CA2064373C - Derives de la piperidine - Google Patents
Derives de la piperidine Download PDFInfo
- Publication number
- CA2064373C CA2064373C CA 2064373 CA2064373A CA2064373C CA 2064373 C CA2064373 C CA 2064373C CA 2064373 CA2064373 CA 2064373 CA 2064373 A CA2064373 A CA 2064373A CA 2064373 C CA2064373 C CA 2064373C
- Authority
- CA
- Canada
- Prior art keywords
- alkyl
- substituted
- nhch2c
- ethyl acetate
- compound
- 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.)
- Expired - Lifetime
Links
- 150000003053 piperidines Chemical class 0.000 title description 9
- 230000002093 peripheral effect Effects 0.000 claims abstract description 10
- 150000003839 salts Chemical class 0.000 claims description 101
- 150000001875 compounds Chemical class 0.000 claims description 98
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 74
- 125000006273 (C1-C3) alkyl group Chemical class 0.000 claims description 70
- 239000001257 hydrogen Substances 0.000 claims description 47
- 229910052739 hydrogen Inorganic materials 0.000 claims description 47
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 32
- 125000000217 alkyl group Chemical group 0.000 claims description 31
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 24
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 22
- -1 C3-C10 -alkenyl Chemical group 0.000 claims description 20
- 125000003342 alkenyl group Chemical group 0.000 claims description 17
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 17
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 15
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 11
- 125000000081 (C5-C8) cycloalkenyl group Chemical group 0.000 claims description 11
- 150000001412 amines Chemical class 0.000 claims description 11
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 11
- 206010010774 Constipation Diseases 0.000 claims description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 9
- 102000003840 Opioid Receptors Human genes 0.000 claims description 9
- 108090000137 Opioid Receptors Proteins 0.000 claims description 9
- 229940127240 opiate Drugs 0.000 claims description 9
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 8
- 229920006395 saturated elastomer Polymers 0.000 claims description 8
- 125000006661 (C4-C6) heterocyclic group Chemical group 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 7
- 208000002551 irritable bowel syndrome Diseases 0.000 claims description 6
- 125000003386 piperidinyl group Chemical group 0.000 claims description 6
- 125000006527 (C1-C5) alkyl group Chemical group 0.000 claims description 5
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
- 206010028813 Nausea Diseases 0.000 claims description 4
- 206010047700 Vomiting Diseases 0.000 claims description 4
- 239000000460 chlorine Substances 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 4
- 230000008693 nausea Effects 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 230000008673 vomiting Effects 0.000 claims description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
- 241000124008 Mammalia Species 0.000 claims description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 3
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- 239000003401 opiate antagonist Substances 0.000 claims description 3
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 230000029936 alkylation Effects 0.000 claims description 2
- 238000005804 alkylation reaction Methods 0.000 claims description 2
- 230000000903 blocking effect Effects 0.000 claims description 2
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 2
- 230000010243 gut motility Effects 0.000 claims description 2
- 229910052740 iodine Inorganic materials 0.000 claims description 2
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims 8
- 125000006374 C2-C10 alkenyl group Chemical group 0.000 claims 2
- MQZOZIODQPLFRF-UHFFFAOYSA-N 2-methylpropyl 2-[[2-benzyl-3-[4-(3-hydroxyphenyl)-3,4-dimethylpiperidin-1-yl]propanoyl]amino]acetate Chemical compound C=1C=CC=CC=1CC(C(=O)NCC(=O)OCC(C)C)CN(CC1C)CCC1(C)C1=CC=CC(O)=C1 MQZOZIODQPLFRF-UHFFFAOYSA-N 0.000 claims 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims 1
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims 1
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 claims 1
- 230000009435 amidation Effects 0.000 claims 1
- 238000007112 amidation reaction Methods 0.000 claims 1
