NZ538339A - Oxadiazoles as modulators of metabotropic glutamate receptor-5 - Google Patents
Oxadiazoles as modulators of metabotropic glutamate receptor-5Info
- Publication number
- NZ538339A NZ538339A NZ538339A NZ53833903A NZ538339A NZ 538339 A NZ538339 A NZ 538339A NZ 538339 A NZ538339 A NZ 538339A NZ 53833903 A NZ53833903 A NZ 53833903A NZ 538339 A NZ538339 A NZ 538339A
- Authority
- NZ
- New Zealand
- Prior art keywords
- piperazine
- phenyl
- carboxylic acid
- ethyl ester
- methyl
- Prior art date
Links
- 108010065028 Metabotropic Glutamate 5 Receptor Proteins 0.000 title claims abstract description 29
- 150000004866 oxadiazoles Chemical class 0.000 title abstract description 3
- 102100038357 Metabotropic glutamate receptor 5 Human genes 0.000 title abstract 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 220
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 37
- 208000035475 disorder Diseases 0.000 claims abstract description 34
- 238000000034 method Methods 0.000 claims abstract description 31
- 208000002193 Pain Diseases 0.000 claims abstract description 20
- 230000001404 mediated effect Effects 0.000 claims abstract description 16
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 10
- 230000008569 process Effects 0.000 claims abstract description 9
- 238000002360 preparation method Methods 0.000 claims abstract description 8
- 208000000094 Chronic Pain Diseases 0.000 claims abstract description 7
- 208000012902 Nervous system disease Diseases 0.000 claims abstract description 7
- 208000005298 acute pain Diseases 0.000 claims abstract description 7
- 230000001684 chronic effect Effects 0.000 claims abstract description 7
- 208000020016 psychiatric disease Diseases 0.000 claims abstract description 7
- 239000000203 mixture Substances 0.000 claims description 96
- WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical compound C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 claims description 71
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 56
- -1 glycero phosphatidyl inositols Chemical class 0.000 claims description 55
- 229910052757 nitrogen Inorganic materials 0.000 claims description 45
- 229910052799 carbon Inorganic materials 0.000 claims description 41
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 40
- 125000004429 atom Chemical group 0.000 claims description 35
- 229910052739 hydrogen Inorganic materials 0.000 claims description 32
- 239000001257 hydrogen Substances 0.000 claims description 32
- 125000005843 halogen group Chemical group 0.000 claims description 26
- 229910052760 oxygen Inorganic materials 0.000 claims description 26
- 102000012777 Metabotropic Glutamate 5 Receptor Human genes 0.000 claims description 25
- 229910052717 sulfur Inorganic materials 0.000 claims description 25
- 125000004494 ethyl ester group Chemical group 0.000 claims description 24
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 22
- RFIOZSIHFNEKFF-UHFFFAOYSA-N piperazine-1-carboxylic acid Chemical compound OC(=O)N1CCNCC1 RFIOZSIHFNEKFF-UHFFFAOYSA-N 0.000 claims description 22
- 230000004913 activation Effects 0.000 claims description 20
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 20
- 150000003839 salts Chemical class 0.000 claims description 19
- 125000004043 oxo group Chemical group O=* 0.000 claims description 18
- 230000002265 prevention Effects 0.000 claims description 17
- 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 claims description 11
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 11
- 239000007995 HEPES buffer Substances 0.000 claims description 10
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 10
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 10
