BG99253A - Epi - epibatydine derivatives - Google Patents

Epi - epibatydine derivatives Download PDF

Info

Publication number: BG99253A
Authority: BG; Bulgaria
Prior art keywords: lower alkyl; general formula; compound; aryl; compounds
Prior art date: 1993-12-09

Application number

BG99253A

Other languages

Bulgarian (bg)

English (en)

Inventor

Csaba Szantay

Zsuzsanna Balogh

Istvan Moldvai

Eszter Temesvari

Attila Mandi

Gabor Blasko

Gyula Simig

Gyoergyi Lax

Sandor Drabant

Margit Csoergo

Maria Somogyi

Blanka Lady

Marton Fekete

Katalin Szemeredi

Istvan Gyertyan

Gabor Gigler

Tamas Szallast

Original Assignee

Egyt Gyogyszervegyeszeti Gyar

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.)

1993-12-09

Filing date

1994-12-09

Publication date

1995-09-29

1993-12-09 Priority claimed from HU9303506A external-priority patent/HUT69382A/hu

1993-12-09 Priority claimed from HU9303507A external-priority patent/HUT69389A/hu

1994-12-09 Application filed by Egyt Gyogyszervegyeszeti Gyar filed Critical Egyt Gyogyszervegyeszeti Gyar

