WO1999055689A1 - Derives de radicicol - Google Patents
Derives de radicicol Download PDFInfo
- Publication number
- WO1999055689A1 WO1999055689A1 PCT/JP1999/002138 JP9902138W WO9955689A1 WO 1999055689 A1 WO1999055689 A1 WO 1999055689A1 JP 9902138 W JP9902138 W JP 9902138W WO 9955689 A1 WO9955689 A1 WO 9955689A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- substituted
- unsubstituted
- compound
- acceptable salt
- pharmaceutically acceptable
- Prior art date
Links
- AECPBJMOGBFQDN-YMYQVXQQSA-N radicicol Chemical class C1CCCC(=O)C[C@H]2[C@H](Cl)C(=O)CC(=O)[C@H]2C(=O)O[C@H](C)C[C@H]2O[C@@H]21 AECPBJMOGBFQDN-YMYQVXQQSA-N 0.000 title claims description 44
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 64
- 150000003839 salts Chemical class 0.000 claims abstract description 42
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 35
- 239000001257 hydrogen Substances 0.000 claims abstract description 35
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 25
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 claims abstract description 19
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 claims abstract description 19
- 125000003302 alkenyloxy group Chemical group 0.000 claims abstract description 15
- 125000001589 carboacyl group Chemical group 0.000 claims abstract description 15
- 125000005843 halogen group Chemical group 0.000 claims abstract description 14
- 125000002947 alkylene group Chemical group 0.000 claims abstract description 7
- 125000000547 substituted alkyl group Chemical group 0.000 claims abstract description 4
- -1 isooxazolyl Chemical group 0.000 claims description 174
- 125000000623 heterocyclic group Chemical group 0.000 claims description 32
- 125000003118 aryl group Chemical group 0.000 claims description 28
- KZNICNPSHKQLFF-UHFFFAOYSA-N succinimide Chemical class O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 claims description 26
- 150000002431 hydrogen Chemical class 0.000 claims description 22
- 125000003342 alkenyl group Chemical group 0.000 claims description 20
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 19
- XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical class C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 claims description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 14
- 239000003814 drug Substances 0.000 claims description 13
- 229960002317 succinimide Drugs 0.000 claims description 12
- 125000006615 aromatic heterocyclic group Chemical group 0.000 claims description 10
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 10
- 125000000335 thiazolyl group Chemical group 0.000 claims description 10
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 9
- 125000002971 oxazolyl group Chemical group 0.000 claims description 8
- 125000004928 piperidonyl group Chemical group 0.000 claims description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 7
- 125000002102 aryl alkyloxo group Chemical group 0.000 claims description 7
- 125000002632 imidazolidinyl group Chemical group 0.000 claims description 7
- 125000002636 imidazolinyl group Chemical group 0.000 claims description 7
- 125000002883 imidazolyl group Chemical group 0.000 claims description 7
- 150000003949 imides Chemical class 0.000 claims description 7
- 125000000160 oxazolidinyl group Chemical group 0.000 claims description 7
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 7
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 7
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 7
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 7
- 125000004665 trialkylsilyl group Chemical group 0.000 claims description 7
- 239000002246 antineoplastic agent Substances 0.000 claims description 6
- 201000010099 disease Diseases 0.000 claims description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 6
- 125000002541 furyl group Chemical group 0.000 claims description 6
- 125000001786 isothiazolyl group Chemical group 0.000 claims description 6
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 6
- 125000005106 triarylsilyl group Chemical group 0.000 claims description 6
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 5
- 125000001422 pyrrolinyl group Chemical group 0.000 claims description 5
- 229940124597 therapeutic agent Drugs 0.000 claims description 4
- 229960003444 immunosuppressant agent Drugs 0.000 claims description 3
- 239000003018 immunosuppressive agent Substances 0.000 claims description 3
- 125000003072 pyrazolidinyl group Chemical group 0.000 claims description 3
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 claims description 3
- 239000005483 tyrosine kinase inhibitor Substances 0.000 claims description 3
- 201000011510 cancer Diseases 0.000 claims description 2
- 230000001861 immunosuppressant effect Effects 0.000 claims description 2
- 150000004917 tyrosine kinase inhibitor derivatives Chemical class 0.000 claims description 2
- 125000005439 maleimidyl group Chemical class C1(C=CC(N1*)=O)=O 0.000 claims 3
- KEQGZUUPPQEDPF-UHFFFAOYSA-N 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione Chemical class CC1(C)N(Cl)C(=O)N(Cl)C1=O KEQGZUUPPQEDPF-UHFFFAOYSA-N 0.000 claims 1
- 230000036039 immunity Effects 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 186
- 230000002401 inhibitory effect Effects 0.000 abstract description 20
- 125000004435 hydrogen atom Chemical class [H]* 0.000 abstract description 11
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 72
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 71
- 150000001412 amines Chemical class 0.000 description 67
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 46
- 239000000203 mixture Substances 0.000 description 46
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 42
- 239000002904 solvent Substances 0.000 description 40
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 39
- 238000000034 method Methods 0.000 description 37
- 238000006243 chemical reaction Methods 0.000 description 34
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 33
- 238000005481 NMR spectroscopy Methods 0.000 description 29
- 239000000243 solution Substances 0.000 description 29
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 28
- 230000008569 process Effects 0.000 description 26
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 26
- 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 26
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 24
- 125000004432 carbon atom Chemical group C* 0.000 description 20
- 210000004027 cell Anatomy 0.000 description 20
- VYGYNVZNSSTDLJ-HKCOAVLJSA-N monorden Natural products CC1CC2OC2C=C/C=C/C(=O)CC3C(C(=CC(=C3Cl)O)O)C(=O)O1 VYGYNVZNSSTDLJ-HKCOAVLJSA-N 0.000 description 20
- 229930192524 radicicol Natural products 0.000 description 20
- 238000012360 testing method Methods 0.000 description 20
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 19
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 19
- 239000002253 acid Substances 0.000 description 18
- FFBHFFJDDLITSX-UHFFFAOYSA-N benzyl N-[2-hydroxy-4-(3-oxomorpholin-4-yl)phenyl]carbamate Chemical compound OC1=C(NC(=O)OCC2=CC=CC=C2)C=CC(=C1)N1CCOCC1=O FFBHFFJDDLITSX-UHFFFAOYSA-N 0.000 description 18
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 17
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 16
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 15
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- 238000004519 manufacturing process Methods 0.000 description 15
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 14
- 238000001816 cooling Methods 0.000 description 14
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 14
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 14
- 101150024075 Mapk1 gene Proteins 0.000 description 13
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 13
- 235000018102 proteins Nutrition 0.000 description 13
- 102000004169 proteins and genes Human genes 0.000 description 13
- 108090000623 proteins and genes Proteins 0.000 description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine hydrate Chemical compound O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 12
- 239000002244 precipitate Substances 0.000 description 12
- 238000010898 silica gel chromatography Methods 0.000 description 12
- 206010028980 Neoplasm Diseases 0.000 description 11
- 230000000259 anti-tumor effect Effects 0.000 description 11
- 239000007864 aqueous solution Substances 0.000 description 11
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 11
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 10
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 10
- 230000000694 effects Effects 0.000 description 10
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 10
- 239000010410 layer Substances 0.000 description 10
- 229920006395 saturated elastomer Polymers 0.000 description 10
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 10
- 102100033479 RAF proto-oncogene serine/threonine-protein kinase Human genes 0.000 description 9
- 101710141955 RAF proto-oncogene serine/threonine-protein kinase Proteins 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 150000003923 2,5-pyrrolediones Chemical class 0.000 description 8
- 239000003795 chemical substances by application Substances 0.000 description 8
- 229940079593 drug Drugs 0.000 description 8
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 8
- 238000001914 filtration Methods 0.000 description 8
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 8
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Substances C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 8
- YBYRMVIVWMBXKQ-UHFFFAOYSA-N phenylmethanesulfonyl fluoride Chemical compound FS(=O)(=O)CC1=CC=CC=C1 YBYRMVIVWMBXKQ-UHFFFAOYSA-N 0.000 description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- CFMZSMGAMPBRBE-UHFFFAOYSA-N 2-hydroxyisoindole-1,3-dione Chemical compound C1=CC=C2C(=O)N(O)C(=O)C2=C1 CFMZSMGAMPBRBE-UHFFFAOYSA-N 0.000 description 7
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 7
- 235000019270 ammonium chloride Nutrition 0.000 description 7
- 230000026731 phosphorylation Effects 0.000 description 7
- 238000006366 phosphorylation reaction Methods 0.000 description 7
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 7
- 125000001424 substituent group Chemical group 0.000 description 7
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 6
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- DGYIJVNZSDYBOE-UHFFFAOYSA-N [CH2]C1=CC=NC=C1 Chemical group [CH2]C1=CC=NC=C1 DGYIJVNZSDYBOE-UHFFFAOYSA-N 0.000 description 6
- 239000012894 fetal calf serum Substances 0.000 description 6
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 6
- 230000003834 intracellular effect Effects 0.000 description 6
- NPRYCHLHHVWLQZ-TURQNECASA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynylpurin-8-one Chemical compound NC1=NC=C2N(C(N(C2=N1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C NPRYCHLHHVWLQZ-TURQNECASA-N 0.000 description 5
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 5
- 239000002585 base Substances 0.000 description 5
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 239000006260 foam Substances 0.000 description 5
- 230000001506 immunosuppresive effect Effects 0.000 description 5
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 5
- KQZLRWGGWXJPOS-NLFPWZOASA-N 1-[(1R)-1-(2,4-dichlorophenyl)ethyl]-6-[(4S,5R)-4-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-5-methylcyclohexen-1-yl]pyrazolo[3,4-b]pyrazine-3-carbonitrile Chemical compound ClC1=C(C=CC(=C1)Cl)[C@@H](C)N1N=C(C=2C1=NC(=CN=2)C1=CC[C@@H]([C@@H](C1)C)N1[C@@H](CCC1)CO)C#N KQZLRWGGWXJPOS-NLFPWZOASA-N 0.000 description 4
- 208000026310 Breast neoplasm Diseases 0.000 description 4
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- 241000699670 Mus sp. Species 0.000 description 4
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 4
- 125000005236 alkanoylamino group Chemical group 0.000 description 4
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
- 229940125877 compound 31 Drugs 0.000 description 4
- 125000000392 cycloalkenyl group Chemical group 0.000 description 4
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 description 4
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 4
- 230000012010 growth Effects 0.000 description 4
- 239000012528 membrane Substances 0.000 description 4
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 4
- 239000012046 mixed solvent Substances 0.000 description 4
- 238000011580 nude mouse model Methods 0.000 description 4
- 229910052698 phosphorus Inorganic materials 0.000 description 4
- 239000011574 phosphorus Substances 0.000 description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 description 4
- 125000004076 pyridyl group Chemical group 0.000 description 4
