HRP20000845A2 - Tetrahydroquinoline derivatives as glycine antagonists - Google Patents
Tetrahydroquinoline derivatives as glycine antagonistsInfo
- Publication number
- HRP20000845A2 HRP20000845A2 HR20000845A HRP20000845A HRP20000845A2 HR P20000845 A2 HRP20000845 A2 HR P20000845A2 HR 20000845 A HR20000845 A HR 20000845A HR P20000845 A HRP20000845 A HR P20000845A HR P20000845 A2 HRP20000845 A2 HR P20000845A2
- Authority
- HR
- Croatia
- Prior art keywords
- phenyl
- group
- chloro
- solution
- tetrahydro
- Prior art date
Links
- 229940127337 Glycine Antagonists Drugs 0.000 title 1
- 125000000147 tetrahydroquinolinyl group Chemical class N1(CCCC2=CC=CC=C12)* 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 170
- 239000000203 mixture Substances 0.000 claims description 88
- -1 hydroxy, amino Chemical group 0.000 claims description 70
- 150000003839 salts Chemical class 0.000 claims description 44
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 36
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 34
- 238000006243 chemical reaction Methods 0.000 claims description 30
- 238000000034 method Methods 0.000 claims description 30
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 27
- 150000002148 esters Chemical class 0.000 claims description 25
- 229910052739 hydrogen Inorganic materials 0.000 claims description 25
- 239000001257 hydrogen Substances 0.000 claims description 25
- 229910052757 nitrogen Inorganic materials 0.000 claims description 23
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 23
- 229910052799 carbon Inorganic materials 0.000 claims description 17
- 125000006239 protecting group Chemical group 0.000 claims description 17
- 238000002360 preparation method Methods 0.000 claims description 16
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 15
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims description 13
- 231100000252 nontoxic Toxicity 0.000 claims description 13
- 230000003000 nontoxic effect Effects 0.000 claims description 13
- 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 claims description 12
- 239000000460 chlorine Substances 0.000 claims description 12
- 229910052801 chlorine Inorganic materials 0.000 claims description 12
- 229920006395 saturated elastomer Polymers 0.000 claims description 12
- 102000004868 N-Methyl-D-Aspartate Receptors Human genes 0.000 claims description 11
- 108090001041 N-Methyl-D-Aspartate Receptors Proteins 0.000 claims description 11
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 11
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical group [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 10
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 10
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 8
- 229910052760 oxygen Inorganic materials 0.000 claims description 8
- 239000001301 oxygen Substances 0.000 claims description 8
- 239000000126 substance Substances 0.000 claims description 8
- FCMZVVRKJTVTQK-UHFFFAOYSA-N 5,7-dichloro-4-(2-oxo-1-phenylpyrrolidin-3-ylidene)-2,3-dihydro-1h-quinoline-2-carboxylic acid Chemical compound C12=C(Cl)C=C(Cl)C=C2NC(C(=O)O)CC1=C(C1=O)CCN1C1=CC=CC=C1 FCMZVVRKJTVTQK-UHFFFAOYSA-N 0.000 claims description 7
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 7
- 230000000694 effects Effects 0.000 claims description 7
- 239000003257 excitatory amino acid Substances 0.000 claims description 7
- 230000002461 excitatory amino acid Effects 0.000 claims description 7
- 125000005842 heteroatom Chemical group 0.000 claims description 7
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 7
- 229910052717 sulfur Inorganic materials 0.000 claims description 7
- 239000011593 sulfur Chemical group 0.000 claims description 7
- 125000005843 halogen group Chemical group 0.000 claims description 6
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 5
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 5
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 5
