RU2349588C2 - Способы получения производных изотиазола - Google Patents
Способы получения производных изотиазола Download PDFInfo
- Publication number
- RU2349588C2 RU2349588C2 RU2007106847/04A RU2007106847A RU2349588C2 RU 2349588 C2 RU2349588 C2 RU 2349588C2 RU 2007106847/04 A RU2007106847/04 A RU 2007106847/04A RU 2007106847 A RU2007106847 A RU 2007106847A RU 2349588 C2 RU2349588 C2 RU 2349588C2
- Authority
- RU
- Russia
- Prior art keywords
- formula
- compound
- carboxylic acid
- isothiazole
- ureido
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 35
- 150000003854 isothiazoles Chemical class 0.000 title description 7
- 150000001875 compounds Chemical class 0.000 claims abstract description 116
- 150000003839 salts Chemical class 0.000 claims abstract description 35
- 125000005842 heteroatom Chemical group 0.000 claims abstract description 23
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 22
- 150000002367 halogens Chemical class 0.000 claims abstract description 19
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 15
- 150000002391 heterocyclic compounds Chemical class 0.000 claims abstract description 6
- 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 5
- 125000003118 aryl group Chemical group 0.000 claims description 101
- 125000000217 alkyl group Chemical group 0.000 claims description 77
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 44
- 238000006243 chemical reaction Methods 0.000 claims description 36
- 239000002904 solvent Substances 0.000 claims description 33
- 229910021529 ammonia Inorganic materials 0.000 claims description 17
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 17
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 11
- 239000000010 aprotic solvent Substances 0.000 claims description 7
- KGKURLCJVMTUAH-UHFFFAOYSA-N methyl 5-amino-3-[(4-bromo-2,6-difluorophenyl)methoxy]-1,2-thiazole-4-carboxylate Chemical group COC(=O)C1=C(N)SN=C1OCC1=C(F)C=C(Br)C=C1F KGKURLCJVMTUAH-UHFFFAOYSA-N 0.000 claims description 6
- HXHAJRMTJXHJJZ-UHFFFAOYSA-N 3-[(4-bromo-2,6-difluorophenyl)methoxy]-5-(4-pyrrolidin-1-ylbutylcarbamoylamino)-1,2-thiazole-4-carboxamide Chemical compound S1N=C(OCC=2C(=CC(Br)=CC=2F)F)C(C(=O)N)=C1NC(=O)NCCCCN1CCCC1 HXHAJRMTJXHJJZ-UHFFFAOYSA-N 0.000 claims description 5
- QBRJZYJMHZZQKY-UHFFFAOYSA-N methyl 3-[(4-bromo-2,6-difluorophenyl)methoxy]-5-methylsulfonyl-1,2-thiazole-4-carboxylate Chemical group S1C(S(C)(=O)=O)=C(C(=O)OC)C(OCC=2C(=CC(Br)=CC=2F)F)=N1 QBRJZYJMHZZQKY-UHFFFAOYSA-N 0.000 claims description 4
- 150000004702 methyl esters Chemical class 0.000 claims description 4
- PJXPORIRXYJDLD-UHFFFAOYSA-N 3-[(4-bromo-2,6-difluorophenyl)methoxy]-5-(4-pyrrolidin-1-ylbutylcarbamoylamino)-1,2-thiazole-4-carboxylic acid Chemical compound S1N=C(OCC=2C(=CC(Br)=CC=2F)F)C(C(=O)O)=C1NC(=O)NCCCCN1CCCC1 PJXPORIRXYJDLD-UHFFFAOYSA-N 0.000 claims description 3
- WVHXBHFWYRJNKU-UHFFFAOYSA-N methyl 3-[(4-bromo-2,6-difluorophenyl)methoxy]-5-(4-pyrrolidin-1-ylbutylcarbamoylamino)-1,2-thiazole-4-carboxylate Chemical compound S1N=C(OCC=2C(=CC(Br)=CC=2F)F)C(C(=O)OC)=C1NC(=O)NCCCCN1CCCC1 WVHXBHFWYRJNKU-UHFFFAOYSA-N 0.000 claims description 3
- KBASJCBTQBVBOG-UHFFFAOYSA-N 3-[(4-chloro-2,6-difluorophenyl)methoxy]-5-(4-pyrrolidin-1-ylbutylcarbamoylamino)-1,2-thiazole-4-carboxamide Chemical class S1N=C(OCC=2C(=CC(Cl)=CC=2F)F)C(C(=O)N)=C1NC(=O)NCCCCN1CCCC1 KBASJCBTQBVBOG-UHFFFAOYSA-N 0.000 claims description 2
- OXWAWKZUTJKCAD-UHFFFAOYSA-N methyl 3-[(4-chloro-2,6-difluorophenyl)methoxy]-5-(4-pyrrolidin-1-ylbutylcarbamoylamino)-1,2-thiazole-4-carboxylate Chemical class S1N=C(OCC=2C(=CC(Cl)=CC=2F)F)C(C(=O)OC)=C1NC(=O)NCCCCN1CCCC1 OXWAWKZUTJKCAD-UHFFFAOYSA-N 0.000 claims description 2
- 150000000565 5-membered heterocyclic compounds Chemical class 0.000 claims 3
- PINKTXRKCALTEU-UHFFFAOYSA-N 3-[(4-bromo-2,6-difluorophenyl)methoxy]-5-methylsulfonyl-1,2-thiazole-4-carboxylic acid Chemical compound BrC1=CC(=C(COC2=NSC(=C2C(=O)O)S(=O)(=O)C)C(=C1)F)F PINKTXRKCALTEU-UHFFFAOYSA-N 0.000 claims 1
- NHLJAQHSXZDKJE-UHFFFAOYSA-N Cl.COC(=O)C=1C(=NSC1NC(=O)NCCCCN1CCCC1)OCC1=C(C=C(C=C1F)Br)F Chemical class Cl.COC(=O)C=1C(=NSC1NC(=O)NCCCCN1CCCC1)OCC1=C(C=C(C=C1F)Br)F NHLJAQHSXZDKJE-UHFFFAOYSA-N 0.000 claims 1
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 claims 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 4
- 201000010099 disease Diseases 0.000 abstract description 3
