JP6694886B2 - ４，５−ジヒドロ−６Ｈ−チエノ［３，２−ｄ］ベンゾアゼピン誘導体及び呼吸器合胞体ウイルス（ＲＳＶ）感染を治療するためのその使用 - Google Patents
４，５−ジヒドロ−６Ｈ−チエノ［３，２−ｄ］ベンゾアゼピン誘導体及び呼吸器合胞体ウイルス（ＲＳＶ）感染を治療するためのその使用 Download PDFInfo
- Publication number
- JP6694886B2 JP6694886B2 JP2017531829A JP2017531829A JP6694886B2 JP 6694886 B2 JP6694886 B2 JP 6694886B2 JP 2017531829 A JP2017531829 A JP 2017531829A JP 2017531829 A JP2017531829 A JP 2017531829A JP 6694886 B2 JP6694886 B2 JP 6694886B2
- Authority
- JP
- Japan
- Prior art keywords
- benzo
- dihydro
- thieno
- azepine
- azaspiro
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 241000725643 Respiratory syncytial virus Species 0.000 title description 49
- 208000015181 infectious disease Diseases 0.000 title description 13
- LCKYQZIXKGGZDS-UHFFFAOYSA-N 5,6-dihydro-4h-thieno[3,2-d][1]benzazepine Chemical class C12=CC=CC=C2NCCC2=C1SC=C2 LCKYQZIXKGGZDS-UHFFFAOYSA-N 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 198
- -1 4- (2- (7-methyl-1H-benzo [d] imidazol-2-yl) -5,6-dihydro-4H-benzo [b] thieno [2,3-d] azepine-6- Carbonyl) phenyl Chemical group 0.000 claims description 138
- 125000000217 alkyl group Chemical group 0.000 claims description 109
- 238000000034 method Methods 0.000 claims description 100
- 229910052739 hydrogen Inorganic materials 0.000 claims description 76
- 239000001257 hydrogen Substances 0.000 claims description 69
- 125000002947 alkylene group Chemical group 0.000 claims description 51
- 125000003545 alkoxy group Chemical group 0.000 claims description 49
- 125000005843 halogen group Chemical group 0.000 claims description 49
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 31
- 206010061603 Respiratory syncytial virus infection Diseases 0.000 claims description 30
- 150000003839 salts Chemical class 0.000 claims description 29
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 23
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 22
- 125000000304 alkynyl group Chemical group 0.000 claims description 21
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims description 20
- 125000003342 alkenyl group Chemical group 0.000 claims description 20
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 19
- 238000011282 treatment Methods 0.000 claims description 18
- 125000004767 (C1-C4) haloalkoxy group Chemical group 0.000 claims description 14
- 239000004480 active ingredient Substances 0.000 claims description 14
- 239000008194 pharmaceutical composition Substances 0.000 claims description 13
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 12
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 12
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 11
- 125000001153 fluoro group Chemical group F* 0.000 claims description 11
- 239000003085 diluting agent Substances 0.000 claims description 7
- 125000004442 acylamino group Chemical group 0.000 claims description 6
- 239000000969 carrier Substances 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 6
- 230000002265 prevention Effects 0.000 claims description 6
- 125000004737 (C1-C6) haloalkoxy group Chemical group 0.000 claims description 5
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 5
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 5
- IWUCXVSUMQZMFG-AFCXAGJDSA-N Ribavirin Chemical compound N1=C(C(=O)N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 IWUCXVSUMQZMFG-AFCXAGJDSA-N 0.000 claims description 5
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- 125000004438 haloalkoxy group Chemical group 0.000 claims description 5
- 229960000402 palivizumab Drugs 0.000 claims description 5
- 108090000623 proteins and genes Proteins 0.000 claims description 5
- 102000004169 proteins and genes Human genes 0.000 claims description 5
- 229960000329 ribavirin Drugs 0.000 claims description 5
- HZCAHMRRMINHDJ-DBRKOABJSA-N ribavirin Natural products O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1N=CN=C1 HZCAHMRRMINHDJ-DBRKOABJSA-N 0.000 claims description 5
- 229940076851 F protein inhibitor Drugs 0.000 claims description 3
- 229940122277 RNA polymerase inhibitor Drugs 0.000 claims description 3
- 125000005237 alkyleneamino group Chemical group 0.000 claims description 3
- 229940121363 anti-inflammatory agent Drugs 0.000 claims description 3
- 239000002260 anti-inflammatory agent Substances 0.000 claims description 3
- 239000003443 antiviral agent Substances 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 111
- 239000000203 mixture Substances 0.000 description 84
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 71
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 66
- 239000000243 solution Substances 0.000 description 57
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 56
- 239000007787 solid Substances 0.000 description 47
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 33
- 235000019439 ethyl acetate Nutrition 0.000 description 33
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 32
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 32
- 238000006243 chemical reaction Methods 0.000 description 29
- 150000002431 hydrogen Chemical class 0.000 description 28
- 239000000463 material Substances 0.000 description 27
- 238000000746 purification Methods 0.000 description 26
- 239000011541 reaction mixture Substances 0.000 description 24
- 239000000543 intermediate Substances 0.000 description 23
- 210000004027 cell Anatomy 0.000 description 22
- 239000002253 acid Substances 0.000 description 20
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 19
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 18
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 18
- 239000003039 volatile agent Substances 0.000 description 17
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 16
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 16
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 16
- 238000004128 high performance liquid chromatography Methods 0.000 description 16
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 16
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 16
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 15
- 238000001914 filtration Methods 0.000 description 15
- AFABGHUZZDYHJO-UHFFFAOYSA-N 2-Methylpentane Chemical compound CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 description 14
- 229910004298 SiO 2 Inorganic materials 0.000 description 14
- 201000010099 disease Diseases 0.000 description 14
- 239000000284 extract Substances 0.000 description 14
- 238000003818 flash chromatography Methods 0.000 description 14
