HU182965B - Process for preparing new n-heterocyclyl-piperidine-4-amine derivatives and acid addition salts thereof - Google Patents
Process for preparing new n-heterocyclyl-piperidine-4-amine derivatives and acid addition salts thereof Download PDFInfo
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- HU182965B HU182965B HU79JA841A HUJA000841A HU182965B HU 182965 B HU182965 B HU 182965B HU 79JA841 A HU79JA841 A HU 79JA841A HU JA000841 A HUJA000841 A HU JA000841A HU 182965 B HU182965 B HU 182965B
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- formula
- compound
- alkyl
- phenyl
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- 150000003839 salts Chemical class 0.000 title claims description 58
- 239000002253 acid Substances 0.000 title claims description 32
- 238000004519 manufacturing process Methods 0.000 title claims description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 166
- -1 1H-benz-imidazol-2-yl Chemical group 0.000 claims abstract description 115
- 239000000739 antihistaminic agent Substances 0.000 claims abstract description 8
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 153
- 239000002585 base Substances 0.000 claims description 134
- 229910052739 hydrogen Inorganic materials 0.000 claims description 85
- 238000000034 method Methods 0.000 claims description 80
- 239000000203 mixture Substances 0.000 claims description 78
- 125000004176 4-fluorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1F)C([H])([H])* 0.000 claims description 64
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 53
- 239000001257 hydrogen Substances 0.000 claims description 48
- 125000000217 alkyl group Chemical group 0.000 claims description 47
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 41
- 238000006243 chemical reaction Methods 0.000 claims description 36
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 34
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 34
- 238000002360 preparation method Methods 0.000 claims description 33
- 239000007858 starting material Substances 0.000 claims description 33
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 30
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 28
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 28
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 25
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 24
- 239000003054 catalyst Substances 0.000 claims description 24
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 23
- 239000003960 organic solvent Substances 0.000 claims description 22
- 125000001424 substituent group Chemical group 0.000 claims description 20
- 229910052757 nitrogen Inorganic materials 0.000 claims description 19
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 18
- UKWHYYKOEPRTIC-UHFFFAOYSA-N mercury(ii) oxide Chemical compound [Hg]=O UKWHYYKOEPRTIC-UHFFFAOYSA-N 0.000 claims description 17
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 17
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 16
- 229910052736 halogen Inorganic materials 0.000 claims description 16
- 150000002367 halogens Chemical class 0.000 claims description 16
- 238000003756 stirring Methods 0.000 claims description 16
- 150000002148 esters Chemical class 0.000 claims description 15
- 239000002904 solvent Substances 0.000 claims description 14
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 13
- 229910052763 palladium Inorganic materials 0.000 claims description 13
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 12
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 12
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 11
- 125000003118 aryl group Chemical group 0.000 claims description 11
- YEXPOXQUZXUXJW-UHFFFAOYSA-N oxolead Chemical compound [Pb]=O YEXPOXQUZXUXJW-UHFFFAOYSA-N 0.000 claims description 11
- 229960000583 acetic acid Drugs 0.000 claims description 10
- 125000003545 alkoxy group Chemical group 0.000 claims description 10
- 125000006239 protecting group Chemical group 0.000 claims description 10
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims description 9
- 239000003795 chemical substances by application Substances 0.000 claims description 9
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 9
- 239000012458 free base Substances 0.000 claims description 9
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 9
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 8
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 8
- 125000003342 alkenyl group Chemical group 0.000 claims description 8
- 230000001387 anti-histamine Effects 0.000 claims description 8
- 125000005059 halophenyl group Chemical group 0.000 claims description 8
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 8
