NO146275B - COMPOSITION COVER, AND PROCEDURE FOR MANUFACTURING THE SAME - Google Patents
COMPOSITION COVER, AND PROCEDURE FOR MANUFACTURING THE SAME Download PDFInfo
- Publication number
- NO146275B NO146275B NO771353A NO771353A NO146275B NO 146275 B NO146275 B NO 146275B NO 771353 A NO771353 A NO 771353A NO 771353 A NO771353 A NO 771353A NO 146275 B NO146275 B NO 146275B
- Authority
- NO
- Norway
- Prior art keywords
- acid
- dihydrofusidic
- salts
- dihydrofusidic acid
- salt
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 10
- 239000000203 mixture Substances 0.000 title description 4
- 238000004519 manufacturing process Methods 0.000 title description 3
- 239000002253 acid Substances 0.000 claims description 34
- 150000003839 salts Chemical class 0.000 claims description 20
- IECPWNUMDGFDKC-MZJAQBGESA-N fusidic acid Chemical compound O[C@@H]([C@@H]12)C[C@H]3\C(=C(/CCC=C(C)C)C(O)=O)[C@@H](OC(C)=O)C[C@]3(C)[C@@]2(C)CC[C@@H]2[C@]1(C)CC[C@@H](O)[C@H]2C IECPWNUMDGFDKC-MZJAQBGESA-N 0.000 claims description 15
- IECPWNUMDGFDKC-UHFFFAOYSA-N Fusicsaeure Natural products C12C(O)CC3C(=C(CCC=C(C)C)C(O)=O)C(OC(C)=O)CC3(C)C1(C)CCC1C2(C)CCC(O)C1C IECPWNUMDGFDKC-UHFFFAOYSA-N 0.000 claims description 14
- 229960004675 fusidic acid Drugs 0.000 claims description 14
- 239000003054 catalyst Substances 0.000 claims description 7
- 230000036571 hydration Effects 0.000 claims description 6
- 238000006703 hydration reaction Methods 0.000 claims description 6
- 239000007868 Raney catalyst Substances 0.000 claims description 3
- 229910000564 Raney nickel Inorganic materials 0.000 claims description 3
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 claims description 3
- 238000005984 hydrogenation reaction Methods 0.000 claims description 3
- 150000001875 compounds Chemical class 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 229910000510 noble metal Inorganic materials 0.000 claims description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 159000000000 sodium salts Chemical class 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 5
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 5
- 229910052739 hydrogen Inorganic materials 0.000 description 5
- 239000001257 hydrogen Substances 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 4
- PAFZNILMFXTMIY-UHFFFAOYSA-N cyclohexylamine Chemical compound NC1CCCCC1 PAFZNILMFXTMIY-UHFFFAOYSA-N 0.000 description 4
- 230000008018 melting Effects 0.000 description 4
- 238000002844 melting Methods 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- 230000003115 biocidal effect Effects 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- GRWKNBPOGBTZMN-UHFFFAOYSA-N 2-benzyl-3-phenylpropane-1,2-diamine Chemical compound C=1C=CC=CC=1CC(N)(CN)CC1=CC=CC=C1 GRWKNBPOGBTZMN-UHFFFAOYSA-N 0.000 description 2
- BFSVOASYOCHEOV-UHFFFAOYSA-N 2-diethylaminoethanol Chemical compound CCN(CC)CCO BFSVOASYOCHEOV-UHFFFAOYSA-N 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 241001465754 Metazoa Species 0.000 description 2
- XTUVJUMINZSXGF-UHFFFAOYSA-N N-methylcyclohexylamine Chemical class CNC1CCCCC1 XTUVJUMINZSXGF-UHFFFAOYSA-N 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 159000000007 calcium salts Chemical class 0.000 description 2
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical class CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- ZNQVEEAIQZEUHB-UHFFFAOYSA-N 2-ethoxyethanol Chemical compound CCOCCO ZNQVEEAIQZEUHB-UHFFFAOYSA-N 0.000 description 1
- OJTHHBCWUMTZEY-UHFFFAOYSA-N 5-methyl-heptanoic acid Chemical compound CCC(C)CCCC(O)=O OJTHHBCWUMTZEY-UHFFFAOYSA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- PAMIQIKDUOTOBW-UHFFFAOYSA-N N-methylcyclohexylamine Natural products CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- 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 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 1
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Substances CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 1
- 125000003668 acetyloxy group Chemical group [H]C([H])([H])C(=O)O[*] 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- -1 benzyl- Chemical group 0.000 description 1
- 230000008033 biological extinction Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- VSGNNIFQASZAOI-UHFFFAOYSA-L calcium acetate Chemical compound [Ca+2].CC([O-])=O.CC([O-])=O VSGNNIFQASZAOI-UHFFFAOYSA-L 0.000 description 1