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical group C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 5
- 150000001732 carboxylic acid derivatives Chemical group 0.000 claims description 5
- 229910052740 iodine Chemical group 0.000 claims description 5
- 239000011734 sodium Substances 0.000 claims description 5
- 229910052708 sodium Inorganic materials 0.000 claims description 5
- 159000000000 sodium salts Chemical class 0.000 claims description 5
- 230000001225 therapeutic effect Effects 0.000 claims description 5
- 125000002947 alkylene group Chemical group 0.000 claims description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 3
- DGJFOKSXPJLLMX-UHFFFAOYSA-N 7-chloro-4-(2,5-dioxo-1-phenylimidazolidin-4-ylidene)-2,3-dihydro-1h-quinoline-2-carboxylic acid Chemical compound C12=CC=C(Cl)C=C2NC(C(=O)O)CC1=C(C1=O)NC(=O)N1C1=CC=CC=C1 DGJFOKSXPJLLMX-UHFFFAOYSA-N 0.000 claims description 3
- NEUYJSROPOLVLU-UHFFFAOYSA-N 7-chloro-4-(2-oxo-1-phenylpiperidin-3-ylidene)-2,3-dihydro-1h-quinoline-2-carboxylic acid Chemical compound C12=CC=C(Cl)C=C2NC(C(=O)O)CC1=C(C1=O)CCCN1C1=CC=CC=C1 NEUYJSROPOLVLU-UHFFFAOYSA-N 0.000 claims description 3
- XDKRVNKVAKCFGW-UHFFFAOYSA-N 7-chloro-4-(2-oxo-1-phenylpyrrolidin-3-ylidene)-2,3-dihydro-1h-quinoline-2-carboxylic acid Chemical group C12=CC=C(Cl)C=C2NC(C(=O)O)CC1=C(C1=O)CCN1C1=CC=CC=C1 XDKRVNKVAKCFGW-UHFFFAOYSA-N 0.000 claims description 3
- 101100295741 Gallus gallus COR4 gene Proteins 0.000 claims description 3
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 claims description 3
- 125000003282 alkyl amino group Chemical group 0.000 claims description 3
- 125000003277 amino group Chemical group 0.000 claims description 3
- 125000001246 bromo group Chemical group Br* 0.000 claims description 3
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 3
- 125000001072 heteroaryl group Chemical group 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- 238000007363 ring formation reaction Methods 0.000 claims description 3
- OKKPHPZRLYFXCK-UHFFFAOYSA-M sodium;7-chloro-4-(2-oxo-1-phenylpyrrolidin-3-ylidene)-2,3-dihydro-1h-quinoline-2-carboxylate Chemical group [Na+].C12=CC=C(Cl)C=C2NC(C(=O)[O-])CC1=C(C1=O)CCN1C1=CC=CC=C1 OKKPHPZRLYFXCK-UHFFFAOYSA-M 0.000 claims description 3
- DJRORXFEVGSQOR-UHFFFAOYSA-N 7-chloro-4-(2-oxo-1-pyridin-3-ylpyrrolidin-3-ylidene)-2,3-dihydro-1H-quinoline-2-carboxylic acid Chemical compound C12=CC=C(Cl)C=C2NC(C(=O)O)CC1=C(C1=O)CCN1C1=CC=CN=C1 DJRORXFEVGSQOR-UHFFFAOYSA-N 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 238000000926 separation method Methods 0.000 claims description 2
- 150000001721 carbon Chemical group 0.000 claims 2
- 241000124008 Mammalia Species 0.000 claims 1
- 239000000969 carrier Substances 0.000 claims 1
- 238000002955 isolation Methods 0.000 claims 1
- 239000000825 pharmaceutical preparation Substances 0.000 claims 1
- 238000002560 therapeutic procedure Methods 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 207
- 239000000243 solution Substances 0.000 description 143
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 139
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 79
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 71
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 69
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 64
- 239000007787 solid Substances 0.000 description 60
- 238000005481 NMR spectroscopy Methods 0.000 description 54
- 239000000543 intermediate Substances 0.000 description 53
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 53
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 51
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 48
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 43
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 40
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 39
- 239000012044 organic layer Substances 0.000 description 38
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 35
- 239000011541 reaction mixture Substances 0.000 description 34
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 33
