AU628026B2 - New acyllabdane derivatives, a process for their preparation,and their use as medicaments - Google Patents
New acyllabdane derivatives, a process for their preparation,and their use as medicaments Download PDFInfo
- Publication number
- AU628026B2 AU628026B2 AU24649/88A AU2464988A AU628026B2 AU 628026 B2 AU628026 B2 AU 628026B2 AU 24649/88 A AU24649/88 A AU 24649/88A AU 2464988 A AU2464988 A AU 2464988A AU 628026 B2 AU628026 B2 AU 628026B2
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- Australia
- Prior art keywords
- formula
- group
- alkyl
- compound
- hereinbefore defined
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Ceased
Links
- 238000000034 method Methods 0.000 title claims description 13
- 239000003814 drug Substances 0.000 title claims description 6
- 238000002360 preparation method Methods 0.000 title claims description 6
- 150000001875 compounds Chemical class 0.000 claims description 58
- 125000000217 alkyl group Chemical group 0.000 claims description 29
- 229910052739 hydrogen Inorganic materials 0.000 claims description 24
- 239000001257 hydrogen Substances 0.000 claims description 24
- -1 amino, substituted amino, hydroxyl Chemical group 0.000 claims description 20
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 18
- 125000003118 aryl group Chemical group 0.000 claims description 17
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 16
- 239000000203 mixture Substances 0.000 claims description 15
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 11
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 11
- 125000006239 protecting group Chemical group 0.000 claims description 10
- 150000003839 salts Chemical class 0.000 claims description 9
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 9
- 230000036772 blood pressure Effects 0.000 claims description 8
- 125000000623 heterocyclic group Chemical group 0.000 claims description 8
- 230000004410 intraocular pressure Effects 0.000 claims description 8
- 230000003287 optical effect Effects 0.000 claims description 8
- 125000001424 substituent group Chemical group 0.000 claims description 8
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 7
- 229910052757 nitrogen Inorganic materials 0.000 claims description 7
- 239000002253 acid Substances 0.000 claims description 6
- 125000002252 acyl group Chemical group 0.000 claims description 6
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 6
- 230000000694 effects Effects 0.000 claims description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 5
- 210000002837 heart atrium Anatomy 0.000 claims description 5
- 238000006243 chemical reaction Methods 0.000 claims description 4
- 125000004985 dialkyl amino alkyl group Chemical group 0.000 claims description 4
- 125000005842 heteroatom Chemical group 0.000 claims description 4
- NWVVVBRKAWDGAB-UHFFFAOYSA-N p-methoxyphenol Chemical compound COC1=CC=C(O)C=C1 NWVVVBRKAWDGAB-UHFFFAOYSA-N 0.000 claims description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 4
- 125000004181 carboxyalkyl group Chemical group 0.000 claims description 3
- 150000002431 hydrogen Chemical class 0.000 claims description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 3
- 230000009090 positive inotropic effect Effects 0.000 claims description 3
- 241000972349 Ocoa Species 0.000 claims description 2
- 150000001412 amines Chemical class 0.000 claims description 2
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 2
- 125000001589 carboacyl group Chemical group 0.000 claims description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 125000000446 sulfanediyl group Chemical group *S* 0.000 claims description 2
- 229920002554 vinyl polymer Polymers 0.000 claims description 2
- 230000008030 elimination Effects 0.000 claims 2
- 238000003379 elimination reaction Methods 0.000 claims 2
- VZLKQEPNZIWSFF-UHFFFAOYSA-N 1-pyrrolidin-1-ylpiperidine Chemical compound C1CCCN1N1CCCCC1 VZLKQEPNZIWSFF-UHFFFAOYSA-N 0.000 claims 1
- 230000001476 alcoholic effect Effects 0.000 claims 1
- 239000000969 carrier Substances 0.000 claims 1
- 125000001664 diethylamino group Chemical group [H]C([H])([H])C([H])([H])N(*)C([H])([H])C([H])([H])[H] 0.000 claims 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims 1
- 239000000546 pharmaceutical excipient Substances 0.000 claims 1
- 125000005505 thiomorpholino group Chemical group 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 36
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 27
- 238000002844 melting Methods 0.000 description 18
- 230000008018 melting Effects 0.000 description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 17
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 14
- XTKDAFGWCDAMPY-UHFFFAOYSA-N azaperone Chemical compound C1=CC(F)=CC=C1C(=O)CCCN1CCN(C=2N=CC=CC=2)CC1 XTKDAFGWCDAMPY-UHFFFAOYSA-N 0.000 description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 11
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 10
- 239000003960 organic solvent Substances 0.000 description 10
- 239000000243 solution Substances 0.000 description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- 150000001761 labdane diterpenoid derivatives Chemical class 0.000 description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- 239000012044 organic layer Substances 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 238000003818 flash chromatography Methods 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 5
- 239000012267 brine Substances 0.000 description 5
- 125000004432 carbon atom Chemical group C* 0.000 description 5
- 239000003208 petroleum Substances 0.000 description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 5
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 5
- OHCQJHSOBUTRHG-KGGHGJDLSA-N FORSKOLIN Chemical compound O=C([C@@]12O)C[C@](C)(C=C)O[C@]1(C)[C@@H](OC(=O)C)[C@@H](O)[C@@H]1[C@]2(C)[C@@H](O)CCC1(C)C OHCQJHSOBUTRHG-KGGHGJDLSA-N 0.000 description 4
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 239000012258 stirred mixture Substances 0.000 description 4
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 229910052736 halogen Inorganic materials 0.000 description 3
- 150000002367 halogens Chemical class 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 229930002697 labdane diterpene Natural products 0.000 description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 150000003254 radicals Chemical class 0.000 description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- 238000005303 weighing Methods 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- 206010002091 Anaesthesia Diseases 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- CKDWPUIZGOQOOM-UHFFFAOYSA-N Carbamyl chloride Chemical compound NC(Cl)=O CKDWPUIZGOQOOM-UHFFFAOYSA-N 0.000 description 2
- SUZLHDUTVMZSEV-UHFFFAOYSA-N Deoxycoleonol Natural products C12C(=O)CC(C)(C=C)OC2(C)C(OC(=O)C)C(O)C2C1(C)C(O)CCC2(C)C SUZLHDUTVMZSEV-UHFFFAOYSA-N 0.000 description 2
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 2
- 241000282326 Felis catus Species 0.000 description 2
- 241000283973 Oryctolagus cuniculus Species 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- 230000037005 anaesthesia Effects 0.000 description 2
