PL58297B1 - - Google Patents
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- PL58297B1 PL58297B1 PL121307A PL12130767A PL58297B1 PL 58297 B1 PL58297 B1 PL 58297B1 PL 121307 A PL121307 A PL 121307A PL 12130767 A PL12130767 A PL 12130767A PL 58297 B1 PL58297 B1 PL 58297B1
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- PL
- Poland
- Prior art keywords
- viomycin
- salt
- substituted
- treated
- acid
- Prior art date
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- GXFAIFRPOKBQRV-GHXCTMGLSA-N Viomycin Chemical class N1C(=O)\C(=C\NC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)C[C@@H](N)CCCN)CNC(=O)[C@@H]1[C@@H]1NC(=N)N[C@@H](O)C1 GXFAIFRPOKBQRV-GHXCTMGLSA-N 0.000 claims description 23
- 229950001272 Viomycin Drugs 0.000 claims description 18
- 108010015940 Viomycin Proteins 0.000 claims description 16
- QAOWNCQODCNURD-UHFFFAOYSA-L sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 7
- 238000000034 method Methods 0.000 claims description 6
- -1 aliphatic monocarboxylic acid Chemical class 0.000 claims description 5
- 229910052751 metal Inorganic materials 0.000 claims description 5
- 239000002184 metal Substances 0.000 claims description 5
- NBIIXXVUZAFLBC-UHFFFAOYSA-K [O-]P([O-])([O-])=O Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 4
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 4
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 claims description 4
- 239000010452 phosphate Substances 0.000 claims description 4
- 239000002244 precipitate Substances 0.000 claims description 4
- 239000000047 product Substances 0.000 claims description 4
- OYPRJOBELJOOCE-UHFFFAOYSA-N calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 3
- 229910052791 calcium Inorganic materials 0.000 claims description 3
- 239000011575 calcium Substances 0.000 claims description 3
- 150000004649 carbonic acid derivatives Chemical class 0.000 claims description 3
- 238000006243 chemical reaction Methods 0.000 claims description 3
- 150000002500 ions Chemical class 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 3
- 150000003839 salts Chemical class 0.000 claims description 3
- 239000011780 sodium chloride Substances 0.000 claims description 3
- 239000002253 acid Substances 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 150000004679 hydroxides Chemical class 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 150000002739 metals Chemical class 0.000 claims description 2
- 125000005341 metaphosphate group Chemical group 0.000 claims description 2
- 239000012429 reaction media Substances 0.000 claims description 2
- CIOAGBVUUVVLOB-UHFFFAOYSA-N strontium Chemical compound [Sr] CIOAGBVUUVVLOB-UHFFFAOYSA-N 0.000 claims description 2
- 229910052712 strontium Inorganic materials 0.000 claims description 2
- RQPZNWPYLFFXCP-UHFFFAOYSA-L barium dihydroxide Chemical class [OH-].[OH-].[Ba+2] RQPZNWPYLFFXCP-UHFFFAOYSA-L 0.000 claims 1
- 238000001914 filtration Methods 0.000 claims 1
- 239000002002 slurry Substances 0.000 claims 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- TZCXTZWJZNENPQ-UHFFFAOYSA-L Barium sulfate Chemical compound [Ba+2].[O-]S([O-])(=O)=O TZCXTZWJZNENPQ-UHFFFAOYSA-L 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- AYJRCSIUFZENHW-UHFFFAOYSA-L Barium carbonate Chemical compound [Ba+2].[O-]C([O-])=O AYJRCSIUFZENHW-UHFFFAOYSA-L 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- 231100000403 acute toxicity Toxicity 0.000 description 2
- 238000004108 freeze drying Methods 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 229940064005 Antibiotic throat preparations Drugs 0.000 description 1
- 229940083879 Antibiotics FOR TREATMENT OF HEMORRHOIDS AND ANAL FISSURES FOR TOPICAL USE Drugs 0.000 description 1
- 229940042052 Antibiotics for systemic use Drugs 0.000 description 1
- 229940042786 Antitubercular Antibiotics Drugs 0.000 description 1
- ITHZDDVSAWDQPZ-UHFFFAOYSA-L Barium acetate Chemical compound [Ba+2].CC([O-])=O.CC([O-])=O ITHZDDVSAWDQPZ-UHFFFAOYSA-L 0.000 description 1
