JP2500279C - - Google Patents

Info

Publication number: JP2500279C
Authority: JP; Japan
Prior art keywords: azabicyclo; diphenylmethyl; octane; cis; trans
Prior art date: 1999-07-05
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.): Expired - Lifetime

Application number

Other languages

English (en)

Japanese (ja)

Original Assignee

メルクシャープエンドドームリミテッド

Publication date

1999-07-05

Links

150000001875 compounds Chemical class 0.000 claims description 86
YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 70
239000000203 mixture Substances 0.000 claims description 50
125000005982 diphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 32
229910052799 carbon Inorganic materials 0.000 claims description 29
-1 3,5-dimethylbenzyloxy Chemical group 0.000 claims description 27
239000011780 sodium chloride Substances 0.000 claims description 26
150000003839 salts Chemical class 0.000 claims description 21
125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 21
229910052739 hydrogen Inorganic materials 0.000 claims description 17
238000006243 chemical reaction Methods 0.000 claims description 14
125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 12
125000000217 alkyl group Chemical group 0.000 claims description 9
125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 8
125000004122 cyclic group Chemical group 0.000 claims description 8
125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
238000004519 manufacturing process Methods 0.000 claims description 6
125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 claims description 5
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 5
125000001424 substituent group Chemical group 0.000 claims description 4
239000002462 tachykinin receptor antagonist Substances 0.000 claims description 3
TVMXDCGIABBOFY-UHFFFAOYSA-N Octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 claims description 2
125000001475 halogen functional group Chemical group 0.000 claims 2
VDWODSPSMJMZQI-UHFFFAOYSA-N 2-methyl-1-azabicyclo[2.2.2]octane Chemical compound C1CN2C(C)CC1CC2 VDWODSPSMJMZQI-UHFFFAOYSA-N 0.000 claims 1
239000000969 carrier Substances 0.000 claims 1
IMNFDUFMRHMDMM-UHFFFAOYSA-N n-heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims 1
RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 50
XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 48
OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 47
YXFVVABEGXRONW-UHFFFAOYSA-N toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 34
VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 33
239000000243 solution Substances 0.000 description 32
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 28
VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 26
MUBZPKHOEPUJKR-UHFFFAOYSA-N oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 24
238000004587 chromatography analysis Methods 0.000 description 21
HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
239000002904 solvent Substances 0.000 description 18
WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 17
239000007787 solid Substances 0.000 description 16
238000005160 1H NMR spectroscopy Methods 0.000 description 15
VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Substances CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 15
125000005843 halogen group Chemical group 0.000 description 14
239000000047 product Substances 0.000 description 14
125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 13
239000000377 silicon dioxide Substances 0.000 description 13
238000003756 stirring Methods 0.000 description 13
ADNPLDHMAVUMIW-CUZNLEPHSA-N (2S)-2-[[(2S)-1-[(2S)-6-amino-2-[[(2S)-1-[(2S)-2-amino-5-(diaminomethylideneamino)pentanoyl]pyrrolidine-2-carbonyl]amino]hexanoyl]pyrrolidine-2-carbonyl]amino]-N-[(2S)-5-amino-1-[[(2S)-1-[[(2S)-1-[[2-[[(2S)-1-[[(2S)-1-amino-4-methylsulfanyl-1-oxobutan-2-y Chemical compound C([C@@H](C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(N)=O)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H]1N(CCC1)C(=O)[C@@H](N)CCCN=C(N)N)C1=CC=CC=C1 ADNPLDHMAVUMIW-CUZNLEPHSA-N 0.000 description 12
102100002996 TAC1 Human genes 0.000 description 12
101700065588 TAC1 Proteins 0.000 description 12
XTHFKEDIFFGKHM-UHFFFAOYSA-N dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 12
239000003480 eluent Substances 0.000 description 12
239000012458 free base Substances 0.000 description 12
125000000473 carbonimidoyl group Chemical group [H]\N=C(/*)* 0.000 description 11
LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 11
125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 11
CSNNHWWHGAXBCP-UHFFFAOYSA-L mgso4 Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 10
UIIMBOGNXHQVGW-UHFFFAOYSA-M NaHCO3 Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 9
