AU2010232750B2 - Substituted azoanthracene derivatives, pharmaceutical compositions, and methods of use thereof - Google Patents

Info

Publication number

AU2010232750B2

AU2010232750B2 AU2010232750A AU2010232750A AU2010232750B2 AU 2010232750 B2 AU2010232750 B2 AU 2010232750B2 AU 2010232750 A AU2010232750 A AU 2010232750A AU 2010232750 A AU2010232750 A AU 2010232750A AU 2010232750 B2 AU2010232750 B2 AU 2010232750B2

Authority

AU

Australia

Prior art keywords

phenyl

carbonyl

dimethyl

compound

isoquinoline

Prior art date

2009-03-30

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

• Espacenet
• Global Dossier
• Discuss

• 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 28
• 238000000034 method Methods 0.000 title claims description 128
• 150000001875 compounds Chemical class 0.000 claims abstract description 426
• 239000000203 mixture Substances 0.000 claims abstract description 170
• 150000003839 salts Chemical class 0.000 claims abstract description 40
• 101001015516 Homo sapiens Glucagon-like peptide 1 receptor Proteins 0.000 claims abstract description 8
• 230000009286 beneficial effect Effects 0.000 claims abstract description 8
• 201000000083 maturity-onset diabetes of the young type 1 Diseases 0.000 claims abstract description 7
• -1 hexahydro- [1,4]dioxino [2,3 -g]isoquinoline-8-carbonyl Chemical group 0.000 claims description 506
• XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Substances CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 84
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 15
• 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 8
• 208000002705 Glucose Intolerance Diseases 0.000 claims description 6
• 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 claims description 5
• 230000004913 activation Effects 0.000 claims description 5
• 239000003085 diluting agent Substances 0.000 claims description 5
• 239000008103 glucose Substances 0.000 claims description 5
• 239000004480 active ingredient Substances 0.000 claims description 4
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
• 201000009104 prediabetes syndrome Diseases 0.000 claims description 4
• 208000032928 Dyslipidaemia Diseases 0.000 claims description 3
• 108010086246 Glucagon-Like Peptide-1 Receptor Proteins 0.000 claims description 3
• 102000007446 Glucagon-Like Peptide-1 Receptor Human genes 0.000 claims description 3
• 206010022489 Insulin Resistance Diseases 0.000 claims description 3
• 208000017170 Lipid metabolism disease Diseases 0.000 claims description 3
• 206010012601 diabetes mellitus Diseases 0.000 claims description 3
• 239000003937 drug carrier Substances 0.000 claims description 3
• 201000001421 hyperglycemia Diseases 0.000 claims description 3
• 208000030159 metabolic disease Diseases 0.000 claims description 3
• 208000001072 type 2 diabetes mellitus Diseases 0.000 claims description 3
• 206010003210 Arteriosclerosis Diseases 0.000 claims description 2
• 201000001320 Atherosclerosis Diseases 0.000 claims description 2
• 210000002237 B-cell of pancreatic islet Anatomy 0.000 claims description 2
• 206010070901 Diabetic dyslipidaemia Diseases 0.000 claims description 2
• 102000051325 Glucagon Human genes 0.000 claims description 2
• 108060003199 Glucagon Proteins 0.000 claims description 2
• 206010018429 Glucose tolerance impaired Diseases 0.000 claims description 2
• 208000031226 Hyperlipidaemia Diseases 0.000 claims description 2
• 206010020772 Hypertension Diseases 0.000 claims description 2
• 208000001145 Metabolic Syndrome Diseases 0.000 claims description 2
• 208000008589 Obesity Diseases 0.000 claims description 2
• 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 claims description 2
• 208000011775 arteriosclerosis disease Diseases 0.000 claims description 2
• 239000008280 blood Substances 0.000 claims description 2
• 210000004369 blood Anatomy 0.000 claims description 2
• 230000001419 dependent effect Effects 0.000 claims description 2
• MASNOZXLGMXCHN-ZLPAWPGGSA-N glucagon Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)C(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C1=CC=CC=C1 MASNOZXLGMXCHN-ZLPAWPGGSA-N 0.000 claims description 2
• 229960004666 glucagon Drugs 0.000 claims description 2
• 208000006575 hypertriglyceridemia Diseases 0.000 claims description 2
• 230000001771 impaired effect Effects 0.000 claims description 2
• 230000003914 insulin secretion Effects 0.000 claims description 2
• 235000020824 obesity Nutrition 0.000 claims description 2
• 208000011580 syndromic disease Diseases 0.000 claims description 2
• 230000029663 wound healing Effects 0.000 claims description 2
• AXNLGNFVQUEODU-UHFFFAOYSA-N 2-[4-(2,3-dimethylpyridin-4-yl)phenyl]propanoic acid Chemical compound CC1=NC=CC(=C1C)C1=CC=C(C=C1)C(C(=O)O)C AXNLGNFVQUEODU-UHFFFAOYSA-N 0.000 claims 10
• YIKYLHBXYYFCEZ-WWKIHPBISA-N (2s)-2-[[(3s,8s)-3-[4-[(3,4-dichlorophenyl)methoxy]phenyl]-7-[(1s)-1-phenylpropyl]-3,6,8,9-tetrahydro-2h-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]amino]-3-(4-pyridin-4-ylphenyl)propanoic acid Chemical compound C([C@H](NC(=O)[C@@H]1CC2=CC=3OC[C@@H](OC=3C=C2CN1[C@@H](CC)C=1C=CC=CC=1)C=1C=CC(OCC=2C=C(Cl)C(Cl)=CC=2)=CC=1)C(O)=O)C(C=C1)=CC=C1C1=CC=NC=C1 YIKYLHBXYYFCEZ-WWKIHPBISA-N 0.000 claims 3
• DEDPYBWOUXWMOX-ZTAAISNPSA-N (2s)-2-[[(3s,8s)-3-[4-[(3,4-dichlorophenyl)methoxy]phenyl]-7-[(1s)-1-phenylpropyl]-3,6,8,9-tetrahydro-2h-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]amino]-3-[4-(2,3-dimethylpyridin-4-yl)phenyl]propanoic acid Chemical compound C([C@H](NC(=O)[C@@H]1CC2=CC=3OC[C@@H](OC=3C=C2CN1[C@@H](CC)C=1C=CC=CC=1)C=1C=CC(OCC=2C=C(Cl)C(Cl)=CC=2)=CC=1)C(O)=O)C(C=C1)=CC=C1C1=CC=NC(C)=C1C DEDPYBWOUXWMOX-ZTAAISNPSA-N 0.000 claims 1
• 208000007342 Diabetic Nephropathies Diseases 0.000 claims 1
• 208000032131 Diabetic Neuropathies Diseases 0.000 claims 1
• 206010012689 Diabetic retinopathy Diseases 0.000 claims 1
• 208000030814 Eating disease Diseases 0.000 claims 1
• 208000019454 Feeding and Eating disease Diseases 0.000 claims 1
• 208000033679 diabetic kidney disease Diseases 0.000 claims 1
• 235000014632 disordered eating Nutrition 0.000 claims 1
• 230000030136 gastric emptying Effects 0.000 claims 1
• XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin Chemical group CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 claims 1
• 229960003105 metformin Drugs 0.000 claims 1
• 230000028327 secretion Effects 0.000 claims 1
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 33
• 201000010099 disease Diseases 0.000 abstract description 17
• 208000035475 disorder Diseases 0.000 abstract description 16
• XEKOWRVHYACXOJ-UHFFFAOYSA-N ethyl acetate Substances CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 419
• 125000001424 substituent group Chemical group 0.000 description 264
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 237
• 235000019439 ethyl acetate Nutrition 0.000 description 174
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical group CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 170
• OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Natural products OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 137
• 239000000243 solution Substances 0.000 description 137
• 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 114
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 112
• 238000006243 chemical reaction Methods 0.000 description 103
• 239000011541 reaction mixture Substances 0.000 description 92
• 239000000047 product Substances 0.000 description 89
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 88
• 125000000217 alkyl group Chemical group 0.000 description 86
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 85
• 239000012267 brine Substances 0.000 description 85
• 239000011734 sodium Substances 0.000 description 79
• 239000012044 organic layer Substances 0.000 description 78
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 75
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 74
• 125000000753 cycloalkyl group Chemical group 0.000 description 72
• IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 70
• 125000001072 heteroaryl group Chemical group 0.000 description 69
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 68
• 125000000623 heterocyclic group Chemical group 0.000 description 68
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 65
• 238000003818 flash chromatography Methods 0.000 description 63
• XMIIGOLPHOKFCH-UHFFFAOYSA-N 3-phenylpropionic acid Chemical compound OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 description 62
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 62
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 61
• 239000000741 silica gel Substances 0.000 description 55
• 229910002027 silica gel Inorganic materials 0.000 description 55
• 229960001866 silicon dioxide Drugs 0.000 description 55
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 54
• 229910052757 nitrogen Inorganic materials 0.000 description 53
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 52
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 51
• 238000005481 NMR spectroscopy Methods 0.000 description 49
• 229910052736 halogen Inorganic materials 0.000 description 49
• 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 48
• 229940095574 propionic acid Drugs 0.000 description 47
• 230000002829 reductive effect Effects 0.000 description 47
• 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 47
• 229910052739 hydrogen Inorganic materials 0.000 description 44
• 239000007787 solid Substances 0.000 description 44
• 239000002904 solvent Substances 0.000 description 43
• 150000002367 halogens Chemical class 0.000 description 42
• 239000001257 hydrogen Substances 0.000 description 42
• 125000003118 aryl group Chemical group 0.000 description 40
• 238000003756 stirring Methods 0.000 description 40
• 125000004093 cyano group Chemical group *C#N 0.000 description 39
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 38
• 229910052938 sodium sulfate Inorganic materials 0.000 description 38
• 235000011152 sodium sulphate Nutrition 0.000 description 38
• 239000010410 layer Substances 0.000 description 37
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 36
• 238000002360 preparation method Methods 0.000 description 36
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 32
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 32
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 31
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 30
• DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 30
• 238000006467 substitution reaction Methods 0.000 description 29
• RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 28
• 229920000728 polyester Polymers 0.000 description 27
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 25
• 125000000304 alkynyl group Chemical group 0.000 description 25
• 235000019260 propionic acid Nutrition 0.000 description 25
• 125000004496 thiazol-5-yl group Chemical group S1C=NC=C1* 0.000 description 24
• 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 23
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 23
• 125000004432 carbon atom Chemical group C* 0.000 description 23
• GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 22
• 238000001035 drying Methods 0.000 description 22
• 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 description 22
• WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 21
• 125000002947 alkylene group Chemical group 0.000 description 21
• 150000001412 amines Chemical class 0.000 description 21
• 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 21
• 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 21
• 125000004571 thiomorpholin-4-yl group Chemical group N1(CCSCC1)* 0.000 description 21
• 239000000284 extract Substances 0.000 description 19
• 239000003921 oil Substances 0.000 description 19
• 235000019198 oils Nutrition 0.000 description 19
• 238000000746 purification Methods 0.000 description 19
• 101150041968 CDC13 gene Proteins 0.000 description 18
• HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 18
• 125000003342 alkenyl group Chemical group 0.000 description 18
• 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 18
• 229920006395 saturated elastomer Polymers 0.000 description 18
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 17
• KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 17
• 229930040373 Paraformaldehyde Natural products 0.000 description 17
• 229920002866 paraformaldehyde Polymers 0.000 description 17
• DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 17
• 238000004440 column chromatography Methods 0.000 description 16
• WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 15
• DTHNMHAUYICORS-KTKZVXAJSA-N Glucagon-like peptide 1 Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1N=CNC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 DTHNMHAUYICORS-KTKZVXAJSA-N 0.000 description 15
• 101800000224 Glucagon-like peptide 1 Proteins 0.000 description 15
• 102100040918 Pro-glucagon Human genes 0.000 description 15
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
• 125000004429 atom Chemical group 0.000 description 14
• 239000000706 filtrate Substances 0.000 description 14
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 14
• 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 13
• 125000005842 heteroatom Chemical group 0.000 description 13
• 125000002971 oxazolyl group Chemical group 0.000 description 13
• 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 description 13
• 238000010898 silica gel chromatography Methods 0.000 description 13
• DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 12
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
• 125000004350 aryl cycloalkyl group Chemical group 0.000 description 12
• KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 12
• 125000004940 pyridazin-4-yl group Chemical group N1=NC=C(C=C1)* 0.000 description 12
• 238000010992 reflux Methods 0.000 description 12
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 11
• 125000004419 alkynylene group Chemical group 0.000 description 11
• 229910052799 carbon Inorganic materials 0.000 description 11
• 125000004367 cycloalkylaryl group Chemical group 0.000 description 11
• 125000005215 cycloalkylheteroaryl group Chemical group 0.000 description 11
• IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 11
• 229910052708 sodium Inorganic materials 0.000 description 11
• 229910052717 sulfur Chemical group 0.000 description 11
• LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 10
• 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 10
• 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 10
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
• SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 10
• CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 10
• CSCPPACGZOOCGX-WFGJKAKNSA-N acetone d6 Chemical compound [2H]C([2H])([2H])C(=O)C([2H])([2H])[2H] CSCPPACGZOOCGX-WFGJKAKNSA-N 0.000 description 10
• 239000002253 acid Substances 0.000 description 10
• 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 10
• 125000004433 nitrogen atom Chemical group N* 0.000 description 10
• 125000003386 piperidinyl group Chemical group 0.000 description 10
• CWERGRDVMFNCDR-UHFFFAOYSA-N thioglycolic acid Chemical compound OC(=O)CS CWERGRDVMFNCDR-UHFFFAOYSA-N 0.000 description 10
• 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 9
• CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
• NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 9
• 125000004450 alkenylene group Chemical group 0.000 description 9
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 9
• 239000012043 crude product Substances 0.000 description 9
• 238000001914 filtration Methods 0.000 description 9
• 239000000543 intermediate Substances 0.000 description 9
• 125000004498 isoxazol-4-yl group Chemical group O1N=CC(=C1)* 0.000 description 9
• BPJQKEYAFMJRCT-PPHPATTJSA-N methyl (3s)-7-hydroxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylate;hydrochloride Chemical compound Cl.C1=C(O)C=C2CN[C@H](C(=O)OC)CC2=C1 BPJQKEYAFMJRCT-PPHPATTJSA-N 0.000 description 9
• VVWRJUBEIPHGQF-MDZDMXLPSA-N propan-2-yl (ne)-n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)\N=N\C(=O)OC(C)C VVWRJUBEIPHGQF-MDZDMXLPSA-N 0.000 description 9
• 125000004307 pyrazin-2-yl group Chemical group [H]C1=C([H])N=C(*)C([H])=N1 0.000 description 9
• 125000002206 pyridazin-3-yl group Chemical group [H]C1=C([H])C([H])=C(*)N=N1 0.000 description 9
• 125000004528 pyrimidin-5-yl group Chemical group N1=CN=CC(=C1)* 0.000 description 9
• 239000000377 silicon dioxide Substances 0.000 description 9
• 239000011593 sulfur Chemical group 0.000 description 9
• XRKPZHXBFXMAAN-LBPRGKRZSA-N 2-o-tert-butyl 3-o-methyl (3s)-6-amino-7-hydroxy-3,4-dihydro-1h-isoquinoline-2,3-dicarboxylate Chemical compound NC1=C(O)C=C2CN(C(=O)OC(C)(C)C)[C@H](C(=O)OC)CC2=C1 XRKPZHXBFXMAAN-LBPRGKRZSA-N 0.000 description 8
• FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 8
• 150000001408 amides Chemical class 0.000 description 8
• 239000012298 atmosphere Substances 0.000 description 8
• 230000015572 biosynthetic process Effects 0.000 description 8
• 125000004122 cyclic group Chemical group 0.000 description 8
• 125000002993 cycloalkylene group Chemical group 0.000 description 8
• CPHKMDBOUKBUGH-BCLYVYGJSA-N methyl (2s)-3-[4-(4-cyanophenyl)phenyl]-2-[[(3s)-3-[4-[(3,4-dichlorophenyl)methoxy]phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]amino]propanoate;hydrochloride Chemical compound Cl.C([C@@H](C(=O)OC)NC(=O)C1NCC2=CC=3O[C@H](COC=3C=C2C1)C=1C=CC(OCC=2C=C(Cl)C(Cl)=CC=2)=CC=1)C(C=C1)=CC=C1C1=CC=C(C#N)C=C1 CPHKMDBOUKBUGH-BCLYVYGJSA-N 0.000 description 8
• 125000004430 oxygen atom Chemical group O* 0.000 description 8
• WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 7
• 125000001397 3-pyrrolyl group Chemical group [H]N1C([H])=C([*])C([H])=C1[H] 0.000 description 7
• VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 7
• FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical group C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 7
• 125000005218 alkyleneheteroaryl group Chemical group 0.000 description 7
• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 7
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 7
• 125000004435 hydrogen atom Chemical group [H]* 0.000 description 7
• NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 7
• 125000002883 imidazolyl group Chemical group 0.000 description 7
• 125000001793 isothiazol-3-yl group Chemical group [H]C1=C([H])C(*)=NS1 0.000 description 7
• 125000000842 isoxazolyl group Chemical group 0.000 description 7
• TVGLTBPQUIEFBT-SQKCAUCHSA-N methyl (2s)-2-amino-3-[4-(2,3-dimethylpyridin-4-yl)phenyl]propanoate;dihydrochloride Chemical compound Cl.Cl.C1=CC(C[C@H](N)C(=O)OC)=CC=C1C1=CC=NC(C)=C1C TVGLTBPQUIEFBT-SQKCAUCHSA-N 0.000 description 7
• 229910052760 oxygen Inorganic materials 0.000 description 7
• 239000001301 oxygen Chemical group 0.000 description 7
• 229910000027 potassium carbonate Inorganic materials 0.000 description 7
• UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 7
• 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 description 7
• 125000000719 pyrrolidinyl group Chemical group 0.000 description 7
• 239000010948 rhodium Substances 0.000 description 7
• 229910000030 sodium bicarbonate Inorganic materials 0.000 description 7
• 235000017557 sodium bicarbonate Nutrition 0.000 description 7
• 125000004495 thiazol-4-yl group Chemical group S1C=NC(=C1)* 0.000 description 7
• GFUZTXDPFFUWSH-LFHRXCRSSA-N (3s)-3-[4-[(3,4-dichlorophenyl)methoxy]phenyl]-7-[(2-methylpropan-2-yl)oxycarbonyl]-3,6,8,9-tetrahydro-2h-[1,4]dioxino[2,3-g]isoquinoline-8-carboxylic acid Chemical compound C1=CC([C@@H]2OC=3C=C4CN(C(CC4=CC=3OC2)C(O)=O)C(=O)OC(C)(C)C)=CC=C1OCC1=CC=C(Cl)C(Cl)=C1 GFUZTXDPFFUWSH-LFHRXCRSSA-N 0.000 description 6
• POZQZZZRGZLOGP-UHFFFAOYSA-N 2-[4-[(3,4-dichlorophenyl)methoxy]phenyl]-2-oxoacetaldehyde Chemical compound C1=C(Cl)C(Cl)=CC=C1COC1=CC=C(C(=O)C=O)C=C1 POZQZZZRGZLOGP-UHFFFAOYSA-N 0.000 description 6
• PUDPGVZTTKAMBN-LBPRGKRZSA-N 2-o-tert-butyl 3-o-methyl (3s)-7-hydroxy-6-nitro-3,4-dihydro-1h-isoquinoline-2,3-dicarboxylate Chemical compound [O-][N+](=O)C1=C(O)C=C2CN(C(=O)OC(C)(C)C)[C@H](C(=O)OC)CC2=C1 PUDPGVZTTKAMBN-LBPRGKRZSA-N 0.000 description 6
• ZMCZFLLAEWLKJP-SVNIRARHSA-N 7-o-tert-butyl 8-o-methyl (3s)-3-[4-[(3,4-dichlorophenyl)methoxy]phenyl]-1,2,3,6,8,9-hexahydropyrido[4,3-g][1,4]benzoxazine-7,8-dicarboxylate Chemical compound C1=CC([C@H]2CNC=3C=C4CC(N(CC4=CC=3O2)C(=O)OC(C)(C)C)C(=O)OC)=CC=C1OCC1=CC=C(Cl)C(Cl)=C1 ZMCZFLLAEWLKJP-SVNIRARHSA-N 0.000 description 6
• XPCPSCNPPWMOKH-MPSNESSQSA-N 7-o-tert-butyl 8-o-methyl (3s)-3-[4-[(3,4-dichlorophenyl)methoxy]phenyl]-3,6,8,9-tetrahydro-2h-[1,4]dioxino[2,3-g]isoquinoline-7,8-dicarboxylate Chemical compound C1=CC([C@H]2COC=3C=C4CC(N(CC4=CC=3O2)C(=O)OC(C)(C)C)C(=O)OC)=CC=C1OCC1=CC=C(Cl)C(Cl)=C1 XPCPSCNPPWMOKH-MPSNESSQSA-N 0.000 description 6
• XPCPSCNPPWMOKH-LBNVMWSVSA-N 7-o-tert-butyl 8-o-methyl (3s,8s)-3-[4-[(3,4-dichlorophenyl)methoxy]phenyl]-3,6,8,9-tetrahydro-2h-[1,4]dioxino[2,3-g]isoquinoline-7,8-dicarboxylate Chemical compound C1=CC([C@H]2COC=3C=C4C[C@H](N(CC4=CC=3O2)C(=O)OC(C)(C)C)C(=O)OC)=CC=C1OCC1=CC=C(Cl)C(Cl)=C1 XPCPSCNPPWMOKH-LBNVMWSVSA-N 0.000 description 6
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
• XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 6
• 229960000583 acetic acid Drugs 0.000 description 6
• 230000029936 alkylation Effects 0.000 description 6
• 238000005804 alkylation reaction Methods 0.000 description 6
• 239000000460 chlorine Substances 0.000 description 6
• 150000002148 esters Chemical class 0.000 description 6
• 125000001153 fluoro group Chemical group F* 0.000 description 6
• 239000007789 gas Substances 0.000 description 6
• 150000002431 hydrogen Chemical group 0.000 description 6
• SEXYDEKFJLXIME-INIZCTEOSA-N methyl (2s)-2-amino-3-[4-(4-cyanophenyl)phenyl]propanoate Chemical compound C1=CC(C[C@H](N)C(=O)OC)=CC=C1C1=CC=C(C#N)C=C1 SEXYDEKFJLXIME-INIZCTEOSA-N 0.000 description 6
• 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 6
• 229910000104 sodium hydride Inorganic materials 0.000 description 6
• LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 6
• 239000000126 substance Substances 0.000 description 6
• 239000000725 suspension Substances 0.000 description 6
• 238000004809 thin layer chromatography Methods 0.000 description 6
• ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 6
• DYUQAZSOFZSPHD-SECBINFHSA-N (1r)-1-phenylpropan-1-ol Chemical compound CC[C@@H](O)C1=CC=CC=C1 DYUQAZSOFZSPHD-SECBINFHSA-N 0.000 description 5
• GFUZTXDPFFUWSH-RPLLCQBOSA-N (3s,8s)-3-[4-[(3,4-dichlorophenyl)methoxy]phenyl]-7-[(2-methylpropan-2-yl)oxycarbonyl]-3,6,8,9-tetrahydro-2h-[1,4]dioxino[2,3-g]isoquinoline-8-carboxylic acid Chemical compound C1=CC([C@@H]2OC=3C=C4CN([C@@H](CC4=CC=3OC2)C(O)=O)C(=O)OC(C)(C)C)=CC=C1OCC1=CC=C(Cl)C(Cl)=C1 GFUZTXDPFFUWSH-RPLLCQBOSA-N 0.000 description 5
• QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical class N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 5
• JXRGUPLJCCDGKG-UHFFFAOYSA-N 4-nitrobenzenesulfonyl chloride Chemical compound [O-][N+](=O)C1=CC=C(S(Cl)(=O)=O)C=C1 JXRGUPLJCCDGKG-UHFFFAOYSA-N 0.000 description 5
• XPCPSCNPPWMOKH-LSYYVWMOSA-N 7-o-tert-butyl 8-o-methyl (3r,8s)-3-[4-[(3,4-dichlorophenyl)methoxy]phenyl]-3,6,8,9-tetrahydro-2h-[1,4]dioxino[2,3-g]isoquinoline-7,8-dicarboxylate Chemical compound C1=CC([C@@H]2COC=3C=C4C[C@H](N(CC4=CC=3O2)C(=O)OC(C)(C)C)C(=O)OC)=CC=C1OCC1=CC=C(Cl)C(Cl)=C1 XPCPSCNPPWMOKH-LSYYVWMOSA-N 0.000 description 5
• 102000003688 G-Protein-Coupled Receptors Human genes 0.000 description 5
• 108090000045 G-Protein-Coupled Receptors Proteins 0.000 description 5
• 101100030361 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) pph-3 gene Proteins 0.000 description 5
• 125000005605 benzo group Chemical group 0.000 description 5
• 235000013877 carbamide Nutrition 0.000 description 5
• 239000003054 catalyst Substances 0.000 description 5
• 239000003153 chemical reaction reagent Substances 0.000 description 5
• 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 5
• 238000005984 hydrogenation reaction Methods 0.000 description 5
• 125000000336 imidazol-5-yl group Chemical group [H]N1C([H])=NC([H])=C1[*] 0.000 description 5
• QUFUUBBLCOBJPH-UHFFFAOYSA-N isoquinoline-7-carboxylic acid Chemical compound C1=CN=CC2=CC(C(=O)O)=CC=C21 QUFUUBBLCOBJPH-UHFFFAOYSA-N 0.000 description 5
• 125000004499 isoxazol-5-yl group Chemical group O1N=CC=C1* 0.000 description 5
• QMEFGOLNZAYOMD-SFHVURJKSA-N methyl (2s)-3-[4-(2,3-dimethylpyridin-4-yl)oxyphenyl]-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoate Chemical compound C1=CC(C[C@@H](C(=O)OC)NC(=O)OC(C)(C)C)=CC=C1OC1=CC=NC(C)=C1C QMEFGOLNZAYOMD-SFHVURJKSA-N 0.000 description 5
• XBXCNNQPRYLIDE-UHFFFAOYSA-M n-tert-butylcarbamate Chemical compound CC(C)(C)NC([O-])=O XBXCNNQPRYLIDE-UHFFFAOYSA-M 0.000 description 5
• 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 5
• 125000003145 oxazol-4-yl group Chemical group O1C=NC(=C1)* 0.000 description 5
• 125000004304 oxazol-5-yl group Chemical group O1C=NC=C1* 0.000 description 5
• 229910052702 rhenium Inorganic materials 0.000 description 5
• 239000012321 sodium triacetoxyborohydride Substances 0.000 description 5
• 208000024891 symptom Diseases 0.000 description 5
• DIDZCKKBVLUIRL-RPLLCQBOSA-N (3s,8s)-3-[4-(cyclohexylmethoxy)phenyl]-7-[(2-methylpropan-2-yl)oxycarbonyl]-3,6,8,9-tetrahydro-2h-[1,4]dioxino[2,3-g]isoquinoline-8-carboxylic acid Chemical compound C1=CC([C@@H]2OC=3C=C4CN([C@@H](CC4=CC=3OC2)C(O)=O)C(=O)OC(C)(C)C)=CC=C1OCC1CCCCC1 DIDZCKKBVLUIRL-RPLLCQBOSA-N 0.000 description 4
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 4
• 125000001607 1,2,3-triazol-1-yl group Chemical group [*]N1N=NC([H])=C1[H] 0.000 description 4
• 125000003626 1,2,4-triazol-1-yl group Chemical group [*]N1N=C([H])N=C1[H] 0.000 description 4
• 125000001462 1-pyrrolyl group Chemical group [*]N1C([H])=C([H])C([H])=C1[H] 0.000 description 4
• NWVNEZVJBGTOPC-UHFFFAOYSA-N 2-bromo-1-[4-[(3,4-dichlorophenyl)methoxy]phenyl]ethanone Chemical compound C1=C(Cl)C(Cl)=CC=C1COC1=CC=C(C(=O)CBr)C=C1 NWVNEZVJBGTOPC-UHFFFAOYSA-N 0.000 description 4
• ICFJDFIWRVTOFU-NSHDSACASA-N 2-o-tert-butyl 3-o-methyl (3s)-6,7-dihydroxy-3,4-dihydro-1h-isoquinoline-2,3-dicarboxylate Chemical compound OC1=C(O)C=C2CN(C(=O)OC(C)(C)C)[C@H](C(=O)OC)CC2=C1 ICFJDFIWRVTOFU-NSHDSACASA-N 0.000 description 4
• JVVRCYWZTJLJSG-UHFFFAOYSA-N 4-dimethylaminophenol Chemical compound CN(C)C1=CC=C(O)C=C1 JVVRCYWZTJLJSG-UHFFFAOYSA-N 0.000 description 4
• 229960000549 4-dimethylaminophenol Drugs 0.000 description 4
• VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-dimethylaminopyridine Substances CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
• RNERNOZXQRPVHP-LDCRUHPQSA-N 7-o-tert-butyl 8-o-methyl (3s)-3-[4-[(3,4-dichlorophenyl)methoxy]phenyl]-3-hydroxy-2,6,8,9-tetrahydro-[1,4]dioxino[2,3-g]isoquinoline-7,8-dicarboxylate Chemical compound C1=CC([C@@]2(O)COC=3C=C4CC(N(CC4=CC=3O2)C(=O)OC(C)(C)C)C(=O)OC)=CC=C1OCC1=CC=C(Cl)C(Cl)=C1 RNERNOZXQRPVHP-LDCRUHPQSA-N 0.000 description 4
• CKDWPUIZGOQOOM-UHFFFAOYSA-N Carbamyl chloride Chemical compound NC(Cl)=O CKDWPUIZGOQOOM-UHFFFAOYSA-N 0.000 description 4
• 239000004215 Carbon black (E152) Substances 0.000 description 4
• BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 4
• 229910004373 HOAc Inorganic materials 0.000 description 4
• RJUFJBKOKNCXHH-UHFFFAOYSA-N Methyl propionate Chemical compound CCC(=O)OC RJUFJBKOKNCXHH-UHFFFAOYSA-N 0.000 description 4
• YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 4
• 150000001204 N-oxides Chemical class 0.000 description 4
• ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 4
• 238000006069 Suzuki reaction reaction Methods 0.000 description 4
• 229940024606 amino acid Drugs 0.000 description 4
• 150000004945 aromatic hydrocarbons Chemical group 0.000 description 4
• 125000000732 arylene group Chemical group 0.000 description 4
• 239000002585 base Substances 0.000 description 4
• WBKFWQBXFREOFH-UHFFFAOYSA-N dichloromethane;ethyl acetate Chemical compound ClCCl.CCOC(C)=O WBKFWQBXFREOFH-UHFFFAOYSA-N 0.000 description 4
• SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 4
• 239000003480 eluent Substances 0.000 description 4
• 239000012458 free base Substances 0.000 description 4
• 125000001188 haloalkyl group Chemical group 0.000 description 4
• 125000005549 heteroarylene group Chemical group 0.000 description 4
• 229930195733 hydrocarbon Natural products 0.000 description 4
• 125000002887 hydroxy group Chemical group [H]O* 0.000 description 4
• 125000002962 imidazol-1-yl group Chemical group [*]N1C([H])=NC([H])=C1[H] 0.000 description 4
• 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 description 4
• 239000012948 isocyanate Substances 0.000 description 4
• GRWIABMEEKERFV-UHFFFAOYSA-N methanol;oxolane Chemical compound OC.C1CCOC1 GRWIABMEEKERFV-UHFFFAOYSA-N 0.000 description 4
• JVKJKADJNQEXEA-QMMMGPOBSA-N methyl (3s)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylate Chemical compound OC1=C(O)C=C2CN[C@H](C(=O)OC)CC2=C1 JVKJKADJNQEXEA-QMMMGPOBSA-N 0.000 description 4
• 125000000843 phenylene group Chemical group C1(=C(C=CC=C1)*)* 0.000 description 4
• 239000000843 powder Substances 0.000 description 4
• 108090000765 processed proteins & peptides Proteins 0.000 description 4
• 125000004353 pyrazol-1-yl group Chemical group [H]C1=NN(*)C([H])=C1[H] 0.000 description 4
• 125000003226 pyrazolyl group Chemical group 0.000 description 4
• 125000004076 pyridyl group Chemical group 0.000 description 4
• 125000002112 pyrrolidino group Chemical group [*]N1C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 4
• 229910052703 rhodium Inorganic materials 0.000 description 4
• MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 4
• 229910000029 sodium carbonate Inorganic materials 0.000 description 4
• 238000003786 synthesis reaction Methods 0.000 description 4
• 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
• HJUGFYREWKUQJT-UHFFFAOYSA-N tetrabromomethane Chemical compound BrC(Br)(Br)Br HJUGFYREWKUQJT-UHFFFAOYSA-N 0.000 description 4
• FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 4
• 125000001425 triazolyl group Chemical group 0.000 description 4
• 239000003039 volatile agent Substances 0.000 description 4
• HWCDMDXESHLLKF-UHFFFAOYSA-N (2,3-dimethylpyridin-4-yl)boronic acid Chemical compound CC1=NC=CC(B(O)O)=C1C HWCDMDXESHLLKF-UHFFFAOYSA-N 0.000 description 3
• NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 3
• GVVCHDNSTMEUCS-MUGJNUQGSA-N (2s,5s)-1-[2-[(2s,5s)-2,5-diethylphospholan-1-yl]phenyl]-2,5-diethylphospholane Chemical compound CC[C@H]1CC[C@H](CC)P1C1=CC=CC=C1P1[C@@H](CC)CC[C@@H]1CC GVVCHDNSTMEUCS-MUGJNUQGSA-N 0.000 description 3
