JP2010501568A5 - - Google Patents
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- Publication number
- JP2010501568A5 JP2010501568A5 JP2009525618A JP2009525618A JP2010501568A5 JP 2010501568 A5 JP2010501568 A5 JP 2010501568A5 JP 2009525618 A JP2009525618 A JP 2009525618A JP 2009525618 A JP2009525618 A JP 2009525618A JP 2010501568 A5 JP2010501568 A5 JP 2010501568A5
- Authority
- JP
- Japan
- Prior art keywords
- alkyl
- cycloalkyl
- dihydro
- isoquinolin
- dimethylbutanamide
- 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.)
- Granted
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- 150000001875 compounds Chemical class 0.000 claims description 570
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 160
- 229910052736 halogen Inorganic materials 0.000 claims description 148
- 150000002367 halogens Chemical class 0.000 claims description 148
- -1 2- (N, N - dimethylamino) ethyl Chemical group 0.000 claims description 133
- 229910052739 hydrogen Inorganic materials 0.000 claims description 115
- 229910052731 fluorine Inorganic materials 0.000 claims description 103
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 99
- 229910052786 argon Inorganic materials 0.000 claims description 99
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 96
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 88
- 229910052801 chlorine Inorganic materials 0.000 claims description 86
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 83
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 79
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 70
- 239000000203 mixture Substances 0.000 claims description 69
- 125000000217 alkyl group Chemical group 0.000 claims description 64
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 60
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 41
- 125000004076 pyridyl group Chemical group 0.000 claims description 41
- 229910052760 oxygen Inorganic materials 0.000 claims description 40
- 229910052717 sulfur Inorganic materials 0.000 claims description 38
- 150000003839 salts Chemical class 0.000 claims description 33
- 229910052763 palladium Inorganic materials 0.000 claims description 30
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 29
- 229910052794 bromium Inorganic materials 0.000 claims description 29
- 125000005842 heteroatom Chemical group 0.000 claims description 29
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 27
- ZEMZPXWZVTUONV-UHFFFAOYSA-N 2-(2-dicyclohexylphosphanylphenyl)-n,n-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 ZEMZPXWZVTUONV-UHFFFAOYSA-N 0.000 claims description 26
- 125000003118 aryl group Chemical group 0.000 claims description 24
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 24
- 239000012453 solvate Substances 0.000 claims description 24
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 23