- 239000001639 calcium acetate Substances 0.000 description 1
- 229960005147 calcium acetate Drugs 0.000 description 1
- 235000011092 calcium acetate Nutrition 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000005868 electrolysis reaction Methods 0.000 description 1
- 150000002169 ethanolamines Chemical class 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- BDAGIHXWWSANSR-NJFSPNSNSA-N hydroxyformaldehyde Chemical compound O[14CH]=O BDAGIHXWWSANSR-NJFSPNSNSA-N 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 231100001231 less toxic Toxicity 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 244000000010 microbial pathogen Species 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 229910003446 platinum oxide Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 229910052707 ruthenium Inorganic materials 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000009738 saturating Methods 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 229910000018 strontium carbonate Inorganic materials 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 238000002211 ultraviolet spectrum Methods 0.000 description 1
Classifications
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
- B65D—CONTAINERS FOR STORAGE OR TRANSPORT OF ARTICLES OR MATERIALS, e.g. BAGS, BARRELS, BOTTLES, BOXES, CANS, CARTONS, CRATES, DRUMS, JARS, TANKS, HOPPERS, FORWARDING CONTAINERS; ACCESSORIES, CLOSURES, OR FITTINGS THEREFOR; PACKAGING ELEMENTS; PACKAGES
- B65D43/00—Lids or covers for rigid or semi-rigid containers
- B65D43/02—Removable lids or covers
- B65D43/0202—Removable lids or covers without integral tamper element
- B65D43/0204—Removable lids or covers without integral tamper element secured by snapping over beads or projections
- B65D43/0212—Removable lids or covers without integral tamper element secured by snapping over beads or projections only on the outside, or a part turned to the outside, of the mouth
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- B—PERFORMING OPERATIONS; TRANSPORTING
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- B65D—CONTAINERS FOR STORAGE OR TRANSPORT OF ARTICLES OR MATERIALS, e.g. BAGS, BARRELS, BOTTLES, BOXES, CANS, CARTONS, CRATES, DRUMS, JARS, TANKS, HOPPERS, FORWARDING CONTAINERS; ACCESSORIES, CLOSURES, OR FITTINGS THEREFOR; PACKAGING ELEMENTS; PACKAGES
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- B65D2543/00175—Shape of the outer periphery having straight sides, e.g. with curved corners four straight sides, e.g. trapezium or diamond
- B65D2543/00194—Shape of the outer periphery having straight sides, e.g. with curved corners four straight sides, e.g. trapezium or diamond square or rectangular
- B65D2543/00203—Shape of the outer periphery having straight sides, e.g. with curved corners four straight sides, e.g. trapezium or diamond square or rectangular specifically square
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- B65D2543/00—Lids or covers essentially for box-like containers
- B65D2543/00009—Details of lids or covers for rigid or semi-rigid containers
- B65D2543/00018—Overall construction of the lid
- B65D2543/00231—Overall construction of the lid made of several pieces
- B65D2543/0024—Overall construction of the lid made of several pieces two pieces, one forming at least the whole skirt, the other forming at least the whole upper part
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- B—PERFORMING OPERATIONS; TRANSPORTING
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- B65D2543/00018—Overall construction of the lid
- B65D2543/00259—Materials used
- B65D2543/00268—Paper
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- B—PERFORMING OPERATIONS; TRANSPORTING
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- B65D2543/00—Lids or covers essentially for box-like containers
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- B65D2543/00018—Overall construction of the lid
- B65D2543/00259—Materials used
- B65D2543/00296—Plastic
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
- B65D—CONTAINERS FOR STORAGE OR TRANSPORT OF ARTICLES OR MATERIALS, e.g. BAGS, BARRELS, BOTTLES, BOXES, CANS, CARTONS, CRATES, DRUMS, JARS, TANKS, HOPPERS, FORWARDING CONTAINERS; ACCESSORIES, CLOSURES, OR FITTINGS THEREFOR; PACKAGING ELEMENTS; PACKAGES
