JP5709889B2 - 新規スピロピペリジン化合物 - Google Patents
新規スピロピペリジン化合物 Download PDFInfo
- Publication number
- JP5709889B2 JP5709889B2 JP2012542076A JP2012542076A JP5709889B2 JP 5709889 B2 JP5709889 B2 JP 5709889B2 JP 2012542076 A JP2012542076 A JP 2012542076A JP 2012542076 A JP2012542076 A JP 2012542076A JP 5709889 B2 JP5709889 B2 JP 5709889B2
- Authority
- JP
- Japan
- Prior art keywords
- compound
- pharmaceutically acceptable
- mmol
- acceptable salt
- compounds
- Prior art date
- 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.)
- Expired - Fee Related
Links
- JUXAVSAMVBLDKO-UHFFFAOYSA-N 1-(1-azabicyclo[2.2.2]octan-3-yl)-3-[3-(1h-indol-3-yl)-1-oxo-1-spiro[1,2-dihydroindene-3,4'-piperidine]-1'-ylpropan-2-yl]urea Chemical class C1N(CC2)CCC2C1NC(=O)NC(C(=O)N1CCC2(C3=CC=CC=C3CC2)CC1)CC1=CNC2=CC=CC=C12 JUXAVSAMVBLDKO-UHFFFAOYSA-N 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims description 187
- 150000003839 salts Chemical class 0.000 claims description 45
- 238000011282 treatment Methods 0.000 claims description 10
- 206010012601 diabetes mellitus Diseases 0.000 claims description 7
- 239000003814 drug Substances 0.000 claims description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- 239000003937 drug carrier Substances 0.000 claims description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 238000002560 therapeutic procedure Methods 0.000 claims description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 70
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 60
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 41
- 239000000203 mixture Substances 0.000 description 40
- 239000000243 solution Substances 0.000 description 40
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 36
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 35
- 238000002360 preparation method Methods 0.000 description 34
- 239000011541 reaction mixture Substances 0.000 description 31
- 238000000034 method Methods 0.000 description 29
- 102100026148 Free fatty acid receptor 1 Human genes 0.000 description 28
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 28
- 239000008103 glucose Substances 0.000 description 28
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 28
- 101000912510 Homo sapiens Free fatty acid receptor 1 Proteins 0.000 description 27
- 235000019439 ethyl acetate Nutrition 0.000 description 25
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 20
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 19
- 238000003556 assay Methods 0.000 description 17
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 15
- 230000000694 effects Effects 0.000 description 15
- 102000005962 receptors Human genes 0.000 description 15
- 108020003175 receptors Proteins 0.000 description 15
- 102000004877 Insulin Human genes 0.000 description 14
- 108090001061 Insulin Proteins 0.000 description 14
- -1 aromatic heterocyclic bromomethyl compound Chemical class 0.000 description 14
- 210000004027 cell Anatomy 0.000 description 14
- 229940125396 insulin Drugs 0.000 description 14
- 102000003728 Peroxisome Proliferator-Activated Receptors Human genes 0.000 description 13
- 108090000029 Peroxisome Proliferator-Activated Receptors Proteins 0.000 description 13
- 239000012267 brine Substances 0.000 description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 229910052938 sodium sulfate Inorganic materials 0.000 description 12
- 235000011152 sodium sulphate Nutrition 0.000 description 12
- 239000007787 solid Substances 0.000 description 12
- 108010016731 PPAR gamma Proteins 0.000 description 11
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 11
- 102000023984 PPAR alpha Human genes 0.000 description 10
- 102100038825 Peroxisome proliferator-activated receptor gamma Human genes 0.000 description 10
- 108091008725 peroxisome proliferator-activated receptors alpha Proteins 0.000 description 10
- 238000010898 silica gel chromatography Methods 0.000 description 10
- 239000011734 sodium Substances 0.000 description 10
- 239000013058 crude material Substances 0.000 description 9
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 8
- 230000004913 activation Effects 0.000 description 8
- 230000027455 binding Effects 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 8
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 7
- 238000009739 binding Methods 0.000 description 7
- 230000002829 reductive effect Effects 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 239000005909 Kieselgur Substances 0.000 description 6
- 238000005481 NMR spectroscopy Methods 0.000 description 6
- 108010015181 PPAR delta Proteins 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 239000011575 calcium Substances 0.000 description 6
- 229910052791 calcium Inorganic materials 0.000 description 6
- NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical compound C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 description 6
