NO753197L - - Google Patents
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- Publication number
- NO753197L NO753197L NO753197A NO753197A NO753197L NO 753197 L NO753197 L NO 753197L NO 753197 A NO753197 A NO 753197A NO 753197 A NO753197 A NO 753197A NO 753197 L NO753197 L NO 753197L
- Authority
- NO
- Norway
- Prior art keywords
- formula
- acid
- compound
- compounds
- dihydro
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 claims description 26
- 239000002253 acid Substances 0.000 claims description 22
- 238000000034 method Methods 0.000 claims description 18
- 239000003054 catalyst Substances 0.000 claims description 9
- 150000003839 salts Chemical class 0.000 claims description 9
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 125000004432 carbon atom Chemical group C* 0.000 claims description 3
- 150000002391 heterocyclic compounds Chemical class 0.000 claims description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 36
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 30
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 12
- 238000002844 melting Methods 0.000 description 11
- 230000008018 melting Effects 0.000 description 11
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- 238000005984 hydrogenation reaction Methods 0.000 description 8
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- 229910052763 palladium Inorganic materials 0.000 description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- 150000001408 amides Chemical class 0.000 description 5
- 150000001540 azides Chemical class 0.000 description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- 238000000354 decomposition reaction Methods 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- -1 alkyl radical Chemical class 0.000 description 3
- FSIZNIXUPRQTLZ-QMTHXVAHSA-N lysergic acid Chemical class C1=CC=C2C3=C[C@@H](C(O)=O)CN(C)[C@@H]3CC3=CN=C1[C]32 FSIZNIXUPRQTLZ-QMTHXVAHSA-N 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 125000006239 protecting group Chemical group 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- ZAGRKAFMISFKIO-UHFFFAOYSA-N Isolysergic acid Natural products C1=CC(C2=CC(CN(C2C2)C)C(O)=O)=C3C2=CNC3=C1 ZAGRKAFMISFKIO-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 150000007933 aliphatic carboxylic acids Chemical class 0.000 description 2
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 2
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000012320 chlorinating reagent Substances 0.000 description 2
- 238000003776 cleavage reaction Methods 0.000 description 2
- 235000019441 ethanol Nutrition 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 238000007327 hydrogenolysis reaction Methods 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 230000000803 paradoxical effect Effects 0.000 description 2
- 239000008363 phosphate buffer Substances 0.000 description 2
- 230000007017 scission Effects 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 2
- 230000007306 turnover Effects 0.000 description 2
- DNXIKVLOVZVMQF-UHFFFAOYSA-N (3beta,16beta,17alpha,18beta,20alpha)-17-hydroxy-11-methoxy-18-[(3,4,5-trimethoxybenzoyl)oxy]-yohimban-16-carboxylic acid, methyl ester Natural products C1C2CN3CCC(C4=CC=C(OC)C=C4N4)=C4C3CC2C(C(=O)OC)C(O)C1OC(=O)C1=CC(OC)=C(OC)C(OC)=C1 DNXIKVLOVZVMQF-UHFFFAOYSA-N 0.000 description 1
- ORBSYPFBZQJNJE-MPKXVKKWSA-N (6ar,9r,10ar)-7-methyl-6,6a,8,9,10,10a-hexahydro-4h-indolo[4,3-fg]quinoline-9-carboxylic acid Chemical class C1=CC([C@H]2C[C@H](CN([C@@H]2C2)C)C(O)=O)=C3C2=CNC3=C1 ORBSYPFBZQJNJE-MPKXVKKWSA-N 0.000 description 1
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- NAMYKGVDVNBCFQ-UHFFFAOYSA-N 2-bromopropane Chemical compound CC(C)Br NAMYKGVDVNBCFQ-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- LCQMZZCPPSWADO-UHFFFAOYSA-N Reserpilin Natural products COC(=O)C1COCC2CN3CCc4c([nH]c5cc(OC)c(OC)cc45)C3CC12 LCQMZZCPPSWADO-UHFFFAOYSA-N 0.000 description 1