- 230000032050 esterification Effects 0.000 claims 1
- 238000005886 esterification reaction Methods 0.000 claims 1
- 230000003301 hydrolyzing effect Effects 0.000 claims 1
- 239000011630 iodine Substances 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 125000006239 protecting group Chemical group 0.000 claims 1
- 238000002360 preparation method Methods 0.000 abstract description 117
- 239000003887 narcotic antagonist Substances 0.000 abstract description 7
- 239000000543 intermediate Substances 0.000 abstract description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 639
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 267
- 229910001868 water Inorganic materials 0.000 description 186
- 239000000047 product Substances 0.000 description 183
- 239000000203 mixture Substances 0.000 description 165
- 239000000463 material Substances 0.000 description 146
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 129
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 126
- 239000002904 solvent Substances 0.000 description 126
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 124
- 239000007787 solid Substances 0.000 description 101
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 99
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 94
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 91
- 238000000034 method Methods 0.000 description 91
- 238000004458 analytical method Methods 0.000 description 90
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 64
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 60
- 238000004440 column chromatography Methods 0.000 description 54
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 50
- 239000000243 solution Substances 0.000 description 48
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 43
- 239000000377 silicon dioxide Substances 0.000 description 43
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 42
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 42
- 239000012044 organic layer Substances 0.000 description 41
- 239000010410 layer Substances 0.000 description 40
- 229910052757 nitrogen Inorganic materials 0.000 description 33
- 239000011541 reaction mixture Substances 0.000 description 29
- 238000006243 chemical reaction Methods 0.000 description 28
- 239000003921 oil Substances 0.000 description 28
- 235000019198 oils Nutrition 0.000 description 28
- 239000006260 foam Substances 0.000 description 26
- 229910000027 potassium carbonate Inorganic materials 0.000 description 25
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 25
- 238000003756 stirring Methods 0.000 description 23
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 22
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 22
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 22
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 21
- 238000001704 evaporation Methods 0.000 description 21
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 20
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 18
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 18
- 230000008020 evaporation Effects 0.000 description 17
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 16
- 239000000908 ammonium hydroxide Substances 0.000 description 16
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 14
- 150000002431 hydrogen Chemical class 0.000 description 14
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 12
- 239000002253 acid Substances 0.000 description 12
- OTXQUGSUXRBUTC-UHFFFAOYSA-N butan-1-ol;toluene Chemical compound CCCCO.CC1=CC=CC=C1 OTXQUGSUXRBUTC-UHFFFAOYSA-N 0.000 description 12
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 12
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 12
- 150000002168 ethanoic acid esters Chemical class 0.000 description 12
- 238000009472 formulation Methods 0.000 description 12
- 150000003840 hydrochlorides Chemical class 0.000 description 12
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 12
- 238000010992 reflux Methods 0.000 description 12
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 11
- 239000007788 liquid Substances 0.000 description 11
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Chemical compound CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 10
- 230000000694 effects Effects 0.000 description 10
