WO1995006032A1 - Inhibiteur de la tyrosine kinase - Google Patents
Inhibiteur de la tyrosine kinase Download PDFInfo
- Publication number
- WO1995006032A1 WO1995006032A1 PCT/JP1994/001368 JP9401368W WO9506032A1 WO 1995006032 A1 WO1995006032 A1 WO 1995006032A1 JP 9401368 W JP9401368 W JP 9401368W WO 9506032 A1 WO9506032 A1 WO 9506032A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- group
- lower alkyl
- dihydroxyphenyl
- furanone
- alkyl group
- Prior art date
Links
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 title claims description 4
- 239000005483 tyrosine kinase inhibitor Substances 0.000 title claims description 4
- 150000004917 tyrosine kinase inhibitor derivatives Chemical class 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 113
- -1 phosphoryloxy group Chemical group 0.000 claims description 622
- 125000000217 alkyl group Chemical group 0.000 claims description 268
- 125000003118 aryl group Chemical group 0.000 claims description 70
- 125000003545 alkoxy group Chemical group 0.000 claims description 56
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 55
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 50
- 125000003342 alkenyl group Chemical group 0.000 claims description 40
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 38
- 239000000203 mixture Substances 0.000 claims description 38
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 32
- 125000003282 alkyl amino group Chemical group 0.000 claims description 27
- 125000004104 aryloxy group Chemical group 0.000 claims description 26
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 25
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 24
- 125000000304 alkynyl group Chemical group 0.000 claims description 22
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 20
- 125000000649 benzylidene group Chemical group [H]C(=[*])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 20
- 229910052757 nitrogen Inorganic materials 0.000 claims description 20
- 125000003277 amino group Chemical group 0.000 claims description 19
- 125000001424 substituent group Chemical group 0.000 claims description 19
- 125000003302 alkenyloxy group Chemical group 0.000 claims description 18
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 18
- 125000005843 halogen group Chemical group 0.000 claims description 17
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 17
- 125000000623 heterocyclic group Chemical group 0.000 claims description 15
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 15
- 125000005195 alkyl amino carbonyloxy group Chemical group 0.000 claims description 14
- 125000003739 carbamimidoyl group Chemical group C(N)(=N)* 0.000 claims description 12
- 150000003839 salts Chemical class 0.000 claims description 12
- 229910052717 sulfur Inorganic materials 0.000 claims description 12
- 125000004434 sulfur atom Chemical group 0.000 claims description 12
- 125000002795 guanidino group Chemical group C(N)(=N)N* 0.000 claims description 11
- 125000004423 acyloxy group Chemical group 0.000 claims description 10
- 125000005092 alkenyloxycarbonyl group Chemical group 0.000 claims description 10
- 125000005278 alkyl sulfonyloxy group Chemical group 0.000 claims description 10
- 125000005133 alkynyloxy group Chemical group 0.000 claims description 10
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 10
- 125000005161 aryl oxy carbonyl group Chemical group 0.000 claims description 9
- RHDGNLCLDBVESU-UHFFFAOYSA-N but-3-en-4-olide Chemical compound O=C1CC=CO1 RHDGNLCLDBVESU-UHFFFAOYSA-N 0.000 claims description 9
- 125000005842 heteroatom Chemical group 0.000 claims description 9
- 125000005279 aryl sulfonyloxy group Chemical group 0.000 claims description 8
- 125000005236 alkanoylamino group Chemical group 0.000 claims description 7
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 7
- 125000004203 4-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 claims description 6
- 125000002252 acyl group Chemical group 0.000 claims description 6
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 6
- 125000006201 3-phenylpropyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 4
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- IWUCXVSUMQZMFG-AFCXAGJDSA-N Ribavirin Chemical compound N1=C(C(=O)N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 IWUCXVSUMQZMFG-AFCXAGJDSA-N 0.000 claims description 3
- 125000003435 aroyl group Chemical group 0.000 claims description 3
- CYQAYERJWZKYML-UHFFFAOYSA-N phosphorus pentasulfide Chemical compound S1P(S2)(=S)SP3(=S)SP1(=S)SP2(=S)S3 CYQAYERJWZKYML-UHFFFAOYSA-N 0.000 claims description 3
- 229940100050 virazole Drugs 0.000 claims description 3
- 125000003143 4-hydroxybenzyl group Chemical group [H]C([*])([H])C1=C([H])C([H])=C(O[H])C([H])=C1[H] 0.000 claims description 2
- 230000002378 acidificating effect Effects 0.000 claims description 2
- 125000005239 aroylamino group Chemical group 0.000 claims description 2
- 125000004429 atom Chemical group 0.000 claims description 2
- 125000004466 alkoxycarbonylamino group Chemical group 0.000 claims 6
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 claims 2
- 125000003682 3-furyl group Chemical group O1C([H])=C([*])C([H])=C1[H] 0.000 claims 2
- 239000001257 hydrogen Substances 0.000 claims 2
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims 2
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 claims 1
- 125000004208 3-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C([H])C(*)=C1[H] 0.000 claims 1
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 1
- 239000004480 active ingredient Substances 0.000 claims 1
- 125000004457 alkyl amino carbonyl group Chemical group 0.000 claims 1
- 125000005115 alkyl carbamoyl group Chemical group 0.000 claims 1
- 125000005333 aroyloxy group Chemical group 0.000 claims 1
- 125000002102 aryl alkyloxo group Chemical group 0.000 claims 1
- 125000005418 aryl aryl group Chemical group 0.000 claims 1
- 125000000732 arylene group Chemical group 0.000 claims 1
- 125000001589 carboacyl group Chemical group 0.000 claims 1
- 229910052736 halogen Inorganic materials 0.000 claims 1
- 150000002367 halogens Chemical class 0.000 claims 1
- 125000004404 heteroalkyl group Chemical group 0.000 claims 1
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical compound C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 claims 1
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 claims 1
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 abstract description 12
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 abstract description 12
- 230000000259 anti-tumor effect Effects 0.000 abstract description 10
- 230000004565 tumor cell growth Effects 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 255
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 182
- 238000005481 NMR spectroscopy Methods 0.000 description 155
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 104
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 99
- 239000000243 solution Substances 0.000 description 77
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 67
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 65
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 55
- CSCPPACGZOOCGX-WFGJKAKNSA-N acetone d6 Chemical compound [2H]C([2H])([2H])C(=O)C([2H])([2H])[2H] CSCPPACGZOOCGX-WFGJKAKNSA-N 0.000 description 55
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 55
- 238000003756 stirring Methods 0.000 description 52
- 238000006243 chemical reaction Methods 0.000 description 49
- 239000002904 solvent Substances 0.000 description 47
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 42
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 42
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 39
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 38
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 36
- 239000000741 silica gel Substances 0.000 description 36
- 229910002027 silica gel Inorganic materials 0.000 description 36
- 239000012044 organic layer Substances 0.000 description 33
- 238000003786 synthesis reaction Methods 0.000 description 32
- 230000015572 biosynthetic process Effects 0.000 description 29
- 239000007787 solid Substances 0.000 description 27
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 26
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 25
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 23
- 238000010898 silica gel chromatography Methods 0.000 description 22
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 21
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 21
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 21
- 235000019253 formic acid Nutrition 0.000 description 21
- 238000010992 reflux Methods 0.000 description 21
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 20
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 20
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 19
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
- 125000004432 carbon atom Chemical group C* 0.000 description 18
- 239000012312 sodium hydride Substances 0.000 description 18
- 229910000104 sodium hydride Inorganic materials 0.000 description 18
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 17
- 238000001816 cooling Methods 0.000 description 17
- 125000006239 protecting group Chemical group 0.000 description 17
