPHXBYKYSZQCZ-UHFFFAOYSA-N 0.000 description 1
- SBZLKBTWCSLSFK-UHFFFAOYSA-N 2-amino-1-[2-chloro-5-(trifluoromethyl)phenyl]ethanone;hydrochloride Chemical compound Cl.NCC(=O)C1=CC(C(F)(F)F)=CC=C1Cl SBZLKBTWCSLSFK-UHFFFAOYSA-N 0.000 description 1
- WBSHNVCNVSNYPH-UHFFFAOYSA-N 2-amino-1-[2-fluoro-5-(trifluoromethyl)phenyl]ethanone;hydrochloride Chemical compound Cl.NCC(=O)C1=CC(C(F)(F)F)=CC=C1F WBSHNVCNVSNYPH-UHFFFAOYSA-N 0.000 description 1
- RFRSDWWFGVBPRT-UHFFFAOYSA-N 2-amino-1-[3-(trifluoromethyl)phenyl]propan-1-one Chemical compound CC(N)C(=O)C1=CC=CC(C(F)(F)F)=C1 RFRSDWWFGVBPRT-UHFFFAOYSA-N 0.000 description 1
- HRGGZKVJDPYKOQ-UHFFFAOYSA-N 2-amino-1-[3-fluoro-5-(trifluoromethyl)phenyl]ethanone;hydrochloride Chemical compound Cl.NCC(=O)C1=CC(F)=CC(C(F)(F)F)=C1 HRGGZKVJDPYKOQ-UHFFFAOYSA-N 0.000 description 1
- IPAYFXBCHAVJHO-UHFFFAOYSA-N 2-amino-1-[4-(trifluoromethyl)phenyl]ethanone Chemical compound NCC(=O)C1=CC=C(C(F)(F)F)C=C1 IPAYFXBCHAVJHO-UHFFFAOYSA-N 0.000 description 1
- IJXQZKCAPFXHPJ-UHFFFAOYSA-N 2-amino-1-[4-(trifluoromethyl)phenyl]propan-1-one Chemical compound CC(N)C(=O)C1=CC=C(C(F)(F)F)C=C1 IJXQZKCAPFXHPJ-UHFFFAOYSA-N 0.000 description 1
- WZPSNPSAYYCJGX-UHFFFAOYSA-N 2-amino-1-[4-fluoro-3-(trifluoromethyl)phenyl]ethanone Chemical compound NCC(=O)C1=CC=C(F)C(C(F)(F)F)=C1 WZPSNPSAYYCJGX-UHFFFAOYSA-N 0.000 description 1
- JXCIEKVLIVDZJH-UHFFFAOYSA-N 2-amino-1-[4-fluoro-3-(trifluoromethyl)phenyl]ethanone;4-methylbenzenesulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1.NCC(=O)C1=CC=C(F)C(C(F)(F)F)=C1 JXCIEKVLIVDZJH-UHFFFAOYSA-N 0.000 description 1
- JOCPGHGWUUBURW-UHFFFAOYSA-N 2-bromo-1-(3-chloro-4-fluorophenyl)ethanone Chemical compound FC1=CC=C(C(=O)CBr)C=C1Cl JOCPGHGWUUBURW-UHFFFAOYSA-N 0.000 description 1
- DTZCJQCEYSGWKC-UHFFFAOYSA-N 2-bromo-1-(3-chloro-4-fluorophenyl)propan-1-one Chemical compound CC(Br)C(=O)C1=CC=C(F)C(Cl)=C1 DTZCJQCEYSGWKC-UHFFFAOYSA-N 0.000 description 1
- KJVRURZDIOVSSQ-UHFFFAOYSA-N 2-bromo-1-(3-chlorophenyl)ethanone Chemical compound ClC1=CC=CC(C(=O)CBr)=C1 KJVRURZDIOVSSQ-UHFFFAOYSA-N 0.000 description 1
- FUWLUTOKEUZKCM-UHFFFAOYSA-N 2-bromo-1-(3-fluorophenyl)propan-1-one Chemical compound CC(Br)C(=O)C1=CC=CC(F)=C1 FUWLUTOKEUZKCM-UHFFFAOYSA-N 0.000 description 1
- YVTHTWZIUKRHCF-UHFFFAOYSA-N 2-bromo-1-[2-chloro-5-(trifluoromethyl)phenyl]ethanone Chemical compound FC(F)(F)C1=CC=C(Cl)C(C(=O)CBr)=C1 YVTHTWZIUKRHCF-UHFFFAOYSA-N 0.000 description 1
- LQPAQYQHUGXFED-UHFFFAOYSA-N 2-bromo-1-[2-fluoro-5-(trifluoromethyl)phenyl]ethanone Chemical compound FC1=CC=C(C(F)(F)F)C=C1C(=O)CBr LQPAQYQHUGXFED-UHFFFAOYSA-N 0.000 description 1
- FTFNETUUEUPDLR-UHFFFAOYSA-N 2-bromo-1-[2-fluoro-5-(trifluoromethyl)phenyl]propan-1-one Chemical compound CC(Br)C(=O)C1=CC(C(F)(F)F)=CC=C1F FTFNETUUEUPDLR-UHFFFAOYSA-N 0.000 description 1
- SEQCPLOHECELDR-UHFFFAOYSA-N 2-bromo-1-[3-(trifluoromethyl)phenyl]propan-1-one Chemical compound CC(Br)C(=O)C1=CC=CC(C(F)(F)F)=C1 SEQCPLOHECELDR-UHFFFAOYSA-N 0.000 description 1
- SQVOBBIFCRMZOB-UHFFFAOYSA-N 2-bromo-1-[3-fluoro-5-(trifluoromethyl)phenyl]ethanone Chemical compound FC1=CC(C(=O)CBr)=CC(C(F)(F)F)=C1 SQVOBBIFCRMZOB-UHFFFAOYSA-N 0.000 description 1
- NFXCMWCJLDRJIM-UHFFFAOYSA-N 2-bromo-1-[4-(trifluoromethyl)phenyl]propan-1-one Chemical compound CC(Br)C(=O)C1=CC=C(C(F)(F)F)C=C1 NFXCMWCJLDRJIM-UHFFFAOYSA-N 0.000 description 1
- BUNOSKWLVXNWEH-UHFFFAOYSA-N 2-bromo-1-[4-fluoro-3-(trifluoromethyl)phenyl]ethanone Chemical compound FC1=CC=C(C(=O)CBr)C=C1C(F)(F)F BUNOSKWLVXNWEH-UHFFFAOYSA-N 0.000 description 1
- YSUIZBQSGDTBHT-UHFFFAOYSA-N 2-bromo-1-[4-fluoro-3-(trifluoromethyl)phenyl]propan-1-one Chemical compound CC(Br)C(=O)C1=CC=C(F)C(C(F)(F)F)=C1 YSUIZBQSGDTBHT-UHFFFAOYSA-N 0.000 description 1
- CEBKHWWANWSNTI-UHFFFAOYSA-N 2-methylbut-3-yn-2-ol Chemical compound CC(C)(O)C#C CEBKHWWANWSNTI-UHFFFAOYSA-N 0.000 description 1
- HRADVHZVMOMEPU-UHFFFAOYSA-N 3-iodopyrrolidine-2,5-dione Chemical compound IC1CC(=O)NC1=O HRADVHZVMOMEPU-UHFFFAOYSA-N 0.000 description 1
- DUFGYCAXVIUXIP-UHFFFAOYSA-N 4,6-dihydroxypyrimidine Chemical compound OC1=CC(O)=NC=N1 DUFGYCAXVIUXIP-UHFFFAOYSA-N 0.000 description 1
- QJRQTWKTKQULMZ-UHFFFAOYSA-N 4-(5-phenyl-1h-imidazol-2-yl)piperidine Chemical compound C1CNCCC1C1=NC(C=2C=CC=CC=2)=CN1 QJRQTWKTKQULMZ-UHFFFAOYSA-N 0.000 description 1
- XZKIHKMTEMTJQX-UHFFFAOYSA-N 4-Nitrophenyl Phosphate Chemical compound OP(O)(=O)OC1=CC=C([N+]([O-])=O)C=C1 XZKIHKMTEMTJQX-UHFFFAOYSA-N 0.000 description 1
- OMHAAEPINOQGRQ-UHFFFAOYSA-N 4-[1,5-dimethyl-4-[3-(trifluoromethyl)phenyl]imidazol-2-yl]piperidine;hydrochloride Chemical compound Cl.CN1C(C)=C(C=2C=C(C=CC=2)C(F)(F)F)N=C1C1CCNCC1 OMHAAEPINOQGRQ-UHFFFAOYSA-N 0.000 description 1
