DK141582B - Process for the preparation of lasalocid antibiotics or pharmaceutically tolerable salts thereof. - Google Patents
Process for the preparation of lasalocid antibiotics or pharmaceutically tolerable salts thereof. Download PDFInfo
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- DK141582B DK141582B DK137675AA DK137675A DK141582B DK 141582 B DK141582 B DK 141582B DK 137675A A DK137675A A DK 137675AA DK 137675 A DK137675 A DK 137675A DK 141582 B DK141582 B DK 141582B
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- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P7/00—Preparation of oxygen-containing organic compounds
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- C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D309/04—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- C12N1/00—Microorganisms, e.g. protozoa; Compositions thereof; Processes of propagating, maintaining or preserving microorganisms or compositions thereof; Processes of preparing or isolating a composition containing a microorganism; Culture media therefor
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Description
(jlf/ (11) FREMLÆG6ELSESSKRIFT 141582 DAMMARS (51) int. Cl.3 C 07 D 407/04 UAINIVIAKK c 12 P 17/16 // c 12 r 1Λ65 (21) Aneegning nr. 1576/75 (22) Indlever« den 1* aPr * 1975 \W® (23) Ljøbedag 1· apr. 1975 \£y (44) Antegningen fremlagt og p inQn fremlaeggeteesskriftet offentliggjort den · aPr · s(cf. (11) PUBLICATION 141582 DAMMARS (51) int. Cl.3 C 07 D 407/04 UAINIVIAK c 12 P 17/16 // c 12 r 1Λ65 (21) Note 1576/75 (22) Filing « the 1 * aPr * 1975 \ W® (23) Bill day 1 Apr 1975 \ £ y (44) The note presented and in accordance with the petition published on the aPr · s
DIREKTORATET FORDIRECTORATE OF
PATENT-OG VAREMÆRKEVÆSENET (3°) Modt« begær« fra denPATENT AND TRADEMARKET (3 °) Received 'desire' from it
2. apr. 1974, 457296, USApr 2 1974, 457296, US
(71) P. HOFPMANN-LA ROCHE & CO. AKTIENGESELLSCHAFT, Grenzacherstrasee 124-184, Postfach, CH-4002 Basel, CH(71) P. HOFPMANN-LA ROCHE & CO. AKTIENGESELLSCHAFT, Grenzacherstrasee 124-184, Postfach, CH-4002 Basel, CH
(72) Opfinder: John Westley, 111 Pollard Road, Mountain Lakes, New Jersey, US.(72) Inventor: John Westley, 111 Pollard Road, Mountain Lakes, New Jersey, US.
(74) Fuldmægtig und« sagene behandling:(74) The Plenipotentiary:
Plougmann & Vingtoft Patentbureau. _____________ (64) Fremgangsmåde til fremstilling af lasalocidantibiotika eller farms?* ceutisk tolerable salte deraf.Plougmann & Vingtoft Patent Office. _____________ (64) Process for the preparation of lasalocid antibiotics or farms? * Ceutically tolerable salts thereof.
Den foreliggende opfindelse angår en fremgangsmåde til fremstilling af hidtil ukendte lasalocidantibiotika eller farmaceutisk tolerable salte deraf, hvilken fremgangsmåde er ejendommelig ved, at der ud fra et råprodukt vundet ved submers og aerob dyrkning af en mikroorganisme af arten Streptomyces X-537 i en assimilerbar carbonhy-drat- og nitrogenkildeholdig naeringsopløsning isoleres lasalocid B, C, D og E med formlen COOH f |3 C/5 R* ,C2H5^The present invention relates to a process for the preparation of novel lasalocide antibiotics or pharmaceutically tolerable salts thereof, characterized in that from a crude product obtained by submersing and aerobically culturing a microorganism of the species Streptomyces X-537 in an assimilable carbonic acid. drate and nitrogen source-containing nutrient solution isolate lasalocide B, C, D and E of the formula COOH f | 3 C / 5 R *, C 2 H 5
H0 V-/ x""C2H5 IH0 V- / x "" C2H5 I
t fj I I V^O^H r1 Ht fj I I V ^ O ^ H r1 H
2 141582 12 3 4 hvor én af