- 239000000284 extract Substances 0.000 description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 6
- 230000003914 insulin secretion Effects 0.000 description 6
- 239000012044 organic layer Substances 0.000 description 6
- 125000006239 protecting group Chemical group 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- 210000002237 B-cell of pancreatic islet Anatomy 0.000 description 5
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 5
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 5
- 239000003638 chemical reducing agent Substances 0.000 description 5
- 239000012043 crude product Substances 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 238000011534 incubation Methods 0.000 description 5
- 239000002609 medium Substances 0.000 description 5
- 239000013612 plasmid Substances 0.000 description 5
- 238000002821 scintillation proximity assay Methods 0.000 description 5
- 108010001515 Galectin 4 Proteins 0.000 description 4
- 102100039556 Galectin-4 Human genes 0.000 description 4
- 101001093899 Homo sapiens Retinoic acid receptor RXR-alpha Proteins 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- 102100035178 Retinoic acid receptor RXR-alpha Human genes 0.000 description 4
- 241000283984 Rodentia Species 0.000 description 4
- 230000029936 alkylation Effects 0.000 description 4
- 238000005804 alkylation reaction Methods 0.000 description 4
- 150000001412 amines Chemical class 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 239000000872 buffer Substances 0.000 description 4
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 4
- 229910000024 caesium carbonate Inorganic materials 0.000 description 4
- 238000002825 functional assay Methods 0.000 description 4
- 238000001727 in vivo Methods 0.000 description 4
- 239000003446 ligand Substances 0.000 description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 4
- 239000012299 nitrogen atmosphere Substances 0.000 description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 4
- HKOOXMFOFWEVGF-UHFFFAOYSA-N phenylhydrazine Chemical compound NNC1=CC=CC=C1 HKOOXMFOFWEVGF-UHFFFAOYSA-N 0.000 description 4
- 239000013641 positive control Substances 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- 101710142060 Free fatty acid receptor 1 Proteins 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 206010022489 Insulin Resistance Diseases 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- 239000011324 bead Substances 0.000 description 3
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 239000012141 concentrate Substances 0.000 description 3
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 238000007446 glucose tolerance test Methods 0.000 description 3
- 125000000623 heterocyclic group Chemical group 0.000 description 3
- 206010022498 insulinoma Diseases 0.000 description 3
- 230000003834 intracellular effect Effects 0.000 description 3
- 208000021255 pancreatic insulinoma Diseases 0.000 description 3
- 229940067157 phenylhydrazine Drugs 0.000 description 3
- HRVXPXCISZSDCC-UHFFFAOYSA-N piperidine-4-carbaldehyde Chemical compound O=CC1CCNCC1 HRVXPXCISZSDCC-UHFFFAOYSA-N 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 238000002810 primary assay Methods 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 238000000159 protein binding assay Methods 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 125000003003 spiro group Chemical group 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- NQRYJNQNLNOLGT-UHFFFAOYSA-N tetrahydropyridine hydrochloride Natural products C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 3
- 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 2
- DGENZVKCTGIDRZ-UHFFFAOYSA-N 3-[4-[(3-phenoxyphenyl)methylamino]phenyl]propanoic acid Chemical compound C1=CC(CCC(=O)O)=CC=C1NCC1=CC=CC(OC=2C=CC=CC=2)=C1 DGENZVKCTGIDRZ-UHFFFAOYSA-N 0.000 description 2
- 125000004203 4-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- LVTBJQIYCQMXQQ-UHFFFAOYSA-N 4-methyl-5-(spiro[indene-1,4'-piperidine]-1'-ylmethyl)-1,3-thiazole-2-carbaldehyde Chemical compound N1=C(C=O)SC(CN2CCC3(CC2)C2=CC=CC=C2C=C3)=C1C LVTBJQIYCQMXQQ-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 239000004215 Carbon black (E152) Substances 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 241000701022 Cytomegalovirus Species 0.000 description 2
- 229940125827 GPR40 agonist Drugs 0.000 description 2
- 239000012981 Hank's balanced salt solution Substances 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- 108060001084 Luciferase Proteins 0.000 description 2
- 239000005089 Luciferase Substances 0.000 description 2
- 241000829100 Macaca mulatta polyomavirus 1 Species 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- 229940126033 PPAR agonist Drugs 0.000 description 2