- 229960001375 lactose Drugs 0.000 description 14
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 13
- 238000010828 elution Methods 0.000 description 13
- 238000009472 formulation Methods 0.000 description 13
- 239000008101 lactose Substances 0.000 description 13
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 210000004072 lung Anatomy 0.000 description 12
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 12
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 12
- 239000000843 powder Substances 0.000 description 12
- 239000002904 solvent Substances 0.000 description 12
- 238000012360 testing method Methods 0.000 description 12
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 12
- 230000005764 inhibitory process Effects 0.000 description 11
- 230000008569 process Effects 0.000 description 11
- 238000010992 reflux Methods 0.000 description 11
- 229920006395 saturated elastomer Polymers 0.000 description 11
- 239000000126 substance Substances 0.000 description 11
- 241000700605 Viruses Species 0.000 description 10
- 150000001412 amines Chemical class 0.000 description 10
- 239000002244 precipitate Substances 0.000 description 10
- AHVYPIQETPWLSZ-UHFFFAOYSA-N N-methyl-pyrrolidine Natural products CN1CC=CC1 AHVYPIQETPWLSZ-UHFFFAOYSA-N 0.000 description 9
- 239000000460 chlorine Substances 0.000 description 9
- 238000009826 distribution Methods 0.000 description 9
- 239000012044 organic layer Substances 0.000 description 9
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 8
- 239000012267 brine Substances 0.000 description 8
- 125000001309 chloro group Chemical group Cl* 0.000 description 8
- 239000003814 drug Substances 0.000 description 8
- 229910052751 metal Inorganic materials 0.000 description 8
- 239000002184 metal Substances 0.000 description 8
- 239000012071 phase Substances 0.000 description 8
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 8
- 239000000725 suspension Substances 0.000 description 8
- 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 7
- RKRWFPSTXGXVKM-UHFFFAOYSA-N 2H-thieno[2,3-d]azepine-2-carboxylic acid Chemical compound S1C(C=C2C1=CC=NC=C2)C(=O)O RKRWFPSTXGXVKM-UHFFFAOYSA-N 0.000 description 7
- 108010068327 4-hydroxyphenylpyruvate dioxygenase Proteins 0.000 description 7
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 7
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 7
- 230000010933 acylation Effects 0.000 description 7
- 238000005917 acylation reaction Methods 0.000 description 7
- 239000002585 base Substances 0.000 description 7
- 239000000706 filtrate Substances 0.000 description 7
- 239000010410 layer Substances 0.000 description 7
- 239000002245 particle Substances 0.000 description 7
- 230000009466 transformation Effects 0.000 description 7
- 239000003643 water by type Substances 0.000 description 7
- DTRBIIDYMYVRNE-UHFFFAOYSA-N 1h-azepine-2-carboxylic acid Chemical compound OC(=O)C1=CC=CC=CN1 DTRBIIDYMYVRNE-UHFFFAOYSA-N 0.000 description 6
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 6
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 6
- 238000005481 NMR spectroscopy Methods 0.000 description 6
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical class OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 150000001408 amides Chemical class 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 6
- 239000003153 chemical reaction reagent Substances 0.000 description 6
- 235000019253 formic acid Nutrition 0.000 description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 6
- 239000003880 polar aprotic solvent Substances 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- DAEPDZWVDSPTHF-UHFFFAOYSA-M sodium pyruvate Chemical compound [Na+].CC(=O)C([O-])=O DAEPDZWVDSPTHF-UHFFFAOYSA-M 0.000 description 6
- 239000000758 substrate Substances 0.000 description 6
- DWJWLMVIJBWYFP-UHFFFAOYSA-N 7-oxa-2-azaspiro[3.5]nonane;oxalic acid Chemical compound OC(=O)C(O)=O.C1NCC11CCOCC1.C1NCC11CCOCC1 DWJWLMVIJBWYFP-UHFFFAOYSA-N 0.000 description 5
- WSVLPVUVIUVCRA-KPKNDVKVSA-N Alpha-lactose monohydrate Chemical compound O.O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O WSVLPVUVIUVCRA-KPKNDVKVSA-N 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 5
- 239000000443 aerosol Substances 0.000 description 5
- 229910002091 carbon monoxide Inorganic materials 0.000 description 5
- 229910052801 chlorine Inorganic materials 0.000 description 5
- 150000002148 esters Chemical class 0.000 description 5
- 230000007062 hydrolysis Effects 0.000 description 5
- 238000006460 hydrolysis reaction Methods 0.000 description 5
- 238000001727 in vivo Methods 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- 239000003921 oil Substances 0.000 description 5
- 235000019198 oils Nutrition 0.000 description 5
- 239000000546 pharmaceutical excipient Substances 0.000 description 5
- 125000006239 protecting group Chemical group 0.000 description 5
- 230000009467 reduction Effects 0.000 description 5
- 238000006722 reduction reaction Methods 0.000 description 5
- 238000000844 transformation Methods 0.000 description 5
- SATBYUZLZBFXED-UHFFFAOYSA-N (4-aminophenyl)methanone Chemical compound NC1=CC=C([C+]=O)C=C1 SATBYUZLZBFXED-UHFFFAOYSA-N 0.000 description 4
- GQIRIWDEZSKOCN-UHFFFAOYSA-N 1-chloro-n,n,2-trimethylprop-1-en-1-amine Chemical compound CN(C)C(Cl)=C(C)C GQIRIWDEZSKOCN-UHFFFAOYSA-N 0.000 description 4
- 0 CC(c(cccc1)c1N(C*1=CC1)CC1)=C1C=O Chemical compound CC(c(cccc1)c1N(C*1=CC1)CC1)=C1C=O 0.000 description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 4
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 4
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 150000007513 acids Chemical class 0.000 description 4
- 235000019270 ammonium chloride Nutrition 0.000 description 4
- 125000004429 atom Chemical group 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- YNHIGQDRGKUECZ-UHFFFAOYSA-L bis(triphenylphosphine)palladium(ii) dichloride Chemical group [Cl-].[Cl-].[Pd+2].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-L 0.000 description 4
- 210000000424 bronchial epithelial cell Anatomy 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 230000000120 cytopathologic effect Effects 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 229910052736 halogen Inorganic materials 0.000 description 4
- 150000002367 halogens Chemical class 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 238000000338 in vitro Methods 0.000 description 4
- 238000011065 in-situ storage Methods 0.000 description 4
- 230000000269 nucleophilic effect Effects 0.000 description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 4
