CA1325634C - Esters d'hexahydro-8-hydroxy-2,6-methano-2h-quinolizin-3 (4h)-one, et composes annexes - Google Patents

Esters d'hexahydro-8-hydroxy-2,6-methano-2h-quinolizin-3 (4h)-one, et composes annexes

Info

Publication number: CA1325634C
Authority: CA; Canada
Prior art keywords: alkyl; hydrogen; formula; phenyl; pharmaceutically acceptable
Prior art date: 1988-04-26
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

CA000597287A

Other languages

English (en)

Inventor

Maurice Ward Gittos

Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)

Aventis Pharmaceuticals Inc

Original Assignee

Merrell Dow Pharmaceuticals Inc

Priority date (The priority date 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 date listed.)

1988-04-26

Filing date

1989-04-20

Publication date

1993-12-28

1989-04-20 Application filed by Merrell Dow Pharmaceuticals Inc filed Critical Merrell Dow Pharmaceuticals Inc

1993-12-28 Application granted granted Critical

1993-12-28 Publication of CA1325634C publication Critical patent/CA1325634C/fr

2010-12-28 Anticipated expiration legal-status Critical

Status Expired - Lifetime legal-status Critical Current

Links

150000001875 compounds Chemical class 0.000 title claims abstract description 62
150000002148 esters Chemical class 0.000 title abstract description 6
NEDMCWSHHDYQAJ-UHFFFAOYSA-N 115956-07-5 Chemical compound C1C2CC(O)CC3N2CC(=O)C1C3 NEDMCWSHHDYQAJ-UHFFFAOYSA-N 0.000 title abstract 2
238000000034 method Methods 0.000 claims abstract description 17
150000003839 salts Chemical class 0.000 claims abstract description 6
239000003930 superacid Substances 0.000 claims abstract description 6
229910001385 heavy metal Inorganic materials 0.000 claims abstract description 4
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 54
239000002253 acid Substances 0.000 claims description 34
239000000203 mixture Substances 0.000 claims description 30
239000001257 hydrogen Substances 0.000 claims description 25
229910052739 hydrogen Inorganic materials 0.000 claims description 25
150000002431 hydrogen Chemical group 0.000 claims description 21
125000000217 alkyl group Chemical group 0.000 claims description 20
-1 tetramethylene, pentamethylene Chemical group 0.000 claims description 19
150000003242 quaternary ammonium salts Chemical class 0.000 claims description 14
238000006243 chemical reaction Methods 0.000 claims description 13
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 13
229910052736 halogen Inorganic materials 0.000 claims description 10
150000002367 halogens Chemical group 0.000 claims description 10
125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 7
MCSAJNNLRCFZED-UHFFFAOYSA-N nitroethane Chemical compound CC[N+]([O-])=O MCSAJNNLRCFZED-UHFFFAOYSA-N 0.000 claims description 7
NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 claims description 6
CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 claims description 6
125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 6
239000002904 solvent Substances 0.000 claims description 6
QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 5
125000004093 cyano group Chemical group *C#N 0.000 claims description 5
125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 5
ZNBGBHISQKMEPA-UHFFFAOYSA-N 2-oxoacetyl chloride Chemical compound ClC(=O)C=O ZNBGBHISQKMEPA-UHFFFAOYSA-N 0.000 claims description 3
239000003937 drug carrier Substances 0.000 claims description 2
125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 20
125000006274 (C1-C3)alkoxy group Chemical group 0.000 claims 4
125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims 4
125000006273 (C1-C3) alkyl group Chemical group 0.000 claims 2
GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical group NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 claims 2
125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims 2
125000004435 hydrogen atom Chemical group [H]* 0.000 claims 1
238000004519 manufacturing process Methods 0.000 claims 1
229910052760 oxygen Inorganic materials 0.000 claims 1
239000008194 pharmaceutical composition Substances 0.000 claims 1
229910052717 sulfur Inorganic materials 0.000 claims 1
