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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