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- PUZPDOWCWNUUKD-UHFFFAOYSA-M sodium fluoride Chemical compound [F-].[Na+] PUZPDOWCWNUUKD-UHFFFAOYSA-M 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 4
- ONDSBJMLAHVLMI-UHFFFAOYSA-N trimethylsilyldiazomethane Chemical compound C[Si](C)(C)[CH-][N+]#N ONDSBJMLAHVLMI-UHFFFAOYSA-N 0.000 description 4
- ABJSOROVZZKJGI-OCYUSGCXSA-N (1r,2r,4r)-2-(4-bromophenyl)-n-[(4-chlorophenyl)-(2-fluoropyridin-4-yl)methyl]-4-morpholin-4-ylcyclohexane-1-carboxamide Chemical compound C1=NC(F)=CC(C(NC(=O)[C@H]2[C@@H](C[C@@H](CC2)N2CCOCC2)C=2C=CC(Br)=CC=2)C=2C=CC(Cl)=CC=2)=C1 ABJSOROVZZKJGI-OCYUSGCXSA-N 0.000 description 3
- STBLNCCBQMHSRC-BATDWUPUSA-N (2s)-n-[(3s,4s)-5-acetyl-7-cyano-4-methyl-1-[(2-methylnaphthalen-1-yl)methyl]-2-oxo-3,4-dihydro-1,5-benzodiazepin-3-yl]-2-(methylamino)propanamide Chemical compound O=C1[C@@H](NC(=O)[C@H](C)NC)[C@H](C)N(C(C)=O)C2=CC(C#N)=CC=C2N1CC1=C(C)C=CC2=CC=CC=C12 STBLNCCBQMHSRC-BATDWUPUSA-N 0.000 description 3
- WZZBNLYBHUDSHF-DHLKQENFSA-N 1-[(3s,4s)-4-[8-(2-chloro-4-pyrimidin-2-yloxyphenyl)-7-fluoro-2-methylimidazo[4,5-c]quinolin-1-yl]-3-fluoropiperidin-1-yl]-2-hydroxyethanone Chemical compound CC1=NC2=CN=C3C=C(F)C(C=4C(=CC(OC=5N=CC=CN=5)=CC=4)Cl)=CC3=C2N1[C@H]1CCN(C(=O)CO)C[C@@H]1F WZZBNLYBHUDSHF-DHLKQENFSA-N 0.000 description 3
- 125000006023 1-pentenyl group Chemical group 0.000 description 3
- 125000004974 2-butenyl group Chemical group C(C=CC)* 0.000 description 3
- 125000006040 2-hexenyl group Chemical group 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- 206010006187 Breast cancer Diseases 0.000 description 3
- 229940126639 Compound 33 Drugs 0.000 description 3
- 229910019142 PO4 Inorganic materials 0.000 description 3
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 3
- PNUZDKCDAWUEGK-CYZMBNFOSA-N Sitafloxacin Chemical compound C([C@H]1N)N(C=2C(=C3C(C(C(C(O)=O)=CN3[C@H]3[C@H](C3)F)=O)=CC=2F)Cl)CC11CC1 PNUZDKCDAWUEGK-CYZMBNFOSA-N 0.000 description 3
- SMNRFWMNPDABKZ-WVALLCKVSA-N [[(2R,3S,4R,5S)-5-(2,6-dioxo-3H-pyridin-3-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [[[(2R,3S,4S,5R,6R)-4-fluoro-3,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-hydroxyphosphoryl]oxy-hydroxyphosphoryl] hydrogen phosphate Chemical compound OC[C@H]1O[C@H](OP(O)(=O)OP(O)(=O)OP(O)(=O)OP(O)(=O)OC[C@H]2O[C@H]([C@H](O)[C@@H]2O)C2C=CC(=O)NC2=O)[C@H](O)[C@@H](F)[C@@H]1O SMNRFWMNPDABKZ-WVALLCKVSA-N 0.000 description 3
- 125000002252 acyl group Chemical group 0.000 description 3
- 125000004423 acyloxy group Chemical group 0.000 description 3
- 150000001540 azides Chemical class 0.000 description 3
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 3
- 229910002092 carbon dioxide Inorganic materials 0.000 description 3
- 229940125878 compound 36 Drugs 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- GGSUCNLOZRCGPQ-UHFFFAOYSA-N diethylaniline Chemical compound CCN(CC)C1=CC=CC=C1 GGSUCNLOZRCGPQ-UHFFFAOYSA-N 0.000 description 3
- VHJLVAABSRFDPM-QWWZWVQMSA-N dithiothreitol Chemical compound SC[C@@H](O)[C@H](O)CS VHJLVAABSRFDPM-QWWZWVQMSA-N 0.000 description 3
- 210000002950 fibroblast Anatomy 0.000 description 3
- FVIZARNDLVOMSU-UHFFFAOYSA-N ginsenoside K Natural products C1CC(C2(CCC3C(C)(C)C(O)CCC3(C)C2CC2O)C)(C)C2C1C(C)(CCC=C(C)C)OC1OC(CO)C(O)C(O)C1O FVIZARNDLVOMSU-UHFFFAOYSA-N 0.000 description 3
- 239000003112 inhibitor Substances 0.000 description 3
- 229910052751 metal Inorganic materials 0.000 description 3
- 239000002184 metal Chemical class 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 125000001715 oxadiazolyl group Chemical group 0.000 description 3
- 239000008194 pharmaceutical composition Substances 0.000 description 3
- 239000010452 phosphate Substances 0.000 description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 3
- 125000005543 phthalimide group Chemical class 0.000 description 3
- 125000005936 piperidyl group Chemical group 0.000 description 3
- 229920002981 polyvinylidene fluoride Polymers 0.000 description 3
- 125000006239 protecting group Chemical group 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 238000006467 substitution reaction Methods 0.000 description 3
- DRDVJQOGFWAVLH-UHFFFAOYSA-N tert-butyl n-hydroxycarbamate Chemical compound CC(C)(C)OC(=O)NO DRDVJQOGFWAVLH-UHFFFAOYSA-N 0.000 description 3
- 125000005505 thiomorpholino group Chemical group 0.000 description 3
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 3
- 229920002554 vinyl polymer Polymers 0.000 description 3
- CDQDMLWGTVLQEE-UHFFFAOYSA-N (1-methylimidazol-2-yl)methanol Chemical compound CN1C=CN=C1CO CDQDMLWGTVLQEE-UHFFFAOYSA-N 0.000 description 2
- UAOUIVVJBYDFKD-XKCDOFEDSA-N (1R,9R,10S,11R,12R,15S,18S,21R)-10,11,21-trihydroxy-8,8-dimethyl-14-methylidene-4-(prop-2-enylamino)-20-oxa-5-thia-3-azahexacyclo[9.7.2.112,15.01,9.02,6.012,18]henicosa-2(6),3-dien-13-one Chemical compound C([C@@H]1[C@@H](O)[C@@]23C(C1=C)=O)C[C@H]2[C@]12C(N=C(NCC=C)S4)=C4CC(C)(C)[C@H]1[C@H](O)[C@]3(O)OC2 UAOUIVVJBYDFKD-XKCDOFEDSA-N 0.000 description 2
- LPGUXCZWQAHKLZ-XBLVEGMJSA-N (1e,3e)-deca-1,3-dien-1-ol Chemical compound CCCCCC\C=C\C=C\O LPGUXCZWQAHKLZ-XBLVEGMJSA-N 0.000 description 2
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 2
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 2
- IUSARDYWEPUTPN-OZBXUNDUSA-N (2r)-n-[(2s,3r)-4-[[(4s)-6-(2,2-dimethylpropyl)spiro[3,4-dihydropyrano[2,3-b]pyridine-2,1'-cyclobutane]-4-yl]amino]-3-hydroxy-1-[3-(1,3-thiazol-2-yl)phenyl]butan-2-yl]-2-methoxypropanamide Chemical compound C([C@H](NC(=O)[C@@H](C)OC)[C@H](O)CN[C@@H]1C2=CC(CC(C)(C)C)=CN=C2OC2(CCC2)C1)C(C=1)=CC=CC=1C1=NC=CS1 IUSARDYWEPUTPN-OZBXUNDUSA-N 0.000 description 2
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 2
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- NAOPGVBLRHCPHI-UHFFFAOYSA-N 2-(chloromethyl)-1,3-oxazole Chemical compound ClCC1=NC=CO1 NAOPGVBLRHCPHI-UHFFFAOYSA-N 0.000 description 2
- MIJDSYMOBYNHOT-UHFFFAOYSA-N 2-(ethylamino)ethanol Chemical compound CCNCCO MIJDSYMOBYNHOT-UHFFFAOYSA-N 0.000 description 2
- 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 2
- YSUIQYOGTINQIN-UZFYAQMZSA-N 2-amino-9-[(1S,6R,8R,9S,10R,15R,17R,18R)-8-(6-aminopurin-9-yl)-9,18-difluoro-3,12-dihydroxy-3,12-bis(sulfanylidene)-2,4,7,11,13,16-hexaoxa-3lambda5,12lambda5-diphosphatricyclo[13.2.1.06,10]octadecan-17-yl]-1H-purin-6-one Chemical compound NC1=NC2=C(N=CN2[C@@H]2O[C@@H]3COP(S)(=O)O[C@@H]4[C@@H](COP(S)(=O)O[C@@H]2[C@@H]3F)O[C@H]([C@H]4F)N2C=NC3=C2N=CN=C3N)C(=O)N1 YSUIQYOGTINQIN-UZFYAQMZSA-N 0.000 description 2
- TVTJUIAKQFIXCE-HUKYDQBMSA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynyl-1H-purine-6,8-dione Chemical compound NC=1NC(C=2N(C(N(C=2N=1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C)=O TVTJUIAKQFIXCE-HUKYDQBMSA-N 0.000 description 2
- 125000006041 3-hexenyl group Chemical group 0.000 description 2
- 125000006042 4-hexenyl group Chemical group 0.000 description 2
- MOUXQYCTQDNCAQ-UHFFFAOYSA-N 4-methyl-2-pyridin-3-yl-1,3-thiazole Chemical compound CC1=CSC(C=2C=NC=CC=2)=N1 MOUXQYCTQDNCAQ-UHFFFAOYSA-N 0.000 description 2
- BKAWJIRCKVUVED-UHFFFAOYSA-N 5-(2-hydroxyethyl)-4-methylthiazole Chemical compound CC=1N=CSC=1CCO BKAWJIRCKVUVED-UHFFFAOYSA-N 0.000 description 2
- FASMXPUFMXBVRL-UHFFFAOYSA-N 5-(chloromethyl)-1h-imidazole;hydron;chloride Chemical compound Cl.ClCC1=CN=CN1 FASMXPUFMXBVRL-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- 102000002260 Alkaline Phosphatase Human genes 0.000 description 2
- 108020004774 Alkaline Phosphatase Proteins 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 2
- 101150029707 ERBB2 gene Proteins 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 108091008794 FGF receptors Proteins 0.000 description 2
- 102000044168 Fibroblast Growth Factor Receptor Human genes 0.000 description 2
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 2
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 2
- JRZJKWGQFNTSRN-UHFFFAOYSA-N Geldanamycin Natural products C1C(C)CC(OC)C(O)C(C)C=C(C)C(OC(N)=O)C(OC)CCC=C(C)C(=O)NC2=CC(=O)C(OC)=C1C2=O JRZJKWGQFNTSRN-UHFFFAOYSA-N 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerol Natural products OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- DHCLVCXQIBBOPH-UHFFFAOYSA-N Glycerol 2-phosphate Chemical compound OCC(CO)OP(O)(O)=O DHCLVCXQIBBOPH-UHFFFAOYSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical class NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 102000009465 Growth Factor Receptors Human genes 0.000 description 2
- 108010009202 Growth Factor Receptors Proteins 0.000 description 2
- 102100034051 Heat shock protein HSP 90-alpha Human genes 0.000 description 2
- 108010004889 Heat-Shock Proteins Proteins 0.000 description 2
- 102000002812 Heat-Shock Proteins Human genes 0.000 description 2
- 101001016865 Homo sapiens Heat shock protein HSP 90-alpha Proteins 0.000 description 2
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 2
- 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 2
- 239000002841 Lewis acid Substances 0.000 description 2
- 108091054455 MAP kinase family Proteins 0.000 description 2
- 102000043136 MAP kinase family Human genes 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- 241000699660 Mus musculus Species 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 2
- 108700020796 Oncogene Proteins 0.000 description 2
- 208000001132 Osteoporosis Diseases 0.000 description 2
- 108091008606 PDGF receptors Proteins 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- 102000011653 Platelet-Derived Growth Factor Receptors Human genes 0.000 description 2
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 2
- 230000010757 Reduction Activity Effects 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 229940123464 Thiazolidinedione Drugs 0.000 description 2
- 108010021119 Trichosanthin Proteins 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- LJOOWESTVASNOG-UFJKPHDISA-N [(1s,3r,4ar,7s,8s,8as)-3-hydroxy-8-[2-[(4r)-4-hydroxy-6-oxooxan-2-yl]ethyl]-7-methyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-yl] (2s)-2-methylbutanoate Chemical compound C([C@H]1[C@@H](C)C=C[C@H]2C[C@@H](O)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)CC1C[C@@H](O)CC(=O)O1 LJOOWESTVASNOG-UFJKPHDISA-N 0.000 description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
- 125000006848 alicyclic heterocyclic group Chemical group 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 230000029936 alkylation Effects 0.000 description 2
- 238000005804 alkylation reaction Methods 0.000 description 2
- 230000006229 amino acid addition Effects 0.000 description 2
- 150000003863 ammonium salts Chemical class 0.000 description 2
- XRWSZZJLZRKHHD-WVWIJVSJSA-N asunaprevir Chemical compound O=C([C@@H]1C[C@H](CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)OC1=NC=C(C2=CC=C(Cl)C=C21)OC)N[C@]1(C(=O)NS(=O)(=O)C2CC2)C[C@H]1C=C XRWSZZJLZRKHHD-WVWIJVSJSA-N 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- KGNDCEVUMONOKF-UGPLYTSKSA-N benzyl n-[(2r)-1-[(2s,4r)-2-[[(2s)-6-amino-1-(1,3-benzoxazol-2-yl)-1,1-dihydroxyhexan-2-yl]carbamoyl]-4-[(4-methylphenyl)methoxy]pyrrolidin-1-yl]-1-oxo-4-phenylbutan-2-yl]carbamate Chemical compound C1=CC(C)=CC=C1CO[C@H]1CN(C(=O)[C@@H](CCC=2C=CC=CC=2)NC(=O)OCC=2C=CC=CC=2)[C@H](C(=O)N[C@@H](CCCCN)C(O)(O)C=2OC3=CC=CC=C3N=2)C1 KGNDCEVUMONOKF-UGPLYTSKSA-N 0.000 description 2
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 2
- 239000001569 carbon dioxide Substances 0.000 description 2
- 230000010261 cell growth Effects 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000007810 chemical reaction solvent Substances 0.000 description 2
- 229940125904 compound 1 Drugs 0.000 description 2
- 229940125797 compound 12 Drugs 0.000 description 2
- 229940126543 compound 14 Drugs 0.000 description 2
- 229940125782 compound 2 Drugs 0.000 description 2
- 229940125833 compound 23 Drugs 0.000 description 2
- 229940125961 compound 24 Drugs 0.000 description 2
- 229940125851 compound 27 Drugs 0.000 description 2
- 229940127204 compound 29 Drugs 0.000 description 2
- 229940126214 compound 3 Drugs 0.000 description 2
- 229940125807 compound 37 Drugs 0.000 description 2
- BGTOWKSIORTVQH-UHFFFAOYSA-N cyclopentanone Chemical compound O=C1CCCC1 BGTOWKSIORTVQH-UHFFFAOYSA-N 0.000 description 2
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical compound NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 description 2
- 238000005828 desilylation reaction Methods 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- 125000005879 dioxolanyl group Chemical group 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 238000002451 electron ionisation mass spectrometry Methods 0.000 description 2
- 210000002919 epithelial cell Anatomy 0.000 description 2