- 125000003435 aroyl group Chemical group 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- OHCQJHSOBUTRHG-UHFFFAOYSA-N colforsin Natural products OC12C(=O)CC(C)(C=C)OC1(C)C(OC(=O)C)C(O)C1C2(C)C(O)CCC1(C)C OHCQJHSOBUTRHG-UHFFFAOYSA-N 0.000 description 2
- 210000001105 femoral artery Anatomy 0.000 description 2
- QMEZUZOCLYUADC-UHFFFAOYSA-N hydrate;dihydrochloride Chemical compound O.Cl.Cl QMEZUZOCLYUADC-UHFFFAOYSA-N 0.000 description 2
- 229940113083 morpholine Drugs 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- DGTNSSLYPYDJGL-UHFFFAOYSA-N phenyl isocyanate Chemical compound O=C=NC1=CC=CC=C1 DGTNSSLYPYDJGL-UHFFFAOYSA-N 0.000 description 2
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 2
- VEPTXBCIDSFGBF-UHFFFAOYSA-M tetrabutylazanium;fluoride;trihydrate Chemical compound O.O.O.[F-].CCCC[N+](CCCC)(CCCC)CCCC VEPTXBCIDSFGBF-UHFFFAOYSA-M 0.000 description 2
- ZFXYFBGIUFBOJW-UHFFFAOYSA-N theophylline Chemical compound O=C1N(C)C(=O)N(C)C2=C1NC=N2 ZFXYFBGIUFBOJW-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- ZKHYAMNFKKHLJM-UHFFFAOYSA-N (8alpha,13R)-8,13-Epoxy-14-labden-11-one Natural products O1C(C)(C=C)CC(=O)C2C3(C)CCCC(C)(C)C3CCC21C ZKHYAMNFKKHLJM-UHFFFAOYSA-N 0.000 description 1
- ATVJXMYDOSMEPO-UHFFFAOYSA-N 3-prop-2-enoxyprop-1-ene Chemical compound C=CCOCC=C ATVJXMYDOSMEPO-UHFFFAOYSA-N 0.000 description 1
- GAWIXWVDTYZWAW-UHFFFAOYSA-N C[CH]O Chemical group C[CH]O GAWIXWVDTYZWAW-UHFFFAOYSA-N 0.000 description 1
- 241001631457 Cannula Species 0.000 description 1
- 241000700198 Cavia Species 0.000 description 1
- 241000700199 Cavia porcellus Species 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical class [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- MZVQCMJNVPIDEA-UHFFFAOYSA-N [CH2]CN(CC)CC Chemical class [CH2]CN(CC)CC MZVQCMJNVPIDEA-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 125000003647 acryloyl group Chemical group O=C([*])C([H])=C([H])[H] 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 238000005904 alkaline hydrolysis reaction Methods 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000009530 blood pressure measurement Methods 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- OJYGBLRPYBAHRT-IPQSZEQASA-N chloralose Chemical compound O1[C@H](C(Cl)(Cl)Cl)O[C@@H]2[C@@H](O)[C@@H]([C@H](O)CO)O[C@@H]21 OJYGBLRPYBAHRT-IPQSZEQASA-N 0.000 description 1
- 229950009941 chloralose Drugs 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- LDHQCZJRKDOVOX-NSCUHMNNSA-N crotonic acid Chemical compound C\C=C\C(O)=O LDHQCZJRKDOVOX-NSCUHMNNSA-N 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- AQEFLFZSWDEAIP-UHFFFAOYSA-N di-tert-butyl ether Chemical compound CC(C)(C)OC(C)(C)C AQEFLFZSWDEAIP-UHFFFAOYSA-N 0.000 description 1
- MHDVGSVTJDSBDK-UHFFFAOYSA-N dibenzyl ether Chemical compound C=1C=CC=CC=1COCC1=CC=CC=C1 MHDVGSVTJDSBDK-UHFFFAOYSA-N 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 210000003191 femoral vein Anatomy 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 1
- OFCCYDUUBNUJIB-UHFFFAOYSA-N n,n-diethylcarbamoyl chloride Chemical compound CCN(CC)C(Cl)=O OFCCYDUUBNUJIB-UHFFFAOYSA-N 0.000 description 1
- WCYMWQIUHPXBKM-UHFFFAOYSA-N n,n-diethylethanamine;ethoxyethane Chemical compound CCOCC.CCN(CC)CC WCYMWQIUHPXBKM-UHFFFAOYSA-N 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 229940053973 novocaine Drugs 0.000 description 1
- 125000002811 oleoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])/C([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
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 125000000913 palmityl 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])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
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 125000003884 phenylalkyl group Chemical group 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 125000004079 stearyl 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])C([H])([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
- 230000000638 stimulation Effects 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 229960000278 theophylline Drugs 0.000 description 1
- LDHQCZJRKDOVOX-UHFFFAOYSA-N trans-crotonic acid Natural products CC=CC(O)=O LDHQCZJRKDOVOX-UHFFFAOYSA-N 0.000 description 1
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/78—Ring systems having three or more relevant rings
- C07D311/92—Naphthopyrans; Hydrogenated naphthopyrans
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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Description
Pro PAT 51,0 kurist Authorized Signat ry enbruck i.V. Lapice
I~
Cr-
B
*ppa. Is i 628026 COMMONWEALTH OF AUSTRALIA PATENTS ACT 1952-69 COMPLETE SPECIFICATION
(ORIGINAL)
Form Class Int. Class Application Number: Lodged: 0 Co plete Specification Lodged: Accepted: .Published: *e Related Art: Name of Applicant: Address of Applicant: i Actual Inventor: Address for Service: HOECHST AKTIENGESELLSCHAFT 45 Bruningstrasse, D-6230 Frankfurt/Main 80, Federal Republic of Germany YATENDRA KHANDELWAL, RAJESHWARI KANNAN, BANSI LAL, ALIHUSSEIN NOMANBHAI DOHADWALLA, RAMANUJAM RAJGOPALAN and RICHARD HELMUT RUPP EDWD. WATERS SONS, 50 QUEEN STREET, MELBOURNE, AUSTRALIA, 3000.
Complete Specification for the invention entitled: NEW ACYLLABDANE DERIVATIVES, A PROCESS FOR THEIR PREPARATION, AND THEIR USE AS MEDICAMENTS The following statement is a full description of this invention, including the best method of performing it known to: I. 1.
1 New acyllabdane derivatives, a process for their preparation, and their use as medicaments.
The present invention relates to labdanes of the formula i HO
OH
OR
7 OR6 in which R denotes vinyl, ethyl, cyclopropyl or CHOHCH 2 0H, 0
II
R
7 denotes ydre a group of the formula -C-A, A denoting OR 2 in which R 2 represents an alkyl group, or denoting N X and Y representing, if they are identical, hydrogen or alkyl, or,
Y
1 0 identical, hydrogen or alkyl, or, if X represents hydrogen or lower alkyl, Y representing an alkyl, substituted alkyl, cycloalkyl, aralkyl, aryl, amino or hydroxyl group, or X and Y, together with the nitrogen atom to which they are bonded, forming a heterocyclic ring which can contain a further hetero atom and can be substituted by an alkyl or aryl group, 1 5 R 6 denotes a group of the formula S 10
N
R
9
R
11 Y1 in which m is an integer from 0 to 10 and n is an integer from 1 to 10, and R 8 and R9 are identical or different and represent hydrogen or a lower alkyl group, or one of the substituents represents hydrogen and the other represents a hydroxyl, thio or aryl group, Rio denotes hydrogen and R 11 denotes hydrogen or a hydroxyl or alkyl group, and
X
1 represents hydrogen if Y represents hydrogen, alkyl, substituted alkyl, alkanoyl, aryl, cycloalkyl, aralkyl, a heterocycle, amino, substituted amino, hydroxyl, acyl, dialkylaminoalkyl, carbamoyl, carboxyalkyl or carbalkoxyalkyl, or X 1 and Y 1 represent, Sif they are identical, alkyl, substituted alkyl, aryl or aralkyl, or, if X represents 2 alkyl, Y 1 represents substituted alkyl, cycloalkyl, aralkyl or a dialkylaminoalkyl group, or X 1 and Y 1 form, together with the nitrogen atom to which they are bonded, a heterocycle which can contain one or more hetero atoms and be optionally substituted once or several times by alkyl, aryl, aralkyl, hydroxyalkyl, hydroxyl or other hetericyclic groups, and to their optical and geometric isomers and their pharmaceutically acceptable acid addition salts.