- FKRCODPIKNYEAC-UHFFFAOYSA-N ethyl propionate Chemical compound CCOC(=O)CC FKRCODPIKNYEAC-UHFFFAOYSA-N 0.000 description 10
- 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 10
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 10
- 241000699670 Mus sp. Species 0.000 description 9
- 229920002472 Starch Polymers 0.000 description 9
- 229960000583 acetic acid Drugs 0.000 description 9
- DUWWHGPELOTTOE-UHFFFAOYSA-N n-(5-chloro-2,4-dimethoxyphenyl)-3-oxobutanamide Chemical compound COC1=CC(OC)=C(NC(=O)CC(C)=O)C=C1Cl DUWWHGPELOTTOE-UHFFFAOYSA-N 0.000 description 9
- 235000019260 propionic acid Nutrition 0.000 description 9
- 235000019698 starch Nutrition 0.000 description 9
- 239000007858 starting material Substances 0.000 description 9
- 238000012360 testing method Methods 0.000 description 9
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 8
- 239000004480 active ingredient Substances 0.000 description 8
- 239000008367 deionised water Substances 0.000 description 8
- 150000002148 esters Chemical class 0.000 description 8
- 239000000706 filtrate Substances 0.000 description 8
- 230000008569 process Effects 0.000 description 8
- 239000008107 starch Substances 0.000 description 8
- CCPHAMSKHBDMDS-UHFFFAOYSA-N Chetoseminudin B Natural products C=1NC2=CC=CC=C2C=1CC1(SC)NC(=O)C(CO)(SC)N(C)C1=O CCPHAMSKHBDMDS-UHFFFAOYSA-N 0.000 description 7
- 241000699666 Mus <mouse, genus> Species 0.000 description 7
- 239000002775 capsule Substances 0.000 description 7
- 239000003153 chemical reaction reagent Substances 0.000 description 7
- OBNCKNCVKJNDBV-UHFFFAOYSA-N ethyl butyrate Chemical compound CCCC(=O)OCC OBNCKNCVKJNDBV-UHFFFAOYSA-N 0.000 description 7
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 7
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 7
- 239000003826 tablet Substances 0.000 description 7
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 7
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- VOPWNXZWBYDODV-UHFFFAOYSA-N Chlorodifluoromethane Chemical compound FC(F)Cl VOPWNXZWBYDODV-UHFFFAOYSA-N 0.000 description 6
- 206010012735 Diarrhoea Diseases 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
- 235000011054 acetic acid Nutrition 0.000 description 6
- DNSISZSEWVHGLH-UHFFFAOYSA-N butanamide Chemical compound CCCC(N)=O DNSISZSEWVHGLH-UHFFFAOYSA-N 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- FVLGPYFFONYLRZ-UHFFFAOYSA-N ethyl 2-benzylprop-2-enoate Chemical compound CCOC(=O)C(=C)CC1=CC=CC=C1 FVLGPYFFONYLRZ-UHFFFAOYSA-N 0.000 description 6
- 125000004494 ethyl ester group Chemical group 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 239000007903 gelatin capsule Substances 0.000 description 6
- 235000019359 magnesium stearate Nutrition 0.000 description 6
- 239000000843 powder Substances 0.000 description 6
- 239000000741 silica gel Substances 0.000 description 6
- 229910002027 silica gel Inorganic materials 0.000 description 6
- 239000011343 solid material Substances 0.000 description 6
- 239000012265 solid product Substances 0.000 description 6
- VRPJIFMKZZEXLR-UHFFFAOYSA-N 2-[(2-methylpropan-2-yl)oxycarbonylamino]acetic acid Chemical compound CC(C)(C)OC(=O)NCC(O)=O VRPJIFMKZZEXLR-UHFFFAOYSA-N 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 239000005557 antagonist Substances 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid group Chemical group C(C1=CC=CC=C1)(=O)O WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 125000004432 carbon atom Chemical group C* 0.000 description 5
- 239000003054 catalyst Substances 0.000 description 5
- NTNZTEQNFHNYBC-UHFFFAOYSA-N ethyl 2-aminoacetate Chemical compound CCOC(=O)CN NTNZTEQNFHNYBC-UHFFFAOYSA-N 0.000 description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 5
- 239000012458 free base Substances 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 239000002808 molecular sieve Substances 0.000 description 5
- 229960005181 morphine Drugs 0.000 description 5
- 239000012056 semi-solid material Substances 0.000 description 5
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 5
- IBYHHJPAARCAIE-UHFFFAOYSA-N 1-bromo-2-chloroethane Chemical compound ClCCBr IBYHHJPAARCAIE-UHFFFAOYSA-N 0.000 description 4
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 4