- 150000002576 ketones Chemical class 0.000 claims description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 8
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 8
- BCIIMDOZSUCSEN-UHFFFAOYSA-N piperidin-4-amine Chemical class NC1CCNCC1 BCIIMDOZSUCSEN-UHFFFAOYSA-N 0.000 claims description 8
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 claims description 8
- 125000003386 piperidinyl group Chemical group 0.000 claims description 8
- 229910052717 sulfur Inorganic materials 0.000 claims description 8
- 239000011593 sulfur Substances 0.000 claims description 8
- 229930192474 thiophene Natural products 0.000 claims description 8
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 7
- GUGOEEXESWIERI-UHFFFAOYSA-N Terfenadine Chemical compound C1=CC(C(C)(C)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 GUGOEEXESWIERI-UHFFFAOYSA-N 0.000 claims description 7
- 238000005903 acid hydrolysis reaction Methods 0.000 claims description 7
- 125000003277 amino group Chemical group 0.000 claims description 7
- 229910021529 ammonia Inorganic materials 0.000 claims description 7
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 7
- 125000004432 carbon atom Chemical group C* 0.000 claims description 7
- 230000000694 effects Effects 0.000 claims description 7
- 125000005843 halogen group Chemical group 0.000 claims description 7
- 229910052760 oxygen Inorganic materials 0.000 claims description 7
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 claims description 6
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 6
- 230000002378 acidificating effect Effects 0.000 claims description 6
- 150000001299 aldehydes Chemical class 0.000 claims description 6
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 6
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 5
- 125000006018 1-methyl-ethenyl group Chemical group 0.000 claims description 5
- 150000001412 amines Chemical class 0.000 claims description 5
- 239000004305 biphenyl Substances 0.000 claims description 5
- 235000010290 biphenyl Nutrition 0.000 claims description 5
- 239000000460 chlorine Substances 0.000 claims description 5
- 229910000042 hydrogen bromide Inorganic materials 0.000 claims description 5
- 238000005984 hydrogenation reaction Methods 0.000 claims description 5
- 239000012948 isocyanate Substances 0.000 claims description 5
- 229910044991 metal oxide Inorganic materials 0.000 claims description 5
- 150000004706 metal oxides Chemical class 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 5
- 150000003585 thioureas Chemical class 0.000 claims description 5
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 4
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 4
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 4
- 241001465754 Metazoa Species 0.000 claims description 4
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 4
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 4
- 238000010511 deprotection reaction Methods 0.000 claims description 4
- 239000012362 glacial acetic acid Substances 0.000 claims description 4
- 230000007062 hydrolysis Effects 0.000 claims description 4
- 238000006460 hydrolysis reaction Methods 0.000 claims description 4
- 125000002883 imidazolyl group Chemical group 0.000 claims description 4
- 150000002540 isothiocyanates Chemical class 0.000 claims description 4
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 claims description 4
- 150000003141 primary amines Chemical class 0.000 claims description 4
- 125000004076 pyridyl group Chemical group 0.000 claims description 4
- 239000012312 sodium hydride Substances 0.000 claims description 4
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 4
- 125000001544 thienyl group Chemical group 0.000 claims description 4
- 125000002861 (C1-C4) alkanoyl group Chemical group 0.000 claims description 3
- 125000006555 (C3-C5) cycloalkyl group Chemical group 0.000 claims description 3
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 claims description 3
- 238000005904 alkaline hydrolysis reaction Methods 0.000 claims description 3
- 125000004457 alkyl amino carbonyl group Chemical group 0.000 claims description 3
- 230000029936 alkylation Effects 0.000 claims description 3
- 238000005804 alkylation reaction Methods 0.000 claims description 3
- 125000005002 aryl methyl group Chemical group 0.000 claims description 3
- 125000004104 aryloxy group Chemical group 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 230000002140 halogenating effect Effects 0.000 claims description 3
- BQPIGGFYSBELGY-UHFFFAOYSA-N mercury(2+) Chemical compound [Hg+2] BQPIGGFYSBELGY-UHFFFAOYSA-N 0.000 claims description 3
- 229910052751 metal Chemical class 0.000 claims description 3
- 239000002184 metal Chemical class 0.000 claims description 3
- 125000001624 naphthyl group Chemical group 0.000 claims description 3
