KR20090113383A - 인돌 유도체 - Google Patents
인돌 유도체 Download PDFInfo
- Publication number
- KR20090113383A KR20090113383A KR1020097019668A KR20097019668A KR20090113383A KR 20090113383 A KR20090113383 A KR 20090113383A KR 1020097019668 A KR1020097019668 A KR 1020097019668A KR 20097019668 A KR20097019668 A KR 20097019668A KR 20090113383 A KR20090113383 A KR 20090113383A
- Authority
- KR
- South Korea
- Prior art keywords
- methyl
- indole
- chloro
- mmol
- alkyl
- 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.)
- Withdrawn
Links
- 150000002475 indoles Chemical class 0.000 title claims abstract description 26
- 229940054051 antipsychotic indole derivative Drugs 0.000 title claims abstract description 16
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 41
- 208000002193 Pain Diseases 0.000 claims abstract description 23
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 17
- 239000001257 hydrogen Substances 0.000 claims abstract description 16
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 16
- 238000011282 treatment Methods 0.000 claims abstract description 12
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 11
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 10
- 150000002367 halogens Chemical class 0.000 claims abstract description 10
- 208000004296 neuralgia Diseases 0.000 claims abstract description 9
- 208000021722 neuropathic pain Diseases 0.000 claims abstract description 9
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 9
- 150000003839 salts Chemical class 0.000 claims abstract description 9
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 9
- 229910005965 SO 2 Inorganic materials 0.000 claims abstract description 8
- 125000001766 1,2,4-oxadiazol-3-yl group Chemical group [H]C1=NC(*)=NO1 0.000 claims abstract description 6
- 125000006615 aromatic heterocyclic group Chemical group 0.000 claims abstract description 5
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 5
- 201000006417 multiple sclerosis Diseases 0.000 claims abstract description 5
- 125000001424 substituent group Chemical group 0.000 claims abstract description 5
- 206010058019 Cancer Pain Diseases 0.000 claims abstract description 4
- 208000000094 Chronic Pain Diseases 0.000 claims abstract description 4
- 239000005977 Ethylene Chemical group 0.000 claims abstract description 4
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims abstract description 4
- 125000000468 ketone group Chemical group 0.000 claims abstract description 3
- -1 carbamoylmethyl Chemical group 0.000 claims description 62
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 56
- 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims description 30
- 239000003814 drug Substances 0.000 claims description 9
- 125000000623 heterocyclic group Chemical group 0.000 claims description 9
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- XLEFTMZVWZNOOZ-SFHVURJKSA-N 2-[(2s)-4-[[3-[7-chloro-1-(oxan-4-ylmethyl)indol-3-yl]-1,2,4-oxadiazol-5-yl]methyl]-2-(hydroxymethyl)piperazin-1-yl]-n-methylacetamide Chemical compound C1[C@@H](CO)N(CC(=O)NC)CCN1CC1=NC(C=2C3=CC=CC(Cl)=C3N(CC3CCOCC3)C=2)=NO1 XLEFTMZVWZNOOZ-SFHVURJKSA-N 0.000 claims description 3
- BHZIJECIQSSJOM-UHFFFAOYSA-N 2-[4-[[3-[7-chloro-1-(oxan-4-ylmethyl)indol-3-yl]-1,2,4-oxadiazol-5-yl]methyl]-1,4-diazepan-1-yl]acetamide Chemical compound C1CN(CC(=O)N)CCCN1CC1=NC(C=2C3=CC=CC(Cl)=C3N(CC3CCOCC3)C=2)=NO1 BHZIJECIQSSJOM-UHFFFAOYSA-N 0.000 claims description 3
- 239000002671 adjuvant Substances 0.000 claims description 3
- 125000000814 indol-3-yl group Chemical group [H]C1=C([H])C([H])=C2N([H])C([H])=C([*])C2=C1[H] 0.000 claims description 3
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 claims description 3
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- IVFUDYBWTMLQFJ-KDURUIRLSA-N tert-butyl (3s,5r)-4-[[3-[7-chloro-1-(oxan-4-ylmethyl)indol-3-yl]-1,2,4-oxadiazol-5-yl]methyl]-3,5-dimethylpiperazine-1-carboxylate Chemical compound C[C@H]1CN(C(=O)OC(C)(C)C)C[C@@H](C)N1CC1=NC(C=2C3=CC=CC(Cl)=C3N(CC3CCOCC3)C=2)=NO1 IVFUDYBWTMLQFJ-KDURUIRLSA-N 0.000 claims description 3
