EA037378B1 - Производные сульфамоилпирроламида и их применение в качестве медикаментов для лечения гепатита b - Google Patents
Производные сульфамоилпирроламида и их применение в качестве медикаментов для лечения гепатита b Download PDFInfo
- Publication number
- EA037378B1 EA037378B1 EA201592200A EA201592200A EA037378B1 EA 037378 B1 EA037378 B1 EA 037378B1 EA 201592200 A EA201592200 A EA 201592200A EA 201592200 A EA201592200 A EA 201592200A EA 037378 B1 EA037378 B1 EA 037378B1
- Authority
- EA
- Eurasian Patent Office
- Prior art keywords
- compound
- mmol
- methyl
- sulfamoyl
- pyrrole
- Prior art date
Links
- 238000011282 treatment Methods 0.000 title claims description 19
- 239000003814 drug Substances 0.000 title claims description 10
- 208000006454 hepatitis Diseases 0.000 title description 2
- SXZUZUQZZIEKBN-UHFFFAOYSA-N 3-sulfamoyl-1H-pyrrole-2-carboxamide Chemical class NC(=O)c1[nH]ccc1S(N)(=O)=O SXZUZUQZZIEKBN-UHFFFAOYSA-N 0.000 title 1
- 231100000283 hepatitis Toxicity 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 635
- 150000003839 salts Chemical class 0.000 claims abstract description 52
- 239000012453 solvate Substances 0.000 claims abstract description 44
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 9
- -1 —OH Chemical group 0.000 claims description 106
- 239000000460 chlorine Substances 0.000 claims description 93
- 229910052739 hydrogen Inorganic materials 0.000 claims description 48
- 239000001257 hydrogen Substances 0.000 claims description 44
- 241000700721 Hepatitis B virus Species 0.000 claims description 38
- 125000001153 fluoro group Chemical group F* 0.000 claims description 37
- 229920006395 saturated elastomer Polymers 0.000 claims description 37
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical group [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 23
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 22
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 21
- 239000011737 fluorine Substances 0.000 claims description 21
- 229910052731 fluorine Inorganic materials 0.000 claims description 21
- 208000015181 infectious disease Diseases 0.000 claims description 21
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 21
- 229910052757 nitrogen Inorganic materials 0.000 claims description 18
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 17
- 150000002431 hydrogen Chemical class 0.000 claims description 17
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 15
- 229910052801 chlorine Inorganic materials 0.000 claims description 15
- 125000005842 heteroatom Chemical group 0.000 claims description 12
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 10
- 125000006528 (C2-C6) alkyl group Chemical group 0.000 claims description 10
- 125000006645 (C3-C4) cycloalkyl group Chemical group 0.000 claims description 10
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 10
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 10
- 229910052794 bromium Inorganic materials 0.000 claims description 10
- 229910052799 carbon Inorganic materials 0.000 claims description 9
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 9
- 125000001424 substituent group Chemical group 0.000 claims description 8
- 239000003937 drug carrier Substances 0.000 claims description 7
- 125000002950 monocyclic group Chemical group 0.000 claims description 7
- 125000003367 polycyclic group Chemical group 0.000 claims description 7
- 230000002265 prevention Effects 0.000 claims description 7
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 6
- 125000003545 alkoxy group Chemical group 0.000 claims description 6
- 229910052760 oxygen Inorganic materials 0.000 claims description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 5
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 5
- JNCMHMUGTWEVOZ-UHFFFAOYSA-N F[CH]F Chemical compound F[CH]F JNCMHMUGTWEVOZ-UHFFFAOYSA-N 0.000 claims description 4
- 108010081348 HRT1 protein Hairy Proteins 0.000 claims description 4
- 102100021881 Hairy/enhancer-of-split related with YRPW motif protein 1 Human genes 0.000 claims description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 4
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 3
- 241000124008 Mammalia Species 0.000 claims description 3