- MOXPVBRFHWWMRO-UHFFFAOYSA-N 4-[1-methyl-4-[3-(trifluoromethyl)phenyl]imidazol-2-yl]piperidine;dihydrochloride Chemical compound Cl.Cl.CN1C=C(C=2C=C(C=CC=2)C(F)(F)F)N=C1C1CCNCC1 MOXPVBRFHWWMRO-UHFFFAOYSA-N 0.000 description 1
- OLYGQJARTUMVIF-UHFFFAOYSA-N 4-[1-methyl-4-[4-(trifluoromethyl)phenyl]imidazol-2-yl]piperidine;dihydrochloride Chemical compound Cl.Cl.CN1C=C(C=2C=CC(=CC=2)C(F)(F)F)N=C1C1CCNCC1 OLYGQJARTUMVIF-UHFFFAOYSA-N 0.000 description 1
- BGIRXPCCMASZIE-UHFFFAOYSA-N 4-[1-propan-2-yl-4-[3-(trifluoromethyl)phenyl]imidazol-2-yl]piperidine;hydrochloride Chemical compound Cl.CC(C)N1C=C(C=2C=C(C=CC=2)C(F)(F)F)N=C1C1CCNCC1 BGIRXPCCMASZIE-UHFFFAOYSA-N 0.000 description 1
- BLUKJQIFHDSICR-UHFFFAOYSA-N 4-[4-(3,4-difluorophenyl)-1-propan-2-ylimidazol-2-yl]piperidine;hydrochloride Chemical compound Cl.CC(C)N1C=C(C=2C=C(F)C(F)=CC=2)N=C1C1CCNCC1 BLUKJQIFHDSICR-UHFFFAOYSA-N 0.000 description 1
- BMCJBUAYEODBHM-UHFFFAOYSA-N 4-[4-(3-chloro-4-fluorophenyl)-1,5-dimethylimidazol-2-yl]piperidine;hydrochloride Chemical compound Cl.CN1C(C)=C(C=2C=C(Cl)C(F)=CC=2)N=C1C1CCNCC1 BMCJBUAYEODBHM-UHFFFAOYSA-N 0.000 description 1
- XWEFHCAHRINDBS-UHFFFAOYSA-N 4-[4-(3-chloro-4-fluorophenyl)-1-ethylimidazol-2-yl]piperidine;hydrochloride Chemical compound Cl.CCN1C=C(C=2C=C(Cl)C(F)=CC=2)N=C1C1CCNCC1 XWEFHCAHRINDBS-UHFFFAOYSA-N 0.000 description 1
- DYHFBBIRZGGFJD-UHFFFAOYSA-N 4-[4-(3-chloro-4-fluorophenyl)-1-propan-2-ylimidazol-2-yl]piperidine;hydrochloride Chemical compound Cl.CC(C)N1C=C(C=2C=C(Cl)C(F)=CC=2)N=C1C1CCNCC1 DYHFBBIRZGGFJD-UHFFFAOYSA-N 0.000 description 1
- FIRPCFOBYFFGSJ-UHFFFAOYSA-N 4-[5-(2,4-dichlorophenyl)-1h-imidazol-2-yl]piperidine Chemical compound ClC1=CC(Cl)=CC=C1C1=CNC(C2CCNCC2)=N1 FIRPCFOBYFFGSJ-UHFFFAOYSA-N 0.000 description 1
- HKCPTSVRFYUBOR-UHFFFAOYSA-N 4-[5-(3-chloro-4-fluorophenyl)-1h-imidazol-2-yl]piperidine;dihydrochloride Chemical compound Cl.Cl.C1=C(Cl)C(F)=CC=C1C1=CN=C(C2CCNCC2)N1 HKCPTSVRFYUBOR-UHFFFAOYSA-N 0.000 description 1
- ZBGFQKIGXQWYCY-UHFFFAOYSA-N 4-[5-(3-chloro-5-fluorophenyl)-1h-imidazol-2-yl]piperidine;hydrochloride Chemical compound Cl.FC1=CC(Cl)=CC(C=2NC(=NC=2)C2CCNCC2)=C1 ZBGFQKIGXQWYCY-UHFFFAOYSA-N 0.000 description 1
- ZLEXWIYFPQFQAM-UHFFFAOYSA-N 4-[5-(3-chlorophenyl)-1h-imidazol-2-yl]piperidine;hydrochloride Chemical compound Cl.ClC1=CC=CC(C=2N=C(NC=2)C2CCNCC2)=C1 ZLEXWIYFPQFQAM-UHFFFAOYSA-N 0.000 description 1
- UXDZOEUAAPXRGP-UHFFFAOYSA-N 4-[5-(4-fluorophenyl)-1h-imidazol-2-yl]piperidine Chemical compound C1=CC(F)=CC=C1C1=CNC(C2CCNCC2)=N1 UXDZOEUAAPXRGP-UHFFFAOYSA-N 0.000 description 1
- WZNSDMAONCCBIL-UHFFFAOYSA-N 4-[5-[2-chloro-5-(trifluoromethyl)phenyl]-1h-imidazol-2-yl]piperidine;dihydrochloride Chemical compound Cl.Cl.FC(F)(F)C1=CC=C(Cl)C(C=2NC(=NC=2)C2CCNCC2)=C1 WZNSDMAONCCBIL-UHFFFAOYSA-N 0.000 description 1
- IYHTUUPGXSJMOG-UHFFFAOYSA-N 4-[5-[2-fluoro-5-(trifluoromethyl)phenyl]-1h-imidazol-2-yl]piperidine;dihydrochloride Chemical compound Cl.Cl.FC1=CC=C(C(F)(F)F)C=C1C1=CN=C(C2CCNCC2)N1 IYHTUUPGXSJMOG-UHFFFAOYSA-N 0.000 description 1
- CFAYAJJPQIFRAL-UHFFFAOYSA-N 4-[5-[3-fluoro-5-(trifluoromethyl)phenyl]-1h-imidazol-2-yl]piperidine;dihydrochloride Chemical compound Cl.Cl.FC(F)(F)C1=CC(F)=CC(C=2NC(=NC=2)C2CCNCC2)=C1 CFAYAJJPQIFRAL-UHFFFAOYSA-N 0.000 description 1
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 1
- NAHFHGPUCSEQTE-UHFFFAOYSA-N 4-[[2-oxo-2-[3-(trifluoromethyl)phenyl]ethyl]carbamoyl]piperidine-1-carboxylic acid Chemical compound C1CN(C(=O)O)CCC1C(=O)NCC(=O)C1=CC=CC(C(F)(F)F)=C1 NAHFHGPUCSEQTE-UHFFFAOYSA-N 0.000 description 1
- BPTCCCTWWAUJRK-UHFFFAOYSA-N 4-chloro-7h-pyrrolo[2,3-d]pyrimidine Chemical compound ClC1=NC=NC2=C1C=CN2 BPTCCCTWWAUJRK-UHFFFAOYSA-N 0.000 description 1
- BIUDHHGROGJSHN-UHFFFAOYSA-N 4-fluoro-3-(trifluoromethyl)benzaldehyde Chemical group FC1=CC=C(C=O)C=C1C(F)(F)F BIUDHHGROGJSHN-UHFFFAOYSA-N 0.000 description 1
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 1
- 125000004199 4-trifluoromethylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C(F)(F)F 0.000 description 1
- KDOPAZIWBAHVJB-UHFFFAOYSA-N 5h-pyrrolo[3,2-d]pyrimidine Chemical compound C1=NC=C2NC=CC2=N1 KDOPAZIWBAHVJB-UHFFFAOYSA-N 0.000 description 1
- OIRHYZZRULXNDV-UHFFFAOYSA-N 6-[4-[4-(3-chloro-4-fluorophenyl)-1-methylimidazol-2-yl]piperidin-1-yl]-7H-purine hydrochloride Chemical compound Cl.Cn1cc(nc1C1CCN(CC1)c1ncnc2[nH]cnc12)-c1ccc(F)c(Cl)c1 OIRHYZZRULXNDV-UHFFFAOYSA-N 0.000 description 1
- NLCLTOUTFGQOMF-UHFFFAOYSA-N 6-[4-[5-[2-fluoro-5-(trifluoromethyl)phenyl]-1h-imidazol-2-yl]piperidin-1-yl]-7h-purine;dihydrochloride Chemical compound Cl.Cl.FC1=CC=C(C(F)(F)F)C=C1C1=CN=C(C2CCN(CC2)C=2C=3NC=NC=3N=CN=2)N1 NLCLTOUTFGQOMF-UHFFFAOYSA-N 0.000 description 1
- DKTOVTKJABYHKT-UHFFFAOYSA-N 6-[4-[5-[3-(trifluoromethyl)phenyl]-1h-imidazol-2-yl]piperidin-1-yl]-7h-purine;hydrochloride Chemical compound Cl.FC(F)(F)C1=CC=CC(C=2NC(=NC=2)C2CCN(CC2)C=2C=3NC=NC=3N=CN=2)=C1 DKTOVTKJABYHKT-UHFFFAOYSA-N 0.000 description 1