- QEVHRUUCFGRFIF-SFWBKIHZSA-N Reserpine Natural products O=C(OC)[C@@H]1[C@H](OC)[C@H](OC(=O)c2cc(OC)c(OC)c(OC)c2)C[C@H]2[C@@H]1C[C@H]1N(C2)CCc2c3c([nH]c12)cc(OC)cc3 QEVHRUUCFGRFIF-SFWBKIHZSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- AOGYCOYQMAVAFD-UHFFFAOYSA-N chlorocarbonic acid Chemical compound OC(Cl)=O AOGYCOYQMAVAFD-UHFFFAOYSA-N 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- WBKFWQBXFREOFH-UHFFFAOYSA-N dichloromethane;ethyl acetate Chemical compound ClCCl.CCOC(C)=O WBKFWQBXFREOFH-UHFFFAOYSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- RHGUXDUPXYFCTE-ZWNOBZJWSA-N ergoline Chemical class C1=CC([C@@H]2[C@H](NCCC2)C2)=C3C2=CNC3=C1 RHGUXDUPXYFCTE-ZWNOBZJWSA-N 0.000 description 1
- 230000000763 evoking effect Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229940126601 medicinal product Drugs 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- ORIBUSCBDFDAIQ-GYYYEOQOSA-N methyl (6ar,9r)-4,6,6a,7,8,9,10,10a-octahydroindolo[4,3-fg]quinoline-9-carboxylate Chemical compound C1=CC(C2[C@H](NC[C@@H](C2)C(=O)OC)C2)=C3C2=CNC3=C1 ORIBUSCBDFDAIQ-GYYYEOQOSA-N 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 229910000510 noble metal Inorganic materials 0.000 description 1
- 150000007530 organic bases Chemical group 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000003791 organic solvent mixture Substances 0.000 description 1
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- BJOIZNZVOZKDIG-MDEJGZGSSA-N reserpine Chemical compound O([C@H]1[C@@H]([C@H]([C@H]2C[C@@H]3C4=C([C]5C=CC(OC)=CC5=N4)CCN3C[C@H]2C1)C(=O)OC)OC)C(=O)C1=CC(OC)=C(OC)C(OC)=C1 BJOIZNZVOZKDIG-MDEJGZGSSA-N 0.000 description 1
- 229960003147 reserpine Drugs 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- MDMGHDFNKNZPAU-UHFFFAOYSA-N roserpine Natural products C1C2CN3CCC(C4=CC=C(OC)C=C4N4)=C4C3CC2C(OC(C)=O)C(OC)C1OC(=O)C1=CC(OC)=C(OC)C(OC)=C1 MDMGHDFNKNZPAU-UHFFFAOYSA-N 0.000 description 1
- 238000007127 saponification reaction Methods 0.000 description 1
- 238000004904 shortening Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 230000002618 waking effect Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
- C07D519/02—Ergot alkaloids of the cyclic peptide type
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Description
Foreliggende oppfinnelse vedrorer en fremgangsmåte for fremstillingThe present invention relates to a method for production
av nye hetrocykliske forbindelser med formel Iof new heterocyclic compounds of formula I
hvori R betyr alkyl med 1-5 karbonatomer. wherein R means alkyl of 1-5 carbon atoms.
R står spesielt for metyl eller.én i a-stillingen til det nitrogen-R stands specifically for methyl or one in the a-position of the nitrogen
atom hvortil R er bundet, forgrenet alkylrest som isoprøpyl.atom to which R is attached, branched alkyl radical such as isopropyl.
Det særegne ved fremgangsmåten i henhold til oppfinnelsen er atThe peculiarity of the method according to the invention is that
a) et reaksjonsdyktig, funksjonelt derivat av en syre med formel II>7 a) a reactive, functional derivative of an acid of formula II>7
hvori R har den ovennevnte betydning, kondenseres med forbindelsen med formel III wherein R has the above meaning, is condensed with the compound of formula III
i saltform eller in salt form or
b) forbindelser med formel IV b) compounds of formula IV
hvori R har den ovennevnte betydning, hydrogeneres i nærvær av en wherein R has the above meaning, is hydrogenated in the presence of a
katalysator.catalyst.
Omsetningen i henhold til fremgangsmåtenThe turnover according to the procedure
a) utgjor en kondensasjonsreaksjon for amider.a) completes a condensation reaction for amides.
Fra ergotkjemien er det kjent hvilke reaksjonsdyktige funksjonelle From ergot chemistry, it is known which reactive functionals
derivater av 9,10-dihydrolysergsyre som kan anvendes ved slike omsetninger og under hvilke betingelser disse omsetninger kan gj ennomfores. derivatives of 9,10-dihydrolysergic acid which can be used in such reactions and under which conditions these reactions can be carried out.
Som r.eaksjonsdyktige funksjonelle derivater av en syre med formel II kan for eksempel anvendes syreklorid-hydrokloridet, syreazidet eller et blandet anhydrid av en syre med formel II med svovelsyre eller trifloureddiksyre. As reactive functional derivatives of an acid of formula II, for example, the acid chloride hydrochloride, the acid azide or a mixed anhydride of an acid of formula II with sulfuric acid or trifluoroacetic acid can be used.
