JP2010537978A5

JP2010537978A5 -

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Publication number: JP2010537978A5
Authority: JP; Japan
Prior art keywords: compound; oct; alkyl; endo; ethyl
Prior art date: 2008-08-26
Legal status : Granted

Application number

JP2010522921A

Other languages

English (en)

Japanese (ja)

Other versions

JP2010537978A (ja

JP5296078B2 (ja

Filing date

2008-08-26

Publication date

2011-10-13

2008-08-26 Application filed filed Critical

2008-08-26 Priority claimed from PCT/US2008/010100 external-priority patent/WO2009029256A1/en

2010-12-09 Publication of JP2010537978A publication Critical patent/JP2010537978A/ja

2011-10-13 Publication of JP2010537978A5 publication Critical patent/JP2010537978A5/ja

2013-09-25 Application granted granted Critical

2013-09-25 Publication of JP5296078B2 publication Critical patent/JP5296078B2/ja

Status Expired - Fee Related legal-status Critical Current

2028-08-26 Anticipated expiration legal-status Critical

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150000001875 compounds Chemical class 0.000 claims description 225
-1 4,4-difluorocyclohexyl Chemical group 0.000 claims description 89
239000000203 mixture Substances 0.000 claims description 69
125000000217 alkyl group Chemical group 0.000 claims description 57
238000006243 chemical reaction Methods 0.000 claims description 49
238000000034 method Methods 0.000 claims description 47
239000001257 hydrogen Substances 0.000 claims description 40
229910052739 hydrogen Inorganic materials 0.000 claims description 40
239000008194 pharmaceutical composition Substances 0.000 claims description 36
230000000694 effects Effects 0.000 claims description 34
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 29
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 29
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 28
150000003839 salts Chemical class 0.000 claims description 27
229960000581 salicylamide Drugs 0.000 claims description 26
125000006652 (C3-C12) cycloalkyl group Chemical group 0.000 claims description 18
125000005843 halogen group Chemical group 0.000 claims description 18
125000001424 substituent group Chemical group 0.000 claims description 18
238000011282 treatment Methods 0.000 claims description 18
241000124008 Mammalia Species 0.000 claims description 17
208000030053 Opioid-Induced Constipation Diseases 0.000 claims description 17
206010054048 Postoperative ileus Diseases 0.000 claims description 17
125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 15
125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 14
201000010099 disease Diseases 0.000 claims description 14
239000003937 drug carrier Substances 0.000 claims description 14
150000002431 hydrogen Chemical class 0.000 claims description 11
125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 8
125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 8
238000004519 manufacturing process Methods 0.000 claims description 7
239000002623 mu opiate receptor antagonist Substances 0.000 claims description 7
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 6
125000001153 fluoro group Chemical group F* 0.000 claims description 5
230000001668 ameliorated effect Effects 0.000 claims description 4
150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 4
125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 claims description 4
229940124636 opioid drug Drugs 0.000 claims description 2
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 101
239000011541 reaction mixture Substances 0.000 description 73
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 55
239000000543 intermediate Substances 0.000 description 49
JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 46
239000000243 solution Substances 0.000 description 45
102000051367 mu Opioid Receptors Human genes 0.000 description 38
108020001612 μ-opioid receptors Proteins 0.000 description 38
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 33
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 32
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 31
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 30
239000000047 product Substances 0.000 description 27
229910052757 nitrogen Inorganic materials 0.000 description 26
239000012044 organic layer Substances 0.000 description 26
238000002360 preparation method Methods 0.000 description 26
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 25
238000012360 testing method Methods 0.000 description 24
IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 23
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 23
DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 23
238000003556 assay Methods 0.000 description 22
KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 21
239000003814 drug Substances 0.000 description 21
235000019439 ethyl acetate Nutrition 0.000 description 20
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 20
238000002953 preparative HPLC Methods 0.000 description 20
239000003921 oil Substances 0.000 description 19
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
235000019198 oils Nutrition 0.000 description 18
229940124597 therapeutic agent Drugs 0.000 description 18
PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 16
238000009472 formulation Methods 0.000 description 16
208000035475 disorder Diseases 0.000 description 15