- BBVIDBNAYOIXOE-UHFFFAOYSA-N 1,2,4-oxadiazole Chemical compound C=1N=CON=1 BBVIDBNAYOIXOE-UHFFFAOYSA-N 0.000 claims description 2
- YGTAZGSLCXNBQL-UHFFFAOYSA-N 1,2,4-thiadiazole Chemical compound C=1N=CSN=1 YGTAZGSLCXNBQL-UHFFFAOYSA-N 0.000 claims description 2
- 235000012054 meals Nutrition 0.000 claims description 2
- 239000000411 inducer Substances 0.000 claims 1
- 238000002560 therapeutic procedure Methods 0.000 claims 1
- 102000009132 CB1 Cannabinoid Receptor Human genes 0.000 abstract description 10
- 239000003557 cannabinoid Substances 0.000 abstract description 9
- 229930003827 cannabinoid Natural products 0.000 abstract description 9
- 108010073366 CB1 Cannabinoid Receptor Proteins 0.000 abstract description 8
- 239000003795 chemical substances by application Substances 0.000 abstract description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 135
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 126
- 150000001875 compounds Chemical class 0.000 description 112
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 63
- 238000000034 method Methods 0.000 description 58
- 239000000203 mixture Substances 0.000 description 58
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 45
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 37
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 36
- 239000000243 solution Substances 0.000 description 31
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 30
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 29
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 28
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 27
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 25
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 24
- 238000006243 chemical reaction Methods 0.000 description 22
- 239000007787 solid Substances 0.000 description 20
- 239000002904 solvent Substances 0.000 description 20
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- 229910021529 ammonia Inorganic materials 0.000 description 18
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 17
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 17
- 210000004027 cell Anatomy 0.000 description 17
- 238000004128 high performance liquid chromatography Methods 0.000 description 16
- 150000001412 amines Chemical class 0.000 description 13
- BLRHMMGNCXNXJL-UHFFFAOYSA-N 1-methylindole Chemical compound C1=CC=C2N(C)C=CC2=C1 BLRHMMGNCXNXJL-UHFFFAOYSA-N 0.000 description 11
- 230000008569 process Effects 0.000 description 11
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
- 239000011541 reaction mixture Substances 0.000 description 10
- 102000005962 receptors Human genes 0.000 description 10
- 108020003175 receptors Proteins 0.000 description 10
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 9
- 230000000694 effects Effects 0.000 description 9
- 235000009518 sodium iodide Nutrition 0.000 description 9
- WMYQAKANKREQLM-UHFFFAOYSA-N 7-chloro-1h-indole Chemical compound ClC1=CC=CC2=C1NC=C2 WMYQAKANKREQLM-UHFFFAOYSA-N 0.000 description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 8
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 8
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 8
- 238000003818 flash chromatography Methods 0.000 description 8
- 230000014509 gene expression Effects 0.000 description 8
- 239000010410 layer Substances 0.000 description 8
- 229910052757 nitrogen Inorganic materials 0.000 description 8
- 239000012044 organic layer Substances 0.000 description 8
- 229940035676 analgesics Drugs 0.000 description 7
- 239000000730 antalgic agent Substances 0.000 description 7
- 239000002585 base Substances 0.000 description 7
- 230000027455 binding Effects 0.000 description 7
- 239000012267 brine Substances 0.000 description 7