Foretrukket anvender man de reaksjonsdyktige funksjonelle derivater som kan erholdes ved omsetning av en syre med formel II med fra et kloreringsmiddel og N-di (lavere) alkylsubstituert syreamid av en alifatisk karbocylsyre med 1-3 karbonatomer. Som kloreringsmiddel kan anvendes for eksempel thionylklorid, phosgen eller oxalylklorid. For dannelsen av det anvendte amidklorid egnede syreamider nevnes for eksempel dimetylformamid eller dimetylacetamid. The reactive functional derivatives that can be obtained by reacting an acid of formula II with a chlorinating agent and N-di (lower) alkyl substituted acid amide of an aliphatic carboxylic acid with 1-3 carbon atoms are preferably used. For example, thionyl chloride, phosgene or oxalyl chloride can be used as a chlorinating agent. Suitable acid amides for the formation of the amide chloride used are, for example, dimethylformamide or dimethylacetamide.
Fremgangsmåten a) gjennomfores i en organisk losningsmiddelblanding. Egnende løsningsmidler er for eksempel kloroform/...métylenklorid, dimetylformamid eller acetonitril. Method a) is carried out in an organic solvent mixture. Suitable solvents are, for example, chloroform/...methylene chloride, dimethylformamide or acetonitrile.
Man arbeider i nærvær av e-t kondensasjonsmiddel. Hensiktsmessig anvendes tertiere organiske baser, for eksempel trietylamin, men foretrukket pyredin. You work in the presence of e-t condensation agent. Appropriately, tertiary organic bases are used, for example triethylamine, but preferably pyridine.
Omsetningen kan gj ennomf ores ved temperaturer, mellom -30 og +20°C. Man kan arbéideuuhder normal trykk. The turnover can be carried out at temperatures between -30 and +20°C. One can arbéideuuhder normal pressure.
Hensiktsmessig anvendes for hvert et mol av forbindelsen med formel III i saltform 1,2 til 2,4 mol av et reaksjonsdyktig funksjonelt derivat av en syre med formel III. Appropriately, for every one mole of the compound of formula III in salt form, 1.2 to 2.4 moles of a reactive functional derivative of an acid of formula III are used.
For forbindelsen med formel III er den foretrukne saltform hydrokloridet. For the compound of formula III, the preferred salt form is the hydrochloride.
Hydrogeneringen (fremgangsmåten b) kan gjennomfores etter de for hydrogenering av meldroyealkaloider til ergolin I-forbindelser kjente metoder. The hydrogenation (method b) can be carried out according to the methods known for the hydrogenation of meldroye alkaloids to ergoline I compounds.
For eksempel opptas et lysergsyrederivat med formel IV i et under reaksjonsbetingelsene inert løsningsmiddel eller losningsmiddelblanding og tilsettes katalysatoren, for eksempel palladiumklorid eller palladium på aktivkull. For example, a lysergic acid derivative of formula IV is taken up in a solvent or solvent mixture that is inert under the reaction conditions and the catalyst, for example palladium chloride or palladium on activated carbon, is added.
Egnende inertef Vilosmingmidler er for eksempel noytrale løsningsmidler som dioxan, amider av alifatiske karbocylsyrer som dimetylformamid eller også lavere alkanoler. Suitable inert surfactants are, for example, neutral solvents such as dioxane, amides of aliphatic carboxylic acids such as dimethylformamide or lower alkanols.
Hydrogeneringen kan gjennomfores ved romtemperatur eller svakt forhoyet temperatur. Trykket er ikke kritisk og kan variere mellom normaltrykk og omtrent 80 atmosfærer overtrykk. Vanlig arbeider man derfor hensiktsmessig under normaltrykk. The hydrogenation can be carried out at room temperature or a slightly elevated temperature. The pressure is not critical and can vary between normal pressure and approximately 80 atmospheres overpressure. You usually therefore work appropriately under normal pressure.
Etter avsluttet hydrogenopptagelse fraf iltreres katalysatoren. After completion of hydrogen uptake, the catalyst is filtered off.
Forbindelsene med formel I kan foreligge i fri form eller saltform, for eksempel som hydroklorid. The compounds of formula I can be present in free form or salt form, for example as hydrochloride.
Fra de fri baser lar seg påkjent måteutvinne syreaddisjonssalterAcid addition salts can be extracted from the free bases in a known manner
og omvendt.and vice versa.
Av de som utgangsprodukt anvendte forbindelser med formel II er de forbindelser hvori. R står for metyl og etyl tidligere kjent. Of the compounds of formula II used as starting product are those compounds in which. R stands for methyl and ethyl previously known.
De nye forbindelser med formel II kan fremstilles analogt med deThe new compounds of formula II can be prepared analogously to those
for fremstilling av 6-nor-6-etyl-9,10-dihydrolysergsyre beskrevne fremgangsmåter. methods described for the production of 6-nor-6-ethyl-9,10-dihydrolysergic acid.