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 3
- 230000000694 effects Effects 0.000 claims description 3
- 125000001246 bromo group Chemical group Br* 0.000 claims description 2
- 238000000034 method Methods 0.000 abstract description 300
- 239000003112 inhibitor Substances 0.000 abstract description 7
- 150000004677 hydrates Chemical class 0.000 abstract description 3
- 230000010076 replication Effects 0.000 abstract description 3
- 238000002560 therapeutic procedure Methods 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 385
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 285
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 258
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 234
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 229
- 239000011541 reaction mixture Substances 0.000 description 225
- 239000000203 mixture Substances 0.000 description 224
- 238000005160 1H NMR spectroscopy Methods 0.000 description 209
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 203
- 239000000843 powder Substances 0.000 description 192
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 177
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 173
- 235000019439 ethyl acetate Nutrition 0.000 description 169
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 144
- 239000007787 solid Substances 0.000 description 129
- 239000000243 solution Substances 0.000 description 124
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 96
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 88
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicon dioxide Inorganic materials O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 87
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 81
- 238000005481 NMR spectroscopy Methods 0.000 description 78
- 230000015572 biosynthetic process Effects 0.000 description 69
- 238000003786 synthesis reaction Methods 0.000 description 67
- 239000002244 precipitate Substances 0.000 description 63
- 239000000047 product Substances 0.000 description 61
- 239000012044 organic layer Substances 0.000 description 60
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 description 59
- 238000004440 column chromatography Methods 0.000 description 55
- 239000002904 solvent Substances 0.000 description 54
- 229910002027 silica gel Inorganic materials 0.000 description 50
- 239000000741 silica gel Substances 0.000 description 50
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 47
- 238000010898 silica gel chromatography Methods 0.000 description 47
- 239000013078 crystal Substances 0.000 description 46
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 45
- 229910052938 sodium sulfate Inorganic materials 0.000 description 45
- 235000011152 sodium sulphate Nutrition 0.000 description 45
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 42
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 42
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 41
- 238000010992 reflux Methods 0.000 description 40
- HHTRAISBAAXRKZ-UHFFFAOYSA-N 5-amino-2-fluorobenzonitrile Chemical compound NC1=CC=C(F)C(C#N)=C1 HHTRAISBAAXRKZ-UHFFFAOYSA-N 0.000 description 39
- 239000003921 oil Substances 0.000 description 38
- 235000019198 oils Nutrition 0.000 description 38
- 238000000113 differential scanning calorimetry Methods 0.000 description 37
- 239000011734 sodium Substances 0.000 description 35
- 238000003756 stirring Methods 0.000 description 34
- 239000000706 filtrate Substances 0.000 description 33
- 239000007821 HATU Substances 0.000 description 30
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 29
- 238000010828 elution Methods 0.000 description 27
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 26
- 239000012267 brine Substances 0.000 description 26
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 26
- AXNUZKSSQHTNPZ-UHFFFAOYSA-N 3,4-difluoroaniline Chemical compound NC1=CC=C(F)C(F)=C1 AXNUZKSSQHTNPZ-UHFFFAOYSA-N 0.000 description 25
- RUSVTHSNIQGSOQ-UHFFFAOYSA-N Cn1cc(cc1C(Cl)=O)S(Cl)(=O)=O Chemical compound Cn1cc(cc1C(Cl)=O)S(Cl)(=O)=O RUSVTHSNIQGSOQ-UHFFFAOYSA-N 0.000 description 24
- 239000012071 phase Substances 0.000 description 24
- 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 23
