OA11978A - Respiratory syncytial virus replication inhibitors. - Google Patents
Respiratory syncytial virus replication inhibitors. Download PDFInfo
- Publication number
- OA11978A OA11978A OA1200100345A OA1200100345A OA11978A OA 11978 A OA11978 A OA 11978A OA 1200100345 A OA1200100345 A OA 1200100345A OA 1200100345 A OA1200100345 A OA 1200100345A OA 11978 A OA11978 A OA 11978A
- Authority
- OA
- OAPI
- Prior art keywords
- methyl
- formula
- amino
- alkyl
- 6alkyl
- Prior art date
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- 241000725643 Respiratory syncytial virus Species 0.000 title description 5
- 230000029812 viral genome replication Effects 0.000 title description 2
- 239000003112 inhibitor Substances 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 227
- -1 hydroxyC1-6alkyl Chemical group 0.000 claims abstract description 216
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 106
- 239000001257 hydrogen Substances 0.000 claims abstract description 68
- 125000001424 substituent group Chemical group 0.000 claims abstract description 52
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims abstract description 46
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 35
- 125000003118 aryl group Chemical group 0.000 claims abstract description 33
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 24
- 150000001412 amines Chemical class 0.000 claims abstract description 22
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 18
- 125000002911 monocyclic heterocycle group Chemical group 0.000 claims abstract description 16
- 239000000651 prodrug Substances 0.000 claims abstract description 15
- 229940002612 prodrug Drugs 0.000 claims abstract description 15
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 13
- 238000011282 treatment Methods 0.000 claims abstract description 13
- 230000009385 viral infection Effects 0.000 claims abstract description 13
- 208000036142 Viral infection Diseases 0.000 claims abstract description 12
- 239000003814 drug Substances 0.000 claims abstract description 12
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims abstract description 12
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims abstract description 12
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 12
- 125000003386 piperidinyl group Chemical group 0.000 claims abstract description 12
- 101100054666 Streptomyces halstedii sch3 gene Proteins 0.000 claims abstract description 8
- 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 8
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims abstract description 6
- 150000001204 N-oxides Chemical class 0.000 claims abstract description 5
- 238000004519 manufacturing process Methods 0.000 claims abstract description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 201
- 239000000203 mixture Substances 0.000 claims description 144
- 239000002904 solvent Substances 0.000 claims description 118
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 97
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 68
- 239000012442 inert solvent Substances 0.000 claims description 41
- 239000002253 acid Substances 0.000 claims description 37
- 150000002431 hydrogen Chemical group 0.000 claims description 37
- 239000002585 base Substances 0.000 claims description 33
- 238000006243 chemical reaction Methods 0.000 claims description 33
- 150000003254 radicals Chemical class 0.000 claims description 32
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 31
- 125000004076 pyridyl group Chemical group 0.000 claims description 30
- 125000000623 heterocyclic group Chemical group 0.000 claims description 22
- 125000002883 imidazolyl group Chemical group 0.000 claims description 22
- 238000000034 method Methods 0.000 claims description 22
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 19
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 17
- 125000006239 protecting group Chemical group 0.000 claims description 15
- 229910052799 carbon Inorganic materials 0.000 claims description 14
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 14
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 12
- 239000003638 chemical reducing agent Substances 0.000 claims description 12
- 239000003795 chemical substances by application Substances 0.000 claims description 11
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 11
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 10
- 238000005576 amination reaction Methods 0.000 claims description 10
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 10
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 10
- 229910021529 ammonia Inorganic materials 0.000 claims description 8
- JKXCZYCVHPKTPK-UHFFFAOYSA-N hydrate;trihydrochloride Chemical compound O.Cl.Cl.Cl JKXCZYCVHPKTPK-UHFFFAOYSA-N 0.000 claims description 8
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 8
- 229910052760 oxygen Inorganic materials 0.000 claims description 8
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 7
- 150000001721 carbon Chemical group 0.000 claims description 7
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 6
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 6
- 239000003937 drug carrier Substances 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 6
- 125000004104 aryloxy group Chemical group 0.000 claims description 5
