DE60313640T2 - 1-(indol-3-yl)carbonyl piperazinderivate - Google Patents
1-(indol-3-yl)carbonyl piperazinderivate Download PDFInfo
- Publication number
- DE60313640T2 DE60313640T2 DE60313640T DE60313640T DE60313640T2 DE 60313640 T2 DE60313640 T2 DE 60313640T2 DE 60313640 T DE60313640 T DE 60313640T DE 60313640 T DE60313640 T DE 60313640T DE 60313640 T2 DE60313640 T2 DE 60313640T2
- Authority
- DE
- Germany
- Prior art keywords
- indol
- carbonyl
- methoxy
- cyclohexylmethyl
- mmol
- 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 - Lifetime
Links
- FBXWDVALKBNEJV-UHFFFAOYSA-N 1h-indol-3-yl(piperazin-1-yl)methanone Chemical class C=1NC2=CC=CC=C2C=1C(=O)N1CCNCC1 FBXWDVALKBNEJV-UHFFFAOYSA-N 0.000 title claims description 28
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 24
- 125000000217 alkyl group Chemical group 0.000 claims description 19
- 208000002193 Pain Diseases 0.000 claims description 15
- 125000003545 alkoxy group Chemical group 0.000 claims description 13
- 125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 13
- 229910052736 halogen Inorganic materials 0.000 claims description 13
- 150000002367 halogens Chemical class 0.000 claims description 13
- 229910052739 hydrogen Inorganic materials 0.000 claims description 12
- 239000001257 hydrogen Substances 0.000 claims description 12
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 11
- 150000003839 salts Chemical class 0.000 claims description 9
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 8
- 125000004851 cyclopentylmethyl group Chemical group C1(CCCC1)C* 0.000 claims description 7
- 239000003814 drug Substances 0.000 claims description 7
- 125000000623 heterocyclic group Chemical group 0.000 claims description 7
- 125000005842 heteroatom Chemical group 0.000 claims description 5
- 229910052760 oxygen Inorganic materials 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- 229910052717 sulfur Inorganic materials 0.000 claims description 5
- 125000000081 (C5-C8) cycloalkenyl group Chemical group 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000005843 halogen group Chemical group 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 125000001424 substituent group Chemical group 0.000 claims description 3
- 125000001041 indolyl group Chemical group 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims 1
- 238000002560 therapeutic procedure Methods 0.000 claims 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 102
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 88
- 238000002451 electron ionisation mass spectrometry Methods 0.000 description 78
- 150000001875 compounds Chemical class 0.000 description 73
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 60
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 59
- 239000000243 solution Substances 0.000 description 51
- 239000000203 mixture Substances 0.000 description 47
- 238000000034 method Methods 0.000 description 35
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 30
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 22
- 239000012458 free base Substances 0.000 description 22
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 21
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 21
- 239000007787 solid Substances 0.000 description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 20
- -1 2- (4-morpholinyl) ethyl side chain Chemical group 0.000 description 19
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 18
- 210000004027 cell Anatomy 0.000 description 16
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- 238000003818 flash chromatography Methods 0.000 description 12
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 11
- 230000000694 effects Effects 0.000 description 10
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 10
- 239000000047 product Substances 0.000 description 10
- 102000005962 receptors Human genes 0.000 description 10