- RKOTXQYWCBGZLP-UHFFFAOYSA-N N-[(2,4-difluorophenyl)methyl]-2-ethyl-9-hydroxy-3-methoxy-1,8-dioxospiro[3H-pyrido[1,2-a]pyrazine-4,3'-oxolane]-7-carboxamide Chemical compound CCN1C(OC)C2(CCOC2)N2C=C(C(=O)NCC3=C(F)C=C(F)C=C3)C(=O)C(O)=C2C1=O RKOTXQYWCBGZLP-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- 150000001408 amides Chemical class 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 4
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 4
- 210000004556 brain Anatomy 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- 238000000354 decomposition reaction Methods 0.000 description 4
- 229940043279 diisopropylamine Drugs 0.000 description 4
- 238000004821 distillation Methods 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 239000004615 ingredient Substances 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 238000004949 mass spectrometry Methods 0.000 description 4
- 238000002844 melting Methods 0.000 description 4
- 230000008018 melting Effects 0.000 description 4
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 229910052708 sodium Inorganic materials 0.000 description 4
- 239000006188 syrup Substances 0.000 description 4
- 235000020357 syrup Nutrition 0.000 description 4
- CMIBUZBMZCBCAT-HOTGVXAUSA-N (2s,3s)-2,3-bis[(4-methylbenzoyl)oxy]butanedioic acid Chemical compound C1=CC(C)=CC=C1C(=O)O[C@H](C(O)=O)[C@@H](C(O)=O)OC(=O)C1=CC=C(C)C=C1 CMIBUZBMZCBCAT-HOTGVXAUSA-N 0.000 description 3
- FEEWUFXEOWANJB-UHFFFAOYSA-N 1,3,4-trimethyl-4-(3-propoxyphenyl)piperidine Chemical compound CCCOC1=CC=CC(C2(C)C(CN(C)CC2)C)=C1 FEEWUFXEOWANJB-UHFFFAOYSA-N 0.000 description 3
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 3
- 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 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 3
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 230000000202 analgesic effect Effects 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 3
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 3
- 235000010980 cellulose Nutrition 0.000 description 3
- 239000001913 cellulose Substances 0.000 description 3
- 229920002678 cellulose Polymers 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 3
- 230000018044 dehydration Effects 0.000 description 3
- 238000006297 dehydration reaction Methods 0.000 description 3
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- YGHYIGJROUGWTK-UHFFFAOYSA-N ethyl 4-[[2-cyclohexyl-4-[4-(3-hydroxyphenyl)-3,4-dimethylpiperidin-1-yl]butanoyl]amino]butanoate;hydrate;hydrochloride Chemical compound O.Cl.C1CCCCC1C(C(=O)NCCCC(=O)OCC)CCN(CC1C)CCC1(C)C1=CC=CC(O)=C1 YGHYIGJROUGWTK-UHFFFAOYSA-N 0.000 description 1
- CXVQSUBJMYZELD-UHFFFAOYSA-N ethyl 4-aminobutanoate;hydrochloride Chemical compound [Cl-].CCOC(=O)CCC[NH3+] CXVQSUBJMYZELD-UHFFFAOYSA-N 0.000 description 1
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
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- 239000007789 gas Substances 0.000 description 1
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- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
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- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
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- 229910052736 halogen Inorganic materials 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 150000002367 halogens Chemical group 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 239000012456 homogeneous solution Substances 0.000 description 1
- 238000007327 hydrogenolysis reaction Methods 0.000 description 1
- QYRFJLLXPINATB-UHFFFAOYSA-N hydron;2,4,5,6-tetrafluorobenzene-1,3-diamine;dichloride Chemical class Cl.Cl.NC1=C(F)C(N)=C(F)C(F)=C1F QYRFJLLXPINATB-UHFFFAOYSA-N 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 238000013101 initial test Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 229940035429 isobutyl alcohol Drugs 0.000 description 1
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 239000011344 liquid material Substances 0.000 description 1
- 239000012263 liquid product Substances 0.000 description 1
- WGOPGODQLGJZGL-UHFFFAOYSA-N lithium;butane Chemical compound [Li+].CC[CH-]C WGOPGODQLGJZGL-UHFFFAOYSA-N 0.000 description 1
- 210000003141 lower extremity Anatomy 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- WSFSSNUMVMOOMR-NJFSPNSNSA-N methanone Chemical compound O=[14CH2] WSFSSNUMVMOOMR-NJFSPNSNSA-N 0.000 description 1
- GSJFXBNYJCXDGI-UHFFFAOYSA-N methyl 2-hydroxyacetate Chemical compound COC(=O)CO GSJFXBNYJCXDGI-UHFFFAOYSA-N 0.000 description 1