1995-09-29 Publication of BG99253A publication Critical patent/BG99253A/bg

Links

150000001875 compounds Chemical class 0.000 claims abstract description 149
-1 amino- Chemical class 0.000 claims abstract description 103
125000000217 alkyl group Chemical group 0.000 claims abstract description 60
150000003839 salts Chemical class 0.000 claims abstract description 43
239000002253 acid Substances 0.000 claims abstract description 36
239000001257 hydrogen Substances 0.000 claims abstract description 19
229910052739 hydrogen Inorganic materials 0.000 claims abstract description 19
125000003118 aryl group Chemical group 0.000 claims abstract description 18
125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 15
125000001072 heteroaryl group Chemical group 0.000 claims abstract description 15
125000003342 alkenyl group Chemical group 0.000 claims abstract description 11
125000000304 alkynyl group Chemical group 0.000 claims abstract description 11
230000000202 analgesic effect Effects 0.000 claims abstract description 10
229910052736 halogen Inorganic materials 0.000 claims abstract description 8
150000002367 halogens Chemical class 0.000 claims abstract description 8
125000003545 alkoxy group Chemical group 0.000 claims abstract description 6
125000000392 cycloalkenyl group Chemical group 0.000 claims abstract description 5
125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims abstract description 4
125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract 5
UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 66
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 45
238000000034 method Methods 0.000 claims description 33
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 19
239000008194 pharmaceutical composition Substances 0.000 claims description 15
238000002360 preparation method Methods 0.000 claims description 15
238000006722 reduction reaction Methods 0.000 claims description 14
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 13
KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 12
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 9
239000000010 aprotic solvent Substances 0.000 claims description 9
239000003054 catalyst Substances 0.000 claims description 9
150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 8
239000003638 chemical reducing agent Substances 0.000 claims description 8
229960000583 acetic acid Drugs 0.000 claims description 7
150000002431 hydrogen Chemical class 0.000 claims description 7
239000007858 starting material Substances 0.000 claims description 7
229910052763 palladium Inorganic materials 0.000 claims description 6
238000007363 ring formation reaction Methods 0.000 claims description 6
238000009903 catalytic hydrogenation reaction Methods 0.000 claims description 5
150000008282 halocarbons Chemical class 0.000 claims description 5
125000001997 phenyl group Chemical class [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
125000004076 pyridyl group Chemical class 0.000 claims description 5
XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 4
ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 claims description 4
229910021626 Tin(II) chloride Inorganic materials 0.000 claims description 4
HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 4
239000004480 active ingredient Substances 0.000 claims description 4
235000011150 stannous chloride Nutrition 0.000 claims description 4
239000011135 tin Substances 0.000 claims description 4
229910052718 tin Inorganic materials 0.000 claims description 4
AXZWODMDQAVCJE-UHFFFAOYSA-L tin(II) chloride (anhydrous) Chemical compound [Cl-].[Cl-].[Sn+2] AXZWODMDQAVCJE-UHFFFAOYSA-L 0.000 claims description 4
239000011701 zinc Substances 0.000 claims description 4
229910052725 zinc Inorganic materials 0.000 claims description 4
241000124008 Mammalia Species 0.000 claims description 3
230000002152 alkylating effect Effects 0.000 claims description 3
230000036592 analgesia Effects 0.000 claims description 3
125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 2
CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 2
125000005278 alkyl sulfonyloxy group Chemical group 0.000 claims description 2
125000005279 aryl sulfonyloxy group Chemical group 0.000 claims description 2
238000003776 cleavage reaction Methods 0.000 claims description 2
239000012362 glacial acetic acid Substances 0.000 claims description 2
229910052742 iron Inorganic materials 0.000 claims description 2
125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 2
230000007017 scission Effects 0.000 claims description 2
239000008096 xylene Substances 0.000 claims description 2
238000005620 Bechamp reaction Methods 0.000 claims 1
125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 claims 1
239000003937 drug carrier Substances 0.000 claims 1
238000010438 heat treatment Methods 0.000 claims 1
125000002252 acyl group Chemical group 0.000 abstract description 3