Forbindelsen med formel III i det folgende kor.tjbe tegnet som aminocyclol - er ny. The compound of formula III in the following cor.tjbe denoted as aminocyclol - is new.
Denne aminocyclol erholdes ved at man fra forbindelsen med formelThis aminocyclol is obtained by starting from the compound of formula
V, W,
hvori står for en selektivt avspaltbar beskyttelsesgruppe av-spalter R^. in which stands for a selectively cleavable protective group de-cleaving R^.
Den selektive avspalting av beskyttelsesgruppen, for eksempel benzyloksykarbonylgruppen, kan g-j ennomf ores analogt med i péptid-kjemien kjente metoder. The selective removal of the protective group, for example the benzyloxycarbonyl group, can be carried out analogously to methods known in peptide chemistry.
Står'R^ for benzyloksykabonylgruppen går man for eksempel frem på fSigende måte: Beskyttelsesgruppen avspaltes ved hydrogenolyse i surt medium. Hydrogeneringen gjennomfores hensiktsmessig i nærvær av en edelmetall— katalysator. Palladium er spesielt egnet for denne reaksjon. Som bærer afor palladium velges for eksempel aktiv kull. Den katalyt-ii . tiske hydrogenolyse gjennomfores under sure betingelser, for eksempel, i nærvær av 1,2 til 1,5 mol.isyre. Egnende reaksjonsmedier er for eksempel blandinger av inerte. organiske løsningsmidler som dimetylformamid med dioksan, eller metanol med tetrahydrofluran, If R^ stands for the benzyloxycarbonyl group, the procedure is, for example, as follows: The protecting group is removed by hydrogenolysis in an acidic medium. The hydrogenation is conveniently carried out in the presence of a noble metal catalyst. Palladium is particularly suitable for this reaction. As a carrier for palladium, activated charcoal is chosen, for example. The catalyst-ii. tical hydrogenolysis is carried out under acidic conditions, for example, in the presence of 1.2 to 1.5 molar hydrochloric acid. Suitable reaction media are, for example, mixtures of inerts. organic solvents such as dimethylformamide with dioxane, or methanol with tetrahydroflurane,
med klorhydrogensyre som syre. Hydrogeneringen gjennomføres hensiktsmessig ved romtemperatur og normaltrykk. with hydrochloric acid as acid. The hydrogenation is conveniently carried out at room temperature and normal pressure.
Forbindelsen med formel V erholdes analogt med kjente metoder, for eksempel fra det tilsvarende syreazid med formel VI. The compound of formula V is obtained analogously by known methods, for example from the corresponding acid azide of formula VI.
Syreazidet med formel VI kan også overfores direkte,ved behandling med tilnærmet den teoretiske mengde vann og syre, for eksempel saltsyre, i et under reaksjonsbetingelsene inert løsningsmiddel i aminocyclolen. The acid azide of formula VI can also be transferred directly, by treatment with approximately the theoretical amount of water and acid, for example hydrochloric acid, in a solvent inert under the reaction conditions in the aminocyclolene.
De ovennevnte aminocyelolsynteser er i prinsippet deltrinn av Curtius-metoden henholdsvis modifikasjoner derav og skjer under anvendelse av forbindelser med formel VII, The above-mentioned aminocellol syntheses are in principle partial steps of the Curtius method or modifications thereof and take place using compounds of formula VII,
hvori R2står for lavere alkyl, for eksempel etyl, som utgangsprodukt. Esterne med formel VII overfores analogt med kjente metoder i deres tilsvarende fri syre, over karbocylkloridet i syreazidet med formel VI, og dette gir etter gjennomføring av de beskrevne forhåndsregler aminocyclolen. in which R2 stands for lower alkyl, for example ethyl, as starting product. The esters of formula VII are transferred analogously to known methods in their corresponding free acid, over the carboxyl chloride in the acid azide of formula VI, and this gives, after carrying out the described preliminary rules, the aminocyclolene.
Fremstillingen med forbindelsene med formel VII kan foretas analogt med kjente metoder under anvendelse av L-isoleucyl-L-prolin-lactam og S+metyl-benzyloksymalonsyremondetylesterklorid som utganga-material. The preparation with the compounds of formula VII can be carried out analogously to known methods using L-isoleucyl-L-proline lactam and S+methyl-benzyloxymalonic acid monoethyl ester chloride as starting material.
Forbindelsene med formel IV kan erholdes analogt med kjente metoder ved omsetning av aminocyclolen med formel rn med et reaksjonsdyktig funksjonelt derivat av den tilsvarende lysergsyre, for eksempel som det fremgår av den eksperimentelle del av denne beskrivelse. The compounds of formula IV can be obtained analogously to known methods by reacting the aminocyclolene of formula rn with a reactive functional derivative of the corresponding lysergic acid, for example as appears from the experimental part of this description.