- 239000012267 brine Substances 0.000 description 32
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 32
- 239000013067 intermediate product Substances 0.000 description 29
- 239000000047 product Substances 0.000 description 28
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 26
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 26
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 25
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 25
- 239000002480 mineral oil Substances 0.000 description 25
- 235000010446 mineral oil Nutrition 0.000 description 25
- 238000004440 column chromatography Methods 0.000 description 24
- 239000002904 solvent Substances 0.000 description 20
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 18
- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 description 17
- 235000019270 ammonium chloride Nutrition 0.000 description 17
- 125000004432 carbon atom Chemical group C* 0.000 description 17
- 239000012043 crude product Substances 0.000 description 17
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 16
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 16
- 238000000746 purification Methods 0.000 description 16
- 238000003756 stirring Methods 0.000 description 16
- 239000000725 suspension Substances 0.000 description 14
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 14
- 238000005160 1H NMR spectroscopy Methods 0.000 description 13
- 238000003818 flash chromatography Methods 0.000 description 13
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 13
- 239000012047 saturated solution Substances 0.000 description 13
- 239000012230 colorless oil Substances 0.000 description 12
- 239000012045 crude solution Substances 0.000 description 12
- PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical compound FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 description 12
- 238000010992 reflux Methods 0.000 description 12
- 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 12
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 10
- 239000000843 powder Substances 0.000 description 10
- MPXAPULVRLDXGU-YOZOHBORSA-N (3R)-2-(5-chloro-2-iodoanilino)-3-methyl-4-[(2-methylpropan-2-yl)oxy]-4-oxo-2-(2-oxoethyl)butanoic acid Chemical compound C[C@@H](C(=O)OC(C)(C)C)C(CC=O)(C(=O)O)NC1=C(C=CC(=C1)Cl)I MPXAPULVRLDXGU-YOZOHBORSA-N 0.000 description 9
- 239000002253 acid Substances 0.000 description 9
- 230000015572 biosynthetic process Effects 0.000 description 9
- 238000001035 drying Methods 0.000 description 9
- 239000004471 Glycine Substances 0.000 description 8
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
- 239000013543 active substance Substances 0.000 description 8
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 8
- 238000002347 injection Methods 0.000 description 8
- 239000007924 injection Substances 0.000 description 8
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 8
- 235000019341 magnesium sulphate Nutrition 0.000 description 8
- 239000003921 oil Substances 0.000 description 8
- 235000019198 oils Nutrition 0.000 description 8
- YSILGYNNTSDLPH-FAQQKDIKSA-N 2-(5-chloro-2-iodoanilino)-2-[(2R)-1-[(2-methylpropan-2-yl)oxy]-1-oxopropan-2-yl]pent-4-enoic acid Chemical compound C[C@@H](C(=O)OC(C)(C)C)C(CC=C)(C(=O)O)NC1=C(C=CC(=C1)Cl)I YSILGYNNTSDLPH-FAQQKDIKSA-N 0.000 description 7
- 241000228245 Aspergillus niger Species 0.000 description 7
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 7
- 108090001060 Lipase Proteins 0.000 description 7
- 102000004882 Lipase Human genes 0.000 description 7
- 208000002193 Pain Diseases 0.000 description 7
- 239000003480 eluent Substances 0.000 description 7
- 239000006260 foam Substances 0.000 description 7
- 230000036407 pain Effects 0.000 description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 7
- 238000011282 treatment Methods 0.000 description 7
- 239000004367 Lipase Substances 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- 125000000217 alkyl group Chemical group 0.000 description 6