• GFUZTXDPFFUWSH-IGKIAQTJSA-N (3r,8s)-3-[4-[(3,4-dichlorophenyl)methoxy]phenyl]-7-[(2-methylpropan-2-yl)oxycarbonyl]-3,6,8,9-tetrahydro-2h-[1,4]dioxino[2,3-g]isoquinoline-8-carboxylic acid Chemical compound C1=CC([C@H]2OC=3C=C4CN([C@@H](CC4=CC=3OC2)C(O)=O)C(=O)OC(C)(C)C)=CC=C1OCC1=CC=C(Cl)C(Cl)=C1 GFUZTXDPFFUWSH-IGKIAQTJSA-N 0.000 description 3
• HIKCRLDSCSWXML-VIFPVBQESA-N (3s)-7-hydroxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid Chemical compound C1=C(O)C=C2CN[C@H](C(=O)O)CC2=C1 HIKCRLDSCSWXML-VIFPVBQESA-N 0.000 description 3
• QHSXSZKLFNISFX-RPLLCQBOSA-N (3s,8s)-3-[3-[(3,4-dichlorophenyl)methoxy]phenyl]-7-[(2-methylpropan-2-yl)oxycarbonyl]-3,6,8,9-tetrahydro-2h-[1,4]dioxino[2,3-g]isoquinoline-8-carboxylic acid Chemical compound C=1C([C@@H]2OC=3C=C4CN([C@@H](CC4=CC=3OC2)C(O)=O)C(=O)OC(C)(C)C)=CC=CC=1OCC1=CC=C(Cl)C(Cl)=C1 QHSXSZKLFNISFX-RPLLCQBOSA-N 0.000 description 3
• 125000001140 1,4-phenylene group Chemical group [H]C1=C([H])C([*:2])=C([H])C([H])=C1[*:1] 0.000 description 3
• ACIZMRQNCPNDGU-UHFFFAOYSA-N 1-[3-[(3,4-dichlorophenyl)methoxy]phenyl]ethanone Chemical compound CC(=O)C1=CC=CC(OCC=2C=C(Cl)C(Cl)=CC=2)=C1 ACIZMRQNCPNDGU-UHFFFAOYSA-N 0.000 description 3
• 238000005160 1H NMR spectroscopy Methods 0.000 description 3
• ICSNLGPSRYBMBD-UHFFFAOYSA-N 2-aminopyridine Chemical compound NC1=CC=CC=N1 ICSNLGPSRYBMBD-UHFFFAOYSA-N 0.000 description 3
• UHGVFJDJGIXSCZ-NSHDSACASA-N 2-o-tert-butyl 3-o-methyl (3s)-7-hydroxy-8-nitro-3,4-dihydro-1h-isoquinoline-2,3-dicarboxylate Chemical class C1=C(O)C([N+]([O-])=O)=C2CN(C(=O)OC(C)(C)C)[C@H](C(=O)OC)CC2=C1 UHGVFJDJGIXSCZ-NSHDSACASA-N 0.000 description 3
• BJDIYRQSJLBFLX-UHFFFAOYSA-N 3-[2-[4-[(3,4-dichlorophenyl)methoxy]phenyl]-2-oxoethoxy]-4-fluorobenzonitrile Chemical compound FC1=CC=C(C#N)C=C1OCC(=O)C(C=C1)=CC=C1OCC1=CC=C(Cl)C(Cl)=C1 BJDIYRQSJLBFLX-UHFFFAOYSA-N 0.000 description 3
• PHCLIPMSNVUELH-UHFFFAOYSA-N 4-bromo-2,3-dimethylpyridine Chemical compound CC1=NC=CC(Br)=C1C PHCLIPMSNVUELH-UHFFFAOYSA-N 0.000 description 3
• GHSRMSJVYMITDX-UHFFFAOYSA-N 6-chloro-2-methyl-3-nitropyridine Chemical compound CC1=NC(Cl)=CC=C1[N+]([O-])=O GHSRMSJVYMITDX-UHFFFAOYSA-N 0.000 description 3
• 102100035861 Cytosolic 5'-nucleotidase 1A Human genes 0.000 description 3
• XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 3
• 206010061818 Disease progression Diseases 0.000 description 3
• 101000802744 Homo sapiens Cytosolic 5'-nucleotidase 1A Proteins 0.000 description 3
• WTDRDQBEARUVNC-LURJTMIESA-N L-DOPA Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-LURJTMIESA-N 0.000 description 3
• BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 3
• RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
• KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 3
• YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical group C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 3
• 125000005275 alkylenearyl group Chemical group 0.000 description 3
• SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 3
• KHYAFFAGZNCWPT-UHFFFAOYSA-N boron;n,n-diethylaniline Chemical compound [B].CCN(CC)C1=CC=CC=C1 KHYAFFAGZNCWPT-UHFFFAOYSA-N 0.000 description 3
• 239000004202 carbamide Substances 0.000 description 3
• 230000003197 catalytic effect Effects 0.000 description 3
• 230000005750 disease progression Effects 0.000 description 3
• 230000032050 esterification Effects 0.000 description 3
• 238000005886 esterification reaction Methods 0.000 description 3
• 125000005677 ethinylene group Chemical group [*:2]C#C[*:1] 0.000 description 3
• MHYCRLGKOZWVEF-UHFFFAOYSA-N ethyl acetate;hydrate Chemical compound O.CCOC(C)=O MHYCRLGKOZWVEF-UHFFFAOYSA-N 0.000 description 3
• 238000000605 extraction Methods 0.000 description 3
• 229910052731 fluorine Inorganic materials 0.000 description 3
• 125000002541 furyl group Chemical group 0.000 description 3
• 239000003877 glucagon like peptide 1 receptor agonist Substances 0.000 description 3
• 238000010438 heat treatment Methods 0.000 description 3
• 125000005349 heteroarylcycloalkyl group Chemical group 0.000 description 3
• IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 3
• 230000007062 hydrolysis Effects 0.000 description 3
• 238000006460 hydrolysis reaction Methods 0.000 description 3
• 125000002140 imidazol-4-yl group Chemical group [H]N1C([H])=NC([*])=C1[H] 0.000 description 3
• RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
• 125000002632 imidazolidinyl group Chemical group 0.000 description 3
• 125000004129 indan-1-yl group Chemical group [H]C1=C([H])C([H])=C2C(=C1[H])C([H])([H])C([H])([H])C2([H])* 0.000 description 3
• 150000002513 isocyanates Chemical class 0.000 description 3
• 125000004500 isothiazol-4-yl group Chemical group S1N=CC(=C1)* 0.000 description 3
• 125000004501 isothiazol-5-yl group Chemical group S1N=CC=C1* 0.000 description 3
• 125000004284 isoxazol-3-yl group Chemical group [H]C1=C([H])C(*)=NO1 0.000 description 3
• 239000000463 material Substances 0.000 description 3
• OGZJASWLLYAZIA-INIZCTEOSA-N methyl (2s)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propanoate Chemical compound C1=CC(C[C@@H](C(=O)OC)NC(=O)OC(C)(C)C)=CC=C1B1OC(C)(C)C(C)(C)O1 OGZJASWLLYAZIA-INIZCTEOSA-N 0.000 description 3
• GTPSYWNNEXIAGW-YLJLHNITSA-N methyl (2s)-2-[[(3s,8s)-3-[4-[(3,4-dichlorophenyl)methoxy]phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]amino]-3-[4-(2,3-dimethylpyridin-4-yl)phenyl]propanoate Chemical compound C([C@@H](C(=O)OC)NC(=O)[C@H]1NCC2=CC=3O[C@H](COC=3C=C2C1)C=1C=CC(OCC=2C=C(Cl)C(Cl)=CC=2)=CC=1)C(C=C1)=CC=C1C1=CC=NC(C)=C1C GTPSYWNNEXIAGW-YLJLHNITSA-N 0.000 description 3
• AEYXEFACMZSBHG-TUYUPMGOSA-N methyl (2s)-2-amino-3-[(2r)-2-[4-[(3,4-dichlorophenyl)methoxy]phenyl]-2,3-dihydro-1,4-benzodioxin-6-yl]propanoate;hydrochloride Chemical compound Cl.C1=CC([C@H]2OC3=CC=C(C=C3OC2)C[C@H](N)C(=O)OC)=CC=C1OCC1=CC=C(Cl)C(Cl)=C1 AEYXEFACMZSBHG-TUYUPMGOSA-N 0.000 description 3
• CBZDDKMGJLYWRG-HNNXBMFYSA-N methyl (2s)-2-amino-3-[4-(2,3-dimethylpyridin-4-yl)oxyphenyl]propanoate Chemical compound C1=CC(C[C@H](N)C(=O)OC)=CC=C1OC1=CC=NC(C)=C1C CBZDDKMGJLYWRG-HNNXBMFYSA-N 0.000 description 3
• IVDOIYGHPJPXFO-NTISSMGPSA-N methyl (2s)-2-amino-3-[4-(4-cyanophenyl)phenyl]propanoate;hydrochloride Chemical compound Cl.C1=CC(C[C@H](N)C(=O)OC)=CC=C1C1=CC=C(C#N)C=C1 IVDOIYGHPJPXFO-NTISSMGPSA-N 0.000 description 3
• FDFQRJWLHKSHPZ-LBPRGKRZSA-N methyl (2s)-3-(4-bromophenyl)-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoate Chemical compound CC(C)(C)OC(=O)N[C@H](C(=O)OC)CC1=CC=C(Br)C=C1 FDFQRJWLHKSHPZ-LBPRGKRZSA-N 0.000 description 3
• UWOYWBGELCFGKB-FXAWDEMLSA-N methyl (2s)-3-[(2s)-2-(4-hydroxyphenyl)-2,3-dihydro-1,4-benzodioxin-6-yl]-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoate Chemical compound C1([C@@H]2OC3=CC=C(C=C3OC2)C[C@@H](C(=O)OC)NC(=O)OC(C)(C)C)=CC=C(O)C=C1 UWOYWBGELCFGKB-FXAWDEMLSA-N 0.000 description 3
• YFMVNOXRBLBCRF-ODTVBPJYSA-N methyl (3s,8s)-3-[3-[(3,4-dichlorophenyl)methoxy]phenyl]-7-[(1s)-1-phenylpropyl]-3,6,8,9-tetrahydro-2h-[1,4]dioxino[2,3-g]isoquinoline-8-carboxylate Chemical compound C=1C([C@@H]2OC=3C=C4CN([C@@H](CC4=CC=3OC2)C(=O)OC)[C@@H](CC)C=2C=CC=CC=2)=CC=CC=1OCC1=CC=C(Cl)C(Cl)=C1 YFMVNOXRBLBCRF-ODTVBPJYSA-N 0.000 description 3
• LJHAPRKTPAREGO-UHFFFAOYSA-N methyl 2-dimethoxyphosphoryl-2-[(2-methylpropan-2-yl)oxycarbonylamino]acetate Chemical compound COC(=O)C(P(=O)(OC)OC)NC(=O)OC(C)(C)C LJHAPRKTPAREGO-UHFFFAOYSA-N 0.000 description 3
• 150000004702 methyl esters Chemical class 0.000 description 3
• 239000002480 mineral oil Substances 0.000 description 3
• 235000010446 mineral oil Nutrition 0.000 description 3
• APOWIBWCHFFTST-UHFFFAOYSA-N n-(6-methyl-5-nitropyridin-2-yl)acetamide Chemical compound CC(=O)NC1=CC=C([N+]([O-])=O)C(C)=N1 APOWIBWCHFFTST-UHFFFAOYSA-N 0.000 description 3
• 150000002828 nitro derivatives Chemical class 0.000 description 3
• QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 3
• 125000004287 oxazol-2-yl group Chemical group [H]C1=C([H])N=C(*)O1 0.000 description 3
• NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
• 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 3
• 125000003373 pyrazinyl group Chemical group 0.000 description 3
• 125000000714 pyrimidinyl group Chemical group 0.000 description 3
• 102000005962 receptors Human genes 0.000 description 3
• 108020003175 receptors Proteins 0.000 description 3
• 150000003335 secondary amines Chemical class 0.000 description 3
• 239000012312 sodium hydride Substances 0.000 description 3
• 235000010288 sodium nitrite Nutrition 0.000 description 3
• 239000012265 solid product Substances 0.000 description 3
• 239000007858 starting material Substances 0.000 description 3
• YZPVIRDQSFKCJS-IWJNXRQDSA-N tert-butyl (3s,8s)-3-[4-[(3,4-dichlorophenyl)methoxy]phenyl]-8-[[(2s)-3-[4-(2,3-dimethylpyridin-4-yl)phenyl]-1-methoxy-1-oxopropan-2-yl]carbamoyl]-3,6,8,9-tetrahydro-2h-[1,4]dioxino[2,3-g]isoquinoline-7-carboxylate Chemical compound C([C@@H](C(=O)OC)NC(=O)[C@H]1N(CC2=CC=3O[C@H](COC=3C=C2C1)C=1C=CC(OCC=2C=C(Cl)C(Cl)=CC=2)=CC=1)C(=O)OC(C)(C)C)C(C=C1)=CC=C1C1=CC=NC(C)=C1C YZPVIRDQSFKCJS-IWJNXRQDSA-N 0.000 description 3
• 125000004523 tetrazol-1-yl group Chemical group N1(N=NN=C1)* 0.000 description 3
• 125000000335 thiazolyl group Chemical group 0.000 description 3
• RRKODOZNUZCUBN-CCAGOZQPSA-N (1z,3z)-cycloocta-1,3-diene Chemical compound C1CC\C=C/C=C\C1 RRKODOZNUZCUBN-CCAGOZQPSA-N 0.000 description 2
• BUDRXDXIUACVTR-QFIPXVFZSA-N (2r)-2-[4-[(3,4-dichlorophenyl)methoxy]phenyl]-2,3-dihydro-1,4-benzodioxine-6-carbaldehyde Chemical compound C1=C(Cl)C(Cl)=CC=C1COC1=CC=C([C@H]2OC3=CC=C(C=O)C=C3OC2)C=C1 BUDRXDXIUACVTR-QFIPXVFZSA-N 0.000 description 2
• CMUGKDLRHYPCSS-QFIPXVFZSA-N (2r)-2-[4-[(3,4-dichlorophenyl)methoxy]phenyl]-2,3-dihydro-1,4-benzodioxine-6-carbonitrile Chemical compound C1=C(Cl)C(Cl)=CC=C1COC1=CC=C([C@H]2OC3=CC=C(C=C3OC2)C#N)C=C1 CMUGKDLRHYPCSS-QFIPXVFZSA-N 0.000 description 2
• YDECNSWOIFUDLC-JOCHJYFZSA-N (2s)-2-[3-[(3,4-dichlorophenyl)methoxy]phenyl]-2,3-dihydro-1,4-benzodioxine-6-carbaldehyde Chemical compound C1=C(Cl)C(Cl)=CC=C1COC1=CC=CC([C@@H]2OC3=CC=C(C=O)C=C3OC2)=C1 YDECNSWOIFUDLC-JOCHJYFZSA-N 0.000 description 2
• BUDRXDXIUACVTR-JOCHJYFZSA-N (2s)-2-[4-[(3,4-dichlorophenyl)methoxy]phenyl]-2,3-dihydro-1,4-benzodioxine-6-carbaldehyde Chemical compound C1=C(Cl)C(Cl)=CC=C1COC1=CC=C([C@@H]2OC3=CC=C(C=O)C=C3OC2)C=C1 BUDRXDXIUACVTR-JOCHJYFZSA-N 0.000 description 2
• CMUGKDLRHYPCSS-JOCHJYFZSA-N (2s)-2-[4-[(3,4-dichlorophenyl)methoxy]phenyl]-2,3-dihydro-1,4-benzodioxine-6-carbonitrile Chemical compound C1=C(Cl)C(Cl)=CC=C1COC1=CC=C([C@@H]2OC3=CC=C(C=C3OC2)C#N)C=C1 CMUGKDLRHYPCSS-JOCHJYFZSA-N 0.000 description 2
• UIPNPFUNPXYKGP-UHFFFAOYSA-N (3S)-6,7-Dihydroxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid Natural products OC1=C(O)C=C2CNC(C(=O)O)CC2=C1 UIPNPFUNPXYKGP-UHFFFAOYSA-N 0.000 description 2
• SQRGFKDNKOISFZ-SVNIRARHSA-N (3s)-3-[4-[(3,4-dichlorophenyl)methoxy]phenyl]-1-methyl-7-[(2-methylpropan-2-yl)oxycarbonyl]-3,6,8,9-tetrahydro-2h-pyrido[4,3-g][1,4]benzoxazine-8-carboxylic acid Chemical compound C1=CC([C@H]2CN(C3=CC=4CC(N(CC=4C=C3O2)C(=O)OC(C)(C)C)C(O)=O)C)=CC=C1OCC1=CC=C(Cl)C(Cl)=C1 SQRGFKDNKOISFZ-SVNIRARHSA-N 0.000 description 2
• MWRGKGDEVBOTCJ-ZCJYOONXSA-N (3s)-3-[4-[(3,4-dichlorophenyl)methoxy]phenyl]-7-[(2-methylpropan-2-yl)oxycarbonyl]-1,2,3,6,8,9-hexahydropyrido[4,3-g][1,4]benzoxazine-8-carboxylic acid Chemical compound C1=CC([C@@H]2OC=3C=C4CN(C(CC4=CC=3NC2)C(O)=O)C(=O)OC(C)(C)C)=CC=C1OCC1=CC=C(Cl)C(Cl)=C1 MWRGKGDEVBOTCJ-ZCJYOONXSA-N 0.000 description 2
• UIPNPFUNPXYKGP-ZETCQYMHSA-N (3s)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid Chemical compound OC1=C(O)C=C2CN[C@H](C(=O)O)CC2=C1 UIPNPFUNPXYKGP-ZETCQYMHSA-N 0.000 description 2
• SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 2
• 125000001989 1,3-phenylene group Chemical group [H]C1=C([H])C([*:1])=C([H])C([*:2])=C1[H] 0.000 description 2
• RAIPHJJURHTUIC-UHFFFAOYSA-N 1,3-thiazol-2-amine Chemical class NC1=NC=CS1 RAIPHJJURHTUIC-UHFFFAOYSA-N 0.000 description 2
• VXNZUUAINFGPBY-UHFFFAOYSA-N 1-Butene Chemical group CCC=C VXNZUUAINFGPBY-UHFFFAOYSA-N 0.000 description 2
• VUWLYIRUBZGJJB-UHFFFAOYSA-N 1-[4-[(3,4-dichlorophenyl)methoxy]phenyl]ethane-1,2-diol Chemical compound C1=CC(C(O)CO)=CC=C1OCC1=CC=C(Cl)C(Cl)=C1 VUWLYIRUBZGJJB-UHFFFAOYSA-N 0.000 description 2
• GEKQPJHLFWEGPX-UHFFFAOYSA-N 1-[4-[(3,4-dichlorophenyl)methoxy]phenyl]ethanone Chemical compound C1=CC(C(=O)C)=CC=C1OCC1=CC=C(Cl)C(Cl)=C1 GEKQPJHLFWEGPX-UHFFFAOYSA-N 0.000 description 2
• IANQTJSKSUMEQM-UHFFFAOYSA-N 1-benzofuran Chemical group C1=CC=C2OC=CC2=C1 IANQTJSKSUMEQM-UHFFFAOYSA-N 0.000 description 2
• OTRZIEWHELCVJX-UHFFFAOYSA-N 1-methoxy-2-(2-methoxyethoxy)ethane;1-methylpyrrolidin-2-one Chemical compound CN1CCCC1=O.COCCOCCOC OTRZIEWHELCVJX-UHFFFAOYSA-N 0.000 description 2
• 125000004134 1-norbornyl group Chemical group [H]C1([H])C([H])([H])C2(*)C([H])([H])C([H])([H])C1([H])C2([H])[H] 0.000 description 2
• YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Chemical compound C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 description 2
• KFEWUCOFCOAYQZ-UHFFFAOYSA-N 2,5-dimethyl-1-oxidopyridin-1-ium Chemical compound CC1=CC=C(C)[N+]([O-])=C1 KFEWUCOFCOAYQZ-UHFFFAOYSA-N 0.000 description 2
• GVGSFHVUBRWBJT-UHFFFAOYSA-N 2,5-dimethyl-4-nitro-1-oxidopyridin-1-ium Chemical compound CC1=C[N+]([O-])=C(C)C=C1[N+]([O-])=O GVGSFHVUBRWBJT-UHFFFAOYSA-N 0.000 description 2
• XWKFPIODWVPXLX-UHFFFAOYSA-N 2,5-dimethylpyridine Chemical compound CC1=CC=C(C)N=C1 XWKFPIODWVPXLX-UHFFFAOYSA-N 0.000 description 2
• FUJSJWRORKKPAI-UHFFFAOYSA-N 2-(2,4-dichlorophenoxy)acetyl chloride Chemical compound ClC(=O)COC1=CC=C(Cl)C=C1Cl FUJSJWRORKKPAI-UHFFFAOYSA-N 0.000 description 2
• MTMONFVFAYLRSG-UHFFFAOYSA-N 2-(4-hydroxyphenyl)-2-oxoacetaldehyde Chemical compound OC1=CC=C(C(=O)C=O)C=C1 MTMONFVFAYLRSG-UHFFFAOYSA-N 0.000 description 2
• CYVWGLODALLLFP-UHFFFAOYSA-N 2-[tert-butyl(diphenyl)silyl]oxy-1-[4-[(3,4-dichlorophenyl)methoxy]phenyl]ethanol Chemical compound C=1C=CC=CC=1[Si](C=1C=CC=CC=1)(C(C)(C)C)OCC(O)C(C=C1)=CC=C1OCC1=CC=C(Cl)C(Cl)=C1 CYVWGLODALLLFP-UHFFFAOYSA-N 0.000 description 2
• YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-UHFFFAOYSA-N 0.000 description 2
• 125000004135 2-norbornyl group Chemical group [H]C1([H])C([H])([H])C2([H])C([H])([H])C1([H])C([H])([H])C2([H])* 0.000 description 2
• 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 2
• 125000004485 2-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])([H])C1([H])* 0.000 description 2
• WUQBOLHUTUTBDT-NRFANRHFSA-N 3-[(2r)-2-[4-[(3,4-dichlorophenyl)methoxy]phenyl]-2-hydroxyethoxy]-4-fluorobenzonitrile Chemical compound C([C@H](O)C=1C=CC(OCC=2C=C(Cl)C(Cl)=CC=2)=CC=1)OC1=CC(C#N)=CC=C1F WUQBOLHUTUTBDT-NRFANRHFSA-N 0.000 description 2
• WUQBOLHUTUTBDT-OAQYLSRUSA-N 3-[(2s)-2-[4-[(3,4-dichlorophenyl)methoxy]phenyl]-2-hydroxyethoxy]-4-fluorobenzonitrile Chemical compound C([C@@H](O)C=1C=CC(OCC=2C=C(Cl)C(Cl)=CC=2)=CC=1)OC1=CC(C#N)=CC=C1F WUQBOLHUTUTBDT-OAQYLSRUSA-N 0.000 description 2
• HJSZIXHADLYANW-UHFFFAOYSA-N 3-[2-[3-[(3,4-dichlorophenyl)methoxy]phenyl]-2-oxoethoxy]-4-fluorobenzonitrile Chemical compound FC1=CC=C(C#N)C=C1OCC(=O)C1=CC=CC(OCC=2C=C(Cl)C(Cl)=CC=2)=C1 HJSZIXHADLYANW-UHFFFAOYSA-N 0.000 description 2
• LUJMEECXHPYQOF-UHFFFAOYSA-N 3-hydroxyacetophenone Chemical compound CC(=O)C1=CC=CC(O)=C1 LUJMEECXHPYQOF-UHFFFAOYSA-N 0.000 description 2
• 125000004575 3-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
• RLJRYMHETNBKOK-UHFFFAOYSA-N 4-(2-acetamido-1,3-thiazol-4-yl)benzenesulfonyl chloride Chemical compound S1C(NC(=O)C)=NC(C=2C=CC(=CC=2)S(Cl)(=O)=O)=C1 RLJRYMHETNBKOK-UHFFFAOYSA-N 0.000 description 2
