DK149186B - Anologifremgangsmaade til fremstilling af n1-(l-(-)--2-hydroxy-4-aminobutyryl)-4-0-(2',6'-diamino-2',6'-dides-oxy-alfa,d-glucopyranosyl)-6-0-(3''-methylamino-3'',4'',6''-tridesoxy-alfa,d-xylohexopyranosyl)-2-desoxytreptamin eller additionssalte deraf - Google Patents
Anologifremgangsmaade til fremstilling af n1-(l-(-)--2-hydroxy-4-aminobutyryl)-4-0-(2',6'-diamino-2',6'-dides-oxy-alfa,d-glucopyranosyl)-6-0-(3''-methylamino-3'',4'',6''-tridesoxy-alfa,d-xylohexopyranosyl)-2-desoxytreptamin eller additionssalte deraf Download PDFInfo
- Publication number
- DK149186B DK149186B DK329876AA DK329876A DK149186B DK 149186 B DK149186 B DK 149186B DK 329876A A DK329876A A DK 329876AA DK 329876 A DK329876 A DK 329876A DK 149186 B DK149186 B DK 149186B
- Authority
- DK
- Denmark
- Prior art keywords
- formula
- compound
- alfa
- xylohexopyranosyl
- hydroxy
- Prior art date
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- 150000003839 salts Chemical class 0.000 title claims description 12
- 238000000034 method Methods 0.000 title claims description 8
- 238000002360 preparation method Methods 0.000 title claims description 3
- -1 L - (-) - 2-HYDROXY-4-AMINOBUTYRYL Chemical class 0.000 title description 5
- 150000001875 compounds Chemical class 0.000 claims description 25
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 6
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 2
- 239000011707 mineral Substances 0.000 claims description 2
- 150000007522 mineralic acids Chemical class 0.000 claims description 2
- 150000007524 organic acids Chemical class 0.000 claims description 2
- 235000005985 organic acids Nutrition 0.000 claims description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 15
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 9
- 241000588724 Escherichia coli Species 0.000 description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 8
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 6
- 241000295644 Staphylococcaceae Species 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 239000011521 glass Substances 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 5
- 239000003054 catalyst Substances 0.000 description 5
- 239000012153 distilled water Substances 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 4
- 229930182566 Gentamicin Natural products 0.000 description 4
- CEAZRRDELHUEMR-URQXQFDESA-N Gentamicin Chemical compound O1[C@H](C(C)NC)CC[C@@H](N)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](NC)[C@@](C)(O)CO2)O)[C@H](N)C[C@@H]1N CEAZRRDELHUEMR-URQXQFDESA-N 0.000 description 4
- 241000588747 Klebsiella pneumoniae Species 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical group [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 235000011114 ammonium hydroxide Nutrition 0.000 description 4
- 230000000844 anti-bacterial effect Effects 0.000 description 4
- 230000001580 bacterial effect Effects 0.000 description 4
- 230000003115 biocidal effect Effects 0.000 description 4
- 229960002518 gentamicin Drugs 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- 238000000338 in vitro Methods 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 125000003535 D-glucopyranosyl group Chemical group [H]OC([H])([H])[C@@]1([H])OC([H])(*)[C@]([H])(O[H])[C@@]([H])(O[H])[C@]1([H])O[H] 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
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- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 3
- 229930182555 Penicillin Natural products 0.000 description 3
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 3
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- 239000002253 acid Substances 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
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- 238000003756 stirring Methods 0.000 description 3
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- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 2
- LEEANUDEDHYDTG-UHFFFAOYSA-N 1,2-dimethoxypropane Chemical compound COCC(C)OC LEEANUDEDHYDTG-UHFFFAOYSA-N 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 241000194032 Enterococcus faecalis Species 0.000 description 2
- 102000008100 Human Serum Albumin Human genes 0.000 description 2
- 108091006905 Human Serum Albumin Proteins 0.000 description 2
- 241000588748 Klebsiella Species 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 2
- 241000588769 Proteus <enterobacteria> Species 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 241000786363 Rhampholeon spectrum Species 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 239000004098 Tetracycline Substances 0.000 description 2
- 229940126575 aminoglycoside Drugs 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 244000052616 bacterial pathogen Species 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
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- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
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- 150000003522 tetracyclines Chemical class 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
- ZWNCJCPLPUBNCZ-UHFFFAOYSA-N 1,2-dimethoxyethane;hydrate Chemical compound O.COCCOC ZWNCJCPLPUBNCZ-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 241000193738 Bacillus anthracis Species 0.000 description 1
- 244000063299 Bacillus subtilis Species 0.000 description 1
- 235000014469 Bacillus subtilis Nutrition 0.000 description 1