- NKRFGTUOGIUDLV-UHFFFAOYSA-N ethyl 7-chloro-4-(2-oxo-1-phenylpyrrolidin-3-ylidene)-2,3-dihydro-1h-quinoline-2-carboxylate Chemical compound C12=CC=C(Cl)C=C2NC(C(=O)OCC)CC1=C(C1=O)CCN1C1=CC=CC=C1 NKRFGTUOGIUDLV-UHFFFAOYSA-N 0.000 description 6
- QJIPWGTVZXAHBS-UHFFFAOYSA-N ethyl 7-chloro-4-(2-oxo-1-pyridin-3-ylpyrrolidin-3-ylidene)-2,3-dihydro-1h-quinoline-2-carboxylate Chemical compound C12=CC=C(Cl)C=C2NC(C(=O)OCC)CC1=C(C1=O)CCN1C1=CC=CN=C1 QJIPWGTVZXAHBS-UHFFFAOYSA-N 0.000 description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 6
- 230000007062 hydrolysis Effects 0.000 description 6
- 238000006460 hydrolysis reaction Methods 0.000 description 6
- 229940040461 lipase Drugs 0.000 description 6
- 235000019421 lipase Nutrition 0.000 description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 6
- 102000004190 Enzymes Human genes 0.000 description 5
- 108090000790 Enzymes Proteins 0.000 description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- 239000003513 alkali Substances 0.000 description 5
- 239000005557 antagonist Substances 0.000 description 5
- 239000008346 aqueous phase Substances 0.000 description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 150000007530 organic bases Chemical class 0.000 description 5
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- 229920000168 Microcrystalline cellulose Polymers 0.000 description 4
- 241000699670 Mus sp. Species 0.000 description 4
- CBENFWSGALASAD-UHFFFAOYSA-N Ozone Chemical compound [O-][O+]=O CBENFWSGALASAD-UHFFFAOYSA-N 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 239000000010 aprotic solvent Substances 0.000 description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 4
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- 230000032050 esterification Effects 0.000 description 4
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- 238000001727 in vivo Methods 0.000 description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 4
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- 230000004770 neurodegeneration Effects 0.000 description 4
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- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
- 229910052938 sodium sulfate Inorganic materials 0.000 description 4
- 235000011152 sodium sulphate Nutrition 0.000 description 4
- QMGVPVSNSZLJIA-FVWCLLPLSA-N strychnine Chemical compound O([C@H]1CC(N([C@H]2[C@H]1[C@H]1C3)C=4C5=CC=CC=4)=O)CC=C1CN1[C@@H]3[C@]25CC1 QMGVPVSNSZLJIA-FVWCLLPLSA-N 0.000 description 4
- 125000005270 trialkylamine group Chemical group 0.000 description 4
- SNICXCGAKADSCV-JTQLQIEISA-N (-)-Nicotine Chemical compound CN1CCC[C@H]1C1=CC=CN=C1 SNICXCGAKADSCV-JTQLQIEISA-N 0.000 description 3
- LBUJPTNKIBCYBY-UHFFFAOYSA-N 1,2,3,4-tetrahydroquinoline Chemical class C1=CC=C2CCCNC2=C1 LBUJPTNKIBCYBY-UHFFFAOYSA-N 0.000 description 3
- MSXVEPNJUHWQHW-UHFFFAOYSA-N 2-methylbutan-2-ol Chemical compound CCC(C)(C)O MSXVEPNJUHWQHW-UHFFFAOYSA-N 0.000 description 3
- WBPAQKQBUKYCJS-ZCFIWIBFSA-N 2-methylpropyl (2r)-2-hydroxypropanoate Chemical compound CC(C)COC(=O)[C@@H](C)O WBPAQKQBUKYCJS-ZCFIWIBFSA-N 0.000 description 3
- FEOMAFDDLHSVMO-UHFFFAOYSA-N 5-chloro-2-iodoaniline Chemical compound NC1=CC(Cl)=CC=C1I FEOMAFDDLHSVMO-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 3
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- 229910052623 talc Inorganic materials 0.000 description 1
- CJIIUHXNKIOWLT-UHFFFAOYSA-N tert-butyl n-[4-(2,4-dibromobutanoylamino)phenyl]carbamate Chemical compound CC(C)(C)OC(=O)NC1=CC=C(NC(=O)C(Br)CCBr)C=C1 CJIIUHXNKIOWLT-UHFFFAOYSA-N 0.000 description 1
- 150000003530 tetrahydroquinolines Chemical class 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 description 1
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 238000005809 transesterification reaction Methods 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- FAQYAMRNWDIXMY-UHFFFAOYSA-N trichloroborane Chemical compound ClB(Cl)Cl FAQYAMRNWDIXMY-UHFFFAOYSA-N 0.000 description 1