125000004435 hydrogen atom Chemical class [H]* 0.000 abstract 2
229940124530 sulfonamide Drugs 0.000 abstract 1
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 198
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 138
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 129
HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 122
239000000243 solution Substances 0.000 description 121
239000000203 mixture Substances 0.000 description 104
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 74
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 73
CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 69
239000002244 precipitate Substances 0.000 description 60
239000011541 reaction mixture Substances 0.000 description 60
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 59
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 38
FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 37
JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 36
239000010410 layer Substances 0.000 description 32
CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 31
238000004440 column chromatography Methods 0.000 description 30
HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 29
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 28
238000006243 chemical reaction Methods 0.000 description 28
239000003921 oil Substances 0.000 description 24
CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 22
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 20
PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 19
239000000047 product Substances 0.000 description 19
229910052938 sodium sulfate Inorganic materials 0.000 description 19
235000011152 sodium sulphate Nutrition 0.000 description 19
239000002904 solvent Substances 0.000 description 19
239000008346 aqueous phase Substances 0.000 description 18
UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 18
239000012044 organic layer Substances 0.000 description 17
239000000377 silicon dioxide Substances 0.000 description 17
238000004587 chromatography analysis Methods 0.000 description 16
NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Chemical compound [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 description 16
238000010992 reflux Methods 0.000 description 16
YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 14
239000012279 sodium borohydride Substances 0.000 description 13
229910000033 sodium borohydride Inorganic materials 0.000 description 13
WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 12
XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 12
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 12
229910000029 sodium carbonate Inorganic materials 0.000 description 12
239000007787 solid Substances 0.000 description 12
UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 11
239000001110 calcium chloride Substances 0.000 description 11
229910001628 calcium chloride Inorganic materials 0.000 description 11
238000001816 cooling Methods 0.000 description 11
229910052943 magnesium sulfate Inorganic materials 0.000 description 11
235000019341 magnesium sulphate Nutrition 0.000 description 11
238000002425 crystallisation Methods 0.000 description 10
230000008025 crystallization Effects 0.000 description 10
239000012043 crude product Substances 0.000 description 9
239000012074 organic phase Substances 0.000 description 9
OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 8
239000012359 Methanesulfonyl chloride Substances 0.000 description 8
IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 8
125000004432 carbon atom Chemical group C* 0.000 description 8
239000000706 filtrate Substances 0.000 description 8
QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 8
239000011698 potassium fluoride Substances 0.000 description 8
235000003270 potassium fluoride Nutrition 0.000 description 8
238000000926 separation method Methods 0.000 description 8
125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 7
PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 7
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
BSESWFZTDFVYOD-UHFFFAOYSA-N C1(=CC=CC=C1)[PH2](C1=CC=CC=C1)C1=CC=CC=C1.[N+](=O)([O-])CCCC(C)=O Chemical compound C1(=CC=CC=C1)[PH2](C1=CC=CC=C1)C1=CC=CC=C1.[N+](=O)([O-])CCCC(C)=O BSESWFZTDFVYOD-UHFFFAOYSA-N 0.000 description 6
241000699670 Mus sp. Species 0.000 description 6
230000010933 acylation Effects 0.000 description 6
238000005917 acylation reaction Methods 0.000 description 6
125000001931 aliphatic group Chemical group 0.000 description 6
229910052786 argon Inorganic materials 0.000 description 6
238000001704 evaporation Methods 0.000 description 6
238000001914 filtration Methods 0.000 description 6
229960005181 morphine Drugs 0.000 description 6
239000003960 organic solvent Substances 0.000 description 6
238000007920 subcutaneous administration Methods 0.000 description 6
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 6