- VFRSADQPWYCXDG-LEUCUCNGSA-N ethyl (2s,5s)-5-methylpyrrolidine-2-carboxylate;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.CCOC(=O)[C@@H]1CC[C@H](C)N1 VFRSADQPWYCXDG-LEUCUCNGSA-N 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- QTQAWLPCGQOSGP-GBTDJJJQSA-N geldanamycin Chemical compound N1C(=O)\C(C)=C/C=C\[C@@H](OC)[C@H](OC(N)=O)\C(C)=C/[C@@H](C)[C@@H](O)[C@H](OC)C[C@@H](C)CC2=C(OC)C(=O)C=C1C2=O QTQAWLPCGQOSGP-GBTDJJJQSA-N 0.000 description 2
- 229940012229 genone Drugs 0.000 description 2
- 235000011187 glycerol Nutrition 0.000 description 2
- AWUCVROLDVIAJX-UHFFFAOYSA-N glycerol 1-phosphate Chemical compound OCC(O)COP(O)(O)=O AWUCVROLDVIAJX-UHFFFAOYSA-N 0.000 description 2
- 239000003966 growth inhibitor Substances 0.000 description 2
- 239000001963 growth medium Substances 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 229940091173 hydantoin Drugs 0.000 description 2
- 150000001469 hydantoins Chemical class 0.000 description 2
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 2
- 125000001041 indolyl group Chemical group 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 2
- 125000000842 isoxazolyl group Chemical group 0.000 description 2
- 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 2
- 108010052968 leupeptin Proteins 0.000 description 2
- 150000007517 lewis acids Chemical class 0.000 description 2
- 239000012139 lysis buffer 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
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 2
- 150000001475 oxazolidinediones Chemical class 0.000 description 2
- 150000002923 oximes Chemical class 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 125000005544 phthalimido group Chemical group 0.000 description 2
- 125000004193 piperazinyl group Chemical group 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 125000005494 pyridonyl group Chemical group 0.000 description 2
- 125000004929 pyrrolidonyl group Chemical group N1(C(CCC1)=O)* 0.000 description 2
- 230000001603 reducing effect Effects 0.000 description 2
- DAJSVUQLFFJUSX-UHFFFAOYSA-M sodium;dodecane-1-sulfonate Chemical compound [Na+].CCCCCCCCCCCCS([O-])(=O)=O DAJSVUQLFFJUSX-UHFFFAOYSA-M 0.000 description 2
- 108700026239 src Genes Proteins 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 150000003536 tetrazoles Chemical class 0.000 description 2
- 150000001467 thiazolidinediones Chemical class 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 230000009466 transformation Effects 0.000 description 2
- 238000000844 transformation Methods 0.000 description 2
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- QSXREDPBMQKKAY-UHFFFAOYSA-N (1-methylpyrazol-4-yl)methanol Chemical compound CN1C=C(CO)C=N1 QSXREDPBMQKKAY-UHFFFAOYSA-N 0.000 description 1
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 1
- SPICLIDXLMIBEV-UHFFFAOYSA-N (2-pyridin-3-yl-1,3-thiazol-5-yl)methanol Chemical compound S1C(CO)=CN=C1C1=CC=CN=C1 SPICLIDXLMIBEV-UHFFFAOYSA-N 0.000 description 1
- MEIRRNXMZYDVDW-MQQKCMAXSA-N (2E,4E)-2,4-hexadien-1-ol Chemical compound C\C=C\C=C\CO MEIRRNXMZYDVDW-MQQKCMAXSA-N 0.000 description 1
- WWTBZEKOSBFBEM-SPWPXUSOSA-N (2s)-2-[[2-benzyl-3-[hydroxy-[(1r)-2-phenyl-1-(phenylmethoxycarbonylamino)ethyl]phosphoryl]propanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound N([C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)O)C(=O)C(CP(O)(=O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1C=CC=CC=1)CC1=CC=CC=C1 WWTBZEKOSBFBEM-SPWPXUSOSA-N 0.000 description 1
- ZGOYAZACEFOHMF-UHFFFAOYSA-N (3,4,5-trimethyl-1H-pyrrol-2-yl)methanol Chemical compound CC=1NC(CO)=C(C)C=1C ZGOYAZACEFOHMF-UHFFFAOYSA-N 0.000 description 1
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 description 1
- VEEGZPWAAPPXRB-BJMVGYQFSA-N (3e)-3-(1h-imidazol-5-ylmethylidene)-1h-indol-2-one Chemical compound O=C1NC2=CC=CC=C2\C1=C/C1=CN=CN1 VEEGZPWAAPPXRB-BJMVGYQFSA-N 0.000 description 1
- AFVDZBIIBXWASR-AATRIKPKSA-N (E)-1,3,5-hexatriene Chemical compound C=C\C=C\C=C AFVDZBIIBXWASR-AATRIKPKSA-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
- OQJBFFCUFALWQL-BUHFOSPRSA-N (ne)-n-(piperidine-1-carbonylimino)piperidine-1-carboxamide Chemical compound C1CCCCN1C(=O)\N=N\C(=O)N1CCCCC1 OQJBFFCUFALWQL-BUHFOSPRSA-N 0.000 description 1
- LRBZCVZSIVOKEB-UHFFFAOYSA-N 1,3,5-trimethylimidazolidine-2,4-dione Chemical compound CC1N(C)C(=O)N(C)C1=O LRBZCVZSIVOKEB-UHFFFAOYSA-N 0.000 description 1
- CFGGPOYIWDAMRZ-UHFFFAOYSA-N 1,3-thiazolidine-2,2-diamine Chemical class NC1(N)NCCS1 CFGGPOYIWDAMRZ-UHFFFAOYSA-N 0.000 description 1
- ZOBPZXTWZATXDG-UHFFFAOYSA-N 1,3-thiazolidine-2,4-dione Chemical compound O=C1CSC(=O)N1 ZOBPZXTWZATXDG-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- YIWGJFPJRAEKMK-UHFFFAOYSA-N 1-(2H-benzotriazol-5-yl)-3-methyl-8-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carbonyl]-1,3,8-triazaspiro[4.5]decane-2,4-dione Chemical compound CN1C(=O)N(c2ccc3n[nH]nc3c2)C2(CCN(CC2)C(=O)c2cnc(NCc3cccc(OC(F)(F)F)c3)nc2)C1=O YIWGJFPJRAEKMK-UHFFFAOYSA-N 0.000 description 1
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 1
- XYHKNCXZYYTLRG-UHFFFAOYSA-N 1h-imidazole-2-carbaldehyde Chemical compound O=CC1=NC=CN1 XYHKNCXZYYTLRG-UHFFFAOYSA-N 0.000 description 1
- VFYFMNCKPJDAPV-UHFFFAOYSA-N 2,2'-(5-oxo-1,3-dioxolan-4,4-diyl)diessigs Chemical compound C1N(C2)CN3CN1CN2C3.OC(=O)CC1(CC(O)=O)OCOC1=O VFYFMNCKPJDAPV-UHFFFAOYSA-N 0.000 description 1
- NHBKXEKEPDILRR-UHFFFAOYSA-N 2,3-bis(butanoylsulfanyl)propyl butanoate Chemical compound CCCC(=O)OCC(SC(=O)CCC)CSC(=O)CCC NHBKXEKEPDILRR-UHFFFAOYSA-N 0.000 description 1
- DZPCYXCBXGQBRN-UHFFFAOYSA-N 2,5-Dimethyl-2,4-hexadiene Chemical compound CC(C)=CC=C(C)C DZPCYXCBXGQBRN-UHFFFAOYSA-N 0.000 description 1
- VZSRBBMJRBPUNF-UHFFFAOYSA-N 2-(2,3-dihydro-1H-inden-2-ylamino)-N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]pyrimidine-5-carboxamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C(=O)NCCC(N1CC2=C(CC1)NN=N2)=O VZSRBBMJRBPUNF-UHFFFAOYSA-N 0.000 description 1
- DOSUQMBAMQLTFF-UHFFFAOYSA-N 2-(2-hydroxyethoxy)isoindole-1,3-dione Chemical compound C1=CC=C2C(=O)N(OCCO)C(=O)C2=C1 DOSUQMBAMQLTFF-UHFFFAOYSA-N 0.000 description 1
- QFPZMJPLWKOVEY-UHFFFAOYSA-N 2-(3,5-diphenyltetrazolidin-2-yl)-4,5-dimethyl-1,3-thiazole Chemical compound S1C(C)=C(C)N=C1N1N(C=2C=CC=CC=2)NC(C=2C=CC=CC=2)N1 QFPZMJPLWKOVEY-UHFFFAOYSA-N 0.000 description 1
- UXFWTIGUWHJKDD-UHFFFAOYSA-N 2-(4-bromobutyl)isoindole-1,3-dione Chemical compound C1=CC=C2C(=O)N(CCCCBr)C(=O)C2=C1 UXFWTIGUWHJKDD-UHFFFAOYSA-N 0.000 description 1
- OIUHSFKEXYXWSD-UHFFFAOYSA-N 2-[3-(6-methylpyridin-2-yl)propoxy]ethanol Chemical compound CC1=CC=CC(CCCOCCO)=N1 OIUHSFKEXYXWSD-UHFFFAOYSA-N 0.000 description 1
- LDLCZOVUSADOIV-UHFFFAOYSA-N 2-bromoethanol Chemical compound OCCBr LDLCZOVUSADOIV-UHFFFAOYSA-N 0.000 description 1
- ZCHCHJQEWYIJDQ-UHFFFAOYSA-N 2-methyl-1,3-oxazole Chemical compound CC1=NC=CO1 ZCHCHJQEWYIJDQ-UHFFFAOYSA-N 0.000 description 1
- WYKOXFDRTSNVGV-UHFFFAOYSA-N 2-pyridin-3-yl-1,3-thiazole-5-carboxylic acid Chemical compound S1C(C(=O)O)=CN=C1C1=CC=CN=C1 WYKOXFDRTSNVGV-UHFFFAOYSA-N 0.000 description 1
- VWZDHGLXYWXXKF-UHFFFAOYSA-N 3,4,5-trimethyl-1h-pyrrole-2-carbaldehyde Chemical compound CC=1NC(C=O)=C(C)C=1C VWZDHGLXYWXXKF-UHFFFAOYSA-N 0.000 description 1
- QBWKPGNFQQJGFY-QLFBSQMISA-N 3-[(1r)-1-[(2r,6s)-2,6-dimethylmorpholin-4-yl]ethyl]-n-[6-methyl-3-(1h-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]-1,2-thiazol-5-amine Chemical compound N1([C@H](C)C2=NSC(NC=3C4=NC=C(N4C=C(C)N=3)C3=CNN=C3)=C2)C[C@H](C)O[C@H](C)C1 QBWKPGNFQQJGFY-QLFBSQMISA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 1
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 1
- NIFAUKBQIAURIM-UHFFFAOYSA-N 4-(chloromethyl)-3,5-dimethyl-1,2-oxazole Chemical compound CC1=NOC(C)=C1CCl NIFAUKBQIAURIM-UHFFFAOYSA-N 0.000 description 1
- IMBBXSASDSZJSX-UHFFFAOYSA-N 4-Carboxypyrazole Chemical compound OC(=O)C=1C=NNC=1 IMBBXSASDSZJSX-UHFFFAOYSA-N 0.000 description 1
- 125000005986 4-piperidonyl group Chemical group 0.000 description 1
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 1
- CQOAMXQYKCRSFJ-UHFFFAOYSA-N 5-(chloromethyl)-2-trityltetrazole Chemical compound N1=C(CCl)N=NN1C(C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 CQOAMXQYKCRSFJ-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 241000251169 Alopias vulpinus Species 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- DJHGAFSJWGLOIV-UHFFFAOYSA-N Arsenic acid Chemical group O[As](O)(O)=O DJHGAFSJWGLOIV-UHFFFAOYSA-N 0.000 description 1
- 229910015900 BF3 Inorganic materials 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- ZBJJDYGJCNTNTH-UHFFFAOYSA-N Betahistine mesilate Chemical group CS(O)(=O)=O.CS(O)(=O)=O.CNCCC1=CC=CC=N1 ZBJJDYGJCNTNTH-UHFFFAOYSA-N 0.000 description 1
- 208000006386 Bone Resorption Diseases 0.000 description 1
- 229940078581 Bone resorption inhibitor Drugs 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-N Carbamic acid Chemical compound NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 241000725101 Clea Species 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 1
- 229940126657 Compound 17 Drugs 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 108010037462 Cyclooxygenase 2 Proteins 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 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
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 1
- SNRUBQQJIBEYMU-UHFFFAOYSA-N Dodecane Natural products CCCCCCCCCCCC SNRUBQQJIBEYMU-UHFFFAOYSA-N 0.000 description 1
- 102000001301 EGF receptor Human genes 0.000 description 1
- 108060006698 EGF receptor Proteins 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- XPDWGBQVDMORPB-UHFFFAOYSA-N Fluoroform Chemical group FC(F)F XPDWGBQVDMORPB-UHFFFAOYSA-N 0.000 description 1
- 229930091371 Fructose Natural products 0.000 description 1
- 239000005715 Fructose Substances 0.000 description 1
- 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 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- 101710113436 GTPase KRas Proteins 0.000 description 1
- 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 1
- 239000004471 Glycine Substances 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- 101001059454 Homo sapiens Serine/threonine-protein kinase MARK2 Proteins 0.000 description 1
- 108010001336 Horseradish Peroxidase Proteins 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- 241000257303 Hymenoptera 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
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 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
- 102000016267 Leptin Human genes 0.000 description 1
- 108010092277 Leptin Proteins 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
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- PEEHTFAAVSWFBL-UHFFFAOYSA-N Maleimide Chemical compound O=C1NC(=O)C=C1 PEEHTFAAVSWFBL-UHFFFAOYSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 108010006519 Molecular Chaperones Proteins 0.000 description 1
- 102000005431 Molecular Chaperones Human genes 0.000 description 1
- AFCARXCZXQIEQB-UHFFFAOYSA-N N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CCNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 AFCARXCZXQIEQB-UHFFFAOYSA-N 0.000 description 1
- OPFJDXRVMFKJJO-ZHHKINOHSA-N N-{[3-(2-benzamido-4-methyl-1,3-thiazol-5-yl)-pyrazol-5-yl]carbonyl}-G-dR-G-dD-dD-dD-NH2 Chemical compound S1C(C=2NN=C(C=2)C(=O)NCC(=O)N[C@H](CCCN=C(N)N)C(=O)NCC(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(N)=O)=C(C)N=C1NC(=O)C1=CC=CC=C1 OPFJDXRVMFKJJO-ZHHKINOHSA-N 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- IHSPRLWFZHPRNC-UHFFFAOYSA-N OCC[NH+]1C=CO[CH-]1 Chemical compound OCC[NH+]1C=CO[CH-]1 IHSPRLWFZHPRNC-UHFFFAOYSA-N 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- JKRZOJADNVOXPM-UHFFFAOYSA-N Oxalic acid dibutyl ester Chemical compound CCCCOC(=O)C(=O)OCCCC JKRZOJADNVOXPM-UHFFFAOYSA-N 0.000 description 1
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 description 1
- 108091000080 Phosphotransferase Proteins 0.000 description 1
- 229920002685 Polyoxyl 35CastorOil Polymers 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 102100038280 Prostaglandin G/H synthase 2 Human genes 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- 102100028904 Serine/threonine-protein kinase MARK2 Human genes 0.000 description 1
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical group [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 208000005718 Stomach Neoplasms Diseases 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- 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 1
- 210000001744 T-lymphocyte Anatomy 0.000 description 1
- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 description 1