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- 101100334117 Caenorhabditis elegans fah-1 gene Proteins 0.000 description 1
- 206010007882 Cellulitis Diseases 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
- 241000588697 Enterobacter cloacae Species 0.000 description 1
- 241000192125 Firmicutes Species 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 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
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 208000032376 Lung infection Diseases 0.000 description 1
- 241000588772 Morganella morganii Species 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-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
- 241000588770 Proteus mirabilis Species 0.000 description 1
- 241000588767 Proteus vulgaris Species 0.000 description 1
- 239000007868 Raney catalyst Substances 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 1
- 241000607142 Salmonella Species 0.000 description 1
- 241000607720 Serratia Species 0.000 description 1
- 206010056430 Staphylococcal sepsis Diseases 0.000 description 1
- 241000191940 Staphylococcus Species 0.000 description 1
- ANLMVXSIPASBFL-UHFFFAOYSA-N Streptamin D Natural products NC1C(O)C(N)C(O)C(O)C1O ANLMVXSIPASBFL-UHFFFAOYSA-N 0.000 description 1
- 241000194017 Streptococcus Species 0.000 description 1
- 206010052428 Wound Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- SHGAZHPCJJPHSC-YCNIQYBTSA-N all-trans-retinoic acid Chemical compound OC(=O)\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-YCNIQYBTSA-N 0.000 description 1
- FXKSEJFHKVNEFI-GCZBSULCSA-N amikacin disulfate Chemical compound [H+].[H+].[H+].[H+].[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O.O([C@@H]1[C@@H](N)C[C@H]([C@@H]([C@H]1O)O[C@@H]1[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O1)O)NC(=O)[C@@H](O)CCN)[C@H]1O[C@H](CN)[C@@H](O)[C@H](O)[C@H]1O FXKSEJFHKVNEFI-GCZBSULCSA-N 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000005228 aryl sulfonate group Chemical group 0.000 description 1
- DCXYFEDJOCDNAF-UHFFFAOYSA-M asparaginate Chemical compound [O-]C(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-M 0.000 description 1
- 235000013405 beer Nutrition 0.000 description 1
- 125000001743 benzylic group Chemical group 0.000 description 1
- 210000000941 bile Anatomy 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 229940106164 cephalexin Drugs 0.000 description 1
- ZAIPMKNFIOOWCQ-UEKVPHQBSA-N cephalexin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@@H]3N(C2=O)C(=C(CS3)C)C(O)=O)=CC=CC=C1 ZAIPMKNFIOOWCQ-UEKVPHQBSA-N 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000001815 facial effect Effects 0.000 description 1
- HHLFWLYXYJOTON-UHFFFAOYSA-N glyoxylic acid Chemical compound OC(=O)C=O HHLFWLYXYJOTON-UHFFFAOYSA-N 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 1
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 1
- 206010022000 influenza Diseases 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007928 intraperitoneal injection Substances 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
- 230000003211 malignant effect Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 210000004400 mucous membrane Anatomy 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- NMHMNPHRMNGLLB-UHFFFAOYSA-N phloretic acid Chemical compound OC(=O)CCC1=CC=C(O)C=C1 NMHMNPHRMNGLLB-UHFFFAOYSA-N 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
- 229910052697 platinum Inorganic materials 0.000 description 1
- QMYDVDBERNLWKB-UHFFFAOYSA-N propane-1,2-diol;hydrate Chemical compound O.CC(O)CO QMYDVDBERNLWKB-UHFFFAOYSA-N 0.000 description 1
- 229940007042 proteus vulgaris Drugs 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 229910052703 rhodium Inorganic materials 0.000 description 1
- 239000010948 rhodium Substances 0.000 description 1
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 1
- 229910052707 ruthenium Inorganic materials 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- ANLMVXSIPASBFL-FAEUDGQSSA-N streptamine Chemical compound N[C@H]1[C@H](O)[C@@H](N)[C@H](O)[C@@H](O)[C@@H]1O ANLMVXSIPASBFL-FAEUDGQSSA-N 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 125000001874 trioxidanyl group Chemical group [*]OOO[H] 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/20—Carbocyclic rings
- C07H15/22—Cyclohexane rings, substituted by nitrogen atoms
- C07H15/222—Cyclohexane rings substituted by at least two nitrogen atoms
- C07H15/226—Cyclohexane rings substituted by at least two nitrogen atoms with at least two saccharide radicals directly attached to the cyclohexane rings
- C07H15/234—Cyclohexane rings substituted by at least two nitrogen atoms with at least two saccharide radicals directly attached to the cyclohexane rings attached to non-adjacent ring carbon atoms of the cyclohexane rings, e.g. kanamycins, tobramycin, nebramycin, gentamicin A2
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Oncology (AREA)
- Animal Behavior & Ethology (AREA)
- Communicable Diseases (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Saccharide Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Description
149186
Opfindelsen angår en analogifremgangsmåde til fremstilling af det hidtil ukendte N1-(L-(-)-2-hydroxy-4-aminobutyry1)-4-0-{2',6'-diamino-2',6'-didesoxy-cC· D-glucopyranosyl)-6-0-{3"-methylamino-3",4",6"-tridesoxy-o6,D-xylohexopyranosyl)-2-desoXystreptamin, med den i kravets indledning angivne almene formel I eller terapeutisk acceptable additionssalte deraf med mineralsyrer eller organiske syrer.