- 230000003463 hyperproliferative effect Effects 0.000 abstract description 3
- 239000000126 substance Substances 0.000 abstract description 3
- 230000000694 effects Effects 0.000 abstract 1
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 114
- -1 dimethylamino, hydroxy, pyrrolidinyl Chemical group 0.000 description 92
- 125000000623 heterocyclic group Chemical group 0.000 description 63
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 57
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 57
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 41
- 239000000203 mixture Substances 0.000 description 37
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 30
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 30
- 125000004430 oxygen atom Chemical group O* 0.000 description 30
- 125000001424 substituent group Chemical group 0.000 description 30
- 125000004434 sulfur atom Chemical group 0.000 description 30
- 125000004122 cyclic group Chemical group 0.000 description 27
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 25
- 125000000041 C6-C10 aryl group Chemical group 0.000 description 23
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 22
- 239000002585 base Substances 0.000 description 21
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 21
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 21
- 229910052799 carbon Inorganic materials 0.000 description 20
- 229910052760 oxygen Inorganic materials 0.000 description 20
- 229910052717 sulfur Inorganic materials 0.000 description 20
- 125000001951 carbamoylamino group Chemical group C(N)(=O)N* 0.000 description 19
- 229910052739 hydrogen Inorganic materials 0.000 description 19
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 18
- 238000002360 preparation method Methods 0.000 description 17
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 16
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 15
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 14
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 14
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 13
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 13
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 description 12
- 125000004432 carbon atom Chemical group C* 0.000 description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 12
- 229940002612 prodrug Drugs 0.000 description 12
- 239000000651 prodrug Substances 0.000 description 12
- 125000006374 C2-C10 alkenyl group Chemical group 0.000 description 11
- 125000005865 C2-C10alkynyl group Chemical group 0.000 description 11
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 11
- 125000001072 heteroaryl group Chemical group 0.000 description 11
- 125000004043 oxo group Chemical group O=* 0.000 description 11
- 125000005843 halogen group Chemical group 0.000 description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- ZLTPDFXIESTBQG-UHFFFAOYSA-N isothiazole Chemical compound C=1C=NSC=1 ZLTPDFXIESTBQG-UHFFFAOYSA-N 0.000 description 9
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 9
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 8
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 8
- 108010053099 Vascular Endothelial Growth Factor Receptor-2 Proteins 0.000 description 8
- 239000002253 acid Substances 0.000 description 8
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 8
- 239000007790 solid phase Substances 0.000 description 8
- 239000000725 suspension Substances 0.000 description 8
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 description 7
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 7
- 150000001408 amides Chemical class 0.000 description 7
- 125000004429 atom Chemical group 0.000 description 7
- 150000003141 primary amines Chemical class 0.000 description 7
- 229920006395 saturated elastomer Polymers 0.000 description 7
- 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 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 6
- 239000003153 chemical reaction reagent Substances 0.000 description 6
- 235000019439 ethyl acetate Nutrition 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 102100033177 Vascular endothelial growth factor receptor 2 Human genes 0.000 description 5
- 238000005804 alkylation reaction Methods 0.000 description 5
- 150000001450 anions Chemical class 0.000 description 5
