RU2536689C2 - Новое производное фенола - Google Patents
Новое производное фенола Download PDFInfo
- Publication number
- RU2536689C2 RU2536689C2 RU2012117786/04A RU2012117786A RU2536689C2 RU 2536689 C2 RU2536689 C2 RU 2536689C2 RU 2012117786/04 A RU2012117786/04 A RU 2012117786/04A RU 2012117786 A RU2012117786 A RU 2012117786A RU 2536689 C2 RU2536689 C2 RU 2536689C2
- Authority
- RU
- Russia
- Prior art keywords
- mixture
- added
- dihydro
- benzothiazole
- solvent
- Prior art date
Links
- 150000002989 phenols Chemical class 0.000 title claims abstract description 20
- 150000001875 compounds Chemical class 0.000 claims abstract description 251
- 239000003814 drug Substances 0.000 claims abstract description 65
- 229940079593 drug Drugs 0.000 claims abstract description 42
- 210000002700 urine Anatomy 0.000 claims abstract description 28
- 230000003424 uricosuric effect Effects 0.000 claims abstract description 27
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 11
- 125000005843 halogen group Chemical group 0.000 claims abstract description 10
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 6
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims abstract description 5
- 239000004480 active ingredient Substances 0.000 claims abstract description 5
- 238000002360 preparation method Methods 0.000 claims abstract description 3
- 125000006728 (C1-C6) alkynyl group Chemical group 0.000 claims abstract 2
- 239000000203 mixture Substances 0.000 claims description 367
- LEHOTFFKMJEONL-UHFFFAOYSA-N Uric Acid Chemical compound N1C(=O)NC(=O)C2=C1NC(=O)N2 LEHOTFFKMJEONL-UHFFFAOYSA-N 0.000 claims description 64
- TVWHNULVHGKJHS-UHFFFAOYSA-N Uric acid Natural products N1C(=O)NC(=O)C2NC(=O)NC21 TVWHNULVHGKJHS-UHFFFAOYSA-N 0.000 claims description 50
- 229940116269 uric acid Drugs 0.000 claims description 50
- 201000010099 disease Diseases 0.000 claims description 32
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 32
- 201000001431 Hyperuricemia Diseases 0.000 claims description 30
- 150000003839 salts Chemical class 0.000 claims description 24
- 238000011282 treatment Methods 0.000 claims description 22
- 201000005569 Gout Diseases 0.000 claims description 20
- 210000004369 blood Anatomy 0.000 claims description 20
- 239000008280 blood Substances 0.000 claims description 20
- 230000029142 excretion Effects 0.000 claims description 17
- 208000024172 Cardiovascular disease Diseases 0.000 claims description 10
- 125000004414 alkyl thio group Chemical group 0.000 claims description 9
- 230000002265 prevention Effects 0.000 claims description 9
- 239000008194 pharmaceutical composition Substances 0.000 claims description 8
- 206010018634 Gouty Arthritis Diseases 0.000 claims description 6
- 206010020772 Hypertension Diseases 0.000 claims description 6
- 210000003734 kidney Anatomy 0.000 claims description 6
- SBCRKZJEEDTVFK-UHFFFAOYSA-N 5-(1,1-dioxo-2h-1,3-benzothiazole-3-carbonyl)-2-hydroxy-3-methylsulfanylbenzonitrile Chemical compound N#CC1=C(O)C(SC)=CC(C(=O)N2C3=CC=CC=C3S(=O)(=O)C2)=C1 SBCRKZJEEDTVFK-UHFFFAOYSA-N 0.000 claims description 5
- 208000017169 kidney disease Diseases 0.000 claims description 5
- VOFLAIHEELWYGO-UHFFFAOYSA-N (3,5-dichloro-4-hydroxyphenyl)-(1,1-dioxo-2h-1,3-benzothiazol-3-yl)methanone Chemical compound C1=C(Cl)C(O)=C(Cl)C=C1C(=O)N1C2=CC=CC=C2S(=O)(=O)C1 VOFLAIHEELWYGO-UHFFFAOYSA-N 0.000 claims description 4
- QHUSRJSYQNJEFQ-UHFFFAOYSA-N 3-chloro-5-(1,1-dioxo-2h-1,3-benzothiazole-3-carbonyl)-2-hydroxybenzonitrile Chemical compound C1=C(C#N)C(O)=C(Cl)C=C1C(=O)N1C2=CC=CC=C2S(=O)(=O)C1 QHUSRJSYQNJEFQ-UHFFFAOYSA-N 0.000 claims description 4
- HJNASESSRLKUIE-UHFFFAOYSA-N 3-cyclopropyl-5-(1,1-dioxo-2h-1,3-benzothiazole-3-carbonyl)-2-hydroxybenzonitrile Chemical compound OC1=C(C#N)C=C(C(=O)N2C3=CC=CC=C3S(=O)(=O)C2)C=C1C1CC1 HJNASESSRLKUIE-UHFFFAOYSA-N 0.000 claims description 4