206010027599 migraine Diseases 0.000 abstract description 14
208000019695 Migraine disease Diseases 0.000 abstract description 12
238000011282 treatment Methods 0.000 abstract description 8
206010047700 Vomiting Diseases 0.000 abstract description 7
230000008673 vomiting Effects 0.000 abstract description 5
239000002254 cytotoxic agent Substances 0.000 abstract description 4
229940127089 cytotoxic agent Drugs 0.000 abstract description 4
238000010561 standard procedure Methods 0.000 abstract description 3
150000001298 alcohols Chemical class 0.000 abstract description 2
150000001735 carboxylic acids Chemical class 0.000 abstract description 2
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract 1
208000035475 disorder Diseases 0.000 abstract 1
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 39
239000000243 solution Substances 0.000 description 31
QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 28
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 16
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
230000000694 effects Effects 0.000 description 8
FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 8
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
238000001704 evaporation Methods 0.000 description 6
230000008020 evaporation Effects 0.000 description 6
RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 6
229960004503 metoclopramide Drugs 0.000 description 6
TTWJBBZEZQICBI-UHFFFAOYSA-N metoclopramide Chemical compound CCN(CC)CCNC(=O)C1=CC(Cl)=C(N)C=C1OC TTWJBBZEZQICBI-UHFFFAOYSA-N 0.000 description 6
239000000047 product Substances 0.000 description 6
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 5
LPIQUOYDBNQMRZ-UHFFFAOYSA-N cyclopentene Chemical compound C1CC=CC1 LPIQUOYDBNQMRZ-UHFFFAOYSA-N 0.000 description 5
239000003085 diluting agent Substances 0.000 description 5
CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
ZPUCINDJVBIVPJ-LJISPDSOSA-N cocaine Chemical compound O([C@H]1C[C@@H]2CC[C@@H](N2C)[C@H]1C(=O)OC)C(=O)C1=CC=CC=C1 ZPUCINDJVBIVPJ-LJISPDSOSA-N 0.000 description 4
238000000605 extraction Methods 0.000 description 4
235000013350 formula milk Nutrition 0.000 description 4
BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
AQHHHDLHHXJYJD-UHFFFAOYSA-N propranolol Chemical compound C1=CC=C2C(OCC(O)CNC(C)C)=CC=CC2=C1 AQHHHDLHHXJYJD-UHFFFAOYSA-N 0.000 description 4
JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 description 4
239000012258 stirred mixture Substances 0.000 description 4
239000006188 syrup Substances 0.000 description 4
235000020357 syrup Nutrition 0.000 description 4
YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
KPJZHOPZRAFDTN-ZRGWGRIASA-N (6aR,9R)-N-[(2S)-1-hydroxybutan-2-yl]-4,7-dimethyl-6,6a,8,9-tetrahydroindolo[4,3-fg]quinoline-9-carboxamide Chemical compound C1=CC(C=2[C@H](N(C)C[C@@H](C=2)C(=O)N[C@H](CO)CC)C2)=C3C2=CN(C)C3=C1 KPJZHOPZRAFDTN-ZRGWGRIASA-N 0.000 description 3
HUHXLHLWASNVDB-UHFFFAOYSA-N 2-(oxan-2-yloxy)oxane Chemical compound O1CCCCC1OC1OCCCC1 HUHXLHLWASNVDB-UHFFFAOYSA-N 0.000 description 3
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 3
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 3
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 3
KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
239000004480 active ingredient Substances 0.000 description 3
125000003545 alkoxy group Chemical group 0.000 description 3
239000002585 base Substances 0.000 description 3
150000001732 carboxylic acid derivatives Chemical class 0.000 description 3
XVSYDLITVYBCBD-UHFFFAOYSA-N cyclopent-3-ene-1-carboxylic acid Chemical compound OC(=O)C1CC=CC1 XVSYDLITVYBCBD-UHFFFAOYSA-N 0.000 description 3
229960004704 dihydroergotamine Drugs 0.000 description 3
HESHRHUZIWVEAJ-JGRZULCMSA-N dihydroergotamine Chemical compound C([C@H]1C(=O)N2CCC[C@H]2[C@]2(O)O[C@@](C(N21)=O)(C)NC(=O)[C@H]1CN([C@H]2[C@@H](C3=CC=CC4=NC=C([C]34)C2)C1)C)C1=CC=CC=C1 HESHRHUZIWVEAJ-JGRZULCMSA-N 0.000 description 3
239000000706 filtrate Substances 0.000 description 3
238000009472 formulation Methods 0.000 description 3
150000004820 halides Chemical class 0.000 description 3