- 125000006615 aromatic heterocyclic group Chemical group 0.000 description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 5
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 5
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 5
- NNXMKFQFURUZQB-UHFFFAOYSA-N 1,2-thiazole-3-thione Chemical compound SC=1C=CSN=1 NNXMKFQFURUZQB-UHFFFAOYSA-N 0.000 description 4
- BEPMYBTTZSNHPS-UHFFFAOYSA-N 1,2-thiazole-4-carboxamide Chemical compound NC(=O)C=1C=NSC=1 BEPMYBTTZSNHPS-UHFFFAOYSA-N 0.000 description 4
- 150000008071 10-membered heterocyclic compounds Chemical class 0.000 description 4
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 4
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 4
- 150000008041 alkali metal carbonates Chemical class 0.000 description 4
- 230000029936 alkylation Effects 0.000 description 4
- 150000001412 amines Chemical group 0.000 description 4
- CREMABGTGYGIQB-UHFFFAOYSA-N carbon carbon Chemical compound C.C CREMABGTGYGIQB-UHFFFAOYSA-N 0.000 description 4
- 239000000460 chlorine Substances 0.000 description 4
- RZJCAPLYUBBPPE-UHFFFAOYSA-N methyl 3-methoxycarbonyloxy-5-methylsulfanyl-1,2-thiazole-4-carboxylate Chemical compound COC(=O)OC1=NSC(SC)=C1C(=O)OC RZJCAPLYUBBPPE-UHFFFAOYSA-N 0.000 description 4
- LELGRSWICDCODU-UHFFFAOYSA-N methyl 5-methylsulfanyl-3-oxo-1,2-thiazole-4-carboxylate Chemical compound COC(=O)C=1C(O)=NSC=1SC LELGRSWICDCODU-UHFFFAOYSA-N 0.000 description 4
- 239000012299 nitrogen atmosphere Substances 0.000 description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
- 239000012453 solvate Substances 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- 239000004215 Carbon black (E152) Substances 0.000 description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 150000007513 acids Chemical group 0.000 description 3
- 229910052783 alkali metal Inorganic materials 0.000 description 3
- 125000003545 alkoxy group Chemical group 0.000 description 3
- 125000000539 amino acid group Chemical group 0.000 description 3
- 125000003277 amino group Chemical group 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 201000011510 cancer Diseases 0.000 description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- 238000010586 diagram Methods 0.000 description 3
- 150000002148 esters Chemical group 0.000 description 3
- CEIPQQODRKXDSB-UHFFFAOYSA-N ethyl 3-(6-hydroxynaphthalen-2-yl)-1H-indazole-5-carboximidate dihydrochloride Chemical compound Cl.Cl.C1=C(O)C=CC2=CC(C3=NNC4=CC=C(C=C43)C(=N)OCC)=CC=C21 CEIPQQODRKXDSB-UHFFFAOYSA-N 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 150000008282 halocarbons Chemical class 0.000 description 3
- 229930195733 hydrocarbon Natural products 0.000 description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 3
- 125000002883 imidazolyl group Chemical group 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 229910052740 iodine Inorganic materials 0.000 description 3
- MGIYRDNGCNKGJU-UHFFFAOYSA-N isothiazolinone Chemical class O=C1C=CSN1 MGIYRDNGCNKGJU-UHFFFAOYSA-N 0.000 description 3
- YELIYGBMHIGZIN-UHFFFAOYSA-N methyl 1,2-thiazole-4-carboxylate Chemical compound COC(=O)C=1C=NSC=1 YELIYGBMHIGZIN-UHFFFAOYSA-N 0.000 description 3
- UWITWVXLWLBPCU-UHFFFAOYSA-N methyl 5-methylsulfonyl-3-oxo-1,2-thiazole-4-carboxylate Chemical compound COC(=O)C=1C(O)=NSC=1S(C)(=O)=O UWITWVXLWLBPCU-UHFFFAOYSA-N 0.000 description 3
- 125000004193 piperazinyl group Chemical group 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Substances C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- 125000005308 thiazepinyl group Chemical group S1N=C(C=CC=C1)* 0.000 description 3
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- 108091000080 Phosphotransferase Proteins 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- GPWFZNXSBNZLHU-UHFFFAOYSA-N S(=O)=S1N=CC=C1 Chemical compound S(=O)=S1N=CC=C1 GPWFZNXSBNZLHU-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 108010073929 Vascular Endothelial Growth Factor A Proteins 0.000 description 2
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 description 2
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 125000002252 acyl group Chemical group 0.000 description 2
- 125000004423 acyloxy group Chemical group 0.000 description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 2
- 125000005907 alkyl ester group Chemical group 0.000 description 2