I den utstrekning fremstillingen av utgangsforbindelsene ikke er be-skrevet er disse kjente eller kan fremstilles etter i og for seg kjente eller analogt med i og for seg kjente metoder. To the extent that the production of the starting compounds is not described, these are known or can be produced according to per se known or analogously to per se known methods.
Forbindelsene med formel I og deres physiologisk tålbare salter utmerker seg ved interessante farmakodynamiske egenskaper og kan folgelig anvendes som legemidler. The compounds of formula I and their physiologically tolerable salts are distinguished by interesting pharmacodynamic properties and can therefore be used as pharmaceuticals.
Ved ikke-narkotiserte rotter med kronisk implanterte EEG-elektroder bevirker de ved oppfinnelsen fremstillbare forbindelser en signifi-kant forlengelse av våkenfåsene, en forkortelse av fasene for dai klassiske og paradoksale sovn og forlengelse av latenstiden til den forste opptreden av paradoksal sovn. In non-anesthetized rats with chronically implanted EEG electrodes, the compounds that can be produced by the invention cause a significant prolongation of the waking phases, a shortening of the phases for then classical and paradoxical sleep and an extension of the latency time to the first appearance of paradoxical sleep.
Videre reduserer de tallet av de med reserpien i katter fremkalte topp-potensialer "corpus geniculatum laterale" (PGO Spikes). Furthermore, they reduce the number of peak potentials "corpus geniculatum laterale" (PGO Spikes) evoked by reserpine in cats.
Disse forandringer er uttrykk for en vigilans forhoyelse. De ved oppfinnelsen fremstillbare forbindelser er derfor indikert for behandling av seribralinsuffiens. These changes are an expression of an increase in vigilance. The compounds that can be prepared by the invention are therefore indicated for the treatment of cerebral insufficiency.
De legemidler, som kan inneholde forbindelsen med formel I i fri form eller i form av dens fysiologisk tålbare addisjonssalter med syrer, kan foreligge for eksempel f form av en losning eller The medicinal products, which may contain the compound of formula I in free form or in the form of its physiologically tolerable addition salts with acids, may be available, for example, in the form of a solution or
tablet som kan fremstilles etter kjente metoder under anvendelse av valige hjelpe- og bærerstoffer. tablet which can be prepared according to known methods using selected excipients and carriers.
I de etterfølgende eksempler er alle temperaturangivelser i grader Celsius. In the following examples, all temperature indications are in degrees Celsius.
EKSEMPEL 1: 2' B- metyl- 51g- sec. butvl- 9, 10- dihydro- ergopeptin.EXAMPLE 1: 2' B- methyl- 51g- sec. butvl-9, 10-dihydro-ergopeptin.
I det folgende benevnt dihydro-6-ergosin.Hereinafter referred to as dihydro-6-ergosine.
I en sulfideringskolbe ble det innfort 300 ml absolutt dimetylformamid, avkjolt til -20°C og ved denne temperatur ble det i lopet av 20 minutter under omroring tildryppet en losning av 12,3 ml 300 ml of absolute dimethylformamide was introduced into a sulphiding flask, cooled to -20°C and at this temperature a solution of 12.3 ml was added dropwise over the course of 20 minutes with stirring
(0, 143 mol) nydestilert oxailylklorid i 65 ml absolutt acetonitril. Den dannede gule suspensjon ble omrort videre i 15 minutter, deretter ble det ved -20°C tildrysset 38,6 g (0,143 mol) vakuumtorret finpulverisert dihydrolysergsyre. Reaksjonsblandingen omrores videre i 30 minutter, idet temperaturen steg. til 0°C. Deretter ble det på nytt avkjolt til -20°C og 143 ml absolutt pyridin ble tildryppet så hurtig som mulig. Deretter ble det tildrysset 31,6 g (0,0713 mol) aminocyclol-hydroklorid ( inneholder . 