235000011054 acetic acid Nutrition 0.000 description 5
230000015572 biosynthetic process Effects 0.000 description 5
239000013078 crystal Substances 0.000 description 5
230000008020 evaporation Effects 0.000 description 5
239000012071 phase Substances 0.000 description 5
238000003786 synthesis reaction Methods 0.000 description 5
238000012360 testing method Methods 0.000 description 5
RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
230000002378 acidificating effect Effects 0.000 description 4
239000011230 binding agent Substances 0.000 description 4
GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 4
229910052794 bromium Inorganic materials 0.000 description 4
229910052799 carbon Inorganic materials 0.000 description 4
OROGSEYTTFOCAN-DNJOTXNNSA-N codeine Chemical compound C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC OROGSEYTTFOCAN-DNJOTXNNSA-N 0.000 description 4
239000000284 extract Substances 0.000 description 4
IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 4
229910000041 hydrogen chloride Inorganic materials 0.000 description 4
229960004127 naloxone Drugs 0.000 description 4
RGPDIGOSVORSAK-STHHAXOLSA-N naloxone hydrochloride Chemical compound Cl.O=C([C@@H]1O2)CC[C@@]3(O)[C@H]4CC5=CC=C(O)C2=C5[C@@]13CCN4CC=C RGPDIGOSVORSAK-STHHAXOLSA-N 0.000 description 4
150000007530 organic bases Chemical class 0.000 description 4
150000004714 phosphonium salts Chemical class 0.000 description 4
125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 4
239000000741 silica gel Substances 0.000 description 4
229910002027 silica gel Inorganic materials 0.000 description 4
239000011975 tartaric acid Substances 0.000 description 4
238000005406 washing Methods 0.000 description 4
241001465754 Metazoa Species 0.000 description 3
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 3
OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 3
KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
150000001299 aldehydes Chemical class 0.000 description 3
150000001338 aliphatic hydrocarbons Chemical class 0.000 description 3
229910001854 alkali hydroxide Inorganic materials 0.000 description 3
150000008044 alkali metal hydroxides Chemical class 0.000 description 3
239000012300 argon atmosphere Substances 0.000 description 3
239000002585 base Substances 0.000 description 3
239000012267 brine Substances 0.000 description 3
150000004649 carbonic acid derivatives Chemical class 0.000 description 3
150000001735 carboxylic acids Chemical class 0.000 description 3
239000003795 chemical substances by application Substances 0.000 description 3
150000008280 chlorinated hydrocarbons Chemical class 0.000 description 3
KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
238000001035 drying Methods 0.000 description 3
230000000694 effects Effects 0.000 description 3
150000004820 halides Chemical class 0.000 description 3
150000002430 hydrocarbons Chemical group 0.000 description 3
239000005457 ice water Substances 0.000 description 3
150000007529 inorganic bases Chemical class 0.000 description 3
239000000543 intermediate Substances 0.000 description 3
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
238000002156 mixing Methods 0.000 description 3
FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 3
VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical class OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 3
229910052698 phosphorus Inorganic materials 0.000 description 3
239000011574 phosphorus Substances 0.000 description 3
HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
238000003756 stirring Methods 0.000 description 3
239000003799 water insoluble solvent Substances 0.000 description 3
NLPRAJRHRHZCQQ-UTLUCORTSA-N (1r,3s,4s)-3-(6-chloropyridin-3-yl)-7-azabicyclo[2.2.1]heptane Chemical compound C1=NC(Cl)=CC=C1[C@H]1[C@@H](N2)CC[C@@H]2C1 NLPRAJRHRHZCQQ-UTLUCORTSA-N 0.000 description 2
AWFZELCPUGEQGQ-NLMNJOOOSA-N (4r,4ar,7s,7ar,12bs)-9-methoxy-3-methyl-2,4,4a,7,7a,13-hexahydro-1h-4,12-methanobenzofuro[3,2-e]isoquinoline-7-ol;dihydrate;hydrochloride Chemical compound O.O.Cl.C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC AWFZELCPUGEQGQ-NLMNJOOOSA-N 0.000 description 2
KIUPCUCGVCGPPA-UHFFFAOYSA-N (5-methyl-2-propan-2-ylcyclohexyl) carbonochloridate Chemical compound CC(C)C1CCC(C)CC1OC(Cl)=O KIUPCUCGVCGPPA-UHFFFAOYSA-N 0.000 description 2
LWRSYTXEQUUTKW-UHFFFAOYSA-N 2,4-dimethoxybenzaldehyde Chemical compound COC1=CC=C(C=O)C(OC)=C1 LWRSYTXEQUUTKW-UHFFFAOYSA-N 0.000 description 2
ALYNCZNDIQEVRV-UHFFFAOYSA-N 4-aminobenzoic acid Chemical compound NC1=CC=C(C(O)=O)C=C1 ALYNCZNDIQEVRV-UHFFFAOYSA-N 0.000 description 2
MBFOTTCUUAIBDW-UHFFFAOYSA-N 5-nitropentan-2-one Chemical compound CC(=O)CCC[N+]([O-])=O MBFOTTCUUAIBDW-UHFFFAOYSA-N 0.000 description 2
AFWWKZCPPRPDQK-UHFFFAOYSA-N 6-chloropyridine-3-carbaldehyde Chemical compound ClC1=CC=C(C=O)C=N1 AFWWKZCPPRPDQK-UHFFFAOYSA-N 0.000 description 2