- 108010039627 Aprotinin Proteins 0.000 description 1
- 108010011485 Aspartame Proteins 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- PTHCMJGKKRQCBF-UHFFFAOYSA-N Cellulose, microcrystalline Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC)C(CO)O1 PTHCMJGKKRQCBF-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 229940122644 Chymotrypsin inhibitor Drugs 0.000 description 1
- GONDYQLPNNMYPN-UHFFFAOYSA-N Cl.Cl.FC=1C=C(C=CC1F)C=1N=C(N(C1)C)C1CCN(CC1)C1=C2N=CNC2=NC=N1 Chemical compound Cl.Cl.FC=1C=C(C=CC1F)C=1N=C(N(C1)C)C1CCN(CC1)C1=C2N=CNC2=NC=N1 GONDYQLPNNMYPN-UHFFFAOYSA-N 0.000 description 1
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 229920002785 Croscarmellose sodium Polymers 0.000 description 1
- 235000019739 Dicalciumphosphate Nutrition 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 241000402754 Erythranthe moschata Species 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 1
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- 208000031226 Hyperlipidaemia Diseases 0.000 description 1
- 108060003951 Immunoglobulin Proteins 0.000 description 1
- 206010022489 Insulin Resistance Diseases 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- GDBQQVLCIARPGH-UHFFFAOYSA-N Leupeptin Natural products CC(C)CC(NC(C)=O)C(=O)NC(CC(C)C)C(=O)NC(C=O)CCCN=C(N)N GDBQQVLCIARPGH-UHFFFAOYSA-N 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- 244000246386 Mentha pulegium Species 0.000 description 1
- 235000016257 Mentha pulegium Nutrition 0.000 description 1
- 235000004357 Mentha x piperita Nutrition 0.000 description 1
- 208000001145 Metabolic Syndrome Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- HSHXDCVZWHOWCS-UHFFFAOYSA-N N'-hexadecylthiophene-2-carbohydrazide Chemical compound CCCCCCCCCCCCCCCCNNC(=O)c1cccs1 HSHXDCVZWHOWCS-UHFFFAOYSA-N 0.000 description 1
- AYCPARAPKDAOEN-LJQANCHMSA-N N-[(1S)-2-(dimethylamino)-1-phenylethyl]-6,6-dimethyl-3-[(2-methyl-4-thieno[3,2-d]pyrimidinyl)amino]-1,4-dihydropyrrolo[3,4-c]pyrazole-5-carboxamide Chemical compound C1([C@H](NC(=O)N2C(C=3NN=C(NC=4C=5SC=CC=5N=C(C)N=4)C=3C2)(C)C)CN(C)C)=CC=CC=C1 AYCPARAPKDAOEN-LJQANCHMSA-N 0.000 description 1
- MQUQNUAYKLCRME-INIZCTEOSA-N N-tosyl-L-phenylalanyl chloromethyl ketone Chemical compound C1=CC(C)=CC=C1S(=O)(=O)N[C@H](C(=O)CCl)CC1=CC=CC=C1 MQUQNUAYKLCRME-INIZCTEOSA-N 0.000 description 1
- 208000008589 Obesity Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 229910019213 POCl3 Inorganic materials 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 239000007868 Raney catalyst Substances 0.000 description 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- 208000006265 Renal cell carcinoma Diseases 0.000 description 1
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 108010073929 Vascular Endothelial Growth Factor A Proteins 0.000 description 1
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 description 1
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 description 1
- OVKMQHKVUWBLSV-UHFFFAOYSA-N [2-(4-chlorophenyl)-2-oxoethyl]azanium;chloride Chemical compound [Cl-].[NH3+]CC(=O)C1=CC=C(Cl)C=C1 OVKMQHKVUWBLSV-UHFFFAOYSA-N 0.000 description 1
- 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 description 1
- VJHCJDRQFCCTHL-UHFFFAOYSA-N acetic acid 2,3,4,5,6-pentahydroxyhexanal Chemical compound CC(O)=O.OCC(O)C(O)C(O)C(O)C=O VJHCJDRQFCCTHL-UHFFFAOYSA-N 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 239000012296 anti-solvent Substances 0.000 description 1
- 229960004405 aprotinin Drugs 0.000 description 1
- 239000011260 aqueous acid Substances 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 239000000605 aspartame Substances 0.000 description 1
- IAOZJIPTCAWIRG-QWRGUYRKSA-N aspartame Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 description 1
- 235000010357 aspartame Nutrition 0.000 description 1
- 229960003438 aspartame Drugs 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 150000001540 azides Chemical class 0.000 description 1
- PXXJHWLDUBFPOL-UHFFFAOYSA-N benzamidine Chemical compound NC(=N)C1=CC=CC=C1 PXXJHWLDUBFPOL-UHFFFAOYSA-N 0.000 description 1
- GPRLTFBKWDERLU-UHFFFAOYSA-N bicyclo[2.2.2]octane Chemical compound C1CC2CCC1CC2 GPRLTFBKWDERLU-UHFFFAOYSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000000480 butynyl group Chemical group [*]C#CC([H])([H])C([H])([H])[H] 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- RBHJBMIOOPYDBQ-UHFFFAOYSA-N carbon dioxide;propan-2-one Chemical compound O=C=O.CC(C)=O RBHJBMIOOPYDBQ-UHFFFAOYSA-N 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- OGEBRHQLRGFBNV-RZDIXWSQSA-N chembl2036808 Chemical compound C12=NC(NCCCC)=NC=C2C(C=2C=CC(F)=CC=2)=NN1C[C@H]1CC[C@H](N)CC1 OGEBRHQLRGFBNV-RZDIXWSQSA-N 0.000 description 1