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 23
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 22
- 125000001072 heteroaryl group Chemical group 0.000 claims description 20
- 206010010904 Convulsion Diseases 0.000 claims description 19
- 238000006243 chemical reaction Methods 0.000 claims description 19
- 125000001424 substituent group Chemical group 0.000 claims description 19
- 125000001544 thienyl group Chemical group 0.000 claims description 19
- XEVJQEIJAXJBKV-UHFFFAOYSA-N n-(4-bromo-2,6-dimethylphenyl)-3,3-dimethylbutanamide Chemical compound CC1=CC(Br)=CC(C)=C1NC(=O)CC(C)(C)C XEVJQEIJAXJBKV-UHFFFAOYSA-N 0.000 claims description 18
- 206010015037 epilepsy Diseases 0.000 claims description 17
- 229910052757 nitrogen Inorganic materials 0.000 claims description 16
- 102000004257 Potassium Channel Human genes 0.000 claims description 15
- 108020001213 potassium channel Proteins 0.000 claims description 15
- 108091006146 Channels Proteins 0.000 claims description 14
- 125000003342 alkenyl group Chemical group 0.000 claims description 14
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 14
- 239000003937 drug carrier Substances 0.000 claims description 13
- BUNUTIAYMZWFOP-UHFFFAOYSA-N n-[2,6-dimethyl-4-[6-(trifluoromethyl)-3,4-dihydro-1h-isoquinolin-2-yl]phenyl]-3,3-dimethylbutanamide Chemical compound CC1=C(NC(=O)CC(C)(C)C)C(C)=CC(N2CC3=CC=C(C=C3CC2)C(F)(F)F)=C1 BUNUTIAYMZWFOP-UHFFFAOYSA-N 0.000 claims description 13
- 125000002971 oxazolyl group Chemical group 0.000 claims description 13
- 125000000335 thiazolyl group Chemical group 0.000 claims description 13
- 125000002541 furyl group Chemical group 0.000 claims description 12
- 108010006746 KCNQ2 Potassium Channel Proteins 0.000 claims description 11
- 102100034354 Potassium voltage-gated channel subfamily KQT member 2 Human genes 0.000 claims description 11
- 125000000304 alkynyl group Chemical group 0.000 claims description 11
- 125000004432 carbon atom Chemical group C* 0.000 claims description 11
- 201000010099 disease Diseases 0.000 claims description 11
- 208000035475 disorder Diseases 0.000 claims description 11
- WSVPGQIOIVUVDN-UHFFFAOYSA-N n-[2-chloro-4-(3,4-dihydro-1h-isoquinolin-2-yl)-6-(trifluoromethyl)phenyl]-3-cyclopentylpropanamide Chemical compound FC(F)(F)C1=CC(N2CC3=CC=CC=C3CC2)=CC(Cl)=C1NC(=O)CCC1CCCC1 WSVPGQIOIVUVDN-UHFFFAOYSA-N 0.000 claims description 11
- IMRNLRWJFWXHIF-UHFFFAOYSA-N n-[2-chloro-4-(7-fluoro-3,4-dihydro-1h-isoquinolin-2-yl)-6-(trifluoromethyl)phenyl]-3,3-dimethylbutanamide Chemical compound C1=C(C(F)(F)F)C(NC(=O)CC(C)(C)C)=C(Cl)C=C1N1CC2=CC(F)=CC=C2CC1 IMRNLRWJFWXHIF-UHFFFAOYSA-N 0.000 claims description 11
- RMPCHGWCNFMAHK-UHFFFAOYSA-N n-[2-chloro-6-(trifluoromethyl)-4-[6-(trifluoromethyl)-3,4-dihydro-1h-isoquinolin-2-yl]phenyl]-3,3-dimethylbutanamide Chemical compound C1=C(C(F)(F)F)C(NC(=O)CC(C)(C)C)=C(Cl)C=C1N1CC2=CC=C(C(F)(F)F)C=C2CC1 RMPCHGWCNFMAHK-UHFFFAOYSA-N 0.000 claims description 11