- FHKPLLOSJHHKNU-INIZCTEOSA-N [(3S)-3-[8-(1-ethyl-5-methylpyrazol-4-yl)-9-methylpurin-6-yl]oxypyrrolidin-1-yl]-(oxan-4-yl)methanone Chemical compound C(C)N1N=CC(=C1C)C=1N(C2=NC=NC(=C2N=1)O[C@@H]1CN(CC1)C(=O)C1CCOCC1)C FHKPLLOSJHHKNU-INIZCTEOSA-N 0.000 description 1
- WREOTYWODABZMH-DTZQCDIJSA-N [[(2r,3s,4r,5r)-3,4-dihydroxy-5-[2-oxo-4-(2-phenylethoxyamino)pyrimidin-1-yl]oxolan-2-yl]methoxy-hydroxyphosphoryl] phosphono hydrogen phosphate Chemical compound O[C@@H]1[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)O[C@H]1N(C=C\1)C(=O)NC/1=N\OCCC1=CC=CC=C1 WREOTYWODABZMH-DTZQCDIJSA-N 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 125000003647 acryloyl group Chemical group O=C([*])C([H])=C([H])[H] 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 1
- 150000008041 alkali metal carbonates Chemical class 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 125000002714 alpha-linolenoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])/C([H])=C([H])\C([H])([H])/C([H])=C([H])\C([H])([H])/C([H])=C([H])\C([H])([H])C([H])([H])[H] 0.000 description 1
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical class [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 description 1
- 230000033115 angiogenesis Effects 0.000 description 1
- 239000004037 angiogenesis inhibitor Substances 0.000 description 1
- 229940121369 angiogenesis inhibitor Drugs 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 125000005427 anthranyl group Chemical group 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 239000000427 antigen Substances 0.000 description 1
- 102000036639 antigens Human genes 0.000 description 1
- 108091007433 antigens Proteins 0.000 description 1
- 150000001499 aryl bromides Chemical class 0.000 description 1
- 125000005116 aryl carbamoyl group Chemical group 0.000 description 1
- 125000004104 aryloxy group Chemical group 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 125000005604 azodicarboxylate group Chemical group 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- MJSHDCCLFGOEIK-UHFFFAOYSA-N benzyl (2,5-dioxopyrrolidin-1-yl) carbonate Chemical compound O=C1CCC(=O)N1OC(=O)OCC1=CC=CC=C1 MJSHDCCLFGOEIK-UHFFFAOYSA-N 0.000 description 1
- 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 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 230000024279 bone resorption Effects 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 235000010216 calcium carbonate Nutrition 0.000 description 1
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 230000005907 cancer growth Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 235000013877 carbamide Nutrition 0.000 description 1
- 229910002091 carbon monoxide Inorganic materials 0.000 description 1
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 150000007942 carboxylates Chemical class 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000024245 cell differentiation Effects 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 229940125773 compound 10 Drugs 0.000 description 1
- 229940125758 compound 15 Drugs 0.000 description 1
- 229940126142 compound 16 Drugs 0.000 description 1
- 229940126086 compound 21 Drugs 0.000 description 1
- 229940126208 compound 22 Drugs 0.000 description 1
- 229940125846 compound 25 Drugs 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 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
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([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
- 229940104302 cytosine Drugs 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000007123 defense Effects 0.000 description 1
- 230000036576 dermal application Effects 0.000 description 1
- 230000000368 destabilizing effect Effects 0.000 description 1
- 235000019700 dicalcium phosphate Nutrition 0.000 description 1
- NFDFQCUYFHCNBW-SCGPFSFSSA-N dienestrol Chemical compound C=1C=C(O)C=CC=1\C(=C/C)\C(=C\C)\C1=CC=C(O)C=C1 NFDFQCUYFHCNBW-SCGPFSFSSA-N 0.000 description 1
- 239000000539 dimer Substances 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 125000005066 dodecenyl group Chemical group C(=CCCCCCCCCCC)* 0.000 description 1
- 125000003438 dodecyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000006196 drop Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 150000002085 enols Chemical class 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-L fumarate(2-) Chemical class [O-]C(=O)\C=C\C([O-])=O VZCYOOQTPOCHFL-OWOJBTEDSA-L 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 206010017758 gastric cancer Diseases 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 230000009036 growth inhibition Effects 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 150000003944 halohydrins Chemical class 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- WFNASTYGEKUMIY-UHFFFAOYSA-N hydron;1h-imidazol-5-ylmethanol;chloride Chemical compound Cl.OCC1=CN=CN1 WFNASTYGEKUMIY-UHFFFAOYSA-N 0.000 description 1
- BNTRVUUJBGBGLZ-UHFFFAOYSA-N hydron;pyridine-4-carbonyl chloride;chloride Chemical compound Cl.ClC(=O)C1=CC=NC=C1 BNTRVUUJBGBGLZ-UHFFFAOYSA-N 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 229940071676 hydroxypropylcellulose Drugs 0.000 description 1
- 208000026278 immune system disease Diseases 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000002198 insoluble material Substances 0.000 description 1
- 230000019736 interleukin-11 production Effects 0.000 description 1
- 230000031146 intracellular signal transduction Effects 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
- 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
- 238000002955 isolation Methods 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 125000000400 lauroyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- NRYBAZVQPHGZNS-ZSOCWYAHSA-N leptin Chemical compound O=C([C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](N)CC(C)C)CCSC)N1CCC[C@H]1C(=O)NCC(=O)N[C@@H](CS)C(O)=O NRYBAZVQPHGZNS-ZSOCWYAHSA-N 0.000 description 1
- 229940039781 leptin Drugs 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 125000005644 linolenyl group Chemical group 0.000 description 1
- 125000002669 linoleoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])/C([H])=C([H])\C([H])([H])/C([H])=C([H])\C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000005645 linoleyl group Chemical group 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 229910003002 lithium salt Inorganic materials 0.000 description 1
- 159000000002 lithium salts Chemical class 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 150000002688 maleic acid derivatives Chemical class 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- HGQQQXMARFJNCP-UHFFFAOYSA-N methyl 1-methylpyrazole-4-carboxylate Chemical compound COC(=O)C=1C=NN(C)C=1 HGQQQXMARFJNCP-UHFFFAOYSA-N 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- HAMGRBXTJNITHG-UHFFFAOYSA-N methyl isocyanate Chemical compound CN=C=O HAMGRBXTJNITHG-UHFFFAOYSA-N 0.000 description 1
- TWIIRMSFZNYMQE-UHFFFAOYSA-N methyl pyrazine-2-carboxylate Chemical compound COC(=O)C1=CN=CC=N1 TWIIRMSFZNYMQE-UHFFFAOYSA-N 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000000329 molecular dynamics simulation Methods 0.000 description 1
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 230000000877 morphologic effect Effects 0.000 description 1
- 210000002464 muscle smooth vascular Anatomy 0.000 description 1
- 125000001419 myristoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000009826 neoplastic cell growth Effects 0.000 description 1
- UZGLIIJVICEWHF-UHFFFAOYSA-N octogen Chemical group [O-][N+](=O)N1CN([N+]([O-])=O)CN([N+]([O-])=O)CN([N+]([O-])=O)C1 UZGLIIJVICEWHF-UHFFFAOYSA-N 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 1
- 210000002997 osteoclast Anatomy 0.000 description 1
- 150000003901 oxalic acid esters Chemical class 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 238000006146 oximation reaction Methods 0.000 description 1
- QUANRIQJNFHVEU-UHFFFAOYSA-N oxirane;propane-1,2,3-triol Chemical compound C1CO1.OCC(O)CO QUANRIQJNFHVEU-UHFFFAOYSA-N 0.000 description 1
- 150000002924 oxiranes Chemical class 0.000 description 1
- 125000001312 palmitoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000000913 palmityl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004115 pentoxy group Chemical group [*]OC([H])([H])C([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 125000000843 phenylene group Chemical class C1(=C(C=CC=C1)*)* 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- UXCDUFKZSUBXGM-UHFFFAOYSA-N phosphoric tribromide Chemical compound BrP(Br)(Br)=O UXCDUFKZSUBXGM-UHFFFAOYSA-N 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
- DCWXELXMIBXGTH-UHFFFAOYSA-N phosphotyrosine Chemical compound OC(=O)C(N)CC1=CC=C(OP(O)(O)=O)C=C1 DCWXELXMIBXGTH-UHFFFAOYSA-N 0.000 description 1
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 1
- 125000001557 phthalyl group Chemical group C(=O)(O)C1=C(C(=O)*)C=CC=C1 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 239000008389 polyethoxylated castor oil Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 125000001325 propanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 125000004307 pyrazin-2-yl group Chemical group [H]C1=C([H])N=C(*)C([H])=N1 0.000 description 1
- LFCWHDGQCWJKCG-UHFFFAOYSA-N pyrazin-2-ylmethanol Chemical compound OCC1=CN=CC=N1 LFCWHDGQCWJKCG-UHFFFAOYSA-N 0.000 description 1
- 125000002755 pyrazolinyl group Chemical group 0.000 description 1
- TXQWFIVRZNOPCK-UHFFFAOYSA-N pyridin-4-ylmethanamine Chemical compound NCC1=CC=NC=C1 TXQWFIVRZNOPCK-UHFFFAOYSA-N 0.000 description 1
- BGUWFUQJCDRPTL-UHFFFAOYSA-N pyridine-4-carbaldehyde Chemical compound O=CC1=CC=NC=C1 BGUWFUQJCDRPTL-UHFFFAOYSA-N 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 108010014186 ras Proteins Proteins 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000008844 regulatory mechanism Effects 0.000 description 1
- ATEBXHFBFRCZMA-VXTBVIBXSA-N rifabutin Chemical compound O([C@](C1=O)(C)O/C=C/[C@@H]([C@H]([C@@H](OC(C)=O)[C@H](C)[C@H](O)[C@H](C)[C@@H](O)[C@@H](C)\C=C\C=C(C)/C(=O)NC(=C2N3)C(=O)C=4C(O)=C5C)C)OC)C5=C1C=4C2=NC13CCN(CC(C)C)CC1 ATEBXHFBFRCZMA-VXTBVIBXSA-N 0.000 description 1
- 229960000885 rifabutin Drugs 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 229920002050 silicone resin Polymers 0.000 description 1
- 238000006884 silylation reaction Methods 0.000 description 1
- 230000008477 smooth muscle tissue growth Effects 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride 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
- 235000011083 sodium citrates Nutrition 0.000 description 1
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 1
- 239000011775 sodium fluoride Substances 0.000 description 1
- 235000013024 sodium fluoride Nutrition 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 125000003696 stearoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- 238000000859 sublimation Methods 0.000 description 1
- 230000008022 sublimation Effects 0.000 description 1
- 125000005017 substituted alkenyl group Chemical group 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 150000003892 tartrate salts Chemical class 0.000 description 1
- OPSQZIGTEBZROY-UHFFFAOYSA-N tert-butyl n-ethyl-n-(2-hydroxyethyl)carbamate Chemical compound OCCN(CC)C(=O)OC(C)(C)C OPSQZIGTEBZROY-UHFFFAOYSA-N 0.000 description 1
- QEMXHQIAXOOASZ-UHFFFAOYSA-N tetramethylammonium Chemical compound C[N+](C)(C)C QEMXHQIAXOOASZ-UHFFFAOYSA-N 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 150000003548 thiazolidines Chemical class 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- HFRXJVQOXRXOPP-UHFFFAOYSA-N thionyl bromide Chemical compound BrS(Br)=O HFRXJVQOXRXOPP-UHFFFAOYSA-N 0.000 description 1
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 238000011824 transgenic rat model Methods 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- TUQOTMZNTHZOKS-UHFFFAOYSA-N tributylphosphine Chemical compound CCCCP(CCCC)CCCC TUQOTMZNTHZOKS-UHFFFAOYSA-N 0.000 description 1
- SBWUUTJBFAAIKT-UHFFFAOYSA-N trimethyl(2-pyrimidin-2-yloxyethyl)silane Chemical compound C[Si](C)(C)CCOC1=NC=CC=N1 SBWUUTJBFAAIKT-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- IHIXIJGXTJIKRB-UHFFFAOYSA-N trisodium vanadate Chemical compound [Na+].[Na+].[Na+].[O-][V]([O-])([O-])=O IHIXIJGXTJIKRB-UHFFFAOYSA-N 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 108091005990 tyrosine-phosphorylated proteins Proteins 0.000 description 1
- 125000001493 tyrosinyl group Chemical group [H]OC1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D313/00—Heterocyclic compounds containing rings of more than six members having one oxygen atom as the only ring hetero atom
Definitions
- the present invention relates to a radicicol derivative or a pharmacologically acceptable salt thereof, which exhibits a tyrosine kinase inhibitory activity and has an antitumor or immunosuppressive action.
