JP6114824B2 - ジメチル安息香酸化合物 - Google Patents
ジメチル安息香酸化合物 Download PDFInfo
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- JP6114824B2 JP6114824B2 JP2015520305A JP2015520305A JP6114824B2 JP 6114824 B2 JP6114824 B2 JP 6114824B2 JP 2015520305 A JP2015520305 A JP 2015520305A JP 2015520305 A JP2015520305 A JP 2015520305A JP 6114824 B2 JP6114824 B2 JP 6114824B2
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- methyl
- dimethyl
- amino
- mmol
- reduced pressure
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- -1 Dimethylbenzoic acid compound Chemical class 0.000 title description 25
- 150000001875 compounds Chemical class 0.000 claims description 172
- 150000003839 salts Chemical class 0.000 claims description 46
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- 238000002441 X-ray diffraction Methods 0.000 claims description 4
- 239000003085 diluting agent Substances 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- 238000001228 spectrum Methods 0.000 claims description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 346
- 230000002829 reductive effect Effects 0.000 description 129
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 126
- 235000019439 ethyl acetate Nutrition 0.000 description 125
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 124
- 239000000243 solution Substances 0.000 description 123
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 104
- 238000002360 preparation method Methods 0.000 description 99
- 230000015572 biosynthetic process Effects 0.000 description 95
- 239000011541 reaction mixture Substances 0.000 description 95
- 239000007787 solid Substances 0.000 description 95
- 238000003786 synthesis reaction Methods 0.000 description 94
- 238000001819 mass spectrum Methods 0.000 description 91
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 72
- 239000012044 organic layer Substances 0.000 description 72
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 67
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 64
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 54
- 238000003818 flash chromatography Methods 0.000 description 50
- 239000000741 silica gel Substances 0.000 description 47
- 229910002027 silica gel Inorganic materials 0.000 description 47
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 46
- 229910052938 sodium sulfate Inorganic materials 0.000 description 46
- 235000011152 sodium sulphate Nutrition 0.000 description 46
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 45
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 43
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 34
- 239000002904 solvent Substances 0.000 description 34
- 239000000203 mixture Substances 0.000 description 33
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 30
- 238000006243 chemical reaction Methods 0.000 description 28
- 229910052757 nitrogen Inorganic materials 0.000 description 27
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 26
- 238000000034 method Methods 0.000 description 25
- 239000003960 organic solvent Substances 0.000 description 25
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 25
- 101001117509 Homo sapiens Prostaglandin E2 receptor EP4 subtype Proteins 0.000 description 23
- 102100024450 Prostaglandin E2 receptor EP4 subtype Human genes 0.000 description 23
- 238000011282 treatment Methods 0.000 description 22
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 21
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 21
- 239000002244 precipitate Substances 0.000 description 20
- 239000000706 filtrate Substances 0.000 description 19
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 18
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 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 18
- 210000004027 cell Anatomy 0.000 description 18
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 16
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 16
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 16
- 201000008482 osteoarthritis Diseases 0.000 description 16
- 206010039073 rheumatoid arthritis Diseases 0.000 description 16