- 238000011282 treatment Methods 0.000 claims description 11
- 150000002148 esters Chemical class 0.000 claims description 10
- BZACFVHATUEBMX-UHFFFAOYSA-N n-[2-chloro-4-(7-fluoro-3,4-dihydro-1h-isoquinolin-2-yl)-6-methylphenyl]-3,3-dimethylbutanamide Chemical compound ClC1=C(NC(=O)CC(C)(C)C)C(C)=CC(N2CC3=CC(F)=CC=C3CC2)=C1 BZACFVHATUEBMX-UHFFFAOYSA-N 0.000 claims description 10
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 10
- 150000003526 tetrahydroisoquinolines Chemical class 0.000 claims description 10
- 239000003085 diluting agent Substances 0.000 claims description 9
- 125000004366 heterocycloalkenyl group Chemical group 0.000 claims description 9
- 125000001786 isothiazolyl group Chemical group 0.000 claims description 9
- AKMBUNDQKZOKEY-UHFFFAOYSA-N n-[2-chloro-4-(6-fluoro-3,4-dihydro-1h-isoquinolin-2-yl)-6-(trifluoromethyl)phenyl]-3-cyclopentylpropanamide Chemical compound C1CC2=CC(F)=CC=C2CN1C(C=C1C(F)(F)F)=CC(Cl)=C1NC(=O)CCC1CCCC1 AKMBUNDQKZOKEY-UHFFFAOYSA-N 0.000 claims description 8
- KEBOLMNDHWAEOH-UHFFFAOYSA-N n-[2-chloro-6-methyl-4-[6-(trifluoromethyl)-3,4-dihydro-1h-isoquinolin-2-yl]phenyl]-3,3-dimethylbutanamide Chemical compound ClC1=C(NC(=O)CC(C)(C)C)C(C)=CC(N2CC3=CC=C(C=C3CC2)C(F)(F)F)=C1 KEBOLMNDHWAEOH-UHFFFAOYSA-N 0.000 claims description 8
- WQHUPXCTCRICTJ-UHFFFAOYSA-N N-[2-chloro-4-(3,4-dihydro-1H-isoquinolin-2-yl)-6-(trifluoromethoxy)phenyl]-3,3-dimethylbutanamide N-[4-(3,4-dihydro-1H-isoquinolin-2-yl)-2-methoxy-6-methylphenyl]-3,3-dimethylbutanamide Chemical compound COc1cc(cc(C)c1NC(=O)CC(C)(C)C)N1CCc2ccccc2C1.CC(C)(C)CC(=O)Nc1c(Cl)cc(cc1OC(F)(F)F)N1CCc2ccccc2C1 WQHUPXCTCRICTJ-UHFFFAOYSA-N 0.000 claims description 7
- 125000002883 imidazolyl group Chemical group 0.000 claims description 7
- JURDKTFYHWIOLE-UHFFFAOYSA-N n-[2-chloro-4-(3,4-dihydro-1h-isoquinolin-2-yl)-6-(trifluoromethyl)phenyl]-3,3-dimethylbutanamide Chemical compound C1=C(C(F)(F)F)C(NC(=O)CC(C)(C)C)=C(Cl)C=C1N1CC2=CC=CC=C2CC1 JURDKTFYHWIOLE-UHFFFAOYSA-N 0.000 claims description 7
- QEQSCTBTOWAMGI-UHFFFAOYSA-N n-[2-chloro-4-(3,4-dihydro-1h-isoquinolin-2-yl)-6-methylphenyl]-3,3-dimethylbutanamide Chemical compound ClC1=C(NC(=O)CC(C)(C)C)C(C)=CC(N2CC3=CC=CC=C3CC2)=C1 QEQSCTBTOWAMGI-UHFFFAOYSA-N 0.000 claims description 7
- PXVUSPQWZDZSJK-UHFFFAOYSA-N n-[4-(3,4-dihydro-1h-isoquinolin-2-yl)-2,6-dimethoxyphenyl]-3,3-dimethylbutanamide Chemical compound COC1=C(NC(=O)CC(C)(C)C)C(OC)=CC(N2CC3=CC=CC=C3CC2)=C1 PXVUSPQWZDZSJK-UHFFFAOYSA-N 0.000 claims description 7
- AYTUSFFMOMITAH-UHFFFAOYSA-N n-[4-(7-fluoro-3,4-dihydro-1h-isoquinolin-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide Chemical compound CC1=C(NC(=O)CC(C)(C)C)C(C)=CC(N2CC3=CC(F)=CC=C3CC2)=C1 AYTUSFFMOMITAH-UHFFFAOYSA-N 0.000 claims description 7
- 239000002904 solvent Substances 0.000 claims description 7