- 229940080774 Peroxisome proliferator-activated receptor gamma agonist Drugs 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- 102000001708 Protein Isoforms Human genes 0.000 description 2
- 108010029485 Protein Isoforms Proteins 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- 108091027981 Response element Proteins 0.000 description 2
- 108010038912 Retinoid X Receptors Proteins 0.000 description 2
- 102000034527 Retinoid X Receptors Human genes 0.000 description 2
- 108010090804 Streptavidin Proteins 0.000 description 2
- CCYHOPKKAORPJN-UHFFFAOYSA-N [5-(bromomethyl)-3-methoxythiophen-2-yl]methanol Chemical compound COC=1C=C(CBr)SC=1CO CCYHOPKKAORPJN-UHFFFAOYSA-N 0.000 description 2
- AQRQWVSHTXJXFO-UHFFFAOYSA-N [5-(bromomethyl)-3-methoxythiophen-2-yl]methoxy-tert-butyl-dimethylsilane Chemical compound COC=1C=C(CBr)SC=1CO[Si](C)(C)C(C)(C)C AQRQWVSHTXJXFO-UHFFFAOYSA-N 0.000 description 2
- GUEDECOLKYPDMX-UHFFFAOYSA-N [5-(spiro[indene-1,4'-piperidine]-1'-ylmethyl)thiophen-2-yl]methanol Chemical compound S1C(CO)=CC=C1CN1CCC2(C3=CC=CC=C3C=C2)CC1 GUEDECOLKYPDMX-UHFFFAOYSA-N 0.000 description 2
- 239000012190 activator Substances 0.000 description 2
- 239000000556 agonist Substances 0.000 description 2
- 150000001299 aldehydes Chemical class 0.000 description 2
- 230000003178 anti-diabetic effect Effects 0.000 description 2
- 239000012148 binding buffer Substances 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 239000013592 cell lysate Substances 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000012761 co-transfection Methods 0.000 description 2
- 239000002299 complementary DNA Substances 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- 238000010511 deprotection reaction Methods 0.000 description 2
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 229940125542 dual agonist Drugs 0.000 description 2
- WVMITIFDHVQLPI-UHFFFAOYSA-N ethyl 2-(2-hydroxypropylamino)-2-oxoacetate Chemical compound CCOC(=O)C(=O)NCC(C)O WVMITIFDHVQLPI-UHFFFAOYSA-N 0.000 description 2
- ITJNGUUXCZIMTD-UHFFFAOYSA-N ethyl 2-oxo-2-(2-oxopropylamino)acetate Chemical compound CCOC(=O)C(=O)NCC(C)=O ITJNGUUXCZIMTD-UHFFFAOYSA-N 0.000 description 2
- ZAQWPBXDXSTCDZ-UHFFFAOYSA-N ethyl 3-[2-fluoro-4-[(5-formyl-4-methoxythiophen-2-yl)methoxy]phenyl]propanoate Chemical compound C1=C(F)C(CCC(=O)OCC)=CC=C1OCC1=CC(OC)=C(C=O)S1 ZAQWPBXDXSTCDZ-UHFFFAOYSA-N 0.000 description 2
- ICUKYTFCHABQFT-UHFFFAOYSA-N ethyl 3-[2-fluoro-4-[[5-(hydroxymethyl)-4-methoxythiophen-2-yl]methoxy]phenyl]propanoate Chemical compound C1=C(F)C(CCC(=O)OCC)=CC=C1OCC1=CC(OC)=C(CO)S1 ICUKYTFCHABQFT-UHFFFAOYSA-N 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical compound CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 description 2
- BRZYSWJRSDMWLG-CAXSIQPQSA-N geneticin Chemical compound O1C[C@@](O)(C)[C@H](NC)[C@@H](O)[C@H]1O[C@@H]1[C@@H](O)[C@H](O[C@@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](C(C)O)O2)N)[C@@H](N)C[C@H]1N BRZYSWJRSDMWLG-CAXSIQPQSA-N 0.000 description 2
- 229930195733 hydrocarbon Natural products 0.000 description 2
- 238000007912 intraperitoneal administration Methods 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- 210000003734 kidney Anatomy 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 150000004668 long chain fatty acids Chemical class 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- MWADWXJPBMFRGL-UHFFFAOYSA-N methyl 3-methoxythiophene-2-carboxylate Chemical compound COC(=O)C=1SC=CC=1OC MWADWXJPBMFRGL-UHFFFAOYSA-N 0.000 description 2
- MCUCRNYGFIPVGH-UHFFFAOYSA-N methyl 5-(bromomethyl)-3-methoxythiophene-2-carboxylate Chemical compound COC(=O)C=1SC(CBr)=CC=1OC MCUCRNYGFIPVGH-UHFFFAOYSA-N 0.000 description 2
- GFOPHLFSDVVYGB-UHFFFAOYSA-N methyl 5-(bromomethyl)thiophene-2-carboxylate Chemical compound COC(=O)C1=CC=C(CBr)S1 GFOPHLFSDVVYGB-UHFFFAOYSA-N 0.000 description 2
- 239000003614 peroxisome proliferator Substances 0.000 description 2
- 239000002307 peroxisome proliferator activated receptor agonist Substances 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 238000006722 reduction reaction Methods 0.000 description 2
- 238000005932 reductive alkylation reaction Methods 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- 238000012453 sprague-dawley rat model Methods 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 230000000638 stimulation Effects 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- TUQOTMZNTHZOKS-UHFFFAOYSA-N tributylphosphine Chemical compound CCCCP(CCCC)CCCC TUQOTMZNTHZOKS-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 239000003981 vehicle Substances 0.000 description 2
- 229910052727 yttrium Inorganic materials 0.000 description 2
- VWQVUPCCIRVNHF-UHFFFAOYSA-N yttrium atom Chemical compound [Y] VWQVUPCCIRVNHF-UHFFFAOYSA-N 0.000 description 2
- DGVVWUTYPXICAM-UHFFFAOYSA-N β‐Mercaptoethanol Chemical compound OCCS DGVVWUTYPXICAM-UHFFFAOYSA-N 0.000 description 2