Saltene kan fås ved fuldstændig eller delvis neutralisation af de fem amingrupper i forbindelsen med formlen I.
Sådanne salte kan f.eks. være et hydrochlorid, et hydrobromid, et nitrat, et sulfat, et phosphat, et acetat, et formiat, et benzoat, et maleat, et fumarat, et succinat, et tartrat, et citrat, et oxalat, et benzylat, et glyoxylat, et asparaginat, et alkan- eller arylsulfo-nat.
Fremgangsmåden ifølge opfindelsen er ejendommelig ved* det i kravets kendetegnende del anførte.
I en foretrukken udførelsesform for fremgangsmåden omsætter man forbindelsen med formlen II' med forbindelsen med formlen II i et opløsningsmiddel, som er en blanding af dimethylformamid og vand. Man kan ligeledes benytte dimethylacetamid, dioxan, tetrahydrofuran, pyri-din, vand, acetone, ethanol, methanol og 1,2-dimethoxyethan alene eller i blanding.
Man omsætter forbindelsen med formlen III' med produktet med formlen III, idet man fortrinsvis anvender et opløsningsmiddel, som er en blanding af vand og 1,2-di-methoxyethan, men man kan ligeledes benytte alene eller i blanding dioxan, dimethylacetamid, dimethylformamid, tetrahydrofuran, propylenglycoldimethylether eller vand.
Overgangen fra forbindelsen med formlen IV til forbindelsen med formlen I sker i nærværelse af hydrogen og en metalkatalysator. Denne katalysator er fortrinsvis palladium, men man kan ligeledes benytte platin, Raney-nikkel, rhodium, nikkel eller ruthenium. Man benytter 2 14918$ fortrinsvis et opløsningsmiddel, som er en blanding af vand og et med vand blandbart opløsningsmiddel såsom dioxan. Man kan ligeledes benytte tetrahydrofuran, 1,2-dimethoxyethan eller propylenglycoldimethylether.
Omdannelsen til salt af forbindelsen med formlen I kan ske ved gængse metoder. Den kan opnås ved indvirkning på denne forbindelse af syrer såsom f.eks. saltsyre, hydrogenbromidsyre, salpetersyre, svovlsyre, phosphor-syre, eddikesyre, benzoesyre, maleinsyre, fumarsyre, ravsyre, vinsyre, citronsyre, oxalsyre, benzylsyre, gly-oxylsyre, asparaginsyre, alkan- og arylsulfonsyrer.
Denne omdannelse til salt udføres fortrinsvis i et opløsningsmiddel eller en blanding af opløsningsmidler såsom vand, ethylether, methanol eller acetone.
Forbindelsen med formlen II, der benyttes som udgangsprodukt ved fremgangsmåden, og sulfatet af produktet med formlen II er beskrevet i belgisk patentskrift 814.724.
Forbindelsen med formlen I og dens additionssalte med syrer har en interessant antibiotisk virkning, dels på grampositive bakterier såsom staphylococcer og navnlig penicillinresistente staphylococcer og streptococcer, dels på gramnegative bakterier, navnlig coliforme bakterier.