Preferred compounds of the formula i are those in which R has the abovementioned meaning, and either a) R 6 represents a group of the formula a R 1 io X -CO-(C)m-(C)n-N I I
R
9 R 11 o oo. •y o s v k e i 3 in which R 8
R
10 R11 X 1 and Y 1 have the abovementioned 0 meaning, and R 7 represents a group of the formula -C-A,
X
A denoting a radical of the formula OR 2 or -N in
Y
which R 2 X and Y have the abovementioned meanings, or 0 b) R. m: d R 7 represent a group of the formula -1-A, x A denoting a radical of the formula -OR 2 or -N in
Y
which R 2 X and Y have the abovementioned meanings, and R represents a group of the formula a R 8
R
1 0 -xi SCO-
(C)-N
R9 R 11 Y1 in which R 8
R
9
R
10 R11, X 1 and Y 1 have the abovementioned meanings.
C The term alky relates to straight-chain or branched saturated hydrocarbon radicals having 1 to 8 carbon atoms such as, for example, methyl, ethyl, propyl, 2- 15 methylpropyl, 1-pentyl, 3-hexyl or 2-octyl and the like.
Preferred alkyl groups have 1 to 6, in particular 1 to 4, carbon atoms.
Suitable examples of substituted alkyl groups are hydroxyalkyl such as hydroxyethyl, carboxyalkyl such as carboxyethyl, and carbalkoxyalkyl such as carbethoxyethyl, or halogenated alkyl.
Suitable cycloalkyl groups are C 3 -C7-cycloalkyl groups, in particular cyclopentyl or cyclohexyL.
An aralkyL group is to be understood to be a phenylalkyl group, preferably phenyl-C.-C 3 -alkyl, for example a 4 benzyl group in which the pheny group can be substituted once or several times by halogen, C 1 -C3-akyL, C 1
-C
3 alkoxy, nitro or trifluoromethyl.
An aryl group is to be understood to be a phenyl group which can be substituted once or several times by substituents such as halogen, C 1
-C
3 -aLky, C 1
-C
3 -alkoxy, nitro or trifluoromethyl.
An acyl group is to be understood to be C 1
-C
6 -akanoy,
C
2
-C
6 -akenoy, C 3
-C
6 -akynoy, aroyl, aralkanoy or a heteroaroyl group having up to 10 carbon atoms, it being possible for one or more carbon atoms to be replaced by oxygen, nitrogen and/or sulfur.
SExampl.es of alkanoyl groups are formyl, acetyl, propionyL, butyryL, isobutyryl, valeryl, palmityl and bromoisobutyr- 15 yl. The alkanoyl groups can contain one or more double bonds, for example an acryloyl, stearyl or oleoyl group.
The alkanoyl groups can also contain one or more triple bonds as well as one or more double bonds. An example of an alkynoy group of this type is the propiolyl group.
A representative of aroyl groups is the benzoyl group in which the phenyL group can be substituted once or several times by substituents such as C 1
-C
3 -akyL, C 1
-C
3 alkoxy, haLogen, nitro and trifluoromethyl. Examples of aralkanoyl and heteroaroyl groups are phenylacety and pyridine-3-carbony groups.
The dialkyLaminoalky groups are to be understood to be those in which each of the alkyl groups contains 1 to 6 carbon atoms, for example diethylaminoethyL.
If X and V or X 1 and Y 1 form, together with the nitrogen atom to which they are bonded, a heterocyclic ring, those which are preferred are piperidine, pyrrotidine, morpho- Line, piperazine, thiomorphotine, imidazole and theophyLLine, each of which can optionally be substituted in one or more positions by C 1
-C
4 -akyL, C 1
-C
4 -aLkoxy, aryl, aryl-CI-C 4 -alkyl, hydroxyl, amino or substituted
C
1
-C
4 -alkyl.
Suitable examples of the salts of the compounds according to the invention with inorganic or organic acids are the hydrochloride, hydrobromide, sulfate, phosphate, acetate, oxalate, tartrate, citrate, maleate or fumarate.
In the formulae depicted here, the various substituents are shown as connected to the labdane nucleus in one of two modes of representation: a full line which indicates a substituent in the B-orientation above the plane of the molecule), and a broken line which indicates a substituent in the a-orientation below o* o the plane of the molecule). All the formulae are drawn in such a way that they depict the compounds in their 15 absolute stereochemical configuration. Where the starting materials having a labdane nucleus are naturally occurring or are derived from natural products they have, as do the final products, a labdane nucleus in the single absolute configuration depicted here. However, the pro- 20 cess according to the invention is also meant for the synthesis of labdanes of the racemic series.
In addition to the optical centers of the labdane nucleus, S the substituents thereon may also have chiral centers which contribute to the optical properties of the com- 25 pounds according to the invention and allow their separation by conventional methods, for example by the use of optically active acids. A wavy line connecting a group to a chiral center indicates that the stereochemistry of the center is unknown, i.e. the group may be present in either of the possible orientations. This invention embraces all the optical isomers and racemic forms of the compounds according to the invention where such compounds have chiral centers in addition to those of the labdane nucleus.
Some of the new, multiply oxidized labdane derivatives -6 according to the invention are Listed in Table 1 which fol Lows.
TabLe 1
OR
7 0%6 If I W a g- t
''IC
41 C C C
CC
49 0* a 4* 400449 44 4
COCH
2 NcI C0OC,' 2 4 7
COCH
2 -N 0
CO(H
2
)N(C
3
CO(CH
2 2
N(CH
3 2
CO(CH
2 2 NQCH3) Co (CH 2 )2-O
CO(CH
2 2 -Nc0 CO
(CM
2 2-
CO(CH
2 CM-d-\
COCH
2 CHNm C12 3
COCH
2 ?1,
COOC
2
HS
CON(C
2
H
5 2
COOC
2
H
5
COOC
2
HS
CON(C
2
HS)
2
COOC
2
H
5
CON(C
2
H
5 2
COOC
2
H
5
CON(C
2
H
5 2
COOC
2
H
5 CON (C 2
H
5 2
CONHC
6
H
5 x HC1 Netting point 268 0
C
HC1 253 0
C
HC1 -H 2 0 MCi HCi HCi HCi 225- 29 0
C
213- 15 0
C
239- 40 0
C
227- 28C 246- 47 0
C
218- 20 0
C
160- 64 0
C
175- 78 0
C
173-7750C 201- HC1*O,5 H120 HC1 HC1 -H20 HC1 5 H120 -7- The invention also relates to a process for the preparation of the new acyllabdanes of the formula I, which comprises reaction of compounds of the formula II
R
Ri'0 0
OH
OH R R10 X oco- t(CM
-N/
R9 Ry in which R 1 denotes a protective group for a hydroxyL group, such as, for example, t-butyLdimethylsiLy, and R, Rg-R 11 and X 1 and Y 1 have the abovementioned meanings, with a mixture of an alkyl haLoformate, for example ethyl chioroformate, and 4-dimethylaminopyridine in organic solvents, such as dichoromethane or ethyl acetate, at temperatures in the range 20 0 C to 70 0 C, to give compounds of the formula III *tI tt\ R S R0 Rt
III
OH
OR7 0 C0-(C)m-(bC) -N g 4 in which R' 1 represents a protective group, R 7 represents
-C-OR
2 in which R 2 denotes Cl-C 8 -alkyL, and R, R 8 -Rll,
X
1
Y
1 m and n have the abovementioned meanings.
