DE69217945T2 - Azanorbornanderivate - Google Patents
AzanorbornanderivateInfo
- Publication number
- DE69217945T2 DE69217945T2 DE69217945T DE69217945T DE69217945T2 DE 69217945 T2 DE69217945 T2 DE 69217945T2 DE 69217945 T DE69217945 T DE 69217945T DE 69217945 T DE69217945 T DE 69217945T DE 69217945 T2 DE69217945 T2 DE 69217945T2
- Authority
- DE
- Germany
- Prior art keywords
- alkyl
- phenyl
- methylamino
- diphenylmethyl
- pyrrolidine
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 150000001875 compounds Chemical class 0.000 claims abstract description 181
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 43
- 208000027866 inflammatory disease Diseases 0.000 claims abstract description 7
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical group C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 93
- -1 phenyl-(C2-C6)alkyl Chemical group 0.000 claims description 86
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 claims description 66
- 239000001257 hydrogen Substances 0.000 claims description 61
- 229910052739 hydrogen Inorganic materials 0.000 claims description 61
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 60
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 57
- UMRZSTCPUPJPOJ-KNVOCYPGSA-N norbornane Chemical compound C1C[C@H]2CC[C@@H]1C2 UMRZSTCPUPJPOJ-KNVOCYPGSA-N 0.000 claims description 43
- 150000003839 salts Chemical class 0.000 claims description 39
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 38
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 38
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 37
- 238000000034 method Methods 0.000 claims description 34
- 208000035475 disorder Diseases 0.000 claims description 32
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 29
- 125000003118 aryl group Chemical group 0.000 claims description 28
- 229910052757 nitrogen Inorganic materials 0.000 claims description 23
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 21
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 21
- 229910052799 carbon Inorganic materials 0.000 claims description 21
- QDZOEBFLNHCSSF-PFFBOGFISA-N (2S)-2-[[(2R)-2-[[(2S)-1-[(2S)-6-amino-2-[[(2S)-1-[(2R)-2-amino-5-carbamimidamidopentanoyl]pyrrolidine-2-carbonyl]amino]hexanoyl]pyrrolidine-2-carbonyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-N-[(2R)-1-[[(2S)-1-[[(2R)-1-[[(2S)-1-[[(2S)-1-amino-4-methyl-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]pentanediamide Chemical compound C([C@@H](C(=O)N[C@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(N)=O)NC(=O)[C@@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](N)CCCNC(N)=N)C1=CC=CC=C1 QDZOEBFLNHCSSF-PFFBOGFISA-N 0.000 claims description 20
- 102100024304 Protachykinin-1 Human genes 0.000 claims description 20
- 101800003906 Substance P Proteins 0.000 claims description 20
- 125000001424 substituent group Chemical group 0.000 claims description 19
- ZZVUWRFHKOJYTH-UHFFFAOYSA-N diphenhydramine Chemical group C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 claims description 17
- 229910052736 halogen Inorganic materials 0.000 claims description 17
- 125000001072 heteroaryl group Chemical group 0.000 claims description 16
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 claims description 15
- 125000004432 carbon atom Chemical group C* 0.000 claims description 14
- 238000002360 preparation method Methods 0.000 claims description 14
- 241000124008 Mammalia Species 0.000 claims description 13
- 125000002541 furyl group Chemical group 0.000 claims description 13
- 125000001624 naphthyl group Chemical group 0.000 claims description 13
- 125000004076 pyridyl group Chemical group 0.000 claims description 13