Disse egenskaber gør forbindelsen med formlen I samt dens terapeutisk acceptable salte egnede til at anvendes som medikamenter, navnlig ved behandlingen af staphylococci såsom staphylococcussepticemi, ondartet an-sigtsstaphylococci, kutan staphylococci, pyodermitis, septiske og suppurante sår, anthrax, phlegmone, ery sipel, primitiv eller efter influenza optrædende akut staphylococci, bronchopneumoni, pulmonære suppurationer og colibacillose. Produktet med formlen I samt dets terapeutisk acceptable salte kan ligeledes anvendes i behandlingen af Klebsiella-, Pseudomonas- og Enterobacterin-fektioner.
3 149186
Forbindelsen med formlen I og dens terapeutisk acceptable salte kan anvendes til fremstilling af farmaceutiske produkter, der som aktiv bestanddel indeholder den nævnte forbindelse eller i det mindste et salt deraf.
Disse farmaceutiske produkter kan indgives ad oral, rektal eller parenteral vej eller lokalt i topisk applikation på huden og slimhinderne.
Den kendte forbindelse (USA patentskrift nr.
3.781.268), som kommer forbindelserne fremstillet ved fremgangsmåden ifølge den foreliggende opfindelse nærmest, er forbindelsen: N1-(L-(-)-2-hydroxy-4-aminobutyryl)-4-0-(61-amino-6' desoxy-ct,D-glucopyranosyl)-6-0-(3"-amino-3"-desoxy-c^,D-xylohexopyranosyl)-2-desoxystreptamin med formlen
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Denne forbindelse går i handelen i form af sulfatet under den internationale betegnelse "Amikacin", I den biologiske dokumentation nedenfor er der anført gunstige sammenligningsforsøg mellem den ved fremgangsmåden Ifølge opfindelsen fremstillede forbindelse med formlen I i form af base eller sulfat og "Amikacin".
Hedenstående eksempler illustrerer fremgangsmåden ifølge opfindelsen.
Eksempel 1.
18^-(1-(-)-2-hydroxy·»4-aminobutyryl )-4-0-(21,6 t-diamino~2 * -6 ♦ — -didesoxy-g.D-gluoopyranosyl )-6 -0-(311 -meth.vlamino-31 * «4 *1« 6»1 ,-tridesoxy-tE,D-xylohexopyranosyl)-2-desoxystreptamin,
Trin A: 4-0-(2’-amino-å '-benzyloxycarbonylamino^^g^didés-oxy-g.D-gl.Pcopyranosyl )-6-0-(3 * t-meth.vlamlno-3t 1,4 ♦ *.
6»'-tridesoxy-a.D-xylohexopyrano.syl^-deaoxystrept- amin> . " . . _
Til 5,5 g 4-0-(2,,6*-diamino-2,,6,-didesoxy-a,D-gluco- •pyranosyl) — -6-0-(3' '-methylamino-3'f,4'* »6' '-tridesoxy-a,D-xylohexopyranosyl)-2-desoxystreptamin opløst i 58 ml destilleret vand sætter man ved 20-25°C 60 ml dimethylformamid.
Man afkøler til -5°C og tilsætter langsomt 3,01 g E'-(ben-zyloxycarbonyloxy)-succinimid opløst i 60 ml dimethylformamid. Man omrører 20 timer ved -5°C og derefter 24 timer ved 20-25°C, Man inddamper til tørhed og optager i vand mættet med n-butanol. Man vasker med butanol mættet med vand. Man inddamper faserne til tørhed, vandig fase: 6,21 g, butanol-fase: 2,82 g,
Ted chromatografi på et lag silicagel med et eluerings-middel bestående af chloroform, methanol og ammoniak i forholdet 4:4:1 konstaterer man, at den vandige fase er rig på det forventede produkt. Man renser denne fase på ionbytter-harpiks af carboxyltype på NH^-form. Man fikserer produktet i vandig opløsning og eluerer derefter med 0,1 ΪΓ fortyndet ammoniakvand og får 1,72 g af det forventede produkt.
5 149186
Trin B: (L-(-) -2-hy droxy-4-benzyloxycarbonylaminobutyry1- »4-0-(2'-amino-å '-benzyloxyoarbonylamino^ 1«6 *-81-desoxy-g,I>-glucopyranosyl )-6-0-(31 ♦-metbylamino--3'*«4* t«6t >-tridesoxy-g.D-xylohexopyranosyl)-2-desoxystreptamin.
Til en opløsning af 1,8 g af produktet fra forrige trin i 14 ml destilleret vand og 14 ml 1,2-dimethoxyethan afkølet til 5°C sætter man i løbet af 1 time 1,1 g N-hydroxy-succinimidester af l-(-)-Y-benzyloxycarbonylamino-g-hydroxy-smørsyre opløst i 28 ml dimethoxyethan.
