TW201625601A - 噻吩－２－基－吡啶－２－基－１ｈ－吡唑－４－羧酸衍生物及其作為可溶性鳥苷酸環化酶活化劑之用途 - Google Patents
噻吩－２－基－吡啶－２－基－１ｈ－吡唑－４－羧酸衍生物及其作為可溶性鳥苷酸環化酶活化劑之用途 Download PDFInfo
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- TW201625601A TW201625601A TW104121397A TW104121397A TW201625601A TW 201625601 A TW201625601 A TW 201625601A TW 104121397 A TW104121397 A TW 104121397A TW 104121397 A TW104121397 A TW 104121397A TW 201625601 A TW201625601 A TW 201625601A
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- Prior art keywords
- methyl
- alkyl
- trifluoromethyl
- pyrazole
- pyridin
- Prior art date
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- 102000007637 Soluble Guanylyl Cyclase Human genes 0.000 title description 41
- 108010007205 Soluble Guanylyl Cyclase Proteins 0.000 title description 41
- ADKNNQOWOFNISC-UHFFFAOYSA-N 1-pyridin-2-yl-3-thiophen-2-ylpyrazole-4-carboxylic acid Chemical class OC(=O)C1=CN(C=2N=CC=CC=2)N=C1C1=CC=CS1 ADKNNQOWOFNISC-UHFFFAOYSA-N 0.000 title 1
- 239000003119 guanylate cyclase activator Substances 0.000 title 1
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- 238000000034 method Methods 0.000 claims abstract description 86
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- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 20
- -1 C 1 -C 4 alkyl Chemical group 0.000 claims description 125
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 83
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- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 21
- 239000003795 chemical substances by application Substances 0.000 claims description 21
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 20
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- 229910052757 nitrogen Inorganic materials 0.000 claims description 15
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- 238000002347 injection Methods 0.000 claims description 12
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- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 11
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- 125000005843 halogen group Chemical group 0.000 claims description 10
- UUEVFMOUBSLVJW-UHFFFAOYSA-N oxo-[[1-[2-[2-[2-[4-(oxoazaniumylmethylidene)pyridin-1-yl]ethoxy]ethoxy]ethyl]pyridin-4-ylidene]methyl]azanium;dibromide Chemical compound [Br-].[Br-].C1=CC(=C[NH+]=O)C=CN1CCOCCOCCN1C=CC(=C[NH+]=O)C=C1 UUEVFMOUBSLVJW-UHFFFAOYSA-N 0.000 claims description 9
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 8
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- 125000001072 heteroaryl group Chemical group 0.000 claims description 7
- 125000005842 heteroatom Chemical group 0.000 claims description 7
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- 229910052717 sulfur Inorganic materials 0.000 claims description 7
- 125000004429 atom Chemical group 0.000 claims description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 6
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- 125000003277 amino group Chemical group 0.000 claims description 3
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- IEHKWSGCTWLXFU-IIBYNOLFSA-N tadalafil Chemical compound C1=C2OCOC2=CC([C@@H]2C3=C([C]4C=CC=CC4=N3)C[C@H]3N2C(=O)CN(C3=O)C)=C1 IEHKWSGCTWLXFU-IIBYNOLFSA-N 0.000 claims description 2
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- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 26