- 238000000451 chemical ionisation Methods 0.000 description 1
- 235000015218 chewing gum Nutrition 0.000 description 1
- 239000012320 chlorinating reagent Substances 0.000 description 1
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 1
- 239000003541 chymotrypsin inhibitor Substances 0.000 description 1
- 238000010549 co-Evaporation Methods 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 229940075614 colloidal silicon dioxide Drugs 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 229940099112 cornstarch Drugs 0.000 description 1
- 229960005168 croscarmellose Drugs 0.000 description 1
- 229960000913 crospovidone Drugs 0.000 description 1
- 239000001767 crosslinked sodium carboxy methyl cellulose Substances 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- LPKNCFYQYOJJKR-UHFFFAOYSA-N cyclopropyl-(4,6-dichloropyrimidin-5-yl)methanone Chemical compound ClC1=NC=NC(Cl)=C1C(=O)C1CC1 LPKNCFYQYOJJKR-UHFFFAOYSA-N 0.000 description 1
- 239000002254 cytotoxic agent Substances 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- 231100000599 cytotoxic agent Toxicity 0.000 description 1
- 230000008021 deposition Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 1
- 229940038472 dicalcium phosphate Drugs 0.000 description 1
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 1
- 229940043279 diisopropylamine Drugs 0.000 description 1
- XPPKVPWEQAFLFU-UHFFFAOYSA-J diphosphate(4-) Chemical compound [O-]P([O-])(=O)OP([O-])([O-])=O XPPKVPWEQAFLFU-UHFFFAOYSA-J 0.000 description 1
- 235000011180 diphosphates Nutrition 0.000 description 1
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 1
- 229940042399 direct acting antivirals protease inhibitors Drugs 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000004043 dyeing Methods 0.000 description 1
- 239000012636 effector Substances 0.000 description 1
- 229920001971 elastomer Polymers 0.000 description 1
- 238000000132 electrospray ionisation Methods 0.000 description 1
- 238000003821 enantio-separation Methods 0.000 description 1
- 210000002889 endothelial cell Anatomy 0.000 description 1
- 229940088598 enzyme Drugs 0.000 description 1
- 239000003797 essential amino acid Substances 0.000 description 1
- 235000020776 essential amino acid Nutrition 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000010685 fatty oil Substances 0.000 description 1
- 239000012894 fetal calf serum Substances 0.000 description 1
- 239000012025 fluorinating agent Substances 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 125000001207 fluorophenyl group Chemical group 0.000 description 1
- 238000005187 foaming Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 229940014259 gelatin Drugs 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 125000005283 haloketone group Chemical group 0.000 description 1
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 1
- 235000001050 hortel pimenta Nutrition 0.000 description 1
- 239000008172 hydrogenated vegetable oil Substances 0.000 description 1
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 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
- 229940071676 hydroxypropylcellulose Drugs 0.000 description 1
- 201000001421 hyperglycemia Diseases 0.000 description 1
- 238000010191 image analysis Methods 0.000 description 1
- 238000010185 immunofluorescence analysis Methods 0.000 description 1
- 102000018358 immunoglobulin Human genes 0.000 description 1
- 229940072221 immunoglobulins Drugs 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- ZPNFWUPYTFPOJU-LPYSRVMUSA-N iniprol Chemical compound C([C@H]1C(=O)NCC(=O)NCC(=O)N[C@H]2CSSC[C@H]3C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@H](C(N[C@H](C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=4C=CC(O)=CC=4)C(=O)N[C@@H](CC=4C=CC=CC=4)C(=O)N[C@@H](CC=4C=CC(O)=CC=4)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CC=4C=CC=CC=4)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC2=O)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](CC=2C=CC=CC=2)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H]2N(CCC2)C(=O)[C@@H](N)CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N2[C@@H](CCC2)C(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CC=2C=CC(O)=CC=2)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N2[C@@H](CCC2)C(=O)N3)C(=O)NCC(=O)NCC(=O)N[C@@H](C)C(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@H](C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@H](C(=O)N1)C(C)C)[C@@H](C)O)[C@@H](C)CC)=O)[C@@H](C)CC)C1=CC=C(O)C=C1 ZPNFWUPYTFPOJU-LPYSRVMUSA-N 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- HVTICUPFWKNHNG-UHFFFAOYSA-N iodoethane Chemical compound CCI HVTICUPFWKNHNG-UHFFFAOYSA-N 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- SRJOCJYGOFTFLH-UHFFFAOYSA-N isonipecotic acid Chemical compound OC(=O)C1CCNCC1 SRJOCJYGOFTFLH-UHFFFAOYSA-N 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 229960001375 lactose Drugs 0.000 description 1