- JVXASWJRFPUFOH-UHFFFAOYSA-N 5-(1,1-dioxo-2h-1,3-benzothiazole-3-carbonyl)-3-ethyl-2-hydroxybenzonitrile Chemical compound N#CC1=C(O)C(CC)=CC(C(=O)N2C3=CC=CC=C3S(=O)(=O)C2)=C1 JVXASWJRFPUFOH-UHFFFAOYSA-N 0.000 claims description 4
- HJNFPLCCPXAZSE-UHFFFAOYSA-N 5-(1,1-dioxo-2h-1,3-benzothiazole-3-carbonyl)-3-ethylsulfanyl-2-hydroxybenzonitrile Chemical compound N#CC1=C(O)C(SCC)=CC(C(=O)N2C3=CC=CC=C3S(=O)(=O)C2)=C1 HJNFPLCCPXAZSE-UHFFFAOYSA-N 0.000 claims description 4
- 206010007027 Calculus urinary Diseases 0.000 claims description 4
- 206010018429 Glucose tolerance impaired Diseases 0.000 claims description 4
- 208000031226 Hyperlipidaemia Diseases 0.000 claims description 4
- 208000008589 Obesity Diseases 0.000 claims description 4
- 235000020824 obesity Nutrition 0.000 claims description 4
- 208000008281 urolithiasis Diseases 0.000 claims description 4
- MTHRZZFLSQRKKO-UHFFFAOYSA-N 5-(1,1-dioxo-2h-1,3-benzothiazole-3-carbonyl)-2-hydroxy-3-(trifluoromethyl)benzonitrile Chemical compound C1=C(C(F)(F)F)C(O)=C(C#N)C=C1C(=O)N1C2=CC=CC=C2S(=O)(=O)C1 MTHRZZFLSQRKKO-UHFFFAOYSA-N 0.000 claims description 3
- OGCQMWGDTFSQEL-UHFFFAOYSA-N 5-(1,1-dioxo-2h-1,3-benzothiazole-3-carbonyl)-3-ethynyl-2-hydroxybenzonitrile Chemical compound C1=C(C#N)C(O)=C(C#C)C=C1C(=O)N1C2=CC=CC=C2S(=O)(=O)C1 OGCQMWGDTFSQEL-UHFFFAOYSA-N 0.000 claims description 3
- 206010003210 Arteriosclerosis Diseases 0.000 claims description 3
- 208000014882 Carotid artery disease Diseases 0.000 claims description 3
- 206010048554 Endothelial dysfunction Diseases 0.000 claims description 3
- 208000001145 Metabolic Syndrome Diseases 0.000 claims description 3
- 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 claims description 3
- 208000011775 arteriosclerosis disease Diseases 0.000 claims description 3
- 208000026106 cerebrovascular disease Diseases 0.000 claims description 3
- 206010012601 diabetes mellitus Diseases 0.000 claims description 3
- 230000008694 endothelial dysfunction Effects 0.000 claims description 3
- 208000032928 Dyslipidaemia Diseases 0.000 claims description 2
- 208000017170 Lipid metabolism disease Diseases 0.000 claims description 2
- 208000007536 Thrombosis Diseases 0.000 claims description 2
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims 1
- 239000000654 additive Substances 0.000 claims 1
- 208000019622 heart disease Diseases 0.000 claims 1
- 239000000126 substance Substances 0.000 abstract description 112
- 230000000694 effects Effects 0.000 abstract description 7
- 125000001188 haloalkyl group Chemical group 0.000 abstract description 5
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 717
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 315
- 239000000243 solution Substances 0.000 description 301
- 230000002829 reductive effect Effects 0.000 description 299
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 294
- 239000002904 solvent Substances 0.000 description 289
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 279
- 230000015572 biosynthetic process Effects 0.000 description 247
- 238000003786 synthesis reaction Methods 0.000 description 246
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 192
- 239000012044 organic layer Substances 0.000 description 185
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 179
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 149
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 147
- 239000012267 brine Substances 0.000 description 147
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 135
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 128
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 96
- 239000007787 solid Substances 0.000 description 91
- 238000006243 chemical reaction Methods 0.000 description 83
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 81
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 72
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 70
- 238000005160 1H NMR spectroscopy Methods 0.000 description 63
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 63
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 56