- 229940102396 methyl bromide Drugs 0.000 description 1
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- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
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- 238000002156 mixing Methods 0.000 description 1
- KVKFRMCSXWQSNT-UHFFFAOYSA-N n,n'-dimethylethane-1,2-diamine Chemical compound CNCCNC KVKFRMCSXWQSNT-UHFFFAOYSA-N 0.000 description 1
- ZAZNANAKBYBBCE-UHFFFAOYSA-N n-(2-amino-2-oxoethyl)-2-cyclohexyl-4-[4-(3-hydroxyphenyl)-3,4-dimethylpiperidin-1-yl]butanamide;hydrate;hydrochloride Chemical compound O.Cl.C1CC(C=2C=C(O)C=CC=2)(C)C(C)CN1CCC(C(=O)NCC(N)=O)C1CCCCC1 ZAZNANAKBYBBCE-UHFFFAOYSA-N 0.000 description 1
- FFWOHVXICLTBBT-UHFFFAOYSA-N n-(4-amino-4-oxobutyl)-2-(cyclohexylmethyl)-3-[4-(3-hydroxyphenyl)-3,4-dimethylpiperidin-1-yl]propanamide;hydrochloride Chemical compound Cl.C1CC(C=2C=C(O)C=CC=2)(C)C(C)CN1CC(C(=O)NCCCC(N)=O)CC1CCCCC1 FFWOHVXICLTBBT-UHFFFAOYSA-N 0.000 description 1
- SMLBUPYQGNANIQ-UHFFFAOYSA-N n-[2-(ethylamino)-2-oxoethyl]-4-[4-(3-hydroxyphenyl)-3,4-dimethylpiperidin-1-yl]-2-phenylbutanamide;hydrate;hydrochloride Chemical compound O.Cl.C=1C=CC=CC=1C(C(=O)NCC(=O)NCC)CCN(CC1C)CCC1(C)C1=CC=CC(O)=C1 SMLBUPYQGNANIQ-UHFFFAOYSA-N 0.000 description 1
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
- DQCKKXVULJGBQN-XFWGSAIBSA-N naltrexone Chemical compound N1([C@@H]2CC3=CC=C(C=4O[C@@H]5[C@](C3=4)([C@]2(CCC5=O)O)CC1)O)CC1CC1 DQCKKXVULJGBQN-XFWGSAIBSA-N 0.000 description 1
- 229960003086 naltrexone Drugs 0.000 description 1
- 239000004081 narcotic agent Substances 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 125000002560 nitrile group Chemical group 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 125000006574 non-aromatic ring group Chemical group 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000010502 orange oil Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000002923 oximes Chemical class 0.000 description 1
- 230000036407 pain Effects 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 230000037035 peripheral opioid activity Effects 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- AHWALFGBDFAJAI-UHFFFAOYSA-N phenyl carbonochloridate Chemical compound ClC(=O)OC1=CC=CC=C1 AHWALFGBDFAJAI-UHFFFAOYSA-N 0.000 description 1
- 125000000286 phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 1
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- HDOWRFHMPULYOA-UHFFFAOYSA-N piperidin-4-ol Chemical class OC1CCNCC1 HDOWRFHMPULYOA-UHFFFAOYSA-N 0.000 description 1
- BIFDXOOJPDHKJH-UHFFFAOYSA-N piperidine-1-carbonyl chloride Chemical compound ClC(=O)N1CCCCC1 BIFDXOOJPDHKJH-UHFFFAOYSA-N 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 239000002574 poison Substances 0.000 description 1
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- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
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- 229920000053 polysorbate 80 Polymers 0.000 description 1
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- 239000011736 potassium bicarbonate Substances 0.000 description 1
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- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 238000004262 preparative liquid chromatography Methods 0.000 description 1
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- MTDPSJQEJVUVBH-UHFFFAOYSA-N propan-2-yl 2-[[2-benzyl-3-[4-(3-hydroxyphenyl)-3,4-dimethylpiperidin-1-yl]propanoyl]amino]acetate;hydrochloride Chemical compound Cl.C=1C=CC=CC=1CC(C(=O)NCC(=O)OC(C)C)CN(CC1C)CCC1(C)C1=CC=CC(O)=C1 MTDPSJQEJVUVBH-UHFFFAOYSA-N 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 description 1
- 125000006308 propyl amino group Chemical group 0.000 description 1
- 238000000159 protein binding assay Methods 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 239000012264 purified product Substances 0.000 description 1
- 150000003233 pyrroles Chemical group 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 229940081974 saccharin Drugs 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 230000007928 solubilization Effects 0.000 description 1
- 238000005063 solubilization Methods 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 210000000278 spinal cord Anatomy 0.000 description 1