• XLWSBDFQAJXCQX-UHFFFAOYSA-N 4-(bromomethyl)-1,2-dichlorobenzene Chemical compound ClC1=CC=C(CBr)C=C1Cl XLWSBDFQAJXCQX-UHFFFAOYSA-N 0.000 description 2
• TVRGNBFSOZCSSE-UHFFFAOYSA-N 4-bromo-2-ethylpyridine Chemical compound CCC1=CC(Br)=CC=N1 TVRGNBFSOZCSSE-UHFFFAOYSA-N 0.000 description 2
• LKTBMKIXEOGAGF-UHFFFAOYSA-N 4-fluoro-3-hydroxybenzonitrile Chemical compound OC1=CC(C#N)=CC=C1F LKTBMKIXEOGAGF-UHFFFAOYSA-N 0.000 description 2
• LTPVSOCPYWDIFU-UHFFFAOYSA-N 4-methoxyphenylethylamine Chemical compound COC1=CC=C(CCN)C=C1 LTPVSOCPYWDIFU-UHFFFAOYSA-N 0.000 description 2
• KRNSYSYRLQDHDK-UHFFFAOYSA-N 6,7-dihydro-5h-cyclopenta[b]pyridine Chemical compound C1=CN=C2CCCC2=C1 KRNSYSYRLQDHDK-UHFFFAOYSA-N 0.000 description 2
• CQXPWEWHJLYDKT-UHFFFAOYSA-N 6-[acetyl(cyclobutylmethyl)amino]-2-methylpyridine-3-sulfonyl chloride Chemical compound C=1C=C(S(Cl)(=O)=O)C(C)=NC=1N(C(=O)C)CC1CCC1 CQXPWEWHJLYDKT-UHFFFAOYSA-N 0.000 description 2
• SXZAJJPHAKPDGL-ZBAATNBSSA-N 7-o-tert-butyl 8-o-methyl (3s)-3-[4-[(3,4-dichlorophenyl)methoxy]phenyl]-1-methyl-3,6,8,9-tetrahydro-2h-pyrido[4,3-g][1,4]benzoxazine-7,8-dicarboxylate Chemical compound C1=CC([C@H]2CN(C)C=3C=C4CC(N(CC4=CC=3O2)C(=O)OC(C)(C)C)C(=O)OC)=CC=C1OCC1=CC=C(Cl)C(Cl)=C1 SXZAJJPHAKPDGL-ZBAATNBSSA-N 0.000 description 2
• RJFHZSNVGYCRAT-LBNVMWSVSA-N 7-o-tert-butyl 8-o-methyl (3s,8s)-3-[3-[(3,4-dichlorophenyl)methoxy]phenyl]-3,6,8,9-tetrahydro-2h-[1,4]dioxino[2,3-g]isoquinoline-7,8-dicarboxylate Chemical compound C=1C([C@H]2COC=3C=C4C[C@H](N(CC4=CC=3O2)C(=O)OC(C)(C)C)C(=O)OC)=CC=CC=1OCC1=CC=C(Cl)C(Cl)=C1 RJFHZSNVGYCRAT-LBNVMWSVSA-N 0.000 description 2
• JHJWDFMAUTZNMI-VWLOTQADSA-N 7-o-tert-butyl 8-o-methyl (8s)-3-[4-[(3,4-dichlorophenyl)methoxy]phenyl]-8,9-dihydro-6h-[1,4]dioxino[2,3-g]isoquinoline-7,8-dicarboxylate Chemical compound C([C@H](N(CC1=CC=2O3)C(=O)OC(C)(C)C)C(=O)OC)C1=CC=2OC=C3C(C=C1)=CC=C1OCC1=CC=C(Cl)C(Cl)=C1 JHJWDFMAUTZNMI-VWLOTQADSA-N 0.000 description 2
• JRLTTZUODKEYDH-UHFFFAOYSA-N 8-methylquinoline Chemical group C1=CN=C2C(C)=CC=CC2=C1 JRLTTZUODKEYDH-UHFFFAOYSA-N 0.000 description 2
• NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
• 125000006374 C2-C10 alkenyl group Chemical group 0.000 description 2
• KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 2
• 108010011459 Exenatide Proteins 0.000 description 2
• 229940089838 Glucagon-like peptide 1 receptor agonist Drugs 0.000 description 2
• OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
• DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
• SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 2
• XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
• WTDRDQBEARUVNC-UHFFFAOYSA-N L-Dopa Natural products OC(=O)C(N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-UHFFFAOYSA-N 0.000 description 2
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
• BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
• 238000006751 Mitsunobu reaction Methods 0.000 description 2
• KFSLWBXXFJQRDL-UHFFFAOYSA-N Peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 description 2
• 238000006929 Pictet-Spengler synthesis reaction Methods 0.000 description 2
• NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
• 239000004793 Polystyrene Substances 0.000 description 2
• SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
• FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
• RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical compound O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 description 2
• 125000003670 adamantan-2-yl group Chemical group [H]C1([H])C(C2([H])[H])([H])C([H])([H])C3([H])C([*])([H])C1([H])C([H])([H])C2([H])C3([H])[H] 0.000 description 2
• 230000006978 adaptation Effects 0.000 description 2
• 239000000556 agonist Substances 0.000 description 2
• 150000001338 aliphatic hydrocarbons Chemical class 0.000 description 2
• 150000001347 alkyl bromides Chemical class 0.000 description 2
• 150000001350 alkyl halides Chemical class 0.000 description 2
• IYABWNGZIDDRAK-UHFFFAOYSA-N allene Chemical group C=C=C IYABWNGZIDDRAK-UHFFFAOYSA-N 0.000 description 2
• 150000001413 amino acids Chemical class 0.000 description 2
• 150000003927 aminopyridines Chemical class 0.000 description 2
• 238000004458 analytical method Methods 0.000 description 2
• 150000001448 anilines Chemical class 0.000 description 2
• MWPLVEDNUUSJAV-UHFFFAOYSA-N anthracene Chemical compound C1=CC=CC2=CC3=CC=CC=C3C=C21 MWPLVEDNUUSJAV-UHFFFAOYSA-N 0.000 description 2
• 239000007864 aqueous solution Substances 0.000 description 2
• UHOVQNZJYSORNB-MZWXYZOWSA-N benzene-d6 Chemical compound [2H]C1=C([2H])C([2H])=C([2H])C([2H])=C1[2H] UHOVQNZJYSORNB-MZWXYZOWSA-N 0.000 description 2
• IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical group C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 description 2
• 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 2
• 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 2
• PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 2
• JUFFVKRROAPVBI-PVOYSMBESA-N chembl1210015 Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(=O)N[C@H]1[C@@H]([C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O)[C@@H](O)[C@@H](CO[C@]3(O[C@@H](C[C@H](O)[C@H](O)CO)[C@H](NC(C)=O)[C@@H](O)C3)C(O)=O)O2)O)[C@@H](CO)O1)NC(C)=O)C(=O)NCC(=O)NCC(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CO)C(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCSC)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)CNC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 JUFFVKRROAPVBI-PVOYSMBESA-N 0.000 description 2
• 239000003795 chemical substances by application Substances 0.000 description 2
• 239000000470 constituent Substances 0.000 description 2
• 238000001816 cooling Methods 0.000 description 2
• OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 description 2
• 125000004976 cyclobutylene group Chemical group 0.000 description 2
• 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 2
• 125000004977 cycloheptylene group Chemical group 0.000 description 2
• HGCIXCUEYOPUTN-UHFFFAOYSA-N cyclohexene Chemical compound C1CCC=CC1 HGCIXCUEYOPUTN-UHFFFAOYSA-N 0.000 description 2
• 125000004956 cyclohexylene group Chemical group 0.000 description 2
• 125000004979 cyclopentylene group Chemical group 0.000 description 2
• 125000004980 cyclopropylene group Chemical group 0.000 description 2
• 238000007872 degassing Methods 0.000 description 2
• WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 description 2
• 239000003814 drug Substances 0.000 description 2
• 238000010828 elution Methods 0.000 description 2
• 238000010931 ester hydrolysis Methods 0.000 description 2
• 125000005678 ethenylene group Chemical group [H]C([*:1])=C([H])[*:2] 0.000 description 2
• UREBWPXBXRYXRJ-UHFFFAOYSA-N ethyl acetate;methanol Chemical compound OC.CCOC(C)=O UREBWPXBXRYXRJ-UHFFFAOYSA-N 0.000 description 2
• 238000001704 evaporation Methods 0.000 description 2
• 230000008020 evaporation Effects 0.000 description 2
• 229960001519 exenatide Drugs 0.000 description 2
• 230000037406 food intake Effects 0.000 description 2
• 238000009472 formulation Methods 0.000 description 2
• 125000000524 functional group Chemical group 0.000 description 2
• 125000001543 furan-2,5-diyl group Chemical group O1C(=CC=C1*)* 0.000 description 2
• 230000002641 glycemic effect Effects 0.000 description 2
• 125000004438 haloalkoxy group Chemical group 0.000 description 2
• 125000004857 imidazopyridinyl group Chemical group N1C(=NC2=C1C=CC=N2)* 0.000 description 2
• 125000004130 indan-2-yl group Chemical group [H]C1=C([H])C([H])=C2C(=C1[H])C([H])([H])C([H])(*)C2([H])[H] 0.000 description 2
• 125000001041 indolyl group Chemical group 0.000 description 2
• 238000001802 infusion Methods 0.000 description 2
• NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 2
• 238000007918 intramuscular administration Methods 0.000 description 2
• 238000001990 intravenous administration Methods 0.000 description 2
• 229910052740 iodine Inorganic materials 0.000 description 2
• INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 2
• 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 2
• 125000001786 isothiazolyl group Chemical group 0.000 description 2
• 238000005304 joining Methods 0.000 description 2
• 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
• BRUKMUWDWWPPBM-IIRRWZJPSA-N methyl (2s)-2-[[(3s,8s)-3-[4-(cyclohexylmethoxy)phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]amino]-3-[4-(2,3-dimethylpyridin-4-yl)oxyphenyl]propanoate Chemical compound C([C@@H](C(=O)OC)NC(=O)[C@H]1NCC2=CC=3O[C@H](COC=3C=C2C1)C=1C=CC(OCC2CCCCC2)=CC=1)C(C=C1)=CC=C1OC1=CC=NC(C)=C1C BRUKMUWDWWPPBM-IIRRWZJPSA-N 0.000 description 2
• ONIFDNPOWHWTKN-IIRRWZJPSA-N methyl (2s)-2-[[(3s,8s)-3-[4-[(3,4-dichlorophenyl)methoxy]phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]amino]-3-[4-(2,3-dimethylpyridin-4-yl)oxyphenyl]propanoate Chemical compound C([C@@H](C(=O)OC)NC(=O)[C@H]1NCC2=CC=3O[C@H](COC=3C=C2C1)C=1C=CC(OCC=2C=C(Cl)C(Cl)=CC=2)=CC=1)C(C=C1)=CC=C1OC1=CC=NC(C)=C1C ONIFDNPOWHWTKN-IIRRWZJPSA-N 0.000 description 2
• JJJKCAAPLWARHE-CKUXDGONSA-N methyl (2s)-2-amino-3-[4-(2,3-dimethylpyridin-4-yl)oxyphenyl]propanoate;dihydrochloride Chemical compound Cl.Cl.C1=CC(C[C@H](N)C(=O)OC)=CC=C1OC1=CC=NC(C)=C1C JJJKCAAPLWARHE-CKUXDGONSA-N 0.000 description 2
• JMUQVEFMAXSRQF-ZOWNYOTGSA-N methyl (2s)-2-amino-3-[5-(4-cyanophenyl)thiophen-2-yl]propanoate;hydrochloride Chemical compound Cl.S1C(C[C@H](N)C(=O)OC)=CC=C1C1=CC=C(C#N)C=C1 JMUQVEFMAXSRQF-ZOWNYOTGSA-N 0.000 description 2
• NQIFXJSLCUJHBB-LBPRGKRZSA-N methyl (2s)-3-(4-hydroxyphenyl)-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoate Chemical compound CC(C)(C)OC(=O)N[C@H](C(=O)OC)CC1=CC=C(O)C=C1 NQIFXJSLCUJHBB-LBPRGKRZSA-N 0.000 description 2
• JQPPZFDAUFVJIL-VIFPVBQESA-N methyl (2s)-3-(5-bromothiophen-2-yl)-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoate Chemical compound CC(C)(C)OC(=O)N[C@H](C(=O)OC)CC1=CC=C(Br)S1 JQPPZFDAUFVJIL-VIFPVBQESA-N 0.000 description 2
• UBXVBIYYOUTSRO-WIOPSUGQSA-N methyl (2s)-3-[(2s)-2-(4-acetyloxyphenyl)-2,3-dihydro-1,4-benzodioxin-6-yl]-2-[(4-nitrophenyl)sulfonylamino]propanoate Chemical compound C1([C@@H]2OC3=CC=C(C=C3OC2)C[C@@H](C(=O)OC)NS(=O)(=O)C=2C=CC(=CC=2)[N+]([O-])=O)=CC=C(OC(C)=O)C=C1 UBXVBIYYOUTSRO-WIOPSUGQSA-N 0.000 description 2
• ITULJIQPZPCOBS-BHBYDHKZSA-N methyl (2s)-3-[(2s)-2-[3-[(3,4-dichlorophenyl)methoxy]phenyl]-2,3-dihydro-1,4-benzodioxin-6-yl]-2-[(4-nitrophenyl)sulfonylamino]propanoate Chemical compound C=1C([C@@H]2OC3=CC=C(C=C3OC2)C[C@@H](C(=O)OC)NS(=O)(=O)C=2C=CC(=CC=2)[N+]([O-])=O)=CC=CC=1OCC1=CC=C(Cl)C(Cl)=C1 ITULJIQPZPCOBS-BHBYDHKZSA-N 0.000 description 2
• RJJDDNNLUJAHLC-WSZLSEGOSA-N methyl (2s)-3-[(2s)-2-[3-[(3,4-dichlorophenyl)methoxy]phenyl]-2,3-dihydro-1,4-benzodioxin-6-yl]-2-[[(1s)-1-phenylpropyl]amino]propanoate Chemical compound C=1C([C@@H]2OC3=CC=C(C=C3OC2)C[C@H](N[C@@H](CC)C=2C=CC=CC=2)C(=O)OC)=CC=CC=1OCC1=CC=C(Cl)C(Cl)=C1 RJJDDNNLUJAHLC-WSZLSEGOSA-N 0.000 description 2
• FHUMOBVHYICPOI-BHBYDHKZSA-N methyl (2s)-3-[(2s)-2-[4-[(3,4-dichlorophenyl)methoxy]phenyl]-2,3-dihydro-1,4-benzodioxin-6-yl]-2-[(4-nitrophenyl)sulfonylamino]propanoate Chemical compound C1=CC([C@@H]2OC3=CC=C(C=C3OC2)C[C@@H](C(=O)OC)NS(=O)(=O)C=2C=CC(=CC=2)[N+]([O-])=O)=CC=C1OCC1=CC=C(Cl)C(Cl)=C1 FHUMOBVHYICPOI-BHBYDHKZSA-N 0.000 description 2
• YLBJCHJGSFAUQU-UCFFOFKASA-N methyl (2s)-3-[2-(4-acetyloxyphenyl)-2,3-dihydro-1,4-benzodioxin-6-yl]-2-aminopropanoate Chemical compound C1OC2=CC(C[C@H](N)C(=O)OC)=CC=C2OC1C1=CC=C(OC(C)=O)C=C1 YLBJCHJGSFAUQU-UCFFOFKASA-N 0.000 description 2
• OSUIIODYUWFPJK-PVCWFJFTSA-N methyl (2s)-3-[3-bromo-4-[1-[4-[(3,4-dichlorophenyl)methoxy]phenyl]-2-hydroxyethoxy]phenyl]-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoate Chemical compound BrC1=CC(C[C@@H](C(=O)OC)NC(=O)OC(C)(C)C)=CC=C1OC(CO)C(C=C1)=CC=C1OCC1=CC=C(Cl)C(Cl)=C1 OSUIIODYUWFPJK-PVCWFJFTSA-N 0.000 description 2
• CXDVNMQGZJJDLH-UJGAEZNTSA-N methyl (2s)-3-[3-bromo-4-[2-[tert-butyl(diphenyl)silyl]oxy-1-[4-[(3,4-dichlorophenyl)methoxy]phenyl]ethoxy]phenyl]-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoate Chemical compound BrC1=CC(C[C@@H](C(=O)OC)NC(=O)OC(C)(C)C)=CC=C1OC(C=1C=CC(OCC=2C=C(Cl)C(Cl)=CC=2)=CC=1)CO[Si](C(C)(C)C)(C=1C=CC=CC=1)C1=CC=CC=C1 CXDVNMQGZJJDLH-UJGAEZNTSA-N 0.000 description 2
• MCSRCZOMLYENHO-IBGZPJMESA-N methyl (2s)-3-[4-(2,3-dimethylpyridin-4-yl)phenyl]-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoate Chemical compound C1=CC(C[C@@H](C(=O)OC)NC(=O)OC(C)(C)C)=CC=C1C1=CC=NC(C)=C1C MCSRCZOMLYENHO-IBGZPJMESA-N 0.000 description 2
• GOUWLKGRUODXDV-IBGZPJMESA-N methyl (2s)-3-[4-(4-cyanophenyl)phenyl]-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoate Chemical compound C1=CC(C[C@@H](C(=O)OC)NC(=O)OC(C)(C)C)=CC=C1C1=CC=C(C#N)C=C1 GOUWLKGRUODXDV-IBGZPJMESA-N 0.000 description 2
• CPHKMDBOUKBUGH-NDOUHODOSA-N methyl (2s)-3-[4-(4-cyanophenyl)phenyl]-2-[[(3r,8s)-3-[4-[(3,4-dichlorophenyl)methoxy]phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]amino]propanoate;hydrochloride Chemical compound Cl.C([C@@H](C(=O)OC)NC(=O)[C@H]1NCC2=CC=3O[C@@H](COC=3C=C2C1)C=1C=CC(OCC=2C=C(Cl)C(Cl)=CC=2)=CC=1)C(C=C1)=CC=C1C1=CC=C(C#N)C=C1 CPHKMDBOUKBUGH-NDOUHODOSA-N 0.000 description 2
• SBRJJILRBNATLO-TXSBWBSASA-N methyl (2s)-3-[4-(4-cyanophenyl)phenyl]-2-[[(3s)-3-[4-[(3,4-dichlorophenyl)methoxy]phenyl]-1-methyl-2,3,6,7,8,9-hexahydropyrido[4,3-g][1,4]benzoxazine-8-carbonyl]amino]propanoate Chemical compound C([C@@H](C(=O)OC)NC(=O)C1NCC2=CC=3O[C@H](CN(C)C=3C=C2C1)C=1C=CC(OCC=2C=C(Cl)C(Cl)=CC=2)=CC=1)C(C=C1)=CC=C1C1=CC=C(C#N)C=C1 SBRJJILRBNATLO-TXSBWBSASA-N 0.000 description 2
• NMYKDBZNMVOAEQ-GUPSHFLSSA-N methyl (2s)-3-[4-(4-cyanophenyl)phenyl]-2-[[(3s)-3-[4-[(3,4-dichlorophenyl)methoxy]phenyl]-2,3,6,7,8,9-hexahydro-1h-pyrido[4,3-g][1,4]benzoxazine-8-carbonyl]amino]propanoate;dihydrochloride Chemical compound Cl.Cl.C([C@@H](C(=O)OC)NC(=O)C1NCC2=CC=3O[C@H](CNC=3C=C2C1)C=1C=CC(OCC=2C=C(Cl)C(Cl)=CC=2)=CC=1)C(C=C1)=CC=C1C1=CC=C(C#N)C=C1 NMYKDBZNMVOAEQ-GUPSHFLSSA-N 0.000 description 2
• COEKCZCWLCNZBB-HSIAUZLTSA-N methyl (2s)-3-[4-(4-cyanophenyl)phenyl]-2-[[(3s)-3-[4-[(3,4-dichlorophenyl)methoxy]phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]amino]propanoate Chemical compound C([C@@H](C(=O)OC)NC(=O)C1NCC2=CC=3O[C@H](COC=3C=C2C1)C=1C=CC(OCC=2C=C(Cl)C(Cl)=CC=2)=CC=1)C(C=C1)=CC=C1C1=CC=C(C#N)C=C1 COEKCZCWLCNZBB-HSIAUZLTSA-N 0.000 description 2
• COEKCZCWLCNZBB-YLJLHNITSA-N methyl (2s)-3-[4-(4-cyanophenyl)phenyl]-2-[[(3s,8s)-3-[4-[(3,4-dichlorophenyl)methoxy]phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]amino]propanoate Chemical compound C([C@@H](C(=O)OC)NC(=O)[C@H]1NCC2=CC=3O[C@H](COC=3C=C2C1)C=1C=CC(OCC=2C=C(Cl)C(Cl)=CC=2)=CC=1)C(C=C1)=CC=C1C1=CC=C(C#N)C=C1 COEKCZCWLCNZBB-YLJLHNITSA-N 0.000 description 2
• OGBLFWFWYDAKSZ-INIZCTEOSA-N methyl (2s)-3-[5-(4-cyanophenyl)thiophen-2-yl]-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoate Chemical compound S1C(C[C@@H](C(=O)OC)NC(=O)OC(C)(C)C)=CC=C1C1=CC=C(C#N)C=C1 OGBLFWFWYDAKSZ-INIZCTEOSA-N 0.000 description 2
• DYKLPYKFQICXER-JHFJJOSTSA-N methyl (3r,8s)-3-[4-[(3,4-dichlorophenyl)methoxy]phenyl]-7-[(1s)-1-phenylpropyl]-3,6,8,9-tetrahydro-2h-[1,4]dioxino[2,3-g]isoquinoline-8-carboxylate Chemical compound C1=CC([C@H]2OC=3C=C4CN([C@@H](CC4=CC=3OC2)C(=O)OC)[C@@H](CC)C=2C=CC=CC=2)=CC=C1OCC1=CC=C(Cl)C(Cl)=C1 DYKLPYKFQICXER-JHFJJOSTSA-N 0.000 description 2
• AWICHGXVMPHEBI-QXTIUPHPSA-N methyl (3s,8s)-3-(4-acetyloxyphenyl)-7-[(1s)-1-phenylpropyl]-3,6,8,9-tetrahydro-2h-[1,4]dioxino[2,3-g]isoquinoline-8-carboxylate Chemical compound C1([C@@H]2OC=3C=C4CN([C@@H](CC4=CC=3OC2)C(=O)OC)[C@@H](CC)C=2C=CC=CC=2)=CC=C(OC(C)=O)C=C1 AWICHGXVMPHEBI-QXTIUPHPSA-N 0.000 description 2