BVBKQVQQJMWSPL-UHFFFAOYSA-N 6-nitro-1-pyridin-3-ylhex-1-en-3-one Chemical compound [O-][N+](=O)CCCC(=O)C=CC1=CC=CN=C1 BVBKQVQQJMWSPL-UHFFFAOYSA-N 0.000 description 2
VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical class CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 2
102000003840 Opioid Receptors Human genes 0.000 description 2
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210000003169 central nervous system Anatomy 0.000 description 1
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150000002440 hydroxy compounds Chemical class 0.000 description 1
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150000004681 metal hydrides Chemical class 0.000 description 1
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WBYWAXJHAXSJNI-UHFFFAOYSA-N methyl p-hydroxycinnamate Natural products OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 description 1
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LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 1
238000013421 nuclear magnetic resonance imaging Methods 0.000 description 1
JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 1
239000003401 opiate antagonist Substances 0.000 description 1
230000003204 osmotic effect Effects 0.000 description 1
235000006408 oxalic acid Nutrition 0.000 description 1
125000004043 oxo group Chemical group O=* 0.000 description 1
TWNQGVIAIRXVLR-UHFFFAOYSA-N oxo(oxoalumanyloxy)alumane Chemical compound O=[Al]O[Al]=O TWNQGVIAIRXVLR-UHFFFAOYSA-N 0.000 description 1
229910052760 oxygen Inorganic materials 0.000 description 1
239000001301 oxygen Substances 0.000 description 1
230000004526 pharmaceutical effect Effects 0.000 description 1
239000000546 pharmaceutical excipient Substances 0.000 description 1
229910000073 phosphorus hydride Inorganic materials 0.000 description 1
239000006187 pill Substances 0.000 description 1
239000003495 polar organic solvent Substances 0.000 description 1
239000011591 potassium Substances 0.000 description 1
229910052700 potassium Inorganic materials 0.000 description 1
230000003389 potentiating effect Effects 0.000 description 1
235000019260 propionic acid Nutrition 0.000 description 1
125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([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
125000003373 pyrazinyl group Chemical group 0.000 description 1
125000002098 pyridazinyl group Chemical group 0.000 description 1
QJZUKDFHGGYHMC-UHFFFAOYSA-N pyridine-3-carbaldehyde Chemical compound O=CC1=CC=CN=C1 QJZUKDFHGGYHMC-UHFFFAOYSA-N 0.000 description 1
125000005400 pyridylcarbonyl group Chemical group N1=C(C=CC=C1)C(=O)* 0.000 description 1
125000000714 pyrimidinyl group Chemical group 0.000 description 1
IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
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238000006798 ring closing metathesis reaction Methods 0.000 description 1
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229920006395 saturated elastomer Polymers 0.000 description 1
238000012216 screening Methods 0.000 description 1
239000011734 sodium Substances 0.000 description 1
229910052708 sodium Inorganic materials 0.000 description 1
235000017557 sodium bicarbonate Nutrition 0.000 description 1
229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
239000003381 stabilizer Substances 0.000 description 1
239000008107 starch Substances 0.000 description 1
235000019698 starch Nutrition 0.000 description 1
238000010972 statistical evaluation Methods 0.000 description 1
IIACRCGMVDHOTQ-UHFFFAOYSA-N sulfamic acid Chemical compound NS(O)(=O)=O IIACRCGMVDHOTQ-UHFFFAOYSA-N 0.000 description 1
BUUPQKDIAURBJP-UHFFFAOYSA-N sulfinic acid Chemical compound OS=O BUUPQKDIAURBJP-UHFFFAOYSA-N 0.000 description 1
150000003461 sulfonyl halides Chemical class 0.000 description 1
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239000011593 sulfur Substances 0.000 description 1
239000003826 tablet Substances 0.000 description 1
239000000454 talc Substances 0.000 description 1
229910052623 talc Inorganic materials 0.000 description 1
235000012222 talc Nutrition 0.000 description 1
235000002906 tartaric acid Nutrition 0.000 description 1
125000000335 thiazolyl group Chemical group 0.000 description 1
125000001544 thienyl group Chemical group 0.000 description 1
GZNAASVAJNXPPW-UHFFFAOYSA-M tin(4+) chloride dihydrate Chemical compound O.O.[Cl-].[Sn+4] GZNAASVAJNXPPW-UHFFFAOYSA-M 0.000 description 1
FWPIDFUJEMBDLS-UHFFFAOYSA-L tin(II) chloride dihydrate Substances O.O.Cl[Sn]Cl FWPIDFUJEMBDLS-UHFFFAOYSA-L 0.000 description 1
230000001988 toxicity Effects 0.000 description 1
231100000419 toxicity Toxicity 0.000 description 1
VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
239000003981 vehicle Substances 0.000 description 1
125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
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238000009736 wetting Methods 0.000 description 1