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 9
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 7
- 125000002541 furyl group Chemical group 0.000 claims description 7
- 125000004076 pyridyl group Chemical group 0.000 claims description 7
- 238000003556 assay Methods 0.000 claims description 6
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 6
- 229960000367 inositol Drugs 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 6
- CDAISMWEOUEBRE-UHFFFAOYSA-N scyllo-inosotol Natural products OC1C(O)C(O)C(O)C(O)C1O CDAISMWEOUEBRE-UHFFFAOYSA-N 0.000 claims description 6
- 238000002560 therapeutic procedure Methods 0.000 claims description 6
- 125000001544 thienyl group Chemical group 0.000 claims description 6
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 6
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 5
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Substances N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 claims description 5
- 229910002091 carbon monoxide Inorganic materials 0.000 claims description 5
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 5
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 claims description 4
- SQUHHTBVTRBESD-UHFFFAOYSA-N Hexa-Ac-myo-Inositol Natural products CC(=O)OC1C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C1OC(C)=O SQUHHTBVTRBESD-UHFFFAOYSA-N 0.000 claims description 4
- 229910019142 PO4 Inorganic materials 0.000 claims description 4
- QOSMNYMQXIVWKY-UHFFFAOYSA-N Propyl levulinate Chemical compound CCCOC(=O)CCC(C)=O QOSMNYMQXIVWKY-UHFFFAOYSA-N 0.000 claims description 4
- INAPMGSXUVUWAF-GCVPSNMTSA-N [(2r,3s,5r,6r)-2,3,4,5,6-pentahydroxycyclohexyl] dihydrogen phosphate Chemical compound OC1[C@H](O)[C@@H](O)C(OP(O)(O)=O)[C@H](O)[C@@H]1O INAPMGSXUVUWAF-GCVPSNMTSA-N 0.000 claims description 4
- 239000003814 drug Substances 0.000 claims description 4
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 4
- 230000002401 inhibitory effect Effects 0.000 claims description 4
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 4
- 125000006217 methyl sulfide group Chemical group [H]C([H])([H])S* 0.000 claims description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
- 235000021317 phosphate Nutrition 0.000 claims description 4
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical compound CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 claims description 4
- RPKPFOKNXKRFTD-UHFFFAOYSA-N tert-butyl n-(1-cyanoethyl)carbamate Chemical compound N#CC(C)NC(=O)OC(C)(C)C RPKPFOKNXKRFTD-UHFFFAOYSA-N 0.000 claims description 4
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 4
- ITHLUXJRCDKRBP-UHFFFAOYSA-N 5-(3-methylphenyl)-3-(piperazin-1-ylmethyl)-1,2,4-oxadiazole Chemical compound CC1=CC=CC(C=2ON=C(CN3CCNCC3)N=2)=C1 ITHLUXJRCDKRBP-UHFFFAOYSA-N 0.000 claims description 3
- 239000004480 active ingredient Substances 0.000 claims description 3
- 150000001408 amides Chemical class 0.000 claims description 3
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 3
- 239000003085 diluting agent Substances 0.000 claims description 3
- QZSLJGWQMVXKEF-UHFFFAOYSA-N ethyl 4-[1-[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]propyl]piperazine-1-carboxylate Chemical compound C1CN(C(=O)OCC)CCN1C(CC)C1=NOC(C=2C=C(Cl)C=CC=2)=N1 QZSLJGWQMVXKEF-UHFFFAOYSA-N 0.000 claims description 3
- NIZQRVXFJWKOGJ-UHFFFAOYSA-N ethyl 4-[[5-(5-chloro-2-fluorophenyl)-1,2-oxazol-3-yl]methyl]piperazine-1-carboxylate Chemical compound C1CN(C(=O)OCC)CCN1CC1=NOC(C=2C(=CC=C(Cl)C=2)F)=C1 NIZQRVXFJWKOGJ-UHFFFAOYSA-N 0.000 claims description 3
- ORTUJEIVHBSTKT-UHFFFAOYSA-N ethyl 4-[cyclopropyl-[5-(2-fluoro-5-methylphenyl)-1,2-oxazol-3-yl]methyl]piperazine-1-carboxylate Chemical compound C1CN(C(=O)OCC)CCN1C(C1=NOC(=C1)C=1C(=CC=C(C)C=1)F)C1CC1 ORTUJEIVHBSTKT-UHFFFAOYSA-N 0.000 claims description 3