- FTVLMFQEYACZNP-UHFFFAOYSA-N trimethylsilyl trifluoromethanesulfonate Chemical compound C[Si](C)(C)OS(=O)(=O)C(F)(F)F FTVLMFQEYACZNP-UHFFFAOYSA-N 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
- 238000003828 vacuum filtration Methods 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- 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
- C07D401/14—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 three or more hetero rings
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Biomedical Technology (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Pain & Pain Management (AREA)
- Hospice & Palliative Care (AREA)
- Psychiatry (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Plural Heterocyclic Compounds (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GBGB9812410.0A GB9812410D0 (en) | 1998-06-10 | 1998-06-10 | Heterocyclic derivatives |
| GBGB9812408.4A GB9812408D0 (en) | 1998-06-10 | 1998-06-10 | Heterocyclic compounds |
| PCT/EP1999/003936 WO1999064411A1 (en) | 1998-06-10 | 1999-06-08 | Tetrahydroquinoline derivatives as glycine antagonists |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| HRP20000845A2 true HRP20000845A2 (en) | 2001-10-31 |
Family
ID=26313826
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| HR20000845A HRP20000845A2 (en) | 1998-06-10 | 2000-12-08 | Tetrahydroquinoline derivatives as glycine antagonists |
Country Status (34)
| Country | Link |
|---|---|
| US (3) | US6362199B1 (de) |
| EP (1) | EP1086093B1 (de) |
| JP (1) | JP2002517492A (de) |
| KR (1) | KR100586762B1 (de) |
| CN (1) | CN1173970C (de) |
| AP (1) | AP2000002008A0 (de) |
| AR (1) | AR018632A1 (de) |
| AT (1) | ATE301650T1 (de) |
| AU (1) | AU753867B2 (de) |
| BG (1) | BG105123A (de) |
| BR (1) | BR9911145A (de) |
| CA (1) | CA2334727C (de) |
| CO (1) | CO5080785A1 (de) |
| CZ (1) | CZ293605B6 (de) |
| DE (1) | DE69926632T2 (de) |
| DK (1) | DK1086093T3 (de) |
| EA (1) | EA003276B1 (de) |
| EE (1) | EE200000733A (de) |
| ES (1) | ES2249010T3 (de) |
| HK (1) | HK1034079A1 (de) |
| HR (1) | HRP20000845A2 (de) |
| HU (1) | HUP0102767A3 (de) |
| ID (1) | ID27845A (de) |
| IL (2) | IL140062A0 (de) |
| IS (1) | IS5746A (de) |
| MY (1) | MY125037A (de) |
| NO (1) | NO321904B1 (de) |
| NZ (1) | NZ508638A (de) |
| OA (1) | OA11564A (de) |
| PE (1) | PE20000724A1 (de) |
| PL (1) | PL197160B1 (de) |
| TR (1) | TR200003652T2 (de) |
| TW (1) | TWI229079B (de) |
| WO (1) | WO1999064411A1 (de) |
Families Citing this family (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| MY125037A (en) * | 1998-06-10 | 2006-07-31 | Glaxo Wellcome Spa | 1,2,3,4 tetrahydroquinoline derivatives |
| US6455734B1 (en) * | 2000-08-09 | 2002-09-24 | Magnesium Diagnostics, Inc. | Antagonists of the magnesium binding defect as therapeutic agents and methods for treatment of abnormal physiological states |
| GB9929037D0 (en) * | 1999-12-08 | 2000-02-02 | Glaxo Wellcome Spa | Heterocyclic derivatives |
| DE10000311A1 (de) | 2000-01-05 | 2001-07-12 | Gruenenthal Gmbh | Aminomethyl-Phonyl-Cyclohexanonderivate |
| DE10005302A1 (de) * | 2000-02-07 | 2002-01-17 | Gruenenthal Gmbh | Substituierte 1,2,3,4-Tetrahydrochinolin-2-carbonsäurederivate |
| DE10137488A1 (de) * | 2001-08-03 | 2003-02-20 | Gruenenthal Gmbh | Salze substituierter 1,2,3,4-Tetrahydrochinolin-2-carbonsäurederivate |
| DE10137487A1 (de) | 2001-08-03 | 2003-03-27 | Gruenenthal Gmbh | Substituierte 5,6,6a,11b-Tetrahydro-7-oxa-6-aza- benzo[c]fluoren-6-carbonsäurederivate |
| JP2006508077A (ja) * | 2002-10-04 | 2006-03-09 | ミレニアム・ファーマシューティカルズ・インコーポレイテッド | 炎症疾患を治療するためのｐｇｄ２レセプタアンタゴニスト |
| US20090181966A1 (en) * | 2002-10-04 | 2009-07-16 | Millennium Pharmaceuticals, Inc. | PGD2 receptor antagonists for the treatment of inflammatory diseases |
| US7504508B2 (en) * | 2002-10-04 | 2009-03-17 | Millennium Pharmaceuticals, Inc. | PGD2 receptor antagonists for the treatment of inflammatory diseases |
| GB0327912D0 (en) * | 2003-12-02 | 2004-01-07 | Glaxo Group Ltd | Medicament |