- 125000001544 thienyl group Chemical group 0.000 claims description 13
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 12
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 11
- 239000003937 drug carrier Substances 0.000 claims description 11
- 150000002367 halogens Chemical class 0.000 claims description 11
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 11
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 10
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 10
- 125000001153 fluoro group Chemical group F* 0.000 claims description 10
- 238000010438 heat treatment Methods 0.000 claims description 10
- 230000002265 prevention Effects 0.000 claims description 10
- 230000008569 process Effects 0.000 claims description 10
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 9
- 125000002619 bicyclic group Chemical group 0.000 claims description 9
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 9
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 8
- 206010020751 Hypersensitivity Diseases 0.000 claims description 8
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 8
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 8
- UWTDFICHZKXYAC-UHFFFAOYSA-N boron;oxolane Chemical compound [B].C1CCOC1 UWTDFICHZKXYAC-UHFFFAOYSA-N 0.000 claims description 8
- 125000001786 isothiazolyl group Chemical group 0.000 claims description 8
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 8
- 125000002971 oxazolyl group Chemical group 0.000 claims description 8
- 239000001301 oxygen Substances 0.000 claims description 8
- 229910052760 oxygen Inorganic materials 0.000 claims description 8
- 125000005493 quinolyl group Chemical group 0.000 claims description 8
- 239000003890 substance P antagonist Substances 0.000 claims description 8
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 8
- 125000000335 thiazolyl group Chemical group 0.000 claims description 8
- 125000001425 triazolyl group Chemical group 0.000 claims description 8
- 125000004204 2-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C([H])=C1[H] 0.000 claims description 7
- 125000000217 alkyl group Chemical group 0.000 claims description 7
- 239000003638 chemical reducing agent Substances 0.000 claims description 7
- 230000000694 effects Effects 0.000 claims description 7
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 6
- 125000004952 trihaloalkoxy group Chemical group 0.000 claims description 6
- 208000019901 Anxiety disease Diseases 0.000 claims description 5
- 208000002193 Pain Diseases 0.000 claims description 5
- 208000028017 Psychotic disease Diseases 0.000 claims description 5
- 208000025747 Rheumatic disease Diseases 0.000 claims description 5
- 239000005864 Sulphur Substances 0.000 claims description 5
- 230000036506 anxiety Effects 0.000 claims description 5
- 125000005982 diphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 5
- 150000002466 imines Chemical class 0.000 claims description 5
- 230000001404 mediated effect Effects 0.000 claims description 5
- CWWARWOPSKGELM-SARDKLJWSA-N methyl (2s)-2-[[(2s)-2-[[2-[[(2s)-2-[[(2s)-2-[[(2s)-5-amino-2-[[(2s)-5-amino-2-[[(2s)-1-[(2s)-6-amino-2-[[(2s)-1-[(2s)-2-amino-5-(diaminomethylideneamino)pentanoyl]pyrrolidine-2-carbonyl]amino]hexanoyl]pyrrolidine-2-carbonyl]amino]-5-oxopentanoyl]amino]-5 Chemical compound C([C@@H](C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)OC)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H]1N(CCC1)C(=O)[C@@H](N)CCCN=C(N)N)C1=CC=CC=C1 CWWARWOPSKGELM-SARDKLJWSA-N 0.000 claims description 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 5
- 102000005962 receptors Human genes 0.000 claims description 5