239000012528 membrane Substances 0.000 description 15
125000006239 protecting group Chemical group 0.000 description 15
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 14
239000002904 solvent Substances 0.000 description 14
239000003826 tablet Substances 0.000 description 14
239000013543 active substance Substances 0.000 description 13
238000000746 purification Methods 0.000 description 13
DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 12
239000002253 acid Substances 0.000 description 12
230000002496 gastric effect Effects 0.000 description 12
229910052763 palladium Inorganic materials 0.000 description 12
235000019441 ethanol Nutrition 0.000 description 11
210000001035 gastrointestinal tract Anatomy 0.000 description 11
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 10
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 10
HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 10
230000001404 mediated effect Effects 0.000 description 10
239000000843 powder Substances 0.000 description 10
239000002775 capsule Substances 0.000 description 9
239000003054 catalyst Substances 0.000 description 9
210000004027 cell Anatomy 0.000 description 9
150000002825 nitriles Chemical class 0.000 description 9
239000000546 pharmaceutical excipient Substances 0.000 description 9
PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 8
238000005481 NMR spectroscopy Methods 0.000 description 8
CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 8
239000012131 assay buffer Substances 0.000 description 8
239000002585 base Substances 0.000 description 8
230000027455 binding Effects 0.000 description 8
239000012267 brine Substances 0.000 description 8
239000002552 dosage form Substances 0.000 description 8
238000003818 flash chromatography Methods 0.000 description 8
238000010992 reflux Methods 0.000 description 8
HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 8
239000000725 suspension Substances 0.000 description 8
XOFLBQFBSOEHOG-UUOKFMHZSA-N γS-GTP Chemical compound C1=2NC(N)=NC(=O)C=2N=CN1[C@@H]1O[C@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=S)[C@@H](O)[C@H]1O XOFLBQFBSOEHOG-UUOKFMHZSA-N 0.000 description 8
XSUXDJHVNPNNFJ-UHFFFAOYSA-N OBOC=C Chemical compound OBOC=C XSUXDJHVNPNNFJ-UHFFFAOYSA-N 0.000 description 7
229940123257 Opioid receptor antagonist Drugs 0.000 description 7
FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 7
229920002472 Starch Polymers 0.000 description 7
239000003795 chemical substances by application Substances 0.000 description 7
239000012043 crude product Substances 0.000 description 7
239000012299 nitrogen atmosphere Substances 0.000 description 7
230000008569 process Effects 0.000 description 7
238000003653 radioligand binding assay Methods 0.000 description 7
235000019698 starch Nutrition 0.000 description 7
AKEJUJNQAAGONA-UHFFFAOYSA-N sulfur trioxide Chemical compound O=S(=O)=O AKEJUJNQAAGONA-UHFFFAOYSA-N 0.000 description 7
125000005500 uronium group Chemical group 0.000 description 7
IDVZODUHKOGHMQ-UHFFFAOYSA-N 3-[8-[2-(2-ethylbutylamino)ethyl]-8-azabicyclo[3.2.1]octan-3-yl]-2-hydroxybenzamide Chemical compound CCC(CC)CNCCN1C(C2)CCC1CC2C1=CC=CC(C(N)=O)=C1O IDVZODUHKOGHMQ-UHFFFAOYSA-N 0.000 description 6
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 6
KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 6
GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 6
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
239000004480 active ingredient Substances 0.000 description 6
239000012298 atmosphere Substances 0.000 description 6
239000006229 carbon black Substances 0.000 description 6
239000003153 chemical reaction reagent Substances 0.000 description 6
KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
239000007903 gelatin capsule Substances 0.000 description 6
239000003701 inert diluent Substances 0.000 description 6
239000008101 lactose Substances 0.000 description 6
239000003446 ligand Substances 0.000 description 6
NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 description 6
230000002093 peripheral effect Effects 0.000 description 6
235000018102 proteins Nutrition 0.000 description 6
102000004169 proteins and genes Human genes 0.000 description 6
108090000623 proteins and genes Proteins 0.000 description 6
239000007787 solid Substances 0.000 description 6
239000008107 starch Substances 0.000 description 6
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0 *N(**C(C=O)=N)c1ccccc1 Chemical compound *N(**C(C=O)=N)c1ccccc1 0.000 description 5
KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 5
AMKVZJOQZLIOSL-UHFFFAOYSA-N 3-bromo-2-fluorobenzonitrile Chemical compound FC1=C(Br)C=CC=C1C#N AMKVZJOQZLIOSL-UHFFFAOYSA-N 0.000 description 5
108010010803 Gelatin Proteins 0.000 description 5
229920000168 Microcrystalline cellulose Polymers 0.000 description 5
102000003840 Opioid Receptors Human genes 0.000 description 5
108090000137 Opioid Receptors Proteins 0.000 description 5
OIJXLIIMXHRJJH-ZXJLXYCOSA-N [3h]diprenorphine Chemical compound N1([C@@H]2CC=3C4=C(C(=CC=3)O)O[C@@H]3[C@]4([C@]22C[C@@H]([C@]3(OC)CC2)C(C)(C)O)C([3H])C1[3H])CC1CC1 OIJXLIIMXHRJJH-ZXJLXYCOSA-N 0.000 description 5
230000004913 activation Effects 0.000 description 5
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125000001309 chloro group Chemical group Cl* 0.000 description 5
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 5