- 238000013222 sprague-dawley male rat Methods 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000007916 tablet composition Substances 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000004853 tetrahydropyridinyl group Chemical group N1(CCCC=C1)* 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- CMQCNTNASCDNGR-UHFFFAOYSA-N toluene;hydrate Chemical compound O.CC1=CC=CC=C1 CMQCNTNASCDNGR-UHFFFAOYSA-N 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 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
- PXXNTAGJWPJAGM-UHFFFAOYSA-N vertaline Natural products C1C2C=3C=C(OC)C(OC)=CC=3OC(C=C3)=CC=C3CCC(=O)OC1CC1N2CCCC1 PXXNTAGJWPJAGM-UHFFFAOYSA-N 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- GSQBIOQCECCMOQ-UHFFFAOYSA-N β-alanine ethyl ester Chemical compound CCOC(=O)CCN GSQBIOQCECCMOQ-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Hydrogenated Pyridines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US66704291A | 1991-03-29 | 1991-03-29 | |
| US677,042 | 1991-03-29 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2064373A1 CA2064373A1 (fr) | 1992-09-30 |
| CA2064373C true CA2064373C (fr) | 2005-08-23 |
Family
ID=24676573
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA 2064373 Expired - Lifetime CA2064373C (fr) | 1991-03-29 | 1992-03-27 | Derives de la piperidine |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA2064373C (fr) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8518962B2 (en) | 2005-03-07 | 2013-08-27 | The University Of Chicago | Use of opioid antagonists |
| US8524731B2 (en) | 2005-03-07 | 2013-09-03 | The University Of Chicago | Use of opioid antagonists to attenuate endothelial cell proliferation and migration |
| US8685995B2 (en) | 2008-03-21 | 2014-04-01 | The University Of Chicago | Treatment with opioid antagonists and mTOR inhibitors |
Families Citing this family (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2521369A1 (fr) * | 2003-04-08 | 2004-10-28 | Progenics Pharmaceuticals, Inc. | Utilisation d'antagonistes des opioides peripheriques, en particulier de methylnaltrexone, dans le traitement du syndrome du colon irritable |
| EP1615646B2 (fr) | 2003-04-08 | 2022-07-27 | Progenics Pharmaceuticals, Inc. | Formulations pharmaceutiques contenant de la methylnaltrexone |
| CN104248763A (zh) | 2005-03-07 | 2014-12-31 | 芝加哥大学 | 阿片样物质拮抗剂用于减少内皮细胞增殖和迁移的用途 |
| US9662325B2 (en) | 2005-03-07 | 2017-05-30 | The University Of Chicago | Use of opioid antagonists to attenuate endothelial cell proliferation and migration |
| AR057035A1 (es) | 2005-05-25 | 2007-11-14 | Progenics Pharm Inc | SíNTESIS DE (R)-N-METILNALTREXONA, COMPOSICIONES FARMACÉUTICAS Y USOS |
| AR057325A1 (es) | 2005-05-25 | 2007-11-28 | Progenics Pharm Inc | Sintesis de (s)-n-metilnaltrexona, composiciones farmaceuticas y usos |
| TWI489984B (zh) | 2006-08-04 | 2015-07-01 | Wyeth Corp | 用於非經腸道傳輸化合物之配方及其用途 |
| CA2682129A1 (fr) | 2007-03-29 | 2008-10-09 | Progenics Pharmaceuticals, Inc. | Formes cristallines et leurs utilisations |
| CA2682125C (fr) | 2007-03-29 | 2015-06-16 | Progenics Pharmaceuticals, Inc. | Antagonistes de recepteurs opioides peripheriques, et leurs utilisations |
| JP5469593B2 (ja) | 2007-03-29 | 2014-04-16 | ワイス・エルエルシー | 末梢性オピオイド受容体アンタゴニストおよびその使用 |
| JP5358587B2 (ja) | 2008-02-06 | 2013-12-04 | プロジェニックス・ファーマシューティカルス・インコーポレイテッド | （ｒ），（ｒ）−２，２’−ビス−メチルナルトレキソンの製造及び用途 |
| CA2676881C (fr) | 2008-09-30 | 2017-04-25 | Wyeth | Antagonistes de recepteurs opioides peripheriques, et leurs utilisations |
-
1992
- 1992-03-27 CA CA 2064373 patent/CA2064373C/fr not_active Expired - Lifetime
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8518962B2 (en) | 2005-03-07 | 2013-08-27 | The University Of Chicago | Use of opioid antagonists |
| US8524731B2 (en) | 2005-03-07 | 2013-09-03 | The University Of Chicago | Use of opioid antagonists to attenuate endothelial cell proliferation and migration |
| US8685995B2 (en) | 2008-03-21 | 2014-04-01 | The University Of Chicago | Treatment with opioid antagonists and mTOR inhibitors |
| US9526723B2 (en) | 2008-03-21 | 2016-12-27 | The University Of Chicago | Treatment with opioid antagonists and mTOR inhibitors |
Also Published As
| Publication number | Publication date |
|---|---|
| CA2064373A1 (fr) | 1992-09-30 |
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Legal Events
| Date | Code | Title | Description |
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| EEER | Examination request | ||
| MKEX | Expiry |