- Radicicol which is represented by the formula (B) and is a metabolite of microorganisms, has antifungal and anticancer effects [Nature, 171: 344 (1953); Neoplasma
- a radicicol derivative in which a phenolic hydroxyl group is modified with various acyl groups has an antitumor effect (Japanese Patent Application Laid-Open No. 4226991). Furthermore, a radicicol derivative in which the phenolic hydroxyl group is modified with an acyl group or an alkyl group has an inhibitory effect on angiogenesis (JP-A-6-279279) or an inhibitory effect on interleukin-11 production (JP-A-8-40893). ) Is disclosed.
- the oxime derivative of genone of the radicicol derivative represented by the formula (C) exhibits an antitumor effect and an immunosuppressive effect (W096 / 33989).
- R 1P and R 2P represent hydrogen, alkanoyl, alkenoyl or tert-butyldimethylsilyl
- Y p represents hydrogen or substituted or unsubstituted lower alkyl
- R 4P represents hydrogen, alkanoyl or alkenoyl, etc.
- X p represents a single bond together with a halogen atom or R 4P
- R 1Q and R 2Q represent a hydrogen atom or acyl, and X Q represents a halogen atom, hydroxy or lower alkoxy
- the ansamycin antibiotic geldanamycin of the formula (E) is a tyrosine kinase. It is known to have inhibitory activity and antitumor activity [Cancer's Research (Cancer Research), Vol. 52, 1721 ⁇ - ⁇ (1992) and Cancer Research (Cancer Research), Vol. 54, 2724 ⁇ - ⁇ (1994) etc.]. These effects are due to the binding of geldanamycin to the molecular chaperone Hsp (heat shock / stress protein) 90, which forms a complex with Hsp90 to express functions, such as Src, ErbB-2, and Lck.
- Hsp heat shock / stress protein
- Tyrosine kinase is an enzyme that catalyzes the transfer of its arsenic acid group to the hydroxyl group of a specific tyrosine residue of a substrate protein using ATP as a phosphate donor, and plays an important role in the regulatory mechanism in intracellular signal transduction Is responsible for.
- Various tyrosine kinase families are known, and the activity of each tyrosine kinase such as Src in colorectal cancer, ErbB-2 in breast cancer and gastric cancer, and Abl in leukemia is known.
- An uncontrolled increase in tyrosine kinase activity causes abnormalities in cell differentiation and proliferation. Therefore, a specific inhibitor of tyrosine kinase is useful for prevention and treatment of various diseases including antitumor agents.
- Lck is a cytosine kinase that is activated when T lymphocytes are activated by antigen stimulation, and inhibitors of this enzyme are useful as immunosuppressants.
- Src is known to be involved in bone resorption in osteoclasts, and this tyrosine kinase inhibitor is thought to act as a bone resorption inhibitor, and is useful as a therapeutic agent for osteoporosis.
- various growth factor receptor tyrosine kinases EGF-R (epithelial cells) Vesicle growth factor receptor: epidermal growth factor receptor, FGF-R (fibroblast growth factor receptor), PDGF-R (platelet-derived growth factor receptor), etc. are useful as a solid cancer growth inhibitor, an angiogenesis inhibitor, a vascular smooth muscle growth inhibitor, and the like. Disclosure of the invention
- An object of the present invention is to provide a novel radicicol derivative or a pharmacologically acceptable salt thereof which exhibits a tyrosine kinase inhibitory activity and has an antitumor or immunosuppressive activity.
- the present invention provides a compound represented by the general formula (I)
- R 1 and R 2 are the same or different and represent hydrogen, alkanoyl, alkenoyl, alkadienol, alkatrienoyl, trialkylsilyl, triarylsilyl, monoalkyldiarylsilyl or dialkylmonoarylsilyl.
- R 3 is NR 5 R 6 (where R 5 is hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted higher alkyl, substituted or unsubstituted Represents a lower cycloalkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heterocyclic group, wherein R 6 is a substituted lower alkyl, a substituted or unsubstituted higher alkyl, a substituted or unsubstituted lower cycloalkyl , Represents a substituted or unsubstituted aryl or a substituted or unsubstituted heterocyclic group), NR 7 C ⁇ R 8 [wherein R 7 represents hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted higher alkyl, substituted or unsubstituted lower
- NRUCOR 12 (where R 11 is substituted or unsubstituted) Represents lower alkyl, substituted or unsubstituted higher alkyl, substituted or unsubstituted lower cycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heterocyclic group.
- R 12 represents lower alkyl, lower alkoxy, lower alkenyloxy, lower alkadienyloxy or lower alkatrienyloxy), substituted lower alkoxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted Alkenyloxy, substituted or unsubstituted alkatrienyloxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkadienyl, substituted or unsubstituted alkatrienyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted Substituted or unsubstituted phenyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted isooxazolyl, substituted or unsubstituted thiazolyl,
- R 1 A and R 2 A have the same meanings as R 1 and R 2 , respectively, X A represents an octogen atom, W represents ⁇ or N—O—Y A —R 3 A (formula among relates Y a and R 3 a salts previous SL Y and R 3 and the Radishiko Le derivative or a pharmaceutically represented by representing] a a a) representing the representative] a ⁇ synonymous allowable respectively.
- compound (I) the compound represented by the general formula (I).
- compound (I) the compound represented by the general formula (I).
- lower means up to 1 to 8 carbon atoms and higher means up to 9 to 30 carbon atoms, unless otherwise specified.
- the alkanoyl includes straight or branched ones having 1 to 30 carbon atoms, for example, formyl, acetyl, propanoyl, isopropanol, bushynoyl, forceproyl, lauroyl, myristoyl, palmitoyl, stearoyl and the like.
- Alkenols include straight-chain or branched ones having 3 to 30 carbon atoms, such as acryloyl, methacryloyl, crotonyl, isocrotonyl, and palmitoleyl.
- Alkadienoyl is a straight or branched chain having 5 to 30 carbon atoms, for example, 2,4-diene dienol, 2,4-hexadienol, 3,5-hepadienol, linoleoyl, 3,5-diene Decadienol, 10, 12-Penya Decadienol and 12,15-Henikosagenol are included.
- Alkatrienoyl is a straight or branched chain having 7 to 30 carbon atoms, for example, 2,4,6-hepnotrienol, linolenoyl, 2,4,6-docosatri. Enol, 8,11,14-icosatrienoyl and 12,15,18-hexosatrienoyl are included.
- Lower alkyl and the alkyl moiety of lower alkoxy include straight-chain or branched, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, terbutyl, pentyl, isopentyl, neopentyl, hexyl, Heptyl, octyl, isooctyl and the like are included, and one of the carbon atoms may be replaced by a silicon atom.
- the alkylene portion of aralkyloxy is a group obtained by removing one hydrogen atom from these lower alkyl groups. Included.
- the alkyl part of the trialkylsilyl, monoalkyldiarylsilyl and dialkylmonoarylsilyl has the same meaning as the lower alkyl.
- Higher alkyls include straight-chain or branched, for example, decyl, dodecyl and hexadecyl.
- aryl examples include phenyl, naphthyl and anthranyl having 6 to 14 carbon atoms.
- the aryl moiety in aralkyloxy, triarylsilyl, monoalkyldiarylsilyl and dialkylmonoarylsilyl has the same meaning as the above aryl.
- alkenyl moiety in alkenyl and alkenyloxy examples include straight-chain or branched having 2 to 30 carbon atoms, for example, vinyl, aryl, toprobenyl, 2-butenyl, 1-pentenyl, 2-hexenyl, dodecenyl and Hexadecenyl and the like are included.
- Examples of the lower alkenyl moiety in lower alkenyloxy include those having 2 to 8 carbon atoms in the alkenyl, for example, vinyl, aryl, toprobenyl, 2-butenyl, 1-pentenyl, 2-hexenyl and the like. Include.
- alkadienyl moiety in alkadienyl and alkadienyloxy examples include 1,3-pentagenenyl, 1,3-hexadenyl, 2,4-hexadenyl, having 4 to 30 carbon atoms, linoleyl, 2,4-decadenyl, .9, 1-tetradecadienyl, 11, 14-icosagenyl and the like are included.
- Examples of the lower alkadienyl moiety in the lower alkadienyloxy include those having 4 to 8 carbon atoms in the alkadienyl, for example, 1,3-pentenyl, 1,3-hexenyl, and 2,4-hexenyl. .
- the alkatrienyl moiety in al-trienyl and al-trienyloxy includes 1,3,5-hexatriene having 6 to 30 carbon atoms.
- Nyl linolenyl, 1,3,5-docosatrienyl, 7,10,13-nonadecatrienyl, 11,14,17-icosatrienyl and the like.
- Examples of the lower alkenyl group in the lower alkarylenyl group include those having 6 to 8 carbon atoms in the above alkenyl group, such as 1,3,5-hexatrienyl.
- Lower cycloalkyl includes those having 3 to 8 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl and the like.
- the heterocyclic group includes an alicyclic heterocyclic group and an aromatic heterocyclic group.
- Examples of the alicyclic heterocyclic group include, for example, 2-pyridonyl, 3-pyridonyl, 4-pyridonyl, 2-pyrrolidonyl, 3-pyrrolidonyl, dioxolanyl, pyrrolidinyl, morpholino, morpholinyl, thiomorpholino, thiomorpholinyl, piperazinyl, pyridolinidinyl, piperidinyl Homopiperazinyl, piperidyl, imidazolinyl, imidazolidinyl, 2-oxazolidonyl, 4-oxazolidinyl, 5-oxazolidinyl, 2-piperidonyl, 3-piperidonyl, 4-piperidonyl, pahydro-2-azepinonyl, perhydro-3-azepinonyl, pahydro 1-hydro-4-azepinonyl, succinimide, phthalimide, gluimide, hydantoin
- aromatic heterocyclic group examples include peracylyl, pyrrolyl, tetrazolyl, phenyl, pyridyl, pyrazolyl, pyrazinyl, indolyl, isoindolyl, furyl, quinolyl, phthalazinyl, pyrimidinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiazolyl, thiazolyl, and thiazolyl. Etc. are included.