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- XJJPICIFAYFZPY-UHFFFAOYSA-N ethyl 1-[6-[3-[[3-(hydroxymethyl)-4-piperidin-4-ylphenoxy]methyl]-5-methylthiophen-2-yl]pyridin-2-yl]-5-(trifluoromethyl)pyrazole-4-carboxylate Chemical compound OCC=1C=C(OCC2=C(SC(=C2)C)C2=CC=CC(=N2)N2N=CC(=C2C(F)(F)F)C(=O)OCC)C=CC=1C1CCNCC1 XJJPICIFAYFZPY-UHFFFAOYSA-N 0.000 description 1
- JZKVITFYVMPLNN-UHFFFAOYSA-N ethyl 1-[6-[3-[[4-[1-(cyclopropanecarbonyl)piperidin-4-yl]-2-methylphenoxy]methyl]-4-cyclopropyl-5-methylthiophen-2-yl]pyridin-2-yl]-5-(trifluoromethyl)pyrazole-4-carboxylate Chemical compound C1(CC1)C(=O)N1CCC(CC1)C1=CC(=C(OCC2=C(SC(=C2C2CC2)C)C2=CC=CC(=N2)N2N=CC(=C2C(F)(F)F)C(=O)OCC)C=C1)C JZKVITFYVMPLNN-UHFFFAOYSA-N 0.000 description 1
- QAHJGTYAYAKLPT-UHFFFAOYSA-N ethyl 1-[6-[3-[[4-[1-(cyclopropanecarbonyl)piperidin-4-yl]-2-methylphenoxy]methyl]thiophen-2-yl]pyridin-2-yl]-5-methylpyrazole-4-carboxylate Chemical compound C1(CC1)C(=O)N1CCC(CC1)C1=CC(=C(OCC2=C(SC=C2)C2=CC=CC(=N2)N2N=CC(=C2C)C(=O)OCC)C=C1)C QAHJGTYAYAKLPT-UHFFFAOYSA-N 0.000 description 1
- ZUWIPAITRPREJH-UHFFFAOYSA-N ethyl 1-[6-[3-[[4-bromo-3-(hydroxymethyl)phenoxy]methyl]-5-methylthiophen-2-yl]pyridin-2-yl]-5-(trifluoromethyl)pyrazole-4-carboxylate Chemical compound BrC1=C(C=C(OCC2=C(SC(=C2)C)C2=CC=CC(=N2)N2N=CC(=C2C(F)(F)F)C(=O)OCC)C=C1)CO ZUWIPAITRPREJH-UHFFFAOYSA-N 0.000 description 1
- NLOTXIZVZLUUHH-UHFFFAOYSA-N ethyl 1-[6-[4-bromo-3-(hydroxymethyl)-5-methylthiophen-2-yl]pyridin-2-yl]-5-(trifluoromethyl)pyrazole-4-carboxylate Chemical compound BrC=1C(=C(SC=1C)C1=CC=CC(=N1)N1N=CC(=C1C(F)(F)F)C(=O)OCC)CO NLOTXIZVZLUUHH-UHFFFAOYSA-N 0.000 description 1
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- MODOGKRTFTXVLG-UHFFFAOYSA-N tert-butyl 4-(2-ethyl-6-methoxypyridin-3-yl)piperidine-1-carboxylate Chemical compound C(C)C1=NC(=CC=C1C1CCN(CC1)C(=O)OC(C)(C)C)OC MODOGKRTFTXVLG-UHFFFAOYSA-N 0.000 description 1
- VMMMLUNNLMPOLP-UHFFFAOYSA-N tert-butyl 4-(2-ethyl-6-oxo-1H-pyridin-3-yl)piperidine-1-carboxylate Chemical compound C(C)C1=NC(=CC=C1C1CCN(CC1)C(=O)OC(C)(C)C)O VMMMLUNNLMPOLP-UHFFFAOYSA-N 0.000 description 1
- NOLPZKMKZPRBEZ-UHFFFAOYSA-N tert-butyl 4-(3-chloro-4-hydroxyphenyl)piperidine-1-carboxylate Chemical compound ClC=1C=C(C=CC=1O)C1CCN(CC1)C(=O)OC(C)(C)C NOLPZKMKZPRBEZ-UHFFFAOYSA-N 0.000 description 1
- DYIXRLOWAQEDDL-UHFFFAOYSA-N tert-butyl 4-(3-ethyl-5-hydroxypyridin-2-yl)piperidine-1-carboxylate Chemical compound C(C)C=1C(=NC=C(C=1)O)C1CCN(CC1)C(=O)OC(C)(C)C DYIXRLOWAQEDDL-UHFFFAOYSA-N 0.000 description 1
- ZPNGPEXRHHJAHO-UHFFFAOYSA-N tert-butyl 4-(3-methyl-4-phenylmethoxyphenyl)piperidine-1-carboxylate Chemical compound C(C1=CC=CC=C1)OC1=C(C=C(C=C1)C1CCN(CC1)C(=O)OC(C)(C)C)C ZPNGPEXRHHJAHO-UHFFFAOYSA-N 0.000 description 1
- GNLMUOBRTDOQID-UHFFFAOYSA-N tert-butyl 4-(4-amino-2-ethylphenyl)piperidine-1-carboxylate Chemical compound NC1=CC(=C(C=C1)C1CCN(CC1)C(=O)OC(C)(C)C)CC GNLMUOBRTDOQID-UHFFFAOYSA-N 0.000 description 1
- CZGMDLYFBULKGX-UHFFFAOYSA-N tert-butyl 4-(4-hydroxy-2-propylphenyl)piperidine-1-carboxylate Chemical compound OC1=CC(=C(C=C1)C1CCN(CC1)C(=O)OC(C)(C)C)CCC CZGMDLYFBULKGX-UHFFFAOYSA-N 0.000 description 1
- VZOZXNXOGIEGKU-UHFFFAOYSA-N tert-butyl 4-(4-methoxy-2-propan-2-ylphenyl)piperidine-1-carboxylate Chemical compound C(C)(C)C1=C(C=CC(=C1)OC)C1CCN(CC1)C(=O)OC(C)(C)C VZOZXNXOGIEGKU-UHFFFAOYSA-N 0.000 description 1