- 238000010898 silica gel chromatography Methods 0.000 description 51
- 239000011541 reaction mixture Substances 0.000 description 50
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 48
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 48
- -1 nitrogen-containing compound Chemical class 0.000 description 36
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 36
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 35
- WOHLSTOWRAOMSG-UHFFFAOYSA-N 2,3-dihydro-1,3-benzothiazole Chemical compound C1=CC=C2SCNC2=C1 WOHLSTOWRAOMSG-UHFFFAOYSA-N 0.000 description 32
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 32
- LULAYUGMBFYYEX-UHFFFAOYSA-N metachloroperbenzoic acid Natural products OC(=O)C1=CC=CC(Cl)=C1 LULAYUGMBFYYEX-UHFFFAOYSA-N 0.000 description 32
- VRVRGVPWCUEOGV-UHFFFAOYSA-N 2-aminothiophenol Chemical compound NC1=CC=CC=C1S VRVRGVPWCUEOGV-UHFFFAOYSA-N 0.000 description 30
- 235000002639 sodium chloride Nutrition 0.000 description 25
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 24
- 238000010533 azeotropic distillation Methods 0.000 description 24
- 229910000027 potassium carbonate Inorganic materials 0.000 description 24
- 239000003960 organic solvent Substances 0.000 description 22
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 22
- 235000019345 sodium thiosulphate Nutrition 0.000 description 22
- 239000010410 layer Substances 0.000 description 21
- 239000000460 chlorine Substances 0.000 description 17
- 238000001914 filtration Methods 0.000 description 17
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 16
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 16
- PQVSTLUFSYVLTO-UHFFFAOYSA-N ethyl n-ethoxycarbonylcarbamate Chemical compound CCOC(=O)NC(=O)OCC PQVSTLUFSYVLTO-UHFFFAOYSA-N 0.000 description 16
- 229940040692 lithium hydroxide monohydrate Drugs 0.000 description 16
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium hydroxide monohydrate Substances [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 16
- 239000000047 product Substances 0.000 description 16
- 125000000217 alkyl group Chemical group 0.000 description 15
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 15
- 150000002148 esters Chemical class 0.000 description 14
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 13
- 238000000034 method Methods 0.000 description 13
- 239000012453 solvate Substances 0.000 description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 12
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 11
- LQZMLBORDGWNPD-UHFFFAOYSA-N N-iodosuccinimide Chemical compound IN1C(=O)CCC1=O LQZMLBORDGWNPD-UHFFFAOYSA-N 0.000 description 11
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 10
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 10
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 10
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 10
- 238000004519 manufacturing process Methods 0.000 description 10
- 238000010992 reflux Methods 0.000 description 10
- 210000001519 tissue Anatomy 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 9
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 9
- 241000700159 Rattus Species 0.000 description 9
- 239000002253 acid Substances 0.000 description 9
- 239000002585 base Substances 0.000 description 9
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 9
- 229920003063 hydroxymethyl cellulose Polymers 0.000 description 9
- 229940031574 hydroxymethyl cellulose Drugs 0.000 description 9
- 125000006239 protecting group Chemical group 0.000 description 9
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 9
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 9
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 8
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 8
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 8
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 8
- 239000012298 atmosphere Substances 0.000 description 8
- 239000003795 chemical substances by application Substances 0.000 description 8