- YSVQUSMRABAJAR-VWLOTQADSA-N (3s)-3-[4-[[5-(spiro[indene-1,4'-piperidine]-1'-ylmethyl)thiophen-2-yl]methoxy]phenyl]hex-4-ynoic acid Chemical compound C1=CC([C@H](CC(O)=O)C#CC)=CC=C1OCC(S1)=CC=C1CN1CCC2(C3=CC=CC=C3C=C2)CC1 YSVQUSMRABAJAR-VWLOTQADSA-N 0.000 description 1
- OYHQOLUKZRVURQ-NTGFUMLPSA-N (9Z,12Z)-9,10,12,13-tetratritiooctadeca-9,12-dienoic acid Chemical compound C(CCCCCCC\C(=C(/C\C(=C(/CCCCC)\[3H])\[3H])\[3H])\[3H])(=O)O OYHQOLUKZRVURQ-NTGFUMLPSA-N 0.000 description 1
- HXKKHQJGJAFBHI-UHFFFAOYSA-N 1-aminopropan-2-ol Chemical compound CC(O)CN HXKKHQJGJAFBHI-UHFFFAOYSA-N 0.000 description 1
- PLEHSLVXSJBCKV-UHFFFAOYSA-N 1-methylspiro[2h-indole-3,4'-piperidine] Chemical compound C12=CC=CC=C2N(C)CC21CCNCC2 PLEHSLVXSJBCKV-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- FWQZFMZGXBBNAP-UHFFFAOYSA-N 2-bromo-4-methyl-5-(spiro[indene-1,4'-piperidine]-1'-ylmethyl)-1,3-thiazole Chemical compound N1=C(Br)SC(CN2CCC3(CC2)C2=CC=CC=C2C=C3)=C1C FWQZFMZGXBBNAP-UHFFFAOYSA-N 0.000 description 1
- UMCMPZBLKLEWAF-BCTGSCMUSA-N 3-[(3-cholamidopropyl)dimethylammonio]propane-1-sulfonate Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(=O)NCCC[N+](C)(C)CCCS([O-])(=O)=O)C)[C@@]2(C)[C@@H](O)C1 UMCMPZBLKLEWAF-BCTGSCMUSA-N 0.000 description 1
- 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 1
- 241000972773 Aulopiformes Species 0.000 description 1
- 239000004342 Benzoyl peroxide Substances 0.000 description 1
- OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical compound C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 description 1
- 201000004569 Blindness Diseases 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- YSVQUSMRABAJAR-UHFFFAOYSA-N CC#CC(CC(O)=O)c(cc1)ccc1OCc1ccc(CN(CC2)CCC22c3ccccc3C=C2)[s]1 Chemical compound CC#CC(CC(O)=O)c(cc1)ccc1OCc1ccc(CN(CC2)CCC22c3ccccc3C=C2)[s]1 YSVQUSMRABAJAR-UHFFFAOYSA-N 0.000 description 1
- LGIUHWQDGPFXSG-VWLOTQADSA-N CC#C[C@@H](CC(O)=O)c(cc1)ccc1OCc1ccc(CN(CC2)CCC22c3ccccc3CC2)[s]1 Chemical compound CC#C[C@@H](CC(O)=O)c(cc1)ccc1OCc1ccc(CN(CC2)CCC22c3ccccc3CC2)[s]1 LGIUHWQDGPFXSG-VWLOTQADSA-N 0.000 description 1
- 0 CC#C[C@@](CC(OC)=O)c(cc1)ccc1OCc1ccc(C*(CC2)CCC22c3ccccc3C=C2)[n]1 Chemical compound CC#C[C@@](CC(OC)=O)c(cc1)ccc1OCc1ccc(C*(CC2)CCC22c3ccccc3C=C2)[n]1 0.000 description 1
- GACNKIZNYLJBDU-SANMLTNESA-N CCOC(C[C@@H](c(cc1)ccc1OCc1ncc(CN(CC2)CCC22c3ccccc3C=C2)[o]1)C#CC)=O Chemical compound CCOC(C[C@@H](c(cc1)ccc1OCc1ncc(CN(CC2)CCC22c3ccccc3C=C2)[o]1)C#CC)=O GACNKIZNYLJBDU-SANMLTNESA-N 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical group NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 1
- 241000282552 Chlorocebus aethiops Species 0.000 description 1
- 102000029816 Collagenase Human genes 0.000 description 1
- 108060005980 Collagenase Proteins 0.000 description 1
- 108020004414 DNA Proteins 0.000 description 1
- 230000004568 DNA-binding Effects 0.000 description 1
- 108010016626 Dipeptides Proteins 0.000 description 1
- 108090000331 Firefly luciferases Proteins 0.000 description 1
- 102000003688 G-Protein-Coupled Receptors Human genes 0.000 description 1
- 108090000045 G-Protein-Coupled Receptors Proteins 0.000 description 1
- 208000018522 Gastrointestinal disease Diseases 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 208000013016 Hypoglycemia Diseases 0.000 description 1
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 1
- 229930182816 L-glutamine Natural products 0.000 description 1
- 206010067125 Liver injury Diseases 0.000 description 1
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 1
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 1
- 238000006751 Mitsunobu reaction Methods 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 241000699660 Mus musculus Species 0.000 description 1
- PHSPJQZRQAJPPF-UHFFFAOYSA-N N-alpha-Methylhistamine Chemical compound CNCCC1=CN=CN1 PHSPJQZRQAJPPF-UHFFFAOYSA-N 0.000 description 1
- 108091034117 Oligonucleotide Proteins 0.000 description 1
- BPQQTUXANYXVAA-UHFFFAOYSA-N Orthosilicate Chemical compound [O-][Si]([O-])([O-])[O-] BPQQTUXANYXVAA-UHFFFAOYSA-N 0.000 description 1
- 102000000536 PPAR gamma Human genes 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 101100244562 Pseudomonas aeruginosa (strain ATCC 15692 / DSM 22644 / CIP 104116 / JCM 14847 / LMG 12228 / 1C / PRS 101 / PAO1) oprD gene Proteins 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- 239000006146 Roswell Park Memorial Institute medium Substances 0.000 description 1
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- 102000006601 Thymidine Kinase Human genes 0.000 description 1
- 108020004440 Thymidine kinase Proteins 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 1
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 1
- BZILPAAVAWTAFT-UHFFFAOYSA-N [5-(spiro[indene-1,4'-piperidine]-1'-ylmethyl)-1,3-oxazol-2-yl]methanol Chemical compound O1C(CO)=NC=C1CN1CCC2(C3=CC=CC=C3C=C2)CC1 BZILPAAVAWTAFT-UHFFFAOYSA-N 0.000 description 1