Man holder reaktionsblandingen under omrøring i 15 timer mellem 5 og 10°C og inddamper til tørhed under vakuum.
Sen tørre ekstrakt chromatograferes på silicagel med et elue-ringsmiddel bestående af chloroform, methanol og ammoniakvand i forholdet 75:25:5 »
Man karakteriserer det forventede produkt, som har en RF-værdi på 0,45 på silicagel og under eluering med en blanding bestående af methanol, chloroform og ammoniakvand i forholdet 2:2:1.
Trin C: N1-(.X-(-)-2-hydroxy-4-amipobutyiyl)-4-0-(2t.6*-dia-mino-2 *-,6 ,-didesoxy-g.S-gljn;copyranosyl)-6-0-(5 * *--methylamino-5 *1,4 *'.61^tridesoxy-g.S-xylohexopyrano-syl)-2-desoxystreptamin.
Til opløsningen af 473 mg af produktet fra forrige trin i 6 ml destilleret vand, 6 ml dioxan og 0,15 ml eddikesyre sætter man ved 20-25°C 90 mg katalysator bestående af palladium (105¾) på kul. Man foretager en hydrogengennem-bobling. Efter 5 timers reaktion tilsætter man 30 mg katalysator. Efter 1 times yderligere gennembobling standser man omrøringen og lader henstå natten over under hydrogenatmosfære. Man frafiltrerer katalysatoren og inddamper til tørhed under vakuum.
Man chromatograferer resten på silicagel med en blanding af methanol, chloroform og ammoniak i forholdet 2:2:1 og får 115 mg af det forventede produkt.
Man renser produktet ved passage over en ionbytter-harpiks af carboxyltype på KH^+-form (eluering med 0,5 H ammoniakvand). Udbyttet ved rensningen er 82,2%.
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Farmakologiske undersøgelser af forbindelsen med formlen i« Antibakteriel virkning in vitro,
Ben antibakterielle virkning måles in vitro ved fortyndingsmetoden i væskeformet milieu.'
Man fremstiller en række glas, hvori man har fordelt samme kvantum næringsmilieu. Man fordeler voksende mængder af det undersøgte antibiotikum og derefter podes hvert glas med en bakteriestamme. Efter en inkubationstid på 18, 24 eller 48 timer i varmeskab ved 37°0 vurderes inhiberingen af bakterievækster ved gennemlysning, hvilket gør det muligt at bestemme de minimale inhiberende koncentrationer (MIC) af forbindelsen, her udtrykt i μg/ml, som base.
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Disse resultater viser« at forbindelsen med formlen I har en god aktivitet over for grampositive og gramnegative kim og navnlig udtalt over for sidstnævnte.
Denne virkning er serlig interessant på visse amino-glycosidresistente stammer*
Forbindelsen med formlen II samt dens sulfat har allerede en god antibiotisk virkning·
Forbindelsen med formlen I har en meget stærkt forøget virkning i forhold til diese to forbindelser, navnlig over for visse normalt aminoglycosidresistente kim.
Væksten i virkningen er navnlig betydelig over for visse stammer af Pseudomonas, Proteus og Klebsiella.
Eksempel 2.
Sulfatet af N^-(Ii-(-)-2-h.ydro:r.y-4-aminobut.vryl).-4-0-(2>.6t- -άί8ΐη1ηο-2«.6 t-didesoxy-tt.D-gluoop.vrano8.7l)-6-0-(5t ^meth.vl-amino-31 '.4* *.61 t‘-tridesox.v»g.D-xylohexopyranos.vl)~2-desory-streptamin.
1,8 g (l-(-)-2-hydroxy-4-aminobutyry1)-4-0-(2»,6 *- -diamino-2’,6'-didesoxy-ajD-glucopyranpsyl) -6-0-(3’1 -methyl-amino-3'f,4f’,61'-tridesoxy~a,D-xylohexopyranosyl)-2-desoxy-streptamin opløses i 120 ml destilleret vand. Ved hjælp af en burette symer man til en pH-værdi på 2 ved tilsætning af 13,5 ml 1 M svovlsyre. Man inddamper opløsningen til 20 ml og filtrerer på sintret glas. Man inddamper atter til 10 ml og tilsætter derpå 200 ml methanol. Man opbevarer den opnåede hvide suspension i 20 timer i køleskab og filtrerer på sintret glas. Man skyller de opnåede hvide krystaller med methanol og tørrer derefter under formindsket tryk. Der fås 1,87 g produkt. Moderludené inddampes til tørhed, og man får et andet udbytte på 0,35 g produkt, = +76,5° +2,5° (c = 0,6i» vand).