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 16
- 229920005654 Sephadex Polymers 0.000 description 16
- 239000012507 Sephadex™ Substances 0.000 description 16
- 239000013078 crystal Substances 0.000 description 16
- 238000001914 filtration Methods 0.000 description 16
- 238000004440 column chromatography Methods 0.000 description 15
- 238000002844 melting Methods 0.000 description 15
- 230000008018 melting Effects 0.000 description 15
- 239000000725 suspension Substances 0.000 description 14
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 13
- 235000011054 acetic acid Nutrition 0.000 description 13
- 238000009835 boiling Methods 0.000 description 13
- 239000010410 layer Substances 0.000 description 13
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 13
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 12
- 239000011541 reaction mixture Substances 0.000 description 12
- WJUFSDZVCOTFON-UHFFFAOYSA-N veratraldehyde Chemical compound COC1=CC=C(C=O)C=C1OC WJUFSDZVCOTFON-UHFFFAOYSA-N 0.000 description 12
- 238000000034 method Methods 0.000 description 11
- 239000011734 sodium Substances 0.000 description 11
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 10
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 10
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 10
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 10
- 230000002401 inhibitory effect Effects 0.000 description 10
- 229910000103 lithium hydride Inorganic materials 0.000 description 10
- 239000002480 mineral oil Substances 0.000 description 10
- 235000010446 mineral oil Nutrition 0.000 description 10
- 238000000746 purification Methods 0.000 description 10
- 125000003762 3,4-dimethoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 0.000 description 9
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- 229910052783 alkali metal Inorganic materials 0.000 description 9
- 235000014113 dietary fatty acids Nutrition 0.000 description 9
- 229930195729 fatty acid Natural products 0.000 description 9
- 239000000194 fatty acid Substances 0.000 description 9
- 239000012442 inert solvent Substances 0.000 description 9
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 8
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 8
- 239000002253 acid Substances 0.000 description 8
- 239000012300 argon atmosphere Substances 0.000 description 8
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 8
- 150000004665 fatty acids Chemical class 0.000 description 8
- 239000005457 ice water Substances 0.000 description 8
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 8
- BUAYFJKMVBIPKA-UHFFFAOYSA-N 4-(3,4-dimethoxyphenyl)-4-oxobutanoic acid Chemical compound COC1=CC=C(C(=O)CCC(O)=O)C=C1OC BUAYFJKMVBIPKA-UHFFFAOYSA-N 0.000 description 7
- SPEUIVXLLWOEMJ-UHFFFAOYSA-N acetaldehyde dimethyl acetal Natural products COC(C)OC SPEUIVXLLWOEMJ-UHFFFAOYSA-N 0.000 description 7
- 210000004027 cell Anatomy 0.000 description 7
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 7
- 239000000126 substance Substances 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 6
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 6
- 238000004587 chromatography analysis Methods 0.000 description 6
- 238000010511 deprotection reaction Methods 0.000 description 6
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 6
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 6
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- 229910000029 sodium carbonate Inorganic materials 0.000 description 6
- 235000017550 sodium carbonate Nutrition 0.000 description 6
- 235000011121 sodium hydroxide Nutrition 0.000 description 6
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 5
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 5
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 5
- 206010028980 Neoplasm Diseases 0.000 description 5
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 5
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 5
- 150000001298 alcohols Chemical class 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 150000002170 ethers Chemical class 0.000 description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 5
- 238000001704 evaporation Methods 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 150000007529 inorganic bases Chemical class 0.000 description 5
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 5
- 238000005259 measurement Methods 0.000 description 5
- 229910052751 metal Inorganic materials 0.000 description 5
- 239000002184 metal Substances 0.000 description 5
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 5
- 239000001632 sodium acetate Substances 0.000 description 5
- 235000017281 sodium acetate Nutrition 0.000 description 5
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 5
- 235000017557 sodium bicarbonate Nutrition 0.000 description 5
- YOYAIZYFCNQIRF-UHFFFAOYSA-N 2,6-dichlorobenzonitrile Chemical compound ClC1=CC=CC(Cl)=C1C#N YOYAIZYFCNQIRF-UHFFFAOYSA-N 0.000 description 4
- IBGBGRVKPALMCQ-UHFFFAOYSA-N 3,4-dihydroxybenzaldehyde Chemical compound OC1=CC=C(C=O)C=C1O IBGBGRVKPALMCQ-UHFFFAOYSA-N 0.000 description 4
- 125000002774 3,4-dimethoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C(OC([H])([H])[H])=C1OC([H])([H])[H])C([H])([H])* 0.000 description 4
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 229910015900 BF3 Inorganic materials 0.000 description 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 4
- IQZLUWLMQNGTIW-UHFFFAOYSA-N acetoveratrone Chemical compound COC1=CC=C(C(C)=O)C=C1OC IQZLUWLMQNGTIW-UHFFFAOYSA-N 0.000 description 4
- 150000001340 alkali metals Chemical class 0.000 description 4
- 150000004703 alkoxides Chemical class 0.000 description 4
- 230000001093 anti-cancer Effects 0.000 description 4
- 239000002246 antineoplastic agent Substances 0.000 description 4
- 201000011510 cancer Diseases 0.000 description 4
- 150000001244 carboxylic acid anhydrides Chemical class 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 238000005227 gel permeation chromatography Methods 0.000 description 4
- 150000004681 metal hydrides Chemical class 0.000 description 4
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 4
- 150000007530 organic bases Chemical class 0.000 description 4
- IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 4
- WYVAMUWZEOHJOQ-UHFFFAOYSA-N propionic anhydride Chemical compound CCC(=O)OC(=O)CC WYVAMUWZEOHJOQ-UHFFFAOYSA-N 0.000 description 4
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- NDVLTYZPCACLMA-UHFFFAOYSA-N silver oxide Chemical compound [O-2].[Ag+].[Ag+] NDVLTYZPCACLMA-UHFFFAOYSA-N 0.000 description 4
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 4
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- 230000000694 effects Effects 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 125000005949 ethanesulfonyloxy group Chemical group 0.000 description 1
- 125000005745 ethoxymethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])* 0.000 description 1
- DECIPOUIJURFOJ-UHFFFAOYSA-N ethoxyquin Chemical group N1C(C)(C)C=C(C)C2=CC(OCC)=CC=C21 DECIPOUIJURFOJ-UHFFFAOYSA-N 0.000 description 1
- WZKCZNJTDZCNMH-UHFFFAOYSA-N ethyl 2-(3,4-dimethoxyphenyl)acetate Chemical compound CCOC(=O)CC1=CC=C(OC)C(OC)=C1 WZKCZNJTDZCNMH-UHFFFAOYSA-N 0.000 description 1
- NTNZTEQNFHNYBC-UHFFFAOYSA-N ethyl 2-aminoacetate Chemical group CCOC(=O)CN NTNZTEQNFHNYBC-UHFFFAOYSA-N 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 239000004744 fabric Substances 0.000 description 1
- 239000012091 fetal bovine serum Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 125000003104 hexanoyl group Chemical group O=C([*])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
- 125000003707 hexyloxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- FUKUFMFMCZIRNT-UHFFFAOYSA-N hydron;methanol;chloride Chemical compound Cl.OC FUKUFMFMCZIRNT-UHFFFAOYSA-N 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 1
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 229910052740 iodine Inorganic materials 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
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 125000005921 isopentoxy group Chemical group 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
- 150000007517 lewis acids Chemical class 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 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
- 239000002207 metabolite Substances 0.000 description 1
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 1
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- CMWTZPSULFXXJA-VIFPVBQESA-N naproxen Chemical group C1=C([C@H](C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-VIFPVBQESA-N 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 125000005484 neopentoxy 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
- 229920001220 nitrocellulos Polymers 0.000 description 1
- PSACHCMMPFMFAJ-UHFFFAOYSA-N nmm n-methylmorpholine Chemical compound CN1CCOCC1.CN1CCOCC1 PSACHCMMPFMFAJ-UHFFFAOYSA-N 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 125000003452 oxalyl group Chemical group *C(=O)C(*)=O 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 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
- 230000011340 peptidyl-tyrosine autophosphorylation Effects 0.000 description 1
- VLTRZXGMWDSKGL-UHFFFAOYSA-M perchlorate Inorganic materials [O-]Cl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-M 0.000 description 1