Suitable protective groups for R 1 are: the methyl ether, t-butyl ether, allyl ether, benzyl ether, triarylmethyL ether, triakylsily ether or tetrahydropyrany ether or esters. It is particularly advantageous to use the t-butyLdimethylsiyL group as protective group. In order to obtain compounds of the formula III in which 0 X
R
7 represents -C-N the compb)unds of the formula y -8 II are treated with the appropriate carbamoyl chloride
X
0/ of the formula Cl--N in the presence of 4-dimethylaminopyridine and hydroquinone monomethyl ether in an organic solvent, such as pyridine, at a temperature in the range 20°C to 30 0 C. The reaction product of the formula III is obtained from the mixture by extraction with an organic solvent, and washing the organic layer with water, drying it over anhydrous sodium sulfate and concentrating in vacuo. A chromatographic method is used for purification.
Compounds of the formula III in which R 1 represents a protective group such as, for example, t-butyldimethylt, silyL are treated with reagents such as tetrabutylammonium fluoride at temperatures in the range 0 to 300C in S15 order to obtain corresponding compounds of the formula I 41 C with R 1
=H.
Compounds of the formula II are prepared by the process 4 4 which is described in EP-A 0,217,372 (HOE 85/F 214), from compounds of the formula IV 31 OR 20 .6 IV x OH
OH
OH
in which R 1 represents a protective group such as tbutyldimethylsilyl, and R represents a vinyl group.
Compounds of the formula IV are prepared from forskolin by the reaction sequence indicated below.
HO R 0 OHI I OH S H
OH
V
VI
9 The 1-OH group in forskolin is prctected with a group RI', as defined above, by methods known to the expert (cf. Reagents for Org. Synth., L.F. Fieser and M. Fieser, John Wiley Sons, Volumes 1 to 11).
The acetyl group in the 7-position in compounds of the formula VI is eliminated by alkaline hydrolysis by methods described in the literature (cf. J.C.S. Perkin I, 769 (1982)), which provides compounds of the formula IV.
Compounds of the formula I can also be obtained starting from compounds of the formula IV. Compounds of the formula IV in which R 1 has the above meaning are treated with carboxylic acids of the formula R 12
R
13
C=CH-
COOH, in which R 12 and R 13 represent hydrogen or an alkyl or aryl group, in the presence of 4-dimethylamino- 15 pyridine and DCC in organic solvents such as dry dimethylformamide, dry ethyl acetate etc., at temperatures in the range 20 to 300C for four hours, and the products of the formula VII R 0 OH
VII
H OCOCH-CR 12
R
13
SOH
in which R 1 and R 12 have the above meanings, is iso- Lated from the reaction mixture by dilution with water, subsequent extraction with organic solvents such as ethyl acetate, washing of the extract with water, drying over anhydrous sodium sulfate, and concentration in vacuo.
Chromatographic methods are used for purification.
In ordfir to obtain compounds of the formula VIII
R
1
I
OH
OH
OCOCH-CR
1 i 2
R
1 3 10 in which R 1 and R 12 have the above meanings, compounds of the formula VII are subsequently treated with alkali such as sodium hydroxide in water-soluble organic solvents such as acetonitrile.
Compounds of the formula VIII are subsequently treated with alkyl haloformate in the presence of pyridine and 4-dimethylaminopyridine in organic solvents such as dichloromethane or ethyl acetate, resulting in compounds of the formula IX in which A represents OR 2 and R 2 and
R
1
R
12 and R 13 have the above meanings, or with the appropriate carbamoyl chloride in the presence of 4dimethylaminopyridine and hydroquinone monomethyl ether in an organic solvent such as pyridine, which yields 'c compounds of the formula IX
IX
OCOA T -ocofl
OCOCH-CR
12
R
13
X
in which A represents N X and Y, and R 1
R
1 2 and 4
R
13 having the above meanings.
Compounds of the formula IX are treated with the appropriate amine of the formula HNX 1
Y
I
in which X 1 and Y1 20 have the abovementioned meanings, in an organic solvent such as dichloromethane, at 20 to 30°C for 16 to 24 hours.
The product is obtained from the reaction mixture by extraction with an organic solvent, washing of the extract with water, drying over anhydrous sodium sulfate and concentration in vacuo. The compounds of the formula I are purified by column chromatography.
The compounds according to the invention, and their salts, have the pharmacological properties attributed to the class of multiply oxidized labdanes and their derivatives. However, they exhibit, in particular, a selective i 11 positive inotropic effect, an effect lowering blood pressure, and a lowering of the intraocular pressure.
This is illustrated by the pharmacological investigations which follow and which were carried out to evaluate the compounds according to the invention, and their salts, and by the results obtained thereby.
Positive inotropic activity The following method was used for this: Guineapigs of both sexes and weighing 400 g are sacrificed, and the heart is removed and placed in Ringer's solution at room temperature. Both the left and the I right atria are then isolated, fixed in an organ holder and placed in a bath containing Ringer's solution and i t maintained at a temperature of 32°C. A mixture of 15 02 and 5% C02 is bubbled through the organ bath.
SElectrical stimulation of the atrium is then carried out.
SThe compound according to the invention is dissolved in water to give a solution of known concentration and is added to the bath. The contractility of the atrium is a 20 recorded for 7 to 10 minutes via an isometric strain 4 gage on a Nihon Kohden 4-channel pen recorder. The activity is expressed on the basis of the resulting data 4 r as the EC 50 t V The results obtained in this model for representative compounds according to the invention are listed in the table which follows.
(as hereinbefore defined), cycloalPwl, aralkyl (as hereinbefore defined), ary 1 11 11 y 1 I 1, 1i:
I
I
^v 1 1 12 i Compound Guineapig atrium
EC
5 0 g/mL
*HCI
OR
6 .44.s
I
o Ir Ir I
(C
C 41 -4 4 I $4 4 0 4 4r 4
CO(CH
2 2
NO
7 CO
(CH
2 2g
COCH
2 NcO
COCH
2 N"7 COOC2H
CON(C
2
H
5 2
COOC
2
H
5
CON(C
2
HS)
2 0,79 1,6 0,44 Measurement of intraocular pressure Measurement of the intraocular pressure rabbits in conscious For this experiment rabbits of both sexes and weighing 2 to 3 kg are used. The intraocular pressure (IOP) is measured with a Schiostz tonometer after corneal anesthesia with 2% strength novocaine solution. A 2% strength solution of a compound according to the invention is prepared, using the stoichiometric amount of 0.1 N HCl, by dissolving it or its salt directly in water. After the initial value has been determined, 100 pl of the solution of the test compound are inetilled into one of the eyes, and the vehicle is instilled into the other eye. The 1OP is measured at defined time intervals, i.e. 0.5, 1, 2, 3, 4 and 5 hours. The percentage decrease in the IOP is calculated using the initial value.