- VNFWTIYUKDMAOP-UHFFFAOYSA-N sphos Chemical compound COC1=CC=CC(OC)=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 VNFWTIYUKDMAOP-UHFFFAOYSA-N 0.000 description 16
- 239000005557 antagonist Substances 0.000 description 15
- 239000005457 ice water Substances 0.000 description 15
- PAQZWJGSJMLPMG-UHFFFAOYSA-N 2,4,6-tripropyl-1,3,5,2$l^{5},4$l^{5},6$l^{5}-trioxatriphosphinane 2,4,6-trioxide Chemical compound CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1 PAQZWJGSJMLPMG-UHFFFAOYSA-N 0.000 description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 12
- 239000012267 brine Substances 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
- 239000011734 sodium Substances 0.000 description 12
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 12
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 12
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 11
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 10
- 230000000694 effects Effects 0.000 description 10
- 208000002193 Pain Diseases 0.000 description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 9
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 9
- 102000005962 receptors Human genes 0.000 description 9
- 108020003175 receptors Proteins 0.000 description 9
- 239000003814 drug Substances 0.000 description 8
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 8
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 8
- ODSPBBWQVLWOPG-UHFFFAOYSA-N 6-chloro-3-methylpyridine-2-carboxylic acid Chemical compound CC1=CC=C(Cl)N=C1C(O)=O ODSPBBWQVLWOPG-UHFFFAOYSA-N 0.000 description 7
- 239000007864 aqueous solution Substances 0.000 description 7
- 206010003246 arthritis Diseases 0.000 description 7
- 238000009739 binding Methods 0.000 description 7
- 239000013078 crystal Substances 0.000 description 7
- 239000012091 fetal bovine serum Substances 0.000 description 7
- SSPQOLHQGAFWCA-UHFFFAOYSA-N methyl 3-[(5-bromo-2-methylbenzoyl)amino]-2,4-dimethylbenzoate Chemical compound COC(=O)C1=CC=C(C)C(NC(=O)C=2C(=CC=C(Br)C=2)C)=C1C SSPQOLHQGAFWCA-UHFFFAOYSA-N 0.000 description 7
- 239000000843 powder Substances 0.000 description 7
- RAXXELZNTBOGNW-UHFFFAOYSA-N 1H-imidazole Chemical compound C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 6
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- 230000027455 binding Effects 0.000 description 6
- 210000004369 blood Anatomy 0.000 description 6
- 239000008280 blood Substances 0.000 description 6
- 208000035475 disorder Diseases 0.000 description 6
- 239000003480 eluent Substances 0.000 description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 6
- 238000002868 homogeneous time resolved fluorescence Methods 0.000 description 6
- 238000000338 in vitro Methods 0.000 description 6
- 239000010410 layer Substances 0.000 description 6
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 6
- 235000019341 magnesium sulphate Nutrition 0.000 description 6
- ARSRTLJLMXSRPV-UHFFFAOYSA-N methyl 4-amino-3,5-dimethylbenzoate Chemical compound COC(=O)C1=CC(C)=C(N)C(C)=C1 ARSRTLJLMXSRPV-UHFFFAOYSA-N 0.000 description 6
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 6
- 238000000926 separation method Methods 0.000 description 6
- LGVRQIKHFHBPSK-UHFFFAOYSA-N 3-[[5-[3-(hydroxymethyl)piperidin-1-yl]-2-methylbenzoyl]amino]-2,4-dimethylbenzoic acid Chemical compound CC1=CC=C(C(O)=O)C(C)=C1NC(=O)C1=CC(N2CC(CO)CCC2)=CC=C1C LGVRQIKHFHBPSK-UHFFFAOYSA-N 0.000 description 5
- WAWBRSOCPNDFAB-UHFFFAOYSA-N 4-[[2-fluoro-5-[3-(hydroxymethyl)piperidin-1-yl]benzoyl]amino]-3,5-dimethylbenzoic acid Chemical compound CC1=CC(C(O)=O)=CC(C)=C1NC(=O)C1=CC(N2CC(CO)CCC2)=CC=C1F WAWBRSOCPNDFAB-UHFFFAOYSA-N 0.000 description 5
- WOJKYHBOHSQZDW-UHFFFAOYSA-N 4-[[6-(4-hydroxypiperidin-1-yl)-3-methylpyridine-2-carbonyl]amino]-3,5-dimethylbenzoic acid Chemical compound CC1=CC=C(N2CCC(O)CC2)N=C1C(=O)NC1=C(C)C=C(C(O)=O)C=C1C WOJKYHBOHSQZDW-UHFFFAOYSA-N 0.000 description 5
- SEENCYZQHCUTSB-UHFFFAOYSA-N 5-bromo-2-methylbenzoic acid Chemical compound CC1=CC=C(Br)C=C1C(O)=O SEENCYZQHCUTSB-UHFFFAOYSA-N 0.000 description 5
- 101001073427 Homo sapiens Prostaglandin E2 receptor EP1 subtype Proteins 0.000 description 5
