ZA200204056B - Substituted 1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocines and the use thereof as medicaments. - Google Patents
Substituted 1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocines and the use thereof as medicaments. Download PDFInfo
- Publication number
- ZA200204056B ZA200204056B ZA200204056A ZA200204056A ZA200204056B ZA 200204056 B ZA200204056 B ZA 200204056B ZA 200204056 A ZA200204056 A ZA 200204056A ZA 200204056 A ZA200204056 A ZA 200204056A ZA 200204056 B ZA200204056 B ZA 200204056B
- Authority
- ZA
- South Africa
- Prior art keywords
- compounds
- methyl
- general formula
- denote
- alkyl
- Prior art date
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- NSLKFRGZLUIUKO-UHFFFAOYSA-N ac1l4avw Chemical class C1C2=CC=CC=C2C2CCNC1C2 NSLKFRGZLUIUKO-UHFFFAOYSA-N 0.000 title description 3
- 239000003814 drug Substances 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 85
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 38
- 229910052739 hydrogen Inorganic materials 0.000 claims description 37
- 239000001257 hydrogen Substances 0.000 claims description 37
- -1 methyloxy, ethyloxy Chemical group 0.000 claims description 24
- 239000002253 acid Substances 0.000 claims description 23
- 150000002431 hydrogen Chemical class 0.000 claims description 20
- 150000003839 salts Chemical class 0.000 claims description 19
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 17
- 108010052164 Sodium Channels Proteins 0.000 claims description 16
- 102000018674 Sodium Channels Human genes 0.000 claims description 16
- 238000000034 method Methods 0.000 claims description 16
- 239000000203 mixture Substances 0.000 claims description 16
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 14
- 229910052731 fluorine Inorganic materials 0.000 claims description 13
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 12
- 229910052794 bromium Inorganic materials 0.000 claims description 12
- 229910052801 chlorine Inorganic materials 0.000 claims description 12
- 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 claims description 10
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 9
- 239000008194 pharmaceutical composition Substances 0.000 claims description 9
- 239000002585 base Substances 0.000 claims description 8
- 230000000747 cardiac effect Effects 0.000 claims description 8
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 7
- 206010021143 Hypoxia Diseases 0.000 claims description 6
- 239000003054 catalyst Substances 0.000 claims description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 6
- 239000000543 intermediate Substances 0.000 claims description 6
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 4
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- 125000006367 bivalent amino carbonyl group Chemical group [H]N([*:1])C([*:2])=O 0.000 claims description 4
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- 229910052987 metal hydride Inorganic materials 0.000 claims description 4
- 150000004681 metal hydrides Chemical class 0.000 claims description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 4
- 125000004674 methylcarbonyl group Chemical group CC(=O)* 0.000 claims description 4
- 230000036407 pain Effects 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
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- 125000000217 alkyl group Chemical group 0.000 claims description 3
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- 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 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 2
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- 238000002425 crystallisation Methods 0.000 description 26
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- 239000000047 product Substances 0.000 description 18
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 15
- 239000002904 solvent Substances 0.000 description 15
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 14
- 238000004587 chromatography analysis Methods 0.000 description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
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- 238000006243 chemical reaction Methods 0.000 description 11
- 239000003960 organic solvent Substances 0.000 description 11
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 9
- 150000001412 amines Chemical class 0.000 description 7
- 150000003840 hydrochlorides Chemical class 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 6
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- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 5
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- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 4
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- 238000003756 stirring Methods 0.000 description 4
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 4
- LKSFMIVSEZLAPD-UHFFFAOYSA-N 10-azatricyclo[7.3.1.02,7]trideca-2(7),3,5-trien-6-ol Chemical class C1C2CCNC1CC1=C2C=CC=C1O LKSFMIVSEZLAPD-UHFFFAOYSA-N 0.000 description 3
- ISNYUQWBWALXEY-UHFFFAOYSA-N Batrachotoxin Natural products C=1CC2(C3=CCC4C5(C)CCC(C4)(O)OC53C(O)C3)OCCN(C)CC32C=1C(C)OC(=O)C=1C(C)=CNC=1C ISNYUQWBWALXEY-UHFFFAOYSA-N 0.000 description 3
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- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 101001135571 Mus musculus Tyrosine-protein phosphatase non-receptor type 2 Proteins 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 239000007868 Raney catalyst Substances 0.000 description 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 208000027520 Somatoform disease Diseases 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 150000001347 alkyl bromides Chemical class 0.000 description 1
- 150000001348 alkyl chlorides Chemical class 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- 150000001351 alkyl iodides Chemical class 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 230000001773 anti-convulsant effect Effects 0.000 description 1
- 239000002635 aromatic organic solvent Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 238000005574 benzylation reaction Methods 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 208000026106 cerebrovascular disease Diseases 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 230000036461 convulsion Effects 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 description 1
- SXZIXHOMFPUIRK-UHFFFAOYSA-N diphenylmethanimine Chemical compound C=1C=CC=CC=1C(=N)C1=CC=CC=C1 SXZIXHOMFPUIRK-UHFFFAOYSA-N 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000012025 fluorinating agent Substances 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 150000002306 glutamic acid derivatives Chemical class 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 150000002466 imines Chemical class 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 150000004658 ketimines Chemical class 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 1
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 description 1
- 229910052808 lithium carbonate Inorganic materials 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 238000006140 methanolysis reaction Methods 0.000 description 1
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 description 1
- WCZAXBXVDLKQGV-UHFFFAOYSA-N n,n-dimethyl-2-(7-oxobenzo[c]fluoren-5-yl)oxyethanamine oxide Chemical compound C12=CC=CC=C2C(OCC[N+](C)([O-])C)=CC2=C1C1=CC=CC=C1C2=O WCZAXBXVDLKQGV-UHFFFAOYSA-N 0.000 description 1