201000010099 disease Diseases 0.000 description 9
KFZMGEQAYNKOFK-UHFFFAOYSA-N iso-propanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 9
239000012299 nitrogen atmosphere Substances 0.000 description 9
238000010992 reflux Methods 0.000 description 9
PNEYBMLMFCGWSK-UHFFFAOYSA-N AI2O3 Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 8
230000035693 Fab Effects 0.000 description 8
102000003141 Tachykinins Human genes 0.000 description 8
108060008037 Tachykinins Proteins 0.000 description 8
239000012298 atmosphere Substances 0.000 description 8
239000002585 base Substances 0.000 description 8
IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
KWYUFKZDYYNOTN-UHFFFAOYSA-M potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 8
238000000746 purification Methods 0.000 description 8
239000011734 sodium Substances 0.000 description 8
206010003246 Arthritis Diseases 0.000 description 7
239000008079 hexane Substances 0.000 description 7
229910000041 hydrogen chloride Inorganic materials 0.000 description 7
239000003921 oil Substances 0.000 description 7
235000019198 oils Nutrition 0.000 description 7
235000006408 oxalic acid Nutrition 0.000 description 7
IAZDPXIOMUYVGZ-WFGJKAKNSA-N DMSO-d6 Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 6
208000002193 Pain Diseases 0.000 description 6
IUBQJLUDMLPAGT-UHFFFAOYSA-N Potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 description 6
239000002253 acid Substances 0.000 description 6
125000001309 chloro group Chemical group Cl* 0.000 description 6
HPQVWDOOUQVBTO-UHFFFAOYSA-N lithium aluminium hydride Substances [Li+].[Al-] HPQVWDOOUQVBTO-UHFFFAOYSA-N 0.000 description 6
OCZDCIYGECBNKL-UHFFFAOYSA-N lithium;alumanuide Chemical compound [Li+].[AlH4-] OCZDCIYGECBNKL-UHFFFAOYSA-N 0.000 description 6
239000012044 organic layer Substances 0.000 description 6
230000036407 pain Effects 0.000 description 6
239000002244 precipitate Substances 0.000 description 6
QXDHXCVJGBTQMK-UHFFFAOYSA-N 1-(bromomethyl)-3,5-dimethylbenzene Chemical compound CC1=CC(C)=CC(CBr)=C1 QXDHXCVJGBTQMK-UHFFFAOYSA-N 0.000 description 5
NMRPBPVERJPACX-UHFFFAOYSA-N 3-Octanol Chemical compound CCCCCC(O)CC NMRPBPVERJPACX-UHFFFAOYSA-N 0.000 description 5
150000001408 amides Chemical class 0.000 description 5
230000000694 effects Effects 0.000 description 5
239000000284 extract Substances 0.000 description 5
239000000706 filtrate Substances 0.000 description 5
239000001257 hydrogen Substances 0.000 description 5
239000010410 layer Substances 0.000 description 5
229910052943 magnesium sulfate Inorganic materials 0.000 description 5
235000019341 magnesium sulphate Nutrition 0.000 description 5
238000000034 method Methods 0.000 description 5
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 5
229910052757 nitrogen Inorganic materials 0.000 description 5
239000006187 pill Substances 0.000 description 5
238000001953 recrystallisation Methods 0.000 description 5
239000003826 tablet Substances 0.000 description 5
GKIOTMSOXQMART-UHFFFAOYSA-N 2-benzhydryl-1-azabicyclo[2.2.2]octan-3-ol Chemical compound OC1C(CC2)CCN2C1C(C=1C=CC=CC=1)C1=CC=CC=C1 GKIOTMSOXQMART-UHFFFAOYSA-N 0.000 description 4
206010001897 Alzheimer's disease Diseases 0.000 description 4
VZGDMQKNWNREIO-UHFFFAOYSA-N Carbon tetrachloride Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 4
RIOQSEWOXXDEQQ-UHFFFAOYSA-N Triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 4
CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
125000003545 alkoxy group Chemical group 0.000 description 4
230000003042 antagnostic Effects 0.000 description 4
239000005557 antagonist Substances 0.000 description 4
239000012267 brine Substances 0.000 description 4
239000003054 catalyst Substances 0.000 description 4
239000002552 dosage form Substances 0.000 description 4
239000003814 drug Substances 0.000 description 4
238000001704 evaporation Methods 0.000 description 4
230000002496 gastric Effects 0.000 description 4
238000004128 high performance liquid chromatography Methods 0.000 description 4
150000003840 hydrochlorides Chemical class 0.000 description 4
239000000543 intermediate Substances 0.000 description 4
150000002576 ketones Chemical class 0.000 description 4
230000003000 nontoxic Effects 0.000 description 4
231100000252 nontoxic Toxicity 0.000 description 4
201000008482 osteoarthritis Diseases 0.000 description 4
235000017557 sodium bicarbonate Nutrition 0.000 description 4
229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
239000000126 substance Substances 0.000 description 4
XEZNGIUYQVAUSS-UHFFFAOYSA-N 18-Crown-6 Chemical compound C1COCCOCCOCCOCCOCCO1 XEZNGIUYQVAUSS-UHFFFAOYSA-N 0.000 description 3
NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 3
AGEZXYOZHKGVCM-UHFFFAOYSA-N Benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 3
206010027599 Migraine Diseases 0.000 description 3
208000008085 Migraine Disorders Diseases 0.000 description 3
SBYHFKPVCBCYGV-UHFFFAOYSA-N Quinuclidine Chemical compound C1CC2CCN1CC2 SBYHFKPVCBCYGV-UHFFFAOYSA-N 0.000 description 3
239000004480 active ingredient Substances 0.000 description 3
238000007792 addition Methods 0.000 description 3
235000019270 ammonium chloride Nutrition 0.000 description 3
230000003197 catalytic Effects 0.000 description 3
235000008504 concentrate Nutrition 0.000 description 3
239000012141 concentrate Substances 0.000 description 3
238000004090 dissolution Methods 0.000 description 3
238000010828 elution Methods 0.000 description 3
150000002148 esters Chemical class 0.000 description 3
UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
239000007788 liquid Substances 0.000 description 3
QDHHCQZDFGDHMP-UHFFFAOYSA-N monochloramine Chemical compound ClN QDHHCQZDFGDHMP-UHFFFAOYSA-N 0.000 description 3
239000012452 mother liquor Substances 0.000 description 3
ZHVULPDNOFUIML-UHFFFAOYSA-N octane;hydrochloride Chemical compound Cl.CCCCCCCC ZHVULPDNOFUIML-UHFFFAOYSA-N 0.000 description 3
ZLMJMSJWJFRBEC-UHFFFAOYSA-N potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 3
WZZYMDMRFBBOOZ-NQCAZLHCSA-L potassium;(2S)-5-oxopyrrolidine-2-carboxylate;(2R)-5-oxopyrrolidine-2-carboxylate Chemical compound [K+].[O-]C(=O)[C@H]1CCC(=O)N1.[O-]C(=O)[C@@H]1CCC(=O)N1 WZZYMDMRFBBOOZ-NQCAZLHCSA-L 0.000 description 3
239000000651 prodrug Substances 0.000 description 3
229940002612 prodrugs Drugs 0.000 description 3
125000006239 protecting group Chemical group 0.000 description 3
239000011541 reaction mixture Substances 0.000 description 3
FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
BZKBCQXYZZXSCO-UHFFFAOYSA-N sodium hydride Chemical compound [H-].[Na+] BZKBCQXYZZXSCO-UHFFFAOYSA-N 0.000 description 3
239000007858 starting material Substances 0.000 description 3
239000012258 stirred mixture Substances 0.000 description 3
239000000725 suspension Substances 0.000 description 3
230000001702 transmitter Effects 0.000 description 3
VZCYOOQTPOCHFL-OWOJBTEDSA-N (E)-but-2-enedioate;hydron Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
HMDQPBSDHHTRNI-UHFFFAOYSA-N 1-(chloromethyl)-3-ethenylbenzene Chemical compound ClCC1=CC=CC(C=C)=C1 HMDQPBSDHHTRNI-UHFFFAOYSA-N 0.000 description 2
ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 2
206010002026 Amyotrophic lateral sclerosis Diseases 0.000 description 2
OZAIFHULBGXAKX-VAWYXSNFSA-N Azobisisobutyronitrile Chemical compound N#CC(C)(C)\N=N\C(C)(C)C#N OZAIFHULBGXAKX-VAWYXSNFSA-N 0.000 description 2
208000006561 Cluster Headache Diseases 0.000 description 2
208000004275 Demyelinating Disease Diseases 0.000 description 2
201000010374 Down syndrome Diseases 0.000 description 2
210000001035 Gastrointestinal Tract Anatomy 0.000 description 2
206010021972 Inflammatory bowel disease Diseases 0.000 description 2
YNESATAKKCNGOF-UHFFFAOYSA-N Lithium bis(trimethylsilyl)amide Chemical group [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 2
PCLIMKBDDGJMGD-UHFFFAOYSA-N N-Bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 2
229910004664 ORa Inorganic materials 0.000 description 2
NROKBHXJSPEDAR-UHFFFAOYSA-M Potassium fluoride Chemical compound [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 description 2
206010039073 Rheumatoid arthritis Diseases 0.000 description 2
RXZBMPWDPOLZGW-XMRMVWPWSA-N Roxithromycin Chemical group O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=N/OCOCCOC)/[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 RXZBMPWDPOLZGW-XMRMVWPWSA-N 0.000 description 2
GEHJYWRUCIMESM-UHFFFAOYSA-L Sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
QIQXTHQIDYTFRH-UHFFFAOYSA-N Stearic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 2
206010044688 Trisomy 21 Diseases 0.000 description 2
ZCHPKWUIAASXPV-UHFFFAOYSA-N acetic acid;methanol Chemical compound OC.CC(O)=O ZCHPKWUIAASXPV-UHFFFAOYSA-N 0.000 description 2
WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 2
150000007513 acids Chemical class 0.000 description 2
229910052783 alkali metal Inorganic materials 0.000 description 2
229910000102 alkali metal hydride Inorganic materials 0.000 description 2
150000008046 alkali metal hydrides Chemical class 0.000 description 2
XAGFODPZIPBFFR-UHFFFAOYSA-N aluminum Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 2
239000007864 aqueous solution Substances 0.000 description 2
239000012300 argon atmosphere Substances 0.000 description 2
235000020127 ayran Nutrition 0.000 description 2
230000005540 biological transmission Effects 0.000 description 2