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 1
- 125000006678 phenoxycarbonyl group Chemical group 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000002953 phosphate buffered saline Substances 0.000 description 1
- 125000005633 phthalidyl group Chemical group 0.000 description 1
- 125000001557 phthalyl group Chemical group C(=O)(O)C1=C(C(=O)*)C=CC=C1 0.000 description 1
- 229920001296 polysiloxane Polymers 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 229940086066 potassium hydrogencarbonate Drugs 0.000 description 1
- 235000011118 potassium hydroxide Nutrition 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 150000003217 pyrazoles Chemical class 0.000 description 1
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical compound OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 description 1
- NWELCUKYUCBVKK-UHFFFAOYSA-N pyridin-2-ylhydrazine Chemical compound NNC1=CC=CC=N1 NWELCUKYUCBVKK-UHFFFAOYSA-N 0.000 description 1
- ZDYVRSLAEXCVBX-UHFFFAOYSA-N pyridinium p-toluenesulfonate Chemical compound C1=CC=[NH+]C=C1.CC1=CC=C(S([O-])(=O)=O)C=C1 ZDYVRSLAEXCVBX-UHFFFAOYSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 239000012047 saturated solution Substances 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
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 description 1
- XGVXKJKTISMIOW-ZDUSSCGKSA-N simurosertib Chemical compound N1N=CC(C=2SC=3C(=O)NC(=NC=3C=2)[C@H]2N3CCC(CC3)C2)=C1C XGVXKJKTISMIOW-ZDUSSCGKSA-N 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 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
- WBQTXTBONIWRGK-UHFFFAOYSA-N sodium;propan-2-olate Chemical compound [Na+].CC(C)[O-] WBQTXTBONIWRGK-UHFFFAOYSA-N 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- AOZJWMKAEWLXPZ-UHFFFAOYSA-N spiro[4H-1,3-benzodioxine-2,1'-cyclohexane] Chemical compound C12(CCCCC1)OCC1=C(O2)C=CC=C1 AOZJWMKAEWLXPZ-UHFFFAOYSA-N 0.000 description 1
- 206010041823 squamous cell carcinoma Diseases 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 229940014800 succinic anhydride Drugs 0.000 description 1
- 125000002730 succinyl group Chemical group C(CCC(=O)*)(=O)* 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 229960004793 sucrose Drugs 0.000 description 1
- 229960004016 sucrose syrup Drugs 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- GFYHSKONPJXCDE-UHFFFAOYSA-N sym-collidine Natural products CC1=CN=C(C)C(C)=C1 GFYHSKONPJXCDE-UHFFFAOYSA-N 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 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
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000005922 tert-pentoxy group Chemical group 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- 101150054171 thf1 gene Proteins 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- LWRYDHOHXNQTSK-UHFFFAOYSA-N thiophene oxide Chemical compound O=S1C=CC=C1 LWRYDHOHXNQTSK-UHFFFAOYSA-N 0.000 description 1
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- DKZBBWMURDFHNE-UHFFFAOYSA-N trans-coniferylaldehyde Natural products COC1=CC(C=CC=O)=CC=C1O DKZBBWMURDFHNE-UHFFFAOYSA-N 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- FAQYAMRNWDIXMY-UHFFFAOYSA-N trichloroborane Chemical compound ClB(Cl)Cl FAQYAMRNWDIXMY-UHFFFAOYSA-N 0.000 description 1
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- 125000005951 trifluoromethanesulfonyloxy group Chemical group 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 239000003656 tris buffered saline Substances 0.000 description 1
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- MWOOGOJBHIARFG-UHFFFAOYSA-N vanillin Chemical compound COC1=CC(C=O)=CC=C1O MWOOGOJBHIARFG-UHFFFAOYSA-N 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/44—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members
- C07D207/444—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members having two doubly-bound oxygen atoms directly attached in positions 2 and 5
- C07D207/456—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members having two doubly-bound oxygen atoms directly attached in positions 2 and 5 with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
- C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
- C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
- C07D261/08—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D263/36—One oxygen atom
- C07D263/42—One oxygen atom attached in position 5
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
- C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
- C07D271/06—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D333/30—Hetero atoms other than halogen
- C07D333/32—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/655—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms
- C07F9/65515—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a five-membered ring
Definitions
- the present invention is useful in the field of medicine, and more specifically, relates to a novel compound that inhibits the growth of tumor cells and exhibits an antitumor effect, and a use thereof.
- the present inventors have screened a wide range of microbial metabolites and found that a novel compound BE-23372M [(E) -3- (3,4-dihydroxy) having tyrosine kinase inhibitory activity and antitumor activity Benzylidene) -5- (3,4-dihydroxyphenyl-2 (3H) -furanone] was disclosed [see Japanese Patent Application Laid-Open No. 4-275284].
- HMPA Hexamethylphosphate triamide HOBT ⁇ H 2 0 1 - hydroxy - 1H-Benzotoriazo Ichiru monohydrate
- the term “lower” means no more than 6 unless the carbon number of the group to which the term is attached is specifically stated.
- the lower alkyl group means a linear or branched alkyl group having 1 to 6 carbon atoms, such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group and a sec-butyl group.
- a methyl group such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group and a sec-butyl group.
- Tert-butyl group pentyl group, isopentyl group, neopentyl group, hexyl group, isohexyl group and the like.
- the lower alkenyl group means a linear or branched alkenyl group having 2 to 6 carbon atoms, such as a vinyl group, a 1-propeninole group, an aryl group, a 1-butenyl group, and a 2-butenyl group. , 3-butenyl group, 1-methylvinyl group, 2-methyl-1-butenyl group and the like.
- the lower alkynyl group means a linear or branched alkynyl group having 2 to 6 carbon atoms, for example, ethynyl group, 2-propynyl group, 2-butynyl group, 3-butynyl group, 2-pentynyl group Group, 2-hexynyl group and the like.
- the cycloalkyl group means a cyclic alkyl group having 3 to 8 carbon atoms, and examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, and a cycloheptyl group.
- the cycloalkyl lower alkyl group means a cycloalkylalkyl group having 4 to 14 carbon atoms in which the lower alkyl group is substituted by the cycloalkyl group, for example, a cyclopropylmethyl group, a 1-cyclopropylethyl group, 2-cyclopro Pyrethyl, cyclobutylmethyl, 1-cyclobutylethyl, 2-cyclobutylethyl, cyclopentylmethyl, 1-cyclopentylethyl, 2-cyclopentylethyl, cyclohexylmethyl, 1-cyclohexylethyl And a 2-cyclohexylethyl group.
- the aryl group means a group having 6 to 12 carbon atoms, and examples thereof include a phenyl group, a naphthyl group, a 4-nitrophenyl group, a 4-carboxyphenyl group, and a 4-methoxyphenyl group. .
- ⁇ reel lower alkyl group means an arylalkyl group having 7 to 14 carbon atoms in which the aryl group is substituted for the lower alkyl group, for example, benzyl group, phenethyl group, 3-phenylpropyl group, Examples thereof include a 4-methoxybenzyl group, a 4-hydroxybenzyl group, a 1-naphthylmethyl group, and a 2-naphthylmethyl group.
- the protected hydroxy group means a hydroxy group protected by a commonly used protecting group.
- the used protecting group include a lower alkyl group such as a methyl group and an ethyl group; for example, a trimethylsilyl group and a t-butyldimethyl group.
- a lower alkylsilyl group such as a silyl group; a lower alkoxymethyl group such as a methoxymethyl group and a 2-methoxyethoxymethyl group; a tetrahydroviranyl group; a benzyl group, a P-methoxybenzizole group, and a 2,4-dimethoxy group;
- Aryl lower alkyl groups such as benzyl group, 0-nitropentenyl group, p-nitropentenyl group, and trityl group; lower alkanol groups such as formyl group and acetyl group; t-butoxycarbonyl group; Lower alkyloxy such as 2-odoethoxycarbonyl and 2,2,2-trichloroethoxycarbonyl Rubonyl group; for example, 2-propenyloxycarbonyl group, 2-chloro-2-propenyloxycarbonyl group, 3-methoxycarbonyl-2-propenyloxycarbonyl group, 2-
- the hydroxy lower alkyl group means a hydroxyalkyl group having 1 to 6 carbon atoms in which the lower alkyl group is substituted by 1 to 2 hydroxy groups. Droxymethyl group, 1-hydroxyethyl group, 2-hydroxyethyl group, 1,2-dihydroxyethyl group, 1-hydroxypropyl group, 2-hydroxypropyl group, 3-hydroxypropyl group, 2,3 -Dihydroxypropyl group and the like.
- the protected hydroxy lower alkyl group means the lower alkyl group having 1 to 6 carbon atoms which is substituted by 1 to 2 protected hydroxy groups, for example, methoxymethyl group, benzyl group.
- an isopropylidene group, a cyclohexylidene group, a benzylidene group, or the like can be used as a protecting group, and specifically, a 1,3-di-0-isopropylidene pentyl group, 1,2 -Di-0-cyclohexylideneethyl group, 2,3-di-0-isopropylidene oryl group.