- WQOXQRCZOLPYPM-UHFFFAOYSA-N dimethyl disulfide Chemical compound CSSC WQOXQRCZOLPYPM-UHFFFAOYSA-N 0.000 description 8
- 125000000524 functional group Chemical group 0.000 description 8
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 8
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 8
- 238000011321 prophylaxis Methods 0.000 description 8
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 7
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 7
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 7
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 7
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 7
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 7
- 229960003511 macrogol Drugs 0.000 description 7
- 230000003647 oxidation Effects 0.000 description 7
- 238000007254 oxidation reaction Methods 0.000 description 7
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 7
- GQWMNVOVQZIPJC-UHFFFAOYSA-N 2-(trifluoromethoxy)phenol Chemical compound OC1=CC=CC=C1OC(F)(F)F GQWMNVOVQZIPJC-UHFFFAOYSA-N 0.000 description 6
- ROFVEXUMMXZLPA-UHFFFAOYSA-N Bipyridyl Chemical compound N1=CC=CC=C1C1=CC=CC=N1 ROFVEXUMMXZLPA-UHFFFAOYSA-N 0.000 description 6
- XJUZRXYOEPSWMB-UHFFFAOYSA-N Chloromethyl methyl ether Chemical compound COCCl XJUZRXYOEPSWMB-UHFFFAOYSA-N 0.000 description 6
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 6
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 6
- 229910021585 Nickel(II) bromide Inorganic materials 0.000 description 6
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 6
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 6
- 125000003545 alkoxy group Chemical group 0.000 description 6
- WHQCHUCQKNIQEC-UHFFFAOYSA-N benzbromarone Chemical compound CCC=1OC2=CC=CC=C2C=1C(=O)C1=CC(Br)=C(O)C(Br)=C1 WHQCHUCQKNIQEC-UHFFFAOYSA-N 0.000 description 6
- 229920002678 cellulose Polymers 0.000 description 6
- 239000001913 cellulose Substances 0.000 description 6
- 235000010980 cellulose Nutrition 0.000 description 6
- 229940061627 chloromethyl methyl ether Drugs 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- DDRJAANPRJIHGJ-UHFFFAOYSA-N creatinine Chemical compound CN1CC(=O)NC1=N DDRJAANPRJIHGJ-UHFFFAOYSA-N 0.000 description 6
- 238000006460 hydrolysis reaction Methods 0.000 description 6
- IPLJNQFXJUCRNH-UHFFFAOYSA-L nickel(2+);dibromide Chemical compound [Ni+2].[Br-].[Br-] IPLJNQFXJUCRNH-UHFFFAOYSA-L 0.000 description 6
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 6
- 238000001308 synthesis method Methods 0.000 description 6
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 6
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 5
- AJMQHWJRSXQFKQ-UHFFFAOYSA-N 5-(1,1-dioxo-2h-1,3-benzothiazole-3-carbonyl)-2-hydroxy-3-iodobenzonitrile Chemical compound C1=C(C#N)C(O)=C(I)C=C1C(=O)N1C2=CC=CC=C2S(=O)(=O)C1 AJMQHWJRSXQFKQ-UHFFFAOYSA-N 0.000 description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 5
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 5
- 229930006000 Sucrose Natural products 0.000 description 5
- 229960002529 benzbromarone Drugs 0.000 description 5
- 239000001569 carbon dioxide Substances 0.000 description 5
- 229910002092 carbon dioxide Inorganic materials 0.000 description 5
- 229910052801 chlorine Inorganic materials 0.000 description 5
- 125000001309 chloro group Chemical group Cl* 0.000 description 5
- 235000011187 glycerol Nutrition 0.000 description 5
- 239000011777 magnesium Substances 0.000 description 5
- 229910052749 magnesium Inorganic materials 0.000 description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 5
- 229940002612 prodrug Drugs 0.000 description 5
- 239000000651 prodrug Substances 0.000 description 5
- 239000007858 starting material Substances 0.000 description 5
- 239000005720 sucrose Substances 0.000 description 5
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 description 5
- BKOOMYPCSUNDGP-UHFFFAOYSA-N 2-methylbut-2-ene Chemical compound CC=C(C)C BKOOMYPCSUNDGP-UHFFFAOYSA-N 0.000 description 4