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 3
- 229920001467 poly(styrenesulfonates) Polymers 0.000 claims description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- RULBZEBXILBXCM-UHFFFAOYSA-N ethyl 4-[1-[5-(2-methylpyridin-4-yl)-1,2-oxazol-3-yl]ethyl]piperazine-1-carboxylate Chemical compound C1CN(C(=O)OCC)CCN1C(C)C1=NOC(C=2C=C(C)N=CC=2)=C1 RULBZEBXILBXCM-UHFFFAOYSA-N 0.000 claims description 2
- MSZXEGISWRVEJL-UHFFFAOYSA-N ethyl 4-[[5-(3-chlorophenyl)-1,2-oxazol-3-yl]methyl]piperazine-1-carboxylate Chemical compound C1CN(C(=O)OCC)CCN1CC1=NOC(C=2C=C(Cl)C=CC=2)=C1 MSZXEGISWRVEJL-UHFFFAOYSA-N 0.000 claims description 2
- WCOPPSVBQXBIFX-UHFFFAOYSA-N ethyl 4-[[5-(3-chlorophenyl)-1,3-oxazol-2-yl]methyl]piperazine-1-carboxylate Chemical compound C1CN(C(=O)OCC)CCN1CC1=NC=C(C=2C=C(Cl)C=CC=2)O1 WCOPPSVBQXBIFX-UHFFFAOYSA-N 0.000 claims description 2
- MKHBQSTYABOSJJ-UHFFFAOYSA-N ethyl 4-[[5-(3-cyanophenyl)-1,2-oxazol-3-yl]methyl]piperazine-1-carboxylate Chemical compound C1CN(C(=O)OCC)CCN1CC1=NOC(C=2C=C(C=CC=2)C#N)=C1 MKHBQSTYABOSJJ-UHFFFAOYSA-N 0.000 claims description 2
- YJRQONRACZKXAR-UHFFFAOYSA-N ethyl 4-[[5-(3-formylphenyl)-1,2-oxazol-3-yl]methyl]piperazine-1-carboxylate Chemical compound C1CN(C(=O)OCC)CCN1CC1=NOC(C=2C=C(C=O)C=CC=2)=C1 YJRQONRACZKXAR-UHFFFAOYSA-N 0.000 claims description 2
- FBCKIMBFWRQSPQ-UHFFFAOYSA-N ethyl 4-[[5-(3-methylphenyl)-1,2,4-oxadiazol-3-yl]methyl]piperazine-1-carboxylate;hydrochloride Chemical compound Cl.C1CN(C(=O)OCC)CCN1CC1=NOC(C=2C=C(C)C=CC=2)=N1 FBCKIMBFWRQSPQ-UHFFFAOYSA-N 0.000 claims description 2
- YLURYVCWGQYISZ-UHFFFAOYSA-N ethyl 4-[[5-(3-methylphenyl)-1,2-oxazol-3-yl]methyl]piperazine-1-carboxylate Chemical compound C1CN(C(=O)OCC)CCN1CC1=NOC(C=2C=C(C)C=CC=2)=C1 YLURYVCWGQYISZ-UHFFFAOYSA-N 0.000 claims description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 2
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 claims 2
- TUDMJGXXGOORCD-UHFFFAOYSA-N 3-(chloromethyl)-5-(3-chlorophenyl)-1,2,4-oxadiazole Chemical compound ClCC1=NOC(C=2C=C(Cl)C=CC=2)=N1 TUDMJGXXGOORCD-UHFFFAOYSA-N 0.000 claims 1
- YCOKTYBAJSXBTK-UHFFFAOYSA-N 3-(chloromethyl)-5-(3-fluorophenyl)-1,2,4-oxadiazole Chemical compound FC1=CC=CC(C=2ON=C(CCl)N=2)=C1 YCOKTYBAJSXBTK-UHFFFAOYSA-N 0.000 claims 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims 1
- AXZAYXJCENRGIM-UHFFFAOYSA-J dipotassium;tetrabromoplatinum(2-) Chemical compound [K+].[K+].[Br-].[Br-].[Br-].[Br-].[Pt+2] AXZAYXJCENRGIM-UHFFFAOYSA-J 0.000 claims 1
- HQSDTPLBOWESIR-AWEZNQCLSA-N ethyl (3s)-3-methyl-4-[[5-(3-methylphenyl)-1,2,4-oxadiazol-3-yl]methyl]piperazine-1-carboxylate Chemical compound C[C@H]1CN(C(=O)OCC)CCN1CC1=NOC(C=2C=C(C)C=CC=2)=N1 HQSDTPLBOWESIR-AWEZNQCLSA-N 0.000 claims 1
- CJJMZZQGSJKNJH-AWEZNQCLSA-N ethyl 4-[(1s)-1-[5-(3-methylphenyl)-1,2,4-oxadiazol-3-yl]ethyl]piperazine-1-carboxylate Chemical compound C1CN(C(=O)OCC)CCN1[C@@H](C)C1=NOC(C=2C=C(C)C=CC=2)=N1 CJJMZZQGSJKNJH-AWEZNQCLSA-N 0.000 claims 1
- XGOMKSDLZRCUOT-UHFFFAOYSA-N ethyl 4-[1-[5-(5-chloro-2-fluorophenyl)-1,2-oxazol-3-yl]ethyl]piperazine-1-carboxylate Chemical compound C1CN(C(=O)OCC)CCN1C(C)C1=NOC(C=2C(=CC=C(Cl)C=2)F)=C1 XGOMKSDLZRCUOT-UHFFFAOYSA-N 0.000 claims 1
- WYSWFJQHNVTKIX-UHFFFAOYSA-N ethyl 4-[[5-(2-fluoro-5-methylphenyl)-1,2-oxazol-3-yl]methyl]piperazine-1-carboxylate Chemical compound C1CN(C(=O)OCC)CCN1CC1=NOC(C=2C(=CC=C(C)C=2)F)=C1 WYSWFJQHNVTKIX-UHFFFAOYSA-N 0.000 claims 1
- LPBRVWWVSJKREL-UHFFFAOYSA-N ethyl 4-[[5-(3-bromophenyl)-1,2,4-oxadiazol-3-yl]methyl]piperazine-1-carboxylate Chemical compound C1CN(C(=O)OCC)CCN1CC1=NOC(C=2C=C(Br)C=CC=2)=N1 LPBRVWWVSJKREL-UHFFFAOYSA-N 0.000 claims 1
