JP6127136B2 - フェノキシエチルピペリジン化合物 - Google Patents
フェノキシエチルピペリジン化合物 Download PDFInfo
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- JP6127136B2 JP6127136B2 JP2015520304A JP2015520304A JP6127136B2 JP 6127136 B2 JP6127136 B2 JP 6127136B2 JP 2015520304 A JP2015520304 A JP 2015520304A JP 2015520304 A JP2015520304 A JP 2015520304A JP 6127136 B2 JP6127136 B2 JP 6127136B2
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- pharmaceutically acceptable
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- -1 Phenoxyethyl piperidine compound Chemical class 0.000 title description 8
- 150000001875 compounds Chemical class 0.000 claims description 103
- 150000003839 salts Chemical class 0.000 claims description 44
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 10
- 239000008194 pharmaceutical composition Substances 0.000 claims description 7
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 3
- 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
- 239000000203 mixture Substances 0.000 description 39
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 35
- 230000002829 reductive effect Effects 0.000 description 33
- 238000000034 method Methods 0.000 description 30
- 239000007787 solid Substances 0.000 description 29
- 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
- 238000002360 preparation method Methods 0.000 description 23
- 238000011282 treatment Methods 0.000 description 22
- 230000015572 biosynthetic process Effects 0.000 description 21
- 238000003786 synthesis reaction Methods 0.000 description 20
- 210000004027 cell Anatomy 0.000 description 18
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 17
- 235000019439 ethyl acetate Nutrition 0.000 description 17
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 17
- 238000005481 NMR spectroscopy Methods 0.000 description 15
- 239000005557 antagonist Substances 0.000 description 15
- 201000008482 osteoarthritis Diseases 0.000 description 15
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 14
- 239000000706 filtrate Substances 0.000 description 14
- 238000001819 mass spectrum Methods 0.000 description 14
- 206010039073 rheumatoid arthritis Diseases 0.000 description 14
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 11
- 229920006395 saturated elastomer Polymers 0.000 description 11
- 239000003814 drug Substances 0.000 description 10
- 230000000694 effects Effects 0.000 description 10
- 239000010410 layer Substances 0.000 description 10
- 239000000047 product Substances 0.000 description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 239000012044 organic layer Substances 0.000 description 9
- 239000012074 organic phase Substances 0.000 description 9
- 102000005962 receptors Human genes 0.000 description 9
- 108020003175 receptors Proteins 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 8
- 239000000741 silica gel Substances 0.000 description 8
- 229910002027 silica gel Inorganic materials 0.000 description 8
- 239000011734 sodium Substances 0.000 description 8
- 208000002193 Pain Diseases 0.000 description 7
- 206010003246 arthritis Diseases 0.000 description 7
- 238000009739 binding Methods 0.000 description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 7
- 239000011780 sodium chloride Substances 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 6