- 108020003175 receptors Proteins 0.000 description 10
- LEXVLCRGSBTKBD-UHFFFAOYSA-N 1-(cyclohexylmethyl)-7-methoxyindole-3-carboxylic acid Chemical compound C1=2C(OC)=CC=CC=2C(C(O)=O)=CN1CC1CCCCC1 LEXVLCRGSBTKBD-UHFFFAOYSA-N 0.000 description 9
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 description 9
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 9
- 229930003827 cannabinoid Natural products 0.000 description 9
- 239000003557 cannabinoid Substances 0.000 description 9
- 239000012230 colorless oil Substances 0.000 description 9
- 229910052938 sodium sulfate Inorganic materials 0.000 description 9
- 235000011152 sodium sulphate Nutrition 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 8
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical group C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 8
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 8
- 239000000556 agonist Substances 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 8
- 239000003921 oil Substances 0.000 description 8
- 235000019198 oils Nutrition 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- 102000009132 CB1 Cannabinoid Receptor Human genes 0.000 description 7
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 7
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 7
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 7
- 230000027455 binding Effects 0.000 description 7
- 238000001914 filtration Methods 0.000 description 7
- 230000014509 gene expression Effects 0.000 description 7
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 7
- 239000012044 organic layer Substances 0.000 description 7
- 239000012312 sodium hydride Substances 0.000 description 7
- 229910000104 sodium hydride Inorganic materials 0.000 description 7
- QPFMBZIOSGYJDE-UHFFFAOYSA-N 1,1,2,2-tetrachloroethane Chemical compound ClC(Cl)C(Cl)Cl QPFMBZIOSGYJDE-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
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- 108010073366 CB1 Cannabinoid Receptor Proteins 0.000 description 6
- 239000004480 active ingredient Substances 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- 239000002244 precipitate Substances 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- FSOPPXYMWZOKRM-UHFFFAOYSA-N 7-methoxy-1h-indole Chemical compound COC1=CC=CC2=C1NC=C2 FSOPPXYMWZOKRM-UHFFFAOYSA-N 0.000 description 5
- 108020004414 DNA Proteins 0.000 description 5
- 239000002585 base Substances 0.000 description 5
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 5
- 239000003480 eluent Substances 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 5
- IBCZLOMXNJRQBF-UHFFFAOYSA-N 1-(1-cyclohexylethylsulfonyl)-4-methylbenzene Chemical compound C=1C=C(C)C=CC=1S(=O)(=O)C(C)C1CCCCC1 IBCZLOMXNJRQBF-UHFFFAOYSA-N 0.000 description 4
- WGCYRFWNGRMRJA-UHFFFAOYSA-N 1-ethylpiperazine Chemical compound CCN1CCNCC1 WGCYRFWNGRMRJA-UHFFFAOYSA-N 0.000 description 4
- 101710187010 Cannabinoid receptor 1 Proteins 0.000 description 4
- 102100033868 Cannabinoid receptor 1 Human genes 0.000 description 4
- 108700008625 Reporter Genes Proteins 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 150000001350 alkyl halides Chemical class 0.000 description 4
- UUWSLBWDFJMSFP-UHFFFAOYSA-N bromomethylcyclohexane Chemical compound BrCC1CCCCC1 UUWSLBWDFJMSFP-UHFFFAOYSA-N 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 239000006185 dispersion Substances 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 4
- HVTICUPFWKNHNG-UHFFFAOYSA-N iodoethane Chemical compound CCI HVTICUPFWKNHNG-UHFFFAOYSA-N 0.000 description 4
- 239000012280 lithium aluminium hydride Substances 0.000 description 4
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 4
- 235000019341 magnesium sulphate Nutrition 0.000 description 4
- 229940005483 opioid analgesics Drugs 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 4