- RLKHFSNWQCZBDC-UHFFFAOYSA-N n-(benzenesulfonyl)-n-fluorobenzenesulfonamide Chemical compound C=1C=CC=CC=1S(=O)(=O)N(F)S(=O)(=O)C1=CC=CC=C1 RLKHFSNWQCZBDC-UHFFFAOYSA-N 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000000324 neuroprotective effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 235000011007 phosphoric acid Nutrition 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 239000003586 protic polar solvent Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 150000003385 sodium Chemical class 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 229910001415 sodium ion Inorganic materials 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 231100000765 toxin Toxicity 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/08—Bronchodilators
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- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
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- A—HUMAN NECESSITIES
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- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
- A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P25/00—Drugs for disorders of the nervous system
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- 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
-
- 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
- A61P25/08—Antiepileptics; Anticonvulsants
-
- 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
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
-
- 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
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- 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
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- 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
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
- C07D221/22—Bridged ring systems
- C07D221/26—Benzomorphans
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D307/06—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to ring carbon atoms
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- Pharmacology & Pharmacy (AREA)
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- Animal Behavior & Ethology (AREA)
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- Neurosurgery (AREA)
- Biomedical Technology (AREA)
- Cardiology (AREA)
- Pain & Pain Management (AREA)
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- Physical Education & Sports Medicine (AREA)
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- Urology & Nephrology (AREA)
- Obesity (AREA)
- Vascular Medicine (AREA)
- Pulmonology (AREA)
- Reproductive Health (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Other In-Based Heterocyclic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Description
PS Case 1/1116-Ausland BOEHRINGER INGELHEIM PHARMA KG
Substituted 1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocines and their use as pharmaceutical compositions
The present invention relates to substituted 1,2,3,4,5,6-hexahydro-2 ,6-methano-3- benzazocines of general formula 1
R'
X 4 37 SX
N
9 1 2
EE R’
RY 7 6 R’
R 1 wherein 10 R1and R2 which may be identical or different denote hydrogen, C 1-Cg-alkyl,
C4-Cg-alkyloxy, OH, F, Cl or Br;
R3 and R3' which may be identical or different denote hydrogen, F, Cl, Br, methyl, ethyl, OH, CF3, methoxy or phenyl, which may optionally be substituted by a group selected from among F, Cl, Br, methyl, ethyl, OH, CF3 and methoxy;
R4, RS and R6 which may be identical or different may denote hydrogen, methyl or ethyl, _
X may denote NH2, NH-( C1-Cg-alkyl), N(C1-Cg-alkyl)9, the two
C4-Cg-alkyl groups of which may be identical or different, NH-COH,
NH-CO(C4-Cg-alkyl) or F;
A may denote -(CH2)3-, -CH2-CH2-O-, -CH2-O-CH2-, -(CH2)4-, -CH(C1-Cg-alkyl)-O-CHo-, -(CH2)2-O-CH2-, -(CH2)3-0-, -(CH2)s5-, -CH2-0-(CH2)3-, -(CH2)2-0-(CH2)2-, -(CH2)3-0-CHy-, -(CH2)4-0-, -CH2-O-CH2-CH2-0O-,
Le o’H CHOTA “HO A>
" a ' CN CN ; Ie =A I=:
PY ) : IRE AS \0y optionally in the form of their racemates, their enantiomers, their diastereomers and mixtures thereof, and optionally the pharmacologically acceptable acid addition salts thereof.
Preferred compounds are those of general formula 1 wherein
R1 and R2 which may be identical or different denote hydrogen, methyl, ethyl, methyloxy, ethyloxy, OH, F, Cl or Br;
R3 and R3' which may be identical or different denote hydrogen, F, CI, Br, methyl, ethyl, OH, CF3, methoxy or phenyl, which is substituted by a group selected from among F, Cl, Br and preferably methyl;
R4, RS and RE which may be identical or different may denote hydrogen or methyl;
X may denote NHp, NH-(methyl), N(methyl)p, NH-(ethyl), N(ethyl)o,
NH-COH, NH-COMe or F;
A may denote -CH2-CH2-O-, -CH2-O-CHa-, -CH(methyl)-O-CH-, -CH(ethyl)-O-CHz-, -CH(isopropyl)-O-CH2-, -(CH2)2-O-CH>-, -(CH2)3-0-, -CH2-0-(CH2)3-, -(CH2)2-0O-(CH2)2-, -(CH2)3-O-CH>-, -(CH2)4-0-, -CH2-O-CH2-CH2-O-,
HAL 1) of Aros 0 Ao optionally in the form of their racemates, their enantiomers, their diastereomers and mixtures thereof, and optionally the pharmacologically acceptable acid addition salts thereof.
Particularly preferred are compounds of general formula 1 wherein
R1and R2 which may be identical or different may denote hydrogen or F;
R3 and R3" which may be identical or different may denote hydrogen, F, CI, Br, CF3 or methyl;
R4, RS and R6 which may be identical or different may denote hydrogen or methyl;
X may denote NH, NH-(methyl), N(methyl)o, NH-COH, NH-COMe or F;
-@
A may denote -CH(methyl)-O-CHo-, -CH2-O-CHo2- or
[1] rors optionally in the form of their racemates, their enantiomers, their diastereomers and mixtures thereof, and optionally the pharmacologically acceptable acid addition salts thereof.
Of particular importance according to the invention are compounds of general formula 1, wherein
R1and RZ which may be identical or different may denote hydrogen or F;
R3 and R3' which may be identical or different may denote hydrogen, F, Cl, Br, CF3 or methyl;
R4, RS and R6 which may be identical or different may denote hydrogen or methyl:
X may denote NH2, NH-(methyl) or NH-COH,;
A may denote -CH(Methyl)-O-CHo-, -CH2-O-CHo- or
Ek “HOA optionally in the form of their racemates, their enantiomers, their diastereomers and mixtures thereof, and optionally the pharmacologically acceptable acid addition salts thereof.
Of comparable importance according to the invention are compounds of general formula 1 wherein
R1and R2 which may be identisal or different may denote hydiogeri ui F;
R3 and R3' may denote hydrogen;
R4, RS and R6 which may be identical or different may denote hydrogen or methyl;
X may denote F,
A may denote -CH(methyl)-O-CH2-, optionally in the form of their racemates, their enantiomers, their diastereomers and mixtures thereof, and optionally the pharmacologically acceptable acid addition salts thereof.
In the abovementioned compounds of general formula 1, R1, if it is other than hydrogen, is preferably in the ortho or para position, most preferably in the ortho position in relation to the bridge A. In the abovementioned compounds of general formula 1, R2, if itis other than hydrogen, is preferably in the ortho position in relation to the bridge A.
oN _
In the abovementioned compounds of general formula 1 , R3, if it is other than hydrogen, is preferably in the 7-position, i.e. in the para position relative to the group
X. In the abovementioned compounds of general formula 1, R3', if it is other than hydrogen, is preferably in the 9-position, i.e. in the ortho position relative to the group
X.
Particularly preferred according to the invention are compounds of formula 1 wherein
R3' denotes hydrogen.