- B65D2543/00—Lids or covers essentially for box-like containers
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- B65D2543/00018—Overall construction of the lid
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- B65D2543/00314—Combination, e.g. laminates, several different materials
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- B—PERFORMING OPERATIONS; TRANSPORTING
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- B65D2543/00—Lids or covers essentially for box-like containers
- B65D2543/00009—Details of lids or covers for rigid or semi-rigid containers
- B65D2543/00342—Central part of the lid
- B65D2543/0037—Flexible or deformable
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
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- B65D2543/00—Lids or covers essentially for box-like containers
- B65D2543/00009—Details of lids or covers for rigid or semi-rigid containers
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- B65D2543/00481—Contact between the container and the lid on the inside or the outside of the container
- B65D2543/0049—Contact between the container and the lid on the inside or the outside of the container on the inside, or a part turned to the inside of the mouth of the container
- B65D2543/00509—Cup
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
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- B65D2543/00—Lids or covers essentially for box-like containers
- B65D2543/00009—Details of lids or covers for rigid or semi-rigid containers
- B65D2543/00444—Contact between the container and the lid
- B65D2543/00481—Contact between the container and the lid on the inside or the outside of the container
- B65D2543/00537—Contact between the container and the lid on the inside or the outside of the container on the outside, or a part turned to the outside of the mouth of the container
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
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- B65D2543/00—Lids or covers essentially for box-like containers
- B65D2543/00009—Details of lids or covers for rigid or semi-rigid containers
- B65D2543/00444—Contact between the container and the lid
- B65D2543/00481—Contact between the container and the lid on the inside or the outside of the container
- B65D2543/00555—Contact between the container and the lid on the inside or the outside of the container on both the inside and the outside
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
- B65D—CONTAINERS FOR STORAGE OR TRANSPORT OF ARTICLES OR MATERIALS, e.g. BAGS, BARRELS, BOTTLES, BOXES, CANS, CARTONS, CRATES, DRUMS, JARS, TANKS, HOPPERS, FORWARDING CONTAINERS; ACCESSORIES, CLOSURES, OR FITTINGS THEREFOR; PACKAGING ELEMENTS; PACKAGES
- B65D2543/00—Lids or covers essentially for box-like containers
- B65D2543/00009—Details of lids or covers for rigid or semi-rigid containers
- B65D2543/00444—Contact between the container and the lid
- B65D2543/00592—Snapping means
- B65D2543/00712—Snapping means on the lid
- B65D2543/00722—Profiles
- B65D2543/0074—Massive bead
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
- B65D—CONTAINERS FOR STORAGE OR TRANSPORT OF ARTICLES OR MATERIALS, e.g. BAGS, BARRELS, BOTTLES, BOXES, CANS, CARTONS, CRATES, DRUMS, JARS, TANKS, HOPPERS, FORWARDING CONTAINERS; ACCESSORIES, CLOSURES, OR FITTINGS THEREFOR; PACKAGING ELEMENTS; PACKAGES
- B65D2543/00—Lids or covers essentially for box-like containers
- B65D2543/00009—Details of lids or covers for rigid or semi-rigid containers
- B65D2543/00444—Contact between the container and the lid
- B65D2543/00592—Snapping means
- B65D2543/00712—Snapping means on the lid
- B65D2543/00787—Periphery concerned
- B65D2543/00805—Segments
Landscapes
- Engineering & Computer Science (AREA)
- Mechanical Engineering (AREA)
- Closures For Containers (AREA)
- Cartons (AREA)
- Road Signs Or Road Markings (AREA)
- Materials For Medical Uses (AREA)
Description
Fremgangsmåte for fremstilling av dihydrofusidinsyre. Process for the production of dihydrofusidic acid.
Nærværende oppfinnelse vedrører en The present invention relates to a
fremgangsmåte for å fremstille en hittil ukjent forbindelse som et derivat av fusidinsyre, tidligere kalt Antibiotikum ZN-6. method for producing a hitherto unknown compound as a derivative of fusidic acid, previously called Antibiotic ZN-6.