• DYKLPYKFQICXER-ODTVBPJYSA-N methyl (3s,8s)-3-[4-[(3,4-dichlorophenyl)methoxy]phenyl]-7-[(1s)-1-phenylpropyl]-3,6,8,9-tetrahydro-2h-[1,4]dioxino[2,3-g]isoquinoline-8-carboxylate Chemical compound C1=CC([C@@H]2OC=3C=C4CN([C@@H](CC4=CC=3OC2)C(=O)OC)[C@@H](CC)C=2C=CC=CC=2)=CC=C1OCC1=CC=C(Cl)C(Cl)=C1 DYKLPYKFQICXER-ODTVBPJYSA-N 0.000 description 2
• KSKRPHSHPQTWJK-MHZLTWQESA-N methyl 3-[(2r)-2-[4-[(3,4-dichlorophenyl)methoxy]phenyl]-2,3-dihydro-1,4-benzodioxin-6-yl]-2-[(2-methylpropan-2-yl)oxycarbonylamino]prop-2-enoate Chemical compound C1=CC([C@H]2OC3=CC=C(C=C3OC2)C=C(NC(=O)OC(C)(C)C)C(=O)OC)=CC=C1OCC1=CC=C(Cl)C(Cl)=C1 KSKRPHSHPQTWJK-MHZLTWQESA-N 0.000 description 2
• ZQZFFJHCMLLJGF-HHHXNRCGSA-N methyl 3-[(2s)-2-[3-[(3,4-dichlorophenyl)methoxy]phenyl]-2,3-dihydro-1,4-benzodioxin-6-yl]-2-[(2-methylpropan-2-yl)oxycarbonylamino]prop-2-enoate Chemical compound C=1C([C@@H]2OC3=CC=C(C=C3OC2)C=C(NC(=O)OC(C)(C)C)C(=O)OC)=CC=CC=1OCC1=CC=C(Cl)C(Cl)=C1 ZQZFFJHCMLLJGF-HHHXNRCGSA-N 0.000 description 2
• GGBRUPXCWGATIH-UHFFFAOYSA-N methyl 4-methyl-2-[(2-methylpropan-2-yl)oxycarbonylamino]-1,3-thiazole-5-carboxylate Chemical compound COC(=O)C=1SC(NC(=O)OC(C)(C)C)=NC=1C GGBRUPXCWGATIH-UHFFFAOYSA-N 0.000 description 2
• 125000002950 monocyclic group Chemical group 0.000 description 2
• IVBVDGOVRUPPAU-UHFFFAOYSA-N n,6-dimethyl-5-nitropyridin-2-amine Chemical compound CNC1=CC=C([N+]([O-])=O)C(C)=N1 IVBVDGOVRUPPAU-UHFFFAOYSA-N 0.000 description 2
• RXLYNDDWAMZCDD-UHFFFAOYSA-N n-(4-methyl-5-nitropyridin-2-yl)acetamide Chemical compound CC(=O)NC1=CC(C)=C([N+]([O-])=O)C=N1 RXLYNDDWAMZCDD-UHFFFAOYSA-N 0.000 description 2
• QIYVKUNPXMATML-UHFFFAOYSA-N n-(5-amino-6-methylpyridin-2-yl)-n-(cyclobutylmethyl)acetamide Chemical compound C=1C=C(N)C(C)=NC=1N(C(=O)C)CC1CCC1 QIYVKUNPXMATML-UHFFFAOYSA-N 0.000 description 2
• 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 2
• 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 2
• 239000012074 organic phase Substances 0.000 description 2
• 229910052763 palladium Inorganic materials 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
• YNPNZTXNASCQKK-UHFFFAOYSA-N phenanthrene Chemical compound C1=CC=C2C3=CC=CC=C3C=CC2=C1 YNPNZTXNASCQKK-UHFFFAOYSA-N 0.000 description 2
• 125000003367 polycyclic group Chemical group 0.000 description 2
• 229920002223 polystyrene Polymers 0.000 description 2
• MWWATHDPGQKSAR-UHFFFAOYSA-N propyne Chemical group CC#C MWWATHDPGQKSAR-UHFFFAOYSA-N 0.000 description 2
• 125000004289 pyrazol-3-yl group Chemical group [H]N1N=C(*)C([H])=C1[H] 0.000 description 2
• 125000002098 pyridazinyl group Chemical group 0.000 description 2
• 125000000168 pyrrolyl group Chemical group 0.000 description 2
• 230000009467 reduction Effects 0.000 description 2
• 238000006722 reduction reaction Methods 0.000 description 2
• 238000006268 reductive amination reaction Methods 0.000 description 2
• 239000011347 resin Substances 0.000 description 2
• 229920005989 resin Polymers 0.000 description 2
• 229910052701 rubidium Inorganic materials 0.000 description 2
• 235000015424 sodium Nutrition 0.000 description 2
• VWDWKYIASSYTQR-UHFFFAOYSA-N sodium nitrate Chemical compound [Na+].[O-][N+]([O-])=O VWDWKYIASSYTQR-UHFFFAOYSA-N 0.000 description 2
• 238000007920 subcutaneous administration Methods 0.000 description 2
• 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 2
• 229940124530 sulfonamide Drugs 0.000 description 2
• 150000003456 sulfonamides Chemical class 0.000 description 2
• 125000004434 sulfur atom Chemical group 0.000 description 2
• XTQHKBHJIVJGKJ-UHFFFAOYSA-N sulfur monoxide Chemical class S=O XTQHKBHJIVJGKJ-UHFFFAOYSA-N 0.000 description 2
• 229910052815 sulfur oxide Inorganic materials 0.000 description 2
• YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 2
• QHUVTWQYVYYCIH-UITVWODBSA-N tert-butyl (3s)-8-[[(2s)-3-[4-(4-cyanophenyl)phenyl]-1-methoxy-1-oxopropan-2-yl]carbamoyl]-3-[4-[(3,4-dichlorophenyl)methoxy]phenyl]-1,2,3,6,8,9-hexahydropyrido[4,3-g][1,4]benzoxazine-7-carboxylate Chemical compound C([C@@H](C(=O)OC)NC(=O)C1N(CC2=CC=3O[C@H](CNC=3C=C2C1)C=1C=CC(OCC=2C=C(Cl)C(Cl)=CC=2)=CC=1)C(=O)OC(C)(C)C)C(C=C1)=CC=C1C1=CC=C(C#N)C=C1 QHUVTWQYVYYCIH-UITVWODBSA-N 0.000 description 2
• HUKROHLIRDDKTD-XSBWBPONSA-N tert-butyl (3s)-8-[[(2s)-3-[4-(4-cyanophenyl)phenyl]-1-methoxy-1-oxopropan-2-yl]carbamoyl]-3-[4-[(3,4-dichlorophenyl)methoxy]phenyl]-3,6,8,9-tetrahydro-2h-[1,4]dioxino[2,3-g]isoquinoline-7-carboxylate Chemical compound C([C@@H](C(=O)OC)NC(=O)C1N(CC2=CC=3O[C@H](COC=3C=C2C1)C=1C=CC(OCC=2C=C(Cl)C(Cl)=CC=2)=CC=1)C(=O)OC(C)(C)C)C(C=C1)=CC=C1C1=CC=C(C#N)C=C1 HUKROHLIRDDKTD-XSBWBPONSA-N 0.000 description 2
• VWTNSISTYUPFBH-IWJNXRQDSA-N tert-butyl (3s,8s)-3-[3-[(3,4-dichlorophenyl)methoxy]phenyl]-8-[[(2s)-3-[4-(2,3-dimethylpyridin-4-yl)phenyl]-1-methoxy-1-oxopropan-2-yl]carbamoyl]-3,6,8,9-tetrahydro-2h-[1,4]dioxino[2,3-g]isoquinoline-7-carboxylate Chemical compound C([C@@H](C(=O)OC)NC(=O)[C@H]1N(CC2=CC=3O[C@H](COC=3C=C2C1)C=1C=C(OCC=2C=C(Cl)C(Cl)=CC=2)C=CC=1)C(=O)OC(C)(C)C)C(C=C1)=CC=C1C1=CC=NC(C)=C1C VWTNSISTYUPFBH-IWJNXRQDSA-N 0.000 description 2
• WBMGIEPKPCDHAD-IWJNXRQDSA-N tert-butyl (3s,8s)-3-[4-(cyclohexylmethoxy)phenyl]-8-[[(2s)-3-[4-(2,3-dimethylpyridin-4-yl)phenyl]-1-methoxy-1-oxopropan-2-yl]carbamoyl]-3,6,8,9-tetrahydro-2h-[1,4]dioxino[2,3-g]isoquinoline-7-carboxylate Chemical compound C([C@@H](C(=O)OC)NC(=O)[C@H]1N(CC2=CC=3O[C@H](COC=3C=C2C1)C=1C=CC(OCC2CCCCC2)=CC=1)C(=O)OC(C)(C)C)C(C=C1)=CC=C1C1=CC=NC(C)=C1C WBMGIEPKPCDHAD-IWJNXRQDSA-N 0.000 description 2
• IUKJGZQDJHHXDK-UHFFFAOYSA-N tert-butyl n-[5-(hydroxymethyl)-4-methyl-1,3-thiazol-2-yl]carbamate Chemical compound CC=1N=C(NC(=O)OC(C)(C)C)SC=1CO IUKJGZQDJHHXDK-UHFFFAOYSA-N 0.000 description 2
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
• 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 2
• 230000001225 therapeutic effect Effects 0.000 description 2
• 125000001544 thienyl group Chemical group 0.000 description 2
• 150000003573 thiols Chemical class 0.000 description 2
• FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
• AQRLNPVMDITEJU-UHFFFAOYSA-N triethylsilane Chemical compound CC[SiH](CC)CC AQRLNPVMDITEJU-UHFFFAOYSA-N 0.000 description 2
• WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 description 2
• 150000003672 ureas Chemical class 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
• 239000003643 water by type Substances 0.000 description 2
• NPLZNDDFVCGRAG-UHFFFAOYSA-N (2-cyanophenyl)boronic acid Chemical compound OB(O)C1=CC=CC=C1C#N NPLZNDDFVCGRAG-UHFFFAOYSA-N 0.000 description 1
• SZGNVQBQNCCWEF-JOCHJYFZSA-N (2s)-2-[3-[(3,4-dichlorophenyl)methoxy]phenyl]-2,3-dihydro-1,4-benzodioxine-6-carbonitrile Chemical compound C1=C(Cl)C(Cl)=CC=C1COC1=CC=CC([C@@H]2OC3=CC=C(C=C3OC2)C#N)=C1 SZGNVQBQNCCWEF-JOCHJYFZSA-N 0.000 description 1
• DNTUMIFJYMBTAD-OCYYOKBKSA-N (2s)-2-[[(3s)-7-benzoyl-3-[4-[(3,4-dichlorophenyl)methoxy]phenyl]-1-methyl-3,6,8,9-tetrahydro-2h-pyrido[4,3-g][1,4]benzoxazine-8-carbonyl]amino]-3-[4-(4-cyanophenyl)phenyl]propanoic acid Chemical compound C([C@H](NC(=O)C1N(CC=2C=C3O[C@H](CN(C3=CC=2C1)C)C=1C=CC(OCC=2C=C(Cl)C(Cl)=CC=2)=CC=1)C(=O)C=1C=CC=CC=1)C(O)=O)C(C=C1)=CC=C1C1=CC=C(C#N)C=C1 DNTUMIFJYMBTAD-OCYYOKBKSA-N 0.000 description 1
• ULNOXUAEIPUJMK-NSHDSACASA-N (2s)-3-(4-bromophenyl)-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoic acid Chemical compound CC(C)(C)OC(=O)N[C@H](C(O)=O)CC1=CC=C(Br)C=C1 ULNOXUAEIPUJMK-NSHDSACASA-N 0.000 description 1
• HHNNFRCLMQFXBA-QMMMGPOBSA-N (2s)-3-(5-bromothiophen-2-yl)-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoic acid Chemical compound CC(C)(C)OC(=O)N[C@H](C(O)=O)CC1=CC=C(Br)S1 HHNNFRCLMQFXBA-QMMMGPOBSA-N 0.000 description 1
• KYOVUVBZSVBLEO-SIORXBAWSA-N (2s)-3-[4-(4-cyanophenyl)phenyl]-2-[[(3s)-3-[4-[(3,4-dichlorophenyl)methoxy]phenyl]-7-(pyridin-2-ylmethyl)-3,6,8,9-tetrahydro-2h-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]amino]propanoic acid Chemical compound C([C@@H](C(=O)O)NC(=O)C1N(CC2=CC=3O[C@H](COC=3C=C2C1)C=1C=CC(OCC=2C=C(Cl)C(Cl)=CC=2)=CC=1)CC=1N=CC=CC=1)C(C=C1)=CC=C1C1=CC=C(C#N)C=C1 KYOVUVBZSVBLEO-SIORXBAWSA-N 0.000 description 1
• XYHIWUWOCXFFNO-NGCAANIMSA-N (3r,8s)-3-[4-[(3,4-dichlorophenyl)methoxy]phenyl]-7-[(1s)-1-phenylpropyl]-3,6,8,9-tetrahydro-2h-[1,4]dioxino[2,3-g]isoquinoline-8-carboxylic acid Chemical compound C1=CC([C@H]2OC=3C=C4CN([C@@H](CC4=CC=3OC2)C(O)=O)[C@@H](CC)C=2C=CC=CC=2)=CC=C1OCC1=CC=C(Cl)C(Cl)=C1 XYHIWUWOCXFFNO-NGCAANIMSA-N 0.000 description 1
• ZDGBHAAILDAGTG-WSZLSEGOSA-N (3s,8s)-3-[3-[(3,4-dichlorophenyl)methoxy]phenyl]-7-[(1s)-1-phenylpropyl]-3,6,8,9-tetrahydro-2h-[1,4]dioxino[2,3-g]isoquinoline-8-carboxylic acid Chemical compound C=1C([C@@H]2OC=3C=C4CN([C@@H](CC4=CC=3OC2)C(O)=O)[C@@H](CC)C=2C=CC=CC=2)=CC=CC=1OCC1=CC=C(Cl)C(Cl)=C1 ZDGBHAAILDAGTG-WSZLSEGOSA-N 0.000 description 1
• XYHIWUWOCXFFNO-WSZLSEGOSA-N (3s,8s)-3-[4-[(3,4-dichlorophenyl)methoxy]phenyl]-7-[(1s)-1-phenylpropyl]-3,6,8,9-tetrahydro-2h-[1,4]dioxino[2,3-g]isoquinoline-8-carboxylic acid Chemical compound C1=CC([C@@H]2OC=3C=C4CN([C@@H](CC4=CC=3OC2)C(O)=O)[C@@H](CC)C=2C=CC=CC=2)=CC=C1OCC1=CC=C(Cl)C(Cl)=C1 XYHIWUWOCXFFNO-WSZLSEGOSA-N 0.000 description 1
• ONTARJNWHFVCLJ-NZQKXSOJSA-N (3s,8s)-7-benzoyl-3-(4-hydroxyphenyl)-3,6,8,9-tetrahydro-2h-[1,4]dioxino[2,3-g]isoquinoline-8-carboxylic acid Chemical compound O([C@H](COC=1C=C2C[C@H]3C(=O)O)C=4C=CC(O)=CC=4)C=1C=C2CN3C(=O)C1=CC=CC=C1 ONTARJNWHFVCLJ-NZQKXSOJSA-N 0.000 description 1
• CEBAHYWORUOILU-UHFFFAOYSA-N (4-cyanophenyl)boronic acid Chemical compound OB(O)C1=CC=C(C#N)C=C1 CEBAHYWORUOILU-UHFFFAOYSA-N 0.000 description 1
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 1
• 125000006681 (C2-C10) alkylene group Chemical group 0.000 description 1
• 125000006376 (C3-C10) cycloalkyl group Chemical group 0.000 description 1
• 125000006586 (C3-C10) cycloalkylene group Chemical group 0.000 description 1
• KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 1
• 125000001359 1,2,3-triazol-4-yl group Chemical group [H]N1N=NC([*])=C1[H] 0.000 description 1
• 125000001506 1,2,3-triazol-5-yl group Chemical group [H]N1N=NC([H])=C1[*] 0.000 description 1
• 125000001305 1,2,4-triazol-3-yl group Chemical group [H]N1N=C([*])N=C1[H] 0.000 description 1
• 125000001414 1,2,4-triazol-5-yl group Chemical group [H]N1N=C([H])N=C1[*] 0.000 description 1
• 125000001376 1,2,4-triazolyl group Chemical group N1N=C(N=C1)* 0.000 description 1
• YZIFVWOCPGPNHB-UHFFFAOYSA-N 1,2-dichloro-4-(chloromethyl)benzene Chemical compound ClCC1=CC=C(Cl)C(Cl)=C1 YZIFVWOCPGPNHB-UHFFFAOYSA-N 0.000 description 1
• 125000004317 1,3,5-triazin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=N1 0.000 description 1
• KEQGZUUPPQEDPF-UHFFFAOYSA-N 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione Chemical compound CC1(C)N(Cl)C(=O)N(Cl)C1=O KEQGZUUPPQEDPF-UHFFFAOYSA-N 0.000 description 1
• VDFVNEFVBPFDSB-UHFFFAOYSA-N 1,3-dioxane Chemical compound C1COCOC1 VDFVNEFVBPFDSB-UHFFFAOYSA-N 0.000 description 1
• YNGDWRXWKFWCJY-UHFFFAOYSA-N 1,4-Dihydropyridine Chemical compound C1C=CNC=C1 YNGDWRXWKFWCJY-UHFFFAOYSA-N 0.000 description 1
• ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical group C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 1
• 125000004806 1-methylethylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
• 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 description 1
• BSLCBYOXMDACSD-UHFFFAOYSA-N 1-oxido-6,7-dihydro-5h-cyclopenta[b]pyridin-1-ium Chemical compound [O-][N+]1=CC=CC2=C1CCC2 BSLCBYOXMDACSD-UHFFFAOYSA-N 0.000 description 1
• ABEXEQSGABRUHS-UHFFFAOYSA-N 16-methylheptadecyl 16-methylheptadecanoate Chemical compound CC(C)CCCCCCCCCCCCCCCOC(=O)CCCCCCCCCCCCCCC(C)C ABEXEQSGABRUHS-UHFFFAOYSA-N 0.000 description 1
• CFMTVTYBZMKULI-UHFFFAOYSA-N 2,3-dimethyl-4-nitro-1-oxidopyridin-1-ium Chemical compound CC1=C(C)[N+]([O-])=CC=C1[N+]([O-])=O CFMTVTYBZMKULI-UHFFFAOYSA-N 0.000 description 1
• HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 1
• NQIBQILAMKZKFE-UHFFFAOYSA-N 2-(5-bromo-2-fluorophenyl)-3-fluoropyridine Chemical compound FC1=CC=C(Br)C=C1C1=NC=CC=C1F NQIBQILAMKZKFE-UHFFFAOYSA-N 0.000 description 1
• SLKLQAMVBKKGMQ-UHFFFAOYSA-N 2-(diethylaminomethyl)-4-[3-(diethylaminomethyl)-4-hydroxy-5-prop-2-enylphenyl]-6-prop-2-enylphenol;dihydrochloride Chemical compound [Cl-].[Cl-].C=CCC1=C(O)C(C[NH+](CC)CC)=CC(C=2C=C(C[NH+](CC)CC)C(O)=C(CC=C)C=2)=C1 SLKLQAMVBKKGMQ-UHFFFAOYSA-N 0.000 description 1
• 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 1
• NXGKPRKPUCSEIL-UHFFFAOYSA-N 2-acetamido-4-methyl-1,3-thiazole-5-sulfonyl chloride Chemical compound CC(=O)NC1=NC(C)=C(S(Cl)(=O)=O)S1 NXGKPRKPUCSEIL-UHFFFAOYSA-N 0.000 description 1
• XHGSCBXRKVMCDO-UHFFFAOYSA-N 2-bromo-1-[3-[(3,4-dichlorophenyl)methoxy]phenyl]ethanone Chemical compound C1=C(Cl)C(Cl)=CC=C1COC1=CC=CC(C(=O)CBr)=C1 XHGSCBXRKVMCDO-UHFFFAOYSA-N 0.000 description 1
• OKDGRDCXVWSXDC-UHFFFAOYSA-N 2-chloropyridine Chemical compound ClC1=CC=CC=N1 OKDGRDCXVWSXDC-UHFFFAOYSA-N 0.000 description 1
• FNRMMDCDHWCQTH-UHFFFAOYSA-N 2-chloropyridine;3-chloropyridine;4-chloropyridine Chemical compound ClC1=CC=NC=C1.ClC1=CC=CN=C1.ClC1=CC=CC=N1 FNRMMDCDHWCQTH-UHFFFAOYSA-N 0.000 description 1
• CSDSSGBPEUDDEE-UHFFFAOYSA-N 2-formylpyridine Chemical compound O=CC1=CC=CC=N1 CSDSSGBPEUDDEE-UHFFFAOYSA-N 0.000 description 1
• 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 description 1
• YMPDUCFKKPWPSU-UHFFFAOYSA-N 2-methyl-6-(methylamino)pyridine-3-sulfonyl chloride Chemical compound CNC1=CC=C(S(Cl)(=O)=O)C(C)=N1 YMPDUCFKKPWPSU-UHFFFAOYSA-N 0.000 description 1
• 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 description 1
• ICFJDFIWRVTOFU-UHFFFAOYSA-N 2-o-tert-butyl 3-o-methyl 6,7-dihydroxy-3,4-dihydro-1h-isoquinoline-2,3-dicarboxylate Chemical compound OC1=C(O)C=C2CN(C(=O)OC(C)(C)C)C(C(=O)OC)CC2=C1 ICFJDFIWRVTOFU-UHFFFAOYSA-N 0.000 description 1
• 125000000389 2-pyrrolyl group Chemical group [H]N1C([*])=C([H])C([H])=C1[H] 0.000 description 1
• 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 description 1
• VRGCYEIGVVTZCC-UHFFFAOYSA-N 3,4,5,6-tetrachlorocyclohexa-3,5-diene-1,2-dione Chemical compound ClC1=C(Cl)C(=O)C(=O)C(Cl)=C1Cl VRGCYEIGVVTZCC-UHFFFAOYSA-N 0.000 description 1
• QEMJYKLHEHHODB-OAQYLSRUSA-N 3-[(2s)-2-[3-[(3,4-dichlorophenyl)methoxy]phenyl]-2-hydroxyethoxy]-4-fluorobenzonitrile Chemical compound C([C@@H](O)C=1C=C(OCC=2C=C(Cl)C(Cl)=CC=2)C=CC=1)OC1=CC(C#N)=CC=C1F QEMJYKLHEHHODB-OAQYLSRUSA-N 0.000 description 1
• 125000003682 3-furyl group Chemical group O1C([H])=C([*])C([H])=C1[H] 0.000 description 1
• 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 description 1
• CGPIONYVXKQZPW-UHFFFAOYSA-N 4-bromo-2,5-dimethylpyridine Chemical compound CC1=CC(Br)=C(C)C=N1 CGPIONYVXKQZPW-UHFFFAOYSA-N 0.000 description 1
• LUDCJEGSWQBSKR-UHFFFAOYSA-N 4-bromo-2-propan-2-ylpyridine Chemical compound CC(C)C1=CC(Br)=CC=N1 LUDCJEGSWQBSKR-UHFFFAOYSA-N 0.000 description 1
• WYLAQZLXZDHAED-UHFFFAOYSA-N 4-bromo-2-propylpyridine Chemical compound CCCC1=CC(Br)=CC=N1 WYLAQZLXZDHAED-UHFFFAOYSA-N 0.000 description 1
• CPVMPCSZGBHELB-UHFFFAOYSA-N 4-bromo-6,7-dihydro-5h-cyclopenta[b]pyridine Chemical compound BrC1=CC=NC2=C1CCC2 CPVMPCSZGBHELB-UHFFFAOYSA-N 0.000 description 1
• BSDGZUDFPKIYQG-UHFFFAOYSA-N 4-bromopyridine Chemical compound BrC1=CC=NC=C1 BSDGZUDFPKIYQG-UHFFFAOYSA-N 0.000 description 1
• FHNRXEYKJBDNKP-UHFFFAOYSA-N 4-methyl-2-[(2-methylpropan-2-yl)oxycarbonylamino]-1,3-thiazole-5-carboxylic acid Chemical compound CC=1N=C(NC(=O)OC(C)(C)C)SC=1C(O)=O FHNRXEYKJBDNKP-UHFFFAOYSA-N 0.000 description 1