125000001246 bromo group Chemical group Br* 0.000 description 2
239000002775 capsule Substances 0.000 description 2
230000000875 corresponding Effects 0.000 description 2
239000012043 crude product Substances 0.000 description 2
238000002425 crystallisation Methods 0.000 description 2
230000005712 crystallization Effects 0.000 description 2
IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
150000002009 diols Chemical class 0.000 description 2
239000003937 drug carrier Substances 0.000 description 2
239000000839 emulsion Substances 0.000 description 2
125000001153 fluoro group Chemical group F* 0.000 description 2
230000005484 gravity Effects 0.000 description 2
KLGZELKXQMTEMM-UHFFFAOYSA-N hydride Chemical compound [H-] KLGZELKXQMTEMM-UHFFFAOYSA-N 0.000 description 2
238000005984 hydrogenation reaction Methods 0.000 description 2
200000000018 inflammatory disease Diseases 0.000 description 2
HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
MBKUHNGECMPIHH-UHFFFAOYSA-N methyl 3-ethenylbenzoate Chemical compound COC(=O)C1=CC=CC(C=C)=C1 MBKUHNGECMPIHH-UHFFFAOYSA-N 0.000 description 2
210000000653 nervous system Anatomy 0.000 description 2
239000003960 organic solvent Substances 0.000 description 2
NBIIXXVUZAFLBC-UHFFFAOYSA-N phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
OAICVXFJPJFONN-UHFFFAOYSA-N phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 2
229910052698 phosphorus Inorganic materials 0.000 description 2
239000011574 phosphorus Substances 0.000 description 2
OCFVSFVLVRNXFJ-UHFFFAOYSA-N potassium hydride Inorganic materials [H-].[K+] OCFVSFVLVRNXFJ-UHFFFAOYSA-N 0.000 description 2
238000002360 preparation method Methods 0.000 description 2
230000002265 prevention Effects 0.000 description 2
102000004196 processed proteins & peptides Human genes 0.000 description 2
108090000765 processed proteins & peptides Proteins 0.000 description 2
BDERNNFJNOPAEC-UHFFFAOYSA-N propanol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
239000003638 reducing agent Substances 0.000 description 2
230000001953 sensory Effects 0.000 description 2
KEAYESYHFKHZAL-UHFFFAOYSA-N sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
229910052708 sodium Inorganic materials 0.000 description 2
238000003786 synthesis reaction Methods 0.000 description 2
210000001519 tissues Anatomy 0.000 description 2
ZMANZCXQSJIPKH-UHFFFAOYSA-N triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 2
238000007738 vacuum evaporation Methods 0.000 description 2
230000024883 vasodilation Effects 0.000 description 2
OJFWESQAJYZOKE-UHFFFAOYSA-N (2-bromo-1,1,1,3,3,3-hexafluoropropan-2-yl)benzene Chemical compound FC(F)(F)C(Br)(C(F)(F)F)C1=CC=CC=C1 OJFWESQAJYZOKE-UHFFFAOYSA-N 0.000 description 1
LNAZSHAWQACDHT-XIYTZBAFSA-N (2R,3R,4S,5R,6S)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2S,3R,4S,5R,6R)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2R,3R,4S,5R,6R)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
FPDDOFWJHHYHOU-UHFFFAOYSA-N (3-ethenylphenyl)methanol Chemical compound OCC1=CC=CC(C=C)=C1 FPDDOFWJHHYHOU-UHFFFAOYSA-N 0.000 description 1
JEIWMMMVZOQQHT-UHFFFAOYSA-N 1,2,2-trimethylcyclopentane-1,3-dicarbonyl chloride Chemical compound CC1(C)C(C(Cl)=O)CCC1(C)C(Cl)=O JEIWMMMVZOQQHT-UHFFFAOYSA-N 0.000 description 1
ZFLRKAMKGYNFPH-UHFFFAOYSA-N 1,3-dichloro-5-(chloromethyl)benzene Chemical compound ClCC1=CC(Cl)=CC(Cl)=C1 ZFLRKAMKGYNFPH-UHFFFAOYSA-N 0.000 description 1
TXVVVEUSVBLDED-UHFFFAOYSA-N 1-(bromomethyl)-2-(trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC=CC=C1CBr TXVVVEUSVBLDED-UHFFFAOYSA-N 0.000 description 1
LZIYAIRGDHSVED-UHFFFAOYSA-N 1-(bromomethyl)-3-chlorobenzene Chemical compound ClC1=CC=CC(CBr)=C1 LZIYAIRGDHSVED-UHFFFAOYSA-N 0.000 description 1
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125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
238000010998 test method Methods 0.000 description 1
238000004809 thin layer chromatography Methods 0.000 description 1
ZSLUVFAKFWKJRC-UHFFFAOYSA-N thorium Chemical compound [Th] ZSLUVFAKFWKJRC-UHFFFAOYSA-N 0.000 description 1
JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 1
QIWRFOJWQSSRJZ-UHFFFAOYSA-N tributyl(ethenyl)stannane Chemical compound CCCC[Sn](CCCC)(CCCC)C=C QIWRFOJWQSSRJZ-UHFFFAOYSA-N 0.000 description 1
UZEVVLMPUHZSOZ-UHFFFAOYSA-N triethylboranuide Chemical compound CC[BH-](CC)CC UZEVVLMPUHZSOZ-UHFFFAOYSA-N 0.000 description 1
USXXUTHCANUHBW-UHFFFAOYSA-N trimethylsilylazanide Chemical compound C[Si](C)(C)[NH-] USXXUTHCANUHBW-UHFFFAOYSA-N 0.000 description 1
201000006704 ulcerative colitis Diseases 0.000 description 1
239000003039 volatile agent Substances 0.000 description 1
238000010626 work up procedure Methods 0.000 description 1