- 231100000252 nontoxic Toxicity 0.000 claims description 3
- 230000003000 nontoxic effect Effects 0.000 claims description 3
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims description 3
- 239000002574 poison Substances 0.000 claims description 3
- 238000006268 reductive amination reaction Methods 0.000 claims description 3
- 150000003335 secondary amines Chemical class 0.000 claims description 3
- 125000000446 sulfanediyl group Chemical group *S* 0.000 claims description 3
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 3
- ORTPEEDBOZIXNC-UHFFFAOYSA-N 2-(4-methoxyphenyl)ethyl methanesulfonate Chemical compound COC1=CC=C(CCOS(C)(=O)=O)C=C1 ORTPEEDBOZIXNC-UHFFFAOYSA-N 0.000 claims description 2
- WMPPDTMATNBGJN-UHFFFAOYSA-N 2-phenylethylbromide Chemical compound BrCCC1=CC=CC=C1 WMPPDTMATNBGJN-UHFFFAOYSA-N 0.000 claims description 2
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 2
- RENMDAKOXSCIGH-UHFFFAOYSA-N Chloroacetonitrile Chemical compound ClCC#N RENMDAKOXSCIGH-UHFFFAOYSA-N 0.000 claims description 2
- 229910000288 alkali metal carbonate Inorganic materials 0.000 claims description 2
- 150000008041 alkali metal carbonates Chemical class 0.000 claims description 2
- 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 2
- 125000001188 haloalkyl group Chemical group 0.000 claims description 2
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 claims description 2
- 229910052753 mercury Inorganic materials 0.000 claims description 2
- 229910000474 mercury oxide Inorganic materials 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- CLPYDQPFQYNIDH-UHFFFAOYSA-N n-piperidin-4-yl-1h-benzimidazol-2-amine Chemical compound C1CNCCC1NC1=NC2=CC=CC=C2N1 CLPYDQPFQYNIDH-UHFFFAOYSA-N 0.000 claims description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 2
- 239000007800 oxidant agent Substances 0.000 claims description 2
- 239000001301 oxygen Substances 0.000 claims description 2
- 229960003424 phenylacetic acid Drugs 0.000 claims description 2
- 239000003279 phenylacetic acid Substances 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims 9
- 239000012442 inert solvent Substances 0.000 claims 6
- 206010029897 Obsessive thoughts Diseases 0.000 claims 3
- GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical group NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 claims 2
- MNZMECMQTYGSOI-UHFFFAOYSA-N acetic acid;hydron;bromide Chemical compound Br.CC(O)=O MNZMECMQTYGSOI-UHFFFAOYSA-N 0.000 claims 2
- 125000005279 aryl sulfonyloxy group Chemical group 0.000 claims 2
- HGBCPYMIZWPKMI-UHFFFAOYSA-N aziridin-1-yl(phenyl)methanone Chemical class C=1C=CC=CC=1C(=O)N1CC1 HGBCPYMIZWPKMI-UHFFFAOYSA-N 0.000 claims 2
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims 2
- 125000006267 biphenyl group Chemical group 0.000 claims 2
- 238000010438 heat treatment Methods 0.000 claims 2
- LWJROJCJINYWOX-UHFFFAOYSA-L mercury dichloride Chemical compound Cl[Hg]Cl LWJROJCJINYWOX-UHFFFAOYSA-L 0.000 claims 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims 2
- 231100000614 poison Toxicity 0.000 claims 2
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims 2
- FWVNIQVKUXPNNK-UHFFFAOYSA-N 2-[4-[2-[4-[[1-[(4-fluorophenyl)methyl]benzimidazol-2-yl]amino]piperidin-1-yl]ethyl]phenoxy]acetonitrile Chemical compound C1=CC(F)=CC=C1CN1C2=CC=CC=C2N=C1NC1CCN(CCC=2C=CC(OCC#N)=CC=2)CC1 FWVNIQVKUXPNNK-UHFFFAOYSA-N 0.000 claims 1
- 125000004174 2-benzimidazolyl group Chemical group [H]N1C(*)=NC2=C([H])C([H])=C([H])C([H])=C12 0.000 claims 1
- VMZCDNSFRSVYKQ-UHFFFAOYSA-N 2-phenylacetyl chloride Chemical compound ClC(=O)CC1=CC=CC=C1 VMZCDNSFRSVYKQ-UHFFFAOYSA-N 0.000 claims 1
- GAWIXWVDTYZWAW-UHFFFAOYSA-N C[CH]O Chemical group C[CH]O GAWIXWVDTYZWAW-UHFFFAOYSA-N 0.000 claims 1
- 125000003302 alkenyloxy group Chemical group 0.000 claims 1
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims 1
- 125000005196 alkyl carbonyloxy group Chemical group 0.000 claims 1
- 230000002152 alkylating effect Effects 0.000 claims 1
- 125000004103 aminoalkyl group Chemical group 0.000 claims 1
- 125000005110 aryl thio group Chemical group 0.000 claims 1
- 239000012059 conventional drug carrier Substances 0.000 claims 1
- 230000002255 enzymatic effect Effects 0.000 claims 1
- 238000005886 esterification reaction Methods 0.000 claims 1
- 125000002541 furyl group Chemical group 0.000 claims 1
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims 1
- 125000002349 hydroxyamino group Chemical group [H]ON([H])[*] 0.000 claims 1
- 125000004464 hydroxyphenyl group Chemical group 0.000 claims 1
- BRMYZIKAHFEUFJ-UHFFFAOYSA-L mercury diacetate Chemical compound CC(=O)O[Hg]OC(C)=O BRMYZIKAHFEUFJ-UHFFFAOYSA-L 0.000 claims 1
- 150000004987 o-phenylenediamines Chemical class 0.000 claims 1