- 230000003389 potentiating effect Effects 0.000 description 4
- 239000002243 precursor Substances 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 239000003380 propellant Substances 0.000 description 4
- 239000003586 protic polar solvent Substances 0.000 description 4
- 238000007363 ring formation reaction Methods 0.000 description 4
- 238000011200 topical administration Methods 0.000 description 4
- 230000029812 viral genome replication Effects 0.000 description 4
- NKRKBYFBKLDCFB-UHFFFAOYSA-N 1,2,3,4-tetrahydro-1-benzazepin-5-one Chemical compound O=C1CCCNC2=CC=CC=C12 NKRKBYFBKLDCFB-UHFFFAOYSA-N 0.000 description 3
- GEYOCULIXLDCMW-UHFFFAOYSA-N 1,2-phenylenediamine Chemical compound NC1=CC=CC=C1N GEYOCULIXLDCMW-UHFFFAOYSA-N 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- QFRWKKWOCPTEKS-UHFFFAOYSA-N 2-chloro-6-methylpyridine-3-carboxamide Chemical compound CC1=CC=C(C(N)=O)C(Cl)=N1 QFRWKKWOCPTEKS-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- FGZQJVUQMYEVHX-UHFFFAOYSA-N CC1=NC(=C(C=C1)C(=O)N)N2CC3(C2)CCOCC3 Chemical compound CC1=NC(=C(C=C1)C(=O)N)N2CC3(C2)CCOCC3 FGZQJVUQMYEVHX-UHFFFAOYSA-N 0.000 description 3
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 3
- 239000007821 HATU Substances 0.000 description 3
- 241000282412 Homo Species 0.000 description 3
- 241000711920 Human orthopneumovirus Species 0.000 description 3
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 3
- 229930182816 L-glutamine Natural products 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- 241000699666 Mus <mouse, genus> Species 0.000 description 3
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 3
- PLXBWHJQWKZRKG-UHFFFAOYSA-N Resazurin Chemical compound C1=CC(=O)C=C2OC3=CC(O)=CC=C3[N+]([O-])=C21 PLXBWHJQWKZRKG-UHFFFAOYSA-N 0.000 description 3
- 229960000583 acetic acid Drugs 0.000 description 3
- 239000008346 aqueous phase Substances 0.000 description 3
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 3
- 229910000024 caesium carbonate Inorganic materials 0.000 description 3
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000012230 colorless oil Substances 0.000 description 3
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 3
- 238000006073 displacement reaction Methods 0.000 description 3
- 229940112141 dry powder inhaler Drugs 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- YJWZTHASBKCTQI-UHFFFAOYSA-N ethyl 6-(4-aminobenzoyl)-4,5-dihydrothieno[3,2-d][1]benzazepine-2-carboxylate Chemical compound C12=CC=CC=C2C=2SC(C(=O)OCC)=CC=2CCN1C(=O)C1=CC=C(N)C=C1 YJWZTHASBKCTQI-UHFFFAOYSA-N 0.000 description 3
- KELWGJODHUOWIM-UHFFFAOYSA-N ethyl 6-(4-nitrobenzoyl)-4,5-dihydrothieno[3,2-d][1]benzazepine-2-carboxylate Chemical compound C12=CC=CC=C2C=2SC(C(=O)OCC)=CC=2CCN1C(=O)C1=CC=C([N+]([O-])=O)C=C1 KELWGJODHUOWIM-UHFFFAOYSA-N 0.000 description 3
- 238000011156 evaluation Methods 0.000 description 3
- 238000005755 formation reaction Methods 0.000 description 3
- 239000012458 free base Substances 0.000 description 3
- 210000002216 heart Anatomy 0.000 description 3
- 239000008267 milk Substances 0.000 description 3
- 210000004080 milk Anatomy 0.000 description 3
- 235000013336 milk Nutrition 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000006199 nebulizer Substances 0.000 description 3
- 235000001968 nicotinic acid Nutrition 0.000 description 3
- 239000011664 nicotinic acid Substances 0.000 description 3
- 150000007530 organic bases Chemical class 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- 125000004430 oxygen atom Chemical group O* 0.000 description 3
- 125000003232 p-nitrobenzoyl group Chemical group [N+](=O)([O-])C1=CC=C(C(=O)*)C=C1 0.000 description 3
- 229910052763 palladium Inorganic materials 0.000 description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 3
- 238000005897 peptide coupling reaction Methods 0.000 description 3
- 238000002953 preparative HPLC Methods 0.000 description 3
- 150000003222 pyridines Chemical class 0.000 description 3
- 230000004044 response Effects 0.000 description 3
- 229940054269 sodium pyruvate Drugs 0.000 description 3
- 239000012453 solvate Substances 0.000 description 3
- 239000004094 surface-active agent Substances 0.000 description 3
- 230000004083 survival effect Effects 0.000 description 3
- 238000000825 ultraviolet detection Methods 0.000 description 3
- 238000003828 vacuum filtration Methods 0.000 description 3
- 239000011534 wash buffer Substances 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- LVGUZGTVOIAKKC-UHFFFAOYSA-N 1,1,1,2-tetrafluoroethane Chemical compound FCC(F)(F)F LVGUZGTVOIAKKC-UHFFFAOYSA-N 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 description 2
- GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical group NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 description 2
- CRYQNMBNIVTUBA-UHFFFAOYSA-N 2-chloro-5-methylpyridine-3-carboxamide Chemical compound CC1=CN=C(Cl)C(C(N)=O)=C1 CRYQNMBNIVTUBA-UHFFFAOYSA-N 0.000 description 2
- ACQXHCHKMFYDPM-UHFFFAOYSA-N 2-chloro-6-methylpyridine-3-carboxylic acid Chemical compound CC1=CC=C(C(O)=O)C(Cl)=N1 ACQXHCHKMFYDPM-UHFFFAOYSA-N 0.000 description 2
- RXTRRIFWCJEMEL-UHFFFAOYSA-N 2-chloropyridine-3-carbonyl chloride Chemical compound ClC(=O)C1=CC=CN=C1Cl RXTRRIFWCJEMEL-UHFFFAOYSA-N 0.000 description 2
- GZOOCJUOEDETNE-UHFFFAOYSA-N 2-ethyl-6-nitroaniline Chemical compound CCC1=CC=CC([N+]([O-])=O)=C1N GZOOCJUOEDETNE-UHFFFAOYSA-N 0.000 description 2
- MLPVBIWIRCKMJV-UHFFFAOYSA-N 2-ethylaniline Chemical compound CCC1=CC=CC=C1N MLPVBIWIRCKMJV-UHFFFAOYSA-N 0.000 description 2
- ZXRJUBLHFHDUJH-UHFFFAOYSA-N 3-ethylbenzene-1,2-diamine Chemical compound CCC1=CC=CC(N)=C1N ZXRJUBLHFHDUJH-UHFFFAOYSA-N 0.000 description 2
- BXRFQSNOROATLV-UHFFFAOYSA-N 4-nitrobenzaldehyde Chemical compound [O-][N+](=O)C1=CC=C(C=O)C=C1 BXRFQSNOROATLV-UHFFFAOYSA-N 0.000 description 2
- SKDHHIUENRGTHK-UHFFFAOYSA-N 4-nitrobenzoyl chloride Chemical compound [O-][N+](=O)C1=CC=C(C(Cl)=O)C=C1 SKDHHIUENRGTHK-UHFFFAOYSA-N 0.000 description 2
- VQPKZNLLZRGNPF-UHFFFAOYSA-N 5-cyclopropyl-2-(7-oxa-2-azaspiro[3.5]nonan-2-yl)pyridine-3-carboxylic acid Chemical compound C1(CC1)C=1C=NC(=C(C(=O)O)C=1)N1CC2(C1)CCOCC2 VQPKZNLLZRGNPF-UHFFFAOYSA-N 0.000 description 2
- SMTMFXHUNHIPQU-UHFFFAOYSA-N 5-ethyl-2-(7-oxa-2-azaspiro[3.5]nonan-2-yl)pyridine-3-carboxylic acid Chemical compound C(C)C=1C=NC(=C(C(=O)O)C=1)N1CC2(C1)CCOCC2 SMTMFXHUNHIPQU-UHFFFAOYSA-N 0.000 description 2