- 239000010410 layer Substances 0.000 description 22
- WRHZVMBBRYBTKZ-UHFFFAOYSA-N pyrrole-2-carboxylic acid Chemical compound OC(=O)C1=CC=CN1 WRHZVMBBRYBTKZ-UHFFFAOYSA-N 0.000 description 22
- YSEMCVGMNUUNRK-UHFFFAOYSA-N 3-chloro-4-fluoroaniline Chemical compound NC1=CC=C(F)C(Cl)=C1 YSEMCVGMNUUNRK-UHFFFAOYSA-N 0.000 description 20
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 20
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 description 20
- NYMDPDNETOLVBS-UHFFFAOYSA-N 4-fluoro-3-methylaniline Chemical compound CC1=CC(N)=CC=C1F NYMDPDNETOLVBS-UHFFFAOYSA-N 0.000 description 19
- 239000000284 extract Substances 0.000 description 19
- SNMLKBMPULDPTA-UWTATZPHSA-N (2r)-1,1,1-trifluoropropan-2-amine Chemical compound C[C@@H](N)C(F)(F)F SNMLKBMPULDPTA-UWTATZPHSA-N 0.000 description 18
- NQVWMPOQWBDSAI-UHFFFAOYSA-N 3-methyloxetan-3-amine Chemical compound CC1(N)COC1 NQVWMPOQWBDSAI-UHFFFAOYSA-N 0.000 description 18
- WZRPUINRCVBBFJ-UHFFFAOYSA-N 5-[(4-fluoro-3-methylphenyl)carbamoyl]-1-methylpyrrole-3-sulfonyl chloride Chemical compound Cc1cc(NC(=O)c2cc(cn2C)S(Cl)(=O)=O)ccc1F WZRPUINRCVBBFJ-UHFFFAOYSA-N 0.000 description 18
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 18
- 238000002425 crystallisation Methods 0.000 description 18
- 230000008025 crystallization Effects 0.000 description 18
- 238000001035 drying Methods 0.000 description 18
- 238000001914 filtration Methods 0.000 description 18
- 239000000377 silicon dioxide Substances 0.000 description 18
- YFBWGBFWVFEGEZ-UHFFFAOYSA-N 1,1,1-trifluoro-2-methylpropan-2-amine Chemical compound CC(C)(N)C(F)(F)F YFBWGBFWVFEGEZ-UHFFFAOYSA-N 0.000 description 17
- BNTNWQPIBPBJOO-UHFFFAOYSA-N 3-chloro-2,4-difluoroaniline Chemical compound NC1=CC=C(F)C(Cl)=C1F BNTNWQPIBPBJOO-UHFFFAOYSA-N 0.000 description 17
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 16
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 16
- 238000006243 chemical reaction Methods 0.000 description 16
- 239000012153 distilled water Substances 0.000 description 16
- 230000002829 reductive effect Effects 0.000 description 16
- 239000000725 suspension Substances 0.000 description 16
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 15
- WAOSZEIIXARGLC-UHFFFAOYSA-N 5-[(3-chloro-4,5-difluorophenyl)carbamoyl]-1-methylpyrrole-3-sulfonyl chloride Chemical compound Cn1cc(cc1C(=O)Nc1cc(F)c(F)c(Cl)c1)S(Cl)(=O)=O WAOSZEIIXARGLC-UHFFFAOYSA-N 0.000 description 15
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 15
- 230000005526 G1 to G0 transition Effects 0.000 description 15
- 125000000217 alkyl group Chemical group 0.000 description 14
- 230000014509 gene expression Effects 0.000 description 14
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 14
- KEQGZUUPPQEDPF-UHFFFAOYSA-N 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione Chemical compound CC1(C)N(Cl)C(=O)N(Cl)C1=O KEQGZUUPPQEDPF-UHFFFAOYSA-N 0.000 description 13
- FMKGJQHNYMWDFJ-CVEARBPZSA-N 2-[[4-(2,2-difluoropropoxy)pyrimidin-5-yl]methylamino]-4-[[(1R,4S)-4-hydroxy-3,3-dimethylcyclohexyl]amino]pyrimidine-5-carbonitrile Chemical compound FC(COC1=NC=NC=C1CNC1=NC=C(C(=N1)N[C@H]1CC([C@H](CC1)O)(C)C)C#N)(C)F FMKGJQHNYMWDFJ-CVEARBPZSA-N 0.000 description 13
- NJXPYZHXZZCTNI-UHFFFAOYSA-N 3-aminobenzonitrile Chemical compound NC1=CC=CC(C#N)=C1 NJXPYZHXZZCTNI-UHFFFAOYSA-N 0.000 description 13
- XTHPWXDJESJLNJ-UHFFFAOYSA-N chlorosulfonic acid Substances OS(Cl)(=O)=O XTHPWXDJESJLNJ-UHFFFAOYSA-N 0.000 description 13
- 229940127113 compound 57 Drugs 0.000 description 13
- DEQYTNZJHKPYEZ-UHFFFAOYSA-N ethyl acetate;heptane Chemical compound CCOC(C)=O.CCCCCCC DEQYTNZJHKPYEZ-UHFFFAOYSA-N 0.000 description 13
- 239000002808 molecular sieve Substances 0.000 description 13
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 13
- RLOQBKJCOAXOLR-UHFFFAOYSA-N 1h-pyrrole-2-carboxamide Chemical compound NC(=O)C1=CC=CN1 RLOQBKJCOAXOLR-UHFFFAOYSA-N 0.000 description 12
- KOWPUNQBGWIERF-UHFFFAOYSA-N 3-bromo-4-fluoroaniline Chemical compound NC1=CC=C(F)C(Br)=C1 KOWPUNQBGWIERF-UHFFFAOYSA-N 0.000 description 12
- BEFPEKUQJGOBLX-UHFFFAOYSA-N 3-methyloxetan-3-amine;hydrochloride Chemical compound Cl.CC1(N)COC1 BEFPEKUQJGOBLX-UHFFFAOYSA-N 0.000 description 12
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 12