Publication	Publication Date	Title
JP2500279B2 (ja)	1996-05-29	アザ二環式化合物、これを含有する医薬組成物及び治療のための使用方法
US5674889A (en)	1997-10-07	Aromatic compounds, compositions containing them and their use in therapy
US5554627A (en)	1996-09-10	Tachykinin antagonists
EP0593615B1 (en)	1996-01-31	Aromatic compounds, compositions containing them and their use in therapy
AU658898B2 (en)	1995-05-04	Substituted 3-aminoquinuclidines
EP0520555B1 (en)	1999-09-01	Azabicyclic compounds, pharmaceutical compositions containing them and their use in therapy
CA2072676A1 (en)	1993-01-06	Azabicyclic compounds, pharmaceutical compositions containing them and their use in therapy
JPH09508901A (ja)	1997-09-09	タキキニン拮抗薬としてのアラルコキシ及びアラルキルチオ置換アザ環式化合物
GB2268931A (en)	1994-01-26	Azabicyclic tachykinin-receptor antagonists
GB2269170A (en)	1994-02-02	Azatricyclic tachykinin antagonists
JPH09506628A (ja)	1997-06-30	モルホリンおよびチオモルホリン系のタキキニン受容体拮抗薬
JPH07503463A (ja)	1995-04-13	カルシウムチャンネル拮抗薬としてのアザビシクロ化合物
WO1996014297A1 (fr)	1996-05-17	Nouveaux derives de lactame
US5716965A (en)	1998-02-10	Substituted 3-aminoquinuclidines
EP0362941B1 (en)	1995-12-20	4-Methyl and 4-ethyl substituted pyrrolidin-2-ones
CA2266565C (en)	2002-03-05	Azabicyclic rotomase inhibitors
JP3541952B2 (ja)	2004-07-14	４−アリールイソインドール鎮痛薬
JP2500279C (es)	1999-07-05
EP0850234B1 (en)	2001-11-28	Novel heterocyclic compounds for the treatment of pain and use thereof
KR100459952B1 (ko)	2004-12-04	피페리디닐아미노메틸 트리플루오로메틸 사이클릭 에테르화합물의 제조 방법
JP2719063B2 (ja)	1998-02-25	置換３−アミノキヌクリジンｐ物質拮抗剤

JP2500279C - - Google Patents

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