- the lower alkoxy group means a straight-chain or branched alkoxy group having 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy.
- the lower alkenyloxy group means a linear or branched alkenyloxy group having 3 to 6 carbon atoms, such as an aryloxy group, a 2-butenyloxy group, a 3-butenyloxy group, a 4-pentenyloxy group, and the like. Is mentioned.
- the lower alkynyloxy group means a linear or branched alkynyloxy group having 3 to 6 carbon atoms, such as a propynyloxy group, a 2-butynyloxy group, a 3-butynyloxy group, and a pentynyloxy group.
- the cycloalkyl lower alkoxy group means a cycloalkyl alkoxy group having 4 to 14 carbon atoms in which the lower alkoxy group is substituted by the cycloalkyl group, for example, a cyclopropyl methoxy group, a 1-cyclopropyl ethoxyquin group.
- An aryloxy group means one having 6 to 12 carbon atoms, such as phenoxy, 4-methoxyphenyl, 4-carboxyphenoxy, 1-naphthyl And a 2-naphthyloxy group.
- the aryl lower alkoxy group refers to an aryl lower alkoxy group having 4 to 14 carbon atoms in which the lower alkoxy group is substituted by the aryl group.
- Examples thereof include a benzyloxy group, a phenethyloxy group, and a 4-methyl
- Examples include a toxicbenzyloxy group, a 4-carboxybenzyloxy group, a 1-naphthylmethyloxy group, and a 2-naphthylmethyl group.
- the lower alkanoyl group means an alkanoyl group having 1 to 6 carbon atoms, for example, formyl group, acetyl group, propionyl group, butyryl group, valeryl group, pivaloyl group, hexanoyl group and the like.
- a lower alkanoyloxy group means an alkanoyloxy group having 1 to 6 carbon atoms. And the like.
- the lower alkenyloxy lower alkyl group means the lower alkyl group substituted with the alkenyloxy group, such as a formyloxymethyl group, an acetyloxymethyl group, a 1-acetyloxyxethyl group. , 2-acetyloxyethyl, propionyloxymethyl, 1-propionyloxyethyl, 2-propionyloxyethyl, and the like.
- the lower alkoxy lower alkyl group means an alkoxyalkyl group in which the lower alkyl group is substituted by the lower alkoxy group, and examples thereof include a methoxymethyl group, a methoxethyl group, an ethoxymethyl group, and a propyloxymethyl group.
- the aryloxy lower alkyl group means the lower alkyl group substituted with the aryloxy group, and examples thereof include a phenokinemethyl group, a 1-naphthyloxymethyl group, and a 2-naphthyloxymethyl group.
- halogen atom examples include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
- lower alkyl group means the lower alkyl group substituted with 1 to 3 halogen atoms, and examples thereof include a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a chloromethyl group, a dichloromethyl group, and a trichloromethyl group.
- Methyl Group bromomethyl group, dibromomethyl group, tribromomethyl group, 1,2-difluoroethyl group, 1,2-dichloroethyl group, 1,2-dibromoethyl group, 2,3-difluoropropyl group, 2,3-dichloro group And a propyl group and a 2,3-dibromopropyl group.
- the protected carboxyl group means a carboxyl group protected by a commonly used protecting group.
- the used protecting group include a methyl group, an ethyl group, a propyl group, an isopropyl group and a t-butyl group.
- a lower alkyl group for example, a halo-lower alkyl group such as a 2,2,2-trichloroethyl group or a 2,2,2-trifluoroethyl group; for example, an acetooxymethyl group, a propionyloxymethyl group, a vivaloyloxy group; Methyl-, 1-acetoxityl,;!-Loweralkanoyloxyalkyl, such as propionyloxyethyl, etc .; for example, 1- (methoxycarboxy) ethyl, 1- (ethoxycarbonyloxy) ethyl, 1 -(Isopropoxycarbonyloxy) lower alkyl group such as ethyl group such as 2-ethyl group; for example, 2-propininole group Lower alkenyl groups such as 2-chloro-2-propyninole group, 3-methoxycarbonyl-2-propenyl group, 2-methyl-2-propeny
- Aryl lower alkyl group for example, (5-substituted-2-oxo-1, 3-dioxol-4-yl) such as (5-methyl-2-oxo-1,3-dioxo-1-yl) methyl group; Yl) methyl group; for example, lower alkylsilyl groups such as trimethylsilyl group and t-butyldimethylsilyl group; indanyl group, phthalidyl group, methoxymethyl group and the like.
- 5-substituted-2-oxo-1, 3-dioxol-4-yl such as (5-methyl-2-oxo-1,3-dioxo-1-yl) methyl group
- Yl) methyl group for example, lower alkylsilyl groups such as trimethylsilyl group and t-butyldimethylsilyl group; indanyl group, phthalidyl group, methoxymethyl group and the like.
- the carboxy lower alkyl group means the above-mentioned lower alkyl group substituted by a carboxy group, and examples thereof include a carboxymethyl group, a 2-carboxyethyl group, and a 3-carboxypropyl group.
- the protected carbonyloxy lower alkyl group means the above lower alkyl group substituted by a carboxy group protected by the above protecting group, for example, methoxycarbonylmethyl group, benzyloxycarbonylmethyl group, Methoxycarbonylethyl group, 3-benzyloxycarbonylpropyl group, etc.
- a carboxy group protected by the above protecting group for example, methoxycarbonylmethyl group, benzyloxycarbonylmethyl group, Methoxycarbonylethyl group, 3-benzyloxycarbonylpropyl group, etc.
- a carboxy lower alkenyl group means the above-mentioned lower alkenyl group substituted by a carboxy group, such as a 1-carboxyvinyl group, a 2-carboxyvinyl group, a 3-carboxy-2-propenyl group, etc. Is mentioned.
- the protected carboxy lower alkenyl group means the above lower alkenyl group substituted by a carboxy group protected by the above protecting group, for example, an I-methoxycarbonylvinyl group, a 2-methyl A methoxycarbonylvinyl group and a 3-benzyloxycarbonyl-2-propininole group.
- the protected amino group means an amino group protected by a commonly used protecting group, and examples of the protecting group include an aryl lower alkylidene group such as a benzylidene group and a P-methoxybenzylidene group; Aryl lower such as p-methoxybenzyl group, 3,4-dimethoxybenzyl group, 0-nitrobenzyl group, p-nitrobenzyl group, benzhydryl group, bis (P-methoxyphenyl) methyl group and trityl group Alkyl group; for example, lower alkanol group such as formyl group, acetyl group, propionyl group, butyryl group, oxalyl group, succinyl group, and vivaloyl group; for example, phthalyl group; for example, chloroacetyl group, dichloroacetyl group, trichloroacetyl group Halo-substituted lower alkanol groups such as trifluor
- the amino lower alkyl group means the lower alkyl group substituted with an amino group, for example, an aminomethyl group, a 1-aminoethyl group, a 2-aminoethynole group, a 1-aminopropyl group, a 2-aminopropyl group, Examples thereof include a 3-aminopropyl group, a toamino-1-methylethyl group, a 2-amino-tomethylethynole group, a 1-aminobutyl group, a 2-aminobutyl group, a 3-aminobutyl group, and a 4-aminobutyl group.
- the protected amino lower alkyl group means the above lower alkyl group substituted by the amino group protected by the above protecting group, for example, benzyloxycarbonylaminomethyl group, 1-t-butoxycarbonyl group.
- examples include a minethyl group, a 2-benzyloxycarbonylaminoethyl group, a 1-N-p-nitrobenzyloxycarbonyl-Nt-butyldimethylsilylaminopropyl group, and the like.
- the aryloxy group means an aryloxy group having 7 to 13 carbon atoms, and examples thereof include a benzoyloxy group, a 4-methoxybenzoyloxy group, a 1-naphthoyloxy group and a 2-naphthoyloxy group.
- N-mono-lower alkyl rubamoyl means a carbamoyl group substituted with one of the above-mentioned lower alkyl groups, such as N-methylcarbamoyl, N-ethylcarbamoyl, N-propyl carbamoyl. , N-butylcarbamoyl group and the like.
- ⁇ , ⁇ -di-lower alkyl group refers to a group that is substituted with two identical or different lower alkyl groups, for example, ⁇ , ⁇ -dimethylcarbamoyl group, ⁇ -ethyl- ⁇ -methylcarbamoyl group, ⁇ , ⁇ -getylcarbamoyl group, ⁇ -ethynole- ⁇ -propylcanolebamoinole group and the like.