- 101001117519 Homo sapiens Prostaglandin E2 receptor EP2 subtype Proteins 0.000 description 5
- 101001117517 Homo sapiens Prostaglandin E2 receptor EP3 subtype Proteins 0.000 description 5
- 102100024448 Prostaglandin E2 receptor EP2 subtype Human genes 0.000 description 5
- 102100024447 Prostaglandin E2 receptor EP3 subtype Human genes 0.000 description 5
- BLRPTPMANUNPDV-UHFFFAOYSA-N Silane Chemical compound [SiH4] BLRPTPMANUNPDV-UHFFFAOYSA-N 0.000 description 5
- MUALRAIOVNYAIW-UHFFFAOYSA-N binap Chemical group C1=CC=CC=C1P(C=1C(=C2C=CC=CC2=CC=1)C=1C2=CC=CC=C2C=CC=1P(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 MUALRAIOVNYAIW-UHFFFAOYSA-N 0.000 description 5
- 239000002158 endotoxin Substances 0.000 description 5
- 230000005764 inhibitory process Effects 0.000 description 5
- 229920006008 lipopolysaccharide Polymers 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- VXCDYRLZDFQUCJ-UHFFFAOYSA-N methyl 3-amino-2,4-dimethylbenzoate Chemical compound COC(=O)C1=CC=C(C)C(N)=C1C VXCDYRLZDFQUCJ-UHFFFAOYSA-N 0.000 description 5
- HDOWRFHMPULYOA-UHFFFAOYSA-N piperidin-4-ol Chemical compound OC1CCNCC1 HDOWRFHMPULYOA-UHFFFAOYSA-N 0.000 description 5
- 229920006395 saturated elastomer Polymers 0.000 description 5
- 229910000077 silane Inorganic materials 0.000 description 5
- RIZUCYSQUWMQLX-UHFFFAOYSA-N 2,3-dimethylbenzoic acid Chemical class CC1=CC=CC(C(O)=O)=C1C RIZUCYSQUWMQLX-UHFFFAOYSA-N 0.000 description 4
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 4
- 239000007995 HEPES buffer Substances 0.000 description 4
- 239000007987 MES buffer Substances 0.000 description 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 239000012131 assay buffer Substances 0.000 description 4
- 239000012298 atmosphere Substances 0.000 description 4
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 4
- 229940098773 bovine serum albumin Drugs 0.000 description 4
- 239000000872 buffer Substances 0.000 description 4
- 238000013262 cAMP assay Methods 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 231100000673 dose–response relationship Toxicity 0.000 description 4
- 230000002526 effect on cardiovascular system Effects 0.000 description 4
- 238000010828 elution Methods 0.000 description 4
- UBXTUCGVTZERIW-UHFFFAOYSA-N ethyl 4-[(6-chloro-3-methylpyridine-2-carbonyl)amino]-3,5-dimethylbenzoate Chemical compound CC1=CC(C(=O)OCC)=CC(C)=C1NC(=O)C1=NC(Cl)=CC=C1C UBXTUCGVTZERIW-UHFFFAOYSA-N 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 239000012528 membrane Substances 0.000 description 4
- JLLLNXJTBCOQFL-UHFFFAOYSA-N methyl 3-[(6-chloro-3-methylpyridine-2-carbonyl)amino]-2,4-dimethylbenzoate Chemical compound COC(=O)C1=CC=C(C)C(NC(=O)C=2C(=CC=C(Cl)N=2)C)=C1C JLLLNXJTBCOQFL-UHFFFAOYSA-N 0.000 description 4
- 238000000634 powder X-ray diffraction Methods 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
- LGRNCIPHZAOULB-UHFFFAOYSA-N tert-butyl-dimethyl-(piperidin-3-ylmethoxy)silane Chemical compound CC(C)(C)[Si](C)(C)OCC1CCCNC1 LGRNCIPHZAOULB-UHFFFAOYSA-N 0.000 description 4
- GCPNPVFWMHBPNS-UHFFFAOYSA-N tert-butyl-dimethyl-piperidin-4-yloxysilane Chemical compound CC(C)(C)[Si](C)(C)OC1CCNCC1 GCPNPVFWMHBPNS-UHFFFAOYSA-N 0.000 description 4
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 4
- 238000002560 therapeutic procedure Methods 0.000 description 4
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 3
- NUKCHPPOSHODMM-UHFFFAOYSA-N 4-[[5-[3-(hydroxymethyl)piperidin-1-yl]-2-methylbenzoyl]amino]-3,5-dimethylbenzoic acid Chemical compound CC1=CC=C(N2CC(CO)CCC2)C=C1C(=O)NC1=C(C)C=C(C(O)=O)C=C1C NUKCHPPOSHODMM-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 3
- 239000012981 Hank's balanced salt solution Substances 0.000 description 3
- 102100035842 Prostaglandin E2 receptor EP1 subtype Human genes 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 3
- 235000019270 ammonium chloride Nutrition 0.000 description 3
- 238000003556 assay Methods 0.000 description 3
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- 239000013058 crude material Substances 0.000 description 3