- GDBQQVLCIARPGH-ULQDDVLXSA-N leupeptin Chemical compound CC(C)C[C@H](NC(C)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C=O)CCCN=C(N)N GDBQQVLCIARPGH-ULQDDVLXSA-N 0.000 description 1
- 108010052968 leupeptin Proteins 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 239000011344 liquid material Substances 0.000 description 1
- 239000006194 liquid suspension Substances 0.000 description 1
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Substances [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 239000012139 lysis buffer Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- FRIJBUGBVQZNTB-UHFFFAOYSA-M magnesium;ethane;bromide Chemical compound [Mg+2].[Br-].[CH2-]C FRIJBUGBVQZNTB-UHFFFAOYSA-M 0.000 description 1
- 210000005075 mammary gland Anatomy 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 229940126601 medicinal product Drugs 0.000 description 1
- COTNUBDHGSIOTA-UHFFFAOYSA-N meoh methanol Chemical compound OC.OC COTNUBDHGSIOTA-UHFFFAOYSA-N 0.000 description 1
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 1
- 229910052753 mercury Inorganic materials 0.000 description 1
- WSFSSNUMVMOOMR-BJUDXGSMSA-N methanone Chemical compound O=[11CH2] WSFSSNUMVMOOMR-BJUDXGSMSA-N 0.000 description 1
- BBCHMKFYIGAFJX-UHFFFAOYSA-N methyl 1-benzylpiperidine-4-carboximidate;hydrochloride Chemical compound Cl.C1CC(C(=N)OC)CCN1CC1=CC=CC=C1 BBCHMKFYIGAFJX-UHFFFAOYSA-N 0.000 description 1
- STZCRXQWRGQSJD-GEEYTBSJSA-M methyl orange Chemical compound [Na+].C1=CC(N(C)C)=CC=C1\N=N\C1=CC=C(S([O-])(=O)=O)C=C1 STZCRXQWRGQSJD-GEEYTBSJSA-M 0.000 description 1
- 229940012189 methyl orange Drugs 0.000 description 1
- 229960001047 methyl salicylate Drugs 0.000 description 1
- 238000001000 micrograph Methods 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000008185 minitablet Substances 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- LKPFBGKZCCBZDK-UHFFFAOYSA-N n-hydroxypiperidine Chemical class ON1CCCCC1 LKPFBGKZCCBZDK-UHFFFAOYSA-N 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 238000010899 nucleation Methods 0.000 description 1
- 235000020824 obesity Nutrition 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- QNDVLZJODHBUFM-WFXQOWMNSA-N okadaic acid Chemical compound C([C@H](O1)[C@H](C)/C=C/[C@H]2CC[C@@]3(CC[C@H]4O[C@@H](C([C@@H](O)[C@@H]4O3)=C)[C@@H](O)C[C@H](C)[C@@H]3[C@@H](CC[C@@]4(OCCCC4)O3)C)O2)C(C)=C[C@]21O[C@H](C[C@@](C)(O)C(O)=O)CC[C@H]2O QNDVLZJODHBUFM-WFXQOWMNSA-N 0.000 description 1
- VEFJHAYOIAAXEU-UHFFFAOYSA-N okadaic acid Natural products CC(CC(O)C1OC2CCC3(CCC(O3)C=CC(C)C4CC(=CC5(OC(CC(C)(O)C(=O)O)CCC5O)O4)C)OC2C(O)C1C)C6OC7(CCCCO7)CCC6C VEFJHAYOIAAXEU-UHFFFAOYSA-N 0.000 description 1
- 230000000174 oncolytic effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 125000005981 pentynyl group Chemical group 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 229940080469 phosphocellulose Drugs 0.000 description 1
- 235000011007 phosphoric acid Nutrition 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- XUWHAWMETYGRKB-UHFFFAOYSA-N piperidin-2-one Chemical compound O=C1CCCCN1 XUWHAWMETYGRKB-UHFFFAOYSA-N 0.000 description 1
- FSDNTQSJGHSJBG-UHFFFAOYSA-N piperidine-4-carbonitrile Chemical compound N#CC1CCNCC1 FSDNTQSJGHSJBG-UHFFFAOYSA-N 0.000 description 1
- 150000003053 piperidines Chemical class 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920000193 polymethacrylate Polymers 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229940068968 polysorbate 80 Drugs 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 1
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229940069328 povidone Drugs 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- ATLPLEZDTSBZQG-UHFFFAOYSA-N propan-2-ylphosphonic acid Chemical compound CC(C)P(O)(O)=O ATLPLEZDTSBZQG-UHFFFAOYSA-N 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- NSETWVJZUWGCKE-UHFFFAOYSA-N propylphosphonic acid Chemical compound CCCP(O)(O)=O NSETWVJZUWGCKE-UHFFFAOYSA-N 0.000 description 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000010926 purge Methods 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 229910052707 ruthenium Inorganic materials 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- 229940081974 saccharin Drugs 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- 239000000565 sealant Substances 0.000 description 1
- 239000013049 sediment Substances 0.000 description 1