- 239000003153 chemical reaction reagent Substances 0.000 claims description 5
- RXWHBDLHIJJDDO-UHFFFAOYSA-N dihydrate;tetrahydrochloride Chemical compound O.O.Cl.Cl.Cl.Cl RXWHBDLHIJJDDO-UHFFFAOYSA-N 0.000 claims description 5
- 235000019253 formic acid Nutrition 0.000 claims description 5
- 231100000252 nontoxic Toxicity 0.000 claims description 5
- 230000003000 nontoxic effect Effects 0.000 claims description 5
- VGKODZCNDHJSOX-UHFFFAOYSA-N trihydrate;tetrahydrochloride Chemical compound O.O.O.Cl.Cl.Cl.Cl VGKODZCNDHJSOX-UHFFFAOYSA-N 0.000 claims description 5
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 4
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 claims description 4
- 239000012458 free base Substances 0.000 claims description 4
- UUBJKHVFGWGJKX-UHFFFAOYSA-N hydrate tetrahydrochloride Chemical compound O.Cl.Cl.Cl.Cl UUBJKHVFGWGJKX-UHFFFAOYSA-N 0.000 claims description 4
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 3
- CBOIHMRHGLHBPB-UHFFFAOYSA-N hydroxymethyl Chemical compound O[CH2] CBOIHMRHGLHBPB-UHFFFAOYSA-N 0.000 claims description 3
- 125000002541 furyl group Chemical group 0.000 claims description 2
- 125000001786 isothiazolyl group Chemical group 0.000 claims description 2
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 2
- 125000001715 oxadiazolyl group Chemical group 0.000 claims description 2
- 125000004193 piperazinyl group Chemical group 0.000 claims description 2
- IURLXCRFCXJEHE-UHFFFAOYSA-N tetrahydrate;tetrahydrochloride Chemical compound O.O.O.O.Cl.Cl.Cl.Cl IURLXCRFCXJEHE-UHFFFAOYSA-N 0.000 claims description 2
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 2
- 125000001544 thienyl group Chemical group 0.000 claims description 2
- 230000009466 transformation Effects 0.000 claims description 2
- 230000003612 virological effect Effects 0.000 claims description 2
- 125000001475 halogen functional group Chemical group 0.000 claims 8
- SGPGESCZOCHFCL-UHFFFAOYSA-N Tilisolol hydrochloride Chemical compound [Cl-].C1=CC=C2C(=O)N(C)C=C(OCC(O)C[NH2+]C(C)(C)C)C2=C1 SGPGESCZOCHFCL-UHFFFAOYSA-N 0.000 claims 5
- HWLWRRBNCCOUCQ-UHFFFAOYSA-N CC(C)O.O.Cl.Cl.Cl.Cl Chemical compound CC(C)O.O.Cl.Cl.Cl.Cl HWLWRRBNCCOUCQ-UHFFFAOYSA-N 0.000 claims 1
- AVHUTYCTCQMCME-UHFFFAOYSA-N ethyl 4-[[3-[(3-hydroxy-6-methylpyridin-2-yl)methyl]-7-methylimidazo[4,5-b]pyridin-2-yl]amino]piperidine-1-carboxylate Chemical compound C1CN(C(=O)OCC)CCC1NC1=NC2=C(C)C=CN=C2N1CC1=NC(C)=CC=C1O AVHUTYCTCQMCME-UHFFFAOYSA-N 0.000 claims 1
- 238000000844 transformation Methods 0.000 claims 1
- 150000004684 trihydrates Chemical class 0.000 claims 1
- 150000003839 salts Chemical class 0.000 abstract description 18
- 206010061603 Respiratory syncytial virus infection Diseases 0.000 abstract description 9
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 abstract description 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 abstract 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract 2
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 abstract 1
- 125000004916 (C1-C6) alkylcarbonyl group Chemical group 0.000 abstract 1
- 239000002184 metal Chemical class 0.000 abstract 1
- 239000000543 intermediate Substances 0.000 description 202
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 173
- 229910001868 water Inorganic materials 0.000 description 170
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 152
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 120
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 89
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 55
- 125000005843 halogen group Chemical group 0.000 description 51
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 51
- 239000003480 eluent Substances 0.000 description 45
- 239000003054 catalyst Substances 0.000 description 42
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 40
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 38
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 37
- 239000000741 silica gel Substances 0.000 description 36
- 229910002027 silica gel Inorganic materials 0.000 description 36
- 229960001866 silicon dioxide Drugs 0.000 description 36
- ZMXDDKWLCZADIW-UHFFFAOYSA-N dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 34
- 235000019441 ethanol Nutrition 0.000 description 34
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 33
- 239000012044 organic layer Substances 0.000 description 32
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 32
- 239000000243 solution Substances 0.000 description 32
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 28
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 28
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 27
- 239000002244 precipitate Substances 0.000 description 27
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 26
- 238000004440 column chromatography Methods 0.000 description 26
- 229910000069 nitrogen hydride Inorganic materials 0.000 description 26
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 18
- 235000015320 potassium carbonate Nutrition 0.000 description 16
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 15
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- 235000011114 ammonium hydroxide Nutrition 0.000 description 15
- 239000000706 filtrate Substances 0.000 description 15