Of particular interest are compounds of general formula 1 selected from the group comprising: - (2R,6S,25%)-10-amino-3-[2(2,6-difluorophenyl-methoxy)-propyi]-1,2,3,4,5,6- hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine-dihydrochloride; - (2R,6S,28")-10-amino-3-[2-(benzyloxy)propyll-1,2,3,4,5,6-hexahydro-6,11,11- trimethyl-2,6-methano-3-benzazocine-dihydrochloride; - (2R,6S,11R,2"S)-10-amino-3-[2(2,6-difluorophenyl-methoxy)-propyl]-1,2,3,4,5,6- hexahydro-6,11-dimethyl-2,6-methano-3-benzazocine-dihydrochloride; - (2R,6S8,11S, 2"S)-10-amino-3-[2(2,6-difluorophenyl-methoxy)-propyl]-1,2,3,4,5,6- hexahydro-6,11-dimethyl-2,6-methano-3-benzazocine-dihydrochloride; © 20 - (2R,6S)-10-amino-3-[2(2,6-difluorophenyl-methoxy)-ethyi]-1,2,3,4,5,6-hexahydro- 6,11,11-trimethyl-2,6-methano-3-benzazocine-dihydrochloride; - (2R,6S,2“S,5"S)-10-amino-3-[5"-phenyl-tetrahydrofuran-2“-yl)methyl}-1,2,3 4,5,6- hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine-dihydrochloride; - (2R,6S,2"S)-10-acetamino-3-[2(benzyloxy)propyl]-1.2,3,4,5,6-hexahydro-6,11,11- trimethyl-2,6-methano-3-benzazocine-hydrochloride; = {2R,088,2"S)=10=avetanifo-3-[2(2,B-difiusioprienyl-methoxy)-propylj-1,2,3,4,5,6- hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine-hydrochloride; - (2R,8S,2“S)-10-formylamino-3-[2(2,6-difluorophenyl-methoxy)-propyl]-1.,2,3.4,5,6- hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine-hydrochloride; - (2R,6S,2"S)-10-methylamino-3-[2(2,6-difluorophenyl-methoxy)-propyl]-1,2,3,4,5,6- hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine-dihydrochloride; - (2R,6S,2"S)-10-dimethylamino-3-[2(2,6-difluorophenyl-methoxy)-propyl]- 1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine- dihydrochloride; - (2R,6S,2"S)-10-ethylamino-3-[2(2,6-difluorophenyl-methoxy)-propyl]-1,2,3,4,5,6- hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine-dihydrochloride; - (2R,6S,2°S)-10-amino-7-methyl-3-[2-(benzyloxy)propyl]-1,2,3,4,5,6-hexahydro- 6,11,11-trimethyl-2,6-methano-3-benzazocine-dihydrochloride;
@ - (2R,6S,2"S)-10-amino-7-methyl-3-[2-(2,6-difluorophenyl-methoxy)propyi}- 1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine- dihydrochloride; - (2R,6S, 2“S)-10-amino-7-chloro-3-[2(benzyloxy)-propyl]-1,2,3,4,5,6-hexahydro- 5 6,11,11-trimethyl-2,6-methano-3-benzazocine-dihydrochloride; - (2R,6S, 2“S)-10-amino-7-chloro-3-[2(2,6-difluorophenyl-methoxy)-propyl]- 1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine- dihydrochloride; - (2R,6S, 2"S)-10-amino-7-bromo-3-[2(benzyloxy)-propyl]-1,2,3,4,5,6-hexahydro- 6,11,11-trimethyl-2,6-methano-3-benzazocine-dihydrochloride; - (2R,8S, 2“S)-10-amino-7-bromo-3-[2(2,6-difluorophenyl-methoxy)-propyl}- 1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine- dihydrochloride; - (2R,6S,2"S)-10-amino-7-fluoro-3-[2-(benzyloxy)propyl]-1,2,3,4,5,6-hexahydro- 6,11,11-trimethyl-2,6-methano-3-benzazocine-dihydrochloride; - (2R,6S,2"S,5"S)-10-amino-7-methyl-3-[5“-phenyl-tetrahydrofuran-2“-yl)methyl]- 1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine- dihydrochloride; - (2R,6S, 2"S)-10-amino-7-trifluoromethyl-3-[2(benzyloxy)-propyl]-1,2,3,4,5,6- hexahydro-6-methyl-2,6-methano-3-benzazocine-dihydrochloride; - (2R,8S, 2"S)-10-amino-7-(4-methylphenyl)-3-[2(2,6-difluorophenyl-methoxy)- propyl]-1,2,3,4,5,6-hexahydro-6-methyl-2,6-methano-3-benzazocine- dihydrochloride;
C1-Cg-alkyl denotes a branched or unbranched hydrocarbon group having 1 to 6 carbon atoms which may optionally also contain ring systems. The alkyl substituents fridy be idetitical oF different and may optionally be siibstituted with one or more halogen atoms, preferably fluorine. Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, neopentyl, hexyl, cyclopropylmethyl, cyclobutyl, cyclopentyl and cyclohexyl. In some cases, common abbreviations are also used for the abovementioned alkyl groups, such as for example Me for methyl, Et for ethyl, prop for propyl etc.
C1-Cg-alkyloxy denotes a branched or unbranched hydrocarbon group having 1 to 6 carbon atoms which is linked via an oxygen atom. The alkyloxy substituents may be identical or different. Examples include methyloxy, ethyloxy, propyloxy, isopropyloxy, butyloxy, isobutyloxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, cyclopropylmethyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy. If desired, the term alkoxy is used for the abovementioned alkyloxy groups. Thus, methoxy may be used instead of methyloxy, ethoxy instead of ethyloxy, propoxy instead of propyloxy,
@ etc. In some cases, the abovementioned alkyloxy groups may be replaced by common abbreviations such as, for example, MeO for methyloxy, EtO for ethyloxy,
PropO for propyloxy, etc.
According to the invention, the double-bonded groups representing group A may be linked to the adjacent groups in both possible orientations.
If desired, the compounds of general formula (1) may be converted into the salts thereof, particularly, for pharmaceutical use, into the pharmacologically acceptable acid addition salts thereof with an inorganic or organic acid. Suitable acids for this purpose include, for example, succinic acid, hydrobromic acid, acetic acid, fumaric acid, maleic acid, methanesulphonic acid, lactic acid, phosphoric acid, hydrochloric acid, sulphuric acid, tartaric acid or citric acid. Mixtures of the abovementioned acids may also be used.
The compounds according to the invention are blockers of the voltage-dependent sodium channel. They are compounds which competitively or non-competitively displace batrachotoxin (BTX) with a high affinity (Kj < 1000 nM) from the binding site on the sodium channel. Such substances exhibit "use-dependency” in blocking the sodium channels, i.e. in order for the substances to bind to the sodium channel the sodium channels first have to be activated. The maximum blockade of the sodium channels is only achieved after repeated stimulation of the sodium channels.
Consequently, the substances preferentially bind to sodium channels which are activated repeatedly.