125000000468 ketone group Chemical group 0.000 description 3
239000000463 material Substances 0.000 description 3
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
229960001186 methysergide Drugs 0.000 description 3
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
238000002360 preparation method Methods 0.000 description 3
239000002464 receptor antagonist Substances 0.000 description 3
229940044551 receptor antagonist Drugs 0.000 description 3
GYSCXPVAKHVAAY-UHFFFAOYSA-N 3-Nonanol Chemical compound CCCCCCC(O)CC GYSCXPVAKHVAAY-UHFFFAOYSA-N 0.000 description 2
OXTNCQMOKLOUAM-UHFFFAOYSA-N 3-Oxoglutaric acid Chemical compound OC(=O)CC(=O)CC(O)=O OXTNCQMOKLOUAM-UHFFFAOYSA-N 0.000 description 2
VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
DUUGKQCEGZLZNO-UHFFFAOYSA-N 5-hydroxyindoleacetic acid Chemical compound C1=C(O)C=C2C(CC(=O)O)=CNC2=C1 DUUGKQCEGZLZNO-UHFFFAOYSA-N 0.000 description 2
RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 2
BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 2
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
XQJMXPAEFMWDOZ-UHFFFAOYSA-N Benzoyltropein Chemical compound CN1C(C2)CCC1CC2OC(=O)C1=CC=CC=C1 XQJMXPAEFMWDOZ-UHFFFAOYSA-N 0.000 description 2
CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
ZNZYKNKBJPZETN-WELNAUFTSA-N Dialdehyde 11678 Chemical compound N1C2=CC=CC=C2C2=C1[C@H](C[C@H](/C(=C/O)C(=O)OC)[C@@H](C=C)C=O)NCC2 ZNZYKNKBJPZETN-WELNAUFTSA-N 0.000 description 2
BUDQDWGNQVEFAC-UHFFFAOYSA-N Dihydropyran Chemical compound C1COC=CC1 BUDQDWGNQVEFAC-UHFFFAOYSA-N 0.000 description 2
ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 2
OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 2
LFTLOKWAGJYHHR-UHFFFAOYSA-N N-methylmorpholine N-oxide Chemical compound CN1(=O)CCOCC1 LFTLOKWAGJYHHR-UHFFFAOYSA-N 0.000 description 2
XUSKKYVRWMAIAX-PBWFPOADSA-N O-Benzoyltropine Natural products O=C(OC1C[C@@H]2[N+](C)[C@H](C1)CC2)c1ccccc1 XUSKKYVRWMAIAX-PBWFPOADSA-N 0.000 description 2
208000002193 Pain Diseases 0.000 description 2
KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
241000212342 Sium Species 0.000 description 2
DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
229960001138 acetylsalicylic acid Drugs 0.000 description 2
150000007513 acids Chemical class 0.000 description 2
230000001154 acute effect Effects 0.000 description 2
229910052783 alkali metal Inorganic materials 0.000 description 2
229960000836 amitriptyline Drugs 0.000 description 2
KRMDCWKBEZIMAB-UHFFFAOYSA-N amitriptyline Chemical compound C1CC2=CC=CC=C2C(=CCCN(C)C)C2=CC=CC=C21 KRMDCWKBEZIMAB-UHFFFAOYSA-N 0.000 description 2
239000011260 aqueous acid Substances 0.000 description 2
WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
230000000903 blocking effect Effects 0.000 description 2
GZUXJHMPEANEGY-UHFFFAOYSA-N bromomethane Chemical compound BrC GZUXJHMPEANEGY-UHFFFAOYSA-N 0.000 description 2
MIOPJNTWMNEORI-UHFFFAOYSA-N camphorsulfonic acid Chemical compound C1CC2(CS(O)(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-UHFFFAOYSA-N 0.000 description 2
239000002775 capsule Substances 0.000 description 2
PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 2
239000000969 carrier Substances 0.000 description 2
239000003054 catalyst Substances 0.000 description 2
ZPEIMTDSQAKGNT-UHFFFAOYSA-N chlorpromazine Chemical compound C1=C(Cl)C=C2N(CCCN(C)C)C3=CC=CC=C3SC2=C1 ZPEIMTDSQAKGNT-UHFFFAOYSA-N 0.000 description 2
229960001076 chlorpromazine Drugs 0.000 description 2
238000004440 column chromatography Methods 0.000 description 2
229960003564 cyclizine Drugs 0.000 description 2
UVKZSORBKUEBAZ-UHFFFAOYSA-N cyclizine Chemical compound C1CN(C)CCN1C(C=1C=CC=CC=1)C1=CC=CC=C1 UVKZSORBKUEBAZ-UHFFFAOYSA-N 0.000 description 2
125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
238000010828 elution Methods 0.000 description 2
229960004943 ergotamine Drugs 0.000 description 2
OFKDAAIKGIBASY-VFGNJEKYSA-N ergotamine Chemical compound C([C@H]1C(=O)N2CCC[C@H]2[C@]2(O)O[C@@](C(N21)=O)(C)NC(=O)[C@H]1CN([C@H]2C(C3=CC=CC4=NC=C([C]34)C2)=C1)C)C1=CC=CC=C1 OFKDAAIKGIBASY-VFGNJEKYSA-N 0.000 description 2