1 mol krystall-dimetylformamid og ^ mol krys tall-te trahydrof ifcariy. molvekt dermed 442,9), hvorved temperaturen steg til -10°C og det dannet seg en orangebrun tykk suspensjon som ble omrort ennå i en time. For opparbeidelsen ble det på nytt avkjolt til -20°C og tildryppet 200 ml fosfatpuffer med ph 4. Deretter ble reaksjonsblandingen uthelt på 2,6 1 2N sodalosning og ekstrahert tre ganger med metylenklorid. Metylenkloridlosningene ble ettervasket med 700 ml vann, deretter torret med natriumsulfat og inndampet til torrhet på rotasjonsinn-damper. Det ble tilbake en skumaktig harpiks som ble kromatografert på den 15-dobbelté mengde aluminiumoksyd med aktivitet II. Det således erholte nesten rene dihydro-6-ergosin ble omkrystallisert frai metylenklorid/metanol. (0.143 mol) of freshly distilled oxalyl chloride in 65 ml of absolute acetonitrile. The yellow suspension formed was stirred further for 15 minutes, then 38.6 g (0.143 mol) vacuum-dried finely powdered dihydrolysergic acid was sprinkled in at -20°C. The reaction mixture is stirred further for 30 minutes, as the temperature rises. to 0°C. It was then cooled again to -20°C and 143 ml of absolute pyridine was added dropwise as quickly as possible. Then 31.6 g (0.0713 mol) of aminocyclol hydrochloride (contains .1 mol of crystal dimethylformamide and ^ mol of crystalline trahydrof ifcariy. molar weight thus 442.9) was sprinkled in, whereupon the temperature rose to -10°C and an orange-brown thick suspension formed which was stirred for another hour. For the work-up, it was again cooled to -20°C and 200 ml of phosphate buffer with pH 4 was added dropwise. The reaction mixture was then poured into 2.6 1 2N soda solution and extracted three times with methylene chloride. The methylene chloride solutions were washed with 700 ml of water, then dried with sodium sulfate and evaporated to dryness on a rotary evaporator. A foamy resin remained which was chromatographed on the 15-fold amount of alumina with activity II. The almost pure dihydro-6-ergosine thus obtained was recrystallized from methylene chloride/methanol.
Smeltepunkt 180-183°C (spalting), [a]!2-0^ -44° (c== 3, pyridin) Melting point 180-183°C (decomposition), [a]!2-0^ -44° (c== 3, pyridine)
Aminocyclolen ble erholt på folgende måte:The aminocyclolene was obtained as follows:
17,2 g av forbindelsen med formel V (R1= C6H5-CH20-CO)17.2 g of the compound of formula V (R1= C6H5-CH20-CO)
(40 mmol) ble opplost i 90 ml absolutt dimetylformamid og helt inn(40 mmol) was dissolved in 90 ml of absolute dimethylformamide and poured in
i en widmerkolbe, som forst var utspylt med nitrogen- Deretter ble det tilsatt 6 g palladiumkatalysator (10% palladium på kull) in a Widmer flask, which was first flushed out with nitrogen - Then 6 g of palladium catalyst (10% palladium on charcoal) was added
og etterspylt med 80 ml absolutt tetrahydrofuran. Etter tilsetning av 8 ml 6,5 N hydrogenklorid i tetrahydrofuran (52 mmol) ble det hydrogenert med engang. Etter avsluttet hydrogenering (25 minutter) and backwashed with 80 ml of absolute tetrahydrofuran. After adding 8 ml of 6.5 N hydrogen chloride in tetrahydrofuran (52 mmol), it was hydrogenated at once. After completion of hydrogenation (25 minutes)
ble katalysatoren frafiltrert og det ble inndampet på rotasjons-inndamper ved maksimalt 2 5°C i vakuum for fjernelse av tetrahydro^u furan og dimetylformamid. Resten ble lost med 100 ml dimetylformamid, og losningen ble gnidd litt en spatel. Aminocyclolen krystalliserer som hydroklorid med ét mol krystall-dimetylform- the catalyst was filtered off and it was evaporated on a rotary evaporator at a maximum of 25°C in vacuum to remove tetrahydrofuran and dimethylformamide. The residue was dissolved with 100 ml of dimethylformamide, and the solution was slightly rubbed with a spatula. Aminocyclolene crystallizes as hydrochloride with one mole of crystal dimethylform-
amid og ^ mol krystall-tetrahydrofuran og smelter etter filtrering og ettervasking med tetrahyrdofuran ved 122-123°C. amide and ^ mol of crystal tetrahydrofuran and melts after filtration and washing with tetrahydrofuran at 122-123°C.
Under syntesen av forbindelsen med formel V (smeltepunkt 188-189°C) ble det dannet folgende mellomprodukter: During the synthesis of the compound of formula V (melting point 188-189°C), the following intermediates were formed:
- ester med formel VII med R2= C2H5(smeltepunkt 124-125°C)- ester of formula VII with R2= C2H5 (melting point 124-125°C)
- den syre som tilsvarer esteren (smeltepunkt 168jC (spalting)) - the acid corresponding to the ester (melting point 168jC (decomposition))
- syreazidet med formel VI som videre forarbeides direkte.- the acid azide of formula VI which is further processed directly.