- 108020003175 receptors Proteins 0.000 claims description 5
- 230000005062 synaptic transmission Effects 0.000 claims description 5
- VDINWIILANKUET-UHFFFAOYSA-N 2-[4-[(2-methoxyphenyl)methylamino]-5-phenylpyrrolidin-3-yl]ethanol Chemical compound COC1=CC=CC=C1CNC1C(C=2C=CC=CC=2)NCC1CCO VDINWIILANKUET-UHFFFAOYSA-N 0.000 claims description 4
- XRMGKNRDJRECLI-UHFFFAOYSA-N 2-[5-benzhydryl-1-benzyl-4-[(2-methoxyphenyl)methylamino]pyrrolidin-3-yl]ethanol Chemical compound COC1=CC=CC=C1CNC1C(C(C=2C=CC=CC=2)C=2C=CC=CC=2)N(CC=2C=CC=CC=2)CC1CCO XRMGKNRDJRECLI-UHFFFAOYSA-N 0.000 claims description 4
- RESWSVKVGXDCQZ-UHFFFAOYSA-N 2-[5-benzhydryl-4-[(5-chloro-2-methoxyphenyl)methylamino]pyrrolidin-3-yl]ethanol Chemical compound COC1=CC=C(Cl)C=C1CNC1C(C(C=2C=CC=CC=2)C=2C=CC=CC=2)NCC1CCO RESWSVKVGXDCQZ-UHFFFAOYSA-N 0.000 claims description 4
- XPLIMHARXAAFIZ-UHFFFAOYSA-N 2-[5-benzhydryl-4-[[2-methoxy-5-(trifluoromethoxy)phenyl]methylamino]pyrrolidin-3-yl]ethanol Chemical compound COC1=CC=C(OC(F)(F)F)C=C1CNC1C(C(C=2C=CC=CC=2)C=2C=CC=CC=2)NCC1CCO XPLIMHARXAAFIZ-UHFFFAOYSA-N 0.000 claims description 4
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims description 4
- 208000027932 Collagen disease Diseases 0.000 claims description 4
- 206010012335 Dependence Diseases 0.000 claims description 4
- 206010016654 Fibrosis Diseases 0.000 claims description 4
- 208000026935 allergic disease Diseases 0.000 claims description 4
- 230000007815 allergy Effects 0.000 claims description 4
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 4
- 239000011203 carbon fibre reinforced carbon Substances 0.000 claims description 4
- 206010009887 colitis Diseases 0.000 claims description 4
- 239000003814 drug Substances 0.000 claims description 4
- 208000024732 dysthymic disease Diseases 0.000 claims description 4
- 230000004761 fibrosis Effects 0.000 claims description 4
- 208000021302 gastroesophageal reflux disease Diseases 0.000 claims description 4
- 230000009610 hypersensitivity Effects 0.000 claims description 4
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- WUBHPPKTNIKCBX-UHFFFAOYSA-N n-[[2-methoxy-5-(trifluoromethoxy)phenyl]methyl]-3-(2h-pyridin-1-yl)bicyclo[2.2.1]heptan-2-amine Chemical compound COC1=CC=C(OC(F)(F)F)C=C1CNC1C(N2C=CC=CC2)C2CCC1C2 WUBHPPKTNIKCBX-UHFFFAOYSA-N 0.000 claims description 4
- 208000004296 neuralgia Diseases 0.000 claims description 4
- 230000002981 neuropathic effect Effects 0.000 claims description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 4
- 208000033808 peripheral neuropathy Diseases 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 230000000392 somatic effect Effects 0.000 claims description 4
- 230000001629 suppression Effects 0.000 claims description 4
- 230000002455 vasospastic effect Effects 0.000 claims description 4
- GQEQQNSXNYYQIC-UHFFFAOYSA-N 2-[4-[(5-tert-butyl-2-methoxyphenyl)methylamino]-5-phenylpyrrolidin-3-yl]ethanol Chemical compound COC1=CC=C(C(C)(C)C)C=C1CNC1C(C=2C=CC=CC=2)NCC1CCO GQEQQNSXNYYQIC-UHFFFAOYSA-N 0.000 claims description 3
- KTAXLXXHUJLLHL-UHFFFAOYSA-N 2-[4-[[2-methoxy-5-(trifluoromethoxy)phenyl]methylamino]-5-phenylpyrrolidin-3-yl]ethanol Chemical compound COC1=CC=C(OC(F)(F)F)C=C1CNC1C(C=2C=CC=CC=2)NCC1CCO KTAXLXXHUJLLHL-UHFFFAOYSA-N 0.000 claims description 3
- KOOMZJWTJMMWFL-UHFFFAOYSA-N 2-[5-benzhydryl-4-[(2-methoxy-4,5-dimethylphenyl)methylamino]pyrrolidin-3-yl]ethanol Chemical compound COC1=CC(C)=C(C)C=C1CNC1C(C(C=2C=CC=CC=2)C=2C=CC=CC=2)NCC1CCO KOOMZJWTJMMWFL-UHFFFAOYSA-N 0.000 claims description 3
- HNBIXAUIFRHXQG-UHFFFAOYSA-N 2-[5-benzhydryl-4-[(2-methoxy-5-propan-2-ylphenyl)methylamino]pyrrolidin-3-yl]ethanol Chemical compound COC1=CC=C(C(C)C)C=C1CNC1C(C(C=2C=CC=CC=2)C=2C=CC=CC=2)NCC1CCO HNBIXAUIFRHXQG-UHFFFAOYSA-N 0.000 claims description 3