E.M.R.spektrum ^0): CH3-CH: 1,21 p.pi'm., dublet, J * 6 Es 0Η3-ιΦ 2,75 P.p.m.
H’ : 5,15 p.p.m.
H1^ s 6,03 p.p.m.
U9186 12 ff*-(1-(-)-2-hydroxy-4-aminobuty ry 1) -4 -0- (2 *, 61 -d i -amino<~2 * ,6 '-didesoxy-a,I)-glucopyrano8yl)-6-0-(3' '-methyl-amino-3 '' ,4 ’ *»6* »-tridesoxy-a,I>-xylohexopyranosyl)-2-desoxy-streptamin, der benyttes som udgangsprodukt i eksempel 2, fremstilles som angivet i eksempel 1 ovenfor.
Farmakologisk undersøgelse af sulfatet ifølge eksempel 2, Antibakteriel virkning in vitro.
Den antibakterielle virkning måles in vitro ved fortyndingsmetoden i væskeformet milieu.
Man fremstiller en række glas, hvori man fordeler samme mængde næringsmilieu. Man fordeler voksende mængder af det undersøgte antibiotikum, og derefter podes hvert glas med en bakteriestamme » Efter inkubation i 18, 24 eller 48 timer i varmeskab ved 37°C vurderes inhiberingen af bakterievæksten ved gennemlysning, hvilket tillader at bestemme de minimale inhiberende koncentrationer (MIC) af produktet, her udtrykt i μg/ml base.
149186 13 MIG i u,g/ml 18 h 24 h 48 h (Staphyloc.occus Milieu 0,4 0,6 1 / aureus + humant albumin } ATCC 5638 5# 0,6 1 5 ίPenicillinfølsom + serum fra føl 10# 0,6 1,5 2 (Staphylococcus Milieu 0,6 0,6 1 > aureus + humant albumin ) 5# 0,6 2 10 ( UC 1128 . ___ ) + serum fra (Penicillin resistent føl 10# 12 5
Staphylococcus aureus Exp. nr. 54146 0,2 0,4 0,6
Staphylococcus aureus Co 15# E cephalexin 5 10 40
Streptococcus poyogenes A 561 0,4 0,4 0,6
Streptococcus faecalis 5432 5 5 10
Streptococcus faecalis 99 F 74 2 5 15
Bacillus subtilis ATCC 6633 0,05 0,05 0,1
Escherichia coli, tetracyclinfølsom ATCC 9637 2 5 20 .
Escherichia coli, tetracyclinresistent : ATCC 11303 0,6 1 1
Escherichia coli Exp. T OggBg 112
Escherichia coli, gentamicinresistent E 55 123 D 0,4 0,4 2 149186 14 MIC 1 ug/ml 18 h 24 h 48 h
Klebsiella pneumoniae Exp. 52 145 0,2 0,2 0,4
Klebsiella pneumoniae 2536 gentamicinresistent 0,4 0,4 0,6
Proteus mit. (indol -) A 235 -2 5 5
Proteus vulgaris (indol +) A 232 2 5 10
Salmonella thyphl murium 420 2 5 20
Enterobacter cloacae 681 0,2 0,4 0,4
Providencia Du 48 10 20 40
Pseudomonas 3935 Exp. gentamicinfølsom 2 5 10
Serratia 2532 gentamicinresistent 225
Eksperimentel infektion med Escherichia coli.
Man undersøger virkningen af sulfatet på en eksperimentel infektion med Escherichia coli på mus. Man inficerer hold på 10 hanmus ved intraperitoneal indsprøjtning af 0,5 ml af en 24 timers kultur i næringsbouillon af stammen Escherichia coli galle fortyndet til 1/6 med destilleret vand.
Man indgiver ved subkutan injektion en bestemt mængde af produktet 1 time, 5 timer og 24 timer efter indsprøjtningen.
Man noterer dødeligheden i løbet af 8 dage,
Eesultaterne er som følger: 15 149186 bd
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149186 16
Sammenligningsforsøg.