• GRBBNZYMXKTQAI-UHFFFAOYSA-N 4-methyl-5-nitropyridin-2-amine Chemical compound CC1=CC(N)=NC=C1[N+]([O-])=O GRBBNZYMXKTQAI-UHFFFAOYSA-N 0.000 description 1
• VEMRABIYJBLARI-UHFFFAOYSA-N 6-(cyclopropylmethylamino)-2-methylpyridine-3-sulfonyl chloride Chemical compound C1=C(S(Cl)(=O)=O)C(C)=NC(NCC2CC2)=C1 VEMRABIYJBLARI-UHFFFAOYSA-N 0.000 description 1
• QXDWGEGBDGGNNW-UHFFFAOYSA-N 6-acetamido-2-methylpyridine-3-sulfonyl chloride Chemical compound CC(=O)NC1=CC=C(S(Cl)(=O)=O)C(C)=N1 QXDWGEGBDGGNNW-UHFFFAOYSA-N 0.000 description 1
• ZWADNRXQZKMSKZ-UHFFFAOYSA-N 6-acetamido-4-methylpyridine-3-sulfonyl chloride Chemical compound CC(=O)NC1=CC(C)=C(S(Cl)(=O)=O)C=N1 ZWADNRXQZKMSKZ-UHFFFAOYSA-N 0.000 description 1
• BLFQWOPORXRBNO-UHFFFAOYSA-N 6-methyl-3-propan-2-ylpyridine-2,5-diamine Chemical compound CC(C)C1=CC(N)=C(C)N=C1N BLFQWOPORXRBNO-UHFFFAOYSA-N 0.000 description 1
• IFOPVANOAWECQM-UHFFFAOYSA-N 6-methyl-5-nitro-n-propan-2-ylpyridin-2-amine Chemical compound CC(C)NC1=CC=C([N+]([O-])=O)C(C)=N1 IFOPVANOAWECQM-UHFFFAOYSA-N 0.000 description 1
• BGMZTBKXOFFTBJ-UHFFFAOYSA-N 6-methyl-5-nitropyridin-2-amine Chemical compound CC1=NC(N)=CC=C1[N+]([O-])=O BGMZTBKXOFFTBJ-UHFFFAOYSA-N 0.000 description 1
• 125000004136 7-norbornyl group Chemical group [H]C1([H])C([H])([H])C2([H])C([H])([H])C([H])([H])C1([H])C2([H])* 0.000 description 1
• RUUPOAWUUXZACM-NZQKXSOJSA-N 7-o-tert-butyl 8-o-methyl (3s,8s)-3-(4-acetyloxyphenyl)-3,6,8,9-tetrahydro-2h-[1,4]dioxino[2,3-g]isoquinoline-7,8-dicarboxylate Chemical compound C1([C@H]2COC=3C=C4C[C@H](N(CC4=CC=3O2)C(=O)OC(C)(C)C)C(=O)OC)=CC=C(OC(C)=O)C=C1 RUUPOAWUUXZACM-NZQKXSOJSA-N 0.000 description 1
• ZUSKOFVHPRJMCG-LBNVMWSVSA-N 7-o-tert-butyl 8-o-methyl (3s,8s)-3-[4-(cyclohexylmethoxy)phenyl]-3,6,8,9-tetrahydro-2h-[1,4]dioxino[2,3-g]isoquinoline-7,8-dicarboxylate Chemical compound C1=CC([C@H]2COC=3C=C4C[C@H](N(CC4=CC=3O2)C(=O)OC(C)(C)C)C(=O)OC)=CC=C1OCC1CCCCC1 ZUSKOFVHPRJMCG-LBNVMWSVSA-N 0.000 description 1
• ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
• IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 1
• KHBQMWCZKVMBLN-UHFFFAOYSA-N Benzenesulfonamide Chemical compound NS(=O)(=O)C1=CC=CC=C1 KHBQMWCZKVMBLN-UHFFFAOYSA-N 0.000 description 1
• 239000005711 Benzoic acid Substances 0.000 description 1
• WPYMKLBDIGXBTP-UHFFFAOYSA-N Benzoic acid Natural products OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
• 241000283690 Bos taurus Species 0.000 description 1
• CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
• WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
• 125000000882 C2-C6 alkenyl group Chemical group 0.000 description 1
• 125000003601 C2-C6 alkynyl group Chemical group 0.000 description 1
• 101100087393 Caenorhabditis elegans ran-2 gene Proteins 0.000 description 1
• 101100086716 Caenorhabditis elegans ran-3 gene Proteins 0.000 description 1
• 241000282472 Canis lupus familiaris Species 0.000 description 1
• 208000024172 Cardiovascular disease Diseases 0.000 description 1
• ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
• 229910021591 Copper(I) chloride Inorganic materials 0.000 description 1
• 238000005750 Corey-Bakshi-Shibata reduction reaction Methods 0.000 description 1
• OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 1
• 241000283086 Equidae Species 0.000 description 1
• 240000003550 Eusideroxylon zwageri Species 0.000 description 1
• 241000282326 Felis catus Species 0.000 description 1
• PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
• WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 1
• 241000282575 Gorilla Species 0.000 description 1
• 241000282412 Homo Species 0.000 description 1
• 206010060378 Hyperinsulinaemia Diseases 0.000 description 1
• 206010021518 Impaired gastric emptying Diseases 0.000 description 1
• 102000004877 Insulin Human genes 0.000 description 1
• 108090001061 Insulin Proteins 0.000 description 1
• 241000764238 Isis Species 0.000 description 1
• 102000036770 Islet Amyloid Polypeptide Human genes 0.000 description 1
• AHLPHDHHMVZTML-BYPYZUCNSA-N L-Ornithine Chemical compound NCCC[C@H](N)C(O)=O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 description 1
• NHTGHBARYWONDQ-JTQLQIEISA-N L-α-methyl-Tyrosine Chemical compound OC(=O)[C@](N)(C)CC1=CC=C(O)C=C1 NHTGHBARYWONDQ-JTQLQIEISA-N 0.000 description 1
• 239000012448 Lithium borohydride Substances 0.000 description 1
• 241000282560 Macaca mulatta Species 0.000 description 1
• OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
• 241000124008 Mammalia Species 0.000 description 1
• 241001465754 Metazoa Species 0.000 description 1
• 239000012359 Methanesulfonyl chloride Substances 0.000 description 1
• 241000699670 Mus sp. Species 0.000 description 1
• 102000007399 Nuclear hormone receptor Human genes 0.000 description 1
• 108020005497 Nuclear hormone receptor Proteins 0.000 description 1
• 235000019502 Orange oil Nutrition 0.000 description 1
• 241000282579 Pan Species 0.000 description 1
• 101150003085 Pdcl gene Proteins 0.000 description 1
• 241001494479 Pecora Species 0.000 description 1
• 241000288906 Primates Species 0.000 description 1
• CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
• 241000700159 Rattus Species 0.000 description 1
• 208000017442 Retinal disease Diseases 0.000 description 1
• 206010038923 Retinopathy Diseases 0.000 description 1
• 241000282887 Suidae Species 0.000 description 1
• QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
• DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 description 1
• YPWFISCTZQNZAU-UHFFFAOYSA-N Thiane Chemical compound C1CCSCC1 YPWFISCTZQNZAU-UHFFFAOYSA-N 0.000 description 1
• 239000007983 Tris buffer Substances 0.000 description 1
• 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 1
• SORGEQQSQGNZFI-UHFFFAOYSA-N [azido(phenoxy)phosphoryl]oxybenzene Chemical compound C=1C=CC=CC=1OP(=O)(N=[N+]=[N-])OC1=CC=CC=C1 SORGEQQSQGNZFI-UHFFFAOYSA-N 0.000 description 1
• 230000001594 aberrant effect Effects 0.000 description 1
• 150000003869 acetamides Chemical class 0.000 description 1
• 230000021736 acetylation Effects 0.000 description 1
• 238000006640 acetylation reaction Methods 0.000 description 1
• 150000000475 acetylene derivatives Chemical class 0.000 description 1
• 230000002378 acidificating effect Effects 0.000 description 1
• 150000007513 acids Chemical class 0.000 description 1
• 239000002671 adjuvant Substances 0.000 description 1
• 150000001299 aldehydes Chemical class 0.000 description 1
• 125000003302 alkenyloxy group Chemical group 0.000 description 1
• 125000005136 alkenylsulfinyl group Chemical group 0.000 description 1
• 125000005137 alkenylsulfonyl group Chemical group 0.000 description 1
• 125000003545 alkoxy group Chemical group 0.000 description 1
• 150000003973 alkyl amines Chemical group 0.000 description 1
• 125000003282 alkyl amino group Chemical group 0.000 description 1
• 125000002877 alkyl aryl group Chemical group 0.000 description 1
• 125000004644 alkyl sulfinyl group Chemical group 0.000 description 1
• 125000004390 alkyl sulfonyl group Chemical group 0.000 description 1
• 125000004414 alkyl thio group Chemical group 0.000 description 1
• 125000005133 alkynyloxy group Chemical group 0.000 description 1
• 125000005134 alkynylsulfinyl group Chemical group 0.000 description 1
• 125000005139 alkynylsulfonyl group Chemical group 0.000 description 1
• HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
• 238000005576 amination reaction Methods 0.000 description 1
• 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 description 1
• 229950003476 aminothiazole Drugs 0.000 description 1
• 235000019270 ammonium chloride Nutrition 0.000 description 1
• 150000008064 anhydrides Chemical class 0.000 description 1
• 229940125708 antidiabetic agent Drugs 0.000 description 1
• 239000003472 antidiabetic agent Substances 0.000 description 1
• 239000008346 aqueous phase Substances 0.000 description 1
• 150000001499 aryl bromides Chemical class 0.000 description 1
• 150000001502 aryl halides Chemical class 0.000 description 1
• 150000001503 aryl iodides Chemical class 0.000 description 1
• 238000003556 assay Methods 0.000 description 1
• 125000004320 azepan-2-yl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])* 0.000 description 1
• 125000004566 azetidin-1-yl group Chemical group N1(CCC1)* 0.000 description 1
• 125000004273 azetidin-2-yl group Chemical group [H]N1C([H])([H])C([H])([H])C1([H])* 0.000 description 1
• 125000004567 azetidin-3-yl group Chemical group N1CC(C1)* 0.000 description 1
• 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 description 1
• 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
• 125000004244 benzofuran-2-yl group Chemical group [H]C1=C(*)OC2=C([H])C([H])=C([H])C([H])=C12 0.000 description 1
• 125000004532 benzofuran-3-yl group Chemical group O1C=C(C2=C1C=CC=C2)* 0.000 description 1
• 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
• 235000010233 benzoic acid Nutrition 0.000 description 1
• 125000004190 benzothiazol-2-yl group Chemical group [H]C1=C([H])C([H])=C2N=C(*)SC2=C1[H] 0.000 description 1
• 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
• PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 1
• HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 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
• 125000002619 bicyclic group Chemical group 0.000 description 1
• 230000004071 biological effect Effects 0.000 description 1
• 239000000090 biomarker Substances 0.000 description 1
• JCZLABDVDPYLRZ-AWEZNQCLSA-N biphenylalanine Chemical class C1=CC(C[C@H](N)C(O)=O)=CC=C1C1=CC=CC=C1 JCZLABDVDPYLRZ-AWEZNQCLSA-N 0.000 description 1
• IPWKHHSGDUIRAH-UHFFFAOYSA-N bis(pinacolato)diboron Chemical compound O1C(C)(C)C(C)(C)OB1B1OC(C)(C)C(C)(C)O1 IPWKHHSGDUIRAH-UHFFFAOYSA-N 0.000 description 1
• ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 description 1
• 230000031709 bromination Effects 0.000 description 1
• 238000005893 bromination reaction Methods 0.000 description 1
• GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
• 229910052794 bromium Inorganic materials 0.000 description 1
• 125000001246 bromo group Chemical group Br* 0.000 description 1
• FLHFTXCMKFVKRP-UHFFFAOYSA-N bromomethylcyclobutane Chemical compound BrCC1CCC1 FLHFTXCMKFVKRP-UHFFFAOYSA-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
• 229940084891 byetta Drugs 0.000 description 1
• 239000006227 byproduct Substances 0.000 description 1
• FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
• 229910000024 caesium carbonate Inorganic materials 0.000 description 1
• 150000004657 carbamic acid derivatives Chemical class 0.000 description 1
• 150000001721 carbon Chemical group 0.000 description 1
• RBHJBMIOOPYDBQ-UHFFFAOYSA-N carbon dioxide;propan-2-one Chemical compound O=C=O.CC(C)=O RBHJBMIOOPYDBQ-UHFFFAOYSA-N 0.000 description 1
• 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 description 1
• 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
• 239000000969 carrier Substances 0.000 description 1
• 229910052801 chlorine Inorganic materials 0.000 description 1
• FZFAMSAMCHXGEF-UHFFFAOYSA-N chloro formate Chemical compound ClOC=O FZFAMSAMCHXGEF-UHFFFAOYSA-N 0.000 description 1
• 125000001309 chloro group Chemical group Cl* 0.000 description 1
• XTHPWXDJESJLNJ-UHFFFAOYSA-N chlorosulfonic acid Substances OS(Cl)(=O)=O XTHPWXDJESJLNJ-UHFFFAOYSA-N 0.000 description 1
• 238000011097 chromatography purification Methods 0.000 description 1
• HOFHLRCDGWSLHX-UHFFFAOYSA-N clamoxyquine Chemical compound C1=CC=NC2=C(O)C(CNCCCN(CC)CC)=CC(Cl)=C21 HOFHLRCDGWSLHX-UHFFFAOYSA-N 0.000 description 1
• 238000002648 combination therapy Methods 0.000 description 1
• 230000001276 controlling effect Effects 0.000 description 1
• OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-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
• 238000002425 crystallisation Methods 0.000 description 1
• 230000008025 crystallization Effects 0.000 description 1
• 229940076286 cupric acetate Drugs 0.000 description 1
• 229940045803 cuprous chloride Drugs 0.000 description 1
• 125000001047 cyclobutenyl group Chemical group C1(=CCC1)* 0.000 description 1
• 125000001162 cycloheptenyl group Chemical group C1(=CCCCCC1)* 0.000 description 1
• 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 description 1
• VSSAZBXXNIABDN-UHFFFAOYSA-N cyclohexylmethanol Chemical compound OCC1CCCCC1 VSSAZBXXNIABDN-UHFFFAOYSA-N 0.000 description 1
• 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 description 1
• 125000000298 cyclopropenyl group Chemical group [H]C1=C([H])C1([H])* 0.000 description 1
• IGSKHXTUVXSOMB-UHFFFAOYSA-N cyclopropylmethanamine Chemical compound NCC1CC1 IGSKHXTUVXSOMB-UHFFFAOYSA-N 0.000 description 1
• 238000006264 debenzylation reaction Methods 0.000 description 1
• 230000007423 decrease Effects 0.000 description 1
• 230000003247 decreasing effect Effects 0.000 description 1
• 230000002939 deleterious effect Effects 0.000 description 1
• 238000010511 deprotection reaction Methods 0.000 description 1
• 238000001212 derivatisation Methods 0.000 description 1
• WMKGGPCROCCUDY-PHEQNACWSA-N dibenzylideneacetone Chemical compound C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 WMKGGPCROCCUDY-PHEQNACWSA-N 0.000 description 1
• 229910001873 dinitrogen Inorganic materials 0.000 description 1
• 150000002009 diols Chemical class 0.000 description 1
• 125000000532 dioxanyl group Chemical group 0.000 description 1
• 125000005879 dioxolanyl group Chemical group 0.000 description 1
• MKRTXPORKIRPDG-UHFFFAOYSA-N diphenylphosphoryl azide Chemical compound C=1C=CC=CC=1P(=O)(N=[N+]=[N-])C1=CC=CC=C1 MKRTXPORKIRPDG-UHFFFAOYSA-N 0.000 description 1
• 230000006806 disease prevention Effects 0.000 description 1
• 239000006185 dispersion Substances 0.000 description 1
• QGBQGMHXBSLYLZ-UHFFFAOYSA-N ditert-butyl-(1-naphthalen-1-ylnaphthalen-2-yl)phosphane Chemical compound C1=CC=C2C(C3=C4C=CC=CC4=CC=C3P(C(C)(C)C)C(C)(C)C)=CC=CC2=C1 QGBQGMHXBSLYLZ-UHFFFAOYSA-N 0.000 description 1
• 238000000132 electrospray ionisation Methods 0.000 description 1
• 238000005516 engineering process Methods 0.000 description 1
• LJQKCYFTNDAAPC-UHFFFAOYSA-N ethanol;ethyl acetate Chemical compound CCO.CCOC(C)=O LJQKCYFTNDAAPC-UHFFFAOYSA-N 0.000 description 1
• OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 1
• WHQLQYRFIHPMNA-UHFFFAOYSA-N ethyl acetate;oxolane Chemical compound C1CCOC1.CCOC(C)=O WHQLQYRFIHPMNA-UHFFFAOYSA-N 0.000 description 1
• 210000001508 eye Anatomy 0.000 description 1
• 239000011737 fluorine Substances 0.000 description 1
• 239000006260 foam Substances 0.000 description 1
• 235000012631 food intake Nutrition 0.000 description 1
• 239000008098 formaldehyde solution Substances 0.000 description 1
• 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
• 125000004281 furazan-3-yl group Chemical group [H]C1=NON=C1* 0.000 description 1
• 239000012362 glacial acetic acid Substances 0.000 description 1
• 230000004110 gluconeogenesis Effects 0.000 description 1
• 230000004153 glucose metabolism Effects 0.000 description 1
• 210000002216 heart Anatomy 0.000 description 1
• 238000004128 high performance liquid chromatography Methods 0.000 description 1
• 150000003840 hydrochlorides Chemical class 0.000 description 1
• 230000003451 hyperinsulinaemic effect Effects 0.000 description 1
• 201000008980 hyperinsulinism Diseases 0.000 description 1
• 238000005417 image-selected in vivo spectroscopy Methods 0.000 description 1