As a resutt, te substances dre tapabie of actifig preferentially in those parts of the body which are pathologically overstimulated. This includes diseases such as arrhythmias, spasms, cardiac and cerebral ischaemia, pain and neurodegenerative diseases of various origins. The following may be mentioned, for example: epilepsy, hypoglycaemia, hypoxia, anoxia, brain trauma, brain oedema, cerebral stroke, perinatal asphyxia, degeneration of the cerebellum, amyotropic lateral sclerosis,
Huntington's disease, Alzheimer's disease, Parkinson's disease, cyclophrenia, hypotonia, cardiac infarct, heart rhythm disorders, angina pectoris, chronic pain, neuropathic pain and local anaesthesia.
Another aspect of the invention therefore relates to the use of compounds of general formula 1 as pharmaceutical compositions, particularly as pharmaceutical compositions in which the blockade of the voltage-dependent sodium channel may have a therapeutic value.
@
The compounds of general formula 1 according to the invention are preferably used to prepare a pharmaceutical composition for the prevention or treatment of arrhythmias, spasms, cardiac and cerebral ischaemias, pain and neurodegenerative disorders.
The compounds of general formula 1 according to the invention are most preferably used as hereinbefore to prepare pharmaceutical compositions for the prevention or treatment of epilepsy, hypoglycaemia, hypoxia, anoxia, brain trauma, brain oedema, cerebral stroke, perinatal asphyxia, degeneration of the cerebellum, amyotropic lateral sclerosis, Huntington's disease, Alzheimer's disease, Parkinson's disease, cyclophrenia, hypotonia, cardiac infarct, heart rhythm disorders, angina pectoris, chronic pain, neuropathic pain and local anaesthesia.
The test system used to detect the blocking effect on the sodium channel is the BTX binding to the sodium channel [S.W. Postma & W.A. Catterall, Mol. Pharmacol 25, 219-227 (1984)] and patch-clamp experiments which can be used to show that the compounds according to the invention block the electrically stimulated sodium channel in a "use-dependent” manner [W.A. Catterall, Trends Pharmacol. Sci., 8, 57- 65 (1987)]. The effect of the substances on various subtypes of sodium channel can be investigated by suitable selection of the cell system (e.g. neuronal, cardiac, DRG cells).
The sodium channel blocking property of the compounds according to the invention can be demonstrated by the blockade of the veratridine-induced glutamate release
IS. Villanueva, P. Freriz, ¥. Dragric, F. Uteyo, Brain Kes. 467, 377-380 (1988)].
Veratridine is a toxin which permanently opens the sodium channel. As a result, there is an increased influx of sodium ions into the cell. By means of the cascade described above, this sodium influx in the neuronal tissue leads to an increased glutamate release. The compounds according to the invention will antagonise this glutamate release.
The anticonvulsant properties of the substances according to the invention have been demonstrated by their protective effect against convulsions induced by a maximum electric shock in mice [M. A. Rogawski & R.J. Porter, Pharmacol. Rev. 42, 223-286 (1990)].
Neuroprotective properties have been demonstrated by the protective effect in a rat-
MCAO model [U. Pschorn & A. J. Carter, J. Stroke Cerebrovascular Diseases, 6, 93-
99 (1996)], a malonate-induced lesion model [ M.F. Beal, Annals of Neurology, 38, 357-366 (1995) and J.B. Schulz, R.T. Matthews, D.R. Henshaw and M.F. Bea,
Neuroscience, 71, 1043-1048 (1996)] and an MPTP-induced degeneration model [J.P. Steiner, et al. Proc. Natl. Acad. Sci. 94, 2019-2024 (1997).
The analgesic effect was shown in a formalin-induced pain model [D. Dubuisson and
S.G. Dennis, Pain, 4, 161-174 (1977)] and in a ligature model [G. J. Bennett & Y.-K.
Xie, Pain 33, 87-107 (1988).
It has also been shown that sodium channel blockers can be used to treat cyclophrenia (manic depressive disease) [J. R. Calabrese, C. Bowden, M.J.
Woyshville; in: Psychopharmacology: The Fourth Generation of Progress (Eds.: D.
E. Bloom and D. J. Kupfer) 1099-1111. New York: Raven Press Ltd.].
The compounds according to the invention 1 may be prepared analogously to methods of synthesis known per se. One possible method of synthesis is shown in diagram 1.
Diagram 1:
R1 R1 7 i
OH J CFs—R- jy
NT A R2 fo NTA R2 ot R3 R4
R® Ra RS R ke R5 2 _ 3
NH, A R2 X NA R2 .
Rr Le R5 R Le R5 1 (where X = amino) 1
The key step is the conversion of the phenol 2 into the compound of formula 1 wherein X = NH; , which is done by means of a Buchwald reaction [J. P. Wolfe, J.
Ahman, J. P. Sadighi, R. A. Singer, S. L. Buchwald, THL 1997, 6367-6370].
The triflates 3 required for this reaction may be prepared from these compounds 2 with trifluoromethanesulphonic acid anhydride in the presence of an auxiliary base.
Suitable auxiliary bases according to the invention include organic amines such as, for example, dimethylaminopyridine, pyridine or tert. amines such as trimethylamine, triethylamine, diisopropylethylamine or DBU (diazabicycloundecene). Of the abovementioned amines, the tert. amines are preferably used, and triethylamine is most preferably used as the auxiliary base. The reaction is carried out in aprotic, organic solvents, preferably in solvents selected from among dimethyiformamide, dimethylacetamide, methylene chloride, toluene or tetrahydrofuran. Methylene chloride should be mentioned as being particularly preferred. The reactions to form the triflates 3 are preferably carried out at temperatures below ambient temperature, more preferably at -50°C to 0°C, most preferably at between -30°C and -5°C. After 0.5to 4 h stirring is continued at ambient temperature until the reaction is complete (about 1-12 h). After working up, the crude products 3 thus obtained are reacted, without further purification, in an aromatic organic solvent, preferably selected from among toluene, benzene or xylene, most preferably toluene, with palladium as catalyst, preferably in the presence of a phosphine ligand, with a nitrogen source, preferably with ketimines, most preferably with benzophenonimine. Suitable palladium catalysts according to the invention include tris(dibenzylidene-acetone)- dipalladium, palladium(il)acetate or tetrakistriphenylphosphine-palladium, for example. Suitable phosphine ligands which may be used include, for example, ligands selected from among DPPF, BINAP, p-tolBINAP, PPho-CHMe-P(tBu)), phosphine-substituted ferrocenes or triphenylphosphine. Tris(dibenzylidene- acetone)-dipalladium/BINAP is preferably used as the catalyst system. The reaction is preferably carried out with the exclusion of moisture and oxygen and preferably at elevated temperature. The solvent used is preferably refluxed during tHe reaction.
The imine adduct obtained as an intermediate can be converted by acid hydrolysis, preferably with dilute inorganic acids, most preferably with dilute hydrochloric acid, into the compounds according to the invention 1 (where X=NH>2). The products are purified by chromatography on silica gel or by crystallisation, preferably by crystallisation of the pharmacologically acceptable acid addition salts, e.g. the hydrochlorides.