- 235000001014 amino acid Nutrition 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 239000000908 ammonium hydroxide Substances 0.000 description 2
- 230000033115 angiogenesis Effects 0.000 description 2
- 125000002393 azetidinyl group Chemical group 0.000 description 2
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 2
- UCMIRNVEIXFBKS-UHFFFAOYSA-N beta-alanine Chemical compound NCCC(O)=O UCMIRNVEIXFBKS-UHFFFAOYSA-N 0.000 description 2
- 125000001246 bromo group Chemical group Br* 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 150000002170 ethers Chemical class 0.000 description 2
- 125000001153 fluoro group Chemical group F* 0.000 description 2
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- CPIXYAJJCRHOTJ-UHFFFAOYSA-N methyl 3-[(2,5-difluoro-4-methylphenyl)methoxy]-5-[4-(3-hydroxypyrrolidin-1-yl)butylcarbamoylamino]-1,2-thiazole-4-carboxylate Chemical compound S1N=C(OCC=2C(=CC(C)=C(F)C=2)F)C(C(=O)OC)=C1NC(=O)NCCCCN1CCC(O)C1 CPIXYAJJCRHOTJ-UHFFFAOYSA-N 0.000 description 1
- DFHHYJAARHLEQQ-UHFFFAOYSA-N methyl 3-[(2,5-difluoro-4-methylphenyl)methoxy]-5-[4-[2-(hydroxymethyl)pyrrolidin-1-yl]butylcarbamoylamino]-1,2-thiazole-4-carboxylate Chemical compound S1N=C(OCC=2C(=CC(C)=C(F)C=2)F)C(C(=O)OC)=C1NC(=O)NCCCCN1CCCC1CO DFHHYJAARHLEQQ-UHFFFAOYSA-N 0.000 description 1
- VTUHZIDTFFCXMG-UHFFFAOYSA-N methyl 3-[(2,5-difluoro-4-methylphenyl)methoxy]-5-[4-[ethyl(2-hydroxyethyl)amino]butylcarbamoylamino]-1,2-thiazole-4-carboxylate Chemical compound COC(=O)C1=C(NC(=O)NCCCCN(CCO)CC)SN=C1OCC1=CC(F)=C(C)C=C1F VTUHZIDTFFCXMG-UHFFFAOYSA-N 0.000 description 1
- ZVCMMPDTVZXUNC-UHFFFAOYSA-N methyl 3-[(2,5-difluoro-4-methylphenyl)methoxy]-5-[6-(dimethylamino)hexylcarbamoylamino]-1,2-thiazole-4-carboxylate Chemical compound S1C(NC(=O)NCCCCCCN(C)C)=C(C(=O)OC)C(OCC=2C(=CC(C)=C(F)C=2)F)=N1 ZVCMMPDTVZXUNC-UHFFFAOYSA-N 0.000 description 1
- LCHPYVGLOSGUFS-UHFFFAOYSA-N methyl 3-[(2,6-difluoro-4-methylphenyl)methoxy]-5-(3-pyrrolidin-1-ylpropylcarbamoylamino)-1,2-thiazole-4-carboxylate Chemical compound N=1SC(NC(=O)NCCCN2CCCC2)=C(C(=O)OC)C=1OCC1=C(F)C=C(C)C=C1F LCHPYVGLOSGUFS-UHFFFAOYSA-N 0.000 description 1
- JXGILVIQYAUXGQ-UHFFFAOYSA-N methyl 3-[(2,6-difluoro-4-methylphenyl)methoxy]-5-(4-pyrrolidin-1-ylbutylcarbamoylamino)-1,2-thiazole-4-carboxylate Chemical compound N=1SC(NC(=O)NCCCCN2CCCC2)=C(C(=O)OC)C=1OCC1=C(F)C=C(C)C=C1F JXGILVIQYAUXGQ-UHFFFAOYSA-N 0.000 description 1
- NQHSCARNYXPEOM-UHFFFAOYSA-N methyl 3-[(2,6-difluoro-4-methylphenyl)methoxy]-5-[(4-hydroxy-5-piperidin-1-ylpentyl)carbamoylamino]-1,2-thiazole-4-carboxylate Chemical compound S1N=C(OCC=2C(=CC(C)=CC=2F)F)C(C(=O)OC)=C1NC(=O)NCCCC(O)CN1CCCCC1 NQHSCARNYXPEOM-UHFFFAOYSA-N 0.000 description 1
- VJPLLECZPVMAMG-UHFFFAOYSA-N methyl 3-[(2,6-difluoro-4-methylphenyl)methoxy]-5-[2-(1-methylpyrrolidin-2-yl)ethylcarbamoylamino]-1,2-thiazole-4-carboxylate Chemical compound N=1SC(NC(=O)NCCC2N(CCC2)C)=C(C(=O)OC)C=1OCC1=C(F)C=C(C)C=C1F VJPLLECZPVMAMG-UHFFFAOYSA-N 0.000 description 1
- ZLAJKDDQOYZOGQ-UHFFFAOYSA-N methyl 3-[(2,6-difluoro-4-methylphenyl)methoxy]-5-[3-(dimethylamino)propylcarbamoylamino]-1,2-thiazole-4-carboxylate Chemical compound S1C(NC(=O)NCCCN(C)C)=C(C(=O)OC)C(OCC=2C(=CC(C)=CC=2F)F)=N1 ZLAJKDDQOYZOGQ-UHFFFAOYSA-N 0.000 description 1
- ZMEXDFWCAWIBTI-UHFFFAOYSA-N methyl 3-[(2-fluoro-4-methylphenyl)methoxy]-5-[3-(4-methylpiperazin-1-yl)propylcarbamoylamino]-1,2-thiazole-4-carboxylate Chemical compound N=1SC(NC(=O)NCCCN2CCN(C)CC2)=C(C(=O)OC)C=1OCC1=CC=C(C)C=C1F ZMEXDFWCAWIBTI-UHFFFAOYSA-N 0.000 description 1
- AOTNUPAPIGHNCS-UHFFFAOYSA-N methyl 3-[(2-fluoro-4-methylphenyl)methoxy]-5-[5-(propan-2-ylamino)pentylcarbamoylamino]-1,2-thiazole-4-carboxylate Chemical compound S1C(NC(=O)NCCCCCNC(C)C)=C(C(=O)OC)C(OCC=2C(=CC(C)=CC=2)F)=N1 AOTNUPAPIGHNCS-UHFFFAOYSA-N 0.000 description 1
- LCZJCNBNQPPCNR-UHFFFAOYSA-N methyl 3-[(3-chloro-2,6-difluoro-4-methylphenyl)methoxy]-5-[4-(dimethylamino)butylcarbamoylamino]-1,2-thiazole-4-carboxylate Chemical compound S1C(NC(=O)NCCCCN(C)C)=C(C(=O)OC)C(OCC=2C(=C(Cl)C(C)=CC=2F)F)=N1 LCZJCNBNQPPCNR-UHFFFAOYSA-N 0.000 description 1
- BYVKQFFUPQPZHS-UHFFFAOYSA-N methyl 3-[(4-bromo-2,3,6-trifluorophenyl)methoxy]-5-(4-pyrrolidin-1-ylbutylcarbamoylamino)-1,2-thiazole-4-carboxylate Chemical compound S1N=C(OCC=2C(=C(F)C(Br)=CC=2F)F)C(C(=O)OC)=C1NC(=O)NCCCCN1CCCC1 BYVKQFFUPQPZHS-UHFFFAOYSA-N 0.000 description 1