- GGYQDYBBXDJOER-UHFFFAOYSA-N ClC1=C(C=CC(=C1)N1CC2=CC=C(C=C2CC1)F)NC(CC(C)(C)C)=O.ClC1=C(C(=CC(=C1)N1CC2=CC=C(C=C2CC1)Cl)C)NC(CC(C)(C)C)=O Chemical compound ClC1=C(C=CC(=C1)N1CC2=CC=C(C=C2CC1)F)NC(CC(C)(C)C)=O.ClC1=C(C(=CC(=C1)N1CC2=CC=C(C=C2CC1)Cl)C)NC(CC(C)(C)C)=O GGYQDYBBXDJOER-UHFFFAOYSA-N 0.000 claims description 6
- 241000124008 Mammalia Species 0.000 claims description 6
- RHIVKINPKAPVFG-UHFFFAOYSA-N n-[2-chloro-4-(6-chloro-3,4-dihydro-1h-isoquinolin-2-yl)-6-(trifluoromethyl)phenyl]-3,3-dimethylbutanamide Chemical compound C1=C(C(F)(F)F)C(NC(=O)CC(C)(C)C)=C(Cl)C=C1N1CC2=CC=C(Cl)C=C2CC1 RHIVKINPKAPVFG-UHFFFAOYSA-N 0.000 claims description 6
- 239000003826 tablet Substances 0.000 claims description 6
- 229910052799 carbon Inorganic materials 0.000 claims description 5
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 5
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 5
- 125000002950 monocyclic group Chemical group 0.000 claims description 5
- XUHYQDMOGPLCHO-UHFFFAOYSA-N n-[2-chloro-4-(6-fluoro-3,4-dihydro-1h-isoquinolin-2-yl)-6-methylphenyl]-3,3-dimethylbutanamide Chemical compound ClC1=C(NC(=O)CC(C)(C)C)C(C)=CC(N2CC3=CC=C(F)C=C3CC2)=C1 XUHYQDMOGPLCHO-UHFFFAOYSA-N 0.000 claims description 5
- JLKZQPXSHYGHBK-UHFFFAOYSA-N n-[2-chloro-4-[6-(trifluoromethyl)-3,4-dihydro-1h-isoquinolin-2-yl]phenyl]-3,3-dimethylbutanamide Chemical compound C1=C(Cl)C(NC(=O)CC(C)(C)C)=CC=C1N1CC2=CC=C(C(F)(F)F)C=C2CC1 JLKZQPXSHYGHBK-UHFFFAOYSA-N 0.000 claims description 5
- LWSAVPZPBLUVQM-UHFFFAOYSA-N n-[4-(6-fluoro-3,4-dihydro-1h-isoquinolin-2-yl)-2-methylphenyl]-3,3-dimethylbutanamide Chemical compound C1=C(NC(=O)CC(C)(C)C)C(C)=CC(N2CC3=CC=C(F)C=C3CC2)=C1 LWSAVPZPBLUVQM-UHFFFAOYSA-N 0.000 claims description 5
- MGZUTAIZUGWMSW-UHFFFAOYSA-N n-[4-(7-fluoro-3,4-dihydro-1h-isoquinolin-2-yl)-2-(trifluoromethyl)phenyl]-3,3-dimethylbutanamide Chemical compound C1=C(C(F)(F)F)C(NC(=O)CC(C)(C)C)=CC=C1N1CC2=CC(F)=CC=C2CC1 MGZUTAIZUGWMSW-UHFFFAOYSA-N 0.000 claims description 5
- 125000005412 pyrazyl group Chemical group 0.000 claims description 5
- 229920006395 saturated elastomer Polymers 0.000 claims description 5
- 239000006188 syrup Substances 0.000 claims description 5
- 235000020357 syrup Nutrition 0.000 claims description 5
- ZXBSPGYOICSREC-UHFFFAOYSA-N n-[2-chloro-4-(6-fluoro-3,4-dihydro-1h-isoquinolin-2-yl)phenyl]-3,3-dimethylbutanamide Chemical compound C1=C(Cl)C(NC(=O)CC(C)(C)C)=CC=C1N1CC2=CC=C(F)C=C2CC1 ZXBSPGYOICSREC-UHFFFAOYSA-N 0.000 claims description 4
- FJNPZKZPWVVSON-UHFFFAOYSA-N n-[4-(6-fluoro-3,4-dihydro-1h-isoquinolin-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide Chemical compound CC1=C(NC(=O)CC(C)(C)C)C(C)=CC(N2CC3=CC=C(F)C=C3CC2)=C1 FJNPZKZPWVVSON-UHFFFAOYSA-N 0.000 claims description 4
- 206010001497 Agitation Diseases 0.000 claims description 3
- 102000003734 Voltage-Gated Potassium Channels Human genes 0.000 claims description 3