Idet man benytter metoden med væskefortynding, som er beskrevet på side 6, får man følgende gunstige resultater: MIC i hg/ml_
Forbindelse med formlen I Amikacin (sulfat) 18 h 24 h 48 h 18 h 24 h 48 h Escherichia coli Du 308 2 2 2 33 5 • " " Du 317 2 2 2 2 3 5 " " " 324 0,6 2 3 2 3 5 " " " 336 5 10 10 10 20 40 " " ” 337 1 1 2 2 2 3 " " " 352 2 2 3 3 3 5 " " " 350 2 2 2 2 3' 5
Klebsiella pneumoniae Du 221 0,4 0,4 0,4 1 1 1 " " " 222 0,4 0,4 1 1 1 1 ” " " 223 0,4 0,6 2 3 3 5 " " " 226 0,4 0,4 1 2 2 2 " " " 229 0,4 0,4 0,4 0,6 1 1 " " " 230 0,4 0,4 0,4 1 1 1 " " " 214 0,4 0,6 0,6 0,6 1 1
Forbindelse med formlen I Amikacin (base)_ _ 18 h 24 h 48 h 18 h 24 h 48 h
Proteus mirabilis D 234 3 5 10 10 10 10 " " D 235 3 5 10 5 10 10 " " D 266 2 3 5 5 10 10 " " D 267 3 5 5 5 10 10 " " D 268 3 5 5 5 5 10
Streptococcus aureus 586476 0,4 0,6 1 2 5 5
Escherichia coli 54127 1 χ χ 2 2 5
Klebsiella pneumoniae Coc 260 0,4 0,4 0,6 0,6 0,6 1
Proteus morganii Du 33 112 125
Claims (1)
- U9186 Patentkrav, Analogifremgangsmåde til fremstilling af -2-hydroxy-4-aminobutyryl)-4-0-(2 · ,6 ,-diamino**2 · ,6 '-cl jjdee-oxy-a,D-glucopyranosyl)-6-0-(3' ’-methylamino-3' ’,4'' ,6' '-tri-desoxy-a,D-xylohexopyranosyl)-2-desoxystreptamin med formlen I ch2 nh2 nh2 /~°\| · kNtt · -o_Ho-ch HHo CH2 OH, O I r o «% sh2 <»<H N ' OH' · (I) eller terapeutisk acceptable additionssalte deraf med mineralsyrer eller organiske syrer, kendetegnet ved, at man omsætter en forbindelse med formlen II CHp NHj, ‘ ΜΗλ h rr æ/—<,_jw· hk2 oh3 o J—o H (iKn A — OH 149186 med forbindelsen med formlen II* IN-0-C-0-CH2~^ ^ (TT · ) <y s w % til opnåelse af forbindelsen med formlen III ch2 hh-c-o-ch2-^ y o nh2 hoN I • liH2 . ch5 0 ho* (ν^Ά } W- (III) OH som man behandler med forbindelsen med formlen III1 <0 Q f " V ^n-o-c-ch-(ch2)2 ΝΚ-ίί-0-0Η2-^ y (III‘) OH o til opnåelse af forbindelsen med formlen I?
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR7522987A FR2318648A1 (fr) | 1975-07-23 | 1975-07-23 | Nouveau derive de la desoxystreptamine et des sels, leur procede de preparation et leur application comme medicaments |
| FR7522987 | 1975-07-23 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DK329876A DK329876A (da) | 1977-01-24 |
| DK149186B true DK149186B (da) | 1986-03-10 |
| DK149186C DK149186C (da) | 1986-09-15 |
Family
ID=9158255
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK329876A DK149186C (da) | 1975-07-23 | 1976-07-22 | Anologifremgangsmaade til fremstilling af n1-(l-(-)--2-hydroxy-4-aminobutyryl)-4-0-(2',6'-diamino-2',6'-dides-oxy-alfa,d-glucopyranosyl)-6-0-(3''-methylamino-3'',4'',6''-tridesoxy-alfa,d-xylohexopyranosyl)-2-desoxytreptamin eller additionssalte deraf |
Country Status (19)
| Country | Link |
|---|---|
| JP (1) | JPS5214746A (da) |
| AT (1) | AT344902B (da) |
| AU (1) | AU503819B2 (da) |
| BE (1) | BE843535A (da) |
| CH (1) | CH598281A5 (da) |
| DD (1) | DD126770A5 (da) |
| DE (1) | DE2630590C2 (da) |
| DK (1) | DK149186C (da) |
| ES (1) | ES450028A1 (da) |
| FR (1) | FR2318648A1 (da) |
| GB (1) | GB1502537A (da) |
| HU (1) | HU175411B (da) |
| IE (1) | IE43582B1 (da) |
| IL (1) | IL49900A (da) |
| LU (1) | LU75266A1 (da) |
| NL (1) | NL7608151A (da) |