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- 239000012299 nitrogen atmosphere Substances 0.000 description 12
- 239000003039 volatile agent Substances 0.000 description 11
- ZVLYNMPVUNEGSL-UHFFFAOYSA-N 1-methyl-4-[(3-methyloxetan-3-yl)sulfamoyl]pyrrole-2-carboxylic acid Chemical compound Cn1cc(cc1C(O)=O)S(=O)(=O)NC1(C)COC1 ZVLYNMPVUNEGSL-UHFFFAOYSA-N 0.000 description 10
- 125000004432 carbon atom Chemical group C* 0.000 description 10
- 239000000543 intermediate Substances 0.000 description 10
- 238000002360 preparation method Methods 0.000 description 10
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 10
- SNMLKBMPULDPTA-REOHCLBHSA-N (2s)-1,1,1-trifluoropropan-2-amine Chemical compound C[C@H](N)C(F)(F)F SNMLKBMPULDPTA-REOHCLBHSA-N 0.000 description 9
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 9
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- FBWOFVFUKXZXKT-UHFFFAOYSA-N 1-(trifluoromethyl)cyclopropan-1-amine Chemical compound FC(F)(F)C1(N)CC1 FBWOFVFUKXZXKT-UHFFFAOYSA-N 0.000 description 8
- GKAWZQUCBBXBST-UHFFFAOYSA-N 3-fluoro-1-methyl-4-[(3-methyloxetan-3-yl)sulfamoyl]pyrrole-2-carboxylic acid Chemical compound Cn1cc(c(F)c1C(O)=O)S(=O)(=O)NC1(C)COC1 GKAWZQUCBBXBST-UHFFFAOYSA-N 0.000 description 8
- IGNFILTZSIUWBS-UHFFFAOYSA-N 4-fluoro-3,5-dimethylaniline Chemical compound CC1=CC(N)=CC(C)=C1F IGNFILTZSIUWBS-UHFFFAOYSA-N 0.000 description 8
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 8
- 239000002253 acid Substances 0.000 description 8
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 8
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- 229910052943 magnesium sulfate Inorganic materials 0.000 description 8
- 235000019341 magnesium sulphate Nutrition 0.000 description 8
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 8
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- BKMMTJMQCTUHRP-GSVOUGTGSA-N (2r)-2-aminopropan-1-ol Chemical compound C[C@@H](N)CO BKMMTJMQCTUHRP-GSVOUGTGSA-N 0.000 description 7
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- BZXPLADBSZWDIH-VWMHFEHESA-N 4-methylbenzenesulfonic acid;(3s)-oxolan-3-amine Chemical compound N[C@H]1CCOC1.CC1=CC=C(S(O)(=O)=O)C=C1 BZXPLADBSZWDIH-VWMHFEHESA-N 0.000 description 7
- KBRBQFMCBXAAQY-UHFFFAOYSA-N 5-ethoxycarbonyl-4-fluoro-1-methylpyrrole-3-sulfonic acid Chemical compound CCOC(=O)c1c(F)c(cn1C)S(O)(=O)=O KBRBQFMCBXAAQY-UHFFFAOYSA-N 0.000 description 7
- AVYVHIKSFXVDBG-UHFFFAOYSA-N N-benzyl-N-hydroxy-2,2-dimethylbutanamide Chemical compound C(C1=CC=CC=C1)N(C(C(CC)(C)C)=O)O AVYVHIKSFXVDBG-UHFFFAOYSA-N 0.000 description 7
- 235000019270 ammonium chloride Nutrition 0.000 description 7
- 239000002552 dosage form Substances 0.000 description 7
- BTSURNRVAKJLGT-UHFFFAOYSA-N methyl 4-chlorosulfonyl-1-methylpyrrole-2-carboxylate Chemical compound COC(=O)C1=CC(S(Cl)(=O)=O)=CN1C BTSURNRVAKJLGT-UHFFFAOYSA-N 0.000 description 7
- 238000002953 preparative HPLC Methods 0.000 description 7
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 description 6
- WRDGNXCXTDDYBZ-UHFFFAOYSA-N 2,3,4-trifluoroaniline Chemical compound NC1=CC=C(F)C(F)=C1F WRDGNXCXTDDYBZ-UHFFFAOYSA-N 0.000 description 6
- RXLFDOQOCRNACG-UHFFFAOYSA-N 3-amino-2,6-difluorobenzonitrile Chemical compound NC1=CC=C(F)C(C#N)=C1F RXLFDOQOCRNACG-UHFFFAOYSA-N 0.000 description 6
- JBBZXOUMFRXWGF-UHFFFAOYSA-N 3-chloro-4,5-difluoroaniline Chemical compound NC1=CC(F)=C(F)C(Cl)=C1 JBBZXOUMFRXWGF-UHFFFAOYSA-N 0.000 description 6
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- 208000026435 phlegm Diseases 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 description 1
- FWZMWMSAGOVWEZ-UHFFFAOYSA-N potassium;hydrofluoride Chemical compound F.[K] FWZMWMSAGOVWEZ-UHFFFAOYSA-N 0.000 description 1
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- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
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- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
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- WRHZVMBBRYBTKZ-UHFFFAOYSA-M pyrrole-2-carboxylate Chemical compound [O-]C(=O)C1=CC=CN1 WRHZVMBBRYBTKZ-UHFFFAOYSA-M 0.000 description 1
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Classifications