- 239000003255 cyclooxygenase 2 inhibitor Substances 0.000 description 3
- XEYBRNLFEZDVAW-ARSRFYASSA-N dinoprostone Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1C\C=C/CCCC(O)=O XEYBRNLFEZDVAW-ARSRFYASSA-N 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
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- 238000003821 enantio-separation Methods 0.000 description 3
- GEMKGDSDLYAIRK-UHFFFAOYSA-N ethyl 4-amino-3,5-dimethylbenzoate Chemical compound CCOC(=O)C1=CC(C)=C(N)C(C)=C1 GEMKGDSDLYAIRK-UHFFFAOYSA-N 0.000 description 3
- 230000002757 inflammatory effect Effects 0.000 description 3
- 239000003112 inhibitor Substances 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- RIFHBFZPEGIOEG-UHFFFAOYSA-N methyl 4-[(6-chloro-3-methylpyridine-2-carbonyl)amino]-3,5-dimethylbenzoate Chemical compound CC1=CC(C(=O)OC)=CC(C)=C1NC(=O)C1=NC(Cl)=CC=C1C RIFHBFZPEGIOEG-UHFFFAOYSA-N 0.000 description 3
- QKXXURVZIZZZEW-UHFFFAOYSA-N methyl 5-amino-3,5-dimethylcyclohexa-1,3-diene-1-carboxylate Chemical compound COC(=O)C1=CC(C)=CC(C)(N)C1 QKXXURVZIZZZEW-UHFFFAOYSA-N 0.000 description 3
- XWPSWOKQWBNRDW-UHFFFAOYSA-N methyl 6-chloro-3-methylpyridine-2-carboxylate Chemical compound COC(=O)C1=NC(Cl)=CC=C1C XWPSWOKQWBNRDW-UHFFFAOYSA-N 0.000 description 3
- 230000007935 neutral effect Effects 0.000 description 3
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- 125000001424 substituent group Chemical group 0.000 description 3
- BIACWLGCCVBYNE-UHFFFAOYSA-N 1-iodo-2,4-dimethyl-3-nitrobenzene Chemical compound CC1=CC=C(I)C(C)=C1[N+]([O-])=O BIACWLGCCVBYNE-UHFFFAOYSA-N 0.000 description 2
- USAPMJKOJBISGB-UHFFFAOYSA-N 2,4-dimethyl-3-[[2-methyl-5-(4-oxopiperidin-1-yl)benzoyl]amino]benzoic acid Chemical compound CC1=CC=C(N2CCC(=O)CC2)C=C1C(=O)NC1=C(C)C=CC(C(O)=O)=C1C USAPMJKOJBISGB-UHFFFAOYSA-N 0.000 description 2
- BKYWPNROPGQIFZ-UHFFFAOYSA-M 2,4-dimethylbenzoate Chemical compound CC1=CC=C(C([O-])=O)C(C)=C1 BKYWPNROPGQIFZ-UHFFFAOYSA-M 0.000 description 2
- ICNCOMYUODLTAI-UHFFFAOYSA-N 2-chloroquinoline-4-carboxylic acid Chemical compound C1=CC=C2C(C(=O)O)=CC(Cl)=NC2=C1 ICNCOMYUODLTAI-UHFFFAOYSA-N 0.000 description 2
- GBLGFLKIRWWEBW-UHFFFAOYSA-N 3,5-dimethyl-4-[[2-methyl-5-(4-oxopiperidin-1-yl)benzoyl]amino]benzoic acid Chemical compound CC1=CC=C(N2CCC(=O)CC2)C=C1C(=O)NC1=C(C)C=C(C(O)=O)C=C1C GBLGFLKIRWWEBW-UHFFFAOYSA-N 0.000 description 2
- SWSCMXZZHFRZLX-UHFFFAOYSA-N 5-bromo-2-(trifluoromethyl)benzoic acid Chemical compound OC(=O)C1=CC(Br)=CC=C1C(F)(F)F SWSCMXZZHFRZLX-UHFFFAOYSA-N 0.000 description 2
- PEXAZYDITWXYNJ-UHFFFAOYSA-N 5-bromo-2-fluorobenzoic acid Chemical compound OC(=O)C1=CC(Br)=CC=C1F PEXAZYDITWXYNJ-UHFFFAOYSA-N 0.000 description 2
- MWBNCZHVEXULBD-ZDUSSCGKSA-N Benzoic acid, 4-[(1s)-1-[[5-chloro-2-(4-fluorophenoxy)benzoyl]amino]ethyl]- Chemical compound N([C@@H](C)C=1C=CC(=CC=1)C(O)=O)C(=O)C1=CC(Cl)=CC=C1OC1=CC=C(F)C=C1 MWBNCZHVEXULBD-ZDUSSCGKSA-N 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- 229910016523 CuKa Inorganic materials 0.000 description 2
- 102100038496 Cysteinyl leukotriene receptor 1 Human genes 0.000 description 2
- 101000882759 Homo sapiens Cysteinyl leukotriene receptor 1 Proteins 0.000 description 2
- 101001009517 Homo sapiens Probable G-protein coupled receptor 32 Proteins 0.000 description 2
- 101000836978 Homo sapiens Sperm-associated antigen 11B Proteins 0.000 description 2
- 101000818522 Homo sapiens fMet-Leu-Phe receptor Proteins 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 206010065390 Inflammatory pain Diseases 0.000 description 2
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- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- JZKNBGRZLPBHPD-UHFFFAOYSA-N ethyl 3,5-dimethyl-4-[[2-methyl-5-(4-oxopiperidin-1-yl)benzoyl]amino]benzoate Chemical compound CC1=CC(C(=O)OCC)=CC(C)=C1NC(=O)C1=CC(N2CCC(=O)CC2)=CC=C1C JZKNBGRZLPBHPD-UHFFFAOYSA-N 0.000 description 1
- GNUOKOOACFQJOP-UHFFFAOYSA-N ethyl 4-[[5-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)-2-methylbenzoyl]amino]-3,5-dimethylbenzoate Chemical compound CC1=CC(C(=O)OCC)=CC(C)=C1NC(=O)C1=CC(N2CCC3(CC2)OCCO3)=CC=C1C GNUOKOOACFQJOP-UHFFFAOYSA-N 0.000 description 1