Mere spesielt vedrører oppfinnelsen en fremgangsmåte for å fremstille dihydrofusidinsyre og dens salter med baser. More particularly, the invention relates to a method for preparing dihydrofusidic acid and its salts with bases.
Fusidinsyre har den molekylare formel C31H480(. og inneholder i molekylet et cyclopentanopolyhydrofenanthren-ring-system som er substituert med to hydr-oxygrupper, en acetoxygruppe, og fire me-thylgrupper, og som i 17-stillingen er for-bundet ved en dobbeltbinding med a-car-atomet i 5-methylheptansyre. Fusidic acid has the molecular formula C31H480(. and contains in the molecule a cyclopentanopolyhydrophenanthrene ring system which is substituted with two hydroxy groups, one acetoxy group and four methyl groups, and which is connected in the 17 position by a double bond with the α-car atom in 5-methylheptanoic acid.
Dihydrofusidinsyre antas å ha struk-turformelen (I) nedenfor, i hvilken den bølgeformet angitte forbindelseslinje angir at dens stereoisomere konfigurasjon ikke ennu er fastlagt med sikkerhet. Dihydrofusidic acid is believed to have the structural formula (I) below, in which the wavy indicated connecting line indicates that its stereoisomeric configuration has not yet been determined with certainty.
Det vil således forstås at dihydrofusidinsyre avledes fra fusidinsyre som foruten en dobbeltbinding ved sidekj edens tertiære karbonatom, inneholder en ytterligere dobbeltbinding ved metning av denne sistnevnte dobbeltbinding. It will thus be understood that dihydrofusidic acid is derived from fusidic acid which, in addition to a double bond at the tertiary carbon atom of the side chain, contains a further double bond upon saturation of this latter double bond.
Ved de vanlige metoder for å isolere dihydrofusidinsyre oppnås denne i form av sitt krystallinske solvat med vann, som inneholder 1/2 mol krystallvann. De karakteristiske trekk for dette hydrat er føl-gende: smeltepunkt: 182 til 184° C; spesi-fikk dreining — [a] <2>D' (i kloroform) — minus 1/2°; ultra-fiolett spectrum (i etha-noi): absorpsjon maksimum ved 220 m^i med en molar ekstinksjonskoeffisient på 8300. By the usual methods for isolating dihydrofusidic acid, this is obtained in the form of its crystalline solvate with water, which contains 1/2 mol of crystal water. The characteristic features of this hydrate are as follows: melting point: 182 to 184° C; specific rotation — [a] <2>D' (in chloroform) — minus 1/2°; ultra-violet spectrum (in etha-noi): absorption maximum at 220 m^i with a molar extinction coefficient of 8300.
Dihydrofusidinsyre karakteriseres ytterligere ved sitt spectrum i det infrarøde område som vist på tegningen, fra hvilket det sees at den oppviser karakteristiske absorpsjonsbånd ved følgende frekvenser uttrykt i mikroner: Dihydrofusidic acid is further characterized by its spectrum in the infrared region as shown in the drawing, from which it is seen that it exhibits characteristic absorption bands at the following frequencies expressed in microns:
Dihydrofusidinsyre er svakt oppløselig i vann. Den er imidlertid en svak syre med evne til å danne en rekke forskjellige salter med organiske eller uorganiske baser, av hvilke salter mange kan brukes for tera-peutiske formål. Blant de salter av størst interesse som er blitt fremstilt, er de vann-oppløselige natrium-, kalium- og ammo-niumsalter; salter med farmasøytisk aksepterbare aminer, slike som .triethylamin, diethylaminoethanol, piperidin, morfolin, cyclohexylamin og ethanolaminer; og salter som er svakt oppløselige i vann, nemlig calcium, magnesium, dibenzyl-ethylen-diamin, benzyl-p-fenylethylamin og procain-salter. Dihydrofusidic acid is slightly soluble in water. However, it is a weak acid with the ability to form a number of different salts with organic or inorganic bases, many of which salts can be used for therapeutic purposes. Among the salts of greatest interest which have been prepared are the water-soluble sodium, potassium and ammonium salts; salts with pharmaceutically acceptable amines, such as triethylamine, diethylaminoethanol, piperidine, morpholine, cyclohexylamine and ethanolamines; and salts which are slightly soluble in water, namely calcium, magnesium, dibenzyl-ethylenediamine, benzyl-p-phenylethylamine and procaine salts.