- YLMZLRDYBCNQOB-UHFFFAOYSA-N ethyl 4-[[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]methyl]-2-oxopiperazine-1-carboxylate Chemical compound C1C(=O)N(C(=O)OCC)CCN1CC1=NOC(C=2C=C(Cl)C=CC=2)=N1 YLMZLRDYBCNQOB-UHFFFAOYSA-N 0.000 claims 1
- MKVHQMLKKPKZSY-UHFFFAOYSA-N ethyl 4-[[5-(3-iodophenyl)-1,2,4-oxadiazol-3-yl]methyl]piperazine-1-carboxylate Chemical compound C1CN(C(=O)OCC)CCN1CC1=NOC(C=2C=C(I)C=CC=2)=N1 MKVHQMLKKPKZSY-UHFFFAOYSA-N 0.000 claims 1
- HVHGZCLMBPGBGL-UHFFFAOYSA-N ethyl 4-[[5-(3-methoxyphenyl)-1,2-oxazol-3-yl]methyl]piperazine-1-carboxylate Chemical compound C1CN(C(=O)OCC)CCN1CC1=NOC(C=2C=C(OC)C=CC=2)=C1 HVHGZCLMBPGBGL-UHFFFAOYSA-N 0.000 claims 1
- BMKSRUNYNPPNOD-UHFFFAOYSA-N ethyl 4-[[5-(5-chloro-2-hydroxyphenyl)-1,2,4-oxadiazol-3-yl]methyl]piperazine-1-carboxylate Chemical compound C1CN(C(=O)OCC)CCN1CC1=NOC(C=2C(=CC=C(Cl)C=2)O)=N1 BMKSRUNYNPPNOD-UHFFFAOYSA-N 0.000 claims 1
- AJRYAYKEPOOUBW-UHFFFAOYSA-N ethyl 4-[[5-(5-cyano-2-fluorophenyl)-1,2-oxazol-3-yl]methyl]piperazine-1-carboxylate Chemical compound C1CN(C(=O)OCC)CCN1CC1=NOC(C=2C(=CC=C(C=2)C#N)F)=C1 AJRYAYKEPOOUBW-UHFFFAOYSA-N 0.000 claims 1
- 235000019253 formic acid Nutrition 0.000 claims 1
- 229940067626 phosphatidylinositols Drugs 0.000 claims 1
- 229910001487 potassium perchlorate Inorganic materials 0.000 claims 1
- VSTPUIRIGPKLPB-UHFFFAOYSA-N propan-2-yl 4-[[5-(3-methylphenyl)-1,2,4-oxadiazol-3-yl]methyl]piperazine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)C)CCN1CC1=NOC(C=2C=C(C)C=CC=2)=N1 VSTPUIRIGPKLPB-UHFFFAOYSA-N 0.000 claims 1
- 238000000926 separation method Methods 0.000 claims 1
- 239000006228 supernatant Substances 0.000 claims 1
- 239000000543 intermediate Substances 0.000 abstract description 17
- 208000025966 Neurological disease Diseases 0.000 abstract description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 378
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 245
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 235
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 198
- 229940093499 ethyl acetate Drugs 0.000 description 126
- 235000019439 ethyl acetate Nutrition 0.000 description 126
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 114
- 238000005481 NMR spectroscopy Methods 0.000 description 102
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 102
- 239000011541 reaction mixture Substances 0.000 description 92
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- 239000007787 solid Substances 0.000 description 83
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- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 75
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- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 65
- 238000000746 purification Methods 0.000 description 63
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- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 61
- 101150041968 CDC13 gene Proteins 0.000 description 59
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- 239000000243 solution Substances 0.000 description 53
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- 238000003756 stirring Methods 0.000 description 52
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- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical group CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 48
- 235000011181 potassium carbonates Nutrition 0.000 description 48
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 42
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- 238000004587 chromatography analysis Methods 0.000 description 39
- 238000006243 chemical reaction Methods 0.000 description 37
- 238000005160 1H NMR spectroscopy Methods 0.000 description 36