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-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
- 239000012141 concentrate Substances 0.000 description 6
- 239000013058 crude material Substances 0.000 description 6
- 238000002868 homogeneous time resolved fluorescence Methods 0.000 description 6
- 238000000338 in vitro Methods 0.000 description 6
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 6
- 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 5
- 108091003079 Bovine Serum Albumin Proteins 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
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 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
- 239000000872 buffer Substances 0.000 description 5
- 239000002158 endotoxin Substances 0.000 description 5
- 239000012091 fetal bovine serum Substances 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 230000005764 inhibitory process Effects 0.000 description 5
- 229920006008 lipopolysaccharide Polymers 0.000 description 5
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-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
- 239000012981 Hank's balanced salt solution Substances 0.000 description 4
- 239000007987 MES buffer Substances 0.000 description 4
- 101150109738 Ptger4 gene Proteins 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 238000013262 cAMP assay Methods 0.000 description 4
- 229910002091 carbon monoxide Inorganic materials 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 239000012230 colorless oil Substances 0.000 description 4
- 208000035475 disorder Diseases 0.000 description 4
- 231100000673 dose–response relationship Toxicity 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 230000002526 effect on cardiovascular system Effects 0.000 description 4
- 238000003818 flash chromatography Methods 0.000 description 4
- 239000012528 membrane Substances 0.000 description 4
- DRSFYQKBJYLNKT-PGRDOPGGSA-N methyl 4-[(1s)-1-[[(2r)-1-(2-phenoxyethyl)piperidine-2-carbonyl]amino]ethyl]benzoate Chemical compound C1=CC(C(=O)OC)=CC=C1[C@H](C)NC(=O)[C@@H]1N(CCOC=2C=CC=CC=2)CCCC1 DRSFYQKBJYLNKT-PGRDOPGGSA-N 0.000 description 4
- 239000003921 oil Substances 0.000 description 4
- 238000002560 therapeutic procedure Methods 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-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
- 102100035842 Prostaglandin E2 receptor EP1 subtype Human genes 0.000 description 3
- 239000008346 aqueous phase Substances 0.000 description 3
- 238000003556 assay Methods 0.000 description 3
- 239000012131 assay buffer Substances 0.000 description 3
- 239000012298 atmosphere Substances 0.000 description 3
- 229940111134 coxibs Drugs 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
- 239000000284 extract Substances 0.000 description 3
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 3
- 229910000041 hydrogen chloride Inorganic materials 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
- LFNXGVQOIUBOOG-JTQLQIEISA-N methyl 4-[(1s)-1-[(2-methylpropan-2-yl)oxycarbonylamino]ethyl]benzoate Chemical compound COC(=O)C1=CC=C([C@H](C)NC(=O)OC(C)(C)C)C=C1 LFNXGVQOIUBOOG-JTQLQIEISA-N 0.000 description 3
- XPOKUVSPRDWYAO-YECZQDJWSA-N methyl 4-[(1s)-1-[[(2r)-piperidine-2-carbonyl]amino]ethyl]benzoate;hydrochloride Chemical compound Cl.C1=CC(C(=O)OC)=CC=C1[C@H](C)NC(=O)[C@@H]1NCCCC1 XPOKUVSPRDWYAO-YECZQDJWSA-N 0.000 description 3