- 229940005483 opioid analgesics Drugs 0.000 description 7
- DCBKCZSYJRZBDB-UHFFFAOYSA-N oxan-4-ylmethyl 4-methylbenzenesulfonate Chemical compound C1=CC(C)=CC=C1S(=O)(=O)OCC1CCOCC1 DCBKCZSYJRZBDB-UHFFFAOYSA-N 0.000 description 7
- 239000002244 precipitate Substances 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- 230000002829 reductive effect Effects 0.000 description 7
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 7
- GKDWAOXRECKROY-UHFFFAOYSA-N 7-chloro-1-(oxan-4-ylmethyl)indole-3-carboxamide Chemical compound C12=C(Cl)C=CC=C2C(C(=O)N)=CN1CC1CCOCC1 GKDWAOXRECKROY-UHFFFAOYSA-N 0.000 description 6
- 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 6
- 108020004414 DNA Proteins 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 239000000556 agonist Substances 0.000 description 6
- 239000003638 chemical reducing agent Substances 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 239000012458 free base Substances 0.000 description 6
- 229910052938 sodium sulfate Inorganic materials 0.000 description 6
- 235000011152 sodium sulphate Nutrition 0.000 description 6
- 239000000725 suspension Substances 0.000 description 6
- NUZXPHIQZUYMOR-DTORHVGOSA-N tert-butyl (3s,5r)-3,5-dimethylpiperazine-1-carboxylate Chemical compound C[C@H]1CN(C(=O)OC(C)(C)C)C[C@@H](C)N1 NUZXPHIQZUYMOR-DTORHVGOSA-N 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 6
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical class CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 5
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 5
- 230000004044 response Effects 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- FQUYSHZXSKYCSY-UHFFFAOYSA-N 1,4-diazepane Chemical group C1CNCCNC1 FQUYSHZXSKYCSY-UHFFFAOYSA-N 0.000 description 4
- JUIKUQOUMZUFQT-UHFFFAOYSA-N 2-bromoacetamide Chemical compound NC(=O)CBr JUIKUQOUMZUFQT-UHFFFAOYSA-N 0.000 description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 4
- 108700008625 Reporter Genes Proteins 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 239000013543 active substance Substances 0.000 description 4
- 235000011114 ammonium hydroxide Nutrition 0.000 description 4
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 4
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 4
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 4
- 125000006239 protecting group Chemical group 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- GGWXEAJNYDUCMK-UHFFFAOYSA-N 1-methyl-2-(oxan-4-yl)indole Chemical compound O1CCC(CC1)C=1N(C2=CC=CC=C2C=1)C GGWXEAJNYDUCMK-UHFFFAOYSA-N 0.000 description 3
- JSLBWEDTRYHMHA-UHFFFAOYSA-N 7-chloro-1-(oxan-4-ylmethyl)indole-3-carbonitrile Chemical compound C1=2C(Cl)=CC=CC=2C(C#N)=CN1CC1CCOCC1 JSLBWEDTRYHMHA-UHFFFAOYSA-N 0.000 description 3
- QRVVMAOTJSMUFO-UHFFFAOYSA-N 7-chloro-1-(oxan-4-ylmethyl)indole-3-carboximidamide Chemical compound C12=C(Cl)C=CC=C2C(C(=N)N)=CN1CC1CCOCC1 QRVVMAOTJSMUFO-UHFFFAOYSA-N 0.000 description 3
- DBCJWTBYVXEBJY-UHFFFAOYSA-N 7-chloro-1h-indole-3-carboxylic acid Chemical compound C1=CC=C2C(C(=O)O)=CNC2=C1Cl DBCJWTBYVXEBJY-UHFFFAOYSA-N 0.000 description 3
- PIIZLMYXLGYWTN-UHFFFAOYSA-N 7-ethyl-1h-indole Chemical compound CCC1=CC=CC2=C1NC=C2 PIIZLMYXLGYWTN-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- 102000018208 Cannabinoid Receptor Human genes 0.000 description 3
- 108050007331 Cannabinoid receptor Proteins 0.000 description 3
- 101710187010 Cannabinoid receptor 1 Proteins 0.000 description 3
- 102100033868 Cannabinoid receptor 1 Human genes 0.000 description 3
- 101000710899 Homo sapiens Cannabinoid receptor 1 Proteins 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 3
- 230000010933 acylation Effects 0.000 description 3
- 238000005917 acylation reaction Methods 0.000 description 3
- 125000005227 alkyl sulfonate group Chemical group 0.000 description 3
- 238000003556 assay Methods 0.000 description 3