- BGYHPSAKNADUOJ-UHFFFAOYSA-N [5-(spiro[indene-1,4'-piperidine]-1'-ylmethyl)-1,3-oxazol-2-yl]methyl methanesulfonate Chemical compound O1C(COS(=O)(=O)C)=NC=C1CN1CCC2(C3=CC=CC=C3C=C2)CC1 BGYHPSAKNADUOJ-UHFFFAOYSA-N 0.000 description 1
- IGUGLOQBLCMITB-UHFFFAOYSA-N [N].C1=CC=C2NCCC2=C1 Chemical compound [N].C1=CC=C2NCCC2=C1 IGUGLOQBLCMITB-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 210000000577 adipose tissue Anatomy 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001408 amides Chemical group 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000006615 aromatic heterocyclic group Chemical group 0.000 description 1
- 239000012131 assay buffer Substances 0.000 description 1
- 238000003149 assay kit Methods 0.000 description 1
- IUKQLMGVFMDQDP-UHFFFAOYSA-N azane;piperidine Chemical compound N.C1CCNCC1 IUKQLMGVFMDQDP-UHFFFAOYSA-N 0.000 description 1
- 125000005604 azodicarboxylate group Chemical group 0.000 description 1
- 239000003855 balanced salt solution Substances 0.000 description 1
- 235000019400 benzoyl peroxide Nutrition 0.000 description 1
- PVSVYTVXIDICAY-UHFFFAOYSA-N benzyl 1-methylspiro[2h-indole-3,4'-piperidine]-1'-carboxylate Chemical compound C12=CC=CC=C2N(C)CC1(CC1)CCN1C(=O)OCC1=CC=CC=C1 PVSVYTVXIDICAY-UHFFFAOYSA-N 0.000 description 1
- ZJQMLJFHCKTCSF-UHFFFAOYSA-N benzyl 4-formylpiperidine-1-carboxylate Chemical compound C1CC(C=O)CCN1C(=O)OCC1=CC=CC=C1 ZJQMLJFHCKTCSF-UHFFFAOYSA-N 0.000 description 1
- XJUPGFXGJQIYQG-UHFFFAOYSA-N benzyl spiro[1,2-dihydroindole-3,4'-piperidine]-1'-carboxylate Chemical compound C1CC2(C3=CC=CC=C3NC2)CCN1C(=O)OCC1=CC=CC=C1 XJUPGFXGJQIYQG-UHFFFAOYSA-N 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 239000012888 bovine serum Substances 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- 125000005997 bromomethyl group Chemical group 0.000 description 1
- 230000005587 bubbling Effects 0.000 description 1
- HQABUPZFAYXKJW-UHFFFAOYSA-O butylazanium Chemical compound CCCC[NH3+] HQABUPZFAYXKJW-UHFFFAOYSA-O 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 229960002424 collagenase Drugs 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 108700023159 delta Opioid Receptors Proteins 0.000 description 1
- 102000048124 delta Opioid Receptors Human genes 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- 208000010643 digestive system disease Diseases 0.000 description 1
- 229940043279 diisopropylamine Drugs 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- VHJLVAABSRFDPM-QWWZWVQMSA-N dithiothreitol Chemical compound SC[C@@H](O)[C@H](O)CS VHJLVAABSRFDPM-QWWZWVQMSA-N 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 238000000132 electrospray ionisation Methods 0.000 description 1
- 238000003821 enantio-separation Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000003797 essential amino acid Substances 0.000 description 1
- 235000020776 essential amino acid Nutrition 0.000 description 1
- 238000010931 ester hydrolysis Methods 0.000 description 1
- IHSMNXDTRPKCCG-LBPRGKRZSA-N ethyl (3s)-3-(4-hydroxyphenyl)hex-4-ynoate Chemical compound CCOC(=O)C[C@H](C#CC)C1=CC=C(O)C=C1 IHSMNXDTRPKCCG-LBPRGKRZSA-N 0.000 description 1
- OWZFULPEVHKEKS-UHFFFAOYSA-N ethyl 2-chloro-2-oxoacetate Chemical compound CCOC(=O)C(Cl)=O OWZFULPEVHKEKS-UHFFFAOYSA-N 0.000 description 1
- ZIUFSWWLZLUAND-UHFFFAOYSA-N ethyl 3-(2-fluoro-4-hydroxyphenyl)propanoate Chemical compound CCOC(=O)CCC1=CC=C(O)C=C1F ZIUFSWWLZLUAND-UHFFFAOYSA-N 0.000 description 1
- GOGWXZVYOLQFAH-UHFFFAOYSA-N ethyl 3-[4-[[5-[[tert-butyl(dimethyl)silyl]oxymethyl]-4-methoxythiophen-2-yl]methoxy]-2-fluorophenyl]propanoate Chemical compound C1=C(F)C(CCC(=O)OCC)=CC=C1OCC1=CC(OC)=C(CO[Si](C)(C)C(C)(C)C)S1 GOGWXZVYOLQFAH-UHFFFAOYSA-N 0.000 description 1
- OALJNMKDYSKDSH-UHFFFAOYSA-N ethyl 5-(bromomethyl)-1,3-oxazole-2-carboxylate Chemical compound CCOC(=O)C1=NC=C(CBr)O1 OALJNMKDYSKDSH-UHFFFAOYSA-N 0.000 description 1
- OQDXZBFUAYYYEY-UHFFFAOYSA-N ethyl 5-(spiro[indene-1,4'-piperidine]-1'-ylmethyl)thiophene-2-carboxylate Chemical compound S1C(C(=O)OCC)=CC=C1CN1CCC2(C3=CC=CC=C3C=C2)CC1 OQDXZBFUAYYYEY-UHFFFAOYSA-N 0.000 description 1
- AVQLWUGRGBPYLN-UHFFFAOYSA-N ethyl 5-methyl-1,3-oxazole-2-carboxylate Chemical compound CCOC(=O)C1=NC=C(C)O1 AVQLWUGRGBPYLN-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 230000001605 fetal effect Effects 0.000 description 1
- 238000003818 flash chromatography Methods 0.000 description 1
- 238000000799 fluorescence microscopy Methods 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 239000008098 formaldehyde solution Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 208000018685 gastrointestinal system disease Diseases 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 230000010030 glucose lowering effect Effects 0.000 description 1
- 230000005484 gravity Effects 0.000 description 1