Ifølge forsøk utført i forbindelse med nærværende oppfinnelse er det blitt funnet at dihydrofusidinsyre og dens salter har en sterk antibakteriell effekt på en rekke patogene mikro-organismer. According to tests carried out in connection with the present invention, it has been found that dihydrofusidic acid and its salts have a strong antibacterial effect on a number of pathogenic micro-organisms.
Dessuten har dihydrofusidinsyre vist seg å være i besiddelse av større effekt på visse mikro-organismer enn fusidinsyre, slik som det vil fremgå av den følgende tabell, i hvilken konsentrasjonene som for-årsaker en 50 pst. inhibisjon, er angitt i |.i g/ml. Furthermore, dihydrofusidic acid has been shown to have a greater effect on certain micro-organisms than fusidic acid, as will be seen from the following table, in which the concentrations causing 50 per cent inhibition are given in |.i g/ ml.
Det er blitt funnet at dihydrofusidinsyre lett kan fremstilles fra fusidinsyre som utgangsmateriale ved metning av den isolerte dobbeltbinding i sistnevnte, og fremgangsmåten ifølge nærværende oppfinnelse omfatter trekkene å utsette fusidinsyre eller et salt av denne for hydrering under betingelser, hvorved fusidin-syremolekylet tilføres to hydrogenatomer, og å utvinne den slik oppnådde dihydrofusidinsyre som sådan eller i form av en av dens salter med baser. It has been found that dihydrofusidic acid can be easily prepared from fusidic acid as starting material by saturating the isolated double bond in the latter, and the method according to the present invention includes the features of subjecting fusidic acid or a salt thereof to hydrogenation under conditions whereby the fusidic acid molecule is supplied with two hydrogen atoms, and recovering the dihydrofusidic acid thus obtained as such or in the form of one of its salts with bases.
Ifølge nevnte metode kan enhver av de kjente fremgangsmåter for hydrering av en C=C-dobbeltbinding brukes. Ved en hen-siktsmessig utførelsesform for oppfinnelsen mettes imidlertid dobbeltbindingen ved en katalytisk hydrering, under anvendelse av en edelmetallkatalysator, f. eks. platina-oxyd, palladium på trekull eller calcium-eller strontiumcarbonat, eller andre bærere med evne til å modifisere aktiviteten av katalysatoren i en ønsket retning, ruthe-nium eller Raney-nikkel. According to said method, any of the known methods for the hydration of a C=C double bond can be used. In an appropriate embodiment of the invention, however, the double bond is saturated by a catalytic hydrogenation, using a noble metal catalyst, e.g. platinum oxide, palladium on charcoal or calcium or strontium carbonate, or other carriers capable of modifying the activity of the catalyst in a desired direction, ruthenium or Raney nickel.
Den katalytiske hydrering utføres med fordel ved atmosfærisk trykk eller ved et The catalytic hydrogenation is advantageously carried out at atmospheric pressure or at a
svakt øket hydrogentrykk og i nærvær av et egnet reaksjonsmedium, fortrinsvis et oppløsningsmiddel for fusidinsyre, slik som ethanol, dioxan, methyl- eller ethyl «cello-solve», eller lignende oppløsningsmidler eller blandinger av disse, og for så vidt visse salter av fusidinsyre brukes som utgangsmateriale, kan hydreringen finne sted i et vandig medium, eller i blandinger av vann og egnede organiske oppløsningsmidler, slik som lavere alkoholer. slightly increased hydrogen pressure and in the presence of a suitable reaction medium, preferably a solvent for fusidic acid, such as ethanol, dioxane, methyl- or ethyl "cello-solve", or similar solvents or mixtures thereof, and insofar as certain salts of fusidic acid are used starting material, the hydration can take place in an aqueous medium, or in mixtures of water and suitable organic solvents, such as lower alcohols.
Eventuelt kan hydreringen utføres ved elektrolyse, i hvilket tilfelle en vandig opp-løsning av et salt av fusidinsyre kan brukes med fordel. Optionally, the hydration can be carried out by electrolysis, in which case an aqueous solution of a salt of fusidic acid can be used with advantage.