As can be seen from the above remarks, the triflates of general formula 3 are of central importance in the synthesis of the compounds of general formula 1 according to the invention.
Accordingly, another aspect of the present invention relates to the intermediate compounds of general formula 3
@
R' 0 OX
PN
F,C 0) NT A R?
Lt = R® rR’ 3 wherein the groups R1, RZ, R3, R3’, R4, RS, R6 and A may be as hereinbefore defined.
In order to synthesise the compounds according to the invention of general formula 1 where X£NH> the following process may be used.
Compounds of formula 1 wherein X = NHC 1-Cg-alkyl or N(C1-Cg-alkyl}2> may be obtained by methods known per se by alkylation of 1 where X=NHo, by reductive amination or by acylation, optionally in the presence of organic bases, with subsequent reduction.
For alkylation, the following method may be used. A compound of general formula 1 where X=NH> is dissolved in a polar organic solvent such as dimethylformamide, dimethylacetamide, methylene chloride, tetrahydrofuran, preferably dimethylformamide or methylene chloride. The resulting solution is mixed with a base and a corresponding alkylating agent. Suitable bases include alkali- and alkaline earth metal hydrides, preferably sodium hydride. Suitable alkylating agents include alkyl halides, such as alkyl chloride, alkyl bromide, particularly alkyl iodide and alkyl tosylatas, masylates; triflates; diclieplsulphates: After conventional wurking up ie alkylated compounds of general formula 1 may be purified by chromatography on silica gel or by crystallisation, optionally in the form of the pharmacologically acceptable addition salts thereof, preferably as hydrochlorides.
In order to prepare the compounds of general formula 1 by reductive amination the amines 1 where X=NH»> are mixed with aldehydes or ketones in the presence of acids such as dilute hydrochloric acid, dilute acetic acid or dilute sulphuric acid, : under otherwise conventional reaction conditions, with cooling, preferably at -50°C to ambient temperature, most preferably between -30°C and 0°C, and the Schiff bases or iminium salts thus formed as intermediates are then reduced. The reduction is carried out using metal hydrides such as sodium borohydride, LiAlH,, Li- alkoxyhydrides, NaBH;, NaBHCN3, NaBH(OAc)s ; sodium borohydride is preferably used. After working up in the usual way, the alkylated compounds of general formula 1 may be purified by chromatography on silica gel or by crystallisation, optionally in
@ the form of their pharmacologically acceptable acid addition salts thereof, preferably as hydrochlorides.
Compounds of formula 1 where X = NHCO(C4-Cg-alkyl) may be prepared by methods known per se by acylating 1 where X=NHo, preferably with acid chlorides or anhydrides. For this, the amino compound of formula 1 where X=NH3 is suspended in an organic solvent, combined with an organic base and the desired acid chloride or anhydride is added. The mixture is kept at ambient temperature for 40 to 60 minutes, preferably 25 to 45 minutes at ambient temperature. Suitable organic solvents are dimethylformamide, dimethylacetamide, methylene chloride, toluene or tetrahydrofuran, methylene chloride being preferred. Suitable organic bases are dimethylaminopyridine, pyridine, tert. amines, e.g. trimethylamine, triethylamine, diisopropylethylamine, DBU (diazabicycloundecene). After working up, the products are purified by chromatography on silica gel or by crystallisation, preferably by crystallisation of the pharmacologically acceptable acid addition salts, e.g. the hydrochlorides.
Starting from the compounds of formula 1 with X = NHCO(C4-Cg-alkyl) which may be obtained by the method described above, compounds of formula 1 with X =
NH(C4-Cg-alkyl) , for example, may also be obtained by reduction with metal hydrides such as LiAlH,, Li-alkoxyhydrides, NaBH4, NaBHCN3;, NaBH(OAc)s, preferably sodium borohydride. These reactions are preferably carried out in ethereal organic solvents, preferably in tetrahydrofuran or dioxan in the presence of
Lewis acids, preferably boron trifluoride etherate, at elevated temperature, preferably above 50°C, most preferably at the reflux temperature of the solvent used. After werking up; the products are purified by chiomatograptiy uli siticd gel or 6y crystallisation, preferably by crystallisation of the pharmacologically acceptable acid addition salts, e.g. the hydrochlorides.
The formylated compounds of formula 1 (X =NHCOH) may be obtained, for example, by reacting the compounds of formula 1 where X=NH2 with formic acid at elevated temperature, preferably at reflux temperature. After working up, the products are purified by chromatography on silica gel or by crystallisation, preferably by crystallisation of the pharmacologically acceptable acid addition salts, e.g. the hydrochlorides.
The fluorine-substituted compounds 1 ( with X= F) may be obtained by methods known per se by diazotisation of 1 where X=NH2 and subsequent decoction with
BF4. Preferably, the reaction is carried out with NOBF, as the diazotisation and
- @ fluorination reagent in ethereal solvents, preferably in tetrahydrofuran or dioxan at elevated temperature, preferably above 50°C, most preferably at the reflux temperature of the solvent used. After working up, the products are purified by chromatography on silica gel or by crystallisation, preferably by crystallisation of the pharmacologically acceptable acid addition salts, e.g. the hydrochlorides.
The 1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocin-10-ols (2) designated as starting compounds in diagram 1 may be obtained using methods known from the prior art. In this context, reference is hereby made to European Patent Application
EP 521422 and the International Patent Applications WO 97/06146 and WO 99/14199.
Compounds of general formula 2_ wherein R3 denotes hydrogen, are prepared starting from the compounds of general formula 4 analogously to the methods of synthesis described in WO99/14199. In order to prepare compounds of general formula 1 wherein R3 does not denote hydrogen, the compounds of general formula 4 first have to be modified. This is done by analogously using methods of synthesis known in principle as described in the following reaction plans. . For example, a p-methyl substituent (R3 equals methyl) may be introduced using the method given in Diagram 2. :
In order to prepare the brominated compound of formula 5 the compounds of formula 4 are dissolved in a suitable solvent, preferably in acetic acid or trifluoroacetic acid, most preferably in a mixture of acetic acid and trifluoroacetic acid and NBS (N-bromosuccinimide) is added batchwise at 0-23°C, preferably at 10°C.
The reastien is sompicte after about 1 to 5 hours. Tire pruduct is Worked Up in the usual way. The products are purified either by crystallisation or by chromatography depending on the crystallisation tendencies of the compounds 5.