XCGSFFUVFURLIX-UHFFFAOYSA-N ergotaminine Natural products C1=C(C=2C=CC=C3NC=C(C=23)C2)C2N(C)CC1C(=O)NC(C(N12)=O)(C)OC1(O)C1CCCN1C(=O)C2CC1=CC=CC=C1 XCGSFFUVFURLIX-UHFFFAOYSA-N 0.000 description 2
NKMWEFJKBGNYQH-UHFFFAOYSA-N ethyl 3,4-dihydroxycyclopentane-1-carboxylate Chemical compound CCOC(=O)C1CC(O)C(O)C1 NKMWEFJKBGNYQH-UHFFFAOYSA-N 0.000 description 2
WCDRGGYHUBTALP-UHFFFAOYSA-N ethyl 9-(2-ethoxy-2-oxoethyl)-3-hydroxy-9-azabicyclo[3.3.1]nonane-7-carboxylate Chemical compound C1C(O)CC2CC(C(=O)OCC)CC1N2CC(=O)OCC WCDRGGYHUBTALP-UHFFFAOYSA-N 0.000 description 2
239000002024 ethyl acetate extract Substances 0.000 description 2
OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 2
CTLAIKSGNQPPLO-UHFFFAOYSA-N ethyl cyclopent-3-ene-1-carboxylate Chemical compound CCOC(=O)C1CC=CC1 CTLAIKSGNQPPLO-UHFFFAOYSA-N 0.000 description 2
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
238000010438 heat treatment Methods 0.000 description 2
235000011167 hydrochloric acid Nutrition 0.000 description 2
229960000443 hydrochloric acid Drugs 0.000 description 2
CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 2
239000012442 inert solvent Substances 0.000 description 2
150000002500 ions Chemical class 0.000 description 2
150000002576 ketones Chemical class 0.000 description 2
239000007788 liquid Substances 0.000 description 2
229910000103 lithium hydride Inorganic materials 0.000 description 2
229910052943 magnesium sulfate Inorganic materials 0.000 description 2
235000019341 magnesium sulphate Nutrition 0.000 description 2
VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 2
BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
210000002569 neuron Anatomy 0.000 description 2
LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 2
229910000489 osmium tetroxide Inorganic materials 0.000 description 2
239000012285 osmium tetroxide Substances 0.000 description 2
RGSFGYAAUTVSQA-UHFFFAOYSA-N pentamethylene Natural products C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 2
125000003367 polycyclic group Chemical group 0.000 description 2
229910000027 potassium carbonate Inorganic materials 0.000 description 2
TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical class [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 2
LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 2
230000003389 potentiating effect Effects 0.000 description 2
229960003712 propranolol Drugs 0.000 description 2
VQMSRUREDGBWKT-UHFFFAOYSA-N quinoline-4-carboxylic acid Chemical compound C1=CC=C2C(C(=O)O)=CC=NC2=C1 VQMSRUREDGBWKT-UHFFFAOYSA-N 0.000 description 2
238000007363 ring formation reaction Methods 0.000 description 2
239000000377 silicon dioxide Substances 0.000 description 2
239000011734 sodium Substances 0.000 description 2
239000012279 sodium borohydride Substances 0.000 description 2
229910000033 sodium borohydride Inorganic materials 0.000 description 2
239000007787 solid Substances 0.000 description 2
238000003756 stirring Methods 0.000 description 2
239000000829 suppository Substances 0.000 description 2
239000000725 suspension Substances 0.000 description 2
XCTYLCDETUVOIP-UHFFFAOYSA-N thiethylperazine Chemical compound C12=CC(SCC)=CC=C2SC2=CC=CC=C2N1CCCN1CCN(C)CC1 XCTYLCDETUVOIP-UHFFFAOYSA-N 0.000 description 2
229960004869 thiethylperazine Drugs 0.000 description 2
QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 2
239000005526 vasoconstrictor agent Substances 0.000 description 2
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238000001990 intravenous administration Methods 0.000 description 1
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INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
239000010410 layer Substances 0.000 description 1
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229910052744 lithium Inorganic materials 0.000 description 1
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VUQUOGPMUUJORT-UHFFFAOYSA-N methyl 4-methylbenzenesulfonate Chemical compound COS(=O)(=O)C1=CC=C(C)C=C1 VUQUOGPMUUJORT-UHFFFAOYSA-N 0.000 description 1
229940102396 methyl bromide Drugs 0.000 description 1
AFVPRVLDAPXRCX-UHFFFAOYSA-N methyl naphthalene-2-sulfonate Chemical compound C1=CC=CC2=CC(S(=O)(=O)OC)=CC=C21 AFVPRVLDAPXRCX-UHFFFAOYSA-N 0.000 description 1