- a nitrogen-containing heterocyclic group formed integrally with adjacent N (the nitrogen-containing heterocyclic group formed integrally with adjacent N may further include ⁇ , S, or another N ) includes, for example, pyrrolidinyl, morpholino, thiomorpholino, piperazinyl, virazolidinyl, pyrazolinyl, piperidino, homopiperazinyl, indolinyl, isoindolinyl, perhydroazepinyl, perhydroazosinyl, indolyl, isoindrill and the like.
- the alkylene the lower alkyl or higher alkyl It includes groups obtained by removing one hydrogen atom from alkyl.
- the halogen atom includes fluorine, chlorine, bromine and iodine atoms.
- Substituents in the substituted lower alkyl, substituted higher alkyl and substituted lower alkoxy are the same or different and have 1 to 3 substituents, such as hydroxy, lower cycloalkyl, lower cycloalkenyl, lower alkoxy, lower alkoxy lower alkoxy, lower alkoxy.
- Lucanoyloxy azide, di-lower alkanoylamino, lower alkenyloxy-power luponylamino, lower alkadienyloxycarbonylamino, lower alkatrienylyloxycarbonylamino, halogen atom, lower alkanol, substituted or unsubstituted aryl, A substituted or unsubstituted heterocyclic group, a substituted or unsubstituted succinimide, a substituted or unsubstituted phthalimide, a substituted or unsubstituted daltarimide, C RNR 13A R 14A (where R 13A and R 14A are the same or Differently, water Element, hydroxy, lower alkyl, lower cycloalkyl, higher alkyl, alkenyl, lower alkoxy, aryl, heterocyclic group or NR 15A R 16A (wherein R 15A and R 16A are the same or different, and hydrogen, lower alkyl
- R 2GA represents hydrogen, lower alkyl, higher alkyl, lower cycloalkyl, aryl or heterocyclic group
- R 21A represents hydrogen, lower alkyl, aryl, aromatic heterocyclic group, lower alkoxy, aralkyloxy.
- NR 22A R 23A (wherein, R 22A and R 23A are the same or different, hydrogen, lower alkyl, or represents Ariru or aromatic heterocyclic group, the N integral with R 22 a and R 23 a are adjacent To form a substituted or unsubstituted nitrogen-containing heterocyclic group).
- Substituents in the substituted alkylene may be the same or different and have 1 to 3 substituents, such as hydroxy, lower alkoxy, lower alkanoyloxy, azide, di-lower alkanoylamino, lower alkenyloxyl-ponylamino, lower alkadenyloxy.
- alkenyl moiety for lower alkyl, higher alkyl, lower cycloalkyl, lower alkoxy, halogen atom, aryl, heterocyclic group, aromatic heterocyclic group, nitrogen-containing heterocyclic group formed integrally with adjacent N, alkenyl and alkenyloxy
- alkenyl moiety, the alkadienyl moiety in alkadienyl and alkadienyloxy, the alkatrienyl moiety in alkatrienyl and alkatrienyloxy, and aralkyloxy are as defined above, respectively.
- the lower alkyl moiety in the lower alkoxy lower alkoxy has the same meaning as the lower alkyl, and the lower alkylene moiety represents a group obtained by removing one hydrogen atom from the lower alkyl.
- the lower alkenyl in the lower alkenyloxycarbonylamino include those having 2 to 8 carbon atoms in the alkenyl, for example, vinyl, aryl, topropropenyl, 2-butenyl, 1-pentenyl, 2-hexenyl and the like.
- Examples of the lower alkadienyl in the lower alkadienyloxycarbonylamino include those having 4 to 8 carbon atoms in the alkadienyl, for example, 1,3-pentenyl, 1,3-hexenyl, 2,4-hexenyl. Etc. are included.
- the lower alkenyl group in the lower alkenyl group includes those having 6 to 8 carbon atoms, for example, 1,3,5-hexatrienyl and the like in the alkatrienyl.
- Lower cycloalkenyl includes those having 4 to 8 carbon atoms, for example, Includes 2-cyclopentenyl, 2-cyclohexenyl and 1,3-cyclopentenyl.
- the lower alkanol in the lower alkanol, lower alkanoyloxy and di-lower alkanoylamino includes straight-chain or branched C 1-8 carbon atoms in the above-mentioned alkanoyl, for example, formyl, acetyl, propanol, isopropanol, and the like. And the like.
- the aryl portion in arylo and arylcarbamoyl is as defined above.
- the heterocyclic group moiety in the carbonyl bonded to the heterocycle has the same meaning as described above. Examples of the group including carbonyl include fluoryl, tenyl, nicotinol, and isonicotinoyl.
- One embodiment of the present invention is a compound in which X is a halogen atom in compound (I).
- Another embodiment of the present invention is a compound (I) in which X is a single bond together with R 4 .
- a compound in which R 1 and R 2 are hydrogen is a preferred example. More preferably, but in a compound is a single bond together with R 4, R 1 and R 2 are hydrogen, R 3 is substitution or unsubstituted pyrrolyl, substituted or unsubstituted furyl, substituted Or unsubstituted phenyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted isothiazolyl, substituted Or unsubstituted tetrazolyl, substituted or unsubstituted pyrimidin
- R 1 and R 2 are hydrogen and R 3 is substituted or unsubstituted oxazolidonyl, substituted or unsubstituted piperidonyl, substituted Or unsubstituted perhydroazepinonyl, substituted or unsubstituted succinimide, substituted or unsubstituted phthalimide, substituted or unsubstituted dalyl imide, substituted or unsubstituted hydantoinyl, substituted or unsubstituted thiazolidinediamine
- the compound include oxonyl, substituted or unsubstituted oxopyrrolidonyl, substituted or unsubstituted maleimide, substituted or unsubstituted thiazolidonyl, and substituted or unsubstituted oxazolidinedionyl. it can.
- the pharmacologically acceptable salts of compound (I) include acid addition salts, metal salts, ammonium salts, organic amine addition salts and amino acid addition salts, and the acid addition salts include hydrochloride and odor.
- Inorganic acid salts such as hydride, sulfate and phosphate, formate, acetate, oxalate, benzoate, methanesulfonate, P-toluenesulfonate, maleate, fumarate And organic acid salts such as tartrate, citrate, succinate and lactate.
- metal salts include alkali metal salts such as lithium salt, sodium salt and potassium salt, and alkali metals such as magnesium salt and calcium salt.
- Examples include earth metal salts, aluminum salts and zinc salts, etc., and ammonium salts include salts such as ammonium and tetramethylammonium. Include addition salts such as phosphorus and piperidine, Examples of the amino acid addition salts of glycine, phenylene Ruaranin, ⁇ scan aspartic acid, Dar evening include addition salts such as tromethamine acid and lysine.
- some of the compounds (I) usually produced from radicicol as starting compounds may include various stereoisomers, positional isomers, tautomers and the like.
- the present invention includes all of these possible isomers and mixtures thereof, and the mixing ratio may be in any ratio.
- the production process of compound (I) mainly includes oximation (Production method 1), alkylation, Consists of the following reaction steps: substitution reaction (Production method 2), halohydrination (Production method 3), desilylation (Production method 4), or acylation (Production method 5). It can be manufactured in combination.
- Radicicol or a compound (F) obtained by a method known from radicicol Japanese Patent Laid-Open No. 4-226991
- radicicol or one of the phenolic hydroxyl groups of radicicol substituted with alkanoyl, alkenoyl, alkadienyl or alkatrienoyl A method known from Radicicol [for example, Journal of the Americas, Chemical, Society (Journal of the
- R la and R 2a wherein R 1 and trialkylsilyl from R 2, Toriari - Rushiriru a monoalkyl di ⁇ Li one Rushiriru and a group remaining after removing dialkyl mono ants one Rushiriru, scale 115 and Shaku 21
- R 1 and R 2 has the same meaning as R 1 and R 2 , respectively, wherein at least one of R 1 and R 2 is trialkylsilyl, triarylsilyl, monoalkyldiarylsilyl or dialkylmonoarylsilyl.
- R 1 R 2 , R 3 and Y are as defined above.
- Compound (Ia) is prepared by converting compound (F) or compound (G) in the presence or absence of an acid in the presence of H 2 N— ⁇ —Y—R 3 (II) (wherein R 3 and ⁇ are as defined above)
- the compound (II) represented by the following formula (II) or an acid addition salt thereof can be obtained.
- a reaction solvent pyridine, chloroform, dichloromethane, ethyl acetate, ether, tetrahydrofuran (THF), dimethylformamide (DMF), acetonitrile, etc. are used alone or in combination, and pyridine or ethyl acetate is preferred.
- c Acids include hydrochloric acid, acetic acid, trifluoroacetic acid, sulfuric acid, p-toluenesulfonic acid, camphorsulfonic acid and the like, and preferably 0.1 to 10 equivalents to compound (F) or compound (G).
- Examples of the acid addition salts of compound (II) include hydrochloride, hydrobromide, sulfate, nitrate, formate, acetate, trifluoroacetate, methanesulfonate, p-toluenesulfonate, and benzoic acid. Acid salts, oxalates, fumarates, maleates, tartrates and the like are used.
- an acid addition salt of the salt compound (II) is used, one or more equivalents, preferably 1 to 10 equivalents of a base, for example, pyridine, triethylamine, diisopropylethylamine are used based on the acid addition salt of the compound (II).
- a base for example, pyridine, triethylamine, diisopropylethylamine
- Amines such as amines, N, N-dimethylaniline and N, N-ethylylaniline
- alkali metal carbonates such as sodium carbonate, potassium carbonate and sodium bicarbonate.
- ⁇ , ⁇ -dimethylaniline or ⁇ , ⁇ -ethylylaniline is used, or pyridine is used also as a solvent.
- the compound (II) or an acid addition salt thereof is used in an amount of 1 equivalent or more, preferably 1 to 5 equivalents, based on the compound (F) or the compound (G).
- the reaction is usually carried out at ⁇ 20 to 100 t, preferably at 20 to 60 ° C., and is completed in 1 to 80 hours.
- Compound (Ia) is obtained by subjecting a hydroxyl group of compound (H) or compound (J) obtained according to a method known from Radicicol (W096 / 33989) to another functional group by alkylation or substitution reaction. Can also be obtained by the step of converting to
- Compound (Ia) is obtained by reacting compound (H) with compound (III) represented by HO—Y—R 3 (III) (wherein R 3 and Y are as defined above) in the presence of a condensing agent. It can be obtained by reacting.
- R 3 is a substituted or unsubstituted succinimide, a substituted or unsubstituted phthalimide, a substituted or unsubstituted daryl imide, a substituted or unsubstituted hydantoinyl, a substituted or unsubstituted thiazolidine
- Compounds that are dionyl, substituted or unsubstituted maleimide, substituted or unsubstituted oxopyrrolidonyl or substituted or unsubstituted oxazolidinedionyl can be prepared by subjecting compound (J) to the presence of a condensing agent.
- reaction solvent toluene, THF, dichloromethane or the like is used alone or as a mixture.
- a mixture of a trivalent phosphorus compound such as triphenylphosphine and tributylphosphine and an azo compound such as getyl azodicarboxylate (DEAD) and 1,1- (azodicarbonyl) dipiperidine are used.
- the compound (III) and the condensing agent are each used in an amount of 1 equivalent or more, preferably 1 to 5 equivalents, based on the compound (H).
- the unsubstituted oxopyrrolidone or the substituted or unsubstituted oxazolidinedione and the condensing agent are each used in an amount of 1 equivalent or more, preferably 1 to 5 equivalents, based on Compound (J).
- the reaction is usually carried out at -20 to 80 ° C, preferably 0 to 30 and is completed in 5 minutes to 48 hours.
- the compound (Ib) can be obtained by opening the epoxide of the compound (Ia) to a halohydrin or the like.
- R 1 R 2 , R 3 and Y are as defined above, X a is a halogen atom, R 4a is hydrogen, formyl, or SO—Z (where Z is as defined above) ) Process 3 _ 1
- those in which R 4a is hydrogen can be obtained by reacting the compound (Ia) with an acid such as hydrochloric acid or hydrobromic acid or with a Lewis acid such as titanium tetrachloride. it can.
- dioxane, THF, ether, black form, dichloromethane, DMF, acetonitrile, methanol, ethyl acetate or the like is used alone or as a mixture.
- the acid or Lewis acid is used in an amount of 1 equivalent or more, preferably 1 to 10 equivalents, relative to compound (Ia).
- the reaction is usually carried out at -20 to 40 ° C, preferably at 0 to 40, and is completed in 10 minutes to 48 hours.