- XOTRLVYRAWIVLC-FJXQXJEOSA-N methyl 4-[(1s)-1-aminoethyl]benzoate;hydrochloride Chemical compound [Cl-].COC(=O)C1=CC=C([C@H](C)[NH3+])C=C1 XOTRLVYRAWIVLC-FJXQXJEOSA-N 0.000 description 3
- 230000003389 potentiating effect Effects 0.000 description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 description 3
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- KECPRZHCNCDSET-VIFPVBQESA-N tert-butyl n-[(1s)-1-(4-bromophenyl)ethyl]carbamate Chemical compound CC(C)(C)OC(=O)N[C@@H](C)C1=CC=C(Br)C=C1 KECPRZHCNCDSET-VIFPVBQESA-N 0.000 description 3
- IUSHVRNYACBVFD-UHFFFAOYSA-N 1-(2,2-dimethoxyethoxy)-4-fluorobenzene Chemical compound COC(OC)COC1=CC=C(F)C=C1 IUSHVRNYACBVFD-UHFFFAOYSA-N 0.000 description 2
- SOZMSEPDYJGBEK-UHFFFAOYSA-N 1-(4-bromophenyl)ethanamine Chemical compound CC(N)C1=CC=C(Br)C=C1 SOZMSEPDYJGBEK-UHFFFAOYSA-N 0.000 description 2
- CNBQYSJVWUILKY-UHFFFAOYSA-N 2,2-dimethoxyethoxycyclohexane Chemical compound COC(OC)COC1CCCCC1 CNBQYSJVWUILKY-UHFFFAOYSA-N 0.000 description 2
- ATJFHEFBESTYKU-UHFFFAOYSA-N 2-(4-fluorophenoxy)acetaldehyde Chemical compound FC1=CC=C(OCC=O)C=C1 ATJFHEFBESTYKU-UHFFFAOYSA-N 0.000 description 2
- FUSFWUFSEJXMRQ-UHFFFAOYSA-N 2-bromo-1,1-dimethoxyethane Chemical compound COC(CBr)OC FUSFWUFSEJXMRQ-UHFFFAOYSA-N 0.000 description 2
- FMJSLPJYTAKVLJ-CQVJSGDESA-N 4-[(1s)-1-[[(2r)-1-(2-phenoxyethyl)piperidine-2-carbonyl]amino]ethyl]benzoic acid;hydrochloride Chemical compound Cl.C([C@@H]1C(=O)N[C@@H](C)C=2C=CC(=CC=2)C(O)=O)CCCN1CCOC1=CC=CC=C1 FMJSLPJYTAKVLJ-CQVJSGDESA-N 0.000 description 2
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-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
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 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
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- OWGUSBISUVLUJF-SDNWHVSQSA-N [(e)-(2-hexylcyclopentylidene)amino]thiourea Chemical compound CCCCCCC1CCC\C1=N/NC(N)=S OWGUSBISUVLUJF-SDNWHVSQSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 description 2
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- LJFLFAFVCNIJIG-CQSZACIVSA-N methyl (2r)-1-(2-phenoxyethyl)piperidine-2-carboxylate Chemical compound COC(=O)[C@H]1CCCCN1CCOC1=CC=CC=C1 LJFLFAFVCNIJIG-CQSZACIVSA-N 0.000 description 2
- IKFBCPJIXMIEMP-LJCORPPDSA-N methyl 4-[(1s)-1-[[(2r)-1-(1-phenoxypropan-2-yl)piperidin-1-ium-2-carbonyl]amino]ethyl]benzoate;2,2,2-trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F.C1=CC(C(=O)OC)=CC=C1[C@H](C)NC(=O)[C@@H]1[NH+](C(C)COC=2C=CC=CC=2)CCCC1 IKFBCPJIXMIEMP-LJCORPPDSA-N 0.000 description 2
- ONQQSDVTMYAWNM-SMDDNHRTSA-N methyl 4-[(1s)-1-[[(2r)-piperidine-2-carbonyl]amino]ethyl]benzoate Chemical compound C1=CC(C(=O)OC)=CC=C1[C@H](C)NC(=O)[C@@H]1NCCCC1 ONQQSDVTMYAWNM-SMDDNHRTSA-N 0.000 description 2
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- DAEPDZWVDSPTHF-UHFFFAOYSA-M sodium pyruvate Chemical compound [Na+].CC(=O)C([O-])=O DAEPDZWVDSPTHF-UHFFFAOYSA-M 0.000 description 2
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- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 1
- YRBGSECIPFIYES-UHFFFAOYSA-N 2-cyclohexyloxyacetaldehyde Chemical compound O=CCOC1CCCCC1 YRBGSECIPFIYES-UHFFFAOYSA-N 0.000 description 1
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- APIXJSLKIYYUKG-UHFFFAOYSA-N 3 Isobutyl 1 methylxanthine Chemical compound O=C1N(C)C(=O)N(CC(C)C)C2=C1N=CN2 APIXJSLKIYYUKG-UHFFFAOYSA-N 0.000 description 1