- 235000011167 hydrochloric acid Nutrition 0.000 description 14
- 229960000443 hydrochloric acid Drugs 0.000 description 14
- 235000019439 ethyl acetate Nutrition 0.000 description 13
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 13
- 235000019341 magnesium sulphate Nutrition 0.000 description 13
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 12
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- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 12
- 239000011541 reaction mixture Substances 0.000 description 12
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 11
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 11
- 230000000840 anti-viral effect Effects 0.000 description 11
- 108010037444 diisopropylglutathione ester Proteins 0.000 description 11
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 10
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- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 10
- 125000001246 bromo group Chemical group Br* 0.000 description 10
- 125000004432 carbon atom Chemical group C* 0.000 description 10
- 125000001309 chloro group Chemical group Cl* 0.000 description 10
- 239000010410 layer Substances 0.000 description 10
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- 229910000104 sodium hydride Inorganic materials 0.000 description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 9
- PCBZRNYXXCIELG-WYFCWLEVSA-N COC1=CC=C(C[C@H](NC(=O)OC2CCCC3(C2)OOC2(O3)C3CC4CC(C3)CC2C4)C(=O)N[C@@H]2[C@@H](CO)O[C@H]([C@@H]2O)N2C=NC3=C2N=CN=C3N(C)C)C=C1 Chemical compound COC1=CC=C(C[C@H](NC(=O)OC2CCCC3(C2)OOC2(O3)C3CC4CC(C3)CC2C4)C(=O)N[C@@H]2[C@@H](CO)O[C@H]([C@@H]2O)N2C=NC3=C2N=CN=C3N(C)C)C=C1 PCBZRNYXXCIELG-WYFCWLEVSA-N 0.000 description 8
- 229940073584 methylene chloride Drugs 0.000 description 8
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- 231100000135 cytotoxicity Toxicity 0.000 description 7
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- 150000001298 alcohols Chemical class 0.000 description 6
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 6
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- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 5
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- 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
- A61K31/4164—1,3-Diazoles
- A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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US7179791B2 (en) | 2001-01-11 | 2007-02-20 | Duke University | Inhibiting GS-FDH to modulate NO bioactivity |
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US6919331B2 (en) | 2001-12-10 | 2005-07-19 | Bristol-Myers Squibb Company | Substituted 2-methyl-benzimidazole respiratory syncytial virus antiviral agents |
WO2003059289A2 (en) | 2002-01-10 | 2003-07-24 | Neurogen Corporation | Melanin concentrating hormone receptor ligands: substituted benzoimidazole analogues |
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EP1545513A2 (en) | 2002-08-09 | 2005-06-29 | Viropharma Incorporated | Compounds, compositions and methods for treating or preventing pneumovirus infection and associated diseases |
CA2495245A1 (en) | 2002-08-09 | 2004-02-19 | Viropharma Incorporated | Compounds, compositions and methods for treating or preventing pneumovirus infection and associated diseases |
BR0314595A (pt) * | 2002-09-20 | 2005-08-09 | Arrow Therapeutics Ltd | Uso de um derivado de benzodiazepina ou um sal farmaceuticamente aceitável deste, inalador ou nebulisador, produto, usos de um produto e de um composto ou sal farmaceuticamente aceitável deste, derivado de benzodiazepina, composto, e, composição farmacêutica |
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DE602004031776D1 (de) | 2003-12-18 | 2011-04-21 | Tibotec Pharm Ltd | Piperidinamino-benzimidazol-derivate al respiratorisches syncytialvirus replikation inhibitoren |
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AR046959A1 (es) * | 2003-12-18 | 2006-01-04 | Tibotec Pharm Ltd | Morfolinilo que contiene bencimidazoles como inhibidores de la replicacion del virus sincitial respiratorio |
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BRPI0606278B8 (pt) * | 2005-03-17 | 2021-05-25 | Janssen R & D Ireland | aminas de 1,3-diidro-benzimidazol-2-ilideno como inibidores de replicação de vírus sincicial respiratório, seu processo de preparação e composição farmacêutica |
TWI370820B (en) | 2005-04-27 | 2012-08-21 | Takeda Pharmaceutical | Fused heterocyclic compounds |
RU2419613C2 (ru) | 2005-06-20 | 2011-05-27 | Тиботек Фармасьютикалз Лтд | Гетероциклиламиноалкилзамещенные бензимидазолы |
PL1896450T3 (pl) * | 2005-06-20 | 2013-01-31 | Janssen Sciences Ireland Uc | 2-podstawione benzimidazole |
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KR20120034772A (ko) | 2006-03-29 | 2012-04-12 | 에프. 호프만-라 로슈 아게 | Mglur2 길항물질로서의 피리딘 및 피리미딘 유도체 |
KR101969689B1 (ko) | 2007-07-12 | 2019-04-16 | 케모센트릭스, 인크. | 염증의 치료를 위한 ccr2 조절물질로서 융합된 헤테로아릴 피리딜과 페닐 벤젠술폰아마이드 |
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EP2424533A4 (en) | 2009-04-27 | 2012-10-17 | High Point Pharmaceuticals Llc | SUBSTITUTED ISOQUINOLINE DERIVATIVES, PHARMACEUTICAL COMPOSITIONS AND THEIR METHODS OF USE AS-SECRETASE INHIBITORS |
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2000
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