- XKQQXMJVWLOPDH-UHFFFAOYSA-N tert-butyl 4-[4-[(2-bromothiophen-3-yl)methoxy]phenyl]piperidine-1-carboxylate Chemical compound BrC=1SC=CC=1COC1=CC=C(C=C1)C1CCN(CC1)C(=O)OC(C)(C)C XKQQXMJVWLOPDH-UHFFFAOYSA-N 0.000 description 1
- QELOANLIBNLHHH-UHFFFAOYSA-N tert-butyl 4-[4-[[2-bromo-4-(trifluoromethyl)thiophen-3-yl]methoxy]phenyl]piperidine-1-carboxylate Chemical compound BrC=1SC=C(C=1COC1=CC=C(C=C1)C1CCN(CC1)C(=O)OC(C)(C)C)C(F)(F)F QELOANLIBNLHHH-UHFFFAOYSA-N 0.000 description 1
- VBGLHBOXTRXGBZ-UHFFFAOYSA-N tert-butyl 6-[(2-bromothiophen-3-yl)methoxy]-3,4-dihydro-1H-isoquinoline-2-carboxylate Chemical compound BrC=1SC=CC=1COC=1C=C2CCN(CC2=CC=1)C(=O)OC(C)(C)C VBGLHBOXTRXGBZ-UHFFFAOYSA-N 0.000 description 1
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 1
- 231100001274 therapeutic index Toxicity 0.000 description 1
- VNVAUIHQJKDHBN-UHFFFAOYSA-N thiophene;hydrobromide Chemical compound Br.C=1C=CSC=1 VNVAUIHQJKDHBN-UHFFFAOYSA-N 0.000 description 1
- 229940098465 tincture Drugs 0.000 description 1
- 150000003613 toluenes Chemical class 0.000 description 1
- 238000003325 tomography Methods 0.000 description 1
- 239000012929 tonicity agent Substances 0.000 description 1
- 239000012443 tonicity enhancing agent Substances 0.000 description 1
- 239000012049 topical pharmaceutical composition Substances 0.000 description 1
- 210000001585 trabecular meshwork Anatomy 0.000 description 1
- 230000037317 transdermal delivery Effects 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- MKPLKVHSHYCHOC-AHTXBMBWSA-N travoprost Chemical compound CC(C)OC(=O)CCC\C=C/C[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1\C=C\[C@@H](O)COC1=CC=CC(C(F)(F)F)=C1 MKPLKVHSHYCHOC-AHTXBMBWSA-N 0.000 description 1
- 229960002368 travoprost Drugs 0.000 description 1
- PBIMIGNDTBRRPI-UHFFFAOYSA-N trifluoro borate Chemical compound FOB(OF)OF PBIMIGNDTBRRPI-UHFFFAOYSA-N 0.000 description 1
- CMSYDJVRTHCWFP-UHFFFAOYSA-N triphenylphosphane;hydrobromide Chemical compound Br.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 CMSYDJVRTHCWFP-UHFFFAOYSA-N 0.000 description 1
- WUUHFRRPHJEEKV-UHFFFAOYSA-N tripotassium borate Chemical compound [K+].[K+].[K+].[O-]B([O-])[O-] WUUHFRRPHJEEKV-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 229960000438 udenafil Drugs 0.000 description 1
- IYFNEFQTYQPVOC-UHFFFAOYSA-N udenafil Chemical compound C1=C(C=2NC=3C(CCC)=NN(C)C=3C(=O)N=2)C(OCCC)=CC=C1S(=O)(=O)NCCC1CCCN1C IYFNEFQTYQPVOC-UHFFFAOYSA-N 0.000 description 1
- 210000003606 umbilical vein Anatomy 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000010455 vermiculite Substances 0.000 description 1
- 229910052902 vermiculite Inorganic materials 0.000 description 1
- 235000019354 vermiculite Nutrition 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- 230000004393 visual impairment Effects 0.000 description 1
- 239000007762 w/o emulsion Substances 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 229920003169 water-soluble polymer Polymers 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 229950000339 xinafoate Drugs 0.000 description 1
- UHVMMEOXYDMDKI-JKYCWFKZSA-L zinc;1-(5-cyanopyridin-2-yl)-3-[(1s,2s)-2-(6-fluoro-2-hydroxy-3-propanoylphenyl)cyclopropyl]urea;diacetate Chemical compound [Zn+2].CC([O-])=O.CC([O-])=O.CCC(=O)C1=CC=C(F)C([C@H]2[C@H](C2)NC(=O)NC=2N=CC(=CC=2)C#N)=C1O UHVMMEOXYDMDKI-JKYCWFKZSA-L 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