EKSEMPEL 2: 6- nor- 6- isopropvl- 2' B- metvl- 5' g- sec. butvl- 9, 10- dihvdro-erqopeptin ( 6- hor- 6- isopropyl- dihvdro- g- erqosin) EXAMPLE 2: 6- nor- 6- isopropvl- 2' B- metvl- 5' g- sec. butvl- 9, 10- dihydro-erqopeptin ( 6- hor- 6- isopropyl- dihydro- g-erqosine)
Det gås frem analogt med eksempel 1, men det anvendes 13,2 g torr 6-nor-6-isoprpyl-dihydrolysergsyre istedet for dihydrolysergsyre og den i overskriften nevnte forbindelse erholdes med smeltepunkt 182-183°C (spalting), [<g>j^<0>= -15,5° (c = 1 metylenklorid). The procedure is analogous to example 1, but 13.2 g dry 6-nor-6-isopropyl-dihydrolysergic acid is used instead of dihydrolysergic acid and the compound mentioned in the title is obtained with a melting point of 182-183°C (cleavage), [<g> j^<0>= -15.5° (c = 1 methylene chloride).
Den som utgangsprodukt anvendte 6-nor-6-isopropyl-9,10-dihydrolysergsyre erholdes for eksempel på folgende måte: a) Alkylering av 6-nor-9,lO-dihydro-lysergsyre-metylester med iso-propylbromid gir 6-nor-6-iisopropyl-9,10-dihydro-lysergsyreme tyles ter som krystalliserer fra etanol i form av fargelose krystaller med smeltepunkt 194°C. tdc\^ ° = -80,2° (c = 0,582 i metylenklord). The 6-nor-6-isopropyl-9,10-dihydrolysergic acid used as starting product is obtained, for example, in the following way: a) Alkylation of 6-nor-9,10-dihydro-lysergic acid methyl ester with isopropyl bromide gives 6-nor- 6-isopropyl-9,10-dihydro-lysergic acid methyl ester which crystallizes from ethanol in the form of colorless crystals with a melting point of 194°C. tdc\^ ° = -80.2° (c = 0.582 in methylene chloride).
b) Forsepning av den under a) erholte ester ved hjelp av natron-b) Saponification of the ester obtained under a) using sodium
lut i metanol/metylenklorid gir 6-nor-6-isopropyl-9,10-dihydrolysergsyre. Speltepunkt 290°C (spaltning) [ccj^^ = -101° (c = 0,6 lye in methanol/methylene chloride gives 6-nor-6-isopropyl-9,10-dihydrolysergic acid. Melting point 290°C (decomposition) [ccj^^ = -101° (c = 0.6
i metanol).in methanol).
EKSEMPEL 3 Dihydro- g- erqosin..EXAMPLE 3 Dihydro-g-erqosin..
5,48 g (0,01 mol) (3-ergosin (smeltepunkt 203-205°C (spating))/Qajp<20>= -140,2° (c = 1 i kloroform) ble lost i 100 ml etylalkohol 5.48 g (0.01 mol) (3-ergosine (melting point 203-205°C (sparing))/Qajp<20>= -140.2° (c = 1 in chloroform) was dissolved in 100 ml of ethyl alcohol
og dimetylformamid og hydrogenert med 2 g palladium-aktivkull-katalysatore (5% palladium) ved normaltrykk og romtemperatur. and dimethylformamide and hydrogenated with 2 g of palladium-activated carbon catalysts (5% palladium) at normal pressure and room temperature.
Etter opptagelse 2,5 1 hydrogen ble reaksjonen mye langsommere og hydrogeneringen ble avbrutt, katalysatoren ble frafiltrert og filt-ratet inndampet til torrhet i vakuum. Resten ble omkrystallisert to ganger fra metylenklorid/metanol hvorved den i overskriften nevnte forbindelse fremkom som .tynnskiktkomatografisk homogent material, smeltepunkt 181-183°C (spalting) ^ajfi^ = -45° (c = 1 i pyridin). After absorption of 2.5 1 hydrogen, the reaction became much slower and the hydrogenation was interrupted, the catalyst was filtered off and the filtrate was evaporated to dryness in vacuo. The residue was recrystallized twice from methylene chloride/methanol whereby the compound mentioned in the title appeared as thin-layer chromatographically homogeneous material, melting point 181-183°C (decomposition) ^ajfi^ = -45° (c = 1 in pyridine).