Classifications

- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/08—Bridged systems
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids

Landscapes

Chemical & Material Sciences (AREA)
Organic Chemistry (AREA)
Health & Medical Sciences (AREA)
General Chemical & Material Sciences (AREA)
Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
Bioinformatics & Cheminformatics (AREA)
Biomedical Technology (AREA)
Neurology (AREA)
Neurosurgery (AREA)
Chemical Kinetics & Catalysis (AREA)
Pain & Pain Management (AREA)
Medicinal Chemistry (AREA)
Engineering & Computer Science (AREA)
Pharmacology & Pharmacy (AREA)
Life Sciences & Earth Sciences (AREA)
Animal Behavior & Ethology (AREA)
General Health & Medical Sciences (AREA)
Public Health (AREA)
Veterinary Medicine (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Nitrogen Condensed Heterocyclic Rings (AREA)
Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

BG99253A 1993-12-09 1994-12-09 Epi - epibatydine derivatives BG99253A (en)

Applications Claiming Priority (2)

Application Number	Priority Date	Filing Date	Title
HU9303506A HUT69382A (en)	1993-12-09	1993-12-09	7-azabicyclo [2.2.1]heptane derivatives and pharmaceutical compositions containing the same and process for the production thereof
HU9303507A HUT69389A (en)	1993-12-09	1993-12-09	Amino-ciklohexane-derivatives and process for their production

Publications (1)

Publication Number	Publication Date
BG99253A true BG99253A (en)	1995-09-29

Family

ID=26318171

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
BG99253A BG99253A (en)	1993-12-09	1994-12-09	Epi - epibatydine derivatives

Country Status (15)

Country	Link
EP (1)	EP0657455A1 (de)
JP (1)	JPH07291974A (de)
KR (1)	KR950017996A (de)
CN (1)	CN1112118A (de)
BE (1)	BE1008622A3 (de)
BG (1)	BG99253A (de)
CA (1)	CA2137611A1 (de)
CZ (1)	CZ308494A3 (de)
ES (1)	ES2095186B1 (de)
FR (1)	FR2713641B1 (de)
GR (1)	GR1002598B (de)
HR (1)	HRP940980A2 (de)
IT (1)	ITMI942483A1 (de)
PL (1)	PL306204A1 (de)
YU (1)	YU71994A (de)

Families Citing this family (9)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
BE1008622A3 (fr) *	1993-12-09	1996-06-04	Egyt Gyogyszervegyeszeti Gyar	Derives de l'epi-epibatidine.
HUT69381A (en) *	1993-12-09	1995-09-28	Egyt Gyogyszervegyeszeti Gyar	Process for producing (2-chloro pyridyl)-7-azabicyclo [2.2.1.]heptane
CA2196979A1 (en) *	1994-08-25	1996-02-29	T. Y. Shen	7-azabicyclo¬2.2.1\|-heptane and -heptene derivatives as cholinergic receptor ligands
EP0955301A3 (de) *	1998-04-27	2001-04-18	Pfizer Products Inc.	7-Aza-bicyclo[2.2.1]-heptan Derivate, deren Herstellung und Verwendung aufgrund ihrer Affinität für neuronale nikotinische Acetylcholin Rezeptoren
CN101084211A (zh) *	2004-09-20	2007-12-05	泽农医药公司	杂环衍生物及其作为治疗剂的用途
US7884125B2 (en)	2008-04-30	2011-02-08	Universiteit Gent	Straightforward entry to 7-azabicyclo[2.2.1]heptane-1-carbonitriles and subsequent synthesis of epibatidine analogues
US8389561B2 (en)	2008-04-30	2013-03-05	Universiteit Gent	Substituted 7-azabicyclo[2.2.1]heptyl derivatives useful for making pharmaceutical compositions
US8809365B2 (en)	2009-11-04	2014-08-19	Universiteit Gent	1-substituted 2-azabicyclo [3.1.1] heptyl derivatives useful as nicotinic acetylcholine receptor modulators for treating neurologic disorders
CN101863892B (zh) *	2010-06-13	2012-05-09	华东理工大学	地棘蛙素及其类似物的制备方法

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
EP0513174B1 (de) *	1990-02-02	1995-08-16	Schering Corporation	4,5-cycloalkano-3-benzazepin-7-ol-derivate und ihre verwendung
US5314899A (en) *	1992-03-03	1994-05-24	The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services	Epibatidine and derivatives, compositions and methods of treating pain
WO1994022868A1 (en) *	1993-04-01	1994-10-13	University Of Virginia	7-azabicyclo-[2.2.1]-heptane and -heptene derivatives as analgesics and anti-inflammatory agents
BE1008622A3 (fr) *	1993-12-09	1996-06-04	Egyt Gyogyszervegyeszeti Gyar	Derives de l'epi-epibatidine.
EP0664293A1 (de) *	1993-12-24	1995-07-26	Duphar International Research B.V	2-Phenyl-7-azabicycloheptane und 6-Phenyl-8-azabicyclo-octane