- DJMKEURPDCVGFR-UHFFFAOYSA-N 6-O-benzyl 2-O-ethyl 4,5-dihydrothieno[3,2-d][1]benzazepine-2,6-dicarboxylate Chemical compound S1C(=CC2=C1C1=C(N(CC2)C(=O)OCC2=CC=CC=C2)C=CC=C1)C(=O)OCC DJMKEURPDCVGFR-UHFFFAOYSA-N 0.000 description 2
- GTUSPZYLQHXJSR-UHFFFAOYSA-N C1N(CC11CCOCC1)C1=C(C(=O)O)C=C(C=N1)C#C[Si](C(C)C)(C(C)C)C(C)C Chemical compound C1N(CC11CCOCC1)C1=C(C(=O)O)C=C(C=N1)C#C[Si](C(C)C)(C(C)C)C(C)C GTUSPZYLQHXJSR-UHFFFAOYSA-N 0.000 description 2
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 2
- 241000400611 Eucalyptus deanei Species 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- 241000725303 Human immunodeficiency virus Species 0.000 description 2
- 206010061598 Immunodeficiency Diseases 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- 230000006181 N-acylation Effects 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 206010035664 Pneumonia Diseases 0.000 description 2
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 description 2
- QWQROGBPSOBNTG-UHFFFAOYSA-N S(=O)(=O)(C1=CC=C(C)C=C1)N1C(CC=CC=C1)=O Chemical compound S(=O)(=O)(C1=CC=C(C)C=C1)N1C(CC=CC=C1)=O QWQROGBPSOBNTG-UHFFFAOYSA-N 0.000 description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 239000012190 activator Substances 0.000 description 2
- 125000001931 aliphatic group Chemical group 0.000 description 2
- 125000003282 alkyl amino group Chemical group 0.000 description 2
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 230000000840 anti-viral effect Effects 0.000 description 2
- 239000012736 aqueous medium Substances 0.000 description 2
- 150000001499 aryl bromides Chemical class 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- GLZXFITXXAMCRJ-UHFFFAOYSA-N azepin-4-one Chemical compound O=C1C=CC=NC=C1 GLZXFITXXAMCRJ-UHFFFAOYSA-N 0.000 description 2
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 2
- GXUHOOAYSCCLSM-UHFFFAOYSA-N benzyl 2-oxo-3H-azepine-1-carboxylate Chemical compound C(=O)(OCC1=CC=CC=C1)N1C(CC=CC=C1)=O GXUHOOAYSCCLSM-UHFFFAOYSA-N 0.000 description 2
- GBKPNWZUXHOUBZ-UHFFFAOYSA-N benzyl 5-chloro-4-formyl-2,3-dihydro-1-benzazepine-1-carboxylate Chemical compound ClC=1C2=C(N(CCC=1C=O)C(=O)OCC1=CC=CC=C1)C=CC=C2 GBKPNWZUXHOUBZ-UHFFFAOYSA-N 0.000 description 2
- ZQHNRKXSXWMEFH-UHFFFAOYSA-N benzyl azepine-1-carboxylate Chemical compound C1=CC=CC=CN1C(=O)OCC1=CC=CC=C1 ZQHNRKXSXWMEFH-UHFFFAOYSA-N 0.000 description 2
- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 description 2
- 239000012455 biphasic mixture Substances 0.000 description 2
- 125000001246 bromo group Chemical group Br* 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 238000011944 chemoselective reduction Methods 0.000 description 2
- QQVDYSUDFZZPSU-UHFFFAOYSA-M chloromethylidene(dimethyl)azanium;chloride Chemical compound [Cl-].C[N+](C)=CCl QQVDYSUDFZZPSU-UHFFFAOYSA-M 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000006184 cosolvent Substances 0.000 description 2
- 239000007822 coupling agent Substances 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- NXQGGXCHGDYOHB-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloropalladium;iron(2+) Chemical compound [Fe+2].Cl[Pd]Cl.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 NXQGGXCHGDYOHB-UHFFFAOYSA-L 0.000 description 2
- PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical compound FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 description 2
- 235000019404 dichlorodifluoromethane Nutrition 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 208000035475 disorder Diseases 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 231100000673 dose–response relationship Toxicity 0.000 description 2
- 210000002919 epithelial cell Anatomy 0.000 description 2
- CWNLZVRJVJTWFZ-UHFFFAOYSA-N ethyl 5,6-dihydro-4H-thieno[3,2-d][1]benzazepine-2-carboxylate hydrochloride Chemical compound Cl.CCOC(=O)c1cc2CCNc3ccccc3-c2s1 CWNLZVRJVJTWFZ-UHFFFAOYSA-N 0.000 description 2
- ZOJJEYADHKUEPN-UHFFFAOYSA-N ethyl 6-(4-amino-2-fluorobenzoyl)-4,5-dihydrothieno[3,2-d][1]benzazepine-2-carboxylate Chemical compound NC1=CC(=C(C(=O)N2C3=C(C4=C(CC2)C=C(S4)C(=O)OCC)C=CC=C3)C=C1)F ZOJJEYADHKUEPN-UHFFFAOYSA-N 0.000 description 2
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 230000005284 excitation Effects 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 150000005748 halopyridines Chemical class 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- 229910052742 iron Inorganic materials 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 230000001404 mediated effect Effects 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- ZVXOPKVDHZGGSF-UHFFFAOYSA-N methyl 5-ethenyl-2-(7-oxa-2-azaspiro[3.5]nonan-2-yl)pyridine-3-carboxylate Chemical compound C1N(CC11CCOCC1)C1=C(C(=O)OC)C=C(C=N1)C=C ZVXOPKVDHZGGSF-UHFFFAOYSA-N 0.000 description 2
- UIMSJZSDMRRHEL-UHFFFAOYSA-N n-(2-ethyl-6-nitrophenyl)acetamide Chemical compound CCC1=CC=CC([N+]([O-])=O)=C1NC(C)=O UIMSJZSDMRRHEL-UHFFFAOYSA-N 0.000 description 2
- 235000005152 nicotinamide Nutrition 0.000 description 2
- 239000011570 nicotinamide Substances 0.000 description 2
- 229960003966 nicotinamide Drugs 0.000 description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 2
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 239000003002 pH adjusting agent Substances 0.000 description 2
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 2
- 244000052769 pathogen Species 0.000 description 2
- 229920000728 polyester Polymers 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 230000000069 prophylactic effect Effects 0.000 description 2
- 230000005180 public health Effects 0.000 description 2
- 230000002685 pulmonary effect Effects 0.000 description 2
- 125000004076 pyridyl group Chemical group 0.000 description 2
- 230000000717 retained effect Effects 0.000 description 2
- 238000004007 reversed phase HPLC Methods 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 238000012216 screening Methods 0.000 description 2
- 239000011550 stock solution Substances 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- QERYCTSHXKAMIS-UHFFFAOYSA-N thiophene-2-carboxylic acid Chemical compound OC(=O)C1=CC=CS1 QERYCTSHXKAMIS-UHFFFAOYSA-N 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 description 2
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 2
- 229920002554 vinyl polymer Polymers 0.000 description 2
- 239000004034 viscosity adjusting agent Substances 0.000 description 2
- 229930195727 α-lactose Natural products 0.000 description 2