II I rr L-:i 13 The results obtained in this model for representative compounds according to the invention are Listed in the table which follows: Compound lOP-lowering effect
*HCI
OR
6 Dose X decrease percentage in IOP Duration (mins) 4$ 4 4 r$ C 4i 44 C C1 C: 4 lr 1444 4 144 4
CO(CH
2 2
NO
CO
(CH
2 2
O
COCH
2
NO
COCH
2
NO
COOC2
H
5
CON(C
2
H
5 2
COOC
2
H
CON(C
2
H
5 2 300 360 420 Determination of the Lowering of blood pressure BLood pressure in cats: Cats of both sexes and weighing 3 to 4 kg are anesthetized with ether and maintained under chloralose anesthesia (70 mg/kg Cannulas are placed in the femoral artery and in the femoral vein to record the blood pressure and to administer the medicament, respectively. The blood pressure in the femoral artery is recorded via a Statham P 23 Db pressure transducer on a Nihon-Kohden pen recorder for physiological purposes.
The compound to be tested is dissolved in distilled water and administered intravenously. The fall in blood pressure and the duration of the effect lowering blood pressure are noted.
1.
14 The results obtained in this model for representative compounds according to the invention are Listed in the ,table which follows: ,Coamp oun d
HCI
OR
7
OR
6 Dose FaLL in Duration (mg/kg) D.P. (ms) .4,4 .6 44 4* 4 a tsr alit a tt t I trtt a C 4 54 IS 4 4 6.4 4 1
I
I it a CI. C a a 4 I I I CO (OW 2 2 NOj
CO(CH
2 2 NcO
COCH
2
O
COCH
2
NO
COOC
2
H
5 CON (C 2 HS) 2
OOC
2
H
5
CON(C
2
H
5 2 The invention is illustrated by the examples which follow: ExampLe 1 Ils-t-ButydimethytsiLyLoxy-78-crotomyLoxy-68,9GL-dihydroxy-8, 13-epoxyLabd-14-en-1--one DicycLohexyLcarbodiimide (2.5 g, 12.14 umoL) is added to a stirred mixture of 4-dimethyLaminopyridine (0.45 g, 3.68 mmoL), crotonic acid (1.0 9, 11.62 mmoL) and la-tbutyLdimethyLsiLyLoxy-8,13-epoxy-6S,70,9(x-trihydroxyLabd- 14-en-lI-one (4.0 g, 8.30 mmoL) in dry DMF (10 mL). The reaction mixture is stirred for four hours and then poured onto ice, and the mixture is extracted with ethyl 115 acetate. The organic Layer is washed with water and then brine, dried over anhydrous sodium sulfate and concentrated. The residue is purified by flash coLumn chromatography using ethyl acetate :petroLeum ether (1 9) as eLuant; melting point 114-160, yield 64 The compound 7B-acryLoyLoxy-1cz-t-butyLdimethyLs iLyLoxy- 6B,9ca-dihydro-8,13-epoxy-Labd-14-en-1 1-one is prepared in a corresponding way.
Example 2 1Q-t-ButyLdiuethys i LyLoxy-6S-crotonyLoxy-7B ,9a-dihydroxy-8,13-epoxyLabd-14-enl1-ofle f C Sodium hydroxide solution (9.6 ml, 1 N) is added, with stirring, to lc-t-butyLdimethyLsi LyLoxy-7B-crotonyLoxy- 66,9c-dihydroxy-8,13-epoxyLabd-14-en-11-one (2.8 g, 5.09 mmol) in acetonitriLe: water (1 320 ml), the mixture is stirred for a further 45 minutes and then concentrated in vacuo, and the residue is extracted with ethyl acetate.
The organic Layer is washed with water and then with 20 brine, dried over anhydrous sodium sulfate and concentrated. The residue is purified by flash column chromatography using ethyl acetote :petroLe.um ether (15 o as eLuant. MeLting point 85-87 0 C, yield 71,2 The compound 60-acryLoyLoxy-1ci-t-butyLdimethyLs iLyloxyj 7$,9(%-dihydroxy-8,13-epoxyLabd-14-en-11-one (melt ing point 164-166 0 C) is prepared in a similar manner.
Exampte 3 1aL-t-ButyLdimethyLsiLyl.oxy-6B-crotoflyLoxy-7B-ethoxycarbonyLoxy-8, 13-epoxy-9et-hydroxytabd-14-en-11-one Ethyl chLoroformate (2.5 ml, 26.14 mmol) is added to a stirred mixture of 4-dimethyLaminopyridine (0.1 g, 0.81 mmoL), pyridline (2.5 ml) and 1(x-t-butyLdilmethyLsiLyLoxy- -16- 68-crotony~oxy-7$,9ct-dihydroxy-8,13-epoxyLabd-14-en-11one (0.8 g, 1.45 mmoL) in dichloromethane (15 WL. The mixture -is stirred overnight and then treated with a further quantity of ethyl chLoroformate (2.0 mL, 20.91 mmoL) and pyridline (2 ml). The mixture is stirred for a further 12 hours, then heated at 60 to 70 0 C for 4 hours and then poured onto ice, and the mixture is extracted with ethyl acetate. The organic Layer is washed with dliLute HCI, water and then brine, dried over anhydrous sodium sulfate and concentrated. Melting point 116-18 0C The following compounds are synthesized in a simiLar manner: Ittf1. 65-AcryLoyLoxy-1ct-t-butyLdimethyLs iLyLoxy-76-ethoxycarbonyLoxy-8,13-epoxy-9ct-hydroxyLabd-14-en-11-one CC 15 2. lc-t-ButyLdimethyLsiLyLoxy-78-ethoxycarbonyLoxy-8,13epoxy-9c-hydroxy-66-piperidinoacetoxyLabd-14-en-11-one C Example 4 6B-AcryLoyLoxy-1cz,9G-dihydroxy--70-ethoxycarbonyLoxy-8, 13epoxytabd-14-en-11-one
C
TetrabutyLammonium fluoride trihydrate (0.89g, 2.54 mmol) C is added to a solution of 6B-acryLoyLl-t-butyLdimethyLsiLyLoxy-?B-ethoxycarbonyLoxy-8,13-epoxy-9a-hydroxyLabd- 14-en-lI-one (1.4 g, 2.3 mmoL) in THF (60 ml), and the mixture is stirred at room temperature for 10 minutes and i- 25 then concentrated in vacuo. The residue is extracted with ethyl acetate,- and the organic Layer is washed with water, dried over anhydrous sodium sulfate and concentrated. The residue is purified by flash column chromatography using acetonitriLe :chloroform diisopropyL ether :petroleum ether (7 :25 25 18), yield 92.3%, o i L The following compounds are synthesized in a similar group, preferably phenyL-Cl-C 3 -aLkyL, for exampLe a
I
p 4 17 manner: 1. 6 8-CrotonyLoxy-1o,9a-dihydroxy-7B-ethoxycarbonyL ox),- 8, 13 -epoxyLabd-14-en-11-one, melt ing point 88-90 0
C.