- XCMXQWVHBDKVCJ-UHFFFAOYSA-N 2-[5-benzhydryl-4-[(2-methoxy-5-propylphenyl)methylamino]pyrrolidin-3-yl]ethanol Chemical compound CCCC1=CC=C(OC)C(CNC2C(NCC2CCO)C(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 XCMXQWVHBDKVCJ-UHFFFAOYSA-N 0.000 claims description 3
- QJYVSAAMZUNXQL-UHFFFAOYSA-N 2-[5-benzhydryl-4-[(2-methoxyphenyl)methylamino]pyrrolidin-3-yl]ethanol Chemical compound COC1=CC=CC=C1CNC1C(C(C=2C=CC=CC=2)C=2C=CC=CC=2)NCC1CCO QJYVSAAMZUNXQL-UHFFFAOYSA-N 0.000 claims description 3
- CPJKTMWEUAIIKK-UHFFFAOYSA-N 2-[5-benzhydryl-4-[(5-butan-2-yl-2-methoxyphenyl)methylamino]pyrrolidin-3-yl]ethanol Chemical compound CCC(C)C1=CC=C(OC)C(CNC2C(NCC2CCO)C(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 CPJKTMWEUAIIKK-UHFFFAOYSA-N 0.000 claims description 3
- FKRJIXUSHJLFOT-UHFFFAOYSA-N 2-[5-benzhydryl-4-[[2-(trifluoromethoxy)phenyl]methylamino]pyrrolidin-3-yl]ethanol Chemical compound C=1C=CC=C(OC(F)(F)F)C=1CNC1C(CCO)CNC1C(C=1C=CC=CC=1)C1=CC=CC=C1 FKRJIXUSHJLFOT-UHFFFAOYSA-N 0.000 claims description 3
- QEDODNSEHXAWGE-UHFFFAOYSA-N 2-benzhydryl-n-[(5-tert-butyl-2-methoxyphenyl)methyl]-4-(2-methoxyethyl)pyrrolidin-3-amine Chemical compound C=1C(C(C)(C)C)=CC=C(OC)C=1CNC1C(CCOC)CNC1C(C=1C=CC=CC=1)C1=CC=CC=C1 QEDODNSEHXAWGE-UHFFFAOYSA-N 0.000 claims description 3
- 230000009471 action Effects 0.000 claims description 3
- 125000004849 alkoxymethyl group Chemical group 0.000 claims description 3
- 239000004305 biphenyl Substances 0.000 claims description 3
- 235000010290 biphenyl Nutrition 0.000 claims description 3
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 claims description 3
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 3
- PUJQYWWUFKFPOG-UHFFFAOYSA-N n-[(2-methoxyphenyl)methyl]-3-(2h-pyridin-1-yl)bicyclo[2.2.1]heptan-2-amine Chemical compound COC1=CC=CC=C1CNC1C(N2C=CC=CC2)C2CCC1C2 PUJQYWWUFKFPOG-UHFFFAOYSA-N 0.000 claims description 3
- 229910052717 sulfur Inorganic materials 0.000 claims description 3
- 239000011593 sulfur Substances 0.000 claims description 3
- NEQGPRPDZQDVGF-FRDKBHKLSA-N 2-[(3r,4s,5s)-5-benzhydryl-4-[(5-tert-butyl-2-methoxyphenyl)methylamino]pyrrolidin-3-yl]ethanol Chemical compound COC1=CC=C(C(C)(C)C)C=C1CN[C@@H]1[C@H](C(C=2C=CC=CC=2)C=2C=CC=CC=2)NC[C@H]1CCO NEQGPRPDZQDVGF-FRDKBHKLSA-N 0.000 claims description 2
- XMPLOIZGCOEKQG-UHFFFAOYSA-N 2-[5-benzhydryl-4-[(2-methoxy-5-propan-2-ylphenyl)methylamino]pyrrolidin-3-yl]acetic acid Chemical compound COC1=CC=C(C(C)C)C=C1CNC1C(C(C=2C=CC=CC=2)C=2C=CC=CC=2)NCC1CC(O)=O XMPLOIZGCOEKQG-UHFFFAOYSA-N 0.000 claims description 2
- OTMKWJKWIKIUDQ-UHFFFAOYSA-N 2-[5-benzhydryl-4-[(5-tert-butyl-2-methylphenyl)methylamino]pyrrolidin-3-yl]ethanol Chemical compound CC1=CC=C(C(C)(C)C)C=C1CNC1C(C(C=2C=CC=CC=2)C=2C=CC=CC=2)NCC1CCO OTMKWJKWIKIUDQ-UHFFFAOYSA-N 0.000 claims description 2
- GUAPYAQOMRPHHD-UHFFFAOYSA-N 2-[5-benzhydryl-4-[[5-tert-butyl-2-(trifluoromethoxy)phenyl]methylamino]pyrrolidin-3-yl]ethanol Chemical compound CC(C)(C)C1=CC=C(OC(F)(F)F)C(CNC2C(NCC2CCO)C(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 GUAPYAQOMRPHHD-UHFFFAOYSA-N 0.000 claims description 2
- QDTIOWBJATZUQX-UHFFFAOYSA-N 3-[5-benzhydryl-4-[(2-methoxy-5-propan-2-ylphenyl)methylamino]pyrrolidin-3-yl]-n',n'-dimethylpropanehydrazide Chemical compound COC1=CC=C(C(C)C)C=C1CNC1C(C(C=2C=CC=CC=2)C=2C=CC=CC=2)NCC1CCC(=O)NN(C)C QDTIOWBJATZUQX-UHFFFAOYSA-N 0.000 claims description 2
- 208000013586 Complex regional pain syndrome type 1 Diseases 0.000 claims description 2
- 201000001947 Reflex Sympathetic Dystrophy Diseases 0.000 claims description 2