125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 1
150000007522 mineralic acids Chemical class 0.000 description 1
NALMPLUMOWIVJC-UHFFFAOYSA-N n,n,4-trimethylbenzeneamine oxide Chemical compound CC1=CC=C([N+](C)(C)[O-])C=C1 NALMPLUMOWIVJC-UHFFFAOYSA-N 0.000 description 1
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BNBNINWPMUTQIE-UHFFFAOYSA-N octahydro-2,6-methano-2h-quinolizin-8-ol Chemical compound C1CN2C3CC(O)CC2CC1C3 BNBNINWPMUTQIE-UHFFFAOYSA-N 0.000 description 1
150000007524 organic acids Chemical class 0.000 description 1
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229910052763 palladium Inorganic materials 0.000 description 1
229960005489 paracetamol Drugs 0.000 description 1
230000007310 pathophysiology Effects 0.000 description 1
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239000000546 pharmaceutical excipient Substances 0.000 description 1
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230000000144 pharmacologic effect Effects 0.000 description 1
SONNWYBIRXJNDC-VIFPVBQESA-N phenylephrine Chemical compound CNC[C@H](O)C1=CC=CC(O)=C1 SONNWYBIRXJNDC-VIFPVBQESA-N 0.000 description 1
229960001802 phenylephrine Drugs 0.000 description 1
229910003446 platinum oxide Inorganic materials 0.000 description 1
IWZKICVEHNUQTL-UHFFFAOYSA-M potassium hydrogen phthalate Chemical compound [K+].OC(=O)C1=CC=CC=C1C([O-])=O IWZKICVEHNUQTL-UHFFFAOYSA-M 0.000 description 1
239000002244 precipitate Substances 0.000 description 1
150000003141 primary amines Chemical class 0.000 description 1
ZJLMKPKYJBQJNH-UHFFFAOYSA-N propane-1,3-dithiol Chemical compound SCCCS ZJLMKPKYJBQJNH-UHFFFAOYSA-N 0.000 description 1
229940043274 prophylactic drug Drugs 0.000 description 1
125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
125000006239 protecting group Chemical group 0.000 description 1
150000008302 pseudopelletierine derivatives Chemical class 0.000 description 1
239000000376 reactant Substances 0.000 description 1
230000036647 reaction Effects 0.000 description 1
239000011541 reaction mixture Substances 0.000 description 1
230000011514 reflex Effects 0.000 description 1
229920006395 saturated elastomer Polymers 0.000 description 1
150000003335 secondary amines Chemical class 0.000 description 1
125000000467 secondary amino group Chemical group [H]N([*:1])[*:2] 0.000 description 1
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230000001953 sensory effect Effects 0.000 description 1
229910052709 silver Inorganic materials 0.000 description 1
239000004332 silver Substances 0.000 description 1
229910052708 sodium Inorganic materials 0.000 description 1
235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
239000011697 sodium iodate Substances 0.000 description 1
235000015281 sodium iodate Nutrition 0.000 description 1
229940032753 sodium iodate Drugs 0.000 description 1
HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
239000011343 solid material Substances 0.000 description 1
239000003506 spasmogen Substances 0.000 description 1
230000000638 stimulation Effects 0.000 description 1
239000000126 substance Substances 0.000 description 1
150000003460 sulfonic acids Chemical class 0.000 description 1
150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
239000001117 sulphuric acid Substances 0.000 description 1
235000011149 sulphuric acid Nutrition 0.000 description 1
208000024891 symptom Diseases 0.000 description 1
239000003826 tablet Substances 0.000 description 1
229910052716 thallium Inorganic materials 0.000 description 1
BKVIYDNLLOSFOA-UHFFFAOYSA-N thallium Chemical compound [Tl] BKVIYDNLLOSFOA-UHFFFAOYSA-N 0.000 description 1
230000001225 therapeutic effect Effects 0.000 description 1
238000002560 therapeutic procedure Methods 0.000 description 1
206010043554 thrombocytopenia Diseases 0.000 description 1
CYHOMWAPJJPNMW-JIGDXULJSA-N tropine Chemical class C1[C@@H](O)C[C@H]2CC[C@@H]1N2C CYHOMWAPJJPNMW-JIGDXULJSA-N 0.000 description 1
210000002700 urine Anatomy 0.000 description 1
230000002792 vascular Effects 0.000 description 1
239000003981 vehicle Substances 0.000 description 1
239000008096 xylene Substances 0.000 description 1