- a compound wherein R4a is formyl can be obtained by reacting the compound (Ia) with a phosphorus oxyhalide such as phosphorus oxychloride or phosphorus oxybromide in DMF.
- a phosphorus oxyhalide such as phosphorus oxychloride or phosphorus oxybromide in DMF.
- the phosphorus oxyhalide is used in an amount of 1 equivalent or more, preferably 2 to 5 equivalents, relative to compound (Ia).
- the reaction is usually carried out at -10 to 40 ° C, preferably at 0 to 40, and is completed in 1 to 48 hours.
- the dimer compound in which R 4a is SO—Z (where Z is as defined above) is obtained by converting the compound (Ia) to a halogenated thiol such as thionyl chloride or thionyl bromide. Can be obtained by reacting with carbonyl.
- a halogenated thiol such as thionyl chloride or thionyl bromide.
- As the solvent DMF, chloroform, dichloromethane, dimethylsulfoxide (DMS0), acetonitrile and the like are used alone or as a mixture.
- the thionyl halide is used in an amount of 1 equivalent or more, preferably 2 to 10 equivalents, based on compound (Ia).
- the reaction is usually carried out at -10 to 40 ° C, preferably at 0 to 40 ° C, and is completed in 1 to 48 hours.
- Compound (Ic) in which at least one of R 1 and R 2 of compound (I) is substituted with trialkylsilyl, triarylsilyl, monoalkyldiarylsilyl or dialkylmonoarylsilyl is removed.
- Compound (Id) can be obtained by silylation.
- R lb , R 2b , R 3 , RY and X are as defined above, and R lc and R 2c are the above trialkylsilyl, triarylsilyl, monoalkyldiaryl in R lb and R 2b ) Where at least one of silyl or dialkylmonoarylsilyl has been replaced by hydrogen)
- Compound (Id) can be obtained by reacting compound (Ic) with a desilylating agent.
- THF trifluoroethyl ether
- chloroform a mixture of benzylammonium fluoride
- dichloromethane a compound that is used alone or as a mixture.
- Tetrabutylammonium fluoride TBAF
- sodium fluoride sodium fluoride
- hydrofluoric acid a mixture of benzylammonium fluoride
- the reaction may be performed by increasing the pH by adding an acid such as acetic acid or hydrochloric acid.
- the desilylating agent is used in an amount of 0.1 equivalent or more, preferably 1 to 10 equivalents, relative to compound (Ic).
- the reaction is usually performed at -20 to 50 ° C, and is completed in 5 minutes to 24 hours.
- Compound (I f) in which at least one of R 1 R 2 and R 4 in compound (I) is alkanoyl, alkenoyl, alkadienol or alkatrienoyl is obtained by acylating the following compound (I e) be able to.
- R 3 , Y and X are as defined above, and R ld , R 2d and R 4b are as defined above for R 1 , R 2 and R 4 , but at least one of them is hydrogen
- R le , R 2 e and R 4 c are those wherein at least one of the hydrogens in the above R 1 d , R 2 d and R 4 b is replaced by alkanoyl, alkenoyl, alkadienoyl or alkatrienoyl. is there)
- Compound (IO is a compound (Ie) comprising at least one equivalent, preferably 1 to 100 equivalents of an acid halide, an acid anhydride or a mixed anhydride containing a desired alkanol, alkenoyl, alkadienoyl or alkatrienoyl, etc. And in the presence of a base.
- DMF, DMS0, chloroform, dichloromethane, toluene and the like are used alone or as a mixture.
- An arbitrary hydroxyl group can be modified by appropriately introducing and removing a protective group for a hydroxyl group, but a plurality of hydroxyl groups can be simultaneously modified.
- the base pyridine, triethylamine, N, N-dimethylaniline, ⁇ , ⁇ -getylaniline and the like are used in an amount of 1 equivalent or more, preferably 1 to 200 equivalents, relative to compound (Ie).
- a base such as pyridine can be used also as a solvent.
- DMAP dimethylaminopyridine
- the reaction is usually performed at -20 to 50, and is completed in 5 minutes to 24 hours.
- the conversion of the functional group of RR 2 , R 3 , RY or X may be performed by a known method other than the above-mentioned method [for example, Comprehensive Organic Transformations (Comprehensive Organic Transformations, R ⁇ C ⁇ Larock (1989)].
- the isolation and purification of the product in the above production method can be carried out by appropriately combining methods used in ordinary organic synthesis, for example, filtration, extraction, washing, drying, concentration, crystallization, various types of chromatography, and the like.
- the intermediate can be subjected to the next reaction without purification.
- the compound (I) When it is desired to obtain a salt of compound (I), the compound (I) may be purified as it is when a salt thereof is obtained, or may be dissolved or suspended in a suitable solvent when obtained in a free form, An acid or a base may be added to form a salt.
- Compound (I) or a pharmaceutically acceptable salt thereof may be present in the form of an adduct with water or various solvents, and these adducts are also included in the present invention.
- Specific examples of the compound (I) are shown in Tables 1 (1) to 1 (3) and 2 (1) to 2 (2).
- Me, Et, l Bu is each methyl in the table described below, Echiru means tert- butyl.
- SR-3Y1 cells were cultured in Dulbecco's modified Eagle's medium (DMEM) containing 10% fetal calf serum (FCS), supplemented with radicicol derivatives at each test concentration, and cultured at 37 t: 5% CO2 for 40 hours.
- Lysis buffer [50 niM Hepes NaOH, H 7.4, 25 m salt (NaCl), 1% nonidet ⁇ -40 ( ⁇ 40), 0.1 ⁇ ⁇ ⁇ ⁇ ⁇ sodium dodecyl sulfonate (SDS) mM Dithiothreitol, 1 mM Ethylenediaminetetraacetic acid (EDTA), 1 mM Phenylmethylsulfonyl fluoride
- Tyrosine phosphorylation inhibitory activity of La Defense Ishikoru derivatives can be represented by a derivative such as the percentage of protein as compared to the case without the addition of drug has tyrosine phosphorylation is halved concentration (IC 5 0).
- test compound shows a strong inhibitory activity on intracellular tyrosine kinase activity, and compound (I) is useful as an inhibitor of tyrosine kinase.
- Test example 2 Rat normal fibroblast 3 ⁇ cell line and its growth inhibition test on V-src oncogene transformed cell SR-3Y1 cell line
- a 96-well microplate 1000 rat normal fibroblast 3Y1-B cell lines or a V-s rc oncogene-transformed cell SR-3Y1 cell line per well were spread.
- the cells were pre-cultured in Dulbecco's modified Eagle's medium (DMEM) containing 10% fetal calf serum (FCS) in a 5% carbon dioxide incubator at 37 ° C for 24 hours.
- DMEM Dulbecco's modified Eagle's medium
- FCS fetal calf serum
- the DMS0 solution of each test compound adjusted to 10 mM was serially diluted in a culture medium, and 501 was added to each well.
- the cells were cultured in a 5% CO 2 incubator at 37 for 72 hours.
- the 3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolidine dissolved in the culture medium was adjusted to a final concentration of 1 mg / ml 5 hours before the end of the culture.
- Dembromide (3- (4,5-dimethylthiazol-2-y 0 -2,5-diphenyl tetrazolium bromide (manufactured by Sigma), hereinafter abbreviated as MTT)) is 50 i 1 per well.
- DMS0 was dispensed at 150 1 per well, and vigorously stirred using a plate mixer. MTT-formazan crystals were completely dissolved. Then, the difference in absorbance between 550 nM and 630 nM was measured using a microplate reader (manufactured by Wako Pure Chemical Industries, Ltd.).
- the cell growth inhibitory activity was calculated as the 50% growth inhibitory concentration (IC 5 ) using the formula of the measurement software (Soft Max Pro) attached to the microplate reader.
- test compound showed stronger cell strength in SR-3Y1 cells compared to 3Y1-B cells.
- Compound (I) is useful as an antitumor agent since it exhibits vesicle growth inhibitory activity.
- mice are arbitrarily divided into groups of 5 mice, and 7.5% cremophor EL (Sigma) / 5% dimethylacetamide (DMA) /87.5% concentration in saline solution
- the test compound dissolved at 10 mg / ml was administered intravenously to mice at a dose of 100 mg / kg once daily for 5 days.
- the antitumor activity of the test compound was represented by the ratio (TZC) of the tumor volume (T) of the test compound-administered group to the tumor volume (C) of the non-drug-treated control group on day 7 after administration of the test compound.
- test compound shows excellent antitumor activity
- compound (I) is useful as an antitumor agent.
- Test Example 4 Intracellular Raf-1 protein reduction activity and Erk2 phosphorylation inhibitory activity Activated K-ras transgenic rat renal epithelial cells
- KNRK 5.2 Cells contain 10% fetal calf serum (FCS) Dulbecco Radase at each test concentration in denatured Eagle's medium (DMEM) Isicol derivative was added, and the cells were cultured at 37 under 5% carbon dioxide for 40 hours. Lysis buffer with cooled cells [HEPES 50 mM NaOH, pH 7.4, 250 mM NaCl
- PVDF polyvinylidene difluoride
- a horseradish peroxidase-labeled primary antibody that reacts with each of the primary antibodies (anti-horse Ig antibody, or anti-mouse Ig antibody,
- the Erk2 phosphorylation inhibitory activity of a radicicol derivative was calculated by calculating the ratio of phosphorylated Erk2 protein (phosphorylated Erk2 protein mass / Erk2 total protein mass) from the results obtained from samples at each drug concentration. It can be indicated by the derivative concentration (IC 50 ) such that the ratio is reduced by half compared to the case where no drug is added.
- Raf-1 protein mass / Erk2 total protein mass the ratio of Raf-1 protein to Erk2 protein (Raf-1 protein mass / Erk2 total protein mass), which does not change the protein mass due to drug treatment, was determined from the sample at each drug concentration. It can be calculated from the results obtained, and can be indicated by the derivative concentration (IC 5Q ) that halves the ratio compared to the case where no drug is added.
- test compound showed an effect of reducing intracellular Raf-1 protein content and an effect of inhibiting Erk2 phosphorylation.
- Compound (I) or a pharmaceutically acceptable salt thereof is administered as it is or orally or parenterally as various pharmaceutical compositions.
- dosage form of such a pharmaceutical composition include tablets, pills, powders, granules, capsules, suppositories, injections, and drops.
- Carriers used in pharmaceutical compositions include, for example, water, distilled water for injection, physiological saline, glucose, fructose, sucrose, mannitol, lactose, starch, corn starch, cellulose, methylcellulose, carboxymethylcellulose, Hydroxy Propylcellulose, alginic acid, talc, sodium citrate, calcium carbonate, calcium hydrogen phosphate, magnesium stearate, urea, silicone resin, sorbitan fatty acid ester, or glycerin fatty acid ester, etc., depending on the type of preparation. It is appropriately selected.
- the dose and frequency of administration of the compound (I) used for the above purpose vary depending on the intended therapeutic effect, administration method, treatment period, age, body weight, etc., and are orally administered or parenterally administered (for example, Injection, infusion, rectal administration by suppository, dermal application, etc.), the dose is usually 0.01 to 20 mg / kg per day for adults, and the frequency of administration is once or several times a day.
- the peak position ( ⁇ ) of the proton nuclear magnetic resonance spectrum (MR) used in Reference Examples and Examples is expressed in parts per million (ppm) from tetramethylsilane to the lower magnetic field side. These were measured at 270 MHz, and the observed shape, coupling constant, and number of protons are shown in parentheses after the ⁇ value of each signal.
- the peak shape is expressed as follows.
- the isomer ratio was about 2: 1.
- the isomer ratio was about 2: 1.
- the isomer ratio was about 2: 1.
- the isomer ratio was about 8: 1.
- the isomer ratio was about 4: 1.
- the isomer ratio was about 8: 1.
- the isomer ratio was about 2: 1.
- the isomer ratio was about 2: 1.
- the isomer ratio was about 1.9: 1.
- Example 1 compound 12 was obtained from radicicol and the hydrochloride of compound m.
- the isomer ratio was about 1.7: 1.
- Compound 13 was obtained from radicicol and compound n according to Example 11.
- the isomer ratio was about 2: 1.
- Compound 14 was obtained from radicicol and compound o according to Example 11.
- the isomer ratio was about 2: 1.
- the isomer ratio was about 2: 1.
- the isomer ratio was about 1.7: 1.
- the isomer ratio was about 2: 1.
- the isomer ratio was about 1.8: 1.
- the isomer ratio was about 1.5: 1.
- the isomer ratio was about 3: 1.
- the isomer ratio was about 1.7: 1.
- Compound 23 was obtained from radicicol and compound x according to Example 11.
- the isomer ratio was about 1.6: 1.
- the isomer ratio was about 2.5: 1.
- the isomer ratio was about 1.7: 1.
- the isomer ratio was about 2.5: 1.
- Compound 27 was obtained from radicicol and the compound according to Example 11.
- the isomer ratio was about 2: 1.
- compound 33 was obtained from the compound, triphenylphosphine, DEAD and 2,4-thiazolidinedione.