- UAIUNKRWKOVEES-UHFFFAOYSA-N 3,3',5,5'-tetramethylbenzidine Chemical compound CC1=C(N)C(C)=CC(C=2C=C(C)C(N)=C(C)C=2)=C1 UAIUNKRWKOVEES-UHFFFAOYSA-N 0.000 description 1
- FNQIYTUXOKTMDM-UHFFFAOYSA-N 3-phenoxypropane-1,2-diol Chemical compound OCC(O)COC1=CC=CC=C1 FNQIYTUXOKTMDM-UHFFFAOYSA-N 0.000 description 1
- SODGOWMUQCSONV-JTNYPFFNSA-N 4-[(1s)-1-[[(2r)-1-(1-phenoxypropan-2-yl)piperidin-1-ium-2-carbonyl]amino]ethyl]benzoic acid;2,2,2-trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F.[NH+]1([C@H](CCCC1)C(=O)N[C@@H](C)C=1C=CC(=CC=1)C(O)=O)C(C)COC1=CC=CC=C1 SODGOWMUQCSONV-JTNYPFFNSA-N 0.000 description 1
- ADSVKUMNMQPBKC-LAUBAEHRSA-N 4-[(1s)-1-[[(2r)-1-(2-phenoxyethyl)piperidine-2-carbonyl]amino]ethyl]benzoic acid Chemical compound C([C@@H]1C(=O)N[C@@H](C)C=2C=CC(=CC=2)C(O)=O)CCCN1CCOC1=CC=CC=C1 ADSVKUMNMQPBKC-LAUBAEHRSA-N 0.000 description 1
- RHMPLDJJXGPMEX-UHFFFAOYSA-N 4-fluorophenol Chemical compound OC1=CC=C(F)C=C1 RHMPLDJJXGPMEX-UHFFFAOYSA-N 0.000 description 1
- 108010088751 Albumins Proteins 0.000 description 1
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Classifications
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- 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
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- 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
- A61K31/45—Non condensed piperidines, e.g. piperocaine having oxo groups directly attached to the heterocyclic ring, e.g. cycloheximide
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- 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
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- 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
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- 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]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Rheumatology (AREA)
- Physical Education & Sports Medicine (AREA)
- Immunology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Pain & Pain Management (AREA)
- Hydrogenated Pyridines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201261665951P | 2012-06-29 | 2012-06-29 | |
| US61/665,951 | 2012-06-29 | ||
| US201361779099P | 2013-03-13 | 2013-03-13 | |
| US61/779,099 | 2013-03-13 | ||
| PCT/US2013/046684 WO2014004229A1 (en) | 2012-06-29 | 2013-06-20 | Phenoxyethyl piperidine compounds |
Publications (3)
| Publication Number | Publication Date |
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| JP2015522018A JP2015522018A (ja) | 2015-08-03 |
| JP2015522018A5 JP2015522018A5 (oth) | 2016-08-04 |
| JP6127136B2 true JP6127136B2 (ja) | 2017-05-10 |
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| AR091429A1 (es) * | 2012-06-29 | 2015-02-04 | Lilly Co Eli | Compuestos de fenoxietil piperidina |
| 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 |
| ME02896B (me) * | 2013-12-17 | 2018-04-20 | Lilly Co Eli | Fenoksietilni derivati prstenastog amina i njihova aktivnost kao modulatora receptora ep4 |
| CR20180323A (es) | 2015-11-20 | 2018-08-06 | Idorsia Pharmaceuticals Ltd | Derivados de indol n-sustituídos como moduladores de los receptores de pge2 |
| EA201992676A1 (ru) | 2017-05-18 | 2020-05-06 | Идорсия Фармасьютиклз Лтд | Фенильные производные в качестве модуляторов pge2 рецепторов |