- 229940093922 Gynecological Antibiotics Drugs 0.000 description 1
- 239000005909 Kieselgur Substances 0.000 description 1
- 229940055726 Pantothenic Acid Drugs 0.000 description 1
- SIOXPEMLGUPBBT-UHFFFAOYSA-N Picolinic acid Chemical class OC(=O)C1=CC=CC=N1 SIOXPEMLGUPBBT-UHFFFAOYSA-N 0.000 description 1
- 229940024982 Topical Antifungal Antibiotics Drugs 0.000 description 1
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Vitamin C Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- HLKMEIITONDPGG-UHFFFAOYSA-L barium(2+);2-hydroxypropanoate Chemical compound [Ba+2].CC(O)C([O-])=O.CC(O)C([O-])=O HLKMEIITONDPGG-UHFFFAOYSA-L 0.000 description 1
- OWLGVZDNMSNYSA-UHFFFAOYSA-L barium(2+);propanoate Chemical compound [Ba+2].CCC([O-])=O.CCC([O-])=O OWLGVZDNMSNYSA-UHFFFAOYSA-L 0.000 description 1
- 230000003115 biocidal Effects 0.000 description 1
- FAPWYRCQGJNNSJ-UBKPKTQASA-L calcium D-pantothenic acid Chemical compound [Ca+2].OCC(C)(C)[C@@H](O)C(=O)NCCC([O-])=O.OCC(C)(C)[C@@H](O)C(=O)NCCC([O-])=O FAPWYRCQGJNNSJ-UBKPKTQASA-L 0.000 description 1
- 229960002079 calcium pantothenate Drugs 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000001419 dependent Effects 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- 229940079866 intestinal antibiotics Drugs 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 150000002763 monocarboxylic acids Chemical class 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- 229940005935 ophthalmologic Antibiotics Drugs 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-L oxalate Chemical compound [O-]C(=O)C([O-])=O MUBZPKHOEPUJKR-UHFFFAOYSA-L 0.000 description 1
- GHOKWGTUZJEAQD-ZETCQYMHSA-N pantothenic acid Natural products OCC(C)(C)[C@@H](O)C(=O)NCCC(O)=O GHOKWGTUZJEAQD-ZETCQYMHSA-N 0.000 description 1
- 235000019161 pantothenic acid Nutrition 0.000 description 1
- 239000011713 pantothenic acid Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 238000002791 soaking Methods 0.000 description 1
- 230000002588 toxic Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Description
Pierwszenstwo: Opublikowano: 30.X.1969 58297 KI. 12 q, 6/01 MKP C07 niti UKD Wspóltwórcy wynalazku: dr Wojciech Sobiczewski, doc. dr Jerzy Cies¬ lak, mgr Andrzej Waszkiewicz, dr Wawrzyniec Chojnowski Wlasciciel patentu: Instytut Antybiotyków, Warszawa (Polska) Sposób otrzymywania pochodnych wiomycyny wynalazek dotyczy sposobu otrzymywania po¬ laczen wiomycyny z alifatycznymi kwasami jed- nokarboksylowymi o ogólnym wzorze R. 3X, w którym R oznacza czasteczke wiomycyny, a X cza¬ steczke alifatycznego kwasu jednokarboksylowego podstawionego lub niepodstawionego.Badania farmakologiczne i kliniczne dowodza, ze wiomycyna wytwarzana i stosowana w postaci siarczanu odznacza sie stosunkowo duza toksycz¬ noscia. Toksycznosc ta w pewnym stopniu zalezy od obecnosci jonu siarczanowego wiazacego wapn w organizmie. Znane sa ponadto sposoby otrzymy¬ wania polaczen wiomycyny z kwasem pantoteno¬ wym, kwasem askorbinowym i kwasami pirydyno- karboksylowymi odznaczajace sie mniejsza tok¬ sycznoscia w stosunku do siarczanu wiomycyny.Sposobem wedlug wynalazku otrzymuje sie po¬ laczenia wiomycyny z alifatycznymi kwasami jed- nokarboksylowymi o ogólnym wzorze Z-CHY- -COOH, w którym Z oznacza atom wodoru albo podstawiony lub niepodstawiony rodnik alkilowy, a Y oznacza atom wodoru, chlorowca, grupe hy¬ droksylowa lub alkoksylowa, Zwiazki te odznacza¬ ja sie dobra rozpuszczalnoscia w wodzie, niska toksycznoscia i nadaja sie do stosowania w róz¬ nych formach farmaceutycznych.Toksycznosc ostra otrzymanych preparatów (LD50) przy podaniu dozylnie wynosi dla octanu wiomy¬ cyny 224 mg/kg, dla propionianu wiomycyny 133 10 15 mg/kg i dla mleczanu wiomycyny 250 mg/kg wagi ciala myszy, podczas gdy toksycznosc ostra siar¬ czanu wiomycyny oznaczona w identycznych wa¬ runkach wynosi LD50 = 174 mg/kg wagi ciala my¬ szy.Sposób wedlug wynalazku polega na tym, ze do wodnego roztworu soli wiomycyny takiej jak siar¬ czan, fosforan, kwasny fosforan, metafosforan lub szczawian dodaje sie odpowiednia stechiometrycz- nie ilosc alifatycznego kwasu jednokarboksylowego podstawionego lub niepodstawionego w obecnosci jonów metali dwuwartosciowych, takich jak wapn, bar lub stront. Jony te wprowadza sie stosujac wodorotlenki lub weglany tych metali, przy czym dodaje sie je przed lub po wprowadzeniu kwasu karboksylowego do srodowiska reakcji. Reakcje prowadzi sie w temperaturze 5—80°C, korzystnie 10—25°C.Po zakonczeniu reakcji i odsaczeniu wytraconej soli metalu dwuwartosciowego, klarowny przesacz odparowuje sie do sucha na wyparce prózniowej lub poddaje sie procesowi liofilizacji. Gotowy pro¬ dukt mozna równiez otrzymac droga zageszczenia wodnego przesaczu do sucha, rozpuszczenia pozo¬ stalosci w niewielkiej ilosci metanolu i wytrace¬ nia przez dodanie eteru etylowego. Po wysuszeniu otrzymanego osadu w eksykatorze prózniowym nad P205 otrzymuje sie polaczenie wiomycyny z kwa¬ sami jednokarboksylowymi z calkowita wydajno- 30 scia rzedu 90^/0. 20 25 582973 Sposób wedlug wynalazku w szczególnosci wy¬ jasniaja nastepujace przyklady: Przyklad I. Do roztworu 4 g octanu barowe¬ go otrzymanego w wyniku dzialania równych ste- chiometrycznie ilosci kwasu octowego i weglanu barowego, dodano roztwór 7,9 g siarczanu wiomy- cyny w 30 ml wody. Po mieszaniu trwajacym 30 minut wydzielony siarczan barowy odsaczono, a przesacz odparowano na wyparce prózniowej do sucha. Pozostalosc rozpuszczono w 20 ml meta¬ nolu, po czym wydzielono gotowy produkt przez dodanie 150 ml eteru etylowego. Osad odsaczono, przemyto eterem, a nastepnie suszono w eksyka- torze prózniowym nad P205 do stalej wagi.Otrzymano 7,2 g octanu wiomycyny o mocy bio¬ logicznej 777 ^ig/mg (teoretyczna moc 770 |xg/mg), co stanowi 88,0% wydajnosci.Przyklad II. Do 5 g propionianu barowego rozpuszczonego w 35 ml wody dodano 8,85 g siar¬ czanu wiomycyny rozpuszczonego w 40 ml wody.Mieszano w ciagu 30 minut, a nastepnie odsaczo¬ no wydzielony ilosciowo siarczan barowy dodajac mala ilosc ziemi okrzemkowej dla ulatwienia sa¬ czenia. Otrzymany przesacz odparowano do sucha na wyparce prózniowej, a nastepnie pozostalosc rozpuszczono w 30 ml metanolu. Wydzielono pro¬ dukt przez dodanie 150 ml eteru etylowego. Osad po przemyciu na saczku eterem przeniesiono do innego naczynia i po rozpuszczeniu w niewielkiej ilosci wody poddano procesowi liofilizacji. Otrzy¬ mano 8,97 g propionianu wiomycyny o mocy bio¬ logicznej 731 ^g/mg (teoretyczna moc 730 ^g/mg), co stanowi 93,5°/o wydajnosci.Przyklad III. Mleczan barowy w ilosci 4 g oraz siarczan wiomycyny w ilosci 6,4 g rozpusz¬ czono w 80 ml wody i po mieszaniu trwajacym 45 minut odsaczono wydzielony osad siarczanu ba- 4 rowego. Dalszy tok postepowania byl identyczny jak w przykladzie II. Otrzymano 6,8 g mleczanu wiomycyny o mocy biologicznej 695 |xg/mg (teore¬ tyczna moc 692 ^g/mg), co stanowi 92,0% wydaj- 5 nosci. PLPreference: Published: October 30, 1969 58297 KI. 12 q, 6/01 MKP C07 niti UKD Contributors to the invention: dr Wojciech Sobiczewski, doc. Dr. Jerzy Cies¬ lak, MA Andrzej Waszkiewicz, Dr. Wawrzyniec Chojnowski Patent owner: Institute of Antibiotics, Warsaw (Poland) Method of obtaining viomycin derivatives The invention relates to a method of obtaining combinations of viomycin with aliphatic monocarboxylic acids of the general formula R. 3X, in which R is a molecule of viomycin, and X is a molecule of a substituted or unsubstituted aliphatic monocarboxylic acid. Pharmacological and clinical studies show that voomycin produced and used in the form of sulphate has a relatively high toxicity. This toxicity is somewhat dependent on the presence of the calcium-binding sulphate ion in the body. There are also known methods for the preparation of combinations of viomycin with pantothenic acid, ascorbic acid and pyridine-carboxylic acids, which are less toxic compared to viomycin sulphate. by the general formula Z-CHY-COOH, in which Z is a hydrogen atom or a substituted