- YXBLPNSWHUPKPH-ZCFIWIBFSA-N (9ar)-3,6,7,8,9,9a-hexahydro-2h-pyrido[1,2-a]pyrazine-1,4-dione Chemical compound C1CCC[C@@H]2C(=O)NCC(=O)N21 YXBLPNSWHUPKPH-ZCFIWIBFSA-N 0.000 description 3
- AEHOLYXYGLDBHZ-UHFFFAOYSA-N 1-(cyclohexylmethyl)-7-methoxyindole-3-carbonyl chloride Chemical compound C1=2C(OC)=CC=CC=2C(C(Cl)=O)=CN1CC1CCCCC1 AEHOLYXYGLDBHZ-UHFFFAOYSA-N 0.000 description 3
- JTLAIKFGRHDNQM-UHFFFAOYSA-N 1-bromo-2-fluoroethane Chemical compound FCCBr JTLAIKFGRHDNQM-UHFFFAOYSA-N 0.000 description 3
- QJRWYBIKLXNYLF-UHFFFAOYSA-N 6-methoxy-1h-indole Chemical compound COC1=CC=C2C=CNC2=C1 QJRWYBIKLXNYLF-UHFFFAOYSA-N 0.000 description 3
- 102000009135 CB2 Cannabinoid Receptor Human genes 0.000 description 3
- 108010073376 CB2 Cannabinoid Receptor Proteins 0.000 description 3
- 102000018208 Cannabinoid Receptor Human genes 0.000 description 3
- 108050007331 Cannabinoid receptor Proteins 0.000 description 3
- 101000710899 Homo sapiens Cannabinoid receptor 1 Proteins 0.000 description 3
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- 208000008238 Muscle Spasticity Diseases 0.000 description 3
- 235000019502 Orange oil Nutrition 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
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
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- XEEBZISSHFFRHG-UHFFFAOYSA-N [1-(cyclohexylmethyl)-7-methoxyindol-3-yl]-(3,3-dimethylpiperazin-1-yl)methanone Chemical compound C1=2C(OC)=CC=CC=2C(C(=O)N2CC(C)(C)NCC2)=CN1CC1CCCCC1 XEEBZISSHFFRHG-UHFFFAOYSA-N 0.000 description 3
- WMPOPJACZVLYEN-INIZCTEOSA-N [1-(cyclohexylmethyl)-7-methoxyindol-3-yl]-[(3s)-3-methylpiperazin-1-yl]methanone Chemical compound C1=2C(OC)=CC=CC=2C(C(=O)N2C[C@H](C)NCC2)=CN1CC1CCCCC1 WMPOPJACZVLYEN-INIZCTEOSA-N 0.000 description 3
- ITYFWPJHVBTJAO-HNNXBMFYSA-N [1-(cyclopentylmethyl)-7-methoxyindol-3-yl]-[(3s)-3-methylpiperazin-1-yl]methanone Chemical compound C1=2C(OC)=CC=CC=2C(C(=O)N2C[C@H](C)NCC2)=CN1CC1CCCC1 ITYFWPJHVBTJAO-HNNXBMFYSA-N 0.000 description 3
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- 229940121363 anti-inflammatory agent Drugs 0.000 description 3
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- 230000015572 biosynthetic process Effects 0.000 description 3
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- 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
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 3
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 3
- IXCSERBJSXMMFS-UHFFFAOYSA-N hcl hcl Chemical compound Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
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- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 3
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- SOUPGWGAPDMYFM-UHFFFAOYSA-N (1,4-dibenzylpiperazin-2-yl)methanol Chemical compound C1CN(CC=2C=CC=CC=2)C(CO)CN1CC1=CC=CC=C1 SOUPGWGAPDMYFM-UHFFFAOYSA-N 0.000 description 2
- JQAOHGMPAAWWQO-QMMMGPOBSA-N (2s)-1-[(2-methylpropan-2-yl)oxycarbonyl]piperidine-2-carboxylic acid Chemical compound CC(C)(C)OC(=O)N1CCCC[C@H]1C(O)=O JQAOHGMPAAWWQO-QMMMGPOBSA-N 0.000 description 2
- ZQEBQGAAWMOMAI-ZETCQYMHSA-N (2s)-1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidine-2-carboxylic acid Chemical compound CC(C)(C)OC(=O)N1CCC[C@H]1C(O)=O ZQEBQGAAWMOMAI-ZETCQYMHSA-N 0.000 description 2
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- SDEMZAXQOIWPPI-UHFFFAOYSA-N 1,4-dibenzyl-2-(fluoromethyl)piperazine Chemical compound C1CN(CC=2C=CC=CC=2)C(CF)CN1CC1=CC=CC=C1 SDEMZAXQOIWPPI-UHFFFAOYSA-N 0.000 description 2
- ICJUEVKACUMGHT-UHFFFAOYSA-N 1-(cyclopentylmethyl)-7-methoxyindole Chemical compound C1=2C(OC)=CC=CC=2C=CN1CC1CCCC1 ICJUEVKACUMGHT-UHFFFAOYSA-N 0.000 description 2
- FAPFUJFYNVAFHI-UHFFFAOYSA-N 1-(cyclopentylmethyl)-7-methoxyindole-3-carboxylic acid Chemical compound C1=2C(OC)=CC=CC=2C(C(O)=O)=CN1CC1CCCC1 FAPFUJFYNVAFHI-UHFFFAOYSA-N 0.000 description 2