- MCQRPQCQMGVWIQ-UHFFFAOYSA-N boron;methylsulfanylmethane Chemical compound [B].CSC MCQRPQCQMGVWIQ-UHFFFAOYSA-N 0.000 claims description 2
- CREMABGTGYGIQB-UHFFFAOYSA-N carbon carbon Chemical compound C.C CREMABGTGYGIQB-UHFFFAOYSA-N 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
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- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 5
- 125000002947 alkylene group Chemical group 0.000 claims 1
- 230000003042 antagnostic effect Effects 0.000 claims 1
- 238000011065 in-situ storage Methods 0.000 claims 1
- 238000006268 reductive amination reaction Methods 0.000 claims 1
- MFPWEWYKQYMWRO-UHFFFAOYSA-N tert-butyl carboxy carbonate Chemical compound CC(C)(C)OC(=O)OC(O)=O MFPWEWYKQYMWRO-UHFFFAOYSA-N 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 abstract description 5
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- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 207
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 187
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 122
- 239000000243 solution Substances 0.000 description 86
- 239000011541 reaction mixture Substances 0.000 description 81
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 60
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 58
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- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 40
- 238000006243 chemical reaction Methods 0.000 description 40
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 37
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 37
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 33
- 239000000047 product Substances 0.000 description 31
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 30
- 239000000203 mixture Substances 0.000 description 30
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 29
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 29
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 27
- 238000005160 1H NMR spectroscopy Methods 0.000 description 26
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 25
- 239000000741 silica gel Substances 0.000 description 24
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- 238000001819 mass spectrum Methods 0.000 description 22
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- APGATCOKFDLOAX-UHFFFAOYSA-N tert-butyl N-[3-(2H-pyridin-1-yl)-2-bicyclo[2.2.1]heptanyl]carbamate Chemical compound N1(CC=CC=C1)C1C2CCC(C1NC(=O)OC(C)(C)C)C2 APGATCOKFDLOAX-UHFFFAOYSA-N 0.000 description 1
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- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
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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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/14—Nitrogen atoms not forming part of a nitro radical
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Neurosurgery (AREA)
- Rheumatology (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Pain & Pain Management (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Luminescent Compositions (AREA)
- Ink Jet (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Fertilizers (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US71988491A | 1991-06-21 | 1991-06-21 | |
| PCT/US1992/004697 WO1993000330A2 (en) | 1991-06-21 | 1992-06-11 | Azanorbornane derivatives |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| DE69217945D1 DE69217945D1 (de) | 1997-04-10 |
| DE69217945T2 true DE69217945T2 (de) | 1997-06-12 |
Family
ID=24891766
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE69217945T Expired - Fee Related DE69217945T2 (de) | 1991-06-21 | 1992-06-11 | Azanorbornanderivate |