- OWUHDTVMENUXMW-UHFFFAOYSA-N ethyl 4-[[6-(4-hydroxypiperidin-1-yl)-3-methylpyridine-2-carbonyl]amino]-3,5-dimethylbenzoate Chemical compound CC1=CC(C(=O)OCC)=CC(C)=C1NC(=O)C1=NC(N2CCC(O)CC2)=CC=C1C OWUHDTVMENUXMW-UHFFFAOYSA-N 0.000 description 1
- BLSVWKSMDLFMFP-UHFFFAOYSA-N ethyl 4-[[6-[4-[tert-butyl(dimethyl)silyl]oxypiperidin-1-yl]-3-methylpyridine-2-carbonyl]amino]-3,5-dimethylbenzoate Chemical compound CC1=CC(C(=O)OCC)=CC(C)=C1NC(=O)C1=NC(N2CCC(CC2)O[Si](C)(C)C(C)(C)C)=CC=C1C BLSVWKSMDLFMFP-UHFFFAOYSA-N 0.000 description 1
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- 235000019253 formic acid Nutrition 0.000 description 1
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- 230000005714 functional activity Effects 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 239000003862 glucocorticoid Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- ZFGMDIBRIDKWMY-PASTXAENSA-N heparin Chemical compound CC(O)=N[C@@H]1[C@@H](O)[C@H](O)[C@@H](COS(O)(=O)=O)O[C@@H]1O[C@@H]1[C@@H](C(O)=O)O[C@@H](O[C@H]2[C@@H]([C@@H](OS(O)(=O)=O)[C@@H](O[C@@H]3[C@@H](OC(O)[C@H](OS(O)(=O)=O)[C@H]3O)C(O)=O)O[C@@H]2O)CS(O)(=O)=O)[C@H](O)[C@H]1O ZFGMDIBRIDKWMY-PASTXAENSA-N 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
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- 229910052740 iodine Inorganic materials 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
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- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 1
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- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- CZQKTUBNPGCJNI-UHFFFAOYSA-N methyl 2,4-dimethyl-3-[[2-methyl-5-(4-oxopiperidin-1-yl)benzoyl]amino]benzoate Chemical compound COC(=O)C1=CC=C(C)C(NC(=O)C=2C(=CC=C(C=2)N2CCC(=O)CC2)C)=C1C CZQKTUBNPGCJNI-UHFFFAOYSA-N 0.000 description 1
- ISGOBJKTOCHBHN-UHFFFAOYSA-N methyl 3-[(2-chloroquinoline-4-carbonyl)amino]-2,4-dimethylbenzoate Chemical compound COC(=O)C1=CC=C(C)C(NC(=O)C=2C3=CC=CC=C3N=C(Cl)C=2)=C1C ISGOBJKTOCHBHN-UHFFFAOYSA-N 0.000 description 1
- FSUBBXAIDUYTFZ-UHFFFAOYSA-N methyl 3-[[2-(4-hydroxypiperidin-1-yl)quinoline-4-carbonyl]amino]-2,4-dimethylbenzoate Chemical compound COC(=O)C1=CC=C(C)C(NC(=O)C=2C3=CC=CC=C3N=C(C=2)N2CCC(O)CC2)=C1C FSUBBXAIDUYTFZ-UHFFFAOYSA-N 0.000 description 1
- LFRAIWXPGASQIF-UHFFFAOYSA-N methyl 3-[[2-[4-[tert-butyl(dimethyl)silyl]oxypiperidin-1-yl]quinoline-4-carbonyl]amino]-2,4-dimethylbenzoate Chemical compound COC(=O)C1=CC=C(C)C(NC(=O)C=2C3=CC=CC=C3N=C(C=2)N2CCC(CC2)O[Si](C)(C)C(C)(C)C)=C1C LFRAIWXPGASQIF-UHFFFAOYSA-N 0.000 description 1
- UJHHBNFACSJABO-UHFFFAOYSA-N methyl 3-[[2-fluoro-5-[3-(hydroxymethyl)piperidin-1-yl]benzoyl]amino]-2,4-dimethylbenzoate Chemical compound COC(=O)C1=CC=C(C)C(NC(=O)C=2C(=CC=C(C=2)N2CC(CO)CCC2)F)=C1C UJHHBNFACSJABO-UHFFFAOYSA-N 0.000 description 1
- NOYIOZREHKWBKQ-UHFFFAOYSA-N methyl 3-[[5-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)-2-methylbenzoyl]amino]-2,4-dimethylbenzoate Chemical compound COC(=O)C1=CC=C(C)C(NC(=O)C=2C(=CC=C(C=2)N2CCC3(CC2)OCCO3)C)=C1C NOYIOZREHKWBKQ-UHFFFAOYSA-N 0.000 description 1
- WEAZFSMXYAKTCZ-UHFFFAOYSA-N methyl 3-[[5-(3-hydroxypiperidin-1-yl)-2-methylbenzoyl]amino]-2,4-dimethylbenzoate Chemical compound COC(=O)C1=CC=C(C)C(NC(=O)C=2C(=CC=C(C=2)N2CC(O)CCC2)C)=C1C WEAZFSMXYAKTCZ-UHFFFAOYSA-N 0.000 description 1
- OXSJHUUUOTXLDV-UHFFFAOYSA-N methyl 3-[[5-(4-hydroxypiperidin-1-yl)-2-(trifluoromethyl)benzoyl]amino]-2,4-dimethylbenzoate Chemical compound COC(=O)C1=CC=C(C)C(NC(=O)C=2C(=CC=C(C=2)N2CCC(O)CC2)C(F)(F)F)=C1C OXSJHUUUOTXLDV-UHFFFAOYSA-N 0.000 description 1
- WITRDJAYJGTMMC-UHFFFAOYSA-N methyl 3-[[5-[3-(hydroxymethyl)piperidin-1-yl]-2-methylbenzoyl]amino]-2,4-dimethylbenzoate Chemical compound COC(=O)C1=CC=C(C)C(NC(=O)C=2C(=CC=C(C=2)N2CC(CO)CCC2)C)=C1C WITRDJAYJGTMMC-UHFFFAOYSA-N 0.000 description 1
- DNYXWBYNJMEKQU-UHFFFAOYSA-N methyl 3-[[5-[3-(hydroxymethyl)pyrrolidin-1-yl]-2-methylbenzoyl]amino]-2,4-dimethylbenzoate Chemical compound COC(=O)C1=CC=C(C)C(NC(=O)C=2C(=CC=C(C=2)N2CC(CO)CC2)C)=C1C DNYXWBYNJMEKQU-UHFFFAOYSA-N 0.000 description 1