- 239000000825 pharmaceutical preparation Substances 0.000 claims 1
- 239000000376 reactant Substances 0.000 claims 1
- 238000007363 ring formation reaction Methods 0.000 claims 1
- 125000000467 secondary amino group Chemical group [H]N([*:1])[*:2] 0.000 claims 1
- 125000001302 tertiary amino group Chemical group 0.000 claims 1
- 229940125715 antihistaminic agent Drugs 0.000 abstract 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 63
- 239000011541 reaction mixture Substances 0.000 description 63
- 239000003480 eluent Substances 0.000 description 47
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 41
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 36
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 32
- 229960001701 chloroform Drugs 0.000 description 32
- 229910052799 carbon Inorganic materials 0.000 description 31
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 30
- 239000000047 product Substances 0.000 description 28
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 27
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 26
- 239000000243 solution Substances 0.000 description 25
- 238000010992 reflux Methods 0.000 description 22
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 21
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 21
- 239000000284 extract Substances 0.000 description 20
- 239000000706 filtrate Substances 0.000 description 18
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 13
- 238000002844 melting Methods 0.000 description 13
- 230000008018 melting Effects 0.000 description 13
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 13
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 12
- 239000000741 silica gel Substances 0.000 description 12
- 229910002027 silica gel Inorganic materials 0.000 description 12
- 238000010898 silica gel chromatography Methods 0.000 description 12
- 238000004440 column chromatography Methods 0.000 description 11
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 10
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 9
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 9
- ZYHQGITXIJDDKC-UHFFFAOYSA-N 2-[2-(2-aminophenyl)ethyl]aniline Chemical group NC1=CC=CC=C1CCC1=CC=CC=C1N ZYHQGITXIJDDKC-UHFFFAOYSA-N 0.000 description 8
- QGJOPFRUJISHPQ-UHFFFAOYSA-N Carbon disulfide Chemical compound S=C=S QGJOPFRUJISHPQ-UHFFFAOYSA-N 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 description 7
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 7
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 7
- 239000012074 organic phase Substances 0.000 description 7
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- GOPHJAFXOPBEHA-UHFFFAOYSA-N ethyl 4-[(3-benzylimidazo[4,5-b]pyridin-2-yl)amino]piperidine-1-carboxylate Chemical compound C1CN(C(=O)OCC)CCC1NC1=NC2=CC=CN=C2N1CC1=CC=CC=C1 GOPHJAFXOPBEHA-UHFFFAOYSA-N 0.000 description 1
- BLQLBGJODBPYFR-UHFFFAOYSA-N ethyl 4-[(6-chloro-1h-benzimidazol-2-yl)amino]piperidine-1-carboxylate Chemical compound C1CN(C(=O)OCC)CCC1NC1=NC2=CC(Cl)=CC=C2N1 BLQLBGJODBPYFR-UHFFFAOYSA-N 0.000 description 1
- GDEBHSGKCAZXEQ-UHFFFAOYSA-N ethyl 4-[(6-fluoro-1h-benzimidazol-2-yl)amino]piperidine-1-carboxylate Chemical compound C1CN(C(=O)OCC)CCC1NC1=NC2=CC(F)=CC=C2N1 GDEBHSGKCAZXEQ-UHFFFAOYSA-N 0.000 description 1
- SHESZUAEWMVGSW-UHFFFAOYSA-N ethyl 4-[(6-methyl-1h-benzimidazol-2-yl)amino]piperidine-1-carboxylate Chemical compound C1CN(C(=O)OCC)CCC1NC1=NC2=CC(C)=CC=C2N1 SHESZUAEWMVGSW-UHFFFAOYSA-N 0.000 description 1
- WRVZFZKPQJCOHX-UHFFFAOYSA-N ethyl 4-[1H-benzimidazol-2-yl(butyl)amino]piperidine-1-carboxylate Chemical compound N=1C2=CC=CC=C2NC=1N(CCCC)C1CCN(C(=O)OCC)CC1 WRVZFZKPQJCOHX-UHFFFAOYSA-N 0.000 description 1
- KMMCSHWHRVGLMQ-UHFFFAOYSA-N ethyl 4-[[1-(4-fluorophenyl)benzimidazol-2-yl]amino]piperidine-1-carboxylate Chemical compound C1CN(C(=O)OCC)CCC1NC1=NC2=CC=CC=C2N1C1=CC=C(F)C=C1 KMMCSHWHRVGLMQ-UHFFFAOYSA-N 0.000 description 1
- CTUCYCZQWKUFNU-UHFFFAOYSA-N ethyl 4-[[2-(benzylamino)-5-chlorophenyl]carbamothioylamino]piperidine-1-carboxylate Chemical compound C1CN(C(=O)OCC)CCC1NC(=S)NC1=CC(Cl)=CC=C1NCC1=CC=CC=C1 CTUCYCZQWKUFNU-UHFFFAOYSA-N 0.000 description 1
- FAZUYZBTSGCVSX-UHFFFAOYSA-N ethyl 4-[[5-chloro-1-[(4-fluorophenyl)methyl]benzimidazol-2-yl]amino]piperidine-1-carboxylate Chemical compound C1CN(C(=O)OCC)CCC1NC1=NC2=CC(Cl)=CC=C2N1CC1=CC=C(F)C=C1 FAZUYZBTSGCVSX-UHFFFAOYSA-N 0.000 description 1
- APGYQNWJFFQIJP-UHFFFAOYSA-N ethyl 4-[butyl-[(2-nitrophenyl)carbamothioyl]amino]piperidine-1-carboxylate Chemical compound C=1C=CC=C([N+]([O-])=O)C=1NC(=S)N(CCCC)C1CCN(C(=O)OCC)CC1 APGYQNWJFFQIJP-UHFFFAOYSA-N 0.000 description 1
- GQQQULCEHJQUJT-UHFFFAOYSA-N ethyl 4-aminopiperidine-1-carboxylate Chemical compound CCOC(=O)N1CCC(N)CC1 GQQQULCEHJQUJT-UHFFFAOYSA-N 0.000 description 1