- WSVLPVUVIUVCRA-ZVYOHNBTSA-N (2r,3r,4s,5r,6s)-2-(hydroxymethyl)-6-[(2r,3s,4r,5r,6r)-4,5,6-trihydroxy-2-(hydroxymethyl)oxan-3-yl]oxyoxane-3,4,5-triol;hydrate Chemical compound O.O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@@H](O)[C@H](O)[C@H]1O WSVLPVUVIUVCRA-ZVYOHNBTSA-N 0.000 description 1
- 125000006583 (C1-C3) haloalkyl group Chemical group 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- 125000005869 (methoxyethoxy)methanyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])OC([H])([H])* 0.000 description 1
- DDMOUSALMHHKOS-UHFFFAOYSA-N 1,2-dichloro-1,1,2,2-tetrafluoroethane Chemical compound FC(F)(Cl)C(F)(F)Cl DDMOUSALMHHKOS-UHFFFAOYSA-N 0.000 description 1
- AYQMNFRCBKOMIA-UHFFFAOYSA-N 1-benzazepin-2-one Chemical compound O=C1C=CC=C2C=CC=CC2=N1 AYQMNFRCBKOMIA-UHFFFAOYSA-N 0.000 description 1
- AVFZOVWCLRSYKC-UHFFFAOYSA-N 1-methylpyrrolidine Chemical compound CN1CCCC1 AVFZOVWCLRSYKC-UHFFFAOYSA-N 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- RDXWPKCFJVVDAS-UHFFFAOYSA-N 1H-[1]benzothiolo[3,2-b]azepine Chemical compound N1C=CC=CC2=C1C1=C(S2)C=CC=C1 RDXWPKCFJVVDAS-UHFFFAOYSA-N 0.000 description 1
- IOHPVZBSOKLVMN-UHFFFAOYSA-N 2-(2-phenylethyl)benzoic acid Chemical compound OC(=O)C1=CC=CC=C1CCC1=CC=CC=C1 IOHPVZBSOKLVMN-UHFFFAOYSA-N 0.000 description 1
- KPIVDNYJNOPGBE-UHFFFAOYSA-N 2-aminonicotinic acid Chemical compound NC1=NC=CC=C1C(O)=O KPIVDNYJNOPGBE-UHFFFAOYSA-N 0.000 description 1
- MMWNKXIFVYQOTK-UHFFFAOYSA-N 2-bromopyridine-3-carboxylic acid Chemical compound OC(=O)C1=CC=CN=C1Br MMWNKXIFVYQOTK-UHFFFAOYSA-N 0.000 description 1
- GQEUIJKKHGAJRM-UHFFFAOYSA-N 2-chloro-1-(5,5,8,8-tetramethyl-3-propoxy-6,7-dihydronaphthalen-2-yl)ethenol Chemical compound CC1(C)CCC(C)(C)C2=C1C=C(C(O)=CCl)C(OCCC)=C2 GQEUIJKKHGAJRM-UHFFFAOYSA-N 0.000 description 1
- HGTOSTXLRLIKCJ-UHFFFAOYSA-N 2-chloro-5-methylpyridine-3-carboxylic acid Chemical compound CC1=CN=C(Cl)C(C(O)=O)=C1 HGTOSTXLRLIKCJ-UHFFFAOYSA-N 0.000 description 1
- MMWFMFZFCKADEL-UHFFFAOYSA-N 2-fluoro-4-nitrobenzoic acid Chemical compound OC(=O)C1=CC=C([N+]([O-])=O)C=C1F MMWFMFZFCKADEL-UHFFFAOYSA-N 0.000 description 1
- UAIUNKRWKOVEES-UHFFFAOYSA-N 3,3',5,5'-tetramethylbenzidine Chemical compound CC1=C(N)C(C)=CC(C=2C=C(C)C(N)=C(C)C=2)=C1 UAIUNKRWKOVEES-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- AXNUJYHFQHQZBE-UHFFFAOYSA-N 3-methylbenzene-1,2-diamine Chemical compound CC1=CC=CC(N)=C1N AXNUJYHFQHQZBE-UHFFFAOYSA-N 0.000 description 1
- WUBBRNOQWQTFEX-UHFFFAOYSA-N 4-aminosalicylic acid Chemical compound NC1=CC=C(C(O)=O)C(O)=C1 WUBBRNOQWQTFEX-UHFFFAOYSA-N 0.000 description 1
- 150000005443 4-nitrobenzoic acid derivatives Chemical class 0.000 description 1
- SNJYGABQLZJUSJ-UHFFFAOYSA-N 5,6-dihydro-4h-thieno[3,2-d][1]benzazepine-2-carboxylic acid Chemical compound C1CNC2=CC=CC=C2C2=C1C=C(C(=O)O)S2 SNJYGABQLZJUSJ-UHFFFAOYSA-N 0.000 description 1
- WUFVHYAXFGSSAW-UHFFFAOYSA-N 5-chloro-1-(4-nitrobenzoyl)-2,3-dihydro-1-benzazepine-4-carbaldehyde Chemical compound C1=CC([N+](=O)[O-])=CC=C1C(=O)N1C2=CC=CC=C2C(Cl)=C(C=O)CC1 WUFVHYAXFGSSAW-UHFFFAOYSA-N 0.000 description 1
- IMRMWDUKKWQGJY-UHFFFAOYSA-N 6-(4-nitrobenzoyl)-4,5-dihydrothieno[3,2-d][1]benzazepine-2-carboxylic acid Chemical compound C12=CC=CC=C2C=2SC(C(=O)O)=CC=2CCN1C(=O)C1=CC=C([N+]([O-])=O)C=C1 IMRMWDUKKWQGJY-UHFFFAOYSA-N 0.000 description 1
- RJQFVEUTTSHMIW-UHFFFAOYSA-N 6-[4-[[5-methyl-2-(7-oxa-2-azaspiro[3.5]nonan-2-yl)pyridine-3-carbonyl]amino]benzoyl]-4,5-dihydrothieno[3,2-d][1]benzazepine-2-carboxylic acid Chemical compound CC=1C=NC(=C(C(=O)NC2=CC=C(C(=O)N3C4=C(C5=C(CC3)C=C(S5)C(=O)O)C=CC=C4)C=C2)C=1)N1CC2(C1)CCOCC2 RJQFVEUTTSHMIW-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-DCSYEGIMSA-N Beta-Lactose Chemical compound OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-DCSYEGIMSA-N 0.000 description 1
- 206010006448 Bronchiolitis Diseases 0.000 description 1
- LGYNZPBAQKAOAD-UHFFFAOYSA-N CC1(C(c2c(CC3)cc(-c4nc(cccc5)c5[nH]4)[s]2)=CC=CC1)N3C(C(C=C1)=CCC1N)=O Chemical compound CC1(C(c2c(CC3)cc(-c4nc(cccc5)c5[nH]4)[s]2)=CC=CC1)N3C(C(C=C1)=CCC1N)=O LGYNZPBAQKAOAD-UHFFFAOYSA-N 0.000 description 1
- GNNRHEHPHKLWHJ-UHFFFAOYSA-N CN(CCC1)c(cccc2)c2C1=O Chemical compound CN(CCC1)c(cccc2)c2C1=O GNNRHEHPHKLWHJ-UHFFFAOYSA-N 0.000 description 1
- LERNTVKEWCAPOY-VOGVJGKGSA-N C[N+]1(C)[C@H]2C[C@H](C[C@@H]1[C@H]1O[C@@H]21)OC(=O)C(O)(c1cccs1)c1cccs1 Chemical compound C[N+]1(C)[C@H]2C[C@H](C[C@@H]1[C@H]1O[C@@H]21)OC(=O)C(O)(c1cccs1)c1cccs1 LERNTVKEWCAPOY-VOGVJGKGSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 206010007559 Cardiac failure congestive Diseases 0.000 description 1
- 208000032170 Congenital Abnormalities Diseases 0.000 description 1
- 206010010356 Congenital anomaly Diseases 0.000 description 1
- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 1
- 229920000742 Cotton Polymers 0.000 description 1
- 201000003883 Cystic fibrosis Diseases 0.000 description 1
- 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 1
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 239000004338 Dichlorodifluoromethane Substances 0.000 description 1
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Divinylene sulfide Natural products C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 1
- 244000166102 Eucalyptus leucoxylon Species 0.000 description 1
- 235000004694 Eucalyptus leucoxylon Nutrition 0.000 description 1
- 229940124602 FDA-approved drug Drugs 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 208000031886 HIV Infections Diseases 0.000 description 1
- 208000037357 HIV infectious disease Diseases 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- 208000005176 Hepatitis C Diseases 0.000 description 1
- 208000019693 Lung disease Diseases 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- HGQAXWZTFJIVNL-UHFFFAOYSA-N N-[4-[2-(1H-benzimidazol-2-yl)-4,5-dihydrothieno[3,2-d][1]benzazepine-6-carbonyl]phenyl]-2-chloro-6-methylpyridine-3-carboxamide Chemical compound N1C(=NC2=C1C=CC=C2)C1=CC2=C(C3=C(N(CC2)C(=O)C2=CC=C(C=C2)NC(C2=C(N=C(C=C2)C)Cl)=O)C=CC=C3)S1 HGQAXWZTFJIVNL-UHFFFAOYSA-N 0.000 description 1
- 235000019502 Orange oil Nutrition 0.000 description 1
- 241000711504 Paramyxoviridae Species 0.000 description 1
- 241000711902 Pneumovirus Species 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 229920001213 Polysorbate 20 Polymers 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 241000288906 Primates Species 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 206010062106 Respiratory tract infection viral Diseases 0.000 description 1
- 206010057190 Respiratory tract infections Diseases 0.000 description 1
- 241000144282 Sigmodon Species 0.000 description 1
- 241000144290 Sigmodon hispidus Species 0.000 description 1