- GQIHRFBPVZDBRJ-UHFFFAOYSA-N methyl 3-[[5-[3-[[tert-butyl(dimethyl)silyl]oxymethyl]piperidin-1-yl]-2-fluorobenzoyl]amino]-2,4-dimethylbenzoate Chemical compound COC(=O)C1=CC=C(C)C(NC(=O)C=2C(=CC=C(C=2)N2CC(CO[Si](C)(C)C(C)(C)C)CCC2)F)=C1C GQIHRFBPVZDBRJ-UHFFFAOYSA-N 0.000 description 1
- PCJARQBUUGUZDA-UHFFFAOYSA-N methyl 3-[[5-[3-[[tert-butyl(dimethyl)silyl]oxymethyl]piperidin-1-yl]-2-methylbenzoyl]amino]-2,4-dimethylbenzoate Chemical compound COC(=O)C1=CC=C(C)C(NC(=O)C=2C(=CC=C(C=2)N2CC(CO[Si](C)(C)C(C)(C)C)CCC2)C)=C1C PCJARQBUUGUZDA-UHFFFAOYSA-N 0.000 description 1
- ZBNRDLOIIRAPBX-UHFFFAOYSA-N methyl 3-[[5-[3-[[tert-butyl(dimethyl)silyl]oxymethyl]pyrrolidin-1-yl]-2-methylbenzoyl]amino]-2,4-dimethylbenzoate Chemical compound COC(=O)C1=CC=C(C)C(NC(=O)C=2C(=CC=C(C=2)N2CC(CO[Si](C)(C)C(C)(C)C)CC2)C)=C1C ZBNRDLOIIRAPBX-UHFFFAOYSA-N 0.000 description 1
- BPLVRIVGWAFBDR-UHFFFAOYSA-N methyl 3-[[5-[4-[tert-butyl(dimethyl)silyl]oxypiperidin-1-yl]-2-(trifluoromethyl)benzoyl]amino]-2,4-dimethylbenzoate Chemical compound COC(=O)C1=CC=C(C)C(NC(=O)C=2C(=CC=C(C=2)N2CCC(CC2)O[Si](C)(C)C(C)(C)C)C(F)(F)F)=C1C BPLVRIVGWAFBDR-UHFFFAOYSA-N 0.000 description 1
- YKPXXSKWMFIBMP-UHFFFAOYSA-N methyl 3-[[6-(4-hydroxy-4-methylpiperidin-1-yl)-3-methylpyridine-2-carbonyl]amino]-2,4-dimethylbenzoate Chemical compound COC(=O)C1=CC=C(C)C(NC(=O)C=2C(=CC=C(N=2)N2CCC(C)(O)CC2)C)=C1C YKPXXSKWMFIBMP-UHFFFAOYSA-N 0.000 description 1
- UEDKSAISISCOGO-UHFFFAOYSA-N methyl 3-[[6-(4-hydroxypiperidin-1-yl)-3-methylpyridine-2-carbonyl]amino]-2,4-dimethylbenzoate Chemical compound COC(=O)C1=CC=C(C)C(NC(=O)C=2C(=CC=C(N=2)N2CCC(O)CC2)C)=C1C UEDKSAISISCOGO-UHFFFAOYSA-N 0.000 description 1
- KZRROEKZRNUUKK-UHFFFAOYSA-N methyl 3-[[6-[3-(hydroxymethyl)piperidin-1-yl]-3-methylpyridine-2-carbonyl]amino]-2,4-dimethylbenzoate Chemical compound COC(=O)C1=CC=C(C)C(NC(=O)C=2C(=CC=C(N=2)N2CC(CO)CCC2)C)=C1C KZRROEKZRNUUKK-UHFFFAOYSA-N 0.000 description 1
- SNNDBOCDCUVKCF-UHFFFAOYSA-N methyl 3-[[6-[3-[[tert-butyl(dimethyl)silyl]oxymethyl]piperidin-1-yl]-3-methylpyridine-2-carbonyl]amino]-2,4-dimethylbenzoate Chemical compound COC(=O)C1=CC=C(C)C(NC(=O)C=2C(=CC=C(N=2)N2CC(CO[Si](C)(C)C(C)(C)C)CCC2)C)=C1C SNNDBOCDCUVKCF-UHFFFAOYSA-N 0.000 description 1
- NKJRFIVHKHIRCG-UHFFFAOYSA-N methyl 4-[(2-chloroquinoline-4-carbonyl)amino]-3,5-dimethylbenzoate Chemical compound CC1=CC(C(=O)OC)=CC(C)=C1NC(=O)C1=CC(Cl)=NC2=CC=CC=C12 NKJRFIVHKHIRCG-UHFFFAOYSA-N 0.000 description 1
- OBSJSJLNMLKSCI-UHFFFAOYSA-N methyl 4-[(5-bromo-2-methylbenzoyl)amino]-3,5-dimethylbenzoate Chemical compound CC1=CC(C(=O)OC)=CC(C)=C1NC(=O)C1=CC(Br)=CC=C1C OBSJSJLNMLKSCI-UHFFFAOYSA-N 0.000 description 1
- FNEWCPLEGFHFIN-UHFFFAOYSA-N methyl 4-[[2-(4-hydroxypiperidin-1-yl)quinoline-4-carbonyl]amino]-3,5-dimethylbenzoate Chemical compound CC1=CC(C(=O)OC)=CC(C)=C1NC(=O)C1=CC(N2CCC(O)CC2)=NC2=CC=CC=C12 FNEWCPLEGFHFIN-UHFFFAOYSA-N 0.000 description 1
- ZUBSKXYOTSZKLY-UHFFFAOYSA-N methyl 4-[[2-[4-[tert-butyl(dimethyl)silyl]oxypiperidin-1-yl]quinoline-4-carbonyl]amino]-3,5-dimethylbenzoate Chemical compound CC1=CC(C(=O)OC)=CC(C)=C1NC(=O)C1=CC(N2CCC(CC2)O[Si](C)(C)C(C)(C)C)=NC2=CC=CC=C12 ZUBSKXYOTSZKLY-UHFFFAOYSA-N 0.000 description 1
- ZGWMGKZLYTWRHM-UHFFFAOYSA-N methyl 4-[[2-fluoro-5-[3-(hydroxymethyl)piperidin-1-yl]benzoyl]amino]-3,5-dimethylbenzoate Chemical compound CC1=CC(C(=O)OC)=CC(C)=C1NC(=O)C1=CC(N2CC(CO)CCC2)=CC=C1F ZGWMGKZLYTWRHM-UHFFFAOYSA-N 0.000 description 1
- RTXKKTSNOLYRHT-UHFFFAOYSA-N methyl 4-[[5-(4-hydroxypiperidin-1-yl)-2-(trifluoromethyl)benzoyl]amino]-3,5-dimethylbenzoate Chemical compound CC1=CC(C(=O)OC)=CC(C)=C1NC(=O)C1=CC(N2CCC(O)CC2)=CC=C1C(F)(F)F RTXKKTSNOLYRHT-UHFFFAOYSA-N 0.000 description 1
- XIAVKUPUEQUXGK-UHFFFAOYSA-N methyl 4-[[5-[3-(hydroxymethyl)piperidin-1-yl]-2-methylbenzoyl]amino]-3,5-dimethylbenzoate Chemical compound CC1=CC(C(=O)OC)=CC(C)=C1NC(=O)C1=CC(N2CC(CO)CCC2)=CC=C1C XIAVKUPUEQUXGK-UHFFFAOYSA-N 0.000 description 1
- DCIRIFPXGSFJRZ-UHFFFAOYSA-N methyl 4-[[5-[3-[[tert-butyl(dimethyl)silyl]oxymethyl]piperidin-1-yl]-2-fluorobenzoyl]amino]-3,5-dimethylbenzoate Chemical compound CC1=CC(C(=O)OC)=CC(C)=C1NC(=O)C1=CC(N2CC(CO[Si](C)(C)C(C)(C)C)CCC2)=CC=C1F DCIRIFPXGSFJRZ-UHFFFAOYSA-N 0.000 description 1
