JP2006525227A5 - - Google Patents
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- JP2006525227A5 JP2006525227A5 JP2005510835A JP2005510835A JP2006525227A5 JP 2006525227 A5 JP2006525227 A5 JP 2006525227A5 JP 2005510835 A JP2005510835 A JP 2005510835A JP 2005510835 A JP2005510835 A JP 2005510835A JP 2006525227 A5 JP2006525227 A5 JP 2006525227A5
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- Prior art keywords
- compound
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- warm
- blooded animal
- Prior art date
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- 150000001875 compounds Chemical class 0.000 claims description 1218
- 238000000034 method Methods 0.000 claims description 596
- 239000000203 mixture Substances 0.000 claims description 437
- 150000003839 salts Chemical class 0.000 claims description 358
- 238000006243 chemical reaction Methods 0.000 claims description 356
- 239000012453 solvate Substances 0.000 claims description 270
- 230000008569 process Effects 0.000 claims description 206
- 241001465754 Metazoa Species 0.000 claims description 144
- 239000003814 drug Substances 0.000 claims description 144
- -1 tosyl halide Chemical class 0.000 claims description 136
- 239000001257 hydrogen Substances 0.000 claims description 133
- 229910052739 hydrogen Inorganic materials 0.000 claims description 133
- 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 111
- 239000002207 metabolite Substances 0.000 claims description 77
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 75
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 72
- 150000002148 esters Chemical class 0.000 claims description 72
- 150000001408 amides Chemical class 0.000 claims description 71
- 239000002243 precursor Substances 0.000 claims description 70
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- UPQQXPKAYZYUKO-UHFFFAOYSA-N 2,2,2-trichloroacetamide Chemical group OC(=N)C(Cl)(Cl)Cl UPQQXPKAYZYUKO-UHFFFAOYSA-N 0.000 claims description 66
- 150000002431 hydrogen Chemical class 0.000 claims description 65
- 125000006239 protecting group Chemical group 0.000 claims description 54
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical group CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 claims description 48
- 108090000862 Ion Channels Proteins 0.000 claims description 46
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- 125000005490 tosylate group Chemical group 0.000 claims description 31
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- MHWUUEBDNXLKJI-UHFFFAOYSA-N 1-(1-aminocyclohexyl)oxycyclohexan-1-amine Chemical compound C1CCCCC1(N)OC1(N)CCCCC1 MHWUUEBDNXLKJI-UHFFFAOYSA-N 0.000 claims description 27
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 25
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical group CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 24
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- 125000000524 functional group Chemical group 0.000 claims description 24
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- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound 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 21
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- 125000005492 nosylate group Chemical group 0.000 claims description 19
- JUSXLWAFYVKNLT-UHFFFAOYSA-N 2-bromobenzenesulfonic acid Chemical group OS(=O)(=O)C1=CC=CC=C1Br JUSXLWAFYVKNLT-UHFFFAOYSA-N 0.000 claims description 18
- PXACTUVBBMDKRW-UHFFFAOYSA-N 4-bromobenzenesulfonic acid Chemical group OS(=O)(=O)C1=CC=C(Br)C=C1 PXACTUVBBMDKRW-UHFFFAOYSA-N 0.000 claims description 18
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- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 4
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- 230000028161 membrane depolarization Effects 0.000 claims description 2
- 230000003213 activating effect Effects 0.000 claims 28
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- 150000004820 halides Chemical group 0.000 claims 11
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 8
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 claims 7
- 125000000037 tert-butyldiphenylsilyl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1[Si]([H])([*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims 7
- 230000007062 hydrolysis Effects 0.000 claims 6
- 238000006460 hydrolysis reaction Methods 0.000 claims 6
- 230000000717 retained effect Effects 0.000 claims 6
- 230000002861 ventricular Effects 0.000 claims 6
- 230000003301 hydrolyzing effect Effects 0.000 claims 3
- MEKOFIRRDATTAG-UHFFFAOYSA-N 2,2,5,8-tetramethyl-3,4-dihydrochromen-6-ol Chemical compound C1CC(C)(C)OC2=C1C(C)=C(O)C=C2C MEKOFIRRDATTAG-UHFFFAOYSA-N 0.000 claims 2
- FGUUSXIOTUKUDN-IBGZPJMESA-N C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 Chemical compound C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 FGUUSXIOTUKUDN-IBGZPJMESA-N 0.000 claims 2
- 238000002425 crystallisation Methods 0.000 claims 2
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- 125000004356 hydroxy functional group Chemical group O* 0.000 description 66
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 57
- JHHZLHWJQPUNKB-SCSAIBSYSA-N (3r)-pyrrolidin-3-ol Chemical compound O[C@@H]1CCNC1 JHHZLHWJQPUNKB-SCSAIBSYSA-N 0.000 description 50
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 45
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- 230000000269 nucleophilic effect Effects 0.000 description 38
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 35
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- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 24
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| JP5004067B2 (ja) * | 2005-10-31 | 2012-08-22 | 東レ・ファインケミカル株式会社 | ベンジルオキシ含窒素環状化合物の製造法 |
| WO2007052578A1 (ja) | 2005-10-31 | 2007-05-10 | Toray Fine Chemicals Co., Ltd. | ベンジルオキシピロリジン誘導体の製造方法および光学活性ベンジルオキシピロリジン誘導体塩酸塩粉体の製造法 |
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