- 108090000013 Voltage-Gated Potassium Channels Proteins 0.000 claims description 3
- 230000004913 activation Effects 0.000 claims description 3
- 239000002775 capsule Substances 0.000 claims description 3
- 239000007910 chewable tablet Substances 0.000 claims 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 claims description 3
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 3
- GVEWDAHCLFVWMC-UHFFFAOYSA-N n-[2-chloro-4-(6-chloro-3,4-dihydro-1h-isoquinolin-2-yl)-6-methylphenyl]-3,3-dimethylbutanamide Chemical compound ClC1=C(NC(=O)CC(C)(C)C)C(C)=CC(N2CC3=CC=C(Cl)C=C3CC2)=C1 GVEWDAHCLFVWMC-UHFFFAOYSA-N 0.000 claims description 3
- WPUMBENDZFWLRX-UHFFFAOYSA-N n-[4-(3,4-dihydro-1h-isoquinolin-2-yl)-2-methoxy-6-methylphenyl]-3,3-dimethylbutanamide Chemical compound CC1=C(NC(=O)CC(C)(C)C)C(OC)=CC(N2CC3=CC=CC=C3CC2)=C1 WPUMBENDZFWLRX-UHFFFAOYSA-N 0.000 claims description 3
- XTXQZLKZKXJJGF-UHFFFAOYSA-N n-[4-(6-chloro-3,4-dihydro-1h-isoquinolin-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide Chemical compound CC1=C(NC(=O)CC(C)(C)C)C(C)=CC(N2CC3=CC=C(Cl)C=C3CC2)=C1 XTXQZLKZKXJJGF-UHFFFAOYSA-N 0.000 claims description 3
- 230000001537 neural effect Effects 0.000 claims description 3
- 230000002265 prevention Effects 0.000 claims description 3
- HHDFWFLUSAHCBR-UHFFFAOYSA-N ClC1=C(C(=CC(=C1)N1CC2=CC=C(C=C2CC1)Cl)OC(F)(F)F)NC(CC(C)(C)C)=O Chemical compound ClC1=C(C(=CC(=C1)N1CC2=CC=C(C=C2CC1)Cl)OC(F)(F)F)NC(CC(C)(C)C)=O HHDFWFLUSAHCBR-UHFFFAOYSA-N 0.000 claims description 2
- 125000003368 amide group Chemical group 0.000 claims description 2
- 229940068682 chewable tablet Drugs 0.000 claims description 2
- 210000000653 nervous system Anatomy 0.000 claims description 2
- AITMPVIQUIXEST-FGUNTGOFSA-N (2s)-n-tert-butyl-1-[(2s,4s,5s)-2-hydroxy-4-[[(1s,2r)-2-hydroxy-2,3-dihydro-1h-inden-1-yl]carbamoyl]-5-phenylhexyl]-4-(pyridin-3-ylmethyl)piperazine-2-carboxamide Chemical compound C([C@@H](O)C[C@@H]([C@H](C)C=1C=CC=CC=1)C(=O)N[C@H]1C2=CC=CC=C2C[C@H]1O)N([C@@H](C1)C(=O)NC(C)(C)C)CCN1CC1=CC=CN=C1 AITMPVIQUIXEST-FGUNTGOFSA-N 0.000 claims 2
- DNSISZSEWVHGLH-UHFFFAOYSA-N butanamide Chemical compound CCCC(N)=O DNSISZSEWVHGLH-UHFFFAOYSA-N 0.000 claims 2
- RPDMTPXOTVBOHB-UHFFFAOYSA-N 1,5-diphenylpenta-1,4-diyn-3-one Chemical compound C=1C=CC=CC=1C#CC(=O)C#CC1=CC=CC=C1 RPDMTPXOTVBOHB-UHFFFAOYSA-N 0.000 claims 1
- JDEUUKYNTHHAQH-UHFFFAOYSA-N 2,2-dimethylbutanamide Chemical compound CCC(C)(C)C(N)=O JDEUUKYNTHHAQH-UHFFFAOYSA-N 0.000 claims 1
- KYRSPWMDUBRRAR-UHFFFAOYSA-N 3,3-dimethyl-2-[2-(trifluoromethyl)phenyl]butanamide Chemical compound FC(F)(F)C1=C(C=CC=C1)C(C(=O)N)C(C)(C)C KYRSPWMDUBRRAR-UHFFFAOYSA-N 0.000 claims 1
- 229940126062 Compound A Drugs 0.000 claims 1
- NYBZDKPEAWWBJW-UHFFFAOYSA-N FC=1C=C2CCN(CC2=CC1)C1=CC(=C(C=C1)NC(CC(C)(C)C)=O)C.ClC1=C(C=CC(=C1)N1CC2=CC=C(C=C2CC1)F)NC(CC(C)(C)C)=O Chemical compound FC=1C=C2CCN(CC2=CC1)C1=CC(=C(C=C1)NC(CC(C)(C)C)=O)C.ClC1=C(C=CC(=C1)N1CC2=CC=C(C=C2CC1)F)NC(CC(C)(C)C)=O NYBZDKPEAWWBJW-UHFFFAOYSA-N 0.000 claims 1