- the lower alkoxycarbonyl group means an alkoxycarbonyl group having the lower alkoxy group, and examples thereof include a methoxycarbonyl group, an ethoxycarbonyl group, and a propyloxycarbonyl group.
- the lower alkenyloxycarbonyl group means an alkenyloxycarbonyl group having the lower alkenyloxy group, for example, aryloxyl. Examples include a bonyl group and a butenyloxycarbonyl group.
- the aryloxycarbonyl group means an aryloxycarbonyl group having the above-mentioned aryloxy group, for example, phenoxycarbonyl group, 1-naphthoxycarbonyl group, 2-naphthoxycarbonyl group and the like. Is mentioned.
- the aryl lower alkoxycarbonyl group means an aryl alkoxycarbonyl group having the aryl lower alkoxy group, such as a benzyloxycarbonyl group, a 1-naphthylmethoxycarbonyl group, and a 2-naphthylmethoxycarbonyl group.
- the lower alkylsulfonyloxy group means an alkylsulfonyloxy group having the lower alkyl group, for example, a methanesulfonyloxy group, an ethanesulfonyloxy group, a propanesulfonyloxy group, an isopropanesulfonyloxy group, Butanesulfonyloxy group and the like.
- the perylsulfonyloxy group means an arylsulfonyloxy group having the aryl group, and examples thereof include a benzenesulfonyloxy group and a p-toluenesulfonyloxy group.
- the di-lower alkoxyphosphoryloxy group means a dialkoxyphosphoryloxy group having two of the above-mentioned lower alkyl groups, and examples thereof include a dimethoxyphosphoryloxy group and a ethoxyphosphoryloxy group.
- the N-mono lower alkylamino group means an amino group substituted with the lower alkyl group, such as an N-methylamino group, an N-ethylamino group, an N-propylamino group, an N-butylamino group, and the like. .
- the protected N-mono-lower alkylamino group means a protected amino group substituted with the lower alkyl group, for example, an N-methyl-Np-nitrobenzyl amino group, an N-acetyl-N-ethylamino group. And the like.
- ⁇ , ⁇ -di-lower alkylamino group means an amino group substituted with the same or different two lower alkyl groups, for example, ⁇ , ⁇ -dimethylamino group, ⁇ -ethyl- ⁇ -methylamino group. , ⁇ , ⁇ -ethylamino group, ⁇ -ethyl- ⁇ -propylamino group, ⁇ , ⁇ -dipropylamino group, ⁇ , ⁇ -dibutylamino group and the like.
- the lower alkanoyl group means an amino group substituted with the lower alkanoyl group, for example, an acetylamino group, a propionylamino group, a butylamino group. A lumino group, a vivaloylamino group and the like.
- the aroylamino group means an amino group substituted with the aroyl group, and examples thereof include a benzoylamino group, a 1-naphthoylamino group, and a 2-naphthoylamino group.
- the N-lower alkylaminocarbonyloxy group means an aminocarboxy group substituted by the lower alkyl group, specifically, N-methylaminocarbonyl group, N-ethylaminocarbonyloxy group. And the like.
- the N, N-di-lower alkylaminocarbonyloxy group means an aminocarbonyl group substituted by the same or different two above-mentioned lower alkyl groups, specifically, ⁇ , ⁇ -dimethylaminocarbonyl And a ⁇ , ⁇ -dimethylaminocarbonyloxy group, a ⁇ -ethyl- ⁇ -methylaminocarbonyloxy group, a ⁇ , ⁇ -dipropylaminocarbonylcarbonyl group, and the like.
- the protected amidino group means an amidino group protected by a commonly used protecting group, and examples of the protecting group include a t-butoxycarbonyl group, a 4-methoxy-2,3,6-trimethylbenzenesulfonyl group, And the like.
- the protected guanidino group means a guanidino group protected by a commonly used protecting group.
- the protective group include t-butoxycarbonyl group, 4-methoxy-2,3,6-trimethylbenzenesulfonyl group, And a mouth group.
- Leaving groups are those commonly used in organic synthetic chemistry, and specifically include halogen atoms, tri-lower alkylammonium groups, methanesulfonyloxy groups, trifluoromethanesulfonyloxy groups, p- And a toluenesulfonyloxy group.
- the compound of the present invention represented by the above formula [1] may be, for example, an inorganic acid salt such as hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, perchlorate or phosphate; Acid addition salts such as organic acid salts such as P-toluenesulfonate, benzenesulfonate, methanesulfonate, oxalate, succinate, tartrate, citrate, fumarate or maleate Or an alkali metal salt such as sodium salt, potassium salt, potassium salt or the like, or an alkaline earth metal salt, and particularly preferably a pharmaceutically acceptable non-toxic salt.
- the compound of the formula [1] may have stereoisomers depending on the mode of the substituent, but the present invention also includes all of these stereoisomers and a mixture thereof.
- the compounds represented by [la] to [Id] can be synthesized, for example, according to the following scheme.
- R 'in [Deprotection] Scheme represents a hydrogen atom, a lower alkyl group, lower alkenyl group, a lower ⁇ Rukiniru group, a cycloalkyl group, a cycloalkyl-lower alkyl group, a Ariru group or Ariru lower alkyl group
- R 3 It is a hydrogen atom, a lower alkyl group, lower-grade alkenyl group, lower alkynyl group, a cycloalkyl group, a cycloalkyl lower alkyl group, Ariru group, Ariru lower alkyl group, a Arukanoiru group or a lower Aroiru group
- R 4 is claim Has the same meaning as 1, and
- R 5 is a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a cycloalkyl group, a cycloalkyl lower alkyl group, an
- ⁇ 3 and ⁇ 3 are the same or different and are a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a cycloalkyl group, a cycloalkyl lower alkyl group, Aryl group, aryl lower alkyl group, hydroxy group, protected hydroxy group, hydroxy lower alkyl group, protected hydroxy lower alkyl group, lower alkoxy group, lower alkenyloxy group, lower alkynyloxy group, aryloxy group, Cycloalkyl lower alkoxy group, aryl lower alkoxy group, lower alkoxy lower alkyl group, aryloxy lower alkyl group, pager Child, halo-lower alkyl group, a force Rubamoi Le group, Nyu- mono-lower alkyl force Rubamoiru group, New, Nyu- di-lower alkyl force Rubamoi , Lower
- a protecting group for a functional group other than the above as a protecting group for a glycol, a normal group such as an isopropylidene group, a cyclohexylidene group, or a benzylidene group may be selected and used according to the reaction conditions. Can be.
- a usual one such as a methylene group, an isopropylidene group or a cyclohexylidene group can be selected and used according to the reaction conditions.
- Examples of the carbonyl protecting group include lower alkyl acetal groups such as an ethylene acetal group, a dimethyl acetal group, and a dimethyl ether group, a 1,3-dithiolan-2-yl group, and a 1,3-dithiane-2 group.
- An ordinary group such as -yl group can be selected and used according to the reaction conditions.
- the compound of the general formula [la] can be prepared by adding 1,3-dicarbonyl disulfide compound [2] and 1 to 5 equivalents of hydroxylamine or a hydrogen halide salt of hydroxylamine to water or methanol, ethanol, or propanol according to a conventional method.
- an inert solvent such as lower alcohols or water-containing lower alcohols, etc.
- the reaction is carried out at a temperature from room temperature to the boiling point of the solvent for 1 hour to 2 days, and the ring is closed.
- the compound of the general formula [lb] can be prepared according to a conventional method by mixing 1,3-dicarboniuihide compound [2] with 1 to 5 equivalents of hydrazine or hydrazine hydrate without solvent, or water, or methanol, ethanol, propanol or the like.
- aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as THF, DME and getyl ether, lower fatty acid amides such as DMA.
- ethers such as THF, DME and getyl ether
- lower fatty acid amides such as DMA.
- secondary amine alkali metal salts such as LDA, LHMDS and KHMDS
- alkali metal hydrides such as lithium hydride, sodium hydride and hydrogenation hydride in an inert solvent.
- an inorganic base such as sodium methoxide, sodium ethoxide, lower alkali metal alkoxide such as t-butoxycali, or an alkali metal such as sodium carbonate, carbon dioxide rim, etc.