@
Me. he : ol "eo NH 8 ~2
R* -_— [ ( | R* R*
R® R Br R° R Br R° a : 4 5 oH ~) Me. N ~) Me. N ~()
Sa — ok
Me R° Rg Me R° ¥ 2 FR i o] 3 z
OH NH OH Nn, A R2 oe — Chr
Me R® i Me R° R 10 2 (where R3 = methyl) = (where R¥ = hydrogen)
Diagram 2:
The benzylation of the compounds 5 to form the compounds 6 is preferably carried out in an organic solvent, preferably in a solvent selected from among dichloromethane, dimethylformamide and dimethylacetamide, particularly preferably in dimethylacetamide. For this, the compounds 5 are dissolved in the solvent and benzyl chloride is added in the presence of a base at a temperature of 0-580°C, particularly preferably at ambient temperature (about 23°C). Suitable bases are organic or inorganic bases. Suitable inorganic bases are the alkali metal- or alkaline earth metal carbonates of lithium, sodium, potassium, calcium such as sodium carbonate, lithium carbonate, potassium carbonate, calcium carbonate and preferably potassium carbonate. Suitable organic bases are preferably organic amines, particularly preferably diisopropylethylamine, triethylamine, cyclic amines such as DBU, or pyridine. After the benzyl chloride has all been added the mixture is stirred for a further 1 to 6, preferably 2 to 4 hours at elevated temperature, preferably at about 50-120°C, particularly preferably at about 100°C, but at most at the boiling temperature of the solvent in question. The product is worked up in the usual way.
The products are purified either by crystallisation or by chromatography depending on the crystallisation tendencies of the compounds 6.
- @
The compounds 7 are prepared from the compounds 6 by reacting with suitable formulating reagents. For this, the compounds 6 are dissolved in a suitable organic solvent, preferably in an anhydrous organic solvent, preferably in an ethereal solvent selected from among diethylether, tetrahydrofuran and dioxan, preferably in diethylether, and butyilithium, preferably dissolved in n-hexane, is added at low temperature, preferably at below -20°C, particularly preferably at a temperature between -50°C and -78°C. After about 0.5 to 2 hours stirring in the temperature range mentioned above, the formulating reagent, preferably dimethyiformamide, is added and stirred for another 0.5 to 2 hours, optionally at slightly elevated temperature, preferably at -30°C to 0°C, particularly preferably at about -10°C. The product is worked up in the usual way. The products are purified either by crystallisation or by chromatography depending on the crystallisation tendencies of the compounds 7.
Reduction of the compounds 7 leads to the methyl compounds 8. For this the compounds 7 are dissolved in a suitable organic solvent, preferably in an anhydrous organic solvent, preferably in an ethereal solvent selected from among diethylether, tetrahydrofuran and dioxan, preferably in tetrahydrofuran, and a suitable reducing agent, preferably a metal salt hydride, particularly preferably NaBH, or NaCNBH;, preferably NaCNBHj3, is added. It is also necessary to add boron trifluoride, or BF s- etherate. After the addition of the reducing agent the mixture is stirred for another 1 to 6 hours, preferably 2 to 4 hours at constant temperature, preferably at ambient temperature. After the addition of a protic solvent, particularly preferably a lower alcohol selected from among methanol, ethanol or isopropanol, particularly preferably methanol and hydrolysis witli arm aqueous decid, preferably With agueous hydrochloric acid, the mixture is stirred for a further 0.5 to 4 hours, optionally at elevated temperature, preferably at a temperature above 50°C, particularly preferably at the reflux temperature of the solvent. The product is worked up in the usual way. The products are purified either by crystallisation or by chromatography depending on the crystallisation tendencies of the compounds 8.
The cleaving of the methoxy group in 8 leads to the hydroxy compounds 9 and is carried out with the use of strong acids, such as Hl and HBr, particularly preferably concentrated HBr at elevated temperature, preferably at more than 50°C, particularly preferably at reflux temperature. There is no need to use a solvent if HBr is used, for example. The reaction is complete after about 1 to 6, preferably 2 to 4 hours. The product is worked up in the usual way. The products are purified either by crystallisation or by chromatography depending on the crystallisation tendencies of
- @ the compounds 9. The cleaving of the methoxy group in 8 to yield the hydroxy compounds 9 may alternatively be carried out using BBr3 analogously to the procedure described for reacting the compounds 17 to obtain the hydroxy compounds 18.
The compounds 10 may be obtained from the compounds 9 by hydrogenolytic cleaving of the benzyl group. This reduction is preferably carried out by catalytic hydrogenation, preferably on palladium catalysts or on Raney nickel, particularly preferably on palladium catalysts in alcoholic solvents, preferably in methanol, at ambient temperature. The product is worked up in the usual way. The products are purified either by crystallisation or by chromatography depending on their crystallisation tendencies.
The compounds of general formula 2 may be prepared starting from the compounds of general formula 10 analogously to the methods of synthesis described in
WO089/14199.
A p-fluoro substituent is introduced by the method shown in diagram 3. To do this, a compound of formula 6 is dissolved in a suitable organic solvent, preferably in an ‘20 anhydrous organic solvent, preferably in an ethereal solvent selected from among diethylether, tetrahydrofuran and dioxan, preferably in diethylether, and buthyllithium, preferably dissolved in n-hexane, is added at low temperature, preferably at below -20°C, particularly preferably at a temperature between -50°C and -78°C. After about 0.5 to 2 hours stirring in the temperature range specified above, a suitable fluorinating agent, preferably N-fluorobenzenesulphonimide, dissolved in one of the selvents mentioned above, is slowly added ard stirring is tontiniued for another 0.5 to 2 hours at constant temperature. The product is worked up in the usual way. The products are purified either by crystallisation or by chromatography depending on their crystallisation tendencies.