- 239000004147 Sorbitan trioleate Substances 0.000 description 1
- PRXRUNOAOLTIEF-ADSICKODSA-N Sorbitan trioleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@@H](OC(=O)CCCCCCC\C=C/CCCCCCCC)[C@H]1OC[C@H](O)[C@H]1OC(=O)CCCCCCC\C=C/CCCCCCCC PRXRUNOAOLTIEF-ADSICKODSA-N 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 238000006069 Suzuki reaction reaction Methods 0.000 description 1
- 239000012317 TBTU Substances 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- CLZISMQKJZCZDN-UHFFFAOYSA-N [benzotriazol-1-yloxy(dimethylamino)methylidene]-dimethylazanium Chemical compound C1=CC=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 CLZISMQKJZCZDN-UHFFFAOYSA-N 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 238000005054 agglomeration Methods 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 125000005907 alkyl ester group Chemical group 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 238000010976 amide bond formation reaction Methods 0.000 description 1
- 238000005576 amination reaction Methods 0.000 description 1
- 229960004909 aminosalicylic acid Drugs 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 150000001448 anilines Chemical class 0.000 description 1
- 230000000890 antigenic effect Effects 0.000 description 1
- 229960005475 antiinfective agent Drugs 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000000010 aprotic solvent Substances 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 238000000889 atomisation Methods 0.000 description 1
- XYOVOXDWRFGKEX-UHFFFAOYSA-N azepine Chemical compound N1C=CC=CC=C1 XYOVOXDWRFGKEX-UHFFFAOYSA-N 0.000 description 1
- LVKIESWJKHVPIN-UHFFFAOYSA-N azepine-1-carboxylic acid Chemical compound OC(=O)N1C=CC=CC=C1 LVKIESWJKHVPIN-UHFFFAOYSA-N 0.000 description 1
- 125000002393 azetidinyl group Chemical group 0.000 description 1
- 210000000270 basal cell Anatomy 0.000 description 1
- NBMKJKDGKREAPL-DVTGEIKXSA-N beclomethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(Cl)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O NBMKJKDGKREAPL-DVTGEIKXSA-N 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- QRUDEWIWKLJBPS-UHFFFAOYSA-N benzotriazole Chemical compound C1=CC=C2N[N][N]C2=C1 QRUDEWIWKLJBPS-UHFFFAOYSA-N 0.000 description 1
- 239000012964 benzotriazole Substances 0.000 description 1
- CJASUXANQFOZOL-UHFFFAOYSA-N benzyl 5-oxo-3,4-dihydro-2H-1-benzazepine-1-carboxylate Chemical compound O=C1C2=C(N(CCC1)C(=O)OCC1=CC=CC=C1)C=CC=C2 CJASUXANQFOZOL-UHFFFAOYSA-N 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 230000007698 birth defect Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 238000006664 bond formation reaction Methods 0.000 description 1
- 125000005620 boronic acid group Chemical class 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 150000007942 carboxylates Chemical group 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000010531 catalytic reduction reaction Methods 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000003833 cell viability Effects 0.000 description 1
- 208000029771 childhood onset asthma Diseases 0.000 description 1
- 239000012320 chlorinating reagent Substances 0.000 description 1
- KYKAJFCTULSVSH-UHFFFAOYSA-N chloro(fluoro)methane Chemical compound F[C]Cl KYKAJFCTULSVSH-UHFFFAOYSA-N 0.000 description 1
- 238000003403 chloroformylation reaction Methods 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 239000000625 cyclamic acid and its Na and Ca salt Substances 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- HCAJEUSONLESMK-UHFFFAOYSA-N cyclohexylsulfamic acid Chemical compound OS(=O)(=O)NC1CCCCC1 HCAJEUSONLESMK-UHFFFAOYSA-N 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- WLVKDFJTYKELLQ-UHFFFAOYSA-N cyclopropylboronic acid Chemical compound OB(O)C1CC1 WLVKDFJTYKELLQ-UHFFFAOYSA-N 0.000 description 1
- 230000001120 cytoprotective effect Effects 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 231100000517 death Toxicity 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 239000011903 deuterated solvents Substances 0.000 description 1
- 229910052805 deuterium Inorganic materials 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 150000004985 diamines Chemical class 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 1
- 230000006806 disease prevention Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 229940088679 drug related substance Drugs 0.000 description 1
- 239000003596 drug target Substances 0.000 description 1
- 230000002900 effect on cell Effects 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- HVCNNTAUBZIYCG-UHFFFAOYSA-N ethyl 2-[4-[(6-chloro-1,3-benzothiazol-2-yl)oxy]phenoxy]propanoate Chemical compound C1=CC(OC(C)C(=O)OCC)=CC=C1OC1=NC2=CC=C(Cl)C=C2S1 HVCNNTAUBZIYCG-UHFFFAOYSA-N 0.000 description 1
- PVBRSNZAOAJRKO-UHFFFAOYSA-N ethyl 2-sulfanylacetate Chemical compound CCOC(=O)CS PVBRSNZAOAJRKO-UHFFFAOYSA-N 0.000 description 1
- KSOSWFZSMNYJMQ-UHFFFAOYSA-N ethyl 6-(2-fluoro-4-nitrobenzoyl)-4,5-dihydrothieno[3,2-d][1]benzazepine-2-carboxylate Chemical compound FC1=C(C(=O)N2C3=C(C4=C(CC2)C=C(S4)C(=O)OCC)C=CC=C3)C=CC(=C1)[N+](=O)[O-] KSOSWFZSMNYJMQ-UHFFFAOYSA-N 0.000 description 1
- POORSXFPZOXFFA-UHFFFAOYSA-N ethyl 6-[4-[[2-(7-oxa-2-azaspiro[3.5]nonan-2-yl)pyridine-3-carbonyl]amino]benzoyl]-4,5-dihydrothieno[3,2-d][1]benzazepine-2-carboxylate Chemical compound C1N(CC11CCOCC1)C1=C(C(=O)NC2=CC=C(C(=O)N3C4=C(C5=C(CC3)C=C(S5)C(=O)OCC)C=CC=C4)C=C2)C=CC=N1 POORSXFPZOXFFA-UHFFFAOYSA-N 0.000 description 1
- JMIGYQVZGKSRJO-UHFFFAOYSA-N ethyl 6-[4-[[5-methyl-2-(7-oxa-2-azaspiro[3.5]nonan-2-yl)pyridine-3-carbonyl]amino]benzoyl]-4,5-dihydrothieno[3,2-d][1]benzazepine-2-carboxylate Chemical compound CC=1C=NC(=C(C(=O)NC2=CC=C(C(=O)N3C4=C(C5=C(CC3)C=C(S5)C(=O)OCC)C=CC=C4)C=C2)C=1)N1CC2(C1)CCOCC2 JMIGYQVZGKSRJO-UHFFFAOYSA-N 0.000 description 1
- 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 description 1
- KZGWPHUWNWRTEP-UHFFFAOYSA-N ethynyl-tri(propan-2-yl)silane Chemical compound CC(C)[Si](C#C)(C(C)C)C(C)C KZGWPHUWNWRTEP-UHFFFAOYSA-N 0.000 description 1
- 230000005713 exacerbation Effects 0.000 description 1
- HJUFTIJOISQSKQ-UHFFFAOYSA-N fenoxycarb Chemical compound C1=CC(OCCNC(=O)OCC)=CC=C1OC1=CC=CC=C1 HJUFTIJOISQSKQ-UHFFFAOYSA-N 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 230000008570 general process Effects 0.000 description 1
- 238000009650 gentamicin protection assay Methods 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 229960004275 glycolic acid Drugs 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 125000001188 haloalkyl group Chemical group 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 208000019622 heart disease Diseases 0.000 description 1