• 125000003037 imidazol-2-yl group Chemical group [H]N1C([*])=NC([H])=C1[H] 0.000 description 1
• 125000004282 imidazolidin-2-yl group Chemical group [H]N1C([H])([H])C([H])([H])N([H])C1([H])* 0.000 description 1
• 230000006872 improvement Effects 0.000 description 1
• MGXWVYUBJRZYPE-YUGYIWNOSA-N incretin Chemical class C([C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(N)=O)C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1C=CC(O)=CC=1)[C@@H](C)O)[C@@H](C)CC)C1=CC=C(O)C=C1 MGXWVYUBJRZYPE-YUGYIWNOSA-N 0.000 description 1
• 239000000859 incretin Substances 0.000 description 1
• 125000000593 indol-1-yl group Chemical group [H]C1=C([H])C([H])=C2N([*])C([H])=C([H])C2=C1[H] 0.000 description 1
• 125000002249 indol-2-yl group Chemical group [H]C1=C([H])C([H])=C2N([H])C([*])=C([H])C2=C1[H] 0.000 description 1
• 125000000814 indol-3-yl group Chemical group [H]C1=C([H])C([H])=C2N([H])C([H])=C([*])C2=C1[H] 0.000 description 1
• PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 1
• RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 1
• 239000004615 ingredient Substances 0.000 description 1
• 238000002347 injection Methods 0.000 description 1
• 239000007924 injection Substances 0.000 description 1
• 229910017053 inorganic salt Inorganic materials 0.000 description 1
• 229940125396 insulin Drugs 0.000 description 1
• 238000012739 integrated shape imaging system Methods 0.000 description 1
• 210000000936 intestine Anatomy 0.000 description 1
• 239000011630 iodine Substances 0.000 description 1
• 125000002346 iodo group Chemical group I* 0.000 description 1
• 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 description 1
• JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 1
• 125000004254 isoquinolin-1-yl group Chemical group [H]C1=C([H])C2=C([H])C([H])=C([H])C([H])=C2C(*)=N1 0.000 description 1
• 125000004551 isoquinolin-3-yl group Chemical group C1=NC(=CC2=CC=CC=C12)* 0.000 description 1
• 125000004552 isoquinolin-4-yl group Chemical group C1=NC=C(C2=CC=CC=C12)* 0.000 description 1
• GARVSVCVQCGHLY-UHFFFAOYSA-N isoquinoline-7,8-dicarboxylic acid Chemical compound C1=CN=CC2=C(C(O)=O)C(C(=O)O)=CC=C21 GARVSVCVQCGHLY-UHFFFAOYSA-N 0.000 description 1
• VMNZQPRIUSJCOH-UHFFFAOYSA-N isoquinoline-8-carboxylic acid Chemical compound C1=NC=C2C(C(=O)O)=CC=CC2=C1 VMNZQPRIUSJCOH-UHFFFAOYSA-N 0.000 description 1
• CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 description 1
• 125000004285 isoxazolidin-3-yl group Chemical group [H]N1OC([H])([H])C([H])([H])C1([H])* 0.000 description 1
• 150000002576 ketones Chemical class 0.000 description 1
• 210000003734 kidney Anatomy 0.000 description 1
• 208000017169 kidney disease Diseases 0.000 description 1
• 239000003446 ligand Substances 0.000 description 1
• 230000037356 lipid metabolism Effects 0.000 description 1
• 239000012280 lithium aluminium hydride Substances 0.000 description 1
• DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 1
• 210000004185 liver Anatomy 0.000 description 1
• 235000019341 magnesium sulphate Nutrition 0.000 description 1
• FRIJBUGBVQZNTB-UHFFFAOYSA-M magnesium;ethane;bromide Chemical compound [Mg+2].[Br-].[CH2-]C FRIJBUGBVQZNTB-UHFFFAOYSA-M 0.000 description 1
• 238000004519 manufacturing process Methods 0.000 description 1
• 238000005259 measurement Methods 0.000 description 1
• 230000009988 metabolic benefit Effects 0.000 description 1
• 230000002503 metabolic effect Effects 0.000 description 1
• 239000002207 metabolite Substances 0.000 description 1
• QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
• OKKJLVBELUTLKV-VMNATFBRSA-N methanol-d1 Chemical compound [2H]OC OKKJLVBELUTLKV-VMNATFBRSA-N 0.000 description 1
• AXGHPDQOHHPZPQ-SQKCAUCHSA-N methyl (2S)-2-amino-3-[4-(6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)phenyl]propanoate dihydrochloride Chemical compound Cl.Cl.C1=CC(C[C@H](N)C(=O)OC)=CC=C1C1=CC=NC2=C1CCC2 AXGHPDQOHHPZPQ-SQKCAUCHSA-N 0.000 description 1
• IVDOIYGHPJPXFO-PKLMIRHRSA-N methyl (2r)-2-amino-3-[4-(4-cyanophenyl)phenyl]propanoate;hydrochloride Chemical compound Cl.C1=CC(C[C@@H](N)C(=O)OC)=CC=C1C1=CC=C(C#N)C=C1 IVDOIYGHPJPXFO-PKLMIRHRSA-N 0.000 description 1
• RIPOSSZLZQIYOB-YLJLHNITSA-N methyl (2s)-2-[[(3s,8s)-3-[4-(cyclohexylmethoxy)phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]amino]-3-[4-(2,3-dimethylpyridin-4-yl)phenyl]propanoate Chemical compound C([C@@H](C(=O)OC)NC(=O)[C@H]1NCC2=CC=3O[C@H](COC=3C=C2C1)C=1C=CC(OCC2CCCCC2)=CC=1)C(C=C1)=CC=C1C1=CC=NC(C)=C1C RIPOSSZLZQIYOB-YLJLHNITSA-N 0.000 description 1
• QESUUXXYIDFJBN-VHYZKNOSSA-N methyl (2s)-2-[[(3s,8s)-7-benzoyl-3-(4-hydroxyphenyl)-3,6,8,9-tetrahydro-2h-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]amino]-3-[4-(2,3-dimethylpyridin-4-yl)phenyl]propanoate Chemical compound C([C@@H](C(=O)OC)NC(=O)[C@H]1N(CC2=CC=3O[C@H](COC=3C=C2C1)C=1C=CC(O)=CC=1)C(=O)C=1C=CC=CC=1)C(C=C1)=CC=C1C1=CC=NC(C)=C1C QESUUXXYIDFJBN-VHYZKNOSSA-N 0.000 description 1
• OOVDEPZODSXAMU-MERQFXBCSA-N methyl (2s)-2-amino-3-(4-hydroxyphenyl)-2-methylpropanoate;hydrochloride Chemical compound Cl.COC(=O)[C@@](C)(N)CC1=CC=C(O)C=C1 OOVDEPZODSXAMU-MERQFXBCSA-N 0.000 description 1
• WCDKVWFWDPQMCU-GXKRWWSZSA-N methyl (2s)-2-amino-3-(4-pyridazin-4-ylphenyl)propanoate;dihydrochloride Chemical compound Cl.Cl.C1=CC(C[C@H](N)C(=O)OC)=CC=C1C1=CC=NN=C1 WCDKVWFWDPQMCU-GXKRWWSZSA-N 0.000 description 1
• JVESDFDDVMRUSG-UTLKBRERSA-N methyl (2s)-2-amino-3-(4-pyridin-3-yloxyphenyl)propanoate;dihydrochloride Chemical compound Cl.Cl.C1=CC(C[C@H](N)C(=O)OC)=CC=C1OC1=CC=CN=C1 JVESDFDDVMRUSG-UTLKBRERSA-N 0.000 description 1
• YNTJMRFPJOFPBB-UTLKBRERSA-N methyl (2s)-2-amino-3-(4-pyridin-3-ylphenyl)propanoate;dihydrochloride Chemical compound Cl.Cl.C1=CC(C[C@H](N)C(=O)OC)=CC=C1C1=CC=CN=C1 YNTJMRFPJOFPBB-UTLKBRERSA-N 0.000 description 1
• GLGPKPQQVWBNHT-UTLKBRERSA-N methyl (2s)-2-amino-3-(4-pyridin-4-yloxyphenyl)propanoate;dihydrochloride Chemical compound Cl.Cl.C1=CC(C[C@H](N)C(=O)OC)=CC=C1OC1=CC=NC=C1 GLGPKPQQVWBNHT-UTLKBRERSA-N 0.000 description 1
• KUYHWWRTSRRQBZ-AWEZNQCLSA-N methyl (2s)-2-amino-3-(4-pyridin-4-ylphenyl)propanoate Chemical compound C1=CC(C[C@H](N)C(=O)OC)=CC=C1C1=CC=NC=C1 KUYHWWRTSRRQBZ-AWEZNQCLSA-N 0.000 description 1
• PIUNBHWGWRIUQG-LTCKWSDVSA-N methyl (2s)-2-amino-3-(4-pyrimidin-4-ylphenyl)propanoate;dihydrochloride Chemical compound Cl.Cl.C1=CC(C[C@H](N)C(=O)OC)=CC=C1C1=CC=NC=N1 PIUNBHWGWRIUQG-LTCKWSDVSA-N 0.000 description 1
• LDJINKGMHULDDJ-RMRYJAPISA-N methyl (2s)-2-amino-3-(4-quinolin-4-ylphenyl)propanoate;dihydrochloride Chemical compound Cl.Cl.C1=CC(C[C@H](N)C(=O)OC)=CC=C1C1=CC=NC2=CC=CC=C12 LDJINKGMHULDDJ-RMRYJAPISA-N 0.000 description 1
• QKUJYEXCHKMXCJ-NXCGSPNESA-N methyl (2s)-2-amino-3-[(2s)-2-[3-[(3,4-dichlorophenyl)methoxy]phenyl]-2,3-dihydro-1,4-benzodioxin-6-yl]propanoate;hydrochloride Chemical compound Cl.C=1C([C@@H]2OC3=CC=C(C=C3OC2)C[C@H](N)C(=O)OC)=CC=CC=1OCC1=CC=C(Cl)C(Cl)=C1 QKUJYEXCHKMXCJ-NXCGSPNESA-N 0.000 description 1
• WZQQREOQRMDGBG-GXKRWWSZSA-N methyl (2s)-2-amino-3-[4-(1-methylpyrazol-4-yl)phenyl]propanoate;dihydrochloride Chemical compound Cl.Cl.C1=CC(C[C@H](N)C(=O)OC)=CC=C1C1=CN(C)N=C1 WZQQREOQRMDGBG-GXKRWWSZSA-N 0.000 description 1
• BOFVVYUFGLYKPK-ZOWNYOTGSA-N methyl (2s)-2-amino-3-[4-(2,5-dimethylpyrazol-3-yl)phenyl]propanoate;hydrochloride Chemical compound Cl.C1=CC(C[C@H](N)C(=O)OC)=CC=C1C1=CC(C)=NN1C BOFVVYUFGLYKPK-ZOWNYOTGSA-N 0.000 description 1
• KZJUKZLKCIDTJH-SQKCAUCHSA-N methyl (2s)-2-amino-3-[4-(2,5-dimethylpyridin-4-yl)phenyl]propanoate;dihydrochloride Chemical compound Cl.Cl.C1=CC(C[C@H](N)C(=O)OC)=CC=C1C1=CC(C)=NC=C1C KZJUKZLKCIDTJH-SQKCAUCHSA-N 0.000 description 1
• ADUBVOOKGZJCOK-LTCKWSDVSA-N methyl (2s)-2-amino-3-[4-(2,6-difluoropyridin-4-yl)phenyl]propanoate;dihydrochloride Chemical compound Cl.Cl.C1=CC(C[C@H](N)C(=O)OC)=CC=C1C1=CC(F)=NC(F)=C1 ADUBVOOKGZJCOK-LTCKWSDVSA-N 0.000 description 1
• WFIWHWIZKZQLQS-SQKCAUCHSA-N methyl (2s)-2-amino-3-[4-(2,6-dimethylpyridin-4-yl)phenyl]propanoate;dihydrochloride Chemical compound Cl.Cl.C1=CC(C[C@H](N)C(=O)OC)=CC=C1C1=CC(C)=NC(C)=C1 WFIWHWIZKZQLQS-SQKCAUCHSA-N 0.000 description 1
• ZOXHCJRTMIFOOK-GXKRWWSZSA-N methyl (2s)-2-amino-3-[4-(2-aminopyridin-4-yl)phenyl]propanoate;dihydrochloride Chemical compound Cl.Cl.C1=CC(C[C@H](N)C(=O)OC)=CC=C1C1=CC=NC(N)=C1 ZOXHCJRTMIFOOK-GXKRWWSZSA-N 0.000 description 1
• MMRUERBYEIBSEU-LTCKWSDVSA-N methyl (2s)-2-amino-3-[4-(2-aminopyrimidin-5-yl)phenyl]propanoate;dihydrochloride Chemical compound Cl.Cl.C1=CC(C[C@H](N)C(=O)OC)=CC=C1C1=CN=C(N)N=C1 MMRUERBYEIBSEU-LTCKWSDVSA-N 0.000 description 1
• FXKGJSZSGGMWLG-SQKCAUCHSA-N methyl (2s)-2-amino-3-[4-(2-ethylpyridin-4-yl)phenyl]propanoate;dihydrochloride Chemical compound Cl.Cl.C1=NC(CC)=CC(C=2C=CC(C[C@H](N)C(=O)OC)=CC=2)=C1 FXKGJSZSGGMWLG-SQKCAUCHSA-N 0.000 description 1
• HTKCBDIOOBGMHO-GXKRWWSZSA-N methyl (2s)-2-amino-3-[4-(2-fluoropyridin-4-yl)phenyl]propanoate;dihydrochloride Chemical compound Cl.Cl.C1=CC(C[C@H](N)C(=O)OC)=CC=C1C1=CC=NC(F)=C1 HTKCBDIOOBGMHO-GXKRWWSZSA-N 0.000 description 1
• VEEWDEKPXLEUIK-UTLKBRERSA-N methyl (2s)-2-amino-3-[4-(2-methoxypyridin-4-yl)phenyl]propanoate;dihydrochloride Chemical compound Cl.Cl.C1=CC(C[C@H](N)C(=O)OC)=CC=C1C1=CC=NC(OC)=C1 VEEWDEKPXLEUIK-UTLKBRERSA-N 0.000 description 1
• HBIVMGDVKRRTDK-LTCKWSDVSA-N methyl (2s)-2-amino-3-[4-(2-methylpyrazol-3-yl)phenyl]propanoate;dihydrochloride Chemical compound Cl.Cl.C1=CC(C[C@H](N)C(=O)OC)=CC=C1C1=CC=NN1C HBIVMGDVKRRTDK-LTCKWSDVSA-N 0.000 description 1
• HMKJGFLHCXAJFP-CKUXDGONSA-N methyl (2s)-2-amino-3-[4-(2-methylpyridin-4-yl)oxyphenyl]propanoate;dihydrochloride Chemical compound Cl.Cl.C1=CC(C[C@H](N)C(=O)OC)=CC=C1OC1=CC=NC(C)=C1 HMKJGFLHCXAJFP-CKUXDGONSA-N 0.000 description 1
• QLEXCAHRRZTNCN-CKUXDGONSA-N methyl (2s)-2-amino-3-[4-(2-methylpyridin-4-yl)phenyl]propanoate;dihydrochloride Chemical compound Cl.Cl.C1=CC(C[C@H](N)C(=O)OC)=CC=C1C1=CC=NC(C)=C1 QLEXCAHRRZTNCN-CKUXDGONSA-N 0.000 description 1
• HOFRMLCEWFGDSO-GXKRWWSZSA-N methyl (2s)-2-amino-3-[4-(2-oxo-1h-pyridin-4-yl)phenyl]propanoate;dihydrochloride Chemical compound Cl.Cl.C1=CC(C[C@H](N)C(=O)OC)=CC=C1C1=CC=NC(O)=C1 HOFRMLCEWFGDSO-GXKRWWSZSA-N 0.000 description 1
• KDBKOPUMAFHOPX-SQKCAUCHSA-N methyl (2s)-2-amino-3-[4-(2-propan-2-ylpyridin-4-yl)phenyl]propanoate;dihydrochloride Chemical compound Cl.Cl.C1=CC(C[C@H](N)C(=O)OC)=CC=C1C1=CC=NC(C(C)C)=C1 KDBKOPUMAFHOPX-SQKCAUCHSA-N 0.000 description 1
• SCYCMIXUYFJDKF-RMRYJAPISA-N methyl (2s)-2-amino-3-[4-(2-propylpyridin-4-yl)phenyl]propanoate;dihydrochloride Chemical compound Cl.Cl.C1=NC(CCC)=CC(C=2C=CC(C[C@H](N)C(=O)OC)=CC=2)=C1 SCYCMIXUYFJDKF-RMRYJAPISA-N 0.000 description 1
• YHERHCNWQURTLQ-UTLKBRERSA-N methyl (2s)-2-amino-3-[4-(3-fluoropyridin-4-yl)phenyl]propanoate;dihydrochloride Chemical compound Cl.Cl.C1=CC(C[C@H](N)C(=O)OC)=CC=C1C1=CC=NC=C1F YHERHCNWQURTLQ-UTLKBRERSA-N 0.000 description 1
• GSOMWHZFPZNEMX-UTLKBRERSA-N methyl (2s)-2-amino-3-[4-(3-methoxypyridin-4-yl)phenyl]propanoate;dihydrochloride Chemical compound Cl.Cl.C1=CC(C[C@H](N)C(=O)OC)=CC=C1C1=CC=NC=C1OC GSOMWHZFPZNEMX-UTLKBRERSA-N 0.000 description 1
• CHHIPTRCZWLGBL-CKUXDGONSA-N methyl (2s)-2-amino-3-[4-(3-methylpyridin-4-yl)phenyl]propanoate;dihydrochloride Chemical compound Cl.Cl.C1=CC(C[C@H](N)C(=O)OC)=CC=C1C1=CC=NC=C1C CHHIPTRCZWLGBL-CKUXDGONSA-N 0.000 description 1
• SWJBPEXDUCZVHQ-HNNXBMFYSA-N methyl (2s)-2-amino-3-[4-(4-chlorophenyl)phenyl]propanoate Chemical compound C1=CC(C[C@H](N)C(=O)OC)=CC=C1C1=CC=C(Cl)C=C1 SWJBPEXDUCZVHQ-HNNXBMFYSA-N 0.000 description 1
• QGCPUNGQJSRSQM-NTISSMGPSA-N methyl (2s)-2-amino-3-[4-(4-cyano-3-fluorophenyl)phenyl]propanoate;hydrochloride Chemical compound Cl.C1=CC(C[C@H](N)C(=O)OC)=CC=C1C1=CC=C(C#N)C(F)=C1 QGCPUNGQJSRSQM-NTISSMGPSA-N 0.000 description 1
• NMCROLOVMHXPSL-HNNXBMFYSA-N methyl (2s)-2-amino-3-[4-(4-fluorophenyl)phenyl]propanoate Chemical compound C1=CC(C[C@H](N)C(=O)OC)=CC=C1C1=CC=C(F)C=C1 NMCROLOVMHXPSL-HNNXBMFYSA-N 0.000 description 1
• ZXBQZVMJOHLRPQ-INIZCTEOSA-N methyl (2s)-2-amino-3-[4-(4-methoxyphenyl)phenyl]propanoate Chemical compound C1=CC(C[C@H](N)C(=O)OC)=CC=C1C1=CC=C(OC)C=C1 ZXBQZVMJOHLRPQ-INIZCTEOSA-N 0.000 description 1
• BOZVHPFMZPKTRE-INIZCTEOSA-N methyl (2s)-2-amino-3-[4-(4-methylphenyl)phenyl]propanoate Chemical compound C1=CC(C[C@H](N)C(=O)OC)=CC=C1C1=CC=C(C)C=C1 BOZVHPFMZPKTRE-INIZCTEOSA-N 0.000 description 1
• FWBUCIPBENKDCL-GXKRWWSZSA-N methyl (2s)-2-amino-3-[4-(6-aminopyridin-3-yl)phenyl]propanoate;dihydrochloride Chemical compound Cl.Cl.C1=CC(C[C@H](N)C(=O)OC)=CC=C1C1=CC=C(N)N=C1 FWBUCIPBENKDCL-GXKRWWSZSA-N 0.000 description 1
• UZQNTNOCMBHTHJ-CKUXDGONSA-N methyl (2s)-2-amino-3-[4-(6-methylpyridin-3-yl)phenyl]propanoate;dihydrochloride Chemical compound Cl.Cl.C1=CC(C[C@H](N)C(=O)OC)=CC=C1C1=CC=C(C)N=C1 UZQNTNOCMBHTHJ-CKUXDGONSA-N 0.000 description 1
• WNBCFEWMVAWWRM-GXKRWWSZSA-N methyl (2s)-2-amino-3-[4-[2-(trifluoromethyl)pyridin-4-yl]phenyl]propanoate;dihydrochloride Chemical compound Cl.Cl.C1=CC(C[C@H](N)C(=O)OC)=CC=C1C1=CC=NC(C(F)(F)F)=C1 WNBCFEWMVAWWRM-GXKRWWSZSA-N 0.000 description 1
• GJKXBQRPEONFLG-CKUXDGONSA-N methyl (2s)-2-amino-3-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]propanoate;dihydrochloride Chemical compound Cl.Cl.C1=CC(C[C@H](N)C(=O)OC)=CC=C1C1=CC=C(N(C)C)N=C1 GJKXBQRPEONFLG-CKUXDGONSA-N 0.000 description 1
• HTGCHTIDQKPGIA-CKUXDGONSA-N methyl (2s)-2-amino-3-[4-[6-(hydroxymethyl)pyridin-3-yl]phenyl]propanoate;dihydrochloride Chemical compound Cl.Cl.C1=CC(C[C@H](N)C(=O)OC)=CC=C1C1=CC=C(CO)N=C1 HTGCHTIDQKPGIA-CKUXDGONSA-N 0.000 description 1
• OLODBSAKHNXKPY-NSHDSACASA-N methyl (2s)-3-(3-bromo-4-hydroxyphenyl)-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoate Chemical compound CC(C)(C)OC(=O)N[C@H](C(=O)OC)CC1=CC=C(O)C(Br)=C1 OLODBSAKHNXKPY-NSHDSACASA-N 0.000 description 1
• AGWKPQQUZAALHO-IBGZPJMESA-N methyl (2s)-3-(4-hydroxyphenyl)-2-methyl-2-(phenylmethoxycarbonylamino)propanoate Chemical compound C([C@@](C)(C(=O)OC)NC(=O)OCC=1C=CC=CC=1)C1=CC=C(O)C=C1 AGWKPQQUZAALHO-IBGZPJMESA-N 0.000 description 1
• DNAFOSMJBHMVEX-IGKIAQTJSA-N methyl (2s)-3-[(2r)-2-[4-[(3,4-dichlorophenyl)methoxy]phenyl]-2,3-dihydro-1,4-benzodioxin-6-yl]-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoate Chemical compound C1=CC([C@H]2OC3=CC=C(C=C3OC2)C[C@@H](C(=O)OC)NC(=O)OC(C)(C)C)=CC=C1OCC1=CC=C(Cl)C(Cl)=C1 DNAFOSMJBHMVEX-IGKIAQTJSA-N 0.000 description 1
• FHUMOBVHYICPOI-FIBWVYCGSA-N methyl (2s)-3-[(2r)-2-[4-[(3,4-dichlorophenyl)methoxy]phenyl]-2,3-dihydro-1,4-benzodioxin-6-yl]-2-[(4-nitrophenyl)sulfonylamino]propanoate Chemical compound C1=CC([C@H]2OC3=CC=C(C=C3OC2)C[C@@H](C(=O)OC)NS(=O)(=O)C=2C=CC(=CC=2)[N+]([O-])=O)=CC=C1OCC1=CC=C(Cl)C(Cl)=C1 FHUMOBVHYICPOI-FIBWVYCGSA-N 0.000 description 1
• PPAPOWBYYFKEST-NGCAANIMSA-N methyl (2s)-3-[(2r)-2-[4-[(3,4-dichlorophenyl)methoxy]phenyl]-2,3-dihydro-1,4-benzodioxin-6-yl]-2-[[(1s)-1-phenylpropyl]amino]propanoate Chemical compound C1=CC([C@H]2OC3=CC=C(C=C3OC2)C[C@H](N[C@@H](CC)C=2C=CC=CC=2)C(=O)OC)=CC=C1OCC1=CC=C(Cl)C(Cl)=C1 PPAPOWBYYFKEST-NGCAANIMSA-N 0.000 description 1
• ZOSBOGJFIOVFCW-ODTVBPJYSA-N methyl (2s)-3-[(2s)-2-(4-acetyloxyphenyl)-2,3-dihydro-1,4-benzodioxin-6-yl]-2-[(4-nitrophenyl)sulfonyl-[(1s)-1-phenylpropyl]amino]propanoate Chemical compound C1([C@@H]2OC3=CC=C(C=C3OC2)C[C@H](N([C@@H](CC)C=2C=CC=CC=2)S(=O)(=O)C=2C=CC(=CC=2)[N+]([O-])=O)C(=O)OC)=CC=C(OC(C)=O)C=C1 ZOSBOGJFIOVFCW-ODTVBPJYSA-N 0.000 description 1
• OGDLZKANMRDWRF-PNIUZAESSA-N methyl (2s)-3-[(2s)-2-(4-acetyloxyphenyl)-2,3-dihydro-1,4-benzodioxin-6-yl]-2-[[(1s)-1-phenylpropyl]amino]propanoate Chemical compound C1([C@@H]2OC3=CC=C(C=C3OC2)C[C@H](N[C@@H](CC)C=2C=CC=CC=2)C(=O)OC)=CC=C(OC(C)=O)C=C1 OGDLZKANMRDWRF-PNIUZAESSA-N 0.000 description 1