- 239000012056 semi-solid material Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 210000001626 skin fibroblast Anatomy 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 229940054269 sodium pyruvate Drugs 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- 239000011343 solid material Substances 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 229940032147 starch Drugs 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 238000004885 tandem mass spectrometry Methods 0.000 description 1
- AEOAGZDJLYGYDQ-UHFFFAOYSA-N tert-butyl 4-(phenacylcarbamoyl)piperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1C(=O)NCC(=O)C1=CC=CC=C1 AEOAGZDJLYGYDQ-UHFFFAOYSA-N 0.000 description 1
- MTOLEMFLYUXUCY-UHFFFAOYSA-N tert-butyl 4-[5-(3-chlorophenyl)-1h-imidazol-2-yl]piperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1C1=NC(C=2C=C(Cl)C=CC=2)=CN1 MTOLEMFLYUXUCY-UHFFFAOYSA-N 0.000 description 1
- VOUYUUQFVACMHT-UHFFFAOYSA-N tert-butyl 4-[[1-[4-fluoro-3-(trifluoromethyl)phenyl]-1-oxopropan-2-yl]carbamoyl]piperidine-1-carboxylate Chemical compound C=1C=C(F)C(C(F)(F)F)=CC=1C(=O)C(C)NC(=O)C1CCN(C(=O)OC(C)(C)C)CC1 VOUYUUQFVACMHT-UHFFFAOYSA-N 0.000 description 1
- ZWFVUTIPIQJWMY-UHFFFAOYSA-N tert-butyl 4-[[2-[2-fluoro-5-(trifluoromethyl)phenyl]-2-oxoethyl]carbamoyl]piperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1C(=O)NCC(=O)C1=CC(C(F)(F)F)=CC=C1F ZWFVUTIPIQJWMY-UHFFFAOYSA-N 0.000 description 1
- RQPHXFYAUANHMN-UHFFFAOYSA-N tert-butyl 4-[[2-[3-fluoro-5-(trifluoromethyl)phenyl]-2-oxoethyl]carbamoyl]piperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1C(=O)NCC(=O)C1=CC(F)=CC(C(F)(F)F)=C1 RQPHXFYAUANHMN-UHFFFAOYSA-N 0.000 description 1
- UQADQTBQNVARAP-UHFFFAOYSA-N tert-butyl 4-cyanopiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(C#N)CC1 UQADQTBQNVARAP-UHFFFAOYSA-N 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- WJKHJLXJJJATHN-UHFFFAOYSA-N trifluoromethanesulfonic anhydride Substances FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
- 210000003606 umbilical vein Anatomy 0.000 description 1
- LSGOVYNHVSXFFJ-UHFFFAOYSA-N vanadate(3-) Chemical compound [O-][V]([O-])([O-])=O LSGOVYNHVSXFFJ-UHFFFAOYSA-N 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 150000003722 vitamin derivatives Chemical class 0.000 description 1
- 235000012431 wafers Nutrition 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Vascular Medicine (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US91733107P | 2007-05-11 | 2007-05-11 | |
| PCT/US2008/062143 WO2008140947A1 (en) | 2007-05-11 | 2008-05-01 | P70 s6 kinase inhibitors |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| EA200971051A1 EA200971051A1 (ru) | 2010-06-30 |
| EA016445B1 true EA016445B1 (ru) | 2012-05-30 |
Family
ID=39765082
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EA200971051A EA016445B1 (ru) | 2007-05-11 | 2008-05-01 | ИНГИБИТОРЫ p70 S6 КИНАЗЫ |
Country Status (33)
Families Citing this family (37)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| UA99284C2 (ru) * | 2007-05-11 | 2012-08-10 | Елі Ліллі Енд Компані | ИНГИБИТОРЫ р70 S6-КИНАЗЫ |
| US8252791B2 (en) * | 2008-08-13 | 2012-08-28 | Jenrin Discovery, Inc. | Purine compounds as cannabinoid receptor blockers |
| AR074072A1 (es) | 2008-11-11 | 2010-12-22 | Lilly Co Eli | Compuesto de imidazol -piperidin -pirrol-pirimidin-6-ona, composicion farmaceutica que lo comprende y su uso para preparar un medicamento util para tratar el glioblastoma multiforme |
| KR20110075015A (ko) * | 2008-11-11 | 2011-07-05 | 일라이 릴리 앤드 캄파니 | Ｐ70 ｓ6 키나제 억제제 및 ｅｇｆｒ 억제제 조합 요법 |
| US20110212977A1 (en) * | 2008-11-11 | 2011-09-01 | Eli Lilly And Company | P70 s6 kinase inhibitor and mtor inhibitor combination therapy |
| HRP20141239T1 (xx) | 2009-02-11 | 2015-03-13 | Merck Patent Gmbh | Novi amino azaheterocikliäśki karboksamidi |
| US9023847B2 (en) | 2009-08-07 | 2015-05-05 | Merck Patent Gmbh | Azaheterocyclic compounds |
| EA020151B1 (ru) * | 2009-10-23 | 2014-09-30 | Эли Лилли Энд Компани | Ингибиторы akt и фармацевтические составы, их содержащие |
| PH12012501581A1 (en) | 2010-02-03 | 2012-10-22 | Signal Pharm Llc | Identification of lkb1 mutation as a predictive biomarker for sensitivity to tor kinase inhibitors |
| UA110113C2 (xx) | 2010-07-29 | 2015-11-25 | Біциклічні азагетероциклічні карбоксаміди | |
| JP6014034B2 (ja) | 2010-07-29 | 2016-10-25 | メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツングＭｅｒｃｋ Ｐａｔｅｎｔ Ｇｅｓｅｌｌｓｃｈａｆｔ ｍｉｔ ｂｅｓｃｈｒａｅｎｋｔｅｒ Ｈａｆｔｕｎｇ | 環式アミンアザヘテロ環式カルボキサミド |
| EP2643313B9 (en) | 2010-11-24 | 2017-02-22 | Merck Patent GmbH | Quinazoline carboxamide azetidines |
| RS56534B1 (sr) * | 2011-09-12 | 2018-02-28 | Merck Patent Gmbh | Novi imidazol akmini kao modulatori aktivnosti kinaza |
| EA028057B1 (ru) | 2011-09-12 | 2017-10-31 | Мерк Патент Гмбх | Производные аминопиримидина для применения в качестве модуляторов киназной активности |
| AU2013312477B2 (en) * | 2012-09-06 | 2018-05-31 | Plexxikon Inc. | Compounds and methods for kinase modulation, and indications therefor |