238000001914 filtration Methods 0.000 description 5
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235000019322 gelatine Nutrition 0.000 description 5
235000011852 gelatine desserts Nutrition 0.000 description 5
RDOIQAHITMMDAJ-UHFFFAOYSA-N loperamide Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(C(=O)N(C)C)CCN(CC1)CCC1(O)C1=CC=C(Cl)C=C1 RDOIQAHITMMDAJ-UHFFFAOYSA-N 0.000 description 5
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235000019359 magnesium stearate Nutrition 0.000 description 5
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239000008108 microcrystalline cellulose Substances 0.000 description 5
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239000012321 sodium triacetoxyborohydride Substances 0.000 description 5
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HZDNNJABYXNPPV-UHFFFAOYSA-N (2-chloro-2-oxoethyl) acetate Chemical group CC(=O)OCC(Cl)=O HZDNNJABYXNPPV-UHFFFAOYSA-N 0.000 description 4
HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 4
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 description 4
XLDKRPQWOSNXHC-UHFFFAOYSA-N 3-bromo-2-phenylmethoxybenzonitrile Chemical compound BrC1=CC=CC(C#N)=C1OCC1=CC=CC=C1 XLDKRPQWOSNXHC-UHFFFAOYSA-N 0.000 description 4
DGGKXQQCVPAUEA-UHFFFAOYSA-N 8-azabicyclo[3.2.1]octane Chemical class C1CCC2CCC1N2 DGGKXQQCVPAUEA-UHFFFAOYSA-N 0.000 description 4
108091003079 Bovine Serum Albumin Proteins 0.000 description 4
CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 4
241000700199 Cavia porcellus Species 0.000 description 4
206010010774 Constipation Diseases 0.000 description 4
241001465754 Metazoa Species 0.000 description 4
NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
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QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
230000036592 analgesia Effects 0.000 description 4
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IPWKHHSGDUIRAH-UHFFFAOYSA-N bis(pinacolato)diboron Chemical compound O1C(C)(C)C(C)(C)OB1B1OC(C)(C)C(C)(C)O1 IPWKHHSGDUIRAH-UHFFFAOYSA-N 0.000 description 4
229940098773 bovine serum albumin Drugs 0.000 description 4
NXQGGXCHGDYOHB-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloropalladium;iron(2+) Chemical compound [Fe+2].Cl[Pd]Cl.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 NXQGGXCHGDYOHB-UHFFFAOYSA-L 0.000 description 4
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238000001727 in vivo Methods 0.000 description 4
102000048260 kappa Opioid Receptors Human genes 0.000 description 4
IUYHWZFSGMZEOG-UHFFFAOYSA-M magnesium;propane;chloride Chemical compound [Mg+2].[Cl-].C[CH-]C IUYHWZFSGMZEOG-UHFFFAOYSA-M 0.000 description 4
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 description 4
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DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 4
JNHGCLCLMOCPCQ-UHFFFAOYSA-N tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-8-azabicyclo[3.2.1]oct-3-ene-8-carboxylate Chemical compound CC(C)(C)OC(=O)N1C(C2)CCC1C=C2B1OC(C)(C)C(C)(C)O1 JNHGCLCLMOCPCQ-UHFFFAOYSA-N 0.000 description 4
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HKBYVUAUFGBOAB-UHFFFAOYSA-N 3-bromo-2-phenylmethoxybenzamide Chemical compound NC(=O)C1=CC=CC(Br)=C1OCC1=CC=CC=C1 HKBYVUAUFGBOAB-UHFFFAOYSA-N 0.000 description 3
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FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 3
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HXBGEZFCNLSHPI-UHFFFAOYSA-N tert-butyl n-[(4,4-difluorocyclohexyl)methyl]-n-(2-oxoethyl)carbamate Chemical compound CC(C)(C)OC(=O)N(CC=O)CC1CCC(F)(F)CC1 HXBGEZFCNLSHPI-UHFFFAOYSA-N 0.000 description 1
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238000010998 test method Methods 0.000 description 1
AOBORMOPSGHCAX-DGHZZKTQSA-N tocofersolan Chemical compound OCCOC(=O)CCC(=O)OC1=C(C)C(C)=C2O[C@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C AOBORMOPSGHCAX-DGHZZKTQSA-N 0.000 description 1
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LLPOLZWFYMWNKH-UHFFFAOYSA-N trans-dihydrocodeinone Natural products C1C(N(CCC234)C)C2CCC(=O)C3OC2=C4C1=CC=C2OC LLPOLZWFYMWNKH-UHFFFAOYSA-N 0.000 description 1
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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
CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 description 1
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ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
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AVCVDUDESCZFHJ-UHFFFAOYSA-N triphenylphosphane;hydrochloride Chemical compound [Cl-].C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1 AVCVDUDESCZFHJ-UHFFFAOYSA-N 0.000 description 1
235000011178 triphosphate Nutrition 0.000 description 1
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UNXRWKVEANCORM-UHFFFAOYSA-N triphosphoric acid Chemical compound OP(O)(=O)OP(O)(=O)OP(O)(O)=O UNXRWKVEANCORM-UHFFFAOYSA-N 0.000 description 1
125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
235000015112 vegetable and seed oil Nutrition 0.000 description 1
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239000002076 α-tocopherol Substances 0.000 description 1
235000004835 α-tocopherol Nutrition 0.000 description 1

JP2010522921A 2007-08-27 2008-08-26 μオピオイド受容体拮抗薬としての８−アザビシクロ［３．２．１］オクチル−２−ヒドロキシベンズアミド化合物 Expired - Fee Related JP5296078B2 (ja)