- 102000016193 Metabotropic glutamate receptors Human genes 0.000 description 35
- 108010010914 Metabotropic glutamate receptors Proteins 0.000 description 35
- LNOQURRKNJKKBU-UHFFFAOYSA-N ethyl piperazine-1-carboxylate Chemical compound CCOC(=O)N1CCNCC1 LNOQURRKNJKKBU-UHFFFAOYSA-N 0.000 description 34
- 238000003818 flash chromatography Methods 0.000 description 34
- 229910052938 sodium sulfate Inorganic materials 0.000 description 33
- 235000011152 sodium sulphate Nutrition 0.000 description 33
- 239000002904 solvent Substances 0.000 description 32
- 229940086542 triethylamine Drugs 0.000 description 31
- 239000012074 organic phase Substances 0.000 description 30
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 27
- 229940098779 methanesulfonic acid Drugs 0.000 description 26
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 25
- 239000012230 colorless oil Substances 0.000 description 21
- 150000002431 hydrogen Chemical group 0.000 description 21
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 20
- 239000012044 organic layer Substances 0.000 description 20
- 102000005962 receptors Human genes 0.000 description 19
- 108020003175 receptors Proteins 0.000 description 19
- 238000007792 addition Methods 0.000 description 17
- 238000007363 ring formation reaction Methods 0.000 description 17
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 16
- 239000000047 product Substances 0.000 description 16
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 15
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 15
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 15
- 210000004027 cell Anatomy 0.000 description 15
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 15
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 14
- 230000015572 biosynthetic process Effects 0.000 description 14
- 230000000694 effects Effects 0.000 description 14
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 13
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 13
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2003
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- 2003-08-08 US US10/636,965 patent/US20040132726A1/en not_active Abandoned
- 2003-08-08 NZ NZ538339A patent/NZ538339A/en unknown
- 2003-08-08 BR BR0313266-8A patent/BR0313266A/pt not_active IP Right Cessation
- 2003-08-08 TW TW096135411A patent/TW200812986A/zh unknown
- 2003-08-08 MX MXPA05001592A patent/MXPA05001592A/es unknown
- 2003-08-08 JP JP2004527912A patent/JP2006506340A/ja active Pending
- 2003-08-08 EP EP03749015A patent/EP1536790A2/en not_active Withdrawn
- 2003-08-08 AU AU2003268064A patent/AU2003268064A1/en not_active Abandoned
- 2003-08-08 CN CNA038238594A patent/CN1691944A/zh active Pending
- 2003-08-08 WO PCT/US2003/024912 patent/WO2004014370A2/en not_active Ceased
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- 2005-03-09 NO NO20051223A patent/NO20051223L/no not_active Application Discontinuation
- 2005-11-10 US US11/270,617 patent/US20060063772A1/en not_active Abandoned
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| WO2004014370A2 (en) | 2004-02-19 |
| CN1691944A (zh) | 2005-11-02 |
| US20060063772A1 (en) | 2006-03-23 |
| TW200424183A (en) | 2004-11-16 |
| MXPA05001592A (es) | 2005-05-05 |
| AR041508A1 (es) | 2005-05-18 |
| US20040132726A1 (en) | 2004-07-08 |
| EP1536790A2 (en) | 2005-06-08 |
| KR20050039846A (ko) | 2005-04-29 |
| WO2004014370A3 (en) | 2004-10-21 |
| TW200812986A (en) | 2008-03-16 |
| NO20051223L (no) | 2005-05-03 |
| AU2003268064A1 (en) | 2004-02-25 |
| JP2006506340A (ja) | 2006-02-23 |
| CA2495120A1 (en) | 2004-02-19 |
| ZA200501101B (en) | 2006-02-22 |
| IL166650A0 (en) | 2006-01-15 |
| BR0313266A (pt) | 2005-06-21 |
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