- an inorganic base such as sodium methoxide, sodium ethoxide, lower alkali metal alkoxide such as t-butoxycali, or an alkali metal such as sodium carbonate, carbon dioxide rim, etc.
- the compound [lb] is prepared by adding 1 to 10 equivalents of the substituted hydrazine compound of the general formula [4] to a 1,3-dicarbonitrile compound [2] without solvent or water or a lower compound such as methanol, ethanol or propanol.
- a 1,3-dicarbonitrile compound [2] without solvent or water or a lower compound such as methanol, ethanol or propanol.
- an inert solvent such as alcoholic or hydrated lower alcoholic, ethers such as THF, 1,4-dioxane and DME, lower fatty acid amides such as DMA. DMF or hydrated lower fatty acid amides. It can be obtained by reacting at a temperature from room temperature to the boiling point of the solvent for 1 hour to 2 days, followed by deprotection if necessary.
- the compound represented by the general formula [lc] is a glycine ester in an amount of 1 to 5 equivalents to the carboxylic acid compound represented by the general formula [5].
- the solvent, methylene chloride, in an inert solvent such as a halogenated hydrocarbon, such as black hole Holm, to the boiling point of 0 ° Celsius to solvents, preferably 2 days 30 minutes 10 ° C ⁇ 50 e C is 1 3 equivalents of DPPA, DCC, EDCI ⁇ HC1, after condensation in the usual manner as required condensing agent CDI, etc.
- the compound of the general formula [7] is converted into 1 to 100 equivalents of a lower carboxylic anhydride such as acetic anhydride, propionic anhydride or the like.
- a lower carboxylic anhydride such as acetic anhydride, propionic anhydride or the like.
- Inorganic bases or sodium methoxides such as ⁇ 5 equivalents of secondary amialkali metal salts such as LDA, LHMDS, KHMDS, etc., and 1 ⁇ 5 equivalents of lithium metal hydrides such as lithium hydride, sodium hydride and lithium hydride.
- alkali metal lower alkoxides such as sodium methoxide, sodium ethoxide, sodium isopropoxide, t-butoxycali, etc.
- a lower alcohol solvent such as methanol, ethanol, propanol, isopropanol, t-butanol
- the reaction is carried out at a temperature of from 0 ° C to the boiling point of the solvent for 30 minutes to 2 hours, and if necessary, deprotected.
- Y 4 is a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a cycloalkyl group, a cycloalkynole lower alkyl group, an aryl group, an aryl lower alkyl group, a lower alkoxy group, a lower alkenyloxy group, a lower alkynyloxy group, an aryloxy group
- a phenyl group optionally having 1 to 3 substituents, or 1 to 3 selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom, which may have 1 to 3 substituents.
- R 8 and R 9 are the same or different and represent a lower alkyl group or an aryl lower alkyl group;
- R 10 has the same meaning as R 5 except for a hydrogen atom; and L represents a leaving group.
- the compound of the general formula [Ie] is obtained by combining the compound of the general formula [20] with 1 to 5 equivalents of the compound of the general formula [8] and 1 to 30 equivalents of a lower fatty acid ammonium salt such as ammonium formate or ammonium acetate. 1 hour to 2 hours at room temperature to the boiling point of the reaction solvent in a lower fatty acid such as formic acid, acetic acid, propionic acid or the like at a temperature of 60 ° C to 110 ° C. React for days and deprotect if necessary.
- a lower fatty acid ammonium salt such as ammonium formate or ammonium acetate.
- the compound of the general formula [Ie] may be deprotected, if necessary, from the compound of the general formula [20] to obtain 3 to 30 equivalents of a lower carboxylic anhydride such as acetic anhydride or propionic anhydride at 0 ° C to 100 ° C. C.
- a lower carboxylic anhydride such as acetic anhydride or propionic anhydride
- the reaction is carried out at 20.degree. 0 to 80 to 1 hour to 12 hours, and the compound of the general formula [21] is obtained by dehydration and ring closure to obtain a compound of the general formula [21].
- the compound of the general formula [K] can be obtained by converting the compound of the general formula [20] to a lower carboxylic anhydride such as acetic anhydride, propionic anhydride or butyric anhydride in an amount of 1 to 20 equivalents, preferably in an inert gas atmosphere.
- a lower carboxylic anhydride such as acetic anhydride, propionic anhydride or butyric anhydride in an amount of 1 to 20 equivalents, preferably in an inert gas atmosphere.
- the starting compound 7-keto acid derivative [20] can be obtained, for example, by the Friedel-Crafts reaction of the compound [18] and the compound [19].
- Inorganic bases such as hydrides, or alkaline metal such as t-butyne hydride
- an inert solvent such as DMF, benzene, toluene, THF, or DME at 0 ° C. to the boiling point of the solvent, preferably 10 ° C.
- the mixture was reacted at 30 ° C. to 70 ° C.
- reaction is carried out at 0 ° C. to the boiling point of the solvent, preferably at 10 ° C. to 100 ° C. for 30 minutes to 2 days to obtain a compound of the general formula [16]. For 2 days at 30 ° C to 120 ° C, preferably at 50 ° C to 100 ° C.
- R 5 when R 5 is a hydrogen atom, it can be produced under the same reaction conditions as described above, except for the step of reacting compound [13] with compound R 1QL .
- the compound of the general formula [13] is According to the method of N. Cohen et al. [J. Org. Chem. 38, pp. 3229-3239], compound [11] is converted to a compound of the general formula 3-20 equivalents according to the method of J. Org. [12] with 1 to 5 equivalents, preferably 1 to 3 equivalents of an alkali metal hydride such as lithium hydride, sodium hydride, or lithium hydride; or an alkali metal hydride such as t-butoxycali. It can also be obtained by reacting for 1 hour to 2 hours at 50 ° C to the boiling point of the reaction solution in the presence of a metal lower alkoxide or the like.
- the compound of general formula [lg] can be obtained, for example, by the following method. According to the method of A ⁇ Kosak et al. [J. Am. Chem. Soc., Vol. 76, 4450-4454 (1954)], the general formula [20] was converted. The compound together with 1 to 3 equivalents of diphosphorus pentasulfide and 10 to 30 equivalents of an organic base such as pyridine, picoline, collidine, lutidine, etc., in a halogenated hydrocarbon solvent such as methylene chloride, chloroform, carbon tetrachloride, etc.
- the product obtained in each of the above steps can be obtained by a known purification method, such as Purification or isolation can be achieved by single or appropriate combination of chromatography, high performance liquid chromatography, thin layer chromatography, recrystallization, solvent extraction, precipitation, or distillation.
- the tyrosine kinase inhibitory activity of the compound according to the present invention was measured as follows.
- A431 cells human epidermoid carcinoma cells, were seeded at a concentration of 5 x 10 4 cells / 0.5 ml Z-well in a 24-well plate using a modified Dulbecco's MEM medium supplemented with 10% fetal bovine serum. % C0 2 in the presence 37 ° C and cultured for 6 days Ru to form a cell layer.
- the compound according to the present invention inhibits the growth of tumor cells and has an anticancer effect.
- various forms can be selected as the administration form when the compound of the present invention is used as an antitumor agent, which is known in the art.
- Pharmaceutical preparations include, for example, liquid preparations such as injections, inhalants, syrups and emulsions, solid preparations such as tablets, capsules and granules, and external preparations such as ointments and suppositories.
- these preparations may optionally contain commonly used additives such as auxiliaries, stabilizers, wetting agents, emulsifiers, absorption promoters or surfactants.
- the additives include distilled water for injection, Ringer's solution, glucose, sucrose syrup, gelatin, edible oil, cocoa butter, ethylene glycol, sucrose, corn starch, magnesium stearate, and talc.
- the dose of the compound of the present invention as a tyrosine kinase inhibitor differs depending on the administration method, the age and weight of the patient, the condition of the patient to be treated, and the like.
- a typical administration method for an adult is oral administration or non-administration.
- the precipitated pale yellow solid is collected by filtration, dissolved in 100 ml of 1N sodium hydroxide solution, washed twice with 50 ml of diethyl ether, and adjusted to pH 2 with concentrated hydrochloric acid at 0 ° C. Analysis The resulting colorless solid is washed twice with 100 ml of water and then twice with 100 ml of ethanol, and dried under reduced pressure to obtain 11.7 g of 3- (3,4-dimethoxybenzoyl) propionic acid as a colorless solid.