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 2
- ZQEBQGAAWMOMAI-UHFFFAOYSA-N 1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidine-2-carboxylic acid Chemical compound CC(C)(C)OC(=O)N1CCCC1C(O)=O ZQEBQGAAWMOMAI-UHFFFAOYSA-N 0.000 description 2
- TXIOGJHPPVXTOY-UHFFFAOYSA-N 1-ethyl-4-methylpiperazine Chemical compound CCN1CCN(C)CC1 TXIOGJHPPVXTOY-UHFFFAOYSA-N 0.000 description 2
- SZSZDBFJCQKTRG-UHFFFAOYSA-N 1h-indole-6-carbonitrile Chemical compound N#CC1=CC=C2C=CNC2=C1 SZSZDBFJCQKTRG-UHFFFAOYSA-N 0.000 description 2
- ICGDKKACLISIAM-UHFFFAOYSA-N 2,3,5,6-tetramethylpiperazine Chemical compound CC1NC(C)C(C)NC1C ICGDKKACLISIAM-UHFFFAOYSA-N 0.000 description 2
- IFNWESYYDINUHV-UHFFFAOYSA-N 2,6-dimethylpiperazine Chemical compound CC1CNCC(C)N1 IFNWESYYDINUHV-UHFFFAOYSA-N 0.000 description 2
- ONUCCUGDWPXAJG-UHFFFAOYSA-N 2-(fluoromethyl)piperazine Chemical compound FCC1CNCCN1 ONUCCUGDWPXAJG-UHFFFAOYSA-N 0.000 description 2
- AFABGHUZZDYHJO-UHFFFAOYSA-N 2-Methylpentane Chemical compound CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 description 2
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- ODFFPRGJZRXNHZ-UHFFFAOYSA-N 5-fluoroindole Chemical compound FC1=CC=C2NC=CC2=C1 ODFFPRGJZRXNHZ-UHFFFAOYSA-N 0.000 description 2
- YTYIMDRWPTUAHP-UHFFFAOYSA-N 6-Chloroindole Chemical compound ClC1=CC=C2C=CNC2=C1 YTYIMDRWPTUAHP-UHFFFAOYSA-N 0.000 description 2
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Classifications
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- 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
- C07D471/04—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
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-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Landscapes
- Health & Medical Sciences (AREA)
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- Organic Chemistry (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
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- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Immunology (AREA)
- Psychiatry (AREA)
- Anesthesiology (AREA)
- Nutrition Science (AREA)
- Otolaryngology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Plural Heterocyclic Compounds (AREA)
- Indole Compounds (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP02077505 | 2002-06-21 | ||
| EP02077505 | 2002-06-21 | ||
| PCT/EP2003/050226 WO2004000832A1 (en) | 2002-06-21 | 2003-06-13 | 1-[(indol-3-yl)carbonyl] piperazine derivatives |
Publications (2)
| Publication Number | Publication Date |
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| DE60313640D1 DE60313640D1 (de) | 2007-06-14 |
| DE60313640T2 true DE60313640T2 (de) | 2007-12-27 |
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| TWI242015B (en) | 1999-11-29 | 2005-10-21 | Akzo Nobel Nv | 6-mercapto-cyclodextrin derivatives: reversal agents for drug-induced neuromuscular block |
| ATE375349T1 (de) | 2002-08-02 | 2007-10-15 | Merck & Co Inc | Substituierte furo(2,3-b)pyridin derivate |
| DE10253426B4 (de) * | 2002-11-15 | 2005-09-22 | Elbion Ag | Neue Hydroxyindole, deren Verwendung als Inhibitoren der Phosphodiesterase 4 und Verfahren zu deren Herstellung |
| EP1696930B1 (en) * | 2003-12-17 | 2007-04-11 | N.V. Organon | Tricyclic 1-((3-indol-3-yl)carbonyl)piperazine derivatives as cannabinoid cb1 receptor agonists |
| 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) |
| BRPI0614692A2 (pt) * | 2005-07-29 | 2009-05-19 | Hoffmann La Roche | derivados de indol-3-il-carbonil-piperidina e piperazina |
| 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 |
| EA200800888A1 (ru) * | 2005-09-23 | 2009-02-27 | Янссен Фармацевтика Н.В. | Модуляторы каннабиноидов на основе замещенных 3-амидотетрагидроиндазолилов |
| TW200848417A (en) | 2007-02-22 | 2008-12-16 | Organon Nv | Indole derivatives |