- MKJDKGOQFHPDBN-UHFFFAOYSA-N methyl 3-[(4-bromo-2,3,6-trifluorophenyl)methoxy]-5-[3-(4-methylpiperazin-1-yl)propylcarbamoylamino]-1,2-thiazole-4-carboxylate Chemical compound S1N=C(OCC=2C(=C(F)C(Br)=CC=2F)F)C(C(=O)OC)=C1NC(=O)NCCCN1CCN(C)CC1 MKJDKGOQFHPDBN-UHFFFAOYSA-N 0.000 description 1
- FTDIVWICRATCPL-UHFFFAOYSA-N methyl 3-[(4-bromo-2,6-difluorophenyl)methoxy]-5-[3-(4-methylpiperazin-1-yl)propylcarbamoylamino]-1,2-thiazole-4-carboxylate Chemical compound S1N=C(OCC=2C(=CC(Br)=CC=2F)F)C(C(=O)OC)=C1NC(=O)NCCCN1CCN(C)CC1 FTDIVWICRATCPL-UHFFFAOYSA-N 0.000 description 1
- XPHZWLFRYRNFAD-UHFFFAOYSA-N methyl 3-[(4-chloro-2,3,6-trifluorophenyl)methoxy]-5-(4-imidazol-1-ylbutylcarbamoylamino)-1,2-thiazole-4-carboxylate Chemical compound S1N=C(OCC=2C(=C(F)C(Cl)=CC=2F)F)C(C(=O)OC)=C1NC(=O)NCCCCN1C=CN=C1 XPHZWLFRYRNFAD-UHFFFAOYSA-N 0.000 description 1
- HCBXWYPSNANGJD-UHFFFAOYSA-N methyl 3-[(4-chloro-2,3,6-trifluorophenyl)methoxy]-5-(4-pyrrolidin-1-ylbutylcarbamoylamino)-1,2-thiazole-4-carboxylate Chemical compound S1N=C(OCC=2C(=C(F)C(Cl)=CC=2F)F)C(C(=O)OC)=C1NC(=O)NCCCCN1CCCC1 HCBXWYPSNANGJD-UHFFFAOYSA-N 0.000 description 1
- KUHWVZGKCZLWSS-UHFFFAOYSA-N methyl 3-[(4-chloro-2,3,6-trifluorophenyl)methoxy]-5-[(3-hydroxy-5-pyrrolidin-1-ylpentyl)carbamoylamino]-1,2-thiazole-4-carboxylate Chemical compound S1N=C(OCC=2C(=C(F)C(Cl)=CC=2F)F)C(C(=O)OC)=C1NC(=O)NCCC(O)CCN1CCCC1 KUHWVZGKCZLWSS-UHFFFAOYSA-N 0.000 description 1
- WJCZOKIWFZIQHM-UHFFFAOYSA-N methyl 3-[(4-chloro-2,3,6-trifluorophenyl)methoxy]-5-[2-(1-methylpyrrolidin-2-yl)ethylcarbamoylamino]-1,2-thiazole-4-carboxylate Chemical compound S1N=C(OCC=2C(=C(F)C(Cl)=CC=2F)F)C(C(=O)OC)=C1NC(=O)NCCC1CCCN1C WJCZOKIWFZIQHM-UHFFFAOYSA-N 0.000 description 1
- WMOWTAFJPWGZTO-UHFFFAOYSA-N methyl 3-[(4-chloro-2,3,6-trifluorophenyl)methoxy]-5-[3-[ethyl(2-hydroxyethyl)amino]propylcarbamoylamino]-1,2-thiazole-4-carboxylate Chemical compound COC(=O)C1=C(NC(=O)NCCCN(CCO)CC)SN=C1OCC1=C(F)C=C(Cl)C(F)=C1F WMOWTAFJPWGZTO-UHFFFAOYSA-N 0.000 description 1
- JHGVRYRMYBWQDU-UHFFFAOYSA-N methyl 3-[(4-chloro-2,3,6-trifluorophenyl)methoxy]-5-[4-[2-(hydroxymethyl)pyrrolidin-1-yl]butylcarbamoylamino]-1,2-thiazole-4-carboxylate Chemical compound S1N=C(OCC=2C(=C(F)C(Cl)=CC=2F)F)C(C(=O)OC)=C1NC(=O)NCCCCN1CCCC1CO JHGVRYRMYBWQDU-UHFFFAOYSA-N 0.000 description 1
- SHHJPDMWHWCATJ-UHFFFAOYSA-N methyl 3-[(4-chloro-2,6-difluorophenyl)methoxy]-5-(4-imidazol-1-ylbutylcarbamoylamino)-1,2-thiazole-4-carboxylate Chemical compound S1N=C(OCC=2C(=CC(Cl)=CC=2F)F)C(C(=O)OC)=C1NC(=O)NCCCCN1C=CN=C1 SHHJPDMWHWCATJ-UHFFFAOYSA-N 0.000 description 1
- SRUSUNCJFHQWCM-UHFFFAOYSA-N methyl 3-[(4-chloro-2,6-difluorophenyl)methoxy]-5-[2-(1-methylpyrrolidin-2-yl)ethylcarbamoylamino]-1,2-thiazole-4-carboxylate Chemical compound S1N=C(OCC=2C(=CC(Cl)=CC=2F)F)C(C(=O)OC)=C1NC(=O)NCCC1CCCN1C SRUSUNCJFHQWCM-UHFFFAOYSA-N 0.000 description 1
- OFFNYFYEOAVTIK-UHFFFAOYSA-N methyl 3-[(4-chloro-2,6-difluorophenyl)methoxy]-5-[3-(4-methylpiperazin-1-yl)propylcarbamoylamino]-1,2-thiazole-4-carboxylate Chemical compound S1N=C(OCC=2C(=CC(Cl)=CC=2F)F)C(C(=O)OC)=C1NC(=O)NCCCN1CCN(C)CC1 OFFNYFYEOAVTIK-UHFFFAOYSA-N 0.000 description 1
- WDFJVRHIASMJTB-UHFFFAOYSA-N methyl 3-[(4-chloro-2,6-difluorophenyl)methoxy]-5-[4-(3,4-dihydroxypyrrolidin-1-yl)butylcarbamoylamino]-1,2-thiazole-4-carboxylate Chemical compound S1N=C(OCC=2C(=CC(Cl)=CC=2F)F)C(C(=O)OC)=C1NC(=O)NCCCCN1CC(O)C(O)C1 WDFJVRHIASMJTB-UHFFFAOYSA-N 0.000 description 1
- DWUFOSZUVFTSQA-UHFFFAOYSA-N methyl 3-[(4-chloro-2,6-difluorophenyl)methoxy]-5-[4-[2-(hydroxymethyl)piperidin-1-yl]butylcarbamoylamino]-1,2-thiazole-4-carboxylate Chemical compound S1N=C(OCC=2C(=CC(Cl)=CC=2F)F)C(C(=O)OC)=C1NC(=O)NCCCCN1CCCCC1CO DWUFOSZUVFTSQA-UHFFFAOYSA-N 0.000 description 1
- CPXGXRLEXKZTST-UHFFFAOYSA-N methyl 3-[(4-chloro-2,6-difluorophenyl)methoxy]-5-[4-[2-(hydroxymethyl)pyrrolidin-1-yl]butylcarbamoylamino]-1,2-thiazole-4-carboxylate Chemical compound S1N=C(OCC=2C(=CC(Cl)=CC=2F)F)C(C(=O)OC)=C1NC(=O)NCCCCN1CCCC1CO CPXGXRLEXKZTST-UHFFFAOYSA-N 0.000 description 1
- MBHIUHQOVYWQAS-UHFFFAOYSA-N methyl 3-[(4-chloro-2,6-difluorophenyl)methoxy]-5-[4-[ethyl(2-hydroxyethyl)amino]butylcarbamoylamino]-1,2-thiazole-4-carboxylate Chemical compound COC(=O)C1=C(NC(=O)NCCCCN(CCO)CC)SN=C1OCC1=C(F)C=C(Cl)C=C1F MBHIUHQOVYWQAS-UHFFFAOYSA-N 0.000 description 1