1994
- 1994-12-06 BE BE9401109A patent/BE1008622A3/fr not_active IP Right Cessation
- 1994-12-06 FR FR9414632A patent/FR2713641B1/fr not_active Expired - Fee Related
- 1994-12-07 CZ CZ943084A patent/CZ308494A3/cs unknown
- 1994-12-08 CA CA002137611A patent/CA2137611A1/en not_active Abandoned
- 1994-12-08 YU YU71994A patent/YU71994A/sh unknown
- 1994-12-09 ES ES09402520A patent/ES2095186B1/es not_active Expired - Lifetime
- 1994-12-09 GR GR940100548A patent/GR1002598B/el unknown
- 1994-12-09 EP EP94119481A patent/EP0657455A1/de not_active Withdrawn
- 1994-12-09 IT IT94MI002483A patent/ITMI942483A1/it unknown
- 1994-12-09 HR HRP9303507A patent/HRP940980A2/hr not_active Application Discontinuation
- 1994-12-09 KR KR1019940033414A patent/KR950017996A/ko not_active Withdrawn
- 1994-12-09 JP JP6306738A patent/JPH07291974A/ja active Pending
- 1994-12-09 CN CN94119383A patent/CN1112118A/zh active Pending
- 1994-12-09 BG BG99253A patent/BG99253A/bg unknown
- 1994-12-09 PL PL94306204A patent/PL306204A1/xx unknown

Also Published As

Publication number	Publication date
ITMI942483A0 (it)	1994-12-09
GR1002598B (el)	1997-02-12
CZ308494A3 (en)	1995-07-12
PL306204A1 (en)	1995-06-12
FR2713641B1 (fr)	1997-04-11
BE1008622A3 (fr)	1996-06-04
HRP940980A2 (en)	1997-06-30
FR2713641A1 (fr)	1995-06-16
ES2095186A1 (es)	1997-02-01
EP0657455A1 (de)	1995-06-14
CA2137611A1 (en)	1995-06-10
YU71994A (sh)	1997-12-05
CN1112118A (zh)	1995-11-22
ITMI942483A1 (it)	1995-06-09
JPH07291974A (ja)	1995-11-07
KR950017996A (ko)	1995-07-22
ES2095186B1 (es)	1997-09-01

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WO2005037783A2 (fr)	2005-04-28	Composes tricycliques comme inhibiteurs de transport de glycine
JPH07119213B2 (ja)	1995-12-20	ムスカリンリセプターアンタゴニスト
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FR2582309A1 (fr)	1986-11-28	Nouveaux derives du morphinane et de la morphine, leur preparation, leur application comme medicaments et les compositions pharmaceutiques les contenant
JP3035356B2 (ja)	2000-04-24	ピロリジニルヒドロキサム酸化合物及びその製造方法
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BG99253A (en)	1995-09-29	Epi - epibatydine derivatives
EP0326106B1 (de)	1994-07-27	Alkylen-diamine
US5356907A (en)	1994-10-18	1-cycloalkylpyridones as analgesics
EP0537993A1 (de)	1993-04-21	Nikotina-Rezeptoraktivität eine Reihe von Arecolonen und Isoarecolonen
EP0053964B1 (de)	1986-05-07	1(4-Chinolyl)äthanol- bzw. -propanolderivate, diese enthaltende Arzneimittel und Verfahren zu ihrer Herstellung
JPH0543576A (ja)	1993-02-23	２０，２１−ジノルエブルナメニンの新規の誘導体、それらの製造方法及び得られる新規の中間体、それらの薬剤としての使用並びにそれらを含有する組成物
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FR2619817A1 (fr)	1989-03-03	Nouvelles beta carbolines 3-substituees, procede et intermediaires de preparation, application a titre de medicaments et compositions pharmaceutiques les renfermant
GB2044250A (en)	1980-10-15	Azepino (1,2,3-m) - carboline compound and processes for preparing the same
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EP0187619A2 (de)	1986-07-16	1,3-disubstituierte Tetrahydropyridine
EP0209275A1 (de)	1987-01-21	Benz-trisubstituierte 2-Aminotetraline