Landscapes

Nitrogen Condensed Heterocyclic Rings (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

CA000597287A 1988-04-26 1989-04-20 Esters d'hexahydro-8-hydroxy-2,6-methano-2h-quinolizin-3 (4h)-one, et composes annexes Expired - Lifetime CA1325634C (fr)

Applications Claiming Priority (2)

Application Number	Priority Date	Filing Date	Title
US18563188A	1988-04-26	1988-04-26
US185,631		1988-04-26

Publications (1)

Publication Number	Publication Date
CA1325634C true CA1325634C (fr)	1993-12-28

Family

ID=22681796

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
CA000597287A Expired - Lifetime CA1325634C (fr)	1988-04-26	1989-04-20	Esters d'hexahydro-8-hydroxy-2,6-methano-2h-quinolizin-3 (4h)-one, et composes annexes

Country Status (9)

Country	Link
CN (1)	CN1035765C (fr)
AR (1)	AR246970A1 (fr)
CA (1)	CA1325634C (fr)
FI (1)	FI91154C (fr)
HU (1)	HU204051B (fr)
IL (1)	IL90082A0 (fr)
NO (1)	NO168106C (fr)
NZ (1)	NZ228853A (fr)
PT (1)	PT90361B (fr)

1989
- 1989-04-20 CA CA000597287A patent/CA1325634C/fr not_active Expired - Lifetime
- 1989-04-21 NZ NZ22885389A patent/NZ228853A/en unknown
- 1989-04-21 AR AR31372789A patent/AR246970A1/es active
- 1989-04-24 HU HU196489A patent/HU204051B/hu unknown
- 1989-04-24 PT PT9036189A patent/PT90361B/pt not_active IP Right Cessation
- 1989-04-25 FI FI891954A patent/FI91154C/fi not_active IP Right Cessation
- 1989-04-25 IL IL90082A patent/IL90082A0/xx unknown
- 1989-04-25 CN CN 89102627 patent/CN1035765C/zh not_active Expired - Lifetime
- 1989-04-25 NO NO891712A patent/NO168106C/no not_active IP Right Cessation