Generelt finner hydreringen sted ved romtemperatur, eller den kan utføres ved høyere temperaturer, og i den tidsperiode som er nødvendig for å fullføre den ønskede selektive hydrering. In general, the hydration takes place at room temperature, or it can be carried out at higher temperatures, and for the time period necessary to complete the desired selective hydration.
Isolering av dihydrofusidinsyre eller et salt av denne kan finne sted efter at til-stedeværende katalysator er blitt filtrert fra ved fordampning av oppløsningsmidlet og omkrystallisering av residuet fra et egnet oppløsningsmiddel, eller en blanding av oppløsningsmidler, for å rense dihydrofusidinsyre eller vedkommende oppnådde salt. Hvis ønsket, kan den isolerte frie syre derefter omdannes til et av dens salter efter kjente metoder, slik som ved nøytra-lisering 'av en oppløsning av syren med den egnede base. Isolation of dihydrofusidic acid or a salt thereof can take place after the catalyst present has been filtered off by evaporation of the solvent and recrystallization of the residue from a suitable solvent, or a mixture of solvents, in order to purify dihydrofusidic acid or the corresponding salt obtained. If desired, the isolated free acid can then be converted into one of its salts by known methods, such as by neutralizing a solution of the acid with the appropriate base.
Dessuten er det blitt funnet at dihydrofusidinsyre i tillegg til å ha samme gunstige resorpsjonsforhold som fusidinsyre, er mindre giftig enn sistnevnte, og den kan med fordel brukes ved den anti-biotiske behandling av visse infeksjonssyk-dommer, særlig ved behandlingen av syk-dommer forårsaket av penicillin-resistente stammer av bakterier, for hvilket formål salter av dihydrofusidinsyre med farma-søytisk aksepterbare baser er.særlig anvendelige. Furthermore, it has been found that dihydrofusidic acid, in addition to having the same favorable resorption conditions as fusidic acid, is less toxic than the latter, and it can be advantageously used in the antibiotic treatment of certain infectious diseases, particularly in the treatment of diseases caused by of penicillin-resistant strains of bacteria, for which purpose salts of dihydrofusidic acid with pharmaceutically acceptable bases are particularly useful.
Den angitte lavere giftighet for dihydrofusidinsyre er blitt fastlagt ved dyre-eksperimenter, ved hvilke dyr (mus) ble gitt drogen intravenøst, subcutant eller oralt. Resultatene vil fremgå av nedenstå-ende tabell, i hvilken tallene representerer LD.(I uttrykt i mg droge administrert pr. kg legemsvekt: The indicated lower toxicity for dihydrofusidic acid has been determined by animal experiments, in which animals (mice) were given the drug intravenously, subcutaneously or orally. The results will appear in the table below, in which the numbers represent LD. (In expressed in mg of drug administered per kg of body weight:
De vannoppløselige salter av dihydrofusidinsyre, og særlig natrium eller kalium-salter, er klinisk anvendelige. The water-soluble salts of dihydrofusidic acid, and especially the sodium or potassium salts, are clinically applicable.
På den annen side kan salter av dihydrofusidinsyre som er lite oppløselige i vann også anvendes og kan f. eks. injiseres i form av en suspensjon i en egnet flytende bærer for å oppnå en depotvirkning og for-lenget virkning av det injiserte antibio-tiske stoff. On the other hand, salts of dihydrofusidic acid which are poorly soluble in water can also be used and can e.g. is injected in the form of a suspension in a suitable liquid carrier to achieve a depot effect and prolonged effect of the injected antibiotic substance.
Oppfinnelsen skal illustreres i de føl-gende eksempler: Eksempel 1. The invention shall be illustrated in the following examples: Example 1.
Dihydrofusidinsyre. Dihydrofusidic acid.
En oppløsning av 7,5 g fusidinsyre i 50 ml 96 pst. ethanol ble rystet ved romtemperatur under hydrogen-trykk på en atmosfære i nærvær av 1,5 g 5 pst. palladium på calciumcarbonat. I løpet av 40 minutter ble 370 ml hydrogen absorbert, og forbru-ket opphørte. Katalysatoren ble fjernet og filtratet bunnfelt med vann og ga 7,4 g material med et smeltepunkt på 182 til 184° C. For analytiske formål ble en prøve omkrystallisert fra benzen og til slutt fra eter. A solution of 7.5 g of fusidic acid in 50 ml of 96% ethanol was shaken at room temperature under hydrogen pressure in an atmosphere in the presence of 1.5 g of 5% palladium on calcium carbonate. In the course of 40 minutes, 370 ml of hydrogen was absorbed, and consumption ceased. The catalyst was removed and the filtrate settled with water to give 7.4 g of material with a melting point of 182 to 184° C. For analytical purposes, a sample was recrystallized from benzene and finally from ether.