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- 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
- C07D207/30—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 two double bonds between ring members or between ring members and non-ring members
- C07D207/34—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 two 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
- C07D207/36—Oxygen or sulfur 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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/401—Proline; Derivatives thereof, e.g. captopril
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- A—HUMAN NECESSITIES
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- 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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/20—Antivirals for DNA viruses
-
- 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
- C07D207/30—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 two double bonds between ring members or between ring members and non-ring members
- C07D207/34—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 two 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
- C07D207/36—Oxygen or sulfur atoms
- C07D207/40—2,5-Pyrrolidine-diones
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 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
- C07D405/02—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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
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- Oncology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Communicable Diseases (AREA)
- Virology (AREA)
- Molecular Biology (AREA)
- Biotechnology (AREA)
- Engineering & Computer Science (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyrrole Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Hydrogenated Pyridines (AREA)
- Medicinal Preparation (AREA)
Applications Claiming Priority (7)
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| EP13168291 | 2013-05-17 | ||
| EP13175181 | 2013-07-04 | ||
| EP13182281 | 2013-08-29 | ||
| EP13191209 | 2013-10-31 | ||
| EP13198160 | 2013-12-18 | ||
| EP14157900 | 2014-03-05 | ||
| PCT/EP2014/060102 WO2014184350A1 (en) | 2013-05-17 | 2014-05-16 | Sulphamoylpyrrolamide derivatives and the use thereof as medicaments for the treatment of hepatitis b |
Publications (2)
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| EA201592200A1 EA201592200A1 (ru) | 2016-03-31 |
| EA037378B1 true EA037378B1 (ru) | 2021-03-22 |
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| EA201592200A EA037378B1 (ru) | 2013-05-17 | 2014-05-16 | Производные сульфамоилпирроламида и их применение в качестве медикаментов для лечения гепатита b |
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| CN106957282B (zh) | 2011-12-21 | 2019-08-30 | 诺维拉治疗公司 | B型肝炎抗病毒剂 |
| CR20210079A (es) | 2012-08-28 | 2021-06-10 | Janssen Sciences Ireland Uc | Sulfamoilarilamidas y su uso como medicamentos para el tratamiento de la hepatitis b |
| EA027194B1 (ru) | 2013-02-28 | 2017-06-30 | Янссен Сайенсиз Айрлэнд Юси | Сульфамоил-ариламиды и их применение в качестве лекарственных препаратов для лечения гепатита b |
| CN105102451B (zh) | 2013-04-03 | 2018-09-18 | 爱尔兰詹森科学公司 | N-苯基-氨甲酰衍生物及其作为药物用于治疗乙型肝炎的用途 |
| JO3603B1 (ar) * | 2013-05-17 | 2020-07-05 | Janssen Sciences Ireland Uc | مشتقات سلفامويل بيرولاميد واستخدامها كادوية لمعالجة التهاب الكبد نوع بي |
| KR102729910B1 (ko) | 2013-05-17 | 2024-11-15 | 인사이트 홀딩스 코포레이션 | Jak 저해제로서 비피라졸 유도체 |
| SMT201800577T1 (it) | 2013-05-17 | 2019-01-11 | Janssen Sciences Ireland Uc | Derivati di sulfamoiltiofenammide e il loro uso come medicinali per il trattamento dell'epatite b |
| SG10201805033XA (en) | 2013-07-25 | 2018-07-30 | Janssen Sciences Ireland Uc | Glyoxamide substituted pyrrolamide derivatives and the use thereof as medicaments for the treatment of hepatitis b |
| SG11201602748XA (en) | 2013-10-23 | 2016-05-30 | Janssen Sciences Ireland Uc | Carboxamide derivatives and the use thereof as medicaments for the treatment of hepatitis b |
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| US9169212B2 (en) | 2014-01-16 | 2015-10-27 | Novira Therapeutics, Inc. | Azepane derivatives and methods of treating hepatitis B infections |
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