KR101732978B1 - 치환된 아조안트라센 유도체, 약제학적 조성물, 및 그것의 사용방법 - Google Patents

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Publication number

KR101732978B1

KR101732978B1 KR1020117024153A KR20117024153A KR101732978B1 KR 101732978 B1 KR101732978 B1 KR 101732978B1 KR 1020117024153 A KR1020117024153 A KR 1020117024153A KR 20117024153 A KR20117024153 A KR 20117024153A KR 101732978 B1 KR101732978 B1 KR 101732978B1

Authority

KR

South Korea

Prior art keywords

phenyl

carbonyl

isoquinoline

dioxino

compound

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.)

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• 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 24
• 238000000034 method Methods 0.000 title claims description 95
• 150000001875 compounds Chemical class 0.000 claims abstract description 298
• 239000000203 mixture Substances 0.000 claims abstract description 180
• 150000003839 salts Chemical class 0.000 claims abstract description 49
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 42
• 201000010099 disease Diseases 0.000 claims abstract description 26
• 208000001072 type 2 diabetes mellitus Diseases 0.000 claims abstract description 14
• 239000003814 drug Substances 0.000 claims abstract description 8
• -1 4-cyclopentylmethoxy-phenyl Chemical group 0.000 claims description 706
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 92
• XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Substances CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 58
• 239000002253 acid Substances 0.000 claims description 25
• 208000006575 hypertriglyceridemia Diseases 0.000 claims description 21
• 239000003085 diluting agent Substances 0.000 claims description 12
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 11
• 108010086246 Glucagon-Like Peptide-1 Receptor Proteins 0.000 claims description 10
• 239000003937 drug carrier Substances 0.000 claims description 10
• 201000001421 hyperglycemia Diseases 0.000 claims description 9
• 208000031226 Hyperlipidaemia Diseases 0.000 claims description 7
• 239000000556 agonist Substances 0.000 claims description 6
• 238000004519 manufacturing process Methods 0.000 claims description 6
• 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 6
• 230000004913 activation Effects 0.000 claims description 5
• 239000004480 active ingredient Substances 0.000 claims description 5
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 5
• 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 4
• 208000030159 metabolic disease Diseases 0.000 claims description 4
• 125000004189 3,4-dichlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(Cl)C([H])=C1* 0.000 claims description 3
• 206010020772 Hypertension Diseases 0.000 claims description 3
• 206010022489 Insulin Resistance Diseases 0.000 claims description 3
• 235000019260 propionic acid Nutrition 0.000 claims description 3
• 230000029663 wound healing Effects 0.000 claims description 3
• 208000032928 Dyslipidaemia Diseases 0.000 claims description 2
• 208000017170 Lipid metabolism disease Diseases 0.000 claims description 2
• 206010067584 Type 1 diabetes mellitus Diseases 0.000 claims description 2
• RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 claims 4
• 208000002705 Glucose Intolerance Diseases 0.000 claims 4
• 239000003112 inhibitor Substances 0.000 claims 4
• 201000009104 prediabetes syndrome Diseases 0.000 claims 4
• 201000001320 Atherosclerosis Diseases 0.000 claims 3
• 102100038831 Peroxisome proliferator-activated receptor alpha Human genes 0.000 claims 3
• 108091008725 peroxisome proliferator-activated receptors alpha Proteins 0.000 claims 3
• 208000007342 Diabetic Nephropathies Diseases 0.000 claims 2
• 208000032131 Diabetic Neuropathies Diseases 0.000 claims 2
• 206010070901 Diabetic dyslipidaemia Diseases 0.000 claims 2
• 206010012689 Diabetic retinopathy Diseases 0.000 claims 2
• 102000007446 Glucagon-Like Peptide-1 Receptor Human genes 0.000 claims 2
• 208000008589 Obesity Diseases 0.000 claims 2
• 108010016731 PPAR gamma Proteins 0.000 claims 2
• 208000033679 diabetic kidney disease Diseases 0.000 claims 2
• 235000020824 obesity Nutrition 0.000 claims 2
• 229960005489 paracetamol Drugs 0.000 claims 2
• 208000011580 syndromic disease Diseases 0.000 claims 2
• 125000001617 2,3-dimethoxy phenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C(OC([H])([H])[H])=C1[H] 0.000 claims 1
• SWLAMJPTOQZTAE-UHFFFAOYSA-N 4-[2-[(5-chloro-2-methoxybenzoyl)amino]ethyl]benzoic acid Chemical compound COC1=CC=C(Cl)C=C1C(=O)NCCC1=CC=C(C(O)=O)C=C1 SWLAMJPTOQZTAE-UHFFFAOYSA-N 0.000 claims 1
• 206010003210 Arteriosclerosis Diseases 0.000 claims 1
• 108010067722 Dipeptidyl Peptidase 4 Proteins 0.000 claims 1
• 102100025012 Dipeptidyl peptidase 4 Human genes 0.000 claims 1
• 102000030914 Fatty Acid-Binding Human genes 0.000 claims 1
• 102000004366 Glucosidases Human genes 0.000 claims 1
• 108010056771 Glucosidases Proteins 0.000 claims 1
• 102000007390 Glycogen Phosphorylase Human genes 0.000 claims 1
• 108010046163 Glycogen Phosphorylase Proteins 0.000 claims 1
• 229940122199 Insulin secretagogue Drugs 0.000 claims 1
• 229940122355 Insulin sensitizer Drugs 0.000 claims 1
• 108010028924 PPAR alpha Proteins 0.000 claims 1
• 102000023984 PPAR alpha Human genes 0.000 claims 1
• 102000000536 PPAR gamma Human genes 0.000 claims 1