- 208000019622 heart disease Diseases 0.000 description 1
- 231100000234 hepatic damage Toxicity 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 102000052080 human FFAR1 Human genes 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 230000002218 hypoglycaemic effect Effects 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 238000012528 insulin ELISA Methods 0.000 description 1
- 210000004153 islets of langerhan Anatomy 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 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
- 230000008818 liver damage Effects 0.000 description 1
- 238000004020 luminiscence type Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 238000002483 medication Methods 0.000 description 1
- 150000004667 medium chain fatty acids Chemical class 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- SEMVRXMFCHXUMD-UHFFFAOYSA-N methyl 3-hydroxythiophene-2-carboxylate Chemical compound COC(=O)C=1SC=CC=1O SEMVRXMFCHXUMD-UHFFFAOYSA-N 0.000 description 1
- YUJMWNYIBNSQPL-UHFFFAOYSA-N methyl 4-methylthiophene-2-carboxylate Chemical compound COC(=O)C1=CC(C)=CS1 YUJMWNYIBNSQPL-UHFFFAOYSA-N 0.000 description 1
- XXNGCPRTANLYMQ-UHFFFAOYSA-N methyl 5-(bromomethyl)-4-methylthiophene-2-carboxylate Chemical compound COC(=O)C1=CC(C)=C(CBr)S1 XXNGCPRTANLYMQ-UHFFFAOYSA-N 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- MBABOKRGFJTBAE-UHFFFAOYSA-N methyl methanesulfonate Chemical compound COS(C)(=O)=O MBABOKRGFJTBAE-UHFFFAOYSA-N 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- OQJBFFCUFALWQL-UHFFFAOYSA-N n-(piperidine-1-carbonylimino)piperidine-1-carboxamide Chemical compound C1CCCCN1C(=O)N=NC(=O)N1CCCCC1 OQJBFFCUFALWQL-UHFFFAOYSA-N 0.000 description 1
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 1
- 201000001119 neuropathy Diseases 0.000 description 1
- 230000007823 neuropathy Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 230000009871 nonspecific binding Effects 0.000 description 1
- 239000012038 nucleophile Substances 0.000 description 1
- 229940127017 oral antidiabetic Drugs 0.000 description 1
- 230000002018 overexpression Effects 0.000 description 1
- 125000004287 oxazol-2-yl group Chemical group [H]C1=C([H])N=C(*)O1 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 208000028169 periodontal disease Diseases 0.000 description 1
- 208000033808 peripheral neuropathy Diseases 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 238000011458 pharmacological treatment Methods 0.000 description 1
- 150000004031 phenylhydrazines Chemical class 0.000 description 1
- 150000003003 phosphines Chemical class 0.000 description 1
- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 description 1
- 150000003053 piperidines Chemical class 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 238000012746 preparative thin layer chromatography Methods 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 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 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 210000005084 renal tissue Anatomy 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 238000011808 rodent model Methods 0.000 description 1
- 235000019515 salmon Nutrition 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 238000003375 selectivity assay Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 210000002027 skeletal muscle Anatomy 0.000 description 1
- JHMKGUPCKJSSEF-UHFFFAOYSA-N spiro[1,2-dihydroindole-3,4'-piperidine] Chemical class C1NC2=CC=CC=C2C11CCNCC1 JHMKGUPCKJSSEF-UHFFFAOYSA-N 0.000 description 1
- QXNXVWNYCKUANQ-UHFFFAOYSA-N spiro[indene-1,4'-piperidine] Chemical compound C1CNCCC21C1=CC=CC=C1C=C2 QXNXVWNYCKUANQ-UHFFFAOYSA-N 0.000 description 1
- CNFMPMUITJAJKC-UHFFFAOYSA-N spiro[indene-1,4'-piperidine];hydrochloride Chemical compound Cl.C1CNCCC21C1=CC=CC=C1C=C2 CNFMPMUITJAJKC-UHFFFAOYSA-N 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000006228 supernatant Substances 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
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical compound C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 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
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 238000011830 transgenic mouse model Methods 0.000 description 1
- RXJKFRMDXUJTEX-UHFFFAOYSA-N triethylphosphine Chemical compound CCP(CC)CC RXJKFRMDXUJTEX-UHFFFAOYSA-N 0.000 description 1
- 241000701161 unidentified adenovirus Species 0.000 description 1
- 238000011144 upstream manufacturing Methods 0.000 description 1
- 230000004584 weight gain Effects 0.000 description 1
- 235000019786 weight gain Nutrition 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- 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
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4747—Quinolines; Isoquinolines spiro-condensed