Claims (1)
- Patent Claims 1) Compounds of general formula 1 =¥ X Sp" | 2 N A R rR’ R' RY s R R 1 whereinR1 and R2 which may be identical or different denote hydrogen, C4-Cg-alkyl,C1-Cg-alkyloxy, OH, F, Cl or Br;R3 and R3' which may be identical or different denote hydrogen, F, Cl, Br, methyl, ethyl, OH, CF3, methoxy or phenyl, which may optionally be substituted by a group selected from among F, Cl, Br, methyl, ethyl, OH, CF3 and methoxy;R4, RS and R6 which may be identical or different may denote hydrogen, methyl or ethyl, X may denote NH», NH-( C1-Cg-alkyl), N(C1-Cg-alkyl)y, the two C1-Cg-7 alkyl groups of which may be identical or different.NH-CQOH.NIH-_CO(C1-Cg-alkyl) or F;A may denote -(CH2)3-, -CH2-CH2-O-~, -CH2-O-CHz-, -(CH2)4-, -CH(C1-Cg-alkyl)-O-CHa-, -(CH2)2-O-CH2-, -(CH2)3-O-, -(CH2)s-, -CH2-0-(CH2)3-, -(CH2)2-0-(CH2)2-, -(CH2)3-O-CH2-, -(CH2)4-O-,-CH2-0O-CH2-CH2-0O-,IV wa oH Rois of Foi optionally in the form of their racemates, their enantiomers, their diastereomers and mixtures thereof, and optionally the pharmacologically acceptable acid addition salts thereof.- @2) Compounds of general formula 1 according to claim 1, wherein R1 and RZ which may be identical or different denote hydrogen, methyl, ethyl, methyloxy, ethyloxy, OH, F, Cl or Br;R3 and R3' which may be identical or different denote hydrogen, F, CI, Br, methyl, ethyl, OH, CF3, methoxy or phenyl, which may optionally be substituted by a group selected from among F, Cl, Br and preferably methyl;R4, RO and R® which may be identical or different may denote hydrogen or methyl; X may denote NHp, NH-(methyl), N(methyl)o, NH-(ethyl), N(ethyl)o, NH-COH, NH-COMe or F;A may denote -CH2-CH2-0-, -CH2-O-CHa-, -CH(methyl)-O-CHo-, -CH(ethyl)-O-CH2-, -CH(isopropyl)-O-CH2-, -(CH2)2-O-CHo-, -(CH2)3-0-, -CH2-0-(CH2)3-, -(CH2)2-O-(CH2)2-, -(CH2)3-O-CHao-, -(CH2)4-0-, -CH2-O-CH2-CH2-0O-, He I, oH SHOES 7 “HoH optionally in the form of their racemates, their enantiomers, their diastereomers and mixtures thereof, and optionally the pharmacologically acceptable acid addition salts thereof. 3) RN Compounds of general formula 1 according to one of claims 1 or 2, wherein R1 and RZ which may be identical or different may denote hydrogen or F; R3 and R3' which may be identical or different may denote hydrogen, F, Cl, Br, CF3 or methyl; R4, RS and R6 which may be identical or different may denote hydrogen or methyl; X may denote NH2, NH-(methyl), N(methyl)o, NH-COH, NH-COMe or F;A may denote -CH(methyl)-O-CHao-, -CH2-O-CH2- or — Aoki optionally in the form of their racemates, their enantiomers, their diastereomers and mixtures thereof, and optionally the pharmacologically acceptable acid addition salts thereof. 4) Compounds of general formula 1 according to claim 1, 2 or 3, wherein R1 and R2 which may be identical or different may denote hydrogen or F; R3 and R3' which may be identical or different may denote hydrogen, F, CI, Br, CF3 or methyl; R4, RO and R® which may be identical or different may denote hydrogen or methyl; X may denote NHo, NH-(methyl) or NH-COH,; A may denote -CH(methyl)-O-CH2-, -CH2-O-CH2- or[7] ~rorfi~ optionally in the form of their racemates, their enantiomers, their diastereomers and mixtures thereof, and optionally the pharmacologically acceptable acid addition salts thereof. 5) Compounds of general formula 1 according to claim 1, 2 or 3, wherein R1 and R2 which may be identical or different may denote hydrogen or F; R3 and R3' may denote hydrogen; R4, RS and R68 which may be identical or different may denote hydrogen or methyl; X may denote F; A - may aenote Ct {methy=C=CHy, CT optionally in the form of their racemates, their enantiomers, their diastereomers and mixtures thereof, and optionally the pharmacologically acceptable acid addition salts thereof. 6) Pharmaceutical preparation, characterised in that it contains one of the compounds of formula 1 according to one of claims 1 to 5 together with conventional : excipients and carriers. 7) Use of one of the compounds of formula 1 according to one of claims 1 to 5 as a pharmaceutical composition.- @ 8) Use of one of the compounds of formula 1 according to one of claims 1 to 5 for preparing a pharmaceutical composition for the prevention or treatment of diseases or disorders in which blockade of the voltage-dependent sodium channel may be of therapeutic value. 9) Use of one of the compounds of formula 1 according to one of claims 1 to 5 for preparing a pharmaceutical composition for the prevention or treatment of arrhythmias, spasms, cardiac and cerebral ischaemia, pain and neurodegenerative diseases. 10) Use of one of the compounds of formula 1 according to one of claims 1 to 5 for preparing a pharmaceutical composition for the prevention or treatment of epilepsy, hypoglycaemia, hypoxia, anoxia, brain trauma, brain oedema, cerebral stroke, perinatal asphyxia, degeneration of the cerebellum, amyotropic lateral sclerosis, Huntington's disease, Alzheimer's disease, Parkinson's disease, cyclophrenia, hypotonia, cardiac infarct, cardiac rhythm disorders, angina pectoris, chronic pain, neuropathic pain or local anaesthesia. 11) Process for preparing compounds of general formula 1 rR’ X A" 8 N Nol Rf ee a oo, rR Ce R 1 wherein the groups R1, R2, R3, R¥, R4, R9, R6 and A may have the meanings given in claims 1-5 and X denotes NHp, characterised in that compounds of general formula 3 R’ 5d jayF.C” 0 NA R2 Nagi R® s R° R 3 wherein the groups R1, RZ, R3, R3’, R4, RS, R6 and A may have the meanings given in claims 1-5, are reacted with a source of nitrogen in an aromatic solvent with palladium catalysis. 12) Intermediate compounds of general formula 3 Rr!O..0 S~F.C 0 NT A R? ox! 4 R3 R 5 3 es R R R 3 wherein the groups R1, RZ, R3, R¥', R4, RS, R6 and A may have the meanings given in claims 1-5. 