- LUBGFMZTGFXIIN-UHFFFAOYSA-N ethyl 4-oxopiperidine-1-carboxylate Chemical compound CCOC(=O)N1CCC(=O)CC1 LUBGFMZTGFXIIN-UHFFFAOYSA-N 0.000 description 1
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 1
- 125000004494 ethyl ester group Chemical class 0.000 description 1
- YSPVHAUJXLGZHP-UHFFFAOYSA-N ethyl piperidine-1-carboxylate Chemical compound CCOC(=O)N1CCCCC1 YSPVHAUJXLGZHP-UHFFFAOYSA-N 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000008098 formaldehyde solution Substances 0.000 description 1
- ZHNUHDYFZUAESO-UHFFFAOYSA-N formamide Substances NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 229940052308 general anesthetics halogenated hydrocarbons Drugs 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 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
- 229960001340 histamine Drugs 0.000 description 1
- 239000012456 homogeneous solution Substances 0.000 description 1
- UUBJKHVFGWGJKX-UHFFFAOYSA-N hydrate tetrahydrochloride Chemical compound O.Cl.Cl.Cl.Cl UUBJKHVFGWGJKX-UHFFFAOYSA-N 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-M iodide Chemical compound [I-] XMBWDFGMSWQBCA-UHFFFAOYSA-M 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 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
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 229940046892 lead acetate Drugs 0.000 description 1
- 229910000464 lead oxide Inorganic materials 0.000 description 1
- 239000003589 local anesthetic agent Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N mandelic acid Chemical compound OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- WSFSSNUMVMOOMR-NJFSPNSNSA-N methanone Chemical compound O=[14CH2] WSFSSNUMVMOOMR-NJFSPNSNSA-N 0.000 description 1
- HRDXJKGNWSUIBT-UHFFFAOYSA-N methoxybenzene Chemical group [CH2]OC1=CC=CC=C1 HRDXJKGNWSUIBT-UHFFFAOYSA-N 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- YCDPBTSAQFQAOG-UHFFFAOYSA-N methyl 4-(1h-benzimidazol-2-ylamino)-3-methylpiperidine-1-carboxylate Chemical compound CC1CN(C(=O)OC)CCC1NC1=NC2=CC=CC=C2N1 YCDPBTSAQFQAOG-UHFFFAOYSA-N 0.000 description 1
- IEGKYTVBMCRSHJ-UHFFFAOYSA-N methyl 4-[[1-[(4-fluorophenyl)methyl]benzimidazol-2-yl]amino]-3-methylpiperidine-1-carboxylate Chemical compound CC1CN(C(=O)OC)CCC1NC1=NC2=CC=CC=C2N1CC1=CC=C(F)C=C1 IEGKYTVBMCRSHJ-UHFFFAOYSA-N 0.000 description 1
- CXHHBNMLPJOKQD-UHFFFAOYSA-N methyl hydrogen carbonate Chemical compound COC(O)=O CXHHBNMLPJOKQD-UHFFFAOYSA-N 0.000 description 1
- 125000004092 methylthiomethyl group Chemical group [H]C([H])([H])SC([H])([H])* 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 1
- LXNDESMSGFNIJL-UHFFFAOYSA-N n,1-dibenzyl-n-[1-(2-phenylethyl)piperidin-4-yl]benzimidazol-2-amine;nitric acid Chemical compound O[N+]([O-])=O.O[N+]([O-])=O.C1CC(N(CC=2C=CC=CC=2)C=2N(C3=CC=CC=C3N=2)CC=2C=CC=CC=2)CCN1CCC1=CC=CC=C1 LXNDESMSGFNIJL-UHFFFAOYSA-N 0.000 description 1
- NTEHWJBQADMGCG-UHFFFAOYSA-N n,n-dimethylformamide;nitrobenzene Chemical compound CN(C)C=O.[O-][N+](=O)C1=CC=CC=C1 NTEHWJBQADMGCG-UHFFFAOYSA-N 0.000 description 1
- NTQFSYCNLNWKED-UHFFFAOYSA-N n-(1-cyclohexylpiperidin-4-yl)-1-[(4-fluorophenyl)methyl]benzimidazol-2-amine Chemical compound C1=CC(F)=CC=C1CN1C2=CC=CC=C2N=C1NC1CCN(C2CCCCC2)CC1 NTQFSYCNLNWKED-UHFFFAOYSA-N 0.000 description 1
- AIAAAKULVUIAJT-UHFFFAOYSA-N n-(1-methylpiperidin-4-yl)-1-phenylbenzimidazol-2-amine Chemical compound C1CN(C)CCC1NC1=NC2=CC=CC=C2N1C1=CC=CC=C1 AIAAAKULVUIAJT-UHFFFAOYSA-N 0.000 description 1
- KNPDSCLCQLIMAQ-UHFFFAOYSA-N n-[1-(2-aminoethyl)piperidin-4-yl]-1-(thiophen-2-ylmethyl)benzimidazol-2-amine Chemical compound C1CN(CCN)CCC1NC1=NC2=CC=CC=C2N1CC1=CC=CS1 KNPDSCLCQLIMAQ-UHFFFAOYSA-N 0.000 description 1
- GYZDWWGDFZXHKT-UHFFFAOYSA-N n-[1-(2-aminoethyl)piperidin-4-yl]-1-[(4-fluorophenyl)methyl]benzimidazol-2-amine;hydrochloride Chemical compound Cl.C1CN(CCN)CCC1NC1=NC2=CC=CC=C2N1CC1=CC=C(F)C=C1 GYZDWWGDFZXHKT-UHFFFAOYSA-N 0.000 description 1
- MYARINOQPGVSFT-UHFFFAOYSA-N n-[1-(2-aminoethyl)piperidin-4-yl]-1-[(4-fluorophenyl)methyl]benzimidazol-2-amine;trihydrochloride Chemical compound Cl.Cl.Cl.C1CN(CCN)CCC1NC1=NC2=CC=CC=C2N1CC1=CC=C(F)C=C1 MYARINOQPGVSFT-UHFFFAOYSA-N 0.000 description 1
- GWKSKHPTEFGFMB-UHFFFAOYSA-N n-[1-(2-aminoethyl)piperidin-4-yl]-1-[(4-methoxyphenyl)methyl]benzimidazol-2-amine Chemical compound C1=CC(OC)=CC=C1CN1C2=CC=CC=C2N=C1NC1CCN(CCN)CC1 GWKSKHPTEFGFMB-UHFFFAOYSA-N 0.000 description 1
- HWKZOQYNFYBPBD-UHFFFAOYSA-N n-[1-(2-aminoethyl)piperidin-4-yl]-1h-benzimidazol-2-amine Chemical compound C1CN(CCN)CCC1NC1=NC2=CC=CC=C2N1 HWKZOQYNFYBPBD-UHFFFAOYSA-N 0.000 description 1
- FRXAJHLZQWOIFY-UHFFFAOYSA-N n-[1-(2-aminoethyl)piperidin-4-yl]-3-(pyridin-2-ylmethyl)imidazo[4,5-b]pyridin-2-amine Chemical compound C1CN(CCN)CCC1NC1=NC2=CC=CN=C2N1CC1=CC=CC=N1 FRXAJHLZQWOIFY-UHFFFAOYSA-N 0.000 description 1
- WGCRGDQEAQIKQA-UHFFFAOYSA-N n-[1-(2-aminoethyl)piperidin-4-yl]-3-(thiophen-2-ylmethyl)imidazo[4,5-b]pyridin-2-amine Chemical compound C1CN(CCN)CCC1NC1=NC2=CC=CN=C2N1CC1=CC=CS1 WGCRGDQEAQIKQA-UHFFFAOYSA-N 0.000 description 1
- WVEHNOYZQWVHDZ-UHFFFAOYSA-N n-[1-(2-phenylethyl)piperidin-4-yl]-1-(2-thiophen-2-ylethyl)benzimidazol-2-amine Chemical compound C1CC(NC=2N(C3=CC=CC=C3N=2)CCC=2SC=CC=2)CCN1CCC1=CC=CC=C1 WVEHNOYZQWVHDZ-UHFFFAOYSA-N 0.000 description 1
- QXEIPXZZVSYYKU-UHFFFAOYSA-N n-[1-(2-phenylethyl)piperidin-4-yl]-n-propan-2-yl-1h-benzimidazol-2-amine Chemical compound N=1C2=CC=CC=C2NC=1N(C(C)C)C(CC1)CCN1CCC1=CC=CC=C1 QXEIPXZZVSYYKU-UHFFFAOYSA-N 0.000 description 1
- PZYLEZXDWSQMAI-UHFFFAOYSA-N n-[1-(2-phenylethyl)piperidin-4-yl]-n-propyl-1h-benzimidazol-2-amine Chemical compound N=1C2=CC=CC=C2NC=1N(CCC)C(CC1)CCN1CCC1=CC=CC=C1 PZYLEZXDWSQMAI-UHFFFAOYSA-N 0.000 description 1
- FCTBYMNLONKGLS-UHFFFAOYSA-N n-[1-(3-aminopropyl)piperidin-4-yl]-1-[(4-fluorophenyl)methyl]benzimidazol-2-amine;hydrate;trihydrochloride Chemical compound O.Cl.Cl.Cl.C1CN(CCCN)CCC1NC1=NC2=CC=CC=C2N1CC1=CC=C(F)C=C1 FCTBYMNLONKGLS-UHFFFAOYSA-N 0.000 description 1
- NORHEQUXRGEKPS-UHFFFAOYSA-N n-[1-[2-(1h-benzimidazol-2-ylamino)ethyl]piperidin-4-yl]-1-[(4-fluorophenyl)methyl]benzimidazol-2-amine Chemical compound C1=CC(F)=CC=C1CN1C2=CC=CC=C2N=C1NC1CCN(CCNC=2NC3=CC=CC=C3N=2)CC1 NORHEQUXRGEKPS-UHFFFAOYSA-N 0.000 description 1
- LLQAFBPPLSGJNB-UHFFFAOYSA-N n-[1-[2-(benzylamino)ethyl]piperidin-4-yl]-1-[(4-fluorophenyl)methyl]benzimidazol-2-amine Chemical compound C1=CC(F)=CC=C1CN1C2=CC=CC=C2N=C1NC1CCN(CCNCC=2C=CC=CC=2)CC1 LLQAFBPPLSGJNB-UHFFFAOYSA-N 0.000 description 1
- NUJYKVDVUYYGQC-UHFFFAOYSA-N n-[1-[2-(dibenzylamino)ethyl]piperidin-4-yl]-1-[(4-fluorophenyl)methyl]benzimidazol-2-amine Chemical compound C1=CC(F)=CC=C1CN1C2=CC=CC=C2N=C1NC1CCN(CCN(CC=2C=CC=CC=2)CC=2C=CC=CC=2)CC1 NUJYKVDVUYYGQC-UHFFFAOYSA-N 0.000 description 1
- HYJWMRBLOJVCGB-UHFFFAOYSA-N n-benzyl-1-[(4-methoxyphenyl)methyl]-n-[1-(2-phenylethyl)piperidin-4-yl]benzimidazol-2-amine Chemical compound C1=CC(OC)=CC=C1CN1C2=CC=CC=C2N=C1N(C1CCN(CCC=2C=CC=CC=2)CC1)CC1=CC=CC=C1 HYJWMRBLOJVCGB-UHFFFAOYSA-N 0.000 description 1
- QGGSAXFVVSPELW-UHFFFAOYSA-N n-benzyl-n-[1-(2-phenylethyl)piperidin-4-yl]-1h-benzimidazol-2-amine Chemical compound C1CC(N(CC=2C=CC=CC=2)C=2NC3=CC=CC=C3N=2)CCN1CCC1=CC=CC=C1 QGGSAXFVVSPELW-UHFFFAOYSA-N 0.000 description 1
- IJDNQMDRQITEOD-UHFFFAOYSA-N n-butane Chemical compound CCCC IJDNQMDRQITEOD-UHFFFAOYSA-N 0.000 description 1
- KFASOZHWOIKPFT-UHFFFAOYSA-N n-methyl-n-[1-(2-phenylethyl)piperidin-4-yl]-1h-benzimidazol-2-amine Chemical compound N=1C2=CC=CC=C2NC=1N(C)C(CC1)CCN1CCC1=CC=CC=C1 KFASOZHWOIKPFT-UHFFFAOYSA-N 0.000 description 1
- OFBQJSOFQDEBGM-UHFFFAOYSA-N n-pentane Natural products CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 1
- 150000002823 nitrates Chemical class 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 150000005181 nitrobenzenes Chemical class 0.000 description 1
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- ZZYXNRREDYWPLN-UHFFFAOYSA-N pyridine-2,3-diamine Chemical class NC1=CC=CN=C1N ZZYXNRREDYWPLN-UHFFFAOYSA-N 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 206010040560 shock Diseases 0.000 description 1
- 229910010271 silicon carbide Inorganic materials 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 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
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
- C07D213/72—Nitrogen atoms
- C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- 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
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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
- C07D211/54—Sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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
- C07D211/56—Nitrogen atoms
- C07D211/58—Nitrogen atoms attached in position 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles 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 in position 2
- C07D235/26—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
- C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
- C07D265/34—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings
- C07D265/36—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings condensed with one six-membered ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Hydrogenated Pyridines (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US89253478A | 1978-04-03 | 1978-04-03 | |
| US06/002,276 US4219559A (en) | 1979-01-10 | 1979-01-10 | N-Heterocyclyl-4-piperidinamines |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| HU182965B true HU182965B (en) | 1984-03-28 |
Family
ID=26670178
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| HU79JA841A HU182965B (en) | 1978-04-03 | 1979-04-03 | Process for preparing new n-heterocyclyl-piperidine-4-amine derivatives and acid addition salts thereof |
Country Status (29)
| Country | Link |
|---|---|
| EP (1) | EP0005318B1 (en, 2012) |
| JP (2) | JPS54151982A (en, 2012) |
| AT (1) | AT373887B (en, 2012) |
| AU (1) | AU523352B2 (en, 2012) |
| BG (1) | BG38164A3 (en, 2012) |
| CA (1) | CA1140119A (en, 2012) |
| CS (1) | CS256358B2 (en, 2012) |
| CY (1) | CY1250A (en, 2012) |
| DE (1) | DE2961740D1 (en, 2012) |
| DK (1) | DK169325B1 (en, 2012) |
| EG (1) | EG13913A (en, 2012) |
| ES (1) | ES479206A1 (en, 2012) |
| FI (1) | FI64801C (en, 2012) |
| GR (1) | GR64907B (en, 2012) |
| HK (1) | HK3184A (en, 2012) |
| HU (1) | HU182965B (en, 2012) |
| IE (1) | IE47818B1 (en, 2012) |
| IL (1) | IL56992A (en, 2012) |
| MY (1) | MY8500046A (en, 2012) |
| NO (2) | NO154058C (en, 2012) |
| NZ (1) | NZ189978A (en, 2012) |
| PH (1) | PH15877A (en, 2012) |
| PL (1) | PL123380B1 (en, 2012) |
| PT (1) | PT69429A (en, 2012) |
| RO (1) | RO79320A (en, 2012) |
| SG (1) | SG29883G (en, 2012) |
| SU (1) | SU1056902A3 (en, 2012) |
| YU (2) | YU42484B (en, 2012) |
| ZA (1) | ZA791557B (en, 2012) |
Families Citing this family (40)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| MA19091A1 (fr) * | 1980-03-10 | 1981-10-01 | Janssen Pharmaceutica Nv | Nouveaux derives de i-(4-aryl-cyclohexyl)piperidine . |
| IN156065B (en, 2012) * | 1982-07-12 | 1985-05-04 | Janssen Pharmaceutica Nv | |
| US4556660A (en) * | 1982-07-12 | 1985-12-03 | Janssen Pharmaceutica N.V. | N-(Bicyclic heterocyclyl)-4-piperidinamines |
| US4634704A (en) * | 1983-10-06 | 1987-01-06 | Janssen Pharmaceutica, N.V. | Anti-allergic five membered heterocyclic ring containing N-(bicyclic heterocycyl)-4-piperidinamines |
| DE3484096D1 (de) * | 1983-11-30 | 1991-03-14 | Janssen Pharmaceutica Nv | Bizyklisches heterozyklyl aufveisende n-(bizyklisches heterozyklyl-4-piperidinamine. |
| JPS60174778A (ja) * | 1984-01-09 | 1985-09-09 | ジヤンセン・フア−マシユ−チカ・ナ−ムロ−ゼ・フエンノ−トシヤツプ | Ｎ−ヘテロシクリル−４−ピペリジンアミン |
| KR930005004B1 (ko) * | 1985-04-15 | 1993-06-11 | 쟈안센 파아마슈우티카 엔. 부이. | 치환된 n-[(4-피페리디닐)알킬]이환 축합 옥사졸아민 및 티아졸아민의 제조방법 |
| GB8515934D0 (en) * | 1985-06-24 | 1985-07-24 | Janssen Pharmaceutica Nv | (4-piperidinomethyl and-hetero)purines |
| EP0232937B1 (en) * | 1986-02-03 | 1992-08-19 | Janssen Pharmaceutica N.V. | Anti-histaminic compositions containing n-heterocyclyl-4-piperidinamines |
| NZ223654A (en) * | 1987-03-09 | 1990-03-27 | Janssen Pharmaceutica Nv | 1-alkyl-substituted-benzimidazole-4-piperidinamines and pharmaceutical compositions |
| FR2618435B1 (fr) * | 1987-07-23 | 1989-10-27 | Synthelabo | Derives de benzimidazole, leur preparation et leur application en therapeutique |
| US5210091A (en) * | 1991-06-24 | 1993-05-11 | Neurosearch A/S | Imidazole compounds and their use |
| FI955523A7 (fi) * | 1993-05-20 | 1995-11-16 | Kissei Pharmaceutical | 1-(2-bentsimidatsolyyli)-1,5-diatsasyklo-oksataaniyhdisteet |
| US5547966A (en) * | 1993-10-07 | 1996-08-20 | Bristol-Myers Squibb Company | Aryl urea and related compounds |
| PL343435A1 (en) * | 1998-03-06 | 2001-08-13 | Janssen Pharmaceutica Nv | Glycine transport inhibitors |
| ATE258928T1 (de) | 1999-06-28 | 2004-02-15 | Janssen Pharmaceutica Nv | Respiratorisches syncytialvirus replikation inhibitoren |
| ES2228559T3 (es) * | 1999-06-28 | 2005-04-16 | Janssen Pharmaceutica N.V. | Inhibidores de la replicacion del virus respiratorio sincintial. |
| BR0011997A (pt) * | 1999-06-28 | 2002-03-05 | Janssen Pharmaceutica Nv | Inibidores da replicação do vìrus sincicial respiratório |
| DE60125335T2 (de) | 2000-03-06 | 2007-07-12 | Acadia Pharmaceuticals Inc., San Diego | Azacyclische verbindungen zur verwendung in der behandlung von mit serotonin verwandten krankheiten |
| CZ20032351A3 (cs) | 2001-02-02 | 2004-08-18 | Tevaápharmaceuticaláindustriesáltd | Způsob výroby substituovaných @@}@@pyridylmethylB sulfinyl @�H@benzimidazolů |
| CA2470575C (en) | 2001-12-28 | 2011-02-22 | Acadia Pharmaceuticals Inc. | Spiroazacyclic compounds as monoamine receptor modulators |
| JP4625637B2 (ja) | 2002-02-22 | 2011-02-02 | シャイア エルエルシー | 活性物質送達系及び活性物質を保護し投与する方法 |
| RU2320646C2 (ru) | 2002-06-24 | 2008-03-27 | Акадиа Фармасьютикалз Инк. | N-замещенные производные пиперидина в качестве агентов серотонинового рецептора |
| US7538222B2 (en) | 2002-06-24 | 2009-05-26 | Acadia Pharmaceuticals, Inc. | N-substituted piperidine derivatives as serotonin receptor agents |
| US7253186B2 (en) | 2002-06-24 | 2007-08-07 | Carl-Magnus Andersson | N-substituted piperidine derivatives as serotonin receptor agents |
| CN1816524B (zh) | 2003-01-16 | 2012-06-27 | 阿卡蒂亚药品公司 | 用于神经退行性疾病的治疗的选择性五羟色胺2a/2c受体反向激动剂 |