• 102100038825 Peroxisome proliferator-activated receptor gamma Human genes 0.000 claims 1
• 229940123518 Sodium/glucose cotransporter 2 inhibitor Drugs 0.000 claims 1
• 229940123464 Thiazolidinedione Drugs 0.000 claims 1
• 239000005557 antagonist Substances 0.000 claims 1
• 208000011775 arteriosclerosis disease Diseases 0.000 claims 1
• 108091022862 fatty acid binding Proteins 0.000 claims 1
• 230000001771 impaired effect Effects 0.000 claims 1
• 229950004994 meglitinide Drugs 0.000 claims 1
• 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims 1
• 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 claims 1
• 150000001467 thiazolidinediones Chemical class 0.000 claims 1
• 208000035475 disorder Diseases 0.000 abstract description 16
• 101001015516 Homo sapiens Glucagon-like peptide 1 receptor Proteins 0.000 abstract description 6
• 230000009286 beneficial effect Effects 0.000 abstract description 3
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 423
• 125000001424 substituent group Chemical group 0.000 description 241
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 226
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical group CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 201
• 235000019439 ethyl acetate Nutrition 0.000 description 177
• 239000000243 solution Substances 0.000 description 162
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 138
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 115
• 238000006243 chemical reaction Methods 0.000 description 102
• 125000000217 alkyl group Chemical group 0.000 description 99
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 92
• 239000011541 reaction mixture Substances 0.000 description 92
• 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 90
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 89
• 239000000047 product Substances 0.000 description 88
• 239000012267 brine Substances 0.000 description 86
• 239000012044 organic layer Substances 0.000 description 84
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 83
• 239000011734 sodium Substances 0.000 description 78
• 125000001072 heteroaryl group Chemical group 0.000 description 77
• 125000000623 heterocyclic group Chemical group 0.000 description 74
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 72
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 68
• IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 68
• 229940093499 ethyl acetate Drugs 0.000 description 67
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 67
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 65
• 238000003818 flash chromatography Methods 0.000 description 63
• 125000000753 cycloalkyl group Chemical group 0.000 description 61
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 59
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 59
• IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 55
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 54
• 239000000741 silica gel Substances 0.000 description 53
• 229910002027 silica gel Inorganic materials 0.000 description 53
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 49
• 125000003118 aryl group Chemical group 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 49
• 230000002829 reductive effect Effects 0.000 description 47
• 229910052757 nitrogen Inorganic materials 0.000 description 45
• 239000007787 solid Substances 0.000 description 44
• 239000002904 solvent Substances 0.000 description 44
• 150000002367 halogens Chemical class 0.000 description 42
• 239000001257 hydrogen Substances 0.000 description 42
• 229910052739 hydrogen Inorganic materials 0.000 description 42
• 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 42
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 40
• 229910052938 sodium sulfate Inorganic materials 0.000 description 40
• 235000011152 sodium sulphate Nutrition 0.000 description 40
• 125000004093 cyano group Chemical group *C#N 0.000 description 39
• 239000010410 layer Substances 0.000 description 37
• 238000003756 stirring Methods 0.000 description 37
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 35
• DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 31
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 30
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 30
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 30
• 125000000304 alkynyl group Chemical group 0.000 description 30
• 238000002360 preparation method Methods 0.000 description 28
• 229920000728 polyester Polymers 0.000 description 27
• 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 26
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 25
• 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 24
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 24
• 125000003342 alkenyl group Chemical group 0.000 description 24
• 125000002947 alkylene group Chemical group 0.000 description 24
• 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 23
• 230000015572 biosynthetic process Effects 0.000 description 23
• 238000006467 substitution reaction Methods 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
• 125000004432 carbon atom Chemical group C* 0.000 description 22
• 150000001412 amines Chemical class 0.000 description 21
• 239000000284 extract Substances 0.000 description 21
• 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 20
• 239000003921 oil Substances 0.000 description 20