- SCBHXFKLYDJABR-UHFFFAOYSA-N methyl 5-(3-pyrrolidin-1-ylpropylcarbamoylamino)-3-[(2,3,6-trifluoro-4-methylphenyl)methoxy]-1,2-thiazole-4-carboxylate Chemical compound N=1SC(NC(=O)NCCCN2CCCC2)=C(C(=O)OC)C=1OCC1=C(F)C=C(C)C(F)=C1F SCBHXFKLYDJABR-UHFFFAOYSA-N 0.000 description 1
- CVUJQFCRESAPAB-UHFFFAOYSA-N methyl 5-(4-pyrrolidin-1-ylbutylcarbamoylamino)-3-[(2,3,6-trifluoro-4-methylphenyl)methoxy]-1,2-thiazole-4-carboxylate Chemical compound N=1SC(NC(=O)NCCCCN2CCCC2)=C(C(=O)OC)C=1OCC1=C(F)C=C(C)C(F)=C1F CVUJQFCRESAPAB-UHFFFAOYSA-N 0.000 description 1
- VBUKUTDXZLGLJK-UHFFFAOYSA-N methyl 5-[(3-hydroxy-5-pyrrolidin-1-ylpentyl)carbamoylamino]-3-[(2,3,6-trifluoro-4-methylphenyl)methoxy]-1,2-thiazole-4-carboxylate Chemical compound S1N=C(OCC=2C(=C(F)C(C)=CC=2F)F)C(C(=O)OC)=C1NC(=O)NCCC(O)CCN1CCCC1 VBUKUTDXZLGLJK-UHFFFAOYSA-N 0.000 description 1
- NXHHPBXWGZXXEJ-UHFFFAOYSA-N methyl 5-[(4-hydroxy-5-piperidin-1-ylpentyl)carbamoylamino]-3-[(2,3,6-trifluoro-4-methylphenyl)methoxy]-1,2-thiazole-4-carboxylate Chemical compound S1N=C(OCC=2C(=C(F)C(C)=CC=2F)F)C(C(=O)OC)=C1NC(=O)NCCCC(O)CN1CCCCC1 NXHHPBXWGZXXEJ-UHFFFAOYSA-N 0.000 description 1
- MHTZXRSRZJZJLU-UHFFFAOYSA-N methyl 5-[2-(1-methylpyrrolidin-2-yl)ethylcarbamoylamino]-3-[(2,3,6-trifluoro-4-methylphenyl)methoxy]-1,2-thiazole-4-carboxylate Chemical compound N=1SC(NC(=O)NCCC2N(CCC2)C)=C(C(=O)OC)C=1OCC1=C(F)C=C(C)C(F)=C1F MHTZXRSRZJZJLU-UHFFFAOYSA-N 0.000 description 1
- GPOPLJUAAZYGCR-UHFFFAOYSA-N methyl 5-[3-(4-methylpiperazin-1-yl)propylcarbamoylamino]-3-[(2,3,6-trifluoro-4-methylphenyl)methoxy]-1,2-thiazole-4-carboxylate Chemical compound N=1SC(NC(=O)NCCCN2CCN(C)CC2)=C(C(=O)OC)C=1OCC1=C(F)C=C(C)C(F)=C1F GPOPLJUAAZYGCR-UHFFFAOYSA-N 0.000 description 1
- DGTJIZCUMVPCGO-UHFFFAOYSA-N methyl 5-[3-(dimethylamino)propylcarbamoylamino]-3-[(2,3,6-trifluoro-4-methylphenyl)methoxy]-1,2-thiazole-4-carboxylate Chemical compound S1C(NC(=O)NCCCN(C)C)=C(C(=O)OC)C(OCC=2C(=C(F)C(C)=CC=2F)F)=N1 DGTJIZCUMVPCGO-UHFFFAOYSA-N 0.000 description 1
- YYRHDUCNMMIWGW-UHFFFAOYSA-N methyl 5-[3-(methylamino)propylcarbamoylamino]-3-[(2,3,6-trifluoro-4-methylphenyl)methoxy]-1,2-thiazole-4-carboxylate Chemical compound COC(=O)C1=C(NC(=O)NCCCNC)SN=C1OCC1=C(F)C=C(C)C(F)=C1F YYRHDUCNMMIWGW-UHFFFAOYSA-N 0.000 description 1
- CTFFWTVCFNCGMC-UHFFFAOYSA-N methyl 5-[3-(propan-2-ylamino)propylcarbamoylamino]-3-[(2,3,6-trifluoro-4-methylphenyl)methoxy]-1,2-thiazole-4-carboxylate Chemical compound S1C(NC(=O)NCCCNC(C)C)=C(C(=O)OC)C(OCC=2C(=C(F)C(C)=CC=2F)F)=N1 CTFFWTVCFNCGMC-UHFFFAOYSA-N 0.000 description 1
- WWLBVCSXBCWFEN-UHFFFAOYSA-N methyl 5-[4-(4-methylpiperazin-1-yl)butylcarbamoylamino]-3-[(2,3,6-trifluoro-4-methylphenyl)methoxy]-1,2-thiazole-4-carboxylate Chemical compound N=1SC(NC(=O)NCCCCN2CCN(C)CC2)=C(C(=O)OC)C=1OCC1=C(F)C=C(C)C(F)=C1F WWLBVCSXBCWFEN-UHFFFAOYSA-N 0.000 description 1
- JTLGSPVHFRXHEH-UHFFFAOYSA-N methyl 5-[4-(diethylamino)butylcarbamoylamino]-3-[(2,3,6-trifluoro-4-methylphenyl)methoxy]-1,2-thiazole-4-carboxylate Chemical compound COC(=O)C1=C(NC(=O)NCCCCN(CC)CC)SN=C1OCC1=C(F)C=C(C)C(F)=C1F JTLGSPVHFRXHEH-UHFFFAOYSA-N 0.000 description 1
- HZGXQPTZUGIFPW-UHFFFAOYSA-N methyl 5-[4-(dimethylamino)butylcarbamoylamino]-3-[(2,3,6-trifluoro-4-methylphenyl)methoxy]-1,2-thiazole-4-carboxylate Chemical compound S1C(NC(=O)NCCCCN(C)C)=C(C(=O)OC)C(OCC=2C(=C(F)C(C)=CC=2F)F)=N1 HZGXQPTZUGIFPW-UHFFFAOYSA-N 0.000 description 1
- UGGHGACOUHZYJQ-UHFFFAOYSA-N methyl 5-[4-[bis(2-hydroxyethyl)amino]butylcarbamoylamino]-3-[(2,6-difluoro-4-methylphenyl)methoxy]-1,2-thiazole-4-carboxylate Chemical compound S1C(NC(=O)NCCCCN(CCO)CCO)=C(C(=O)OC)C(OCC=2C(=CC(C)=CC=2F)F)=N1 UGGHGACOUHZYJQ-UHFFFAOYSA-N 0.000 description 1
- MYKPGOKEWWAGII-UHFFFAOYSA-N methyl 5-[4-[ethyl(2-hydroxyethyl)amino]butylcarbamoylamino]-3-[(2,3,6-trifluoro-4-methylphenyl)methoxy]-1,2-thiazole-4-carboxylate Chemical compound COC(=O)C1=C(NC(=O)NCCCCN(CCO)CC)SN=C1OCC1=C(F)C=C(C)C(F)=C1F MYKPGOKEWWAGII-UHFFFAOYSA-N 0.000 description 1
- ZLEFCSJAIHQAAR-UHFFFAOYSA-N methyl 5-[[3-aminopropyl(methyl)carbamoyl]amino]-3-[(2,3,6-trifluoro-4-methylphenyl)methoxy]-1,2-thiazole-4-carboxylate Chemical compound S1C(NC(=O)N(C)CCCN)=C(C(=O)OC)C(OCC=2C(=C(F)C(C)=CC=2F)F)=N1 ZLEFCSJAIHQAAR-UHFFFAOYSA-N 0.000 description 1
- XYTHHHJAZPUVJA-UHFFFAOYSA-N methyl 5-[[3-hydroxy-5-(propan-2-ylamino)pentyl]carbamoylamino]-3-[(2,3,6-trifluoro-4-methylphenyl)methoxy]-1,2-thiazole-4-carboxylate Chemical compound COC(=O)C=1C(=NSC1NC(=O)NCCC(CCNC(C)C)O)OCC1=C(C(=C(C=C1F)C)F)F XYTHHHJAZPUVJA-UHFFFAOYSA-N 0.000 description 1