- CBHOOMGKXCMKIR-UHFFFAOYSA-N azane;methanol Chemical compound N.OC CBHOOMGKXCMKIR-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- 229910052794 bromium Inorganic materials 0.000 description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 3
- 210000004978 chinese hamster ovary cell Anatomy 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 3
- 125000001041 indolyl group Chemical group 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 238000006722 reduction reaction Methods 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 230000001105 regulatory effect Effects 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 239000012312 sodium hydride Substances 0.000 description 3
- 229910000104 sodium hydride Inorganic materials 0.000 description 3
- 230000000638 stimulation Effects 0.000 description 3
- FMLPQHJYUZTHQS-MRVPVSSYSA-N tert-butyl (3r)-3-methylpiperazine-1-carboxylate Chemical compound C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1 FMLPQHJYUZTHQS-MRVPVSSYSA-N 0.000 description 3
- DQKVZWAEWJUKAX-UHFFFAOYSA-N thiane-4-carbonitrile Chemical compound N#CC1CCSCC1 DQKVZWAEWJUKAX-UHFFFAOYSA-N 0.000 description 3
- SCKSQOIXSGPVJS-UHFFFAOYSA-N thiane-4-carboxylic acid Chemical compound OC(=O)C1CCSCC1 SCKSQOIXSGPVJS-UHFFFAOYSA-N 0.000 description 3
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 3
- JOMNTHCQHJPVAZ-RXMQYKEDSA-N (2r)-2-methylpiperazine Chemical compound C[C@@H]1CNCCN1 JOMNTHCQHJPVAZ-RXMQYKEDSA-N 0.000 description 2
- SUNMBRGCANLOEG-UHFFFAOYSA-N 1,3-dichloroacetone Chemical compound ClCC(=O)CCl SUNMBRGCANLOEG-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- ZOEUHLLPJRYXDI-OKZTUQRJSA-N 2-[(2r,6s)-4-[[3-[7-chloro-1-(oxan-4-ylmethyl)indol-3-yl]-1,2,4-oxadiazol-5-yl]methyl]-2,6-dimethylpiperazin-1-yl]acetamide;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.C1[C@@H](C)N(CC(N)=O)[C@@H](C)CN1CC1=NC(C=2C3=CC=CC(Cl)=C3N(CC3CCOCC3)C=2)=NO1 ZOEUHLLPJRYXDI-OKZTUQRJSA-N 0.000 description 2
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 2
- VNRJGEMERJZKLQ-UHFFFAOYSA-N 2-piperazin-1-ylacetamide Chemical compound NC(=O)CN1CCNCC1 VNRJGEMERJZKLQ-UHFFFAOYSA-N 0.000 description 2
- WFCSWCVEJLETKA-UHFFFAOYSA-N 2-piperazin-1-ylethanol Chemical compound OCCN1CCNCC1 WFCSWCVEJLETKA-UHFFFAOYSA-N 0.000 description 2
- AGJMYRPRXJGALC-UHFFFAOYSA-N 4-(chloromethyl)-2-[7-chloro-1-(oxan-4-ylmethyl)indol-3-yl]-1,3-thiazole Chemical compound ClCC1=CSC(C=2C3=CC=CC(Cl)=C3N(CC3CCOCC3)C=2)=N1 AGJMYRPRXJGALC-UHFFFAOYSA-N 0.000 description 2
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
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Classifications
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- 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
- C07D417/04—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 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4245—Oxadiazoles
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- 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
- C07D413/04—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 directly linked by a ring-member-to-ring-member bond
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- Chemical & Material Sciences (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
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Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
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| EP07102870.8 | 2007-02-22 | ||
| EP07102870 | 2007-02-22 | ||
| PCT/EP2008/052141 WO2008101995A1 (en) | 2007-02-22 | 2008-02-21 | Indole derivatives |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| KR20090113383A true KR20090113383A (ko) | 2009-10-30 |
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| KR1020097019668A Withdrawn KR20090113383A (ko) | 2007-02-22 | 2008-02-21 | 인돌 유도체 |
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| EP (1) | EP2125795B1 (enExample) |
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| WO (1) | WO2008101995A1 (enExample) |