-
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4535—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom, e.g. pizotifen
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- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/472—Non-condensed isoquinolines, e.g. papaverine
- A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
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- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0048—Eye, e.g. artificial tears
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Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Organic Chemistry (AREA)
- Epidemiology (AREA)
- Ophthalmology & Optometry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
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| US10364256B2 (en) | 2015-10-06 | 2019-07-30 | Glaxosmithkline Intellectual Property Development Limited | Biaryl pyrazoles as NRF2 regulators |
| EP3371167A1 (en) | 2015-10-06 | 2018-09-12 | GlaxoSmithKline Intellectual Property Development Limited | Arylcyclohexyl pyrazoles as nrf2 regulators |
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| WO2017201683A1 (en) | 2016-05-25 | 2017-11-30 | Merck Sharp & Dohme Corp. | Substituted tetrahydroisoquinoline compounds useful as gpr120 agonists |
| JPWO2018016611A1 (ja) | 2016-07-22 | 2019-05-09 | トーアエイヨー株式会社 | 緑内障治療薬 |
| CN109890379A (zh) | 2016-10-11 | 2019-06-14 | 拜耳制药股份公司 | 包含sGC活化剂和盐皮质激素受体拮抗剂的组合产品 |
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| CN102056907B (zh) | 2008-04-04 | 2014-12-31 | 武田药品工业株式会社 | 杂环衍生物及其用途 |
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| MX2013006053A (es) | 2010-12-07 | 2013-06-18 | Bayer Ip Gmbh | Acidos 1-bencilcicloalquilcarboxilicos sustituidos y su uso. |
| WO2012122340A1 (en) | 2011-03-10 | 2012-09-13 | Boehringer Ingelheim International Gmbh | Soluble guanylate cyclase activators |
| DE102011007272A1 (de) | 2011-04-13 | 2012-10-18 | Bayer Pharma Aktiengesellschaft | Verzweigte 3-Phenylpropionsäure-Derivate und ihre Verwendung |
| US8815857B2 (en) | 2011-08-12 | 2014-08-26 | Boehringer Ingelheim International Gmbh | Soluble guanylate cyclase activators |
| JP5565645B1 (ja) | 2012-10-09 | 2014-08-06 | Ｄｉｃ株式会社 | バンプクッション |
| US10265314B2 (en) | 2013-07-25 | 2019-04-23 | Bayer Pharma Aktiengesellschaft | SGC stimulators in combination with additional treatment for the therapy of cystic fibrosis |
| US20160214956A1 (en) | 2013-09-05 | 2016-07-28 | Glaxosmithkline Intellectual Property Development Limited | Novel soluble guanylate cyclase activators and their use |
-
2015
- 2015-07-01 TW TW104121397A patent/TW201625601A/zh unknown
- 2015-07-02 US US15/320,813 patent/US9765067B2/en not_active Expired - Fee Related
- 2015-07-02 JP JP2016574921A patent/JP2017519025A/ja not_active Withdrawn
- 2015-07-02 CN CN201580036308.4A patent/CN106470989A/zh not_active Withdrawn
- 2015-07-02 WO PCT/IB2015/055007 patent/WO2016001876A1/en not_active Ceased
- 2015-07-02 EP EP15742104.1A patent/EP3164399A1/en not_active Withdrawn
Also Published As
| Publication number | Publication date |
|---|---|
| EP3164399A1 (en) | 2017-05-10 |
| WO2016001876A1 (en) | 2016-01-07 |
| US20170197950A1 (en) | 2017-07-13 |
| US9765067B2 (en) | 2017-09-19 |
| JP2017519025A (ja) | 2017-07-13 |
| CN106470989A (zh) | 2017-03-01 |
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