• 235000019198 oils Nutrition 0.000 description 20
• WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 19
• 238000005481 NMR spectroscopy Methods 0.000 description 19
• 125000004307 pyrazin-2-yl group Chemical group [H]C1=C([H])N=C(*)C([H])=N1 0.000 description 19
• 238000003786 synthesis reaction Methods 0.000 description 19
• 229920006395 saturated elastomer Polymers 0.000 description 18
• 229930040373 Paraformaldehyde Natural products 0.000 description 17
• 229920002866 paraformaldehyde Polymers 0.000 description 17
• 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 description 17
• 230000008569 process Effects 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
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 16
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 16
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 16
• 238000004440 column chromatography Methods 0.000 description 16
• 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 16
• 238000000746 purification Methods 0.000 description 16
• WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 15
• KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 15
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
• 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 15
• 150000002148 esters Chemical class 0.000 description 15
• 125000004498 isoxazol-4-yl group Chemical group O1N=CC(=C1)* 0.000 description 15
• 150000004702 methyl esters Chemical class 0.000 description 15
• 125000002206 pyridazin-3-yl group Chemical group [H]C1=C([H])C([H])=C(*)N=N1 0.000 description 15
• 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 14
• 125000004419 alkynylene group Chemical group 0.000 description 14
• 125000004429 atom Chemical group 0.000 description 14
• 239000000706 filtrate Substances 0.000 description 14
• 125000004528 pyrimidin-5-yl group Chemical group N1=CN=CC(=C1)* 0.000 description 14
• 125000004571 thiomorpholin-4-yl group Chemical group N1(CCSCC1)* 0.000 description 14
• RAXXELZNTBOGNW-UHFFFAOYSA-N 1H-imidazole Chemical compound C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 13
• 125000003545 alkoxy group Chemical group 0.000 description 13
• 125000005842 heteroatom Chemical group 0.000 description 13
• 125000004304 oxazol-5-yl group Chemical group O1C=NC=C1* 0.000 description 13
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• 238000010898 silica gel chromatography Methods 0.000 description 13
• 125000004496 thiazol-5-yl group Chemical group S1C=NC=C1* 0.000 description 13
• 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
• 125000004499 isoxazol-5-yl group Chemical group O1N=CC=C1* 0.000 description 12
• 125000002971 oxazolyl group Chemical group 0.000 description 12
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 12
• 238000010992 reflux Methods 0.000 description 12
• 125000004450 alkenylene group Chemical group 0.000 description 11
• 238000001035 drying Methods 0.000 description 11
• 125000003386 piperidinyl group Chemical group 0.000 description 11
• 125000004940 pyridazin-4-yl group Chemical group N1=NC=C(C=C1)* 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
• 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 description 10
• DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-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
• XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 10
• 125000004367 cycloalkylaryl group Chemical group 0.000 description 10
• 125000005215 cycloalkylheteroaryl group Chemical group 0.000 description 10
• 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 10
• 125000004433 nitrogen atom Chemical group N* 0.000 description 10
• 229910052708 sodium Inorganic materials 0.000 description 10
• 125000004495 thiazol-4-yl group Chemical group S1C=NC(=C1)* 0.000 description 10
• RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 9
• FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 9
• 229910052799 carbon Inorganic materials 0.000 description 9
• 239000012043 crude product Substances 0.000 description 9
• 238000001914 filtration Methods 0.000 description 9
• 125000004435 hydrogen atom Chemical group [H]* 0.000 description 9
• 239000000543 intermediate Substances 0.000 description 9
• 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 description 9
• 239000000377 silicon dioxide Substances 0.000 description 9
• FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 8
• VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 8
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
• 102100032882 Glucagon-like peptide 1 receptor Human genes 0.000 description 8
• 239000012298 atmosphere Substances 0.000 description 8
• 125000004122 cyclic group Chemical group 0.000 description 8
• 125000002993 cycloalkylene group Chemical group 0.000 description 8
• 125000001793 isothiazol-3-yl group Chemical group [H]C1=C([H])C(*)=NS1 0.000 description 8
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• 125000004430 oxygen atom Chemical group O* 0.000 description 8
• 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 8
• 229910000030 sodium bicarbonate Inorganic materials 0.000 description 8
• 235000017557 sodium bicarbonate Nutrition 0.000 description 8
• 229910052717 sulfur Inorganic materials 0.000 description 8
• 125000000437 thiazol-2-yl group Chemical group [H]C1=C([H])N=C(*)S1 0.000 description 8
• WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 7
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• 239000000859 incretin Substances 0.000 description 1
• 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 1
• 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 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
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• 229940125396 insulin Drugs 0.000 description 1
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• 210000002660 insulin-secreting cell Anatomy 0.000 description 1
• 238000012739 integrated shape imaging system Methods 0.000 description 1
• 239000011630 iodine Substances 0.000 description 1
• 229910052740 iodine Inorganic materials 0.000 description 1
• 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 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
• 150000002545 isoxazoles Chemical class 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
• 239000004973 liquid crystal related substance Substances 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
• FRIJBUGBVQZNTB-UHFFFAOYSA-M magnesium;ethane;bromide Chemical compound [Mg+2].[Br-].[CH2-]C FRIJBUGBVQZNTB-UHFFFAOYSA-M 0.000 description 1
• 239000012528 membrane Substances 0.000 description 1
• 230000002503 metabolic effect Effects 0.000 description 1
• 230000004060 metabolic process 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
• 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
• IKJYXHJKOWUBIE-YLJLHNITSA-N methyl (2s)-2-[[(3s,8s)-3-[3-[(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=C(OCC=2C=C(Cl)C(Cl)=CC=2)C=CC=1)C(C=C1)=CC=C1C1=CC=NC(C)=C1C IKJYXHJKOWUBIE-YLJLHNITSA-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
• 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
• 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 1
• 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 1
• KHONQNXQXZDOFB-INIZCTEOSA-N methyl (2s)-2-amino-3-[4-(2,3-dimethylpyridin-4-yl)phenyl]propanoate Chemical compound C1=CC(C[C@H](N)C(=O)OC)=CC=C1C1=CC=NC(C)=C1C KHONQNXQXZDOFB-INIZCTEOSA-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
• 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
• ZPGYXIVFYCKLQK-SFHVURJKSA-N methyl (2s)-2-amino-3-[4-(4-cyanophenyl)phenyl]-2-methylpropanoate Chemical compound C1=CC(C[C@](C)(N)C(=O)OC)=CC=C1C1=CC=C(C#N)C=C1 ZPGYXIVFYCKLQK-SFHVURJKSA-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
• 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 1
• 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 1
• 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 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
• 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
• 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 1
• 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 1
• 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 1
• 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 1
• COEKCZCWLCNZBB-HKGQQODZSA-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 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-HKGQQODZSA-N 0.000 description 1
• 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 1
• 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 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
• 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
• 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 1
• 239000002808 molecular sieve Substances 0.000 description 1
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• 125000002757 morpholinyl group Chemical group 0.000 description 1
• FMASTMURQSHELY-UHFFFAOYSA-N n-(4-fluoro-2-methylphenyl)-3-methyl-n-[(2-methyl-1h-indol-4-yl)methyl]pyridine-4-carboxamide Chemical compound C1=CC=C2NC(C)=CC2=C1CN(C=1C(=CC(F)=CC=1)C)C(=O)C1=CC=NC=C1C FMASTMURQSHELY-UHFFFAOYSA-N 0.000 description 1
• 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 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
• 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 1
• KJXQYUNYEYJWJM-UHFFFAOYSA-N n-(5-amino-6-methylpyridin-2-yl)acetamide Chemical compound CC(=O)NC1=CC=C(N)C(C)=N1 KJXQYUNYEYJWJM-UHFFFAOYSA-N 0.000 description 1
• HUZAGNKSHDCFDO-UHFFFAOYSA-N n-(cyclobutylmethyl)-n-(6-methyl-5-nitropyridin-2-yl)acetamide Chemical compound C=1C=C([N+]([O-])=O)C(C)=NC=1N(C(=O)C)CC1CCC1 HUZAGNKSHDCFDO-UHFFFAOYSA-N 0.000 description 1
• MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 1
• RLXBPRIONFCBAA-UHFFFAOYSA-N n-[4-[4-(2-methylpropylsulfamoyl)phenyl]-1,3-thiazol-2-yl]acetamide Chemical compound C1=CC(S(=O)(=O)NCC(C)C)=CC=C1C1=CSC(NC(C)=O)=N1 RLXBPRIONFCBAA-UHFFFAOYSA-N 0.000 description 1
• 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 1
• GNZCSGYHILBXLL-UHFFFAOYSA-N n-tert-butyl-6,7-dichloro-3-methylsulfonylquinoxalin-2-amine Chemical compound ClC1=C(Cl)C=C2N=C(S(C)(=O)=O)C(NC(C)(C)C)=NC2=C1 GNZCSGYHILBXLL-UHFFFAOYSA-N 0.000 description 1
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• 201000001119 neuropathy Diseases 0.000 description 1
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• QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 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
• 125000006504 o-cyanobenzyl group Chemical group [H]C1=C([H])C(C#N)=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
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