2. 6 8-Crotonytoxcy-7B-N,N-diethyLaminocarbonyLoxy..19a-.
dihydroxy-8, l 3 -epoxyLabd-14-en-11-one, melting point 76-79 0 C 3. 68-Ac ryloyL oxy-?0-N,N-d jethyL am inocarbonyLoxy- 1a,9czdihydroxy-8, 13-epoxyLabd-14-en-11-one, melting point 168-70 0
C.
4. 1a,9cz-D ihydroxy-78-ethoxycarbonyL-8, 13-epoxy-6Bpiper idinoacetoxyLabd-14-en-11-one.
78-N,N-D iethyt aminocarbonyLoxy-cx,9-dihydroxy-8, 13- It. epoxy- 6 B-piperidinoacetoxyLabd-.en-11-one.
6. 7B-AniJ.inocarbonyloxy-lt,9cC-dihydroxy-8, 13-epoxy- 6B-morpholinoacetoxy-labd-1 4-en-il-one.
Vt 4, Example 60-AcrytoyLoxy-lcs-t-butyLdisethyts C ft aminocarbonyLoxy-8,13,-epoxy-9ci-hydroxyLabd-14-en-11-one VC t C C added to a stirred mixture of 4-dimethyLaminopyridine (0.1 g, 0.81 mmoL), hydroquinone monomethyL ether (0.05 g, 0.4 mmoL) and 60-acryLoyLoxy-l1t-t-butyLdimethyLsiLyLoxy- 7B,9a-dihydroxy-8,l3-epoxyLabd-14-en-1l-one (1.5 g, 2.79 mmoL) in pyridine (10 ml, the mixture is heated to refLux for 16 hours, a further quantity of N,N-diethyLcarbamoyL chloride (2 ml, 5.75 smoL) is added, and the mixture is heated to reftux for a further three hours and then concentrated in vacuo. The residue is extracted with ethyl acetate, and the organic Layer is washed with dliLute HCL, water and then brine, dried over anhydrous sodium sulfate and concentrated'. The residue is purified by flash column chromatography using chloroform.: diisopropyl ether :petroleum ether (I 1 yield one or more positions by Cl-C 4 -aLkyL, Cl-C 4 -aLkoxy, 18 The following compounds are synthesized in a similar manner: 1. la-t-ButyLdimethyLsi lyloxy-78-N,N-diethyLaminocarbonytoxy-8,13-epoxy-9a-hydroxy-68-piperidinoacetoxyLabd- 14-en-li-one.
2. 1Q-t-ButyLdimethyLs iLyLoxy-6$-crotonyLoy~y-7B-N,NdiethyLaminocarbonoxy-8,13-epoxy-9a-hydroxyLabd-14en-i1 1-one Example 6 70-N,N-DiethyLauinocarbonytoxy-c,9cs-dihydroxy-8,13epoxy-60-(3'-morphoL inopropionyLoxy)Labd-14-ea-11-one gift MorphoLine (1.5 mL, 17.2 mmol) is added to a stirred so!ution of 68-acryLoyLoxy-78-N,N-diethyLaminocarbonyLoxy-1a,9a-dihydroxy-8, 13-epoxyLabd-14-en-1 1-one (0.42 g, 0.80 mmoL) in dichLoromethane (15 ml), and the mixture is stirred at room temperature for a further 16 hours and then concentrated. The residue is extracted with ethyl acetate, and the organic phase is washed with water and brine, dried over anhydrous sodium sulfate and concen- :20 trated in vacuo. The residue is purified by flash column chromatography using ethyl acetate :petroleum ether triethyLamine (65 35 1) as eLuant. Melting point 180-82 0 C, recrystallized from chloroform/petroleum ether.
The following compounds are prepared in a simiLar manner: 1. 70-N,N-DiethyLaminocarbonytoxy-lc ,9c-dihydroxy-8,13epoxy-60-(3-piperidinobutyryLoxy)Labd-14-en-11-one.
2. 1c,9-Dihydroxy-7B-ethoxycarbonyLoxy-8,13-epoxy-60- (3'-piperidinobutyryLoxy)Labd-14-en-11-one.
3. 1oi,9cL-Dihydroxy-7B-ethoxycarbonyLoxy-8,13-epoxy-60- Some of the new, multiply oxidizedLabdane derivatives 19 (3'-morphoLinopropionytLoxy)Labd-14-en-11-one.
4. 1(1,90i-,Dihydroxy-68-(3 -N,N-dimethyLaminopropionyLoxy)- 78-ethoxycarbonyLoxy-8, 13-epoxyLabd-14-en-1 1-one.
78-N,N-D iethylamino-1ci,9c-dihydroxy-6-31-dimethyLaminopropionyLoxy)-8, 13-epoxyt abd-14-en-1 1-one.
Example 7 iethytaminocarbonyLoxy-1ct,9cL-dihydroxy-8, 13epoxy-6B-(3'-.orphot inopropionytoxy) Labd 14-en-i 1-one hydrochLoride hemihydrate I I10 Diethyl ether (10 mL, saturated with dry HCI gas at 2 0 0 0) is added to a methanolic soLution of 78-N,N-di- (,forethyLaminocarbonyLoxy-lea,9ox-dihydroxy-8, 13-epoxy-66-C3 morphoLinopropionyLoxy)Labd-14-en-11-one (0.3 g in 3 ml of methanol), the mixture is diluted with excess dry dliethyL ether, and the precipitate which has separated out is removed by filtration. Recrystallization of the oT solid from methanol/ether provides 7B-N,N-diethyLaminocarbonyLoxy-l1%,9ct-dihydroxy-8,13-epoxy-6B-(3'-morphoLino- C CC C41 propionyLoxy) Labd-14-en-1 1-one hydrochloridle hemihydrate, yield 95%, melting point 160-64 0
C.
The following compounds are synthesized in a similar manner: 1. 7B-N,N-D iethyLaminocarbonyLoxy-la,9a-dihydroxy-68-(3 N,N-dimethyLaminopropionyLoxy)-8, 13-epoxyLabd-14-en- 11-one hydrochloridle, melting point 239-240 0
C.
2. 78-N,N-D iethyLaminocarbonyLoxy-1et,9a-dihydroxy-8, 13epoxy-68-(3'-piperidinoipropionyL)Labd-14-en-11-one hydrochloride, metting point 246-247 0
C.,
3. 7B-N,N-DiethyLaminocarbonyLoxy-1a,9ct-dihydroxy-8, 13epoxy-6B-(3'-piperidinobutyryLoxy)Labd-14-en-1 1-one hydrochloride, melting point 173-175 OC.