Country Status (18)
| Country | Link |
|---|---|
| US (1) | US5604252A (cg-RX-API-DMAC10.html) |
| EP (1) | EP0591333B1 (cg-RX-API-DMAC10.html) |
| KR (1) | KR940701384A (cg-RX-API-DMAC10.html) |
| AT (1) | ATE149497T1 (cg-RX-API-DMAC10.html) |
| AU (1) | AU2188992A (cg-RX-API-DMAC10.html) |
| CA (1) | CA2111335A1 (cg-RX-API-DMAC10.html) |
| DE (1) | DE69217945T2 (cg-RX-API-DMAC10.html) |
| DK (1) | DK0591333T3 (cg-RX-API-DMAC10.html) |
| FI (1) | FI935726A7 (cg-RX-API-DMAC10.html) |
| HU (1) | HUT68957A (cg-RX-API-DMAC10.html) |
| IE (1) | IE921987A1 (cg-RX-API-DMAC10.html) |
| IL (1) | IL102208A0 (cg-RX-API-DMAC10.html) |
| MX (1) | MX9203053A (cg-RX-API-DMAC10.html) |
| NO (1) | NO934727D0 (cg-RX-API-DMAC10.html) |
| PT (1) | PT100607A (cg-RX-API-DMAC10.html) |
| TW (1) | TW202432B (cg-RX-API-DMAC10.html) |
| WO (1) | WO1993000330A2 (cg-RX-API-DMAC10.html) |
| ZA (1) | ZA924527B (cg-RX-API-DMAC10.html) |
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| US5232929A (en) | 1990-11-28 | 1993-08-03 | Pfizer Inc. | 3-aminopiperidine derivatives and related nitrogen containing heterocycles and pharmaceutical compositions and use |
| US5364943A (en) * | 1991-11-27 | 1994-11-15 | Pfizer Inc. | Preparation of substituted piperidines |
| EP0919245A3 (en) | 1991-09-20 | 2000-11-15 | Glaxo Group Limited | NK-1 receptor antagonist and a systemic antiinflammatory corticosteroid for the treatment of emesis |
| ES2164657T3 (es) * | 1992-05-18 | 2002-03-01 | Pfizer | Derivados aza-biciclicos puenteados como antagonistas de la sustancia p. |
| AU4396193A (en) * | 1992-08-04 | 1994-03-03 | Pfizer Inc. | 3-benzylamino-2-phenyl-piperidine derivatives as substance p receptor antagonists |
| EP1114823A3 (en) * | 1992-08-19 | 2001-07-18 | Pfizer Inc. | Substituted benzylamino nitrogen containing non-aromatic heterocycles |
| JP2722279B2 (ja) * | 1992-12-10 | 1998-03-04 | ファイザー・インク． | アミノメチレンで置換した非芳香族複素環式化合物及びサブスタンスｐのアンタゴニストとしての使用 |
| FR2700472B1 (fr) | 1993-01-19 | 1995-02-17 | Rhone Poulenc Rorer Sa | Association synergisante ayant un effet antagoniste des récepteurs NK1 et NK2. |
| US5340826A (en) * | 1993-02-04 | 1994-08-23 | Pfizer Inc. | Pharmaceutical agents for treatment of urinary incontinence |
| US5635510A (en) * | 1993-05-06 | 1997-06-03 | Merrell Pharmaceuticals Inc. | Substituted pyrrolidin-3-yl-alkyl-piperidines |
| US5393762A (en) * | 1993-06-04 | 1995-02-28 | Pfizer Inc. | Pharmaceutical agents for treatment of emesis |
| EP0653208A3 (en) * | 1993-11-17 | 1995-10-11 | Pfizer | Substance P antagonists for the treatment or prevention of sunburn. |
| EP0659409A3 (en) * | 1993-11-23 | 1995-08-09 | Pfizer | Substance P antagonists for the inhibition of angiogenesis. |
| EP0655246A1 (en) * | 1993-11-30 | 1995-05-31 | Pfizer Inc. | Substance P antagonists for the treatment of disorders caused by helicobacter pylori or other spiral urease-positive gram-negative bacteria |
| NZ292683A (en) | 1994-08-25 | 1998-07-28 | Merrell Pharma Inc | Piperidine derivatives |
| FR2728165A1 (fr) | 1994-12-19 | 1996-06-21 | Oreal | Utilisation d'un antagoniste de substance p pour le traitement des rougeurs cutanees d'origine neurogene |
| FR2728166A1 (fr) | 1994-12-19 | 1996-06-21 | Oreal | Composition topique contenant un antagoniste de substance p |
| FR2728169A1 (fr) | 1994-12-19 | 1996-06-21 | Oreal | Utilisation d'un antagoniste de substance p pour le traitement des prurits et des dysesthesies oculaires ou palpebrales |
| KR100414321B1 (ko) * | 1995-04-13 | 2004-02-18 | 아벤티스 파마슈티칼스 인크. | 타치키닌수용체길항활성을갖는신규한치환된피페라진유도체 |
| TW458774B (en) | 1995-10-20 | 2001-10-11 | Pfizer | Antiemetic pharmaceutical compositions |