• YLBJCHJGSFAUQU-QFBILLFUSA-N methyl (2s)-3-[(2s)-2-(4-acetyloxyphenyl)-2,3-dihydro-1,4-benzodioxin-6-yl]-2-aminopropanoate Chemical compound C1([C@@H]2OC3=CC=C(C=C3OC2)C[C@H](N)C(=O)OC)=CC=C(OC(C)=O)C=C1 YLBJCHJGSFAUQU-QFBILLFUSA-N 0.000 description 1
• XMDDUGULQPUMIB-JCYRPKCISA-N methyl (2s)-3-[(2s)-2-(4-hydroxyphenyl)-2,3-dihydro-1,4-benzodioxin-6-yl]-2-[[(1s)-1-phenylpropyl]amino]propanoate Chemical compound C1([C@@H]2OC3=CC=C(C=C3OC2)C[C@H](N[C@@H](CC)C=2C=CC=CC=2)C(=O)OC)=CC=C(O)C=C1 XMDDUGULQPUMIB-JCYRPKCISA-N 0.000 description 1
• XVWMHDVHFPHVOB-RPLLCQBOSA-N methyl (2s)-3-[(2s)-2-[3-[(3,4-dichlorophenyl)methoxy]phenyl]-2,3-dihydro-1,4-benzodioxin-6-yl]-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoate Chemical compound C=1C([C@@H]2OC3=CC=C(C=C3OC2)C[C@@H](C(=O)OC)NC(=O)OC(C)(C)C)=CC=CC=1OCC1=CC=C(Cl)C(Cl)=C1 XVWMHDVHFPHVOB-RPLLCQBOSA-N 0.000 description 1
• WGXVUDWIBURIEX-VHYZKNOSSA-N methyl (2s)-3-[(2s)-2-[3-[(3,4-dichlorophenyl)methoxy]phenyl]-2,3-dihydro-1,4-benzodioxin-6-yl]-2-[(4-nitrophenyl)sulfonyl-[(1s)-1-phenylpropyl]amino]propanoate Chemical compound C=1C([C@@H]2OC3=CC=C(C=C3OC2)C[C@H](N([C@@H](CC)C=2C=CC=CC=2)S(=O)(=O)C=2C=CC(=CC=2)[N+]([O-])=O)C(=O)OC)=CC=CC=1OCC1=CC=C(Cl)C(Cl)=C1 WGXVUDWIBURIEX-VHYZKNOSSA-N 0.000 description 1
• DNAFOSMJBHMVEX-RPLLCQBOSA-N methyl (2s)-3-[(2s)-2-[4-[(3,4-dichlorophenyl)methoxy]phenyl]-2,3-dihydro-1,4-benzodioxin-6-yl]-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoate Chemical compound C1=CC([C@@H]2OC3=CC=C(C=C3OC2)C[C@@H](C(=O)OC)NC(=O)OC(C)(C)C)=CC=C1OCC1=CC=C(Cl)C(Cl)=C1 DNAFOSMJBHMVEX-RPLLCQBOSA-N 0.000 description 1
• PPAPOWBYYFKEST-WSZLSEGOSA-N methyl (2s)-3-[(2s)-2-[4-[(3,4-dichlorophenyl)methoxy]phenyl]-2,3-dihydro-1,4-benzodioxin-6-yl]-2-[[(1s)-1-phenylpropyl]amino]propanoate Chemical compound C1=CC([C@@H]2OC3=CC=C(C=C3OC2)C[C@H](N[C@@H](CC)C=2C=CC=CC=2)C(=O)OC)=CC=C1OCC1=CC=C(Cl)C(Cl)=C1 PPAPOWBYYFKEST-WSZLSEGOSA-N 0.000 description 1
• LXOYICPHPKAIRO-YDNXMHBPSA-N methyl (2s)-3-[2-(4-acetyloxyphenyl)-2,3-dihydro-1,4-benzodioxin-6-yl]-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoate Chemical compound C1OC2=CC(C[C@@H](C(=O)OC)NC(=O)OC(C)(C)C)=CC=C2OC1C1=CC=C(OC(C)=O)C=C1 LXOYICPHPKAIRO-YDNXMHBPSA-N 0.000 description 1
• DNAFOSMJBHMVEX-BXXZMZEQSA-N methyl (2s)-3-[2-[4-[(3,4-dichlorophenyl)methoxy]phenyl]-2,3-dihydro-1,4-benzodioxin-6-yl]-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoate Chemical compound C1OC2=CC(C[C@@H](C(=O)OC)NC(=O)OC(C)(C)C)=CC=C2OC1C(C=C1)=CC=C1OCC1=CC=C(Cl)C(Cl)=C1 DNAFOSMJBHMVEX-BXXZMZEQSA-N 0.000 description 1
• CPHKMDBOUKBUGH-ROYBKCIRSA-N methyl (2s)-3-[4-(4-cyanophenyl)phenyl]-2-[[(3s,8s)-3-[4-[(3,4-dichlorophenyl)methoxy]phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]amino]propanoate;hydrochloride Chemical compound Cl.C([C@@H](C(=O)OC)NC(=O)[C@H]1NCC2=CC=3O[C@H](COC=3C=C2C1)C=1C=CC(OCC=2C=C(Cl)C(Cl)=CC=2)=CC=1)C(C=C1)=CC=C1C1=CC=C(C#N)C=C1 CPHKMDBOUKBUGH-ROYBKCIRSA-N 0.000 description 1
• LPDXYVVKLAIOTG-QRPNPIFTSA-N methyl (3s)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylate;hydrochloride Chemical compound Cl.OC1=C(O)C=C2CN[C@H](C(=O)OC)CC2=C1 LPDXYVVKLAIOTG-QRPNPIFTSA-N 0.000 description 1
• JZBIYTPQIYMPQM-JYFHCDHNSA-N methyl (3s,8s)-3-(4-acetyloxyphenyl)-7-benzoyl-3,6,8,9-tetrahydro-2h-[1,4]dioxino[2,3-g]isoquinoline-8-carboxylate Chemical compound O([C@H](COC=1C=C2C[C@H]3C(=O)OC)C=4C=CC(OC(C)=O)=CC=4)C=1C=C2CN3C(=O)C1=CC=CC=C1 JZBIYTPQIYMPQM-JYFHCDHNSA-N 0.000 description 1
• AVDQGIMBHNKULH-NLJOTIRTSA-N methyl (3s,8s)-3-(4-hydroxyphenyl)-7-[(1s)-1-phenylpropyl]-3,6,8,9-tetrahydro-2h-[1,4]dioxino[2,3-g]isoquinoline-8-carboxylate Chemical compound C1([C@@H]2OC=3C=C4CN([C@@H](CC4=CC=3OC2)C(=O)OC)[C@@H](CC)C=2C=CC=CC=2)=CC=C(O)C=C1 AVDQGIMBHNKULH-NLJOTIRTSA-N 0.000 description 1
• LTCNMAXNNIYTLU-UHFFFAOYSA-N methyl 2-[4-[(3,4-dichlorophenyl)methoxy]phenyl]-2-hydroxyacetate Chemical compound C1=CC(C(O)C(=O)OC)=CC=C1OCC1=CC=C(Cl)C(Cl)=C1 LTCNMAXNNIYTLU-UHFFFAOYSA-N 0.000 description 1
• SNRYGKFTMWDHME-UHFFFAOYSA-N methyl 2-amino-3-[4-(6-cyanopyridin-3-yl)phenyl]propanoate;dihydrochloride Chemical compound Cl.Cl.C1=CC(CC(N)C(=O)OC)=CC=C1C1=CC=C(C#N)N=C1 SNRYGKFTMWDHME-UHFFFAOYSA-N 0.000 description 1
• KSKRPHSHPQTWJK-HHHXNRCGSA-N methyl 3-[(2S)-2-[4-[(3,4-dichlorophenyl)methoxy]phenyl]-2,3-dihydro-1,4-benzodioxin-6-yl]-2-[(2-methylpropan-2-yl)oxycarbonylamino]prop-2-enoate Chemical compound C1=CC([C@@H]2OC3=CC=C(C=C3OC2)C=C(NC(=O)OC(C)(C)C)C(=O)OC)=CC=C1OCC1=CC=C(Cl)C(Cl)=C1 KSKRPHSHPQTWJK-HHHXNRCGSA-N 0.000 description 1
• 125000004312 morpholin-2-yl group Chemical group [H]N1C([H])([H])C([H])([H])OC([H])(*)C1([H])[H] 0.000 description 1
• 125000004572 morpholin-3-yl group Chemical group N1C(COCC1)* 0.000 description 1
• 125000002757 morpholinyl group Chemical group 0.000 description 1
• HJZGXXPOKWGQHH-UHFFFAOYSA-N n-(4-phenyl-1,3-thiazol-2-yl)acetamide Chemical compound S1C(NC(=O)C)=NC(C=2C=CC=CC=2)=C1 HJZGXXPOKWGQHH-UHFFFAOYSA-N 0.000 description 1
• IHZJIMFVFYNPMM-UHFFFAOYSA-N n-(5-amino-4-methylpyridin-2-yl)acetamide Chemical compound CC(=O)NC1=CC(C)=C(N)C=N1 IHZJIMFVFYNPMM-UHFFFAOYSA-N 0.000 description 1
• MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 1
• 125000001624 naphthyl group Chemical group 0.000 description 1
• 230000000955 neuroendocrine Effects 0.000 description 1
• 201000001119 neuropathy Diseases 0.000 description 1
• 230000007823 neuropathy Effects 0.000 description 1
• 238000006396 nitration reaction Methods 0.000 description 1
• 125000006574 non-aromatic ring group Chemical group 0.000 description 1
• 231100000252 nontoxic Toxicity 0.000 description 1
• 230000003000 nontoxic effect Effects 0.000 description 1
• 102000006255 nuclear receptors Human genes 0.000 description 1
• 108020004017 nuclear receptors Proteins 0.000 description 1
• 229940126701 oral medication Drugs 0.000 description 1
• 239000010502 orange oil Substances 0.000 description 1
• 210000000056 organ Anatomy 0.000 description 1
• 125000004288 oxazolidin-2-yl group Chemical group [H]N1C([H])([H])C([H])([H])OC1([H])* 0.000 description 1
• LVSJDHGRKAEGLX-UHFFFAOYSA-N oxolane;2,2,2-trifluoroacetic acid Chemical compound C1CCOC1.OC(=O)C(F)(F)F LVSJDHGRKAEGLX-UHFFFAOYSA-N 0.000 description 1
• YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 1
• 230000001991 pathophysiological effect Effects 0.000 description 1
• 230000035778 pathophysiological process Effects 0.000 description 1
• 239000008188 pellet Substances 0.000 description 1
• 239000000813 peptide hormone Substances 0.000 description 1
• 125000006551 perfluoro alkylene group Chemical group 0.000 description 1
• 230000002093 peripheral effect Effects 0.000 description 1
• 210000002856 peripheral neuron Anatomy 0.000 description 1
• 208000033808 peripheral neuropathy Diseases 0.000 description 1
• 239000008177 pharmaceutical agent Substances 0.000 description 1
• 125000001791 phenazinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3N=C12)* 0.000 description 1
• 150000002989 phenols Chemical class 0.000 description 1
• AHWALFGBDFAJAI-UHFFFAOYSA-N phenyl carbonochloridate Chemical compound ClC(=O)OC1=CC=CC=C1 AHWALFGBDFAJAI-UHFFFAOYSA-N 0.000 description 1
• 230000035790 physiological processes and functions Effects 0.000 description 1
• 125000004193 piperazinyl group Chemical group 0.000 description 1
• 125000004574 piperidin-2-yl group Chemical group N1C(CCCC1)* 0.000 description 1
• 125000004483 piperidin-3-yl group Chemical group N1CC(CCC1)* 0.000 description 1
• 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 description 1
• 230000008092 positive effect Effects 0.000 description 1
• SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 1
• GCYXWQUSHADNBF-AAEALURTSA-N preproglucagon 78-108 Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1N=CNC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 GCYXWQUSHADNBF-AAEALURTSA-N 0.000 description 1
• 230000002265 prevention Effects 0.000 description 1
• 102000004196 processed proteins & peptides Human genes 0.000 description 1
• VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-UHFFFAOYSA-N 0.000 description 1
• 230000000069 prophylactic effect Effects 0.000 description 1
• 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
• 230000017854 proteolysis Effects 0.000 description 1
• 125000001042 pteridinyl group Chemical group N1=C(N=CC2=NC=CN=C12)* 0.000 description 1
• 239000012264 purified product Substances 0.000 description 1
• 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
• 125000004290 pyrazolidin-3-yl group Chemical group [H]N1N([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
• 125000003072 pyrazolidinyl group Chemical group 0.000 description 1
• 125000004159 quinolin-2-yl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C([H])C(*)=NC2=C1[H] 0.000 description 1
• 125000004548 quinolin-3-yl group Chemical group N1=CC(=CC2=CC=CC=C12)* 0.000 description 1
• 125000004549 quinolin-4-yl group Chemical group N1=CC=C(C2=CC=CC=C12)* 0.000 description 1
• 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
• 238000011160 research Methods 0.000 description 1
• VEMKTZHHVJILDY-UHFFFAOYSA-N resmethrin Chemical compound CC1(C)C(C=C(C)C)C1C(=O)OCC1=COC(CC=2C=CC=CC=2)=C1 VEMKTZHHVJILDY-UHFFFAOYSA-N 0.000 description 1
• 230000004044 response Effects 0.000 description 1
• 230000003979 response to food Effects 0.000 description 1
• 238000007363 ring formation reaction Methods 0.000 description 1
• 229930195734 saturated hydrocarbon Natural products 0.000 description 1
• 239000012047 saturated solution Substances 0.000 description 1
• 239000002002 slurry Substances 0.000 description 1
• 150000003384 small molecules Chemical class 0.000 description 1
• 239000011780 sodium chloride Substances 0.000 description 1
• BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
• 239000004317 sodium nitrate Substances 0.000 description 1
• 235000010344 sodium nitrate Nutrition 0.000 description 1
• PVGBHEUCHKGFQP-UHFFFAOYSA-N sodium;n-[5-amino-2-(4-aminophenyl)sulfonylphenyl]sulfonylacetamide Chemical compound [Na+].CC(=O)NS(=O)(=O)C1=CC(N)=CC=C1S(=O)(=O)C1=CC=C(N)C=C1 PVGBHEUCHKGFQP-UHFFFAOYSA-N 0.000 description 1
• 239000011343 solid material Substances 0.000 description 1
• 238000000527 sonication Methods 0.000 description 1
• 241000894007 species Species 0.000 description 1
• 239000007921 spray Substances 0.000 description 1
• 239000007929 subcutaneous injection Substances 0.000 description 1
• 238000010254 subcutaneous injection Methods 0.000 description 1
• PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical compound [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 description 1
• 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
• QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
• 230000001629 suppression Effects 0.000 description 1
• 230000002194 synthesizing effect Effects 0.000 description 1
• YZPVIRDQSFKCJS-RNMNAOLMSA-N tert-butyl (3r,8s)-3-[4-[(3,4-dichlorophenyl)methoxy]phenyl]-8-[[(2s)-3-[4-(2,3-dimethylpyridin-4-yl)phenyl]-1-methoxy-1-oxopropan-2-yl]carbamoyl]-3,6,8,9-tetrahydro-2h-[1,4]dioxino[2,3-g]isoquinoline-7-carboxylate Chemical compound C([C@@H](C(=O)OC)NC(=O)[C@H]1N(CC2=CC=3O[C@@H](COC=3C=C2C1)C=1C=CC(OCC=2C=C(Cl)C(Cl)=CC=2)=CC=1)C(=O)OC(C)(C)C)C(C=C1)=CC=C1C1=CC=NC(C)=C1C YZPVIRDQSFKCJS-RNMNAOLMSA-N 0.000 description 1
• NAJRDKZEBVDHFC-TYQMUXPXSA-N tert-butyl (3s,8s)-3-[3-[(3,4-dichlorophenyl)methoxy]phenyl]-8-[[(2s)-3-[4-(2,3-dimethylpyridin-4-yl)oxyphenyl]-1-methoxy-1-oxopropan-2-yl]carbamoyl]-3,6,8,9-tetrahydro-2h-[1,4]dioxino[2,3-g]isoquinoline-7-carboxylate Chemical compound C([C@@H](C(=O)OC)NC(=O)[C@H]1N(CC2=CC=3O[C@H](COC=3C=C2C1)C=1C=C(OCC=2C=C(Cl)C(Cl)=CC=2)C=CC=1)C(=O)OC(C)(C)C)C(C=C1)=CC=C1OC1=CC=NC(C)=C1C NAJRDKZEBVDHFC-TYQMUXPXSA-N 0.000 description 1
• FVVBJJMPVXUBQZ-VLSLJKOQSA-N tert-butyl (3s,8s)-8-[[(2s)-3-[4-(2,3-dimethylpyridin-4-yl)phenyl]-1-methoxy-1-oxopropan-2-yl]carbamoyl]-3-(4-hydroxyphenyl)-3,6,8,9-tetrahydro-2h-[1,4]dioxino[2,3-g]isoquinoline-7-carboxylate Chemical compound C([C@@H](C(=O)OC)NC(=O)[C@H]1N(CC2=CC=3O[C@H](COC=3C=C2C1)C=1C=CC(O)=CC=1)C(=O)OC(C)(C)C)C(C=C1)=CC=C1C1=CC=NC(C)=C1C FVVBJJMPVXUBQZ-VLSLJKOQSA-N 0.000 description 1
• QWTOBIKHNFOXGS-UHFFFAOYSA-N tert-butyl 3,6,8,9-tetrahydro-2H-[1,4]dioxino[2,3-g]isoquinoline-7-carboxylate Chemical compound C(C)(C)(C)OC(=O)N1CC=2C=C3C(=CC=2CC1)OCCO3 QWTOBIKHNFOXGS-UHFFFAOYSA-N 0.000 description 1
• BDQIJTVAKAGCHG-UHFFFAOYSA-N tert-butyl 6h-[1,4]dioxino[2,3-g]isoquinoline-7-carboxylate Chemical compound O1C=COC2=C1C=C1CN(C(=O)OC(C)(C)C)C=CC1=C2 BDQIJTVAKAGCHG-UHFFFAOYSA-N 0.000 description 1
• XMXIFYUQKOMUJR-UHFFFAOYSA-N tert-butyl n-[5-(bromomethyl)-4-methyl-1,3-thiazol-2-yl]carbamate Chemical compound CC=1N=C(NC(=O)OC(C)(C)C)SC=1CBr XMXIFYUQKOMUJR-UHFFFAOYSA-N 0.000 description 1
• JKBGHFXEMZZLFY-UHFFFAOYSA-N tert-butyl n-[5-(bromomethyl)pyridin-2-yl]carbamate Chemical compound CC(C)(C)OC(=O)NC1=CC=C(CBr)C=N1 JKBGHFXEMZZLFY-UHFFFAOYSA-N 0.000 description 1
• BORDVYKLAFQRSP-UHFFFAOYSA-N tert-butyl n-[5-(hydroxymethyl)pyridin-2-yl]carbamate Chemical compound CC(C)(C)OC(=O)NC1=CC=C(CO)C=N1 BORDVYKLAFQRSP-UHFFFAOYSA-N 0.000 description 1
• MHYGQXWCZAYSLJ-UHFFFAOYSA-N tert-butyl-chloro-diphenylsilane Chemical compound C=1C=CC=CC=1[Si](Cl)(C(C)(C)C)C1=CC=CC=C1 MHYGQXWCZAYSLJ-UHFFFAOYSA-N 0.000 description 1
• 150000003512 tertiary amines Chemical class 0.000 description 1
• 125000004192 tetrahydrofuran-2-yl group Chemical group [H]C1([H])OC([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
• 125000004187 tetrahydropyran-2-yl group Chemical group [H]C1([H])OC([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
• 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
• RAOIDOHSFRTOEL-UHFFFAOYSA-N tetrahydrothiophene Chemical compound C1CCSC1 RAOIDOHSFRTOEL-UHFFFAOYSA-N 0.000 description 1
• CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
• 229940124597 therapeutic agent Drugs 0.000 description 1
• 238000002560 therapeutic procedure Methods 0.000 description 1
• 125000000437 thiazol-2-yl group Chemical group [H]C1=C([H])N=C(*)S1 0.000 description 1
• 125000004300 thiazolidin-2-yl group Chemical group [H]N1C([H])([H])C([H])([H])SC1([H])* 0.000 description 1
• 125000003396 thiol group Chemical group [H]S* 0.000 description 1
• 125000004569 thiomorpholin-2-yl group Chemical group N1CC(SCC1)* 0.000 description 1
• 125000004570 thiomorpholin-3-yl group Chemical group N1C(CSCC1)* 0.000 description 1
• 229930192474 thiophene Natural products 0.000 description 1
• 231100000419 toxicity Toxicity 0.000 description 1
• 230000001988 toxicity Effects 0.000 description 1
• 230000037317 transdermal delivery Effects 0.000 description 1
• UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 1
• NHDIQVFFNDKAQU-UHFFFAOYSA-N tripropan-2-yl borate Chemical compound CC(C)OB(OC(C)C)OC(C)C NHDIQVFFNDKAQU-UHFFFAOYSA-N 0.000 description 1
• LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
• 238000001665 trituration Methods 0.000 description 1
• AQLJVWUFPCUVLO-UHFFFAOYSA-N urea hydrogen peroxide Chemical compound OO.NC(N)=O AQLJVWUFPCUVLO-UHFFFAOYSA-N 0.000 description 1
• 238000010200 validation analysis Methods 0.000 description 1
• 210000005166 vasculature Anatomy 0.000 description 1
• 239000003981 vehicle Substances 0.000 description 1
• 238000005406 washing Methods 0.000 description 1
• 238000010626 work up procedure Methods 0.000 description 1