4. 78-N,N-DiethyLaminocarbonyLoxy-lz,9c'-dihydroxy-8, 13epoxy-65-piperidinoacetoxyLabd-14-en-l 1-one hydrochloride, melting point 253 0
C.
5. 6B-(3'-N,N-D imethyLaminopropionyLoxy)-1a,9a-dihydroxy- 78-ethoxycarbonyLoxy-8,13-epoxyLabd-14-en-11-one hydrochLoride hemihydrate, melting point 213-215 0
C.
6. la,9a-Dihydroxy-76-ethoxycarbonyLoxy-8, 13-epoxy-68-- (3'-piper idinopropionyLoxy) Labd-14-en-1 1-one hydrochloride, melting point 227-228 0
C.
C r 7. 1c,9c-Dihydroxy-7B-ethoxycarbonyLoxy-8, 13-epoxy-66- (3'-morphoL inopropionyLoxy)Labd-14-en-11-one hydrochloride, melting point 218-220 0
C.
C 4.C 8. lci,9c-D ihydroxy-78-ethoxycarbonyLoxy-8, 13-epoxy-68- (3'-piperidinobutyryLoxy) Labd-14-en-11-one hydrachloride, melting point 175-178 0
C.
~e 9. 1a,9a-Dihydroxy-78-ethoxycarbonyLoxy-8, 13-epoxy-6Bpiper idinoacetoxyLabd-14-en-1 1-one hydrochloride, meLting point 2680C.
a a 4 10. 7B-Anilinocarbonyloxy-loc,%-dihydroxy-8,13-epoxy-63morpholinoacetoxy-labd-1 4-en-i 1-one hydrochloride sequihydrate, melting point 201-205 0
C.
Example 8 7B-Anilino-carbonyloxy-1c-t-butyldimethylsilyloxy-8, 13-epoxy- 9of-hydroxy-6B-morpholino acetoxy-labd-1 4-en-i 1-one Phenylisocyanate (0.075 ml, 0.69 mmol) was added to a stirred mixture of 1o(-t-butyldimethylsilyloxy-7B,9d-dihydroxy- 8,1 3-epoxy-6B-morpholinoacetoxy-labd-1 4-en-il-one (0.385 g, L I i i'l S 20a 0.632 mmol), triethylamine (0.096 ml, 0.688 mmol) in toluene ml). The reaction mixture was refluxed for 17 hrs. Another i aliquot of phenyl isocyanate (0.3 ml, 2.76 mmol) was added to the reaction mixture and refluxed for additional 3 hrs. The reaction mixture was concentrated under vacuo and extracted with chloroform. The organic layer was washed with water, saturated sodium chloride solution, dried over sodium sulphate and concentrated. The residue on purification by flash chromatography using ethyl acetate:pet. ether:acetonitrile (6:13:1) as eluent gave the pure product as a thick oil. Yield 90 I 4 C 4 I t 4 4 t t.
I
f t t t
Claims (7)
1. A compound of the formula I HO OH 's OR 7 OR 6 in which R denotes vinyl, ethyl, cyclopropyl or CHOHCH 2 OH, 0 II R 7 denotes hydegen, a group of the formula -C-A, A denoting OR 2 in which R 2 represents an alkyl group, X or denoting N X and Y representing, if they are identical, hydrogen or alkyl, Y or, if X represents hydrogen or lower alkyl, Y representing an alkyl, substituted alkyl (as hereinbefore defined), cycloalkyl, aralkyl (as hereinbefore defined), aryl (as i t hereinbefore defined), amino or hydroxyl group, or X and Y, together with the nitrogen atom to which they are bonded, forming a heterocyclic ring which can contain a further hetero atom and can be substituted by an alkyl or aryl (as hereinbefore defined) group, R 6 denotes a group of the formula lie Rio X R 8 R 10 x -CO-(C)m-(C)n-N R 9 R 1 1 in which m is an integer from 0 to 10 and n is an integer from 1 to 10, and Re and R 9 are identical or different and represent hydrogen or a lower alkyl group, or one of the substituents represents hydrogen and the other represents a hydroxyl, thio or aryl (as hereinbefore defined) group, Rio denotes hydrogen and R 11 denotes hydrogen or a A/-d hydroxyl or alkyl group, and X1 represents hydrogen if Y1 represents hydrogen, alkyi, w substituted alkyl, alkanoyl, aryl (as hereinbefore defined), cycloalkyl, aralkyl (as <i v /i 'li tives. However, they exhibit, in particular, a selective 3 -1 I 33 1 3 ;33" 1 ;333 3~ 22 hereinbefore defined), a heterocycle, amino, substituted amino, hydroxyl, acyl (as hereinbefore defined), dialkylaminoalkyl, carbamoyl, carboxyalkyl or carbalkoxyalkyl, or X1 and Y1 represent, if they are identical, alkyl, substituted alkyl (as hereinbefore defined), aryl (as hereinbefore defined) or aralkyl (as hereinbefore defined), or, if X 1 represents alkyl, Y 1 represents substituted alkyl (as hereinbefore defined), cycloalkyl, aralkyl (as hereinbefore defined) or a dialkylaminoalkyl group, or X 1 and Y 1 form, together with the nitrogen atom to which they are bonded, a heterocycle which can contain one or more hetero atoms and be optionally substituted once or several times by alkyl, aryl (as hereinbefore defined), aralkyl (as hereinbefore defined), hydroxyalkyl, hydroxyl or other heterocyclic groups and its optical and geometric isomers and its pharmaceutically acceptable acid addition salts.
2. A compound of the formula i as claimed in claim 1, in which R denotes the vinyl group, and R6 and R 7 have the indicated meanings, its optical and geometric isomers and pharmaceutically acceptable acid addition salts.
3. A compound of the formula i as claimed in claim 2, in which R 6 denotes a group of the formula *4* 0 Rg Rio X, II I I R R11 Y' 1\ I4 in which Rs, Rg, and Rio and R 11 are identical or different and each denote hydrogen or methyl, the total of m and n is an integer from 1 to 5, either Xi andY 1 are identical and 4 denote hydrogen or Cl--C 4 -alkyl, or one of the substitutents denotes hydrogen and the other denotes a C-C 4 -alkyl group, or X 1 and Y 1 represents, together with the nitrogen atom to which they are bonded, piperidino, pyrrolidine, morpholino, piperazino or thiomorpholino, *adaical-substituted in one or more positions by C 1 -C 4 -alkyl, C 1 C 4 -alkoxy, aryl (as herein before defined), aryl-C-C 4 -alkyl, hydroxyl, amino 0 II or substituted C 1 -C 4 -alkyl, and R 7 denotes the radical in which A represents ~~I 14:: V aC1-C 4 -alkoxy group or a group of the formula X, in which X and Y have the said -N Y meanings, its optical and geometric isomers and pharmaceutically acceptable acid addition salts.
4. A compound the formula I as claimed in claims 3, in which Re represents a group of the formula 0 -C -(CH2)m--NQ O 0 II in which m denotes the number 1 or 2, and R 7 represents the radical in which A denotes the ethoxy or diethylamino group, its optical and geometric isomers and pharmaceutically acceptable acid addition salts.