| RU2387642C2 (ru) | 2007-10-31 | 2010-04-27 | Общество С Ограниченной Ответственностью "Бинатех" | Производные 5-замещенных индол-3-карбоновой кислоты, обладающие противовирусной активностью, способ их получения и применение |
| GB201106817D0 (en) * | 2011-04-21 | 2011-06-01 | Astex Therapeutics Ltd | New compound |
| ES2883289T3 (es) | 2013-12-20 | 2021-12-07 | Astex Therapeutics Ltd | Compuestos heterocíclicos bicíclicos y sus usos en terapia |
| EP3737680A1 (en) | 2018-01-08 | 2020-11-18 | F. Hoffmann-La Roche AG | Octahydropyrido[1,2-alpha]pyrazines as magl inhibitors |
| CN108752342A (zh) * | 2018-08-17 | 2018-11-06 | 西安瑞联新材料股份有限公司 | 1-H-吡啶并[1,2-a]-6-氢吡嗪-1,4-二酮的制备方法 |
| CN111100063B (zh) * | 2018-10-25 | 2022-05-17 | 南京药石科技股份有限公司 | 一种合成2-氟甲基取代的吡咯烷、哌啶以及哌嗪衍生物的制备方法 |
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| CA2071529C (en) * | 1989-12-28 | 2001-03-20 | Donna Lee Romero | Diaromatic substituted anti-aids compounds |
| WO1998006715A1 (en) | 1996-08-09 | 1998-02-19 | Smithkline Beecham Corporation | Novel piperazine containing compounds |
| AU1887401A (en) * | 1999-12-14 | 2001-06-25 | Nippon Shinyaku Co. Ltd. | Medicinal composition |
| EP1254115A2 (en) | 2000-02-11 | 2002-11-06 | Bristol-Myers Squibb Company | Cannabinoid receptor modulators, their processes of preparation, and use of cannabinoid receptor modulators for treating respiratory and non-respiratory diseases |
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2003
- 2003-06-11 TW TW092115888A patent/TW200402417A/zh unknown
- 2003-06-13 AU AU2003250245A patent/AU2003250245B2/en not_active Ceased
- 2003-06-13 RS YUP-1111/04A patent/RS111104A/sr unknown
- 2003-06-13 DE DE60313640T patent/DE60313640T2/de not_active Expired - Lifetime
- 2003-06-13 MX MXPA04012856A patent/MXPA04012856A/es active IP Right Grant
- 2003-06-13 AT AT03760704T patent/ATE361290T1/de active
- 2003-06-13 KR KR10-2004-7020734A patent/KR20050009755A/ko not_active Ceased
- 2003-06-13 BR BR0311960-2A patent/BR0311960A/pt not_active IP Right Cessation
- 2003-06-13 PL PL03375152A patent/PL375152A1/xx not_active Application Discontinuation
- 2003-06-13 EP EP03760704A patent/EP1549637B1/en not_active Expired - Lifetime
- 2003-06-13 CN CNB038170906A patent/CN1298716C/zh not_active Expired - Fee Related
- 2003-06-13 ES ES03760704T patent/ES2285183T3/es not_active Expired - Lifetime
- 2003-06-13 PT PT03760704T patent/PT1549637E/pt unknown
- 2003-06-13 RU RU2005101349/04A patent/RU2318821C2/ru not_active IP Right Cessation
- 2003-06-13 CA CA2490141A patent/CA2490141C/en not_active Expired - Fee Related
- 2003-06-13 DK DK03760704T patent/DK1549637T3/da active
- 2003-06-13 WO PCT/EP2003/050226 patent/WO2004000832A1/en not_active Ceased
- 2003-06-13 JP JP2004514874A patent/JP4408804B2/ja not_active Expired - Fee Related
- 2003-06-13 NZ NZ537143A patent/NZ537143A/en unknown
- 2003-06-13 SI SI200330855T patent/SI1549637T1/sl unknown
- 2003-06-13 US US10/518,279 patent/US7304064B2/en not_active Expired - Fee Related
- 2003-06-13 UA UA20041210112A patent/UA78317C2/uk unknown
- 2003-06-13 HR HR20041186A patent/HRP20041186A2/xx not_active Application Discontinuation
- 2003-06-18 PE PE2003000614A patent/PE20040578A1/es not_active Application Discontinuation
- 2003-06-19 AR ARP030102174A patent/AR040274A1/es unknown
-
2004
- 2004-12-06 IL IL16557204A patent/IL165572A0/xx unknown
- 2004-12-07 NO NO20045351A patent/NO20045351L/no not_active Application Discontinuation
- 2004-12-09 IS IS7590A patent/IS2443B/is unknown
- 2004-12-13 ZA ZA200410057A patent/ZA200410057B/en unknown
- 2004-12-21 EC EC2004005503A patent/ECSP045503A/es unknown
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2005
- 2005-01-20 CO CO05004561A patent/CO5680419A2/es not_active Application Discontinuation
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2007
- 2007-06-18 CY CY20071100804T patent/CY1107677T1/el unknown
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