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| FR2741262B1 (fr) | 1995-11-20 | 1999-03-05 | Oreal | Utilisation d'un antagoniste de tnf-alpha pour le traitement des rougeurs cutanees d'origine neurogene |
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| CA2324116A1 (en) * | 1999-10-25 | 2001-04-25 | Susan Beth Sobolov-Jaynes | Nk-1 receptor antagonists and eletriptan for the treatment of migraine |
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| US20020049211A1 (en) * | 2000-09-06 | 2002-04-25 | Sobolov-Jaynes Susan Beth | Combination treatment for depression and anxiety |
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| US20110218176A1 (en) | 2006-11-01 | 2011-09-08 | Barbara Brooke Jennings-Spring | Compounds, methods, and treatments for abnormal signaling pathways for prenatal and postnatal development |
| EP2805945B1 (en) | 2007-01-10 | 2019-04-03 | MSD Italia S.r.l. | Amide substituted indazoles as poly(ADP-ribose)polymerase (PARP) inhibitors |
| JP5319518B2 (ja) | 2007-04-02 | 2013-10-16 | Ｍｓｄ株式会社 | インドールジオン誘導体 |
| AU2008269154B2 (en) | 2007-06-27 | 2014-06-12 | Merck Sharp & Dohme Llc | 4-carboxybenzylamino derivatives as histone deacetylase inhibitors |
| CA2717509A1 (en) | 2008-03-03 | 2009-09-11 | Tiger Pharmatech | Tyrosine kinase inhibitors |
| US9156812B2 (en) | 2008-06-04 | 2015-10-13 | Bristol-Myers Squibb Company | Crystalline form of 6-[(4S)-2-methyl-4-(2-naphthyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]pyridazin-3-amine |
| UA105182C2 (ru) | 2008-07-03 | 2014-04-25 | Ньюрексон, Інк. | Бензоксазины, бензотиазины и родственные соединения, которые имеют ингибирующую nos активность |
| US8691825B2 (en) | 2009-04-01 | 2014-04-08 | Merck Sharp & Dohme Corp. | Inhibitors of AKT activity |
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| EA020553B1 (ru) | 2009-05-12 | 2014-12-30 | Олбани Молекьюлар Рисерч, Инк. | 7-([1,2,4]ТРИАЗОЛО[1,5-α]ПИРИДИН-6-ИЛ)-4-(3,4-ДИХЛОРФЕНИЛ)-1,2,3,4-ТЕТРАГИДРОИЗОХИНОЛИН, ФАРМАЦЕВТИЧЕСКАЯ КОМПОЗИЦИЯ НА ЕГО ОСНОВЕ И СПОСОБЫ ЛЕЧЕНИЯ НЕВРОЛОГИЧЕСКИХ И ПСИХИЧЕСКИХ РАССТРОЙСТВ |
| CN102638981B (zh) | 2009-10-14 | 2015-07-22 | 默沙东公司 | 提高p53活性的取代的哌啶和其用途 |
| US8999957B2 (en) | 2010-06-24 | 2015-04-07 | Merck Sharp & Dohme Corp. | Heterocyclic compounds as ERK inhibitors |
| EP2601293B1 (en) | 2010-08-02 | 2017-12-06 | Sirna Therapeutics, Inc. | RNA INTERFERENCE MEDIATED INHIBITION OF CATENIN (CADHERIN-ASSOCIATED PROTEIN), BETA 1 (CTNNB1) GENE EXPRESSION USING SHORT INTERFERING NUCLEIC ACID (siNA) |
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| EP2608669B1 (en) | 2010-08-23 | 2016-06-22 | Merck Sharp & Dohme Corp. | NOVEL PYRAZOLO[1,5-a]PYRIMIDINE DERIVATIVES AS mTOR INHIBITORS |
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| EP3919620A1 (en) | 2012-05-02 | 2021-12-08 | Sirna Therapeutics, Inc. | Short interfering nucleic acid (sina) compositions |
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| US20140206667A1 (en) | 2012-11-14 | 2014-07-24 | Michela Gallagher | Methods and compositions for treating schizophrenia |
| PL2925888T3 (pl) | 2012-11-28 | 2018-03-30 | Merck Sharp & Dohme Corp. | Kompozycje i sposoby do stosowania w leczeniu nowotworów |
| KR102196882B1 (ko) | 2012-12-20 | 2020-12-30 | 머크 샤프 앤드 돔 코포레이션 | Hdm2 억제제로서의 치환된 이미다조피리딘 |
| WO2014120748A1 (en) | 2013-01-30 | 2014-08-07 | Merck Sharp & Dohme Corp. | 2,6,7,8 substituted purines as hdm2 inhibitors |
| US20160194368A1 (en) | 2013-09-03 | 2016-07-07 | Moderna Therapeutics, Inc. | Circular polynucleotides |
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| EP3706747B1 (en) | 2017-11-08 | 2025-09-03 | Merck Sharp & Dohme LLC | Prmt5 inhibitors |