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/10—Spiro-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Diabetes (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Hematology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Obesity (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Endocrinology (AREA)
- Emergency Medicine (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US26518109P | 2009-11-30 | 2009-11-30 | |
| US61/265,181 | 2009-11-30 | ||
| PCT/US2010/057359 WO2011066183A1 (en) | 2009-11-30 | 2010-11-19 | Novel spiropiperidine compounds |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| JP2013512277A JP2013512277A (ja) | 2013-04-11 |
| JP2013512277A5 JP2013512277A5 (enExample) | 2013-11-14 |
| JP5709889B2 true JP5709889B2 (ja) | 2015-04-30 |
Family
ID=43384775
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2012542076A Expired - Fee Related JP5709889B2 (ja) | 2009-11-30 | 2010-11-19 | 新規スピロピペリジン化合物 |
Country Status (26)
| Country | Link |
|---|---|
| US (1) | US8822486B2 (enExample) |
| EP (1) | EP2507228B1 (enExample) |
| JP (1) | JP5709889B2 (enExample) |
| KR (1) | KR101410103B1 (enExample) |
| CN (1) | CN102648195B (enExample) |
| AR (1) | AR078948A1 (enExample) |
| AU (1) | AU2010324987B2 (enExample) |
| BR (1) | BR112012012903A2 (enExample) |
| CA (1) | CA2781292C (enExample) |
| CL (1) | CL2012001321A1 (enExample) |
| CR (1) | CR20120296A (enExample) |
| DO (1) | DOP2012000139A (enExample) |
| EA (1) | EA020507B1 (enExample) |
| EC (1) | ECSP12011930A (enExample) |
| ES (1) | ES2526568T3 (enExample) |
| GT (1) | GT201200164A (enExample) |
| IL (1) | IL219594A0 (enExample) |
| MA (1) | MA33840B1 (enExample) |
| MX (1) | MX2012006233A (enExample) |
| NZ (1) | NZ600203A (enExample) |
| PE (1) | PE20121474A1 (enExample) |
| PH (1) | PH12012501052A1 (enExample) |
| TN (1) | TN2012000248A1 (enExample) |
| TW (1) | TW201141866A (enExample) |
| WO (1) | WO2011066183A1 (enExample) |
| ZA (1) | ZA201203055B (enExample) |
Families Citing this family (20)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AR078522A1 (es) | 2009-10-15 | 2011-11-16 | Lilly Co Eli | Compuesto de espiropiperidina, composicion farmaceutica que lo comprende, su uso para preparar un medicamento util para tratar diabetes y compuesto intermediario para su sintesis |
| CN104710381A (zh) | 2009-12-25 | 2015-06-17 | 持田制药株式会社 | 新的3-羟基-5-芳基异噻唑衍生物 |
| US9040525B2 (en) | 2010-10-08 | 2015-05-26 | Mochida Pharmaceutical Co., Ltd. | Cyclic amide derivative |
| BR112013027883A2 (pt) | 2011-04-27 | 2017-08-08 | Mochida Pharm Co Ltd | novo derivado de 1-óxido de 3-hidroxiisotiazol |
| US9072758B2 (en) | 2011-04-28 | 2015-07-07 | Mochida Pharmaceutical Co., Ltd. | Cyclic amide derivative |
| TWI537262B (zh) * | 2011-08-17 | 2016-06-11 | 美國禮來大藥廠 | 供治療糖尿病使用之新穎１，２，３，４－四氫喹啉衍生物 |
| ES2690145T3 (es) * | 2013-03-14 | 2018-11-19 | Janssen Pharmaceutica Nv | Agonistas de GPR120 para el tratamiento de diabetes de tipo 2 |
| US10011609B2 (en) | 2013-11-14 | 2018-07-03 | Cadila Healthcare Limited | Heterocyclic compounds |
| US9957219B2 (en) | 2013-12-04 | 2018-05-01 | Merck Sharp & Dohme Corp. | Antidiabetic bicyclic compounds |
| EP3102198B1 (en) | 2014-02-06 | 2020-08-26 | Merck Sharp & Dohme Corp. | Antidiabetic compounds |
| WO2018166855A1 (en) | 2017-03-16 | 2018-09-20 | Basf Se | Heterobicyclic substituted dihydroisoxazoles |
| UA126458C2 (uk) | 2018-02-13 | 2022-10-05 | Гіліад Сайєнсіз, Інк. | Інгібітори pd-1/pd-l1 |
| US10899735B2 (en) | 2018-04-19 | 2021-01-26 | Gilead Sciences, Inc. | PD-1/PD-L1 inhibitors |
| EP3820572B1 (en) | 2018-07-13 | 2023-08-16 | Gilead Sciences, Inc. | Pd-1/pd-l1 inhibitors |
| AU2019366355B2 (en) | 2018-10-24 | 2022-10-13 | Gilead Sciences, Inc. | PD-1/PD-L1 inhibitors |
| CN110590767B (zh) * | 2019-08-29 | 2021-10-08 | 南方科技大学 | 一种合成amg837的方法 |
| WO2021071837A1 (en) | 2019-10-07 | 2021-04-15 | Kallyope, Inc. | Gpr119 agonists |
| TW202140440A (zh) | 2020-02-28 | 2021-11-01 | 美商克力歐普股份有限公司 | Gpr40激動劑 |
| UY39222A (es) | 2020-05-19 | 2021-11-30 | Kallyope Inc | Activadores de la ampk |
| AU2021297323A1 (en) | 2020-06-26 | 2023-02-16 | Kallyope, Inc. | AMPK activators |
Family Cites Families (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SE0202133D0 (sv) * | 2002-07-08 | 2002-07-08 | Astrazeneca Ab | Novel compounds |
| CA2520114A1 (en) | 2003-04-04 | 2004-10-21 | Merck & Co., Inc. | Acylated spiropiperidine derivatives as melanocortin-4 receptor agonists |
| JP2007510662A (ja) | 2003-11-04 | 2007-04-26 | エリクシアー ファーマシューティカルズ， インコーポレイテッド | 治療化合物およびその使用 |
| AU2005220728B2 (en) | 2004-02-27 | 2009-08-06 | Amgen Inc. | Compounds, pharmaceutical compositions and methods for use in treating metabolic disorders |
| JP4859665B2 (ja) | 2004-03-30 | 2012-01-25 | 武田薬品工業株式会社 | アルコキシフェニルプロパン酸誘導体 |
| WO2006028239A1 (ja) * | 2004-09-07 | 2006-03-16 | Banyu Pharmaceutical Co., Ltd. | カルバモイル置換スピロ誘導体 |