or unsubstituted alkyl radical, and Y is a hydrogen atom, a halogen atom, a hydroxyl or an alkoxy group. These compounds are distinguished by good solubility in water, low toxicity and are suitable for use in various pharmaceutical forms. The acute toxicity of the preparations obtained (LD50) when administered intravenously is 224 mg / kg for viomycin acetate, 133 mg / kg for viomycin propionate and 250 mg / kg for viomycin lactate. the weight of the mouse, while the acute toxicity of viomycin sulfate, determined under identical conditions, is LD50 = 174 mg / kg of the weight of the mouse. According to the invention, an appropriate stoichiometric amount of an aliphatic monocarboxylic acid substituted or unsubstituted in the presence of divalent metal ions such as calcium is added to an aqueous solution of a salt of viomycin such as sulfate, phosphate, acid phosphate, metaphosphate or oxalate. bar or strontium. These ions are introduced using the hydroxides or carbonates of these metals, and they are added either before or after the carboxylic acid is introduced into the reaction medium. The reaction temperature is 5-80 ° C, preferably 10-25 ° C. After the reaction is completed and the precipitated divalent metal salt has been filtered off, the clear filtrate is evaporated to dryness in a vacuum evaporator or subjected to a lyophilization process. The finished product can also be obtained by concentrating the aqueous filtrate to dryness, dissolving the residue in a little methanol and triturating it by adding diethyl ether. After drying the obtained precipitate in a vacuum desiccator over P2O5, a combination of viomycin with monocarboxylic acids is obtained with a total yield of the order of 90%. The method according to the invention is illustrated in particular by the following examples: Example 1 To a solution of 4 g of barium acetate obtained by the treatment of stoichiometrically equal amounts of acetic acid and barium carbonate, a solution of 7.9 g of viomycin sulfate was added. in 30 ml of water. After stirring for 30 minutes, the barium sulphate which has separated out is filtered off, and the filtrate is evaporated to dryness in a vacuum evaporator. The residue was dissolved in 20 ml of methanol and the finished product was isolated by adding 150 ml of diethyl ether. The precipitate was filtered off, washed with ether and then dried in a vacuum desiccator over P2O5 until constant weight. 7.2 g of viomycin acetate with a biological strength of 777 µg / mg (theoretical strength 770 µg / mg) was obtained, which is 88 , 0% yield. Example II. To 5 g of barium propionate dissolved in 35 ml of water, 8.85 g of viomycin sulphate dissolved in 40 ml of water was added. The mixture was stirred for 30 minutes, and then the quantitatively separated barium sulphate was drained off, adding a small amount of diatomaceous earth to facilitate soaking. . The obtained filtrate was evaporated to dryness in a vacuum evaporator, and then the residue was dissolved in 30 ml of methanol. The product was isolated by adding 150 ml of diethyl ether. After washing on the filter with ether, the sediment was transferred to another vessel and, after dissolving it in a small amount of water, it was subjected to the lyophilization process. The yield was 8.97 g of viomycin propionate with a biological strength of 731 g / mg (theoretical strength 730 g / mg), a yield of 93.5%. Barium lactate, 4 g, and viomycin sulphate, 6.4 g, were dissolved in 80 ml of water, and the separated precipitate of barium sulphate was filtered off after stirring for 45 minutes. The further course of action was identical to that in example II. The yield was 6.8 g of viomycin lactate with a biological strength of 695 µg / mg (theoretical strength 692 µg / mg), which is 92.0% of the yield. PL
Claims (5)
Publications (1)
| Publication Number | Publication Date |
|---|---|
| PL58297B1 true PL58297B1 (en) | 1969-08-25 |
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