- XMJHPCRAQCTCFT-UHFFFAOYSA-N methyl chloroformate Chemical compound COC(Cl)=O XMJHPCRAQCTCFT-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000004593 naphthyridinyl group Chemical group N1=C(C=CC2=CC=CN=C12)* 0.000 description 1
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 229960003104 ornithine Drugs 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 229940014662 pantothenate Drugs 0.000 description 1
- 235000019161 pantothenic acid Nutrition 0.000 description 1
- 239000011713 pantothenic acid Substances 0.000 description 1
- FHHJDRFHHWUPDG-UHFFFAOYSA-N peroxysulfuric acid Chemical class OOS(O)(=O)=O FHHJDRFHHWUPDG-UHFFFAOYSA-N 0.000 description 1
- 150000003014 phosphoric acid esters Chemical class 0.000 description 1
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical group CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 201000001514 prostate carcinoma Diseases 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 125000001042 pteridinyl group Chemical group N1=C(N=CC2=NC=CN=C12)* 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000002755 pyrazolinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 229960001860 salicylate Drugs 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 125000000467 secondary amino group Chemical group [H]N([*:1])[*:2] 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 description 1
- JVBXVOWTABLYPX-UHFFFAOYSA-L sodium dithionite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])=O JVBXVOWTABLYPX-UHFFFAOYSA-L 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
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000005958 tetrahydrothienyl group Chemical group 0.000 description 1
- 125000004632 tetrahydrothiopyranyl group Chemical group S1C(CCCC1)* 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 229910021381 transition metal chloride Inorganic materials 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- FTVLMFQEYACZNP-UHFFFAOYSA-N trimethylsilyl trifluoromethanesulfonate Chemical compound C[Si](C)(C)OS(=O)(=O)C(F)(F)F FTVLMFQEYACZNP-UHFFFAOYSA-N 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D275/00—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings
- C07D275/02—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings not condensed with other rings
- C07D275/03—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings not condensed with other rings 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Diabetes (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Hematology (AREA)
- Endocrinology (AREA)
- Emergency Medicine (AREA)
- Obesity (AREA)
- Ophthalmology & Optometry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Thiazole And Isothizaole Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US60454204P | 2004-08-26 | 2004-08-26 | |
| US60/604,542 | 2004-08-26 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| RU2007106847A RU2007106847A (ru) | 2008-08-27 |
| RU2349588C2 true RU2349588C2 (ru) | 2009-03-20 |
Family
ID=36000502
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| RU2007106847/04A RU2349588C2 (ru) | 2004-08-26 | 2005-08-02 | Способы получения производных изотиазола |
Country Status (21)
| Country | Link |
|---|---|
| US (2) | US8884025B2 (enExample) |
| EP (1) | EP1784183B1 (enExample) |
| JP (2) | JP5100390B2 (enExample) |
| KR (1) | KR100893977B1 (enExample) |
| CN (1) | CN101043888B (enExample) |
| AR (1) | AR050613A1 (enExample) |
| AT (1) | ATE542533T1 (enExample) |
| AU (1) | AU2005280451B2 (enExample) |
| BR (1) | BRPI0514667A (enExample) |
| CA (1) | CA2578023C (enExample) |
| DK (1) | DK1784183T3 (enExample) |
| ES (1) | ES2378994T3 (enExample) |
| IL (1) | IL181063A0 (enExample) |
| MX (1) | MX2007002246A (enExample) |
| NO (1) | NO20071319L (enExample) |
| PL (1) | PL1784183T3 (enExample) |
| PT (1) | PT1784183E (enExample) |
| RU (1) | RU2349588C2 (enExample) |
| TW (1) | TWI361688B (enExample) |
| WO (1) | WO2006026034A2 (enExample) |
| ZA (1) | ZA200701016B (enExample) |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| MX2007002246A (es) | 2004-08-26 | 2007-04-20 | Pfizer Prod Inc | Procedimientos para la preparacion de derivados de isotiazol. |
| ES2623652T3 (es) | 2011-12-28 | 2017-07-11 | Allergan, Inc. | Derivados de 3-fenil-5-ureidoisotiazol-4-carboximida y 3-amino-5-fenilisotiazol como inhibidores de cinasa |