- HTYRGKAHTWHATB-UHFFFAOYSA-N methyl 4-[[5-[3-[[tert-butyl(dimethyl)silyl]oxymethyl]piperidin-1-yl]-2-methylbenzoyl]amino]-3,5-dimethylbenzoate Chemical compound CC1=CC(C(=O)OC)=CC(C)=C1NC(=O)C1=CC(N2CC(CO[Si](C)(C)C(C)(C)C)CCC2)=CC=C1C HTYRGKAHTWHATB-UHFFFAOYSA-N 0.000 description 1
- CHALVWOTAVMTFK-UHFFFAOYSA-N methyl 4-[[6-(4,4-difluoropiperidin-1-yl)-3-methylpyridine-2-carbonyl]amino]-3,5-dimethylbenzoate Chemical compound CC1=CC(C(=O)OC)=CC(C)=C1NC(=O)C1=NC(N2CCC(F)(F)CC2)=CC=C1C CHALVWOTAVMTFK-UHFFFAOYSA-N 0.000 description 1
- TZEHCOWHWBTMCF-UHFFFAOYSA-N methyl 4-[[6-(4-methoxypiperidin-1-yl)-3-methylpyridine-2-carbonyl]amino]-3,5-dimethylbenzoate Chemical compound C1CC(OC)CCN1C1=CC=C(C)C(C(=O)NC=2C(=CC(=CC=2C)C(=O)OC)C)=N1 TZEHCOWHWBTMCF-UHFFFAOYSA-N 0.000 description 1
- YTPAWTSBBDELOH-UHFFFAOYSA-N methyl 4-[[6-[3-(hydroxymethyl)piperidin-1-yl]-3-methylpyridine-2-carbonyl]amino]-3,5-dimethylbenzoate Chemical compound CC1=CC(C(=O)OC)=CC(C)=C1NC(=O)C1=NC(N2CC(CO)CCC2)=CC=C1C YTPAWTSBBDELOH-UHFFFAOYSA-N 0.000 description 1
- DKKIOCYBDVCUHZ-UHFFFAOYSA-N methyl 4-[[6-[3-(hydroxymethyl)pyrrolidin-1-yl]-3-methylpyridine-2-carbonyl]amino]-3,5-dimethylbenzoate Chemical compound CC1=CC(C(=O)OC)=CC(C)=C1NC(=O)C1=NC(N2CC(CO)CC2)=CC=C1C DKKIOCYBDVCUHZ-UHFFFAOYSA-N 0.000 description 1
- DBYMUWHHJQOHGK-UHFFFAOYSA-N methyl 4-[[6-[3-[[tert-butyl(dimethyl)silyl]oxymethyl]piperidin-1-yl]-3-methylpyridine-2-carbonyl]amino]-3,5-dimethylbenzoate Chemical compound CC1=CC(C(=O)OC)=CC(C)=C1NC(=O)C1=NC(N2CC(CO[Si](C)(C)C(C)(C)C)CCC2)=CC=C1C DBYMUWHHJQOHGK-UHFFFAOYSA-N 0.000 description 1
- AXLMAJOGCCKNES-UHFFFAOYSA-N methyl 4-[[6-[3-[[tert-butyl(dimethyl)silyl]oxymethyl]pyrrolidin-1-yl]-3-methylpyridine-2-carbonyl]amino]-3,5-dimethylbenzoate Chemical compound CC1=CC(C(=O)OC)=CC(C)=C1NC(=O)C1=NC(N2CC(CO[Si](C)(C)C(C)(C)C)CC2)=CC=C1C AXLMAJOGCCKNES-UHFFFAOYSA-N 0.000 description 1
- 210000001616 monocyte Anatomy 0.000 description 1
- RIVIDPPYRINTTH-UHFFFAOYSA-N n-ethylpropan-2-amine Chemical compound CCNC(C)C RIVIDPPYRINTTH-UHFFFAOYSA-N 0.000 description 1
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 1
- 230000009871 nonspecific binding Effects 0.000 description 1
- 229940094443 oxytocics prostaglandins Drugs 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 229960003531 phenolsulfonphthalein Drugs 0.000 description 1
- 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 description 1
- 239000013612 plasmid Substances 0.000 description 1
- 229920001155 polypropylene Polymers 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- IUTZJUYLKWNRJT-UHFFFAOYSA-M potassium;6-chloro-3-methylpyridine-2-carboxylate Chemical compound [K+].CC1=CC=C(Cl)N=C1C([O-])=O IUTZJUYLKWNRJT-UHFFFAOYSA-M 0.000 description 1
- OMSJUFBWVWHPNF-UHFFFAOYSA-M potassium;6-chloropyridine-2-carboxylate Chemical compound [K+].[O-]C(=O)C1=CC=CC(Cl)=N1 OMSJUFBWVWHPNF-UHFFFAOYSA-M 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000002953 preparative HPLC Methods 0.000 description 1
- 150000003180 prostaglandins Chemical class 0.000 description 1
- 229940127293 prostanoid Drugs 0.000 description 1
- 150000003814 prostanoids Chemical class 0.000 description 1
- ZUFQODAHGAHPFQ-UHFFFAOYSA-N pyridoxine hydrochloride Chemical compound Cl.CC1=NC=C(CO)C(CO)=C1O ZUFQODAHGAHPFQ-UHFFFAOYSA-N 0.000 description 1
- 229960004172 pyridoxine hydrochloride Drugs 0.000 description 1
- 235000019171 pyridoxine hydrochloride Nutrition 0.000 description 1
- 239000011764 pyridoxine hydrochloride Substances 0.000 description 1
- 239000010453 quartz Substances 0.000 description 1
- 150000003248 quinolines Chemical class 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 238000004366 reverse phase liquid chromatography Methods 0.000 description 1
- 238000011808 rodent model Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 229940054269 sodium pyruvate Drugs 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 230000009870 specific binding Effects 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- BWQLJNMKURWZIR-UHFFFAOYSA-N tert-butyl-dimethyl-(pyrrolidin-3-ylmethoxy)silane Chemical compound CC(C)(C)[Si](C)(C)OCC1CCNC1 BWQLJNMKURWZIR-UHFFFAOYSA-N 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