- LCARXXDVYQTVNF-UHFFFAOYSA-N 2h-1,3-benzothiazol-3-yl-(3,5-dichloro-4-methoxyphenyl)methanone Chemical compound C1=C(Cl)C(OC)=C(Cl)C=C1C(=O)N1C2=CC=CC=C2SC1 LCARXXDVYQTVNF-UHFFFAOYSA-N 0.000 description 4
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Classifications
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- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
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- C07D417/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing aromatic rings
Landscapes
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Thiazole And Isothizaole Compounds (AREA)
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| RU2772043C2 (ru) * | 2017-04-28 | 2022-05-16 | Фудзи Якухин Ко., Лтд. | Кристаллическая форма и соль 3-(3,5-дихлор-4-гидроксибензоил)- 1,1-диоксо-2,3-дигидро-1,3-бензотиазола |
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| JP5851802B2 (ja) | 2011-03-30 | 2016-02-03 | 富士重工業株式会社 | 炭素繊維強化樹脂複合材用ドリル |
| WO2015191034A1 (en) * | 2014-06-09 | 2015-12-17 | Baylor College Of Medicine | Small molecule xanthine oxidase inhibitors and methods of use |
| JP6719475B2 (ja) * | 2015-09-04 | 2020-07-08 | サントリーホールディングス株式会社 | ウレアーゼ活性阻害剤 |
| EP3348557B1 (en) * | 2015-09-10 | 2020-04-29 | Jiangsu Atom Bioscience And Pharmaceutical Co., Ltd | Imidazo[1,2a]pyridines for treating or preventing hyperuricemia or gout |
| CN105675557B (zh) * | 2016-01-07 | 2019-01-25 | 济南大学 | 基于苯炔荧光试剂检测硫脲含量的新方法 |
| JP2019524747A (ja) | 2016-07-18 | 2019-09-05 | アースローシ セラピューティクス,インク. | 痛風または高尿酸血症に関連する症状を処置または予防するための化合物、組成物、および方法 |
| TWI766986B (zh) * | 2017-04-28 | 2022-06-11 | 日商富士藥品股份有限公司 | 3-(3,5-二氯-4-羥基苯甲醯)-1,1-二氧-2,3-二氫-1,3-苯并噻唑之結晶形及鹽 |
| CN109928890B (zh) * | 2017-12-15 | 2021-11-09 | 重庆常捷医药有限公司 | 一种托伐普坦中间体2-甲基-4-n-(2-甲基苯甲酰)苯甲酸的制备方法 |
| CN113164439A (zh) | 2018-12-06 | 2021-07-23 | 安索治疗公司 | 用于治疗或预防痛风或高尿酸血症的方法 |
| KR20210100677A (ko) | 2018-12-06 | 2021-08-17 | 아쓰로시 테라퓨틱스, 인크. | 통풍 또는 고뇨산혈증의 치료 또는 예방을 위한 화합물의 결정형 |
| CA3159300A1 (en) * | 2019-12-09 | 2021-06-17 | Tadashi Inoue | Solid pharmaceutical preparation |
| CN111675675A (zh) * | 2020-07-17 | 2020-09-18 | 苏州明锐医药科技有限公司 | 多替诺德的制备方法 |
| CN111662247A (zh) * | 2020-07-17 | 2020-09-15 | 苏州明锐医药科技有限公司 | 一种多替诺德的合成方法 |
| CN112430221B (zh) * | 2020-11-20 | 2023-06-23 | 成都诺和晟泰生物科技有限公司 | 用于预防、治疗或减轻高尿酸血症或痛风的化合物及其应用 |
| WO2022169974A1 (en) | 2021-02-05 | 2022-08-11 | Nexys Therapeutics, Inc. | Inhibitors of urat1 and pharmaceutical uses thereof |
| CN114903879B (zh) * | 2022-06-23 | 2023-10-31 | 东北大学 | 3-烃基苯酚衍生物在制备预防或治疗高脂血症及相关代谢性疾病产品中的用途 |
| CN115160314B (zh) * | 2022-07-28 | 2023-12-05 | 南方医科大学 | 杂环芳酰胺类化合物及其制备方法和应用 |
| WO2025085662A1 (en) | 2023-10-17 | 2025-04-24 | Vanderbilt University | Compounds for tocolytic use |
| CN118580197A (zh) * | 2023-11-16 | 2024-09-03 | 广东东阳光药业股份有限公司 | 一种多替诺雷制备方法及其应用 |
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| EP1767531A4 (en) | 2004-06-10 | 2011-01-05 | Torii Pharmaceutical Co Ltd | 6-HYDROXYBENZBROMARONE OR SALTING MEDICAL COMPOSITIONS CONTAINING THEREOF |
| JP3988832B2 (ja) | 2004-11-29 | 2007-10-10 | 日本たばこ産業株式会社 | 窒素含有縮合環化合物及びその用途 |
| EP1985297A1 (en) * | 2006-01-27 | 2008-10-29 | Japan Tobacco, Inc. | Carboxylic acid compound and use thereof |
| US20080305169A1 (en) * | 2006-05-26 | 2008-12-11 | Japan Tobacco Inc. | Pharmaceutical Compositions Comprising Nitrogen-Containing Fused Ring Coumpounds |
| US20080064871A1 (en) * | 2006-05-26 | 2008-03-13 | Japan Tobacco Inc. | Production Method of Nitrogen-Containing Fused Ring Compounds |
| WO2008062740A1 (fr) * | 2006-11-20 | 2008-05-29 | Japan Tobacco Inc. | Composé azoté à anneaux fusionnés et son utilisation |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2772043C2 (ru) * | 2017-04-28 | 2022-05-16 | Фудзи Якухин Ко., Лтд. | Кристаллическая форма и соль 3-(3,5-дихлор-4-гидроксибензоил)- 1,1-диоксо-2,3-дигидро-1,3-бензотиазола |
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