| SE (1) | SE427461B (da) |
| SU (1) | SU656528A3 (da) |
| ZA (1) | ZA763895B (da) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2435481A1 (fr) * | 1978-09-06 | 1980-04-04 | Roussel Uclaf | Nouveaux aminoglycosides derives de la desoxystreptamine et leurs sels, procede de preparation et application a titre de medicaments |
| USD975431S1 (en) * | 2020-12-18 | 2023-01-17 | Wonderland Switzerland Ag | Infant carrier |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| BE786201A (fr) * | 1971-07-13 | 1973-01-12 | Bristol Myers Co | Procede de preparation d'antibiotiques |
| FR2228474A1 (en) * | 1973-05-10 | 1974-12-06 | Roussel Uclaf | Amino-glycoside deriv as an antibacterial agent - prepd by a stepwise process from a substd 2-O-ethoxycarbonyl D-xylohexopyranoside |
| US3959255A (en) | 1973-05-10 | 1976-05-25 | Roussel-Uclaf | Antibiotic aminoglycosides, and process of preparation |
-
1975
- 1975-07-23 FR FR7522987A patent/FR2318648A1/fr active Granted
-
1976
- 1976-06-15 SE SE7606795A patent/SE427461B/xx not_active IP Right Cessation
- 1976-06-24 IL IL49900A patent/IL49900A/xx unknown
- 1976-06-29 LU LU75266A patent/LU75266A1/xx unknown
- 1976-06-29 BE BE168417A patent/BE843535A/xx not_active IP Right Cessation
- 1976-06-30 ZA ZA763895A patent/ZA763895B/xx unknown
- 1976-07-07 DE DE2630590A patent/DE2630590C2/de not_active Expired
- 1976-07-09 HU HU76RO891A patent/HU175411B/hu not_active IP Right Cessation
- 1976-07-15 SU SU762379559A patent/SU656528A3/ru active
- 1976-07-21 AU AU16083/76A patent/AU503819B2/en not_active Expired
- 1976-07-21 DD DD193995A patent/DD126770A5/xx unknown
- 1976-07-22 DK DK329876A patent/DK149186C/da active
- 1976-07-22 NL NL7608151A patent/NL7608151A/xx not_active Application Discontinuation
- 1976-07-22 ES ES450028A patent/ES450028A1/es not_active Expired
- 1976-07-23 IE IE1639/76A patent/IE43582B1/en unknown
- 1976-07-23 JP JP51087399A patent/JPS5214746A/ja active Granted
- 1976-07-23 GB GB30746/76A patent/GB1502537A/en not_active Expired
- 1976-07-23 CH CH948776A patent/CH598281A5/xx not_active IP Right Cessation
- 1976-07-23 AT AT545176A patent/AT344902B/de not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| AU503819B2 (en) | 1979-09-20 |
| SE427461B (sv) | 1983-04-11 |
| AU1608376A (en) | 1978-01-26 |
| DE2630590A1 (de) | 1977-02-10 |
| ES450028A1 (es) | 1977-08-01 |
| IL49900A0 (en) | 1976-08-31 |
| IE43582B1 (en) | 1981-04-08 |
| FR2318648A1 (fr) | 1977-02-18 |
| HU175411B (hu) | 1980-07-28 |
| FR2318648B1 (da) | 1978-10-06 |
| SU656528A3 (ru) | 1979-04-05 |
| JPS5214746A (en) | 1977-02-03 |
| CH598281A5 (da) | 1978-04-28 |
| ATA545176A (de) | 1977-12-15 |
| LU75266A1 (da) | 1977-03-18 |
| DK329876A (da) | 1977-01-24 |
| IL49900A (en) | 1979-05-31 |
| DD126770A5 (da) | 1977-08-10 |
| JPS619318B2 (da) | 1986-03-22 |
| GB1502537A (en) | 1978-03-01 |
| DE2630590C2 (de) | 1984-08-09 |
| NL7608151A (nl) | 1977-01-25 |
| AT344902B (de) | 1978-08-25 |
| DK149186C (da) | 1986-09-15 |
| IE43582L (en) | 1977-01-23 |
| SE7606795L (sv) | 1977-01-24 |
| BE843535A (fr) | 1976-12-29 |
| ZA763895B (en) | 1977-08-31 |
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