- Example 31 compound 33 was treated with TBAF and then separated by high performance liquid chromatography to obtain compound 34 (high polarity) and compound 35 (low polarity).
- compound 36 was obtained from the compound, triphenylphosphine, DEAD and trimethylhydantoin.
- N- ⁇ 4-[(4-pyridylmethyl) amino] was obtained from tert-butyl N- (4-aminobutyroxy) amine and 4-pyridinecarboxaldehyde according to steps 113 of Reference Example 1.
- a trifluoroacetate of compound c was obtained according to Steps 1-4 of Reference Example 1.
- trifluoroacetate of compound f was obtained from tert-butyl N- ⁇ 2-hydroxy-3-[(4-pyridyl) methylamino] propoxy ⁇ potassium rubinate.
- N-Ethyl-N- [2- (phthalimidoxy) ethyl] tert-butyl rubamate (3.50 g) was dissolved in 30 ml of chloroform and added with 0.60 ml of hydrazine monohydrate. Stir for 15 minutes. The resulting precipitate was separated by filtration, and 3.00 ml of a 4N hydrogen chloride / ethyl acetate solution was added to the filtrate. The solvent was removed under reduced pressure to obtain 2.60 g of the compound i hydrochloride.
- N-ethyl-N-ethyl-N- (2-hydroxyethyl) carbamate is obtained from N-ethyl-N- (2-hydroxyethyl) carbamate, N-hydroxyfurimide, triphenylphosphine and DEAD.
- the hydrochloride of compound j was obtained according to Steps 9-13 of Reference Example 9.
- Step 9_2 of Reference Example 9 2- [3- (6-methyl-2-pyridyl) propoxy] ethanol, N-hydroxyfurimide, triphenylphosphine and N- ⁇ 2- [ After obtaining 3-(6-methyl-2-pyridyl) propoxy] ethoxy ⁇ phthalimide, a hydrochloride of the compound m was obtained according to Step 9-13 of Reference Example 9.
- N- (cinnamyloxy) furimide was obtained from cas alcohol, N-hydroxyphenylimide, triphenylphosphine and DEAD, and then the compound was prepared according to Reference Example 11. got n.
- Step 15-4 of Reference Example 15 a hydrochloride of Compound Q was obtained from 4-[(phthalimidoxy) methyl] imidazole.
- trimethyl-2-imidazole carboxyaldehyde was obtained from 2-imidazolecarboxaldehyde, carboxylamide and methyl iodide.
- Step 9-2 of Reference Example 9 2-hydroxymethyl-1-methylimidazole, N-hydroxyphthalimide, triphenylphosphine, and N-[(trimethyl-2-imidazolyl) methoxy] phenol were obtained from DEAD. After obtaining the imide, a hydrochloride of the compound r was obtained according to Step 15-4 of Reference Example 15.
- Reference Example 1 9 [(3,5-Dimethyl-4-isoxazolyl) methoxy] amine (compound) According to Step 1-1 of Reference Example 1, 4-chloromethyl-3,5-dimethylisoxazole was used. After obtaining 4-[(phthalimidoxy) methyl] -3,5-dimethylisoxazole, a hydrochloride of compound t was obtained according to Step 15-4 of Reference Example 15.
- Step 9-2 of Reference Example 9 5- (2-hydroxyethyl) -4-methylthiazole, N-hydroxyphthalimide, triphenylphosphine and DEAD were used to give [2- (phthalyl) After obtaining [midoxy) ethyl] -4-methylthiazole, a hydrochloride of compound u was obtained according to Step 15-4 of Reference Example 15.
- Step 1-1 in Reference Example 1 5-[(phthalimidoxy) methyl] -2- (triphenylmethyl) tetramer was obtained from 5- (chloromethyl) -2- (triphenylmethyl) tetrazole. A sol was obtained.
- Step 15-1 of Reference Example 15 5-[(phthalimidoxy) methyl] tetrazole was used to give 5-[(phthalimidoxy) methyl] -trimethyltetrazole and 5-[(phthalimidoxy) methyl]- 2-Methyltetrazole was obtained.
- compound X was obtained from 5-[(phthalimidoxy) methyl] -trimethyltetrazole.
- Step 15-2 of Reference Example 15 2- (hydroxymethyl) pyrazine was obtained from methyl 2-pyrazinecarboxylate.
- Step 9-2 of Reference Example 9 2-[(phthalimidoxy) ) After obtaining methyl] pyrazine, a hydrochloride of compound z was obtained according to Step 9-3 of Reference Example 9.
- step 28-1 and step 28-2 of Example 28 trifluoroacetate of compound dd was obtained using cyclohexanone instead of cyclopentanone.
- N- (2-hydroxyethoxy) furimide was obtained from 2-bromoethanol, N-hydroxyphthalimide and potassium carbonate.
- Process 3 0-2 N- (2-hydroxyethoxy) furimide was obtained from 2-bromoethanol, N-hydroxyphthalimide and potassium carbonate.
- the present invention provides a novel radicicol derivative or a pharmacologically acceptable salt thereof, which has a tyrosine kinase inhibitory activity and has an antitumor or immunosuppressive activity.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
L'invention concerne des composés représentés par la formule (I), présentant une activité d'inhibition de la tyrosine kinase ou des sels de ceux-ci. Dans cette formule R1 et R2 représentent chacun hydrogène, alcanoyle, etc.; Y représente alkylène éventuellement substitué; R3 représente NR?5R6 (où R5¿ représente hydrogène, alkyle inférieur éventuellement substitué, etc.; et R6 représente alkyle substitué, etc.), NR?7COR8 [où R7¿ représente hydrogène, alkyle éventuellement substitué, etc.; et R8 représente alkyle inférieur substitué, alcoxy inférieur substitué, NR?9R10 (où R9 et R10¿ représentent chacun hydrogène, alkyle inférieur éventuellement substitué, etc.)], NR?11COR12 (où R11¿ représente alkyle inférieur éventuellement substitué, etc.; et R12 représente alkyle inférieur, alcoxy inférieur, etc.), alcoxy inférieur substitué, alkényloxy substitué, etc.; X représente halogéno et forme avec R4 une liaison unique; et R4 forme avec X une liaison unique ou représente hydrogène, alcanoyle, etc.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU35344/99A AU3534499A (en) | 1998-04-24 | 1999-04-22 | Radicicol derivatives |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP11494198 | 1998-04-24 | ||
JP10/114941 | 1998-04-24 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1999055689A1 true WO1999055689A1 (fr) | 1999-11-04 |
Family
ID=14650450
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/JP1999/002138 WO1999055689A1 (fr) | 1998-04-24 | 1999-04-22 | Derives de radicicol |
Country Status (2)
Country | Link |
---|---|
AU (1) | AU3534499A (fr) |
WO (1) | WO1999055689A1 (fr) |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2005000778A1 (fr) | 2003-06-27 | 2005-01-06 | Kyowa Hakko Kogyo Co., Ltd. | Inhibiteur de proteines de la famille hsp90 |
JP2006501147A (ja) * | 2002-04-25 | 2006-01-12 | ユニバーシティー オブ コネティカット ヘルス センター | 非ワクチン治療法の治療効果を改善するための熱ショックタンパク質の使用 |
US7115651B2 (en) | 2000-08-25 | 2006-10-03 | Sloan-Kettering Institute For Cancer Research | Macrocycles and uses thereof |
WO2009105755A2 (fr) | 2008-02-21 | 2009-08-27 | Nexgenix Pharmaceuticals | Composés de promédicaments macrocycliques utilisés comme agents thérapeutiques |
US8067412B2 (en) | 2006-08-11 | 2011-11-29 | Universite De Strasbourg | Macrocyclic compounds useful as inhibitors of kinases and HSP90 |
EP2583678A2 (fr) | 2004-06-24 | 2013-04-24 | Novartis Vaccines and Diagnostics, Inc. | Immunopotentiateurs de petites molécules et dosages pour leur détection |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1996033989A1 (fr) * | 1995-04-26 | 1996-10-31 | Kyowa Hakko Kogyo Co., Ltd. | Derives de radicicol |
WO1998018780A1 (fr) * | 1996-10-25 | 1998-05-07 | Kyowa Hakko Kogyo Co., Ltd. | Derives de radicicol |
-
1999
- 1999-04-22 WO PCT/JP1999/002138 patent/WO1999055689A1/fr active Application Filing
- 1999-04-22 AU AU35344/99A patent/AU3534499A/en not_active Abandoned
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1996033989A1 (fr) * | 1995-04-26 | 1996-10-31 | Kyowa Hakko Kogyo Co., Ltd. | Derives de radicicol |
WO1998018780A1 (fr) * | 1996-10-25 | 1998-05-07 | Kyowa Hakko Kogyo Co., Ltd. | Derives de radicicol |
Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7115651B2 (en) | 2000-08-25 | 2006-10-03 | Sloan-Kettering Institute For Cancer Research | Macrocycles and uses thereof |
JP2006501147A (ja) * | 2002-04-25 | 2006-01-12 | ユニバーシティー オブ コネティカット ヘルス センター | 非ワクチン治療法の治療効果を改善するための熱ショックタンパク質の使用 |
WO2005000778A1 (fr) | 2003-06-27 | 2005-01-06 | Kyowa Hakko Kogyo Co., Ltd. | Inhibiteur de proteines de la famille hsp90 |
EP2583678A2 (fr) | 2004-06-24 | 2013-04-24 | Novartis Vaccines and Diagnostics, Inc. | Immunopotentiateurs de petites molécules et dosages pour leur détection |
US8067412B2 (en) | 2006-08-11 | 2011-11-29 | Universite De Strasbourg | Macrocyclic compounds useful as inhibitors of kinases and HSP90 |
US8450305B2 (en) | 2006-08-11 | 2013-05-28 | Universite De Strasbourg | Macrocyclic compounds useful as inhibitors of kinases and HSP90 |
WO2009105755A2 (fr) | 2008-02-21 | 2009-08-27 | Nexgenix Pharmaceuticals | Composés de promédicaments macrocycliques utilisés comme agents thérapeutiques |
Also Published As
Publication number | Publication date |
---|---|
AU3534499A (en) | 1999-11-16 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US20230301974A1 (en) | Processes of making and crystalline forms of a mdm2 inhibitor | |
CN100372849C (zh) | 作为半胱氨酸蛋白酶抑制剂的吡咯并嘧啶化合物 | |
US9643977B2 (en) | Necroptosis inhibitors and methods of use therefor | |
JP2021519325A (ja) | N−複素環式5員環含有カプシドタンパク質のアセンブリの阻害剤、その医薬組成物および使用 | |
US6239168B1 (en) | Radicicol derivatives | |
RU2503673C2 (ru) | Новое производное 5-фторурацила | |
JP4164645B2 (ja) | Dgat阻害剤 | |
JP2005501848A (ja) | 2h−フタラジン−1−オンおよびその使用方法 | |
EA030637B1 (ru) | 5-[(пиперазин-1-ил)-3-оксопропил]имидазолидин-2,4-дионовые производные в качестве ингибиторов adamts для лечения остеоартрита | |
EP2406263A1 (fr) | Derives de pyrazolo[1,5-a]-1,3,5-triazines, leur preparation et leur application en therapeutique | |
EP2976338B1 (fr) | N-(2-cyano-hétérocyclyl)pyrazolo-pyridones en tant qu'inhibiteurs de la janus kinase | |
AU759328B2 (en) | Benzoylpyridazines | |
US20200231576A1 (en) | Vinylheterocycles as rho-associated coiled-coil kinase (rock) inhibitors | |
WO1999055689A1 (fr) | Derives de radicicol | |
EP2725024A1 (fr) | Composé hétérocyclique azole, procédé de préparation, composition pharmaceutique et utilisation | |
US12043640B2 (en) | Prodrugs of STAT3 inhibitors | |
CN1034333C (zh) | 用作止痛药和消炎剂的咪唑并吡唑衍生物的制备方法 | |
JP3999861B2 (ja) | 新規ピリダジン誘導体及びこれを有効成分とする医薬 | |
WO2021032857A1 (fr) | Composés et leur utilisation pour le traitement de maladies infectieuses et du cancer | |
CN112480100B (zh) | 吡咯烷酮衍生物 | |
JP2724396B2 (ja) | 骨粗鬆症予防治療剤 | |
JP2003113183A (ja) | リウマチ治療剤 | |
EP0428106A1 (fr) | Pyridyloxazolones-2 utiles comme inhibiteurs de la protéinekinase C | |
CZ20001145A3 (cs) | Tricyklické triazolobenzazepinové deriváty |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AK | Designated states |
Kind code of ref document: A1 Designated state(s): AU BG BR CA CN CZ HU ID IL IN JP KR MX NO NZ PL RO SG SI SK UA US VN ZA |
|
AL | Designated countries for regional patents |
Kind code of ref document: A1 Designated state(s): AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE |
|
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
DFPE | Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101) | ||
NENP | Non-entry into the national phase |
Ref country code: KR |
|
122 | Ep: pct application non-entry in european phase |