Ved å erstatte palladium med 1 g Raney-nikkel og ved et trykk på 3 atmosfærer, ble det oppnådd samme mengde dihydrofusidinsyre. By replacing the palladium with 1 g of Raney nickel and at a pressure of 3 atmospheres, the same amount of dihydrofusidic acid was obtained.
Analyse: Analysis:
Kalkulert C^H^O,.. 1/2 H,0: C 70,55; H 9,74 Funnet C31<H>50O0.1/2 H26: C 70,48; H 9,76 Calculated C^H^O,.. 1/2 H,0: C 70.55; H 9.74 Found C31<H>50O0.1/2 H26: C 70.48; H 9.76
Eksempel 2. Example 2.
Natriumsaltet av dihydrofusidinsyre. The sodium salt of dihydrofusidic acid.
Til en suspensjon av 5,19 dihydrofusidinsyre i 25 ml ethanol ble 1,2 ml 33 pst. vandig natriumhydroksyd tilsatt under om-røring. 50 ml aceton ble tilsatt til den re-sulterende oppløsning for å bunnfelle natriumsaltet, som efter henstand ble filtrert, vasket med aceton og tørret. To a suspension of 5.19 dihydrofusidic acid in 25 ml of ethanol, 1.2 ml of 33% aqueous sodium hydroxide was added with stirring. 50 ml of acetone was added to the resulting solution to precipitate the sodium salt, which was filtered after settling, washed with acetone and dried.
Det infra-røde spectrum (KBr) viste sterke absorpsjonsbånd ved 7,85, 7,22, 6,38, 5,85, 3,41 og 2,95 mikroner. The infrared spectrum (KBr) showed strong absorption bands at 7.85, 7.22, 6.38, 5.85, 3.41 and 2.95 microns.
Eksempel 3. Example 3.
Natriumsaltet av dihydrofusidinsyre. The sodium salt of dihydrofusidic acid.
En oppløsning av natriumsaltet av fusidinsyre (55 g) i absolutt ethanol (500 ml) ble rystet ved romtemperatur under en hydrogen-atmosfære i nærvær av 5 pst. palladium på calciumcarbonat (10 g). Når 2,57 liter hydrogen var absorbert, ble hydreringen stoppet og katalysatoren fjernet ved filtrering. A solution of the sodium salt of fusidic acid (55 g) in absolute ethanol (500 ml) was shaken at room temperature under a hydrogen atmosphere in the presence of 5% palladium on calcium carbonate (10 g). When 2.57 liters of hydrogen had been absorbed, the hydrogenation was stopped and the catalyst removed by filtration.
Filtratet ble konsentrert i vakuum til 250 ml og aceton (250 ml) ble tilsatt. Efter henstand ble natriumsaltet av dihydrofusidinsyre, som skilte seg ut, samlet opp, vasket med aceton og tørret. The filtrate was concentrated in vacuo to 250 mL and acetone (250 mL) was added. After standing, the sodium salt of dihydrofusidic acid which separated was collected, washed with acetone and dried.
Eksempel 4. Example 4.
Calciumsaltet av dihydrofusidinsyre. The calcium salt of dihydrofusidic acid.
Til en oppløsning av natriumsaltet av dihydrofusidinsyre (520 mg) i methanol (5 ml) ble 20 pst. vandig calciumacetat To a solution of the sodium salt of dihydrofusidic acid (520 mg) in methanol (5 ml) was added 20% aqueous calcium acetate
(1 ml) tilsatt. Det krystallinske calciumsaltet av dihydrofusidinsyre, som skilte seg (1 ml) added. The crystalline calcium salt of dihydrofusidic acid, which separated
ut, ble samlet opp, vasket med vann og tør-ret. Smeltepunkt: 214° C (spaltning). out, was collected, washed with water and dried. Melting point: 214° C (decomposition).