| AU2013203714B2 (en) | 2012-10-18 | 2015-12-03 | Signal Pharmaceuticals, Llc | Inhibition of phosphorylation of PRAS40, GSK3-beta or P70S6K1 as a marker for TOR kinase inhibitory activity |
| CN105051043B (zh) | 2012-11-16 | 2017-05-10 | 默克专利有限公司 | 用作激酶活性调节剂的新颖的杂环类衍生物 |
| EP2920154B1 (en) * | 2012-11-16 | 2017-10-11 | Merck Patent GmbH | Novel imidazol-piperidinyl derivatives as modulators of kinase activity |
| JP6290917B2 (ja) | 2012-11-29 | 2018-03-07 | メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツングＭｅｒｃｋ Ｐａｔｅｎｔ Ｇｅｓｅｌｌｓｃｈａｆｔ ｍｉｔ ｂｅｓｃｈｒａｅｎｋｔｅｒ Ｈａｆｔｕｎｇ | アザキナゾリンカルボキサミド誘導体 |
| KR20150124957A (ko) | 2013-03-11 | 2015-11-06 | 메르크 파텐트 게엠베하 | 키나아제 활성의 조절인자로서 (6-[4-1h-이미다졸-2-일)피페리딘-1-일]피리미딘-4-아민 유도체 |
| CN105339008A (zh) | 2013-04-17 | 2016-02-17 | 西格诺药品有限公司 | 用于治疗癌症的包括tor激酶抑制剂和n-(3-(5-氟-2-(4-(2-甲氧基乙氧基)苯基氨基)嘧啶-4-基氨基)苯基)丙烯酰胺的组合疗法 |
| BR112015026257B1 (pt) | 2013-04-17 | 2022-12-20 | Signal Pharmaceuticals, Llc | Uso de um composto dihidropirazino-pirazina e enzalutamida, composição farmacêutica que os compreende, e kit |
| EP2986321A1 (en) | 2013-04-17 | 2016-02-24 | Signal Pharmaceuticals, LLC | Combination therapy comprising a tor kinase inhibitor and a cytidine analog for treating cancer |
| JP6382945B2 (ja) | 2013-04-17 | 2018-08-29 | シグナル ファーマシューティカルズ，エルエルシー | ジヒドロピラジノ−ピラジンによる癌治療 |
| MX368286B (es) | 2013-04-17 | 2019-09-27 | Signal Pharm Llc | Terapia de combinacion que comprende un inhibidor de tor cinasa y un compuesto de quinazolinona 5-sustituida para tratar cancer. |
| HK1221150A1 (zh) | 2013-04-17 | 2017-05-26 | 西格诺药品有限公司 | 用二氢吡嗪并-吡嗪类对癌症的治疗 |
| MX393164B (es) | 2013-04-17 | 2025-03-21 | Signal Pharm Llc | Formulaciones farmacéuticas, proceso, formas sólidas y métodos de uso relacionados con 1-etil-7-(2-metil-6-(1h-1,2,4-triazol-3-ii)piridin-3-ii)-3,4-dihidropirazino[2,3-b]pirazin-2(1h)-ona. |
| NZ629486A (en) | 2013-05-29 | 2017-11-24 | Signal Pharm Llc | Pharmaceutical compositions of 7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-((trans)-4-methoxycyclohexyl)-3,4-dihydropyrazino [2,3-b]pyrazin-2(1h)-one, a solid form thereof and methods of their use |
| WO2015134536A1 (en) * | 2014-03-04 | 2015-09-11 | Plexxikon Inc. | Compounds and methods for kinase modulation, and indications therefor |
| NZ725361A (en) | 2014-04-03 | 2022-09-30 | Merck Patent Gmbh | Combinations of cancer therapeutics |
| EP3131551A4 (en) | 2014-04-16 | 2017-09-20 | Signal Pharmaceuticals, LLC | SOLID FORMS COMPRISING 1-ETHYL-7-(2-METHYL-6-(1H-1,2,4-TRIAZOL-3-YL) PYRIDIN-3-YL)-3,4-DIHYDROPYRAZINO(2,3-b)PYRAZIN-2(1H)-ONE, AND A COFORMER, COMPOSITIONS AND METHODS OF USE THEREOF |
| NZ714742A (en) | 2014-04-16 | 2017-04-28 | Signal Pharm Llc | Solid forms of 1-ethyl-7-(2-methyl-6-(1h-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1h)-one, compositions thereof and methods of their use |
| WO2016040078A1 (en) * | 2014-09-10 | 2016-03-17 | Eli Lilly And Company | Substituted phenyl imidazolyl piperidyl compounds as p70s6k1 inhibitors |
| WO2016164641A1 (en) | 2015-04-08 | 2016-10-13 | Plexxikon Inc. | Compounds and methods for kinase modulation, and indications therefor |
| CN106187899B (zh) * | 2016-06-28 | 2019-07-16 | 绍兴文理学院 | 一种氟代氮杂芳烃的合成方法 |
| IL271491B2 (en) | 2017-06-22 | 2023-09-01 | Celgene Corp | Treatment of carcinoma of the liver characterized by hepatitis b virus infection |
| JP2023551408A (ja) | 2020-11-16 | 2023-12-08 | メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツング | がん処置のためのキナーゼインヒビター組み合わせ |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005117909A2 (en) * | 2004-04-23 | 2005-12-15 | Exelixis, Inc. | Kinase modulators and methods of use |
| WO2008075109A1 (en) * | 2006-12-21 | 2008-06-26 | Astex Therapeutics Limited | Substituted piperidines having protein kinase inhibiting activity |
Family Cites Families (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NL1004346C2 (nl) | 1996-10-23 | 1998-04-24 | Dsm Nv | Werkwijze voor het scheiden van een mengsel van enantiomeren in een geschikt oplosmiddel. |
| PA8474101A1 (es) | 1998-06-19 | 2000-09-29 | Pfizer Prod Inc | Compuestos de pirrolo [2,3-d] pirimidina |
| MY179032A (en) | 2004-10-25 | 2020-10-26 | Cancer Research Tech Ltd | Ortho-condensed pyridine and pyrimidine derivatives (e.g.purines) as protein kinase inhibitors |
| JP5274842B2 (ja) | 2004-12-28 | 2013-08-28 | エグゼリクシス， インコーポレイテッド | 免疫疾患、炎症疾患および増殖疾患の処置のためのセリン−スレオニンキナーゼモジュレーター（ｐ７０Ｓ６Ｋ、Ａｋｔ−１およびＡｋｔ−２）としての［１Ｈ−ピペラゾ［３，４−ｄ］ピリミジン−４−イル］−ピペラジンまたは［１Ｈ−ピペラゾ［３，４−ｄ］ピリミジン−４−イル］−ピペラジン化合物 |
| JP5114395B2 (ja) | 2005-06-30 | 2013-01-09 | プロシディオン・リミテッド | Ｇｐｃｒアゴニスト |
| US20090082370A1 (en) | 2006-04-25 | 2009-03-26 | Neil Thomas Thompson | Pharmaceutical Combinations of PK Inhibitors and Other Active Agents |