| US10947234B2 (en) | 2017-11-08 | 2021-03-16 | Merck Sharp & Dohme Corp. | PRMT5 inhibitors |
| WO2020033284A1 (en) | 2018-08-07 | 2020-02-13 | Merck Sharp & Dohme Corp. | Prmt5 inhibitors |
| EP3833668B1 (en) | 2018-08-07 | 2025-03-19 | Merck Sharp & Dohme LLC | Prmt5 inhibitors |
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| WO2020254552A2 (en) * | 2019-06-19 | 2020-12-24 | Grünenthal GmbH | Substituted pyrrolidine amides v |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB8823605D0 (en) * | 1988-10-07 | 1988-11-16 | Merck Sharp & Dohme | Therapeutic agents |
| WO1990005525A1 (en) * | 1988-11-23 | 1990-05-31 | Pfizer Inc. | Quinuclidine derivatives as substance p antagonists |
| UA41251C2 (uk) * | 1990-01-04 | 2001-09-17 | Пфайзер, Інк. | Гідровані азотвмісні гетероциклічні сполуки, похідні піперидину, фармацевтична композиція та спосіб пригнічення активності речовини р в організмі |
| AU648317B2 (en) * | 1990-06-01 | 1994-04-21 | Pfizer Inc. | 3-amino-2-aryl quinuclidines, process for their preparation and pharmaceutical compositions containing them |
| JP2514137B2 (ja) * | 1990-07-23 | 1996-07-10 | フアイザー・インコーポレイテツド | キヌクリジン誘導体 |
| FI931370L (fi) * | 1990-09-28 | 1993-03-26 | Pfizer | Kvaeve innehaollande analoger av icke-aromatiska heterocykliska foereningar med en fusionerad ring |
-
1992
- 1992-06-01 TW TW081104272A patent/TW202432B/zh active
- 1992-06-11 US US08/167,851 patent/US5604252A/en not_active Expired - Fee Related
- 1992-06-11 KR KR1019930703962A patent/KR940701384A/ko not_active Withdrawn
- 1992-06-11 AU AU21889/92A patent/AU2188992A/en not_active Abandoned
- 1992-06-11 FI FI935726A patent/FI935726A7/fi not_active Application Discontinuation
- 1992-06-11 HU HU9303666A patent/HUT68957A/hu unknown
- 1992-06-11 WO PCT/US1992/004697 patent/WO1993000330A2/en not_active Ceased
- 1992-06-11 AT AT92913342T patent/ATE149497T1/de not_active IP Right Cessation
- 1992-06-11 CA CA002111335A patent/CA2111335A1/en not_active Abandoned
- 1992-06-11 DK DK92913342.9T patent/DK0591333T3/da active
- 1992-06-11 EP EP92913342A patent/EP0591333B1/en not_active Expired - Lifetime
- 1992-06-11 DE DE69217945T patent/DE69217945T2/de not_active Expired - Fee Related
- 1992-06-15 IL IL102208A patent/IL102208A0/xx unknown
- 1992-06-19 MX MX9203053A patent/MX9203053A/es unknown
- 1992-06-19 ZA ZA924527A patent/ZA924527B/xx unknown
- 1992-06-19 PT PT100607A patent/PT100607A/pt not_active Application Discontinuation
- 1992-07-01 IE IE198792A patent/IE921987A1/en not_active Application Discontinuation
-
1993
- 1993-12-20 NO NO934727A patent/NO934727D0/no unknown
Also Published As
| Publication number | Publication date |
|---|---|
| ATE149497T1 (de) | 1997-03-15 |
| FI935726A0 (fi) | 1993-12-20 |
| DK0591333T3 (da) | 1997-05-20 |
| NO934727L (no) | 1993-12-20 |
| EP0591333A1 (en) | 1994-04-13 |
| PT100607A (pt) | 1993-08-31 |
| DE69217945D1 (de) | 1997-04-10 |
| WO1993000330A2 (en) | 1993-01-07 |
| IE921987A1 (en) | 1992-12-30 |
| KR940701384A (ko) | 1994-05-28 |
| US5604252A (en) | 1997-02-18 |
| EP0591333B1 (en) | 1997-03-05 |
| IL102208A0 (en) | 1993-01-14 |
| HUT68957A (en) | 1995-08-28 |
| FI935726L (fi) | 1993-12-20 |
| MX9203053A (es) | 1992-12-01 |
| WO1993000330A3 (en) | 1993-03-04 |
| NO934727D0 (no) | 1993-12-20 |
| CA2111335A1 (en) | 1993-01-07 |
| AU2188992A (en) | 1993-01-25 |
| ZA924527B (en) | 1993-12-20 |
| TW202432B (cg-RX-API-DMAC10.html) | 1993-03-21 |
| HU9303666D0 (en) | 1994-04-28 |
| FI935726A7 (fi) | 1993-12-20 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| 8364 | No opposition during term of opposition | ||
| 8339 | Ceased/non-payment of the annual fee |