| CN103833665B (zh) * | 2014-02-24 | 2015-09-23 | 杰达维（上海）医药科技发展有限公司 | 一种新的合成异噻唑的方法 |
| US9353093B2 (en) | 2014-10-07 | 2016-05-31 | Allergan, Inc. | Indole-1-carboxamides as kinase inhibitors |
| US9403803B2 (en) | 2014-10-08 | 2016-08-02 | Allergan, Inc. | Indole-3-carboxamides as kinase inhibitors |
| US9359336B2 (en) | 2014-10-09 | 2016-06-07 | Allergan, Inc. | Heterocycle-substituted pyridyl benzothiophenes as kinase inhibitors |
| US9371314B2 (en) | 2014-10-09 | 2016-06-21 | Allergan, Inc. | Pyridyl benzothiophenes as kinase inhibitors |
| KR20250121146A (ko) * | 2022-12-28 | 2025-08-11 | 비양 테라퓨틱스 컴퍼니 리미티드 | 단백질 티로신 키나제 억제제 및 이의 의약적 용도 |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999062890A1 (en) * | 1998-06-04 | 1999-12-09 | Pfizer Products Inc. | Isothiazole derivatives useful as anticancer agents |
| RU2002131639A (ru) * | 2000-04-26 | 2004-07-10 | Ферринг Б.В. | Ингибиторы дипептидилпептидазы iv |
Family Cites Families (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2408234A1 (de) * | 1974-02-21 | 1975-09-04 | Celamerck Gmbh & Co Kg | Isothiazolylharnstoffe |
| US4059433A (en) * | 1976-06-18 | 1977-11-22 | Fmc Corporation | 3-Alkoxyisothiazole derivatives as herbicides |
| IL72093A0 (en) * | 1983-06-20 | 1984-10-31 | Lilly Co Eli | N'-substituted(3-alkyl-5-isothiazolyl)urea derivatives |
| HN2000000051A (es) * | 1999-05-19 | 2001-02-02 | Pfizer Prod Inc | Derivados heterociclicos utiles como agentes anticancerosos |
| GB0010188D0 (en) * | 2000-04-26 | 2000-06-14 | Ferring Bv | Inhibitors of dipeptidyl peptidase IV |
| JP4511352B2 (ja) * | 2002-07-25 | 2010-07-28 | ファイザー・インク | 抗癌薬として有用なイソチアゾール誘導体 |
| US20060035954A1 (en) * | 2004-08-11 | 2006-02-16 | Sharma Padam N | Ammonolysis process for the preparation of intermediates for DPP IV inhibitors |
| MX2007002246A (es) | 2004-08-26 | 2007-04-20 | Pfizer Prod Inc | Procedimientos para la preparacion de derivados de isotiazol. |
-
2005
- 2005-08-02 MX MX2007002246A patent/MX2007002246A/es active IP Right Grant
- 2005-08-02 AT AT05778840T patent/ATE542533T1/de active
- 2005-08-02 ES ES05778840T patent/ES2378994T3/es not_active Expired - Lifetime
- 2005-08-02 AU AU2005280451A patent/AU2005280451B2/en not_active Ceased
- 2005-08-02 CN CN2005800284337A patent/CN101043888B/zh not_active Expired - Fee Related
- 2005-08-02 BR BRPI0514667-4A patent/BRPI0514667A/pt active Search and Examination
- 2005-08-02 US US11/574,046 patent/US8884025B2/en not_active Expired - Fee Related
- 2005-08-02 JP JP2007537876A patent/JP5100390B2/ja not_active Expired - Fee Related
- 2005-08-02 WO PCT/US2005/027398 patent/WO2006026034A2/en not_active Ceased
- 2005-08-02 CA CA2578023A patent/CA2578023C/en not_active Expired - Fee Related
- 2005-08-02 PT PT05778840T patent/PT1784183E/pt unknown
- 2005-08-02 EP EP05778840A patent/EP1784183B1/en not_active Expired - Lifetime
- 2005-08-02 RU RU2007106847/04A patent/RU2349588C2/ru not_active IP Right Cessation
- 2005-08-02 PL PL05778840T patent/PL1784183T3/pl unknown
- 2005-08-02 KR KR1020077004371A patent/KR100893977B1/ko not_active Expired - Fee Related
- 2005-08-02 DK DK05778840.8T patent/DK1784183T3/da active
- 2005-08-22 TW TW094128618A patent/TWI361688B/zh not_active IP Right Cessation
- 2005-08-23 AR ARP050103539A patent/AR050613A1/es not_active Application Discontinuation
-
2007
- 2007-01-30 IL IL181063A patent/IL181063A0/en unknown
- 2007-02-02 ZA ZA200701016A patent/ZA200701016B/xx unknown
- 2007-03-09 NO NO20071319A patent/NO20071319L/no not_active Application Discontinuation
-
2012
- 2012-03-30 JP JP2012079463A patent/JP5498524B2/ja not_active Expired - Fee Related
-
2014
- 2014-11-10 US US14/537,093 patent/US9371298B2/en not_active Expired - Fee Related
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999062890A1 (en) * | 1998-06-04 | 1999-12-09 | Pfizer Products Inc. | Isothiazole derivatives useful as anticancer agents |
| US6235764B1 (en) * | 1998-06-04 | 2001-05-22 | Pfizer Inc. | Isothiazole derivatives useful as anticancer agents |
| US6548526B2 (en) * | 1998-06-04 | 2003-04-15 | Pfizer Inc | Isothiazole derivatives useful as anticancer agents |
| RU2002131639A (ru) * | 2000-04-26 | 2004-07-10 | Ферринг Б.В. | Ингибиторы дипептидилпептидазы iv |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MM4A | The patent is invalid due to non-payment of fees |
Effective date: 20180803 |