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 claims 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims 1
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- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 48
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- 238000004809 thin layer chromatography Methods 0.000 description 21
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- 229960003312 retigabine Drugs 0.000 description 17
- 238000012360 testing method Methods 0.000 description 17
- 241001465754 Metazoa Species 0.000 description 16
- 125000001188 haloalkyl group Chemical group 0.000 description 16
- GAOGWONUOUYZFD-UHFFFAOYSA-N 4-bromo-2-chloro-6-(trifluoromethyl)aniline Chemical compound NC1=C(Cl)C=C(Br)C=C1C(F)(F)F GAOGWONUOUYZFD-UHFFFAOYSA-N 0.000 description 14
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 14
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 14
- 235000019439 ethyl acetate Nutrition 0.000 description 14
- 238000010992 reflux Methods 0.000 description 13
- 241000700159 Rattus Species 0.000 description 12
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 12
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 11
- 230000000694 effects Effects 0.000 description 11
- 239000000725 suspension Substances 0.000 description 11
- UWYZHKAOTLEWKK-UHFFFAOYSA-N tetrahydro-isoquinoline Natural products C1=CC=C2CNCCC2=C1 UWYZHKAOTLEWKK-UHFFFAOYSA-N 0.000 description 11
- 241000699670 Mus sp. Species 0.000 description 10
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-
2007
- 2007-08-22 MX MX2009002002A patent/MX2009002002A/es active IP Right Grant
- 2007-08-22 EP EP07837199.4A patent/EP2061465B1/en active Active
- 2007-08-22 AU AU2007288253A patent/AU2007288253B2/en active Active
- 2007-08-22 CA CA2661462A patent/CA2661462C/en active Active
- 2007-08-22 NZ NZ575652A patent/NZ575652A/en unknown
- 2007-08-22 ES ES07837199T patent/ES2420960T3/es active Active
- 2007-08-22 DK DK07837199.4T patent/DK2061465T3/da active
- 2007-08-22 PT PT78371994T patent/PT2061465E/pt unknown
- 2007-08-22 CN CNA2007800392650A patent/CN101563085A/zh active Pending
- 2007-08-22 WO PCT/US2007/018571 patent/WO2008024398A2/en not_active Ceased
- 2007-08-22 SG SG2011060944A patent/SG174095A1/en unknown
- 2007-08-22 US US11/894,877 patent/US8293911B2/en active Active
- 2007-08-22 KR KR1020097005943A patent/KR20090079191A/ko not_active Withdrawn
- 2007-08-22 RU RU2009110172/15A patent/RU2009110172A/ru not_active Application Discontinuation
- 2007-08-22 BR BRPI0716715-6A patent/BRPI0716715B1/pt active IP Right Grant
- 2007-08-22 PL PL07837199T patent/PL2061465T3/pl unknown
- 2007-08-22 JP JP2009525618A patent/JP5419691B2/ja active Active
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