- 208000002672 hepatitis B Diseases 0.000 description 1
- UKACHOXRXFQJFN-UHFFFAOYSA-N heptafluoropropane Chemical compound FC(F)C(F)(F)C(F)(F)F UKACHOXRXFQJFN-UHFFFAOYSA-N 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 208000033519 human immunodeficiency virus infectious disease Diseases 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 208000026278 immune system disease Diseases 0.000 description 1
- 238000012744 immunostaining Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- 238000010829 isocratic elution Methods 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 229960000448 lactic acid Drugs 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 239000006193 liquid solution Substances 0.000 description 1
- 239000006194 liquid suspension Substances 0.000 description 1
- 230000004807 localization Effects 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 208000030500 lower respiratory tract disease Diseases 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- MOMQDEDQGJAKII-UHFFFAOYSA-N methyl 5-bromo-2-chloropyridine-3-carboxylate Chemical compound COC(=O)C1=CC(Br)=CN=C1Cl MOMQDEDQGJAKII-UHFFFAOYSA-N 0.000 description 1
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 1
- 238000003801 milling Methods 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- DUWWHGPELOTTOE-UHFFFAOYSA-N n-(5-chloro-2,4-dimethoxyphenyl)-3-oxobutanamide Chemical compound COC1=CC(OC)=C(NC(=O)CC(C)=O)C=C1Cl DUWWHGPELOTTOE-UHFFFAOYSA-N 0.000 description 1
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229940100662 nasal drops Drugs 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 229960003512 nicotinic acid Drugs 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 239000012038 nucleophile Substances 0.000 description 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
- 239000010502 orange oil Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- VATYWCRQDJIRAI-UHFFFAOYSA-N p-aminobenzaldehyde Chemical compound NC1=CC=C(C=O)C=C1 VATYWCRQDJIRAI-UHFFFAOYSA-N 0.000 description 1
- WLJNZVDCPSBLRP-UHFFFAOYSA-N pamoic acid Chemical compound C1=CC=C2C(CC=3C4=CC=CC=C4C=C(C=3O)C(=O)O)=C(O)C(C(O)=O)=CC2=C1 WLJNZVDCPSBLRP-UHFFFAOYSA-N 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 230000007310 pathophysiology Effects 0.000 description 1
- 239000012026 peptide coupling reagents Substances 0.000 description 1
- 125000005010 perfluoroalkyl group Chemical group 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000012716 precipitator Substances 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 229940107700 pyruvic acid Drugs 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 238000011946 reduction process Methods 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 208000020029 respiratory tract infectious disease Diseases 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 125000006413 ring segment Chemical group 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 238000007873 sieving Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 238000005549 size reduction Methods 0.000 description 1
- RYYKJJJTJZKILX-UHFFFAOYSA-M sodium octadecanoate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC([O-])=O RYYKJJJTJZKILX-UHFFFAOYSA-M 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 235000019337 sorbitan trioleate Nutrition 0.000 description 1
- 229960000391 sorbitan trioleate Drugs 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000001694 spray drying Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 229940036185 synagis Drugs 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 229960000257 tiotropium bromide Drugs 0.000 description 1
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 1
- 238000011277 treatment modality Methods 0.000 description 1
- 229940029284 trichlorofluoromethane Drugs 0.000 description 1
- PBIMIGNDTBRRPI-UHFFFAOYSA-N trifluoro borate Chemical compound FOB(OF)OF PBIMIGNDTBRRPI-UHFFFAOYSA-N 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- JOYRKODLDBILNP-UHFFFAOYSA-N urethane group Chemical group NC(=O)OCC JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 1
- 125000005500 uronium group Chemical group 0.000 description 1
- 229960005486 vaccine Drugs 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 239000003021 water soluble solvent Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229930195724 β-lactose Natural products 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
-
- 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
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Virology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pain & Pain Management (AREA)
- Molecular Biology (AREA)
- Communicable Diseases (AREA)
- Rheumatology (AREA)
- Oncology (AREA)
- Pulmonology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP14199020.0 | 2014-12-18 | ||
| EP14199020 | 2014-12-18 | ||
| EP15158516.3 | 2015-03-10 | ||
| EP15158516 | 2015-03-10 | ||
| PCT/GB2015/054081 WO2016097761A1 (en) | 2014-12-18 | 2015-12-18 | 4,5-dihydro-6h-thieno[3,2-d]benzazepine derivatives and their use to treat respiratory syncytial virus (rsv) infections |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| JP2017537949A JP2017537949A (ja) | 2017-12-21 |
| JP2017537949A5 JP2017537949A5 (OSRAM) | 2019-02-07 |
| JP6694886B2 true JP6694886B2 (ja) | 2020-05-20 |
Family
ID=55066661
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2017531829A Active JP6694886B2 (ja) | 2014-12-18 | 2015-12-18 | ４，５−ジヒドロ−６Ｈ−チエノ［３，２−ｄ］ベンゾアゼピン誘導体及び呼吸器合胞体ウイルス（ＲＳＶ）感染を治療するためのその使用 |
Country Status (4)
| Country | Link |
|---|---|
| US (1) | US10160772B2 (OSRAM) |
| EP (1) | EP3233867B1 (OSRAM) |
| JP (1) | JP6694886B2 (OSRAM) |
| WO (1) | WO2016097761A1 (OSRAM) |
Families Citing this family (23)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108200760B (zh) | 2015-07-22 | 2022-04-01 | 英安塔制药有限公司 | 作为rsv抑制剂的苯并二氮杂䓬衍生物 |
| EP3402799B1 (en) | 2016-01-15 | 2022-05-04 | Enanta Pharmaceuticals, Inc. | Heterocyclic compounds as rsv inhibitors |
| WO2018129287A1 (en) | 2017-01-06 | 2018-07-12 | Enanta Pharmaceuticals, Inc. | Heteroaryldiazepine derivatives as rsv inhibitors |
| US10450263B2 (en) | 2017-02-10 | 2019-10-22 | Southern Research Institute | Benzo annulenes as antiviral agents |
| EP3582784B1 (en) | 2017-02-16 | 2022-06-08 | Enanta Pharmaceuticals, Inc. | Processes for the preparation of benzodiazepine derivatives |