| CN110621671A (zh) | 2017-05-18 | 2019-12-27 | 爱杜西亚药品有限公司 | 作为pge2受体调节剂的苯并呋喃及苯并噻吩衍生物 |
| CN110621667A (zh) | 2017-05-18 | 2019-12-27 | 爱杜西亚药品有限公司 | 嘧啶衍生物 |
| EP3625224B1 (en) | 2017-05-18 | 2021-08-04 | Idorsia Pharmaceuticals Ltd | N-substituted indole derivatives |
| PL3625228T3 (pl) | 2017-05-18 | 2021-12-20 | Idorsia Pharmaceuticals Ltd | Pochodne pirymidyny jako modulatory receptora pge2 |
| EP3889134B1 (en) * | 2019-01-22 | 2024-09-25 | Keythera (Suzhou) Pharmaceuticals Co. Ltd. | Compound for inhibiting pge2/ep4 signaling transduction inhibiting, preparation method therefor, and medical uses thereof |
| US20230390303A1 (en) | 2020-11-13 | 2023-12-07 | Ono Pharmaceutical Co., Ltd. | Cancer treatment by combination of ep4 antagonist and immune checkpoint inhibitor |
| GB202211232D0 (en) | 2022-08-02 | 2022-09-14 | Heptares Therapeutics Ltd | Prostaglandin EP4 receptor agonist compounds |
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| DE2500157C2 (de) | 1975-01-03 | 1983-09-15 | Hoechst Ag, 6230 Frankfurt | N-Acyl-4-(2-aminoäthyl)-benzoesäuren, deren Salze und Ester, Verfahren zu deren Herstellung und deren Verwendung |
| WO2003077910A1 (en) * | 2002-03-18 | 2003-09-25 | Pfizer Products Inc. | Methods of treatment with selective ep4 receptor agonists |
| CA2511255C (en) * | 2003-01-10 | 2009-04-07 | F. Hoffmann-La Roche Ag | 2-piperidone derivatives as prostaglandin agonists |
| CN1867551B (zh) * | 2003-09-03 | 2013-09-11 | 拉夸里亚创药株式会社 | 作为前列腺素e2拮抗剂的苯基或吡啶基酰胺化合物 |
| US20050105732A1 (en) | 2003-11-17 | 2005-05-19 | Hutchings George T. | Systems and methods for delivering pre-encrypted content to a subscriber terminal |
| AP2006003769A0 (en) * | 2004-05-04 | 2006-10-31 | Pfizer | Ortho substituted aryl or heteroaryl amide compounds |
| CN1950333A (zh) * | 2004-05-04 | 2007-04-18 | 辉瑞大药厂 | 取代的甲基芳基或杂芳基酰胺化合物 |
| US7592364B2 (en) * | 2006-02-28 | 2009-09-22 | Allergan, Inc. | Substituted gamma lactams as therapeutic agents |
| EP2013169B1 (en) | 2006-04-24 | 2012-08-22 | Merck Canada Inc. | Indole amide derivatives as ep4 receptor antagonists |
| EP2035376B1 (en) | 2006-06-12 | 2014-08-27 | Merck Canada Inc. | Indoline amide derivatives as ep4 receptor ligands |
| WO2008092860A1 (en) * | 2007-01-30 | 2008-08-07 | Janssen Pharmaceutica N.V. | Bicyclic derivatives as ep4 agonists |
| EP2565191B1 (en) * | 2008-05-14 | 2014-10-08 | Astellas Pharma Inc. | 4-(Indol-7-ylcarbonylaminomethyl)cyclohexanecarboxylic acid derivatives as EP4 receptor antagonists useful for the treatment of chronic renal failure or diabetic nephropathy |
| WO2010019796A1 (en) | 2008-08-14 | 2010-02-18 | Chemietek, Llc | Heterocyclic amide derivatives as ep4 receptor antagonists |
| ES2600355T3 (es) | 2010-02-22 | 2017-02-08 | Raqualia Pharma Inc. | Uso de un antagonista del receptor EP4 en el tratamiento de dermatitis de contacto alérgica y psoriasis |
| CA2806121C (en) * | 2010-09-21 | 2018-10-09 | Eisai R&D Management Co., Ltd. | Pharmaceutical composition |
| EP2729141B1 (en) | 2011-07-04 | 2015-12-09 | Rottapharm Biotech S.r.l. | Cyclic amine derivatives as ep4 receptor agonists |
| EP2729445B1 (en) | 2011-07-04 | 2015-10-21 | Rottapharm Biotech S.r.l. | Cyclic amine derivatives as ep4 receptor antagonists |
| AR091429A1 (es) * | 2012-06-29 | 2015-02-04 | Lilly Co Eli | Compuestos de fenoxietil piperidina |
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