- the aqueous layer is adjusted to pH 2 with 6N hydrochloric acid, extracted twice with 50 ml of ethyl acetate, and the organic layer is dried over anhydrous magnesium sulfate.
- 6-Hydroxynicotinic acid 500 mg
- silver oxide 1.84 g
- toluene 30 ml
- benzyl bromide 1.07 ml
- the insolubles were removed by filtration, and the filtrate was concentrated under reduced pressure.
- reaction mixture again - a 78 e C acetic acid Echiru 40ml and 0.01N HCl 10ml and added to separate liquid cooled to a residue after concentration under reduced pressure was added methanol 0.5ml organic layer was washed with water and saturated brine, anhydrous magnesium sulfate The residue obtained by drying and concentration under reduced pressure is purified by Sephadex TM LH-20 column chromatography (methanol) to obtain 13.8 mg of the title compound as white crystals.
- the reaction solution was cooled again to -78 ° C, 0.5 ml of methanol was added, and the mixture was concentrated under reduced pressure.40 ml of ethyl acetate and 10 ml of 0.01 N hydrochloric acid were added to the residue, and the mixture was separated. The organic layer was washed with water and saturated saline, and then anhydrous magnesium sulfate And concentrated under reduced pressure to give a residue, which is purified by Sephadex TM LH-20 column chromatography (methanol) to obtain 12.4 mg of the title compound as white crystals.
- Examples 3 to 8 are synthesized by synthesizing a 1,3-diketone compound as a raw material in the same manner as in Reference Example 1, and cyclizing to a pyrazole derivative with hydrazine and deprotecting in the same manner as in Example 2. .
- Example 22 the compounds of the following Examples 22 to 86 were prepared by condensing a corresponding carbonyl compound of the general formula [8] and a 7-keto acid derivative of the general formula [21] in the presence of a base, followed by ring closure. It is synthesized by a method of treating with boron halide.
- Example 91 the compound was synthesized from 5- (3,4-diacetoxyphenyl) -2 (3H) -furanone and 4-hydroxy-3-hydroxymethylbenzaldehyde.
- Example 97 to 115 were obtained in the same manner as in Example 96 by obtaining a 5-substituted-2 (3H) -thiophenone derivative and then condensing each with the corresponding carbonyl compound of the general formula (8) under acidic conditions. And, if necessary, deprotected with boron tribromide.
- Example 117 to 123 The compounds of Examples 117 to 123 are synthesized in the same manner as in Example 116.
- the methyl ester 136mg was dissolved in methanol 5 ml, addition of 2N hydroxide sodium ⁇ anhydrous solution lml, stirred for 30 minutes at room temperature, adjust the P H of the reaction solution to 2-3 with ice-cooling under 1N hydrochloric acid, acetic Echiru Extract with 80 ml.
- the organic layer is washed with a small amount of saturated saline, dried over anhydrous sodium sulfate, and the solvent is distilled off under reduced pressure to obtain 130 mg of 4-oxo-4- (1-phenyl-2-pyridone-5-yl) butyric acid. .
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Abstract
L'invention concerne un composé représenté par la formule (I) et ses utilisations. Ce composé inhibe fortement une tyrosine kinase et supprime la croissance des cellules tumorales, ce qui le rend utile dans les applications médicinales, avec des perspectives intéressantes d'emploi comme agent antitumoral.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU74672/94A AU7467294A (en) | 1993-08-20 | 1994-08-18 | Tyrosine kinase inhibitor |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP5/228232 | 1993-08-20 | ||
JP22823293 | 1993-08-20 | ||
JP27622393 | 1993-10-07 | ||
JP5/276223 | 1993-10-07 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1995006032A1 true WO1995006032A1 (fr) | 1995-03-02 |
Family
ID=26528129
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/JP1994/001368 WO1995006032A1 (fr) | 1993-08-20 | 1994-08-18 | Inhibiteur de la tyrosine kinase |
Country Status (2)
Country | Link |
---|---|
AU (1) | AU7467294A (fr) |
WO (1) | WO1995006032A1 (fr) |
Cited By (27)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0713869A3 (fr) * | 1994-11-25 | 1996-06-19 | Lonza Ag | |
WO1998056756A1 (fr) * | 1997-06-12 | 1998-12-17 | Cheil Jedang Corporation | Derives acides des catecholamines et compositions pharmaceutiques les contenant |
KR100332273B1 (ko) * | 1995-07-26 | 2002-06-20 | 디. 제이. 우드, 스피겔 알렌 제이 | 엔-(아로일)글리신하이드록삼산유도체및이와관련된화합물 |
US6410540B1 (en) | 1998-08-28 | 2002-06-25 | Scios, Inc. | Inhibitors of p38-αkinase |
US6541477B2 (en) | 1999-08-27 | 2003-04-01 | Scios, Inc. | Inhibitors of p38-a kinase |
US6743815B2 (en) | 1998-08-07 | 2004-06-01 | Chiron Corporation | Estrogen receptor modulators |
US7163945B2 (en) | 2004-04-29 | 2007-01-16 | Pharmix Corp. | Compositions and treatments for inhibiting kinase and/or HMG-CoA reductase |
US7183285B2 (en) | 2004-04-29 | 2007-02-27 | Pharmix Corp. | Compositions and treatments for inhibiting kinase and/or HMG-CoA reductase |
US7199126B2 (en) | 2004-04-29 | 2007-04-03 | Pharmix Corporation | Compositions and treatments for inhibiting kinase and/or HMG-CoA reductase |
US7572820B2 (en) | 2006-09-29 | 2009-08-11 | Smithkline Beecham Corporation | Chemical compounds |
US8691849B2 (en) | 2008-09-02 | 2014-04-08 | Janssen Pharmaceuticals, Inc. | 3-azabicyclo[3.1.0]hexyl derivatives as modulators of metabotropic glutamate receptors |
US8691813B2 (en) | 2008-11-28 | 2014-04-08 | Janssen Pharmaceuticals, Inc. | Indole and benzoxazine derivatives as modulators of metabotropic glutamate receptors |
US8841323B2 (en) | 2006-03-15 | 2014-09-23 | Janssen Pharmaceuticals, Inc. | 1, 4-disubstituted 3-cyano-pyridone derivatives and their use as positive allosteric modulators of MGLUR2-receptors |
US8906939B2 (en) | 2007-03-07 | 2014-12-09 | Janssen Pharmaceuticals, Inc. | 3-cyano-4-(4-tetrahydropyran-phenyl)-pyridin-2-one derivatives |
US8937060B2 (en) | 2009-05-12 | 2015-01-20 | Janssen Pharmaceuticals, Inc. | 1,2,4-triazolo [4,3-A] pyridine derivatives and their use for the treatment of prevention of neurological and psychiatric disorders |
US8946205B2 (en) | 2009-05-12 | 2015-02-03 | Janssen Pharmaceuticals, Inc. | 1,2,4-triazolo[4,3-a]pyridine derivatives and their use as positive allosteric modulators of mGluR2 receptors |
US8993591B2 (en) | 2010-11-08 | 2015-03-31 | Janssen Pharmaceuticals, Inc. | 1,2,4-triazolo[4,3-a] pyridine derivatives and their use as positive allosteric modulators of MGLUR2 receptors |
US9012448B2 (en) | 2010-11-08 | 2015-04-21 | Janssen Pharmaceuticals, Inc. | 1,2,4-triazolo[4,3-a]pyridine derivatives and their use as positive allosteric modulators of MGLUR2 receptors |
US9067891B2 (en) | 2007-03-07 | 2015-06-30 | Janssen Pharmaceuticals, Inc. | 1,4-disubstituted 3-cyano-pyridone derivatives and their use as positive allosteric modulators of mGluR2-receptors |