Eksempel 5. Example 5.
N- methylcyclohexylaminsaltet av dihydrofusidinsyre. The N-methylcyclohexylamine salt of dihydrofusidic acid.
Til 5 ml av en 10 pst.'s oppløsning av To 5 ml of a 10 percent solution of
dihydrofusidinsyre i aceton ble N-methyl-cyclohexylamin (0,15 ml) tilsatt. Det krystallinske bunnfall som dannet seg ble dihydrofusidic acid in acetone, N-methyl-cyclohexylamine (0.15 ml) was added. The crystalline precipitate that formed became
samlet opp og omkrystallisert fra metha- collected and recrystallized from metha-
nol-acetonitril og gir 520 mg av det ønskede produkt med smeltepunkt 194,0 til 194,5° C. nol-acetonitrile and gives 520 mg of the desired product with a melting point of 194.0 to 194.5° C.
På lignende måte ble saltene med triethylamin, diethylaminoethanol, piperidin, morfolin, cyclohexylamin, mono- og di-ethanolamin, dibenzyl-ethylen-diamin, benzyl-|3-fenylethylamin, og procainsalt fremstilt. In a similar manner, the salts with triethylamine, diethylaminoethanol, piperidine, morpholine, cyclohexylamine, mono- and di-ethanolamine, dibenzyl-ethylenediamine, benzyl-|3-phenylethylamine, and procaine salt were prepared.
Claims (2)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB15883/76A GB1574145A (en) | 1976-04-20 | 1976-04-20 | Composite lid |
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| Publication Number | Publication Date |
|---|---|
| NO771353L NO771353L (en) | 1977-10-21 |
| NO146275B true NO146275B (en) | 1982-05-24 |
| NO146275C NO146275C (en) | 1982-09-01 |
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| AU (1) | AU506977B2 (en) |
| BE (1) | BE853772A (en) |
| CH (1) | CH614677A5 (en) |
| DE (1) | DE2717298C3 (en) |
| DK (1) | DK147935C (en) |
| FR (1) | FR2348863A1 (en) |
| GB (1) | GB1574145A (en) |
| IE (1) | IE44915B1 (en) |
| NL (1) | NL187619C (en) |
| NO (1) | NO146275C (en) |
| SE (1) | SE433070B (en) |
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-
1976
- 1976-04-20 GB GB15883/76A patent/GB1574145A/en not_active Expired
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1977
- 1977-04-06 IE IE733/77A patent/IE44915B1/en not_active IP Right Cessation
- 1977-04-18 AU AU24383/77A patent/AU506977B2/en not_active Expired
- 1977-04-18 DK DK170477A patent/DK147935C/en not_active IP Right Cessation
- 1977-04-18 FR FR7711570A patent/FR2348863A1/en active Granted
- 1977-04-19 SE SE7704473A patent/SE433070B/en not_active IP Right Cessation
- 1977-04-19 DE DE2717298A patent/DE2717298C3/en not_active Expired
- 1977-04-19 NO NO771353A patent/NO146275C/en unknown
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| FR2348863B1 (en) | 1980-02-01 |
| DK147935C (en) | 1985-08-19 |
| NL187619B (en) | 1991-07-01 |
| NL7704299A (en) | 1977-10-24 |
| CH614677A5 (en) | 1979-12-14 |
| DE2717298B2 (en) | 1979-06-21 |
| NO771353L (en) | 1977-10-21 |
| IE44915L (en) | 1977-10-20 |
| GB1574145A (en) | 1980-09-03 |
| FR2348863A1 (en) | 1977-11-18 |
| AU506977B2 (en) | 1980-01-31 |
| DK170477A (en) | 1977-10-21 |
| DE2717298C3 (en) | 1980-02-21 |
| DE2717298A1 (en) | 1977-11-10 |
| SE7704473L (en) | 1977-10-21 |
| BE853772A (en) | 1977-10-20 |
| NL187619C (en) | 1991-12-02 |
| SE433070B (en) | 1984-05-07 |
| NO146275C (en) | 1982-09-01 |
| AU2438377A (en) | 1978-10-26 |
| IE44915B1 (en) | 1982-05-19 |
| DK147935B (en) | 1985-01-14 |
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