13) Process for preparing compounds of general formula 1 rR! X ayy 8 N Lt R® s R R 1 wherein the groups R1; RZ; R3; RY; RY; RS; RB and A may have the meanings given in claims 1-5, characterised in that compounds of general formula 1_ wherein X denotes NH2 a) are reacted with a base and a corresponding alkylating agent, in a polar organic solvent, to form compounds of general formula 1 wherein X denotes NH-( C4- Cg-alkyl) or N(C1-Cg-alkyl)o, or b) are reacted with aldehydes or ketones, with cooling, in the presence of acids, and the Schiff bases or iminium salts thus formed as intermediates are subsequently reduced with metal hydrides to form compounds of general formula 1 wherein X denotes NH-( C1-Cg-alkyl) or N(C4-Cg-alkyl)o, or c) are reacted, in the presence of a base, with an acid chloride or anhydride to form compounds of general formula 1 wherein X denotes NHCO( C1-Cg-alkyl),or d) the compounds of formula 1 wherein X denotes NHCO( C,-Cs-alkyl), obtained according to step c), are then optionally reduced with metal hydrides, using Lewis acids as catalysts, to obtain compounds of general formula 1 wherein X denotes NH-( C,-Cg-alkyl) or N(C4-Ce-alkyl),, or e) are converted at elevated temperature into the compounds of general formula 1 wherein X denotes NHCOH by reacting with formic acid, or f) are reacted by diazotisation and subsequent decoction with BF, to form the compounds of formula 1 wherein X denotes F. 14) A compound according to claim 1, substantially as herein described and exemplified and/or described with reference to the accompanying drawings.15) An intermediate compound according to claim 12, substantially as herein described and exemplified and/or described with reference to the accompanying drawings.16) A pharmaceutical preparation according to claim 6, substantially as herein described and exemplified and/or described with reference to the accompanying drawings.17) Use according to any of claims 7, 8, 9 or 10, substantially as herein described - © @id exeinipiinica anaior aoserised with references to the accompanying drawings. 18) A process according to claim 11 or 13, substantially as herein described and exemplified and/or described with reference to the accompanying drawings.AMENDED SHEET
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
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DE19957156A DE19957156A1 (en) | 1999-11-27 | 1999-11-27 | New amino and fluoro substituted 1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocine derivatives useful in treatment of e.g. arrythmias, spasms, ischaemia, pain and neurodegenerative disorders |
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ZA200204056B true ZA200204056B (en) | 2003-07-30 |
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ZA200204056A ZA200204056B (en) | 1999-11-27 | 2002-05-22 | Substituted 1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocines and the use thereof as medicaments. |
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EP (1) | EP1235809B1 (en) |
JP (1) | JP2003519687A (en) |
KR (1) | KR20020058042A (en) |
CN (1) | CN1177825C (en) |
AR (1) | AR026586A1 (en) |
AT (1) | ATE254108T1 (en) |
AU (1) | AU5789701A (en) |
BG (1) | BG106682A (en) |
BR (1) | BR0015786A (en) |
CA (1) | CA2383114C (en) |
CO (1) | CO5251469A1 (en) |
CZ (1) | CZ20022120A3 (en) |
DE (2) | DE19957156A1 (en) |
DK (1) | DK1235809T3 (en) |
EA (1) | EA005681B1 (en) |
EE (1) | EE200200267A (en) |
ES (1) | ES2210036T3 (en) |
HK (1) | HK1052176A1 (en) |
HR (1) | HRP20020460A2 (en) |
HU (1) | HUP0204169A3 (en) |
IL (1) | IL149607A0 (en) |
MX (1) | MXPA02003822A (en) |
NO (1) | NO20022457D0 (en) |
NZ (1) | NZ519758A (en) |
PL (1) | PL355493A1 (en) |
PT (1) | PT1235809E (en) |
SK (1) | SK9302002A3 (en) |
TR (1) | TR200302031T4 (en) |
UA (1) | UA72566C2 (en) |
UY (1) | UY26448A1 (en) |
WO (1) | WO2001051471A1 (en) |
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ZA (1) | ZA200204056B (en) |
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DE10204276A1 (en) * | 2002-02-02 | 2003-08-07 | Boehringer Ingelheim Pharma | N-Allyloxyethyl-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocines and their use as pharmaceuticals |
US6683089B2 (en) | 2002-02-02 | 2004-01-27 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | N-allyoxyethyl-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocine-10-ols |
JP6400592B2 (en) * | 2012-11-09 | 2018-10-03 | パーデュー、ファーマ、リミテッド、パートナーシップ | Benzomorphan analogs and uses thereof |
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DE4121821A1 (en) * | 1991-07-02 | 1993-01-14 | Boehringer Ingelheim Kg | NEW BENZOMORPHANE AND ITS USE AS A MEDICAMENT |
US5354758A (en) * | 1992-12-16 | 1994-10-11 | Japan Tobacco Inc. | Benzomorphans useful as NMDA receptor antagonists |
DE19740110A1 (en) * | 1997-09-12 | 1999-03-18 | Boehringer Ingelheim Pharma | New hydroxy substituted benzomorphan derivatives |
DE19907874A1 (en) * | 1999-02-23 | 2000-08-24 | Boehringer Ingelheim Pharma | New N-substituted hexahydro-2,6-methano-3-benzazocin-10-ol derivatives, as tension-dependent sodium channel blockers useful for treating e.g. arrhythmia, spasms, pain or neurodegenerative diseases |
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1999
- 1999-11-27 DE DE19957156A patent/DE19957156A1/en not_active Withdrawn
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2000
- 2000-11-21 PT PT00993781T patent/PT1235809E/en unknown
- 2000-11-21 SK SK930-2002A patent/SK9302002A3/en unknown
- 2000-11-21 CA CA002383114A patent/CA2383114C/en not_active Expired - Fee Related
- 2000-11-21 JP JP2001551853A patent/JP2003519687A/en active Pending
- 2000-11-21 DE DE50004455T patent/DE50004455D1/en not_active Expired - Fee Related
- 2000-11-21 ES ES00993781T patent/ES2210036T3/en not_active Expired - Lifetime
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- 2000-11-21 CZ CZ20022120A patent/CZ20022120A3/en unknown
- 2000-11-21 UA UA2002065301A patent/UA72566C2/en unknown
- 2000-11-21 BR BR0015786-4A patent/BR0015786A/en not_active Expired - Fee Related
- 2000-11-21 WO PCT/EP2000/011585 patent/WO2001051471A1/en not_active Application Discontinuation
- 2000-11-21 EE EEP200200267A patent/EE200200267A/en unknown
- 2000-11-21 EP EP00993781A patent/EP1235809B1/en not_active Expired - Lifetime
- 2000-11-21 AU AU57897/01A patent/AU5789701A/en not_active Abandoned
- 2000-11-21 DK DK00993781T patent/DK1235809T3/en active
- 2000-11-21 YU YU37902A patent/YU37902A/en unknown
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- 2000-11-21 CN CNB008162530A patent/CN1177825C/en not_active Expired - Fee Related
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- 2000-11-21 PL PL00355493A patent/PL355493A1/en not_active Application Discontinuation
- 2000-11-21 MX MXPA02003822A patent/MXPA02003822A/en unknown
- 2000-11-21 TR TR2003/02031T patent/TR200302031T4/en unknown
- 2000-11-21 AT AT00993781T patent/ATE254108T1/en not_active IP Right Cessation
- 2000-11-21 EA EA200200491A patent/EA005681B1/en not_active IP Right Cessation
- 2000-11-21 IL IL14960700A patent/IL149607A0/en unknown
- 2000-11-23 AR ARP000106183A patent/AR026586A1/en not_active Suspension/Interruption
- 2000-11-24 CO CO00090163A patent/CO5251469A1/en not_active Application Discontinuation
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- 2002-05-24 NO NO20022457A patent/NO20022457D0/en not_active Application Discontinuation
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