5. A process for the preparation of a compound of the formula I as claimed in claim 1, which comprises reaction of a compound orthe formula II CIi C C c C C I CI C (CO C SC C C i;i:B i a i caLcutatea using tne iflit IL vaLue. -24- ~R OHI 6 OH6 RB 1 0 X OCO M-C n-N/ I In R 9 R 1 1 in which R 1 is a protective group for an alcoholic hydroxyl group, and R 8 to R 11 and X 1 and Y 2 have the said meanings, either a) with a mixture of an alkyL haloformate and 4- dlimethyLaminopyridline to give a compound of the formula III R 1 C OH OR 7 C)M1C) -N/ R 9 R 1 1 4 in which R 7 represents a radlical of the formula 4* 0 two&". 1 -C-0-R 2 with R 2 representing Cl-C 8 -aLkyL, 4: or a t b) with a mixture of a compound of the formula X CL-C-N and 4-dimethylaminopyridine and hydro- quinone monomethyL ether to give a compound of the formuLa III in which R 7 represents a radlical of C0 X the formula -C-N in which X and Y have the same meanings, c) elimination, by customary methods, of the protec- tive group Ri' from a compound of the formula III, resulting in a compound of the formula I in Sur OrC IFIULCU. which R 1 denotes hydrogen, or d) reaction of a compound of the formula ix 0 R'O ".O OH OCOA OCOCH=CR 12 R 13 in which R 1 represents a protective group, A has the abovementioned meaning, and R 12 and R 13 each represent hydrogen or a lower alkyl or aryl group, with an Xl amine of the formula HN in which X, and Y, have the said meanings, and Y subsequent elimination, by customary methods, of the protective group Ri', resulting in a compound of the formula I in which R, is hydrogen.
6. A medicament containing a compound as claimed in claim 1 and customary S ~auxiliaries and vehicles.
7. A method of preparation of a medicament having a positive inotropic effect or an effect lowering the intraocular pressure or lowering the blood pressure comprising admixing in a pharmacologically effective ratio, an effective amount of a compound as claimed in claim 1, with pharmaceutically effective carriers and excipients. n DATED this 18th day of May, 1992. S' HOECHST AKTIENGESELLSCHAFT WATERMARK PATENT TRADEMARK ATTORNEYS THE ATRIUM 290 BURWOOD ROAD HAW, HORN VICTORIA 3i22 AUSTRALIA
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DE3737353 | 1987-11-04 | ||
DE19873737353 DE3737353A1 (en) | 1987-11-04 | 1987-11-04 | NEW ACYLLABDANE DERIVATIVES, A METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS MEDICINAL PRODUCTS |
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AU24649/88A Ceased AU628026B2 (en) | 1987-11-04 | 1988-11-03 | New acyllabdane derivatives, a process for their preparation,and their use as medicaments |
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EP (1) | EP0315097A3 (en) |
JP (1) | JPH01151572A (en) |
KR (1) | KR890008132A (en) |
AU (1) | AU628026B2 (en) |
DE (1) | DE3737353A1 (en) |
DK (1) | DK613888A (en) |
HU (1) | HUT50805A (en) |
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PT (1) | PT88923B (en) |
ZA (1) | ZA888194B (en) |
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US4999351A (en) * | 1989-01-11 | 1991-03-12 | Hoechst-Roussel Pharmaceuticals, Inc. | 7-aryl and heteroaryl ethers of desacetylforskolin |
US5177207A (en) * | 1989-01-11 | 1993-01-05 | Hoechst-Roussel Pharmaceuticals, Inc. | 7-aryl and heteroaryl ethers of desacetylforskolin |
Citations (3)
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AU5423686A (en) * | 1985-03-01 | 1986-09-04 | Hoechst-Roussel Pharmaceuticals Incorporated | Labd-14-en-11-one derivatives |
AU1741288A (en) * | 1987-06-06 | 1988-12-08 | Hoechst Aktiengesellschaft | New polyoxygenated labdane derivatives, a process for their preparation, and their use as medicaments |
AU3452189A (en) * | 1988-05-09 | 1989-11-09 | Hoechst-Roussel Pharmaceuticals Incorporated | Hydrazinocarbonyloxylabdanes, a process for their preparation and their use as medicaments |
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GB1594115A (en) * | 1976-10-21 | 1981-07-30 | Hoechst Ag | Polyoxygenated labdane derivatives |
AU591196B2 (en) * | 1985-11-15 | 1989-11-30 | Nippon Kayaku Kabushiki Kaisha | Novel forskolin derivatives |
DE3623300A1 (en) * | 1986-07-11 | 1988-01-21 | Hoechst Ag | 7-ACYLOXY-6-AMINOACYLOXYPOLYOXYLABDANE, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS A MEDICINAL PRODUCT |
FI875699A (en) * | 1986-12-29 | 1988-06-30 | Hoechst Roussel Pharma | NYA KARBAMOYLOXILABDANER, MELLANPRODUKTER OCH FOERFARANDEN FOER DERAS FRAMSTAELLNING SAMT DERAS ANVAENDNING SAOSOM LAEKEMEDEL. |
HU201921B (en) * | 1987-06-29 | 1991-01-28 | Nippon Kayaku Kk | New process for producing 6-acylforscholine derivatives |
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1987
- 1987-11-04 DE DE19873737353 patent/DE3737353A1/en not_active Withdrawn
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1988
- 1988-10-29 EP EP88118073A patent/EP0315097A3/en not_active Withdrawn
- 1988-11-02 JP JP63276362A patent/JPH01151572A/en active Pending
- 1988-11-02 KR KR1019880014361A patent/KR890008132A/en not_active Application Discontinuation
- 1988-11-02 HU HU885682A patent/HUT50805A/en unknown
- 1988-11-02 ZA ZA888194A patent/ZA888194B/en unknown
- 1988-11-03 PT PT88923A patent/PT88923B/en not_active IP Right Cessation
- 1988-11-03 AU AU24649/88A patent/AU628026B2/en not_active Ceased
- 1988-11-03 DK DK613888A patent/DK613888A/en not_active Application Discontinuation
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AU5423686A (en) * | 1985-03-01 | 1986-09-04 | Hoechst-Roussel Pharmaceuticals Incorporated | Labd-14-en-11-one derivatives |
AU1741288A (en) * | 1987-06-06 | 1988-12-08 | Hoechst Aktiengesellschaft | New polyoxygenated labdane derivatives, a process for their preparation, and their use as medicaments |
AU3452189A (en) * | 1988-05-09 | 1989-11-09 | Hoechst-Roussel Pharmaceuticals Incorporated | Hydrazinocarbonyloxylabdanes, a process for their preparation and their use as medicaments |
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AU2464988A (en) | 1989-05-25 |
EP0315097A2 (en) | 1989-05-10 |
EP0315097A3 (en) | 1990-07-04 |
DK613888A (en) | 1989-05-05 |
PT88923A (en) | 1988-12-01 |
DE3737353A1 (en) | 1989-05-18 |
PT88923B (en) | 1993-01-29 |
JPH01151572A (en) | 1989-06-14 |
IN170600B (en) | 1992-04-18 |
KR890008132A (en) | 1989-07-08 |
ZA888194B (en) | 1989-07-26 |
HUT50805A (en) | 1990-03-28 |
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