| ZA (1) | ZA200905265B (enExample) |
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| TWI330635B (en) | 2004-03-05 | 2010-09-21 | Organon Nv | (indol-3-yl)-heterocycle derivatives |
| US7763732B2 (en) * | 2005-08-24 | 2010-07-27 | N.V. Organon | Indole derivatives |
| TW200848417A (en) | 2007-02-22 | 2008-12-16 | Organon Nv | Indole derivatives |
| JP2012504137A (ja) * | 2008-09-29 | 2012-02-16 | アボット・ラボラトリーズ | インドール誘導体およびインドリン誘導体ならびにそれらの使用方法 |
| CN105394046B (zh) | 2010-10-25 | 2019-03-01 | 范德比尔特大学 | 用于抑制昆虫宿主感觉的组合物 |
| WO2012154403A2 (en) | 2011-05-06 | 2012-11-15 | Vanderbilt University | Composition for inhibition of insect sensing |
| CN102757427A (zh) * | 2012-07-09 | 2012-10-31 | 陕西科技大学 | 2-氨基-5-异二氢吲哚-1,3-二酮甲基1,3,4-噻二唑及其制备方法 |
| CN113749102A (zh) | 2015-03-25 | 2021-12-07 | 范德比尔特大学 | 作为orco介导的气味感觉干扰剂的二元组合物 |
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| US4939138A (en) | 1988-12-29 | 1990-07-03 | Sterling Drug Inc. | 2- and 3-aminomethyl-6-arylcarbonyl-2,3-dihydropyrrolo(1,2,3-DE)-1,4-benzoxazines |
| TWI292316B (en) * | 1999-10-11 | 2008-01-11 | Sod Conseils Rech Applic | Pharmaceutical composition of thiazole derivatives intended to inhibit mao and/or lipidic peroxidation and/or to act as modulators of sodium channels and the use thereof |
| US6653304B2 (en) | 2000-02-11 | 2003-11-25 | Bristol-Myers Squibb Co. | Cannabinoid receptor modulators, their processes of preparation, and use of cannabinoid receptor modulators for treating respiratory and non-respiratory diseases |
| AUPR118000A0 (en) | 2000-11-02 | 2000-11-23 | Amrad Operations Pty. Limited | Therapeutic molecules and methods |
| US7173027B2 (en) | 2001-01-29 | 2007-02-06 | University Of Connecticut | Receptor selective cannabimimetic aminoalkylindoles |
| TWI248438B (en) * | 2001-04-10 | 2006-02-01 | Sod Conseils Rech Applic | Derivatives of heterocycles with 5 members, their preparation and their use as medicaments |
| TW200402417A (en) | 2002-06-21 | 2004-02-16 | Akzo Nobel Nv | 1-[(Indol-3-yl)carbonyl]piperazine derivatives |
| ES2284076T3 (es) | 2003-12-17 | 2007-11-01 | N.V. Organon | Derivados triciclicos de 1-(indol-3-il)carbonil)piperazina como agonistas del receptor de cannabinoides cb1. |
| TWI330635B (en) * | 2004-03-05 | 2010-09-21 | Organon Nv | (indol-3-yl)-heterocycle derivatives |
| EP1904068A1 (en) * | 2005-07-11 | 2008-04-02 | N.V. Organon | Synergistic combination for the treatment of pain (cannabioid receptor agonist and opiod receptor agonist) |
| TW200745096A (en) | 2005-08-23 | 2007-12-16 | Organon Nv | Indole derivatives |
| US7763732B2 (en) | 2005-08-24 | 2010-07-27 | N.V. Organon | Indole derivatives |
| TW200848417A (en) | 2007-02-22 | 2008-12-16 | Organon Nv | Indole derivatives |
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2008
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2009
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Also Published As
| Publication number | Publication date |
|---|---|
| MX2009008316A (es) | 2009-08-12 |
| ZA200905265B (en) | 2010-04-28 |
| WO2008101995A1 (en) | 2008-08-28 |
| IL199848A0 (en) | 2010-04-15 |
| EP2125795A1 (en) | 2009-12-02 |
| AR065393A1 (es) | 2009-06-03 |
| PE20090112A1 (es) | 2009-02-26 |
| JP2010519278A (ja) | 2010-06-03 |
| US20080207598A1 (en) | 2008-08-28 |
| BRPI0807867A2 (pt) | 2014-06-03 |
| JP5324476B2 (ja) | 2013-10-23 |
| AU2008219226A1 (en) | 2008-08-28 |
| CL2008000514A1 (es) | 2008-06-20 |
| US7655645B2 (en) | 2010-02-02 |
| EP2125795B1 (en) | 2013-03-20 |
| ECSP099593A (es) | 2009-09-29 |
| CN101616914B (zh) | 2012-10-10 |
| RU2009135255A (ru) | 2011-03-27 |
| TW200848417A (en) | 2008-12-16 |
| CA2678147A1 (en) | 2008-08-28 |
| AU2008219226B2 (en) | 2013-02-07 |
| CN101616914A (zh) | 2009-12-30 |
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| PC1203 | Withdrawal of no request for examination | ||
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