US9085577B2 (en) | 2009-05-12 | 2015-07-21 | Janssen Pharmaceuticals, Inc. | 7-aryl-1,2,4-triazolo[4,3-A]pyridine derivatives and their use as positive allosteric modulators of mGluR2 receptors |
US9114138B2 (en) | 2007-09-14 | 2015-08-25 | Janssen Pharmaceuticals, Inc. | 1′,3′-disubstituted-4-phenyl-3,4,5,6-tetrahydro-2H,1′H-[1,4′] bipyridinyl-2′-ones |
US9271967B2 (en) | 2010-11-08 | 2016-03-01 | Janssen Pharmaceuticals, Inc. | 1,2,4-triazolo[4,3-a]pyridine derivatives and their use as positive allosteric modulators of mGluR2 receptors |
JP2017518345A (ja) * | 2014-06-17 | 2017-07-06 | サントル ナスィオナル ド ラ ルシェルシュ スィアンティフィク(セ.エン.エル.エス.) | がん及び過剰な血管新生に関連する疾患を治療するための新規の3−アリール−4−カテコール−ピロール−n−プロパノール化合物及びその誘導体の使用 |
US9708315B2 (en) | 2013-09-06 | 2017-07-18 | Janssen Pharmaceutica Nv | 1,2,4-triazolo[4,3-a]pyridine compounds and their use as positive allosteric modulators of MGLUR2 receptors |
US10106542B2 (en) | 2013-06-04 | 2018-10-23 | Janssen Pharmaceutica Nv | Substituted 6,7-dihydropyrazolo[1,5-a]pyrazines as negative allosteric modulators of mGluR2 receptors |
US10537573B2 (en) | 2014-01-21 | 2020-01-21 | Janssen Pharmaceutica Nv | Combinations comprising positive allosteric modulators or orthosteric agonists of metabotropic glutamatergic receptor subtype 2 and their use |
US11369606B2 (en) | 2014-01-21 | 2022-06-28 | Janssen Pharmaceutica Nv | Combinations comprising positive allosteric modulators or orthosteric agonists of metabotropic glutamatergic receptor subtype 2 and their use |
Citations (1)
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JPH04275284A (ja) * | 1991-03-04 | 1992-09-30 | Banyu Pharmaceut Co Ltd | 抗腫瘍性物質be−23372m及びその製造法 |
-
1994
- 1994-08-18 AU AU74672/94A patent/AU7467294A/en not_active Abandoned
- 1994-08-18 WO PCT/JP1994/001368 patent/WO1995006032A1/fr active Application Filing
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
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JPH04275284A (ja) * | 1991-03-04 | 1992-09-30 | Banyu Pharmaceut Co Ltd | 抗腫瘍性物質be−23372m及びその製造法 |
Non-Patent Citations (2)
Title |
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HELV. CHEM. ACTA., 54(1), 343-51 (1971). * |
LIEBIGS ANN. CHEM., (4), 777-9 (1986). * |
Cited By (39)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0713869A3 (fr) * | 1994-11-25 | 1996-06-19 | Lonza Ag | |
US5760236A (en) * | 1994-11-25 | 1998-06-02 | Lonza, Ltd. | Di and trisubstituted pyridines |
KR100332273B1 (ko) * | 1995-07-26 | 2002-06-20 | 디. 제이. 우드, 스피겔 알렌 제이 | 엔-(아로일)글리신하이드록삼산유도체및이와관련된화합물 |
WO1998056756A1 (fr) * | 1997-06-12 | 1998-12-17 | Cheil Jedang Corporation | Derives acides des catecholamines et compositions pharmaceutiques les contenant |
US6743815B2 (en) | 1998-08-07 | 2004-06-01 | Chiron Corporation | Estrogen receptor modulators |
US6869969B2 (en) | 1998-08-07 | 2005-03-22 | Chiron Corporation | Estrogen receptor modulators |
US6410540B1 (en) | 1998-08-28 | 2002-06-25 | Scios, Inc. | Inhibitors of p38-αkinase |
US6541477B2 (en) | 1999-08-27 | 2003-04-01 | Scios, Inc. | Inhibitors of p38-a kinase |
US7199126B2 (en) | 2004-04-29 | 2007-04-03 | Pharmix Corporation | Compositions and treatments for inhibiting kinase and/or HMG-CoA reductase |
US7183285B2 (en) | 2004-04-29 | 2007-02-27 | Pharmix Corp. | Compositions and treatments for inhibiting kinase and/or HMG-CoA reductase |
US7163945B2 (en) | 2004-04-29 | 2007-01-16 | Pharmix Corp. | Compositions and treatments for inhibiting kinase and/or HMG-CoA reductase |
US8841323B2 (en) | 2006-03-15 | 2014-09-23 | Janssen Pharmaceuticals, Inc. | 1, 4-disubstituted 3-cyano-pyridone derivatives and their use as positive allosteric modulators of MGLUR2-receptors |
US8026262B2 (en) | 2006-09-29 | 2011-09-27 | Glaxosmithkline Llc | Chemical compounds |
US8673948B2 (en) | 2006-09-29 | 2014-03-18 | GlaxoSmithKline, LLC | Chemical compounds |
US7572820B2 (en) | 2006-09-29 | 2009-08-11 | Smithkline Beecham Corporation | Chemical compounds |
US8906939B2 (en) | 2007-03-07 | 2014-12-09 | Janssen Pharmaceuticals, Inc. | 3-cyano-4-(4-tetrahydropyran-phenyl)-pyridin-2-one derivatives |
US9067891B2 (en) | 2007-03-07 | 2015-06-30 | Janssen Pharmaceuticals, Inc. | 1,4-disubstituted 3-cyano-pyridone derivatives and their use as positive allosteric modulators of mGluR2-receptors |
US11071729B2 (en) | 2007-09-14 | 2021-07-27 | Addex Pharmaceuticals S.A. | 1′,3′-disubstituted-4-phenyl-3,4,5,6-tetrahydro-2H,1′H-[1,4′]bipyridinyl-2′-ones |
US9132122B2 (en) | 2007-09-14 | 2015-09-15 | Janssen Pharmaceuticals, Inc. | 1′,3′-disubstituted-4-phenyl-3,4,5,6-tetrahydro-2H,1′H-[1,4′]bipyridinyl-2′-ones |
US9114138B2 (en) | 2007-09-14 | 2015-08-25 | Janssen Pharmaceuticals, Inc. | 1′,3′-disubstituted-4-phenyl-3,4,5,6-tetrahydro-2H,1′H-[1,4′] bipyridinyl-2′-ones |
US8691849B2 (en) | 2008-09-02 | 2014-04-08 | Janssen Pharmaceuticals, Inc. | 3-azabicyclo[3.1.0]hexyl derivatives as modulators of metabotropic glutamate receptors |
US8691813B2 (en) | 2008-11-28 | 2014-04-08 | Janssen Pharmaceuticals, Inc. | Indole and benzoxazine derivatives as modulators of metabotropic glutamate receptors |
US8937060B2 (en) | 2009-05-12 | 2015-01-20 | Janssen Pharmaceuticals, Inc. | 1,2,4-triazolo [4,3-A] pyridine derivatives and their use for the treatment of prevention of neurological and psychiatric disorders |
US8946205B2 (en) | 2009-05-12 | 2015-02-03 | Janssen Pharmaceuticals, Inc. | 1,2,4-triazolo[4,3-a]pyridine derivatives and their use as positive allosteric modulators of mGluR2 receptors |
US9085577B2 (en) | 2009-05-12 | 2015-07-21 | Janssen Pharmaceuticals, Inc. | 7-aryl-1,2,4-triazolo[4,3-A]pyridine derivatives and their use as positive allosteric modulators of mGluR2 receptors |
US10071095B2 (en) | 2009-05-12 | 2018-09-11 | Janssen Pharmaceuticals, Inc. | 1,2,4-triazolo [4,3-A] pyridine derivatives and their use for the treatment of neurological and psychiatric disorders |
US9226930B2 (en) | 2009-05-12 | 2016-01-05 | Janssen Pharmaceuticals, Inc. | 1,2,4-triazolo [4,3-a] pyridine derivatives and their use for the treatment of prevention of neurological and psychiatric disorders |
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US10106542B2 (en) | 2013-06-04 | 2018-10-23 | Janssen Pharmaceutica Nv | Substituted 6,7-dihydropyrazolo[1,5-a]pyrazines as negative allosteric modulators of mGluR2 receptors |
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JP2017518345A (ja) * | 2014-06-17 | 2017-07-06 | サントル ナスィオナル ド ラ ルシェルシュ スィアンティフィク(セ.エン.エル.エス.) | がん及び過剰な血管新生に関連する疾患を治療するための新規の3−アリール−4−カテコール−ピロール−n−プロパノール化合物及びその誘導体の使用 |
Also Published As
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---|---|
AU7467294A (en) | 1995-03-21 |
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