- C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/40—Oxygen atoms
- C07D211/42—Oxygen atoms attached in position 3 or 5
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/40—Oxygen atoms
- C07D211/44—Oxygen atoms attached in position 4
- C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/10—Spiro-condensed systems
- C07D491/113—Spiro-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
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- Public Health (AREA)
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- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Rheumatology (AREA)
- General Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Immunology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Engineering & Computer Science (AREA)
- Pain & Pain Management (AREA)
- Physical Education & Sports Medicine (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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Applications Claiming Priority (5)
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| US61/778,969 | 2013-03-13 | ||
| PCT/US2013/046685 WO2014004230A1 (en) | 2012-06-29 | 2013-06-20 | Dimethyl-benzoic acid compounds |
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| US20110015221A1 (en) * | 2003-12-23 | 2011-01-20 | Pierre Fabre Medicament | Pharmaceutical composition of vinflunine which is intended for parenteral administration preparation method thereof and use of same |
| TWI572597B (zh) * | 2012-06-29 | 2017-03-01 | 美國禮來大藥廠 | 二甲基－苯甲酸化合物 |
| EP2765128A1 (en) * | 2013-02-07 | 2014-08-13 | Almirall, S.A. | Substituted benzamides with activity towards EP4 receptors |
| TWI636046B (zh) | 2013-05-17 | 2018-09-21 | 美國禮來大藥廠 | 苯氧基乙基二氫－１ｈ－異喹啉化合物 |
| JP6200596B2 (ja) | 2013-12-17 | 2017-09-20 | イーライ リリー アンド カンパニー | ジメチル安息香酸化合物 |
| US10189788B2 (en) | 2014-09-09 | 2019-01-29 | Bayer Pharma Aktiengesellschaft | Substituted N,2-diarylquinoline-4-carboxamides and the use thereof as anti-inflammatory agents |
| CR20180323A (es) | 2015-11-20 | 2018-08-06 | Idorsia Pharmaceuticals Ltd | Derivados de indol n-sustituídos como moduladores de los receptores de pge2 |
| PE20191616A1 (es) * | 2017-04-10 | 2019-11-05 | Bayer Ag | N-ariletil-2-arilquinolina-4-carboxamidas sustituidas y su uso |
| TWI770157B (zh) * | 2017-04-10 | 2022-07-11 | 德商拜耳廠股份有限公司 | 經取代之n-芳基乙基-2-胺基喹啉-4-甲醯胺及其用途 |
| PE20191787A1 (es) | 2017-05-18 | 2019-12-24 | Idorsia Pharmaceuticals Ltd | Derivados de indol n-sustituidos |
| KR102612140B1 (ko) | 2017-05-18 | 2023-12-08 | 이도르시아 파마슈티컬스 리미티드 | 피리미딘 유도체 |
| AR111808A1 (es) | 2017-05-18 | 2019-08-21 | Idorsia Pharmaceuticals Ltd | Derivados de pirimidina como moduladores del receptor de pge2 |
| EA201992676A1 (ru) | 2017-05-18 | 2020-05-06 | Идорсия Фармасьютиклз Лтд | Фенильные производные в качестве модуляторов pge2 рецепторов |
| US11325899B2 (en) | 2017-05-18 | 2022-05-10 | Idorsia Pharmaceuticals Ltd | Benzofurane and benzothiophene derivatives as PGE2 receptor modulators |
| JP7816164B2 (ja) | 2020-11-13 | 2026-02-18 | 小野薬品工業株式会社 | Ｅｐ４拮抗薬と免疫チェックポイント阻害物質との併用によるがん治療 |
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| MXPA06003123A (es) | 2003-09-22 | 2006-05-31 | Euro Celtique Sa | Agentes terapeuticos utiles para el tratamiento del dolor. |
| US7326732B2 (en) | 2004-02-12 | 2008-02-05 | Pharmagene Laboratories Limited | EP2 receptor agonists |
| CA2654811A1 (en) * | 2006-06-12 | 2007-12-21 | Merck Frosst Canada Ltd. | Indoline amide derivatives as ep4 receptor ligands |
| KR20090122931A (ko) * | 2007-03-26 | 2009-12-01 | 아스테라스 세이야쿠 가부시키가이샤 | 오르니틴 유도체 |
| WO2012004293A2 (de) | 2010-07-08 | 2012-01-12 | Bayer Cropscience Ag | Insektizide und fungizide wirkstoffkombinationen |
| CA2831978A1 (en) | 2011-03-03 | 2012-09-07 | Universitat Des Saarlandes | Biaryl derivatives as selective 17beta-hydroxysteroid dehydrogenase type 2 inhibitors |
| TWI572597B (zh) * | 2012-06-29 | 2017-03-01 | 美國禮來大藥廠 | 二甲基－苯甲酸化合物 |
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