| WO2007125321A2 (en) | 2006-04-25 | 2007-11-08 | Astex Therapeutics Limited | Purine and deazapurine derivatives as pharmaceutical compounds |
| WO2008012635A2 (en) | 2006-07-26 | 2008-01-31 | Pfizer Products Inc. | Amine derivatives useful as anticancer agents |
| UA99284C2 (ru) * | 2007-05-11 | 2012-08-10 | Елі Ліллі Енд Компані | ИНГИБИТОРЫ р70 S6-КИНАЗЫ |
-
2008
- 2008-01-05 UA UAA200911422A patent/UA99284C2/ru unknown
- 2008-04-23 TW TW097114908A patent/TWI423805B/zh not_active IP Right Cessation
- 2008-04-29 PE PE2008000756A patent/PE20090887A1/es not_active Application Discontinuation
- 2008-04-29 AR ARP080101808A patent/AR066344A1/es unknown
- 2008-04-29 CL CL2008001230A patent/CL2008001230A1/es unknown
- 2008-05-01 BR BRPI0811212-6A2A patent/BRPI0811212A2/pt not_active IP Right Cessation
- 2008-05-01 MX MX2009012075A patent/MX2009012075A/es active IP Right Grant
- 2008-05-01 CN CN2008800156864A patent/CN101679439B/zh not_active Expired - Fee Related
- 2008-05-01 EA EA200971051A patent/EA016445B1/ru not_active IP Right Cessation
- 2008-05-01 AU AU2008251692A patent/AU2008251692B2/en not_active Ceased
- 2008-05-01 JP JP2010507532A patent/JP5503532B2/ja not_active Expired - Fee Related
- 2008-05-01 SI SI200831223T patent/SI2148880T1/sl unknown
- 2008-05-01 HR HRP20140611AT patent/HRP20140611T1/hr unknown
- 2008-05-01 DK DK08747285.8T patent/DK2148880T3/da active
- 2008-05-01 RS RS20140385A patent/RS53451B/sr unknown
- 2008-05-01 PL PL08747285T patent/PL2148880T3/pl unknown
- 2008-05-01 PT PT87472858T patent/PT2148880E/pt unknown
- 2008-05-01 MY MYPI20094763A patent/MY154898A/en unknown
- 2008-05-01 KR KR1020097023455A patent/KR101088219B1/ko not_active Expired - Fee Related
- 2008-05-01 NZ NZ580423A patent/NZ580423A/en not_active IP Right Cessation
- 2008-05-01 WO PCT/US2008/062143 patent/WO2008140947A1/en not_active Ceased
- 2008-05-01 CA CA2687265A patent/CA2687265C/en not_active Expired - Fee Related
- 2008-05-01 EP EP08747285.8A patent/EP2148880B1/en active Active
- 2008-05-01 ES ES08747285.8T patent/ES2483726T3/es active Active
-
2009
- 2009-03-02 US US12/396,103 patent/US8093383B2/en not_active Expired - Fee Related
- 2009-10-15 IL IL201564A patent/IL201564A/en not_active IP Right Cessation
- 2009-10-28 TN TNP2009000446A patent/TN2009000446A1/fr unknown
- 2009-11-09 EC EC2009009721A patent/ECSP099721A/es unknown
- 2009-11-10 DO DO2009000257A patent/DOP2009000257A/es unknown
- 2009-11-10 CO CO09127778A patent/CO6241109A2/es active IP Right Grant
- 2009-11-10 GT GT200900292A patent/GT200900292A/es unknown
- 2009-11-10 CR CR11106A patent/CR11106A/es unknown
- 2009-12-07 MA MA32404A patent/MA31433B1/fr unknown
-
2011
- 2011-11-30 US US13/307,560 patent/US20120071490A1/en not_active Abandoned
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005117909A2 (en) * | 2004-04-23 | 2005-12-15 | Exelixis, Inc. | Kinase modulators and methods of use |
| WO2008075109A1 (en) * | 2006-12-21 | 2008-06-26 | Astex Therapeutics Limited | Substituted piperidines having protein kinase inhibiting activity |
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EA016445B1 (ru) | ИНГИБИТОРЫ p70 S6 КИНАЗЫ | |
| US20250188080A1 (en) | Imidazolonylquinoline compounds and therapeutic uses thereof | |
| TWI774758B (zh) | C5-苯胺喹唑啉化合物及其治療癌症之用途 | |
| EA027984B1 (ru) | Аминохинолины в качестве ингибиторов rip2 киназы | |
| JP2017125029A (ja) | ５′−置換ヌクレオシド化合物 | |
| EP3576742B1 (en) | 6-[3,5-dihalogeno-4-(morpholin-4-yl)phenyl]-5-methyl-4,5-dihydropyridazin-3(2h)-one, modulators of pde3a or 3b for use in the treatment of cancer | |
| EP3679031A1 (en) | Inhibitors of wdr5 protein-protein binding | |
| EP3166945B1 (en) | Novel triazolopyrimidinone or triazolopyridinone derivatives, and use thereof | |
| AU2019297889A1 (en) | Biaryl ether-type quinazoline derivatives | |
| EP4188929B1 (en) | Substituted pyrrolo-pyridinone derivatives and therapeutic uses thereof | |
| AU2017405244A1 (en) | Novel pyrrolopyridine derivative, method for producing same, and use thereof | |
| US20220098201A1 (en) | The monohydrate of rogaratinib hydrochloride and solid states thereof | |
| HK1140767B (en) | P70 s6 kinase inhibitors | |
| KR20250056126A (ko) | 신규 퀴녹살린 화합물, 이의 제조방법 및 이의 용도 | |
| JP2026509598A (ja) | アゼチジンｐａｒｐ１阻害剤の結晶形態 | |
| CN121358726A (zh) | 取代的杂环化合物 | |
| EP4211140A1 (en) | Heterocyclic pericondensed cdc7 kinase inhibitors for the treatment of cancer | |
| HK40061019A (en) | Pyrrolopyrazole derivative |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MM4A | Lapse of a eurasian patent due to non-payment of renewal fees within the time limit in the following designated state(s) |
Designated state(s): AM AZ BY KZ KG MD TJ TM |
|
| MM4A | Lapse of a eurasian patent due to non-payment of renewal fees within the time limit in the following designated state(s) |
Designated state(s): RU |