| CA2598133A1 (en) * | 2005-02-24 | 2006-08-31 | Millennium Pharmaceuticals, Inc. | Pgd2 receptor antagonists for the treatment of inflammatory diseases |
Family Cites Families (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2024516C1 (ru) * | 1989-02-02 | 1994-12-15 | Яманути Фармасьютикал Ко., Лтд. | Способ получения производного тетрагидробензимидазола или его фармацевтически приемлемой соли |
| US4902695A (en) * | 1989-02-13 | 1990-02-20 | Eli Lilly And Company | Excitatory amino acid receptor antagonists |
| US5231102A (en) * | 1989-03-08 | 1993-07-27 | Merck Sharp & Dohme, Ltd. | Tetrahydroquinoline derivatives useful for neurodegenerative disorders |
| IL93610A0 (en) * | 1989-03-08 | 1990-12-23 | Merck Sharp & Dohme | Tetrahydroquinoline derivatives,their preparation and pharmaceutical compositions containing them |
| US5529999A (en) | 1994-03-04 | 1996-06-25 | Eli Lilly And Company | Antitumor compositions and methods of treatment |
| CA2232509A1 (en) | 1995-09-29 | 1997-04-10 | Glaxo Wellcome Spa | Tetrahydroquinolines as nmda antagonists |
| GB9617305D0 (en) * | 1996-08-17 | 1996-09-25 | Glaxo Wellcome Spa | Heterocyclic compounds |
| MY125037A (en) * | 1998-06-10 | 2006-07-31 | Glaxo Wellcome Spa | 1,2,3,4 tetrahydroquinoline derivatives |
-
1999
- 1999-06-07 MY MYPI99002298A patent/MY125037A/en unknown
- 1999-06-08 AR ARP990102714A patent/AR018632A1/es active IP Right Grant
- 1999-06-08 WO PCT/EP1999/003936 patent/WO1999064411A1/en active IP Right Grant
- 1999-06-08 AT AT99927911T patent/ATE301650T1/de active
- 1999-06-08 AP APAP/P/2000/002008A patent/AP2000002008A0/en unknown
- 1999-06-08 EA EA200001165A patent/EA003276B1/ru not_active IP Right Cessation
- 1999-06-08 IL IL14006299A patent/IL140062A0/xx active IP Right Grant
- 1999-06-08 NZ NZ508638A patent/NZ508638A/en not_active IP Right Cessation
- 1999-06-08 OA OA1200000335A patent/OA11564A/en unknown
- 1999-06-08 CA CA002334727A patent/CA2334727C/en not_active Expired - Fee Related
- 1999-06-08 CN CNB998094145A patent/CN1173970C/zh not_active Expired - Fee Related
- 1999-06-08 US US09/719,188 patent/US6362199B1/en not_active Expired - Fee Related
- 1999-06-08 EE EEP200000733A patent/EE200000733A/xx unknown
- 1999-06-08 EP EP99927911A patent/EP1086093B1/de not_active Expired - Lifetime
- 1999-06-08 TR TR2000/03652T patent/TR200003652T2/xx unknown
- 1999-06-08 CO CO99035699A patent/CO5080785A1/es unknown
- 1999-06-08 ID IDW20010061A patent/ID27845A/id unknown
- 1999-06-08 DK DK99927911T patent/DK1086093T3/da active
- 1999-06-08 DE DE69926632T patent/DE69926632T2/de not_active Expired - Lifetime
- 1999-06-08 PE PE1999000511A patent/PE20000724A1/es not_active Application Discontinuation
- 1999-06-08 KR KR1020007013994A patent/KR100586762B1/ko not_active IP Right Cessation
- 1999-06-08 ES ES99927911T patent/ES2249010T3/es not_active Expired - Lifetime
- 1999-06-08 PL PL344694A patent/PL197160B1/pl not_active IP Right Cessation
- 1999-06-08 JP JP2000553420A patent/JP2002517492A/ja active Pending
- 1999-06-08 CZ CZ20004587A patent/CZ293605B6/cs not_active IP Right Cessation
- 1999-06-08 HU HU0102767A patent/HUP0102767A3/hu unknown
- 1999-06-08 AU AU45092/99A patent/AU753867B2/en not_active Ceased
- 1999-06-08 BR BR9911145-4A patent/BR9911145A/pt not_active Application Discontinuation
- 1999-06-17 TW TW088110159A patent/TWI229079B/zh not_active IP Right Cessation
-
2000
- 2000-11-30 IS IS5746A patent/IS5746A/is unknown
- 2000-12-04 IL IL140062A patent/IL140062A/en not_active IP Right Cessation
- 2000-12-07 NO NO20006227A patent/NO321904B1/no not_active IP Right Cessation
- 2000-12-08 HR HR20000845A patent/HRP20000845A2/hr not_active Application Discontinuation
-
2001
- 2001-01-08 BG BG105123A patent/BG105123A/xx unknown
- 2001-07-03 HK HK01104579A patent/HK1034079A1/xx not_active IP Right Cessation
- 2001-11-16 US US09/990,513 patent/US6413985B1/en not_active Expired - Fee Related
-
2002
- 2002-05-14 US US10/145,258 patent/US6495566B2/en not_active Expired - Fee Related
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