6-ergosin ble framstilt på folgende måte:6-ergosine was prepared as follows:
24,1 g lysergsyre ble suspendert i 270 ml acetonitril og avkjolt til -20°C. Véd denne temperatur lot man i lopet av ca. 4 minutter tildryppe an blanding av 12,5 ml trifluoreddiksyreanhydrid, 6,88 ml trifluoreddiksyre og 100 ml acetonitril. Det ble etterrort i 5 minutter, ved -20°C ble det tildrysset 26,6 g aminocyclol-hydroklorid og med en gang deretter ved -20°C ble 90 ml pyridin tildryppet så hurtig som mulig, hvorved temperaturen steg til 0°C. Deretter ble det etterrort i \\ time ved 0°C/på nytt avkjolt 24.1 g of lysergic acid was suspended in 270 ml of acetonitrile and cooled to -20°C. At this temperature, over the course of approx. 4 minutes add dropwise a mixture of 12.5 ml of trifluoroacetic anhydride, 6.88 ml of trifluoroacetic acid and 100 ml of acetonitrile. It was stirred for 5 minutes, at -20°C 26.6 g of aminocyclol hydrochloride were sprinkled in and immediately afterwards at -20°C 90 ml of pyridine was added dropwise as quickly as possible, whereby the temperature rose to 0°C. It was then allowed to stand for \\ hour at 0°C/cooled again
til -20°C og tildryppet 2 70 ml fosfatpuffer med ph 4. Deretter ble reaksjonsblandingen uthelt på 11- 2N sodalosning og ekstrahert 3 ganger med etylenklorid. Metylénkloridlosningen ble ettervasket med vann, torret og inndampet. Det ble tilbake et skum som ble renset på den 30-dobbelte mengde aluminiumoksyd med metylenklorid 0,4 til 0,6% metanol. (3-ergosinet ble vasket med metylenklorid/ to -20°C and added dropwise 2 70 ml of phosphate buffer with ph 4. The reaction mixture was then poured into 11-2N soda solution and extracted 3 times with ethylene chloride. The methylene chloride solution was washed with water, dried and evaporated. A foam remained which was purified on the 30-fold amount of alumina with methylene chloride 0.4 to 0.6% methanol. (The 3-ergosine was washed with methylene chloride/
0,6 til 1% metanol fra kolonnen og omkrystallisert fra metylenklorid etylassetat. 0.6 to 1% methanol from the column and recrystallized from methylene chloride ethyl acetate.
Etter omkrystallisering ble 6-ergosinet torret under hoyvakuum. Smeltepunkt 203 til 205°C, [aj^° = +11,1° (c = 3,5 i pyridin) After recrystallization, the 6-ergosine was dried under high vacuum. Melting point 203 to 205°C, [aj^° = +11.1° (c = 3.5 in pyridine)
EKSEMPEL 4; 6- nor- 6 isopropyl- 21B- metvi- 5' g- sec. butvl- 9, 10-dihydro- erqopeptin ( 6- nor- 6- isoprpvl- dihvdro- B- erqosin) EXAMPLE 4; 6- nor- 6 isopropyl- 21B- metvi- 5' g- sec. butvl- 9, 10-dihydro- erqopeptin (6- nor- 6- isoprpvl- dihydro- B- erqosine)
Det gås frem analogt med eksempel 3 og erholdes ved hydrogenering av 6-nor-6-isopropyl-6-ergosin den i overskriften nevnte forbindelse med smeltepunkt 182-183°C (spalting) Proceed analogously to example 3 and obtain by hydrogenation of 6-nor-6-isopropyl-6-ergosine the compound mentioned in the title with melting point 182-183°C (cleavage)
Wq<0>= 15,5° (c = 1 i metylenklorid). Wq<0>= 15.5° (c = 1 in methylene chloride).
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CH (1) | CH602765A5 (en) |
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DK (1) | DK420375A (en) |
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CH649300A5 (en) * | 1981-08-07 | 1985-05-15 | Sandoz Ag | ERGOPEPTIN DERIVATIVES, THEIR PRODUCTION AND USE. |
DE3303616A1 (en) * | 1982-02-12 | 1983-08-25 | Sandoz-Patent-GmbH, 7850 Lörrach | MOTHER CORNAL CALOIDS, METHOD FOR THE PRODUCTION THEREOF AND PHARMACEUTICAL PREPARATIONS CONTAINING THESE COMPOUNDS |
BE895842A (en) * | 1982-02-12 | 1983-08-08 | Sandoz Sa | NOVEL ERGOPEPTIDE ALKALOIDS, THEIR PREPARATION AND THEIR USE AS MEDICAMENTS |
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FR2285885B1 (en) | 1979-09-14 |
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DD122532A5 (en) | 1976-10-12 |
FI752616A (en) | 1976-03-28 |
FR2285885A1 (en) | 1976-04-23 |
SE7510552L (en) | 1976-03-29 |
AU506218B2 (en) | 1979-12-20 |
NL7511178A (en) | 1976-03-30 |
DE2541426A1 (en) | 1976-04-15 |
GB1519505A (en) | 1978-07-26 |
CH602765A5 (en) | 1978-07-31 |
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IL48179A (en) | 1978-06-15 |
ES441257A1 (en) | 1977-07-01 |
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