| JP2009543860A (ja) * | 2006-07-19 | 2009-12-10 | アストラゼネカ・アクチエボラーグ | 新規三環系スピロピペリジン化合物、それらの合成およびケモカイン受容体活性モジュレーターとしてのそれらの使用 |
| US20090247560A1 (en) * | 2006-09-28 | 2009-10-01 | Banyu Pharmaceutical Co., Ltd. | Diaryl ketimine derivative |
| PL2125827T3 (pl) * | 2006-12-29 | 2011-04-29 | Hoffmann La Roche | Pochodne azaspiro |
| ES2446419T3 (es) * | 2007-04-16 | 2014-03-07 | Amgen, Inc | Moduladores de GPR40 de ácidos bifenilfenoxi, tiofenil y aminofenilpropanoico sustituidos |
| RU2490250C2 (ru) * | 2007-10-26 | 2013-08-20 | Джапан Тобакко Инк. | Спиросоединения и их фармацевтическое применение |
| AR078522A1 (es) | 2009-10-15 | 2011-11-16 | Lilly Co Eli | Compuesto de espiropiperidina, composicion farmaceutica que lo comprende, su uso para preparar un medicamento util para tratar diabetes y compuesto intermediario para su sintesis |
| US8530413B2 (en) | 2010-06-21 | 2013-09-10 | Sanofi | Heterocyclically substituted methoxyphenyl derivatives with an oxo group, processes for preparation thereof and use thereof as medicaments |
| TW201221505A (en) | 2010-07-05 | 2012-06-01 | Sanofi Sa | Aryloxyalkylene-substituted hydroxyphenylhexynoic acids, process for preparation thereof and use thereof as a medicament |
-
2010
- 2010-11-08 AR ARP100104151A patent/AR078948A1/es not_active Application Discontinuation
- 2010-11-10 TW TW099138725A patent/TW201141866A/zh unknown
- 2010-11-19 NZ NZ600203A patent/NZ600203A/xx not_active IP Right Cessation
- 2010-11-19 WO PCT/US2010/057359 patent/WO2011066183A1/en not_active Ceased
- 2010-11-19 US US13/505,470 patent/US8822486B2/en not_active Expired - Fee Related
- 2010-11-19 BR BR112012012903A patent/BR112012012903A2/pt not_active IP Right Cessation
- 2010-11-19 EP EP10784390.6A patent/EP2507228B1/en active Active
- 2010-11-19 MX MX2012006233A patent/MX2012006233A/es not_active Application Discontinuation
- 2010-11-19 AU AU2010324987A patent/AU2010324987B2/en not_active Ceased
- 2010-11-19 PE PE2012000730A patent/PE20121474A1/es not_active Application Discontinuation
- 2010-11-19 EA EA201290416A patent/EA020507B1/ru not_active IP Right Cessation
- 2010-11-19 PH PH1/2012/501052A patent/PH12012501052A1/en unknown
- 2010-11-19 KR KR1020127013788A patent/KR101410103B1/ko not_active Expired - Fee Related
- 2010-11-19 JP JP2012542076A patent/JP5709889B2/ja not_active Expired - Fee Related
- 2010-11-19 CA CA2781292A patent/CA2781292C/en not_active Expired - Fee Related
- 2010-11-19 ES ES10784390.6T patent/ES2526568T3/es active Active
- 2010-11-19 CN CN201080054116.3A patent/CN102648195B/zh not_active Expired - Fee Related
-
2012
- 2012-04-25 ZA ZA2012/03055A patent/ZA201203055B/en unknown
- 2012-05-03 IL IL219594A patent/IL219594A0/en unknown
- 2012-05-15 DO DO2012000139A patent/DOP2012000139A/es unknown
- 2012-05-20 EC ECSP12011930 patent/ECSP12011930A/es unknown
- 2012-05-22 TN TNP2012000248A patent/TN2012000248A1/en unknown
- 2012-05-23 CL CL2012001321A patent/CL2012001321A1/es unknown
- 2012-05-28 GT GT201200164A patent/GT201200164A/es unknown
- 2012-05-30 CR CR20120296A patent/CR20120296A/es not_active Application Discontinuation
- 2012-06-21 MA MA34993A patent/MA33840B1/fr unknown
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP5709889B2 (ja) | 新規スピロピペリジン化合物 | |
| KR101570624B1 (ko) | 당뇨병의 치료에 유용한 신규 1,2,3,4-테트라히드로퀴놀린 유도체 | |
| JP2013508279A (ja) | スピロピペリジン化合物および糖尿病治療のためのその医薬用途 | |
| RU2650506C2 (ru) | Агонист рецептора gpr40, способы его получения и фармацевтические композиции, содержащие его в качестве активного ингредиента | |
| CA2750859C (en) | Estrogen related receptor modulators and uses thereof | |
| WO2005095338A1 (ja) | アルコキシフェニルプロパン酸誘導体 | |
| CZ20012387A3 (cs) | Derivát benzopyranu a benzoxepinu, způsob jejich přípravy, jejich pouľití a farmaceutický prostředek, který je obsahuje | |
| CN103224492B (zh) | 14-芳基醚穿心莲內酯衍生物及其制备方法和应用 | |
| CA2587207A1 (en) | Niacin receptor agonists, compositions containing such compounds and methods of treatment | |
| EP1891026A2 (en) | Cycloalkylidene compounds as selective estrogen receptor modulators |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20130930 |
|
| A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20130930 |
|
| A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20140924 |
|
| A977 | Report on retrieval |
Free format text: JAPANESE INTERMEDIATE CODE: A971007 Effective date: 20140925 |
|
| A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20141217 |
|
| TRDD | Decision of grant or rejection written | ||
| A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20150217 |
|
| A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20150303 |
|
| R150 | Certificate of patent or registration of utility model |
Ref document number: 5709889 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
| LAPS | Cancellation because of no payment of annual fees |