| US10752598B2 (en) | 2017-06-07 | 2020-08-25 | Enanta Pharmaceuticals, Inc. | Aryldiazepine derivatives as RSV inhibitors |
| WO2019006295A1 (en) * | 2017-06-30 | 2019-01-03 | Enanta Pharmaceuticals, Inc. | HETEROCYCLIC COMPOUNDS AS RSV INHIBITORS |
| WO2019006291A1 (en) * | 2017-06-30 | 2019-01-03 | Enanta Pharmaceuticals, Inc. | HETEROCYCLIC COMPOUNDS AS RSV INHIBITORS |
| AU2018339068B2 (en) | 2017-09-29 | 2022-12-15 | Enanta Pharmaceuticals, Inc. | Combination pharmaceutical agents as RSV inhibitors |
| US10647711B2 (en) | 2017-11-13 | 2020-05-12 | Enanta Pharmaceuticals, Inc. | Azepin-2-one derivatives as RSV inhibitors |
| MX394621B (es) | 2017-11-13 | 2025-03-24 | Enanta Pharm Inc | Procesos para la resolucion de los derivados de la benzodiazepina-2-ona y de la benzoazepin-2-ona |
| US11066357B2 (en) | 2017-12-26 | 2021-07-20 | Southern Research Institute | Benzoannulene derivatives as antiviral agents |
| WO2019199908A1 (en) | 2018-04-11 | 2019-10-17 | Enanta Pharmaceuticals, Inc. | Heterocyclic compounds as rsv inhibitors |
| PH12021552201A1 (en) | 2019-03-18 | 2022-05-30 | Enanta Pharm Inc | Benzodiazepine derivatives as rsv inhibitors |
| US11179400B2 (en) | 2019-04-09 | 2021-11-23 | Enanta Pharmaceuticals, Inc. | Heterocyclic compounds as RSV inhibitors |
| MX2022003984A (es) | 2019-10-04 | 2022-07-27 | Enanta Pharm Inc | Compuestos heterociclicos antivirales. |
| US11505558B1 (en) | 2019-10-04 | 2022-11-22 | Enanta Pharmaceuticals, Inc. | Antiviral heterocyclic compounds |
| UY39032A (es) | 2020-01-24 | 2021-07-30 | Enanta Pharm Inc | Compuestos heterocíclicos como agentes antivirales |
| US11534439B2 (en) | 2020-07-07 | 2022-12-27 | Enanta Pharmaceuticals, Inc. | Dihydroquinoxaline and dihydropyridopyrazine derivatives as RSV inhibitors |
| US11945824B2 (en) | 2020-10-19 | 2024-04-02 | Enanta Pharmaceuticals, Inc. | Heterocyclic compounds as anti-viral agents |
| US11945830B2 (en) | 2021-02-26 | 2024-04-02 | Enanta Pharmaceuticals, Inc. | Antiviral heterocyclic compounds |
| AR129003A1 (es) | 2022-04-07 | 2024-07-03 | Enanta Pharm Inc | Compuestos heterocíclicos antivirales |
| US12162857B2 (en) | 2022-04-27 | 2024-12-10 | Enanta Pharmaceuticals, Inc. | Antiviral compounds |
Family Cites Families (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5693635A (en) | 1993-07-29 | 1997-12-02 | American Cyanamid Company | Tricyclic benzazepine vasopressin antagonists |
| EE200100558A (et) | 1999-04-28 | 2002-12-16 | Aventis Pharma Deutschland Gmbh | Triarüülhappe derivaat, seda sisaldav farmatseutiline kompositsioon ja ühendi raviotstarbeline kasutamine |
| WO2011005842A1 (en) | 2009-07-09 | 2011-01-13 | Gilead Sciences, Inc. | Anti-rsv compounds |
| WO2011046954A1 (en) | 2009-10-13 | 2011-04-21 | Ligand Pharmaceuticals Inc. | Hematopoietic growth factor mimetic small molecule compounds and their uses |
| PT2598483T (pt) | 2010-07-29 | 2020-10-12 | Rigel Pharmaceuticals Inc | Compostos heterocíclicos de ativação de ampk e métodos de utilização dos mesmos |
| US9464065B2 (en) | 2011-03-24 | 2016-10-11 | The Scripps Research Institute | Compounds and methods for inducing chondrogenesis |
| WO2016022464A1 (en) | 2014-08-05 | 2016-02-11 | Alios Biopharma, Inc. | Combination therapy for treating a paramyxovirus |
| EP3204389B1 (en) | 2014-10-10 | 2019-06-26 | Pulmocide Limited | Novel 5,6-dihydro-4h-benzo[b]thieno-[2,3-d]azepine derivative |
| HUE048905T2 (hu) | 2014-12-05 | 2020-08-28 | Pulmocide Ltd | Antimikotikus vegyület |
| EP3402799B1 (en) | 2016-01-15 | 2022-05-04 | Enanta Pharmaceuticals, Inc. | Heterocyclic compounds as rsv inhibitors |
| MY197217A (en) | 2016-02-03 | 2023-06-01 | Janssen Sciences Ireland Uc | Combination products for the treatment of rsv |
-
2015
- 2015-12-18 JP JP2017531829A patent/JP6694886B2/ja active Active
- 2015-12-18 WO PCT/GB2015/054081 patent/WO2016097761A1/en not_active Ceased
- 2015-12-18 US US15/524,472 patent/US10160772B2/en active Active
- 2015-12-18 EP EP15818022.4A patent/EP3233867B1/en active Active
Also Published As
| Publication number | Publication date |
|---|---|
| JP2017537949A (ja) | 2017-12-21 |
| US20170355718A1 (en) | 2017-12-14 |
| WO2016097761A1 (en) | 2016-06-23 |
| US10160772B2 (en) | 2018-12-25 |
| EP3233867A1 (en) | 2017-10-25 |
| EP3233867B1 (en) | 2018-10-17 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP6694886B2 (ja) | ４，５−ジヒドロ−６Ｈ−チエノ［３，２−ｄ］ベンゾアゼピン誘導体及び呼吸器合胞体ウイルス（ＲＳＶ）感染を治療するためのその使用 | |
| US10626126B2 (en) | Compounds | |
| JP2017531039A (ja) | 新規５，６−ジヒドロ−４Ｈ−ベンゾ［ｂ］チエノ−［２，３−ｄ］アゼピン誘導体 | |
| CN104144921B (zh) | 药物化合物 | |
| CN110229140B (zh) | 戊二酰亚胺衍生物、其用途、基于所述衍生物的药物组合物及戊二酰亚胺衍生物的制备方法 | |
| CN104245695A (zh) | 用于治疗病毒性感染的哌啶基-嘧啶衍生物 | |
| CN101243055A (zh) | 二氢嘧啶酮多聚体及其作为人中性粒细胞弹性蛋白酶抑制剂的用途 | |
| KR20170039275A (ko) | 인플루엔자 바이러스 감염에 사용하기 위한 인돌 | |
| JP2018087210A (ja) | 脾臓チロシンキナーゼｉ（ｓｙｋ）阻害剤としての２−（２−アミノシクロヘキシル）アミノピリミジン−５−カルボキサミド類 | |
| KR20160128416A (ko) | 아미드 화합물, 그의 제조방법, 및 rna 함유 및/또는 dna 함유 바이러스에 의해 유발된 질환, 및 동반 질환의 예방 및 치료제로서의 용도 | |
| TW201609733A (zh) | 新穎化合物 | |
| CN115698011B (zh) | Pb2抑制剂及其制备方法和用途 | |
| CN111148734B (zh) | 吡咯-2-甲酰胺类化合物及其制备方法和用途 | |
| WO2020135195A1 (zh) | 氨基吡啶类化合物及其制备方法和用途 | |
| JP6071012B2 (ja) | ４−アミノ−３−フェニルアミノ−６−フェニルピラゾロ［３，４−ｄ］ピリミジン誘導体、その製造および抗ウイルス剤としての使用 | |
| CN116253740A (zh) | 环状双苄基异喹啉类化合物及其制备方法和应用 | |
| RU2773333C2 (ru) | ЗАМЕЩЕННЫЕ ИМИДАЗО[1,2-b]ПИРИДАЗИНЫ, ЗАМЕЩЕННЫЕ ИМИДАЗО[1,5-b]ПИРИДАЗИНЫ, РОДСТВЕННЫЕ СОЕДИНЕНИЯ И ИХ ПРИМЕНЕНИЕ ДЛЯ ЛЕЧЕНИЯ ПАТОЛОГИЧЕСКИХ СОСТОЯНИЙ | |
| CN119698277A (zh) | 作为治疗剂的cGAS活性抑制剂 | |
| WO2025050636A1 (zh) | 大环吡唑并嘧啶类化合物及其用途 | |
| EA047132B1 (ru) | Антивирусные гетероциклические соединения | |
| HK1120790A (en) | Dihydropyrimidone multimers and their use as human neutrophil elastase inhibitors | |
| HK1228899B (zh) | 戊二酰亚胺衍生物、其用途、基於所述衍生物的药物组合物及戊二酰亚胺衍生物的制备方法 | |
| HK1212985B (zh) | 化合物 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20181212 |
|
| A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20181212 |
|
| A977 | Report on retrieval |
Free format text: JAPANESE INTERMEDIATE CODE: A971007 Effective date: 20190912 |
|
| A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20190924 |
|
| A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20191204 |
|
| TRDD | Decision of grant or rejection written | ||
| A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20200324 |
|
| A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20200420 |
|
| R150 | Certificate of patent or registration of utility model |
Ref document number: 6694886 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |