DD202552A5 - Heterocyclische derivate - Google Patents
Heterocyclische derivate Download PDFInfo
- Publication number
- DD202552A5 DD202552A5 DD82238231A DD23823182A DD202552A5 DD 202552 A5 DD202552 A5 DD 202552A5 DD 82238231 A DD82238231 A DD 82238231A DD 23823182 A DD23823182 A DD 23823182A DD 202552 A5 DD202552 A5 DD 202552A5
- Authority
- DD
- German Democratic Republic
- Prior art keywords
- carbon atoms
- radical
- alkyl
- ring
- compound
- Prior art date
Links
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 33
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 28
- 150000002357 guanidines Chemical class 0.000 claims abstract description 21
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims abstract description 18
- 239000002253 acid Substances 0.000 claims abstract description 17
- 150000003839 salts Chemical class 0.000 claims abstract description 14
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims abstract description 12
- 229910052731 fluorine Inorganic materials 0.000 claims abstract description 12
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 10
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims abstract description 9
- 239000001257 hydrogen Substances 0.000 claims abstract description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 8
- 229910052801 chlorine Inorganic materials 0.000 claims abstract description 8
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims abstract description 6
- 125000000843 phenylene group Chemical group C1(=C(C=CC=C1)*)* 0.000 claims abstract description 5
- 125000002947 alkylene group Chemical group 0.000 claims abstract description 4
- 229910052794 bromium Inorganic materials 0.000 claims abstract description 4
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims abstract 4
- 125000002993 cycloalkylene group Chemical group 0.000 claims abstract 2
- -1 ethylene, phenylene Chemical group 0.000 claims description 171
- 150000001875 compounds Chemical class 0.000 claims description 112
- 238000000034 method Methods 0.000 claims description 59
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 42
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 41
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 39
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 29
- 230000008569 process Effects 0.000 claims description 25
- 229910052757 nitrogen Inorganic materials 0.000 claims description 24
- 229910052760 oxygen Inorganic materials 0.000 claims description 21
- 239000001301 oxygen Substances 0.000 claims description 20
- 125000001424 substituent group Chemical group 0.000 claims description 20
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 16
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 16
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 15
- ZRALSGWEFCBTJO-UHFFFAOYSA-N anhydrous guanidine Natural products NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 claims description 14
- 239000000460 chlorine Substances 0.000 claims description 14
- 125000002883 imidazolyl group Chemical group 0.000 claims description 13
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 13
- 125000001113 thiadiazolyl group Chemical group 0.000 claims description 13
- 125000000335 thiazolyl group Chemical group 0.000 claims description 13
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 12
- 125000002541 furyl group Chemical group 0.000 claims description 12
- 125000001715 oxadiazolyl group Chemical group 0.000 claims description 12
- 125000002971 oxazolyl group Chemical group 0.000 claims description 12
- 229910052717 sulfur Inorganic materials 0.000 claims description 12
- 125000004434 sulfur atom Chemical group 0.000 claims description 12
- 125000001544 thienyl group Chemical group 0.000 claims description 12
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 12
- 150000001412 amines Chemical class 0.000 claims description 11
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 11
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 11
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 claims description 10
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 claims description 10
- 125000001425 triazolyl group Chemical group 0.000 claims description 10
- 125000003118 aryl group Chemical group 0.000 claims description 9
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 8
- 125000004429 atom Chemical group 0.000 claims description 8
- 125000004122 cyclic group Chemical group 0.000 claims description 8
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 8
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 claims description 8
- 101000588924 Anthopleura elegantissima Delta-actitoxin-Ael1a Proteins 0.000 claims description 7
- XZMCDFZZKTWFGF-UHFFFAOYSA-N Cyanamide Chemical compound NC#N XZMCDFZZKTWFGF-UHFFFAOYSA-N 0.000 claims description 7
- 229940083094 guanine derivative acting on arteriolar smooth muscle Drugs 0.000 claims description 7
- 125000001072 heteroaryl group Chemical group 0.000 claims description 7
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 7
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 6
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims description 6
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 6
- 229910052799 carbon Inorganic materials 0.000 claims description 6
- 125000004446 heteroarylalkyl group Chemical group 0.000 claims description 6
- 238000002360 preparation method Methods 0.000 claims description 6
- 125000003363 1,3,5-triazinyl group Chemical group N1=C(N=CN=C1)* 0.000 claims description 5
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 5
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical group C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims description 5
- 125000005078 alkoxycarbonylalkyl group Chemical group 0.000 claims description 5
- MDFFNEOEWAXZRQ-UHFFFAOYSA-N aminyl Chemical compound [NH2] MDFFNEOEWAXZRQ-UHFFFAOYSA-N 0.000 claims description 5
- 125000001246 bromo group Chemical group Br* 0.000 claims description 5
- 125000004181 carboxyalkyl group Chemical group 0.000 claims description 5
- 239000011737 fluorine Substances 0.000 claims description 5
- 125000005842 heteroatom Chemical group 0.000 claims description 5
- 239000011593 sulfur Substances 0.000 claims description 5
- 125000001376 1,2,4-triazolyl group Chemical group N1N=C(N=C1)* 0.000 claims description 4
- NSPMIYGKQJPBQR-UHFFFAOYSA-N 4H-1,2,4-triazole Chemical compound C=1N=CNN=1 NSPMIYGKQJPBQR-UHFFFAOYSA-N 0.000 claims description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 4
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 4
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 4
- 239000012458 free base Substances 0.000 claims description 4
- 125000005843 halogen group Chemical group 0.000 claims description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 3
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 3
- 125000001589 carboacyl group Chemical group 0.000 claims description 3
- JEVCWSUVFOYBFI-UHFFFAOYSA-N cyanyl Chemical compound N#[C] JEVCWSUVFOYBFI-UHFFFAOYSA-N 0.000 claims description 3
- 125000001188 haloalkyl group Chemical group 0.000 claims description 3
- ORTFAQDWJHRMNX-UHFFFAOYSA-N hydroxidooxidocarbon(.) Chemical group O[C]=O ORTFAQDWJHRMNX-UHFFFAOYSA-N 0.000 claims description 3
- 238000003780 insertion Methods 0.000 claims description 3
- 230000037431 insertion Effects 0.000 claims description 3
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- KKFDJZZADQONDE-UHFFFAOYSA-N (hydridonitrato)hydroxidocarbon(.) Chemical group O[C]=N KKFDJZZADQONDE-UHFFFAOYSA-N 0.000 claims description 2
- 125000002373 5 membered heterocyclic group Chemical group 0.000 claims description 2
- 125000004070 6 membered heterocyclic group Chemical group 0.000 claims description 2
- 125000003277 amino group Chemical group 0.000 claims description 2
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 2
- 150000001450 anions Chemical class 0.000 claims description 2
- 125000006615 aromatic heterocyclic group Chemical group 0.000 claims description 2
- 125000001153 fluoro group Chemical group F* 0.000 claims description 2
- 239000012634 fragment Substances 0.000 claims description 2
- 150000002367 halogens Chemical group 0.000 claims description 2
- 125000005224 heteroarylcarbonylamino group Chemical group 0.000 claims description 2
- 125000002950 monocyclic group Chemical group 0.000 claims description 2
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims 94
- 125000003545 alkoxy group Chemical group 0.000 claims 4
- 125000003342 alkenyl group Chemical group 0.000 claims 3
- 125000000304 alkynyl group Chemical group 0.000 claims 3
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims 2
- 125000005236 alkanoylamino group Chemical group 0.000 claims 2
- 125000005115 alkyl carbamoyl group Chemical group 0.000 claims 2
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 claims 1
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims 1
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims 1
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims 1
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims 1
- 125000001054 5 membered carbocyclic group Chemical group 0.000 claims 1
- 125000004008 6 membered carbocyclic group Chemical group 0.000 claims 1
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 claims 1
- 125000004466 alkoxycarbonylamino group Chemical group 0.000 claims 1
- 125000004685 alkoxythiocarbonyl group Chemical group 0.000 claims 1
- 125000000278 alkyl amino alkyl group Chemical group 0.000 claims 1
- 125000003282 alkyl amino group Chemical group 0.000 claims 1
- 125000005153 alkyl sulfamoyl group Chemical group 0.000 claims 1
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims 1
- 125000004414 alkyl thio group Chemical group 0.000 claims 1
- 125000004103 aminoalkyl group Chemical group 0.000 claims 1
- 125000003435 aroyl group Chemical group 0.000 claims 1
- 125000005239 aroylamino group Chemical group 0.000 claims 1
- 125000001769 aryl amino group Chemical group 0.000 claims 1
- 125000005162 aryl oxy carbonyl amino group Chemical group 0.000 claims 1
- 125000002619 bicyclic group Chemical group 0.000 claims 1
- 125000001951 carbamoylamino group Chemical group C(N)(=O)N* 0.000 claims 1
- 238000007796 conventional method Methods 0.000 claims 1
- 125000004985 dialkyl amino alkyl group Chemical group 0.000 claims 1
- 125000004663 dialkyl amino group Chemical group 0.000 claims 1
- 125000005117 dialkylcarbamoyl group Chemical group 0.000 claims 1
- 125000004404 heteroalkyl group Chemical group 0.000 claims 1
- 125000001096 oxamoylamino group Chemical group C(C(=O)N)(=O)N* 0.000 claims 1
- 239000003485 histamine H2 receptor antagonist Substances 0.000 abstract description 8
- 239000008194 pharmaceutical composition Substances 0.000 abstract description 7
- 230000027119 gastric acid secretion Effects 0.000 abstract description 6
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical group CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 abstract description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- 101100242909 Streptococcus pneumoniae (strain ATCC BAA-255 / R6) pbpA gene Proteins 0.000 abstract 3
- 101100269618 Streptococcus pneumoniae serotype 4 (strain ATCC BAA-334 / TIGR4) aliA gene Proteins 0.000 abstract 3
- 101100354192 Streptococcus pneumoniae serotype 4 (strain ATCC BAA-334 / TIGR4) exp5 gene Proteins 0.000 abstract 3
- 101100505001 Streptococcus pneumoniae serotype 4 (strain ATCC BAA-334 / TIGR4) glpO gene Proteins 0.000 abstract 3
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 abstract 1
- XTFIVUDBNACUBN-UHFFFAOYSA-N 1,3,5-trinitro-1,3,5-triazinane Chemical compound [O-][N+](=O)N1CN([N+]([O-])=O)CN([N+]([O-])=O)C1 XTFIVUDBNACUBN-UHFFFAOYSA-N 0.000 abstract 1
- 101100439974 Streptococcus pneumoniae serotype 4 (strain ATCC BAA-334 / TIGR4) clpE gene Proteins 0.000 abstract 1
- 101100072620 Streptomyces griseus ind2 gene Proteins 0.000 abstract 1
- 101150109310 msrAB1 gene Proteins 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 228
- 239000000203 mixture Substances 0.000 description 146
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 117
- 239000000243 solution Substances 0.000 description 117
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 95
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 92
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 84
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 68
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 66
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 63
- 230000008018 melting Effects 0.000 description 61
- 238000002844 melting Methods 0.000 description 61
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 60
- 235000019439 ethyl acetate Nutrition 0.000 description 58
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 44
- 239000007858 starting material Substances 0.000 description 44
- 150000003254 radicals Chemical class 0.000 description 41
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 34
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 32
- 238000006243 chemical reaction Methods 0.000 description 32
- 239000002904 solvent Substances 0.000 description 32
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 28
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 28
- 239000007787 solid Substances 0.000 description 28
- 125000002795 guanidino group Chemical group C(N)(=N)N* 0.000 description 24
- 239000003921 oil Substances 0.000 description 24
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 23
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 21
- 239000000284 extract Substances 0.000 description 21
- UKWHYYKOEPRTIC-UHFFFAOYSA-N mercury(ii) oxide Chemical compound [Hg]=O UKWHYYKOEPRTIC-UHFFFAOYSA-N 0.000 description 20
- 229920006395 saturated elastomer Polymers 0.000 description 20
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 19
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical group C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 18
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Chemical group C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 18
- 238000012360 testing method Methods 0.000 description 18
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 17
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 17
- 229960001340 histamine Drugs 0.000 description 17
- SNTWKPAKVQFCCF-UHFFFAOYSA-N 2,3-dihydro-1h-triazole Chemical compound N1NC=CN1 SNTWKPAKVQFCCF-UHFFFAOYSA-N 0.000 description 16
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 16
- 239000000706 filtrate Substances 0.000 description 16
- 239000011976 maleic acid Substances 0.000 description 16
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 16
- GOXVPASJCHROBY-UHFFFAOYSA-N 1,1,1-trifluoro-2-isothiocyanatoethane Chemical compound FC(F)(F)CN=C=S GOXVPASJCHROBY-UHFFFAOYSA-N 0.000 description 15
- 239000007789 gas Substances 0.000 description 15
- 239000000047 product Substances 0.000 description 14
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 13
- 235000011114 ammonium hydroxide Nutrition 0.000 description 13
- 238000009835 boiling Methods 0.000 description 13
- 239000003085 diluting agent Substances 0.000 description 13
- 239000003480 eluent Substances 0.000 description 13
- 238000000746 purification Methods 0.000 description 13
- 239000000725 suspension Substances 0.000 description 13
- 210000001519 tissue Anatomy 0.000 description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Natural products CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 12
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 12
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 11
- 239000010410 layer Substances 0.000 description 11
- 239000002244 precipitate Substances 0.000 description 11
- 239000012312 sodium hydride Substances 0.000 description 11
- 229910000104 sodium hydride Inorganic materials 0.000 description 11
- 238000003756 stirring Methods 0.000 description 11
- 241000282472 Canis lupus familiaris Species 0.000 description 10
- RFFFKMOABOFIDF-UHFFFAOYSA-N Pentanenitrile Chemical compound CCCCC#N RFFFKMOABOFIDF-UHFFFAOYSA-N 0.000 description 10
- 229910021529 ammonia Inorganic materials 0.000 description 10
- 239000008346 aqueous phase Substances 0.000 description 10
- 239000006185 dispersion Substances 0.000 description 10
- ODUCDPQEXGNKDN-UHFFFAOYSA-N nitroxyl Chemical compound O=N ODUCDPQEXGNKDN-UHFFFAOYSA-N 0.000 description 10
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 10
- 230000028327 secretion Effects 0.000 description 10
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 9
- 235000019270 ammonium chloride Nutrition 0.000 description 9
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 9
- 230000005764 inhibitory process Effects 0.000 description 9
- 239000000463 material Substances 0.000 description 9
- 238000003820 Medium-pressure liquid chromatography Methods 0.000 description 8
- FKRCODPIKNYEAC-UHFFFAOYSA-N ethyl propionate Chemical compound CCOC(=O)CC FKRCODPIKNYEAC-UHFFFAOYSA-N 0.000 description 8
- 238000002474 experimental method Methods 0.000 description 8
- 239000003208 petroleum Substances 0.000 description 8
- 229910000027 potassium carbonate Inorganic materials 0.000 description 8
- 235000011181 potassium carbonates Nutrition 0.000 description 8
- 238000010992 reflux Methods 0.000 description 8
- LLJKEQMAYLRVBR-UHFFFAOYSA-N 1,1,2,2-tetrafluoro-3-isothiocyanatopropane Chemical compound FC(F)C(F)(F)CN=C=S LLJKEQMAYLRVBR-UHFFFAOYSA-N 0.000 description 7
- OYUNTGBISCIYPW-UHFFFAOYSA-N 2-chloroprop-2-enenitrile Chemical compound ClC(=C)C#N OYUNTGBISCIYPW-UHFFFAOYSA-N 0.000 description 7
- NWWWGAKVHCSAEU-UHFFFAOYSA-N 5-bromopentanenitrile Chemical compound BrCCCCC#N NWWWGAKVHCSAEU-UHFFFAOYSA-N 0.000 description 7
- RMMXTBMQSGEXHJ-UHFFFAOYSA-N Aminophenazone Chemical compound O=C1C(N(C)C)=C(C)N(C)N1C1=CC=CC=C1 RMMXTBMQSGEXHJ-UHFFFAOYSA-N 0.000 description 7
- 229910004373 HOAc Inorganic materials 0.000 description 7
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 7
- 241000700159 Rattus Species 0.000 description 7
- 229960000212 aminophenazone Drugs 0.000 description 7
- 239000000872 buffer Substances 0.000 description 7
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 7
- 238000010438 heat treatment Methods 0.000 description 7
- 239000011734 sodium Substances 0.000 description 7
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 239000002480 mineral oil Substances 0.000 description 6
- 235000010446 mineral oil Nutrition 0.000 description 6
- 229910052698 phosphorus Inorganic materials 0.000 description 6
- 238000012746 preparative thin layer chromatography Methods 0.000 description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Chemical group COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 6
- 108020003175 receptors Proteins 0.000 description 6
- 102000005962 receptors Human genes 0.000 description 6
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Classifications
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- 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
- C07D213/73—Unsubstituted amino or imino radicals
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- 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
- C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three 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
- C07D231/16—Halogen atoms or nitro radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three 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
- C07D231/38—Nitrogen atoms
- C07D231/40—Acylated on said nitrogen atom
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
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- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/42—One nitrogen atom
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/52—Two oxygen atoms
- C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
- C07D239/545—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/04—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
- C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles 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
- C07D249/14—Nitrogen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
- C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D257/04—Five-membered rings
- C07D257/06—Five-membered rings with nitrogen atoms directly attached to the ring carbon atom
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB8108407 | 1981-03-18 | ||
GB8132680 | 1981-10-29 |
Publications (1)
Publication Number | Publication Date |
---|---|
DD202552A5 true DD202552A5 (de) | 1983-09-21 |
Family
ID=26278795
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
DD82238231A DD202552A5 (de) | 1981-03-18 | 1982-03-17 | Heterocyclische derivate |
Country Status (18)
Country | Link |
---|---|
US (1) | US4795755A (pt) |
EP (1) | EP0060697B1 (pt) |
AU (1) | AU556079B2 (pt) |
CA (1) | CA1200549A (pt) |
DD (1) | DD202552A5 (pt) |
DE (1) | DE3274856D1 (pt) |
DK (1) | DK121282A (pt) |
ES (4) | ES8306476A1 (pt) |
FI (1) | FI820882L (pt) |
GR (1) | GR76470B (pt) |
IE (1) | IE52764B1 (pt) |
IL (1) | IL65160A (pt) |
IN (1) | IN158869B (pt) |
NO (1) | NO820870L (pt) |
NZ (1) | NZ200042A (pt) |
PL (1) | PL137088B1 (pt) |
PT (1) | PT74599B (pt) |
ZW (1) | ZW3682A1 (pt) |
Families Citing this family (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA1233818A (en) * | 1981-03-09 | 1988-03-08 | David J. Gilman | Guanidine derivatives as histamine h-2 receptor antagonists |
CA1211111A (en) * | 1982-02-15 | 1986-09-09 | Isao Yanagisawa | Process for preparing novel pyrimidone compounds |
US4808589A (en) * | 1982-02-20 | 1989-02-28 | Smith Kline & French Laboratories Limited | Pyrimidone derivatives |
GB8316779D0 (en) * | 1982-09-07 | 1983-07-27 | Ici Plc | Process |
US4585781A (en) * | 1982-12-31 | 1986-04-29 | Glaxo Group Limited | Heterocyclic derivatives |
GB8401751D0 (en) * | 1984-01-24 | 1984-02-29 | Ici Plc | Guanidine derivatives |
GB8421427D0 (en) * | 1984-08-23 | 1984-09-26 | Smith Kline French Lab | Chemical compounds |
WO1994026715A1 (en) * | 1993-05-11 | 1994-11-24 | Smithkline Beecham Plc | Amidine derivatives as gastric acid secretion inhibitors |
EP2822931B1 (en) | 2012-03-09 | 2017-05-03 | Inception 2, Inc. | Triazolone compounds and uses thereof |
MX2015007433A (es) | 2012-12-20 | 2015-12-07 | Inception 2 Inc | Compuestos de triazolona y usos de los mismos. |
EA201690230A1 (ru) | 2013-09-06 | 2016-07-29 | Инсепшн 2, Инк. | Соединения триазолона и их применения |
US20230349922A1 (en) | 2020-08-11 | 2023-11-02 | Université De Strasbourg | H2 Blockers Targeting Liver Macrophages for the Prevention and Treatment of Liver Disease and Cancer |
Family Cites Families (17)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
NZ186965A (en) * | 1977-04-20 | 1980-02-21 | Ici Ltd | Guanidino derivatives and pharmaceutical compositions |
BE866155A (fr) * | 1977-04-20 | 1978-10-19 | Ici Ltd | Nouveaux derives de la guanidine |
GB2001624B (en) * | 1977-04-20 | 1982-03-03 | Ici Ltd | Guanidine derivatives processes for their manufacture and pharmaceutical compositions containing them |
US4165378A (en) * | 1977-04-20 | 1979-08-21 | Ici Americas Inc. | Guanidine derivatives of imidazoles and thiazoles |
JPS5444660A (en) * | 1977-08-29 | 1979-04-09 | Yamanouchi Pharmaceut Co Ltd | Heterocyclic compound and its preparation |
DE2835695A1 (de) * | 1977-08-29 | 1979-03-15 | Yamanouchi Pharma Co Ltd | Neue heterocyclische verbindungen, verfahren zu ihrer herstellung und arzneimittel, die diese enthalten |
DE2961923D1 (en) * | 1978-01-18 | 1982-03-11 | Ici Plc | Antisecretory guanidine derivatives, processes for their manufacture and pharmaceutical compositions containing them |
EP0006679B1 (en) * | 1978-05-24 | 1982-07-21 | Imperial Chemical Industries Plc | Antisecretory thiadiazole derivatives, processes for their manufacture and pharmaceutical compositions containing them |
EP0014057B1 (en) * | 1979-01-18 | 1985-01-02 | Imperial Chemical Industries Plc | Guanidine derivatives, processes for their manufacture and pharmaceutical compositions containing them |
PH16099A (en) * | 1979-03-06 | 1983-06-24 | Yamanouchi Pharma Co Ltd | Guanidinothiazole compounds,process for preparing them and medical composition containing them |
JPS6056143B2 (ja) * | 1979-08-02 | 1985-12-09 | 山之内製薬株式会社 | アミジン誘導体ならびにその製造法 |
US4242351A (en) * | 1979-05-07 | 1980-12-30 | Imperial Chemical Industries Limited | Antisecretory oxadiazoles and pharmaceutical compositions containing them |
GR71929B (pt) * | 1979-11-13 | 1983-08-19 | Ici Ltd | |
FI73423C (fi) * | 1980-02-29 | 1987-10-09 | Otsuka Pharma Co Ltd | Foerfarande foer framstaellning av farmakologiskt verksamma tetrazolderivat. |
EP0045155B1 (en) * | 1980-07-30 | 1985-01-02 | Imperial Chemical Industries Plc | Guanidine derivatives |
GB2085871B (en) * | 1980-08-08 | 1984-07-25 | Kotobuki Seiyaku Co Ltd | New 3-substituted-2-propenimidamides and method of manufacturing the same |
AU7474881A (en) * | 1980-08-27 | 1982-03-04 | Glaxo Group Limited | 1,2,4-triazole derivatives |
-
1982
- 1982-02-23 IN IN149/DEL/82A patent/IN158869B/en unknown
- 1982-02-24 IE IE394/82A patent/IE52764B1/en unknown
- 1982-02-26 ZW ZW36/82A patent/ZW3682A1/xx unknown
- 1982-03-01 US US06/353,384 patent/US4795755A/en not_active Expired - Fee Related
- 1982-03-03 IL IL65160A patent/IL65160A/xx unknown
- 1982-03-04 AU AU81137/82A patent/AU556079B2/en not_active Ceased
- 1982-03-08 GR GR67523A patent/GR76470B/el unknown
- 1982-03-12 DE DE8282301279T patent/DE3274856D1/de not_active Expired
- 1982-03-12 EP EP82301279A patent/EP0060697B1/en not_active Expired
- 1982-03-15 FI FI820882A patent/FI820882L/fi not_active Application Discontinuation
- 1982-03-15 PL PL1982235453A patent/PL137088B1/pl unknown
- 1982-03-17 PT PT74599A patent/PT74599B/pt unknown
- 1982-03-17 CA CA000398640A patent/CA1200549A/en not_active Expired
- 1982-03-17 NZ NZ200042A patent/NZ200042A/en unknown
- 1982-03-17 NO NO820870A patent/NO820870L/no unknown
- 1982-03-17 DD DD82238231A patent/DD202552A5/de unknown
- 1982-03-18 ES ES510583A patent/ES8306476A1/es not_active Expired
- 1982-03-18 DK DK121282A patent/DK121282A/da not_active Application Discontinuation
-
1983
- 1983-01-31 ES ES519402A patent/ES519402A0/es active Granted
- 1983-01-31 ES ES519401A patent/ES8403440A1/es not_active Expired
- 1983-01-31 ES ES519403A patent/ES519403A0/es active Granted
Also Published As
Publication number | Publication date |
---|---|
IE52764B1 (en) | 1988-02-17 |
DE3274856D1 (en) | 1987-02-05 |
NZ200042A (en) | 1985-08-30 |
EP0060697B1 (en) | 1986-12-30 |
PT74599B (en) | 1983-11-07 |
ES519401A0 (es) | 1984-03-16 |
IL65160A (en) | 1986-04-29 |
PL137088B1 (en) | 1986-04-30 |
FI820882L (fi) | 1982-09-19 |
ES8403441A1 (es) | 1984-03-16 |
ZW3682A1 (en) | 1983-10-26 |
IN158869B (pt) | 1987-02-07 |
ES510583A0 (es) | 1983-06-01 |
NO820870L (no) | 1982-09-20 |
EP0060697A1 (en) | 1982-09-22 |
AU556079B2 (en) | 1986-10-23 |
ES8406424A1 (es) | 1984-07-16 |
PT74599A (en) | 1982-04-01 |
AU8113782A (en) | 1982-09-23 |
PL235453A1 (en) | 1983-03-28 |
ES8403440A1 (es) | 1984-03-16 |
DK121282A (da) | 1982-09-19 |
ES519403A0 (es) | 1984-03-16 |
ES8306476A1 (es) | 1983-06-01 |
GR76470B (pt) | 1984-08-10 |
IE820394L (en) | 1982-09-18 |
CA1200549A (en) | 1986-02-11 |
US4795755A (en) | 1989-01-03 |
ES519402A0 (es) | 1984-07-16 |
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