| WO2005058874A1 (en) | 2003-12-18 | 2005-06-30 | Tibotec Pharmaceuticals Ltd. | 5- or 6-substituted benzimidazole derivatives as inhibitors of respiratory syncytial virus replication |
| AR046771A1 (es) | 2003-12-18 | 2005-12-21 | Tibotec Pharm Ltd | Derivados piperidina-amino-bencimidazol como inhibidores de la replicacion del virus sincitial respiratorio |
| RU2379302C2 (ru) | 2003-12-18 | 2010-01-20 | Тиботек Фармасьютикалз Лтд. | Аминобензимидазолы и бензимидазолы в качестве ингибиторов репликации респираторно-синцитиального вируса |
| US20050261278A1 (en) | 2004-05-21 | 2005-11-24 | Weiner David M | Selective serotonin receptor inverse agonists as therapeutics for disease |
| US7820695B2 (en) | 2004-05-21 | 2010-10-26 | Acadia Pharmaceuticals, Inc. | Selective serotonin receptor inverse agonists as therapeutics for disease |
| US7790899B2 (en) | 2004-09-27 | 2010-09-07 | Acadia Pharmaceuticals, Inc. | Synthesis of N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N′-(4-(2-methylpropyloxy)phenylmethyl)carbamide and its tartrate salt and crystalline forms |
| AU2005289635A1 (en) | 2004-09-27 | 2006-04-06 | Acadia Pharmaceuticals Inc. | Salts of N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N'-(4-(2-methylpropyloxy)phenylmethyl) carbamide and their preparation |
| AU2008228833B9 (en) | 2007-03-19 | 2013-10-24 | Acadia Pharmaceuticals Inc. | Combinations of 5-HT2A inverse agonists and antagonists with antipsychotics |
| PT3325444T (pt) | 2015-07-20 | 2021-09-22 | Acadia Pharm Inc | Métodos para preparar n-(4-fluorobenzil)-n-(1-metilpiperidina-4-il)-n'-(4-(2-metilpropiloxi)fenilmetil)carbamida e o seu sal de tartarato e forma polimórfica c |
| WO2017165635A1 (en) | 2016-03-25 | 2017-09-28 | Acadia Pharmaceuticals Inc. | Combination of pimavanserin and cytochrome p450 modulators |
| US10953000B2 (en) | 2016-03-25 | 2021-03-23 | Acadia Pharmaceuticals Inc. | Combination of pimavanserin and cytochrome P450 modulators |
| WO2018118626A1 (en) | 2016-12-20 | 2018-06-28 | Acadia Pharmaceuticals Inc. | Pimavanserin alone or in combination for use in the treatment of alzheimer's disease psychosis |
| EP3615028A1 (en) | 2017-04-28 | 2020-03-04 | Acadia Pharmaceuticals Inc. | Pimavanserin for treating impulse control disorder |
| EP3675827A1 (en) | 2017-08-30 | 2020-07-08 | Acadia Pharmaceuticals Inc. | Formulations of pimavanserin |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2857391A (en) * | 1955-04-15 | 1958-10-21 | Merck & Co Inc | Aminomethylbenzimidazoles |
| US2971005A (en) * | 1958-10-17 | 1961-02-07 | Merck & Co Inc | Nu-substituted derivatives of 2-benzylaminobenzimidazoles |
| BE788065A (fr) * | 1971-08-26 | 1973-02-26 | Degussa | Nouvelles aza-benzimidazoles et procede pour leur preparation |
-
1979
- 1979-03-19 CA CA000323763A patent/CA1140119A/en not_active Expired
- 1979-03-21 AU AU45296/79A patent/AU523352B2/en not_active Expired
- 1979-03-23 NZ NZ189978A patent/NZ189978A/en unknown
- 1979-03-29 DK DK129879A patent/DK169325B1/da not_active IP Right Cessation
- 1979-03-29 GR GR58721A patent/GR64907B/el unknown
- 1979-03-30 RO RO7997082A patent/RO79320A/ro unknown
- 1979-03-30 DE DE7979300525T patent/DE2961740D1/de not_active Expired
- 1979-03-30 CY CY1250A patent/CY1250A/xx unknown
- 1979-03-30 EP EP79300525A patent/EP0005318B1/en not_active Expired
- 1979-04-01 EG EG200/79A patent/EG13913A/xx active
- 1979-04-02 ES ES479206A patent/ES479206A1/es not_active Expired
- 1979-04-02 ZA ZA791557A patent/ZA791557B/xx unknown
- 1979-04-02 NO NO791097A patent/NO154058C/no unknown
- 1979-04-02 CS CS792227A patent/CS256358B2/cs unknown
- 1979-04-02 IL IL56992A patent/IL56992A/xx unknown
- 1979-04-02 JP JP3844779A patent/JPS54151982A/ja active Granted
- 1979-04-02 FI FI791084A patent/FI64801C/fi not_active IP Right Cessation
- 1979-04-02 AT AT0242579A patent/AT373887B/de not_active IP Right Cessation
- 1979-04-03 YU YU784/79A patent/YU42484B/xx unknown
- 1979-04-03 PL PL1979214648A patent/PL123380B1/pl unknown
- 1979-04-03 HU HU79JA841A patent/HU182965B/hu unknown
- 1979-04-03 SU SU792747000A patent/SU1056902A3/ru active
- 1979-04-03 PH PH22344A patent/PH15877A/en unknown
- 1979-04-03 PT PT69429A patent/PT69429A/pt unknown
- 1979-04-03 BG BG043114A patent/BG38164A3/xx unknown
- 1979-08-08 IE IE676/79A patent/IE47818B1/en not_active IP Right Cessation
-
1983
- 1983-03-02 YU YU502/83A patent/YU43158B/xx unknown
- 1983-05-26 SG SG298/83A patent/SG29883G/en unknown
-
1984
- 1984-01-12 HK HK31/84A patent/HK3184A/en not_active IP Right Cessation
- 1984-06-25 NO NO842563A patent/NO154090C/no unknown
-
1985
- 1985-12-30 MY MY46/85A patent/MY8500046A/xx unknown
-
1988
- 1988-06-14 JP JP63144898A patent/JPH01117880A/ja active Granted
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| HU90 | Patent valid on 900628 |