Also Published As

Publication number	Publication date
PT90361B (pt)	1994-07-29
IL90082A0 (en)	1989-12-15
NO891712D0 (no)	1989-04-25
FI891954A7 (fi)	1989-10-27
HU204051B (en)	1991-11-28
FI91154B (fi)	1994-02-15
AR246970A1 (es)	1994-10-31
NO891712L (no)	1989-10-27
FI891954A0 (fi)	1989-04-25
NO168106C (no)	1992-01-15
PT90361A (pt)	1989-11-10
NZ228853A (en)	1990-12-21
CN1037901A (zh)	1989-12-13
NO168106B (no)	1991-10-07
CN1035765C (zh)	1997-09-03
HUT50172A (en)	1989-12-28
FI91154C (fi)	1994-05-25

Legal Events

Date	Code	Title	Description
2010-12-28	MKEX	Expiry
2023-05-26	MKEX	Expiry	Effective date: 20101228

Publication	Publication Date	Title
US4906755A (en)	1990-03-06	Esters of hexahydro-8-hydroxy-2,6-methano-2H-quinolizin-3-(4H)-one and related compounds
EP0266730B1 (fr)	1994-08-10	Esters de l'hexahydro-8-hydroxy-2,6-méthano-2H-quinolizin-3-(4H)-one et composés apparentés
US5011846A (en)	1991-04-30	Medicament compositions derived from quinolizine and quinolizinone and methods of use thereof
JPH11502861A (ja)	1999-03-09	サブスタンスｐアンタゴニストとしての置換ベンゾラクタム化合物
JPH089613B2 (ja)	1996-01-31	Ｎ−（アリールオキシアルキル）ヘテロアリール−８−アザビシクロ〔３．２．１〕オクタン、中間体およびそれらの製法
EP0064317B1 (fr)	1986-02-26	Dérivés du pyrrolo (2,3-d) carbazole, procédé pour leur préparation et leur application thérapeutique
NO140348B (no)	1979-05-07	Analogifremgangsmaate til fremstilling av nye terapeutisk aktive 3-(amino-2-hydroksypropoksy)-isoindolin-1-on-forbindelser
JPH01313477A (ja)	1989-12-18	トランス‐ヘキサヒドロ‐８‐ヒドロキシ‐２，６‐メタノ‐２ｈ‐キノリジン‐３（４ｈ）‐オンのインドール‐３‐カルボン酸エステル類の製法
CA1325634C (fr)	1993-12-28	Esters d'hexahydro-8-hydroxy-2,6-methano-2h-quinolizin-3 (4h)-one, et composes annexes
JPH10505333A (ja)	1998-05-26	イミダゾピリジン−アゾリジノン
US4163853A (en)	1979-08-07	1-(P-phenoxy)benzyl-1,2,3,4,5,6,7,8-octahydroisoquinolines
EP0329932B1 (fr)	1995-10-18	Utilisation des dérivés de la quinolizine et de la quinolizinone pour la manufacture des médicaments
JPH10505332A (ja)	1998-05-26	アシルイミダゾピリジン
IL26424A (en)	1970-08-19	10-or 11-piperidyl-dibenzo(a,d)cycloheptadiene derivatives and their preparation
USRE30452E (en)	1980-12-16	3-Phenoxymorphinans and derivatives thereof
Saxton	1965	Alkaloids of Alstonia Species
SU824894A3 (ru)	1981-04-23	Способ получени производных октагидроили гЕКСАгидРО-бЕНзО/ / циКлОгЕпТА/ /пиРАНОВ
US4214084A (en)	1980-07-22	Ethanopyrrolo[1,2-b]isoquinolines
KR810000689B1 (ko)	1981-06-22	스피로〔인돌린-3,4'-피페리딘]의 제조방법
EP0492020A1 (fr)	1992-07-01	Utilisation de certains esters de la hexahydro-8-hydroxy-2,6-méthano-2H-quinolizine-3(4H)-one et des composés apparentés pour le traitement des maladies cognitives
EP0329905A1 (fr)	1989-08-30	Utilisation des dérivés de la quinolizine et de la quinolizinone pour la manufacture des médicaments pour l'augmentation de la motilité gastrique
EP0329902A1 (fr)	1989-08-30	Utilisation des dérivés de la quinolizinone et de la quinolizine pour la manufacture des médicaments pour le traitement de la psychose
JPS6176489A (ja)	1986-04-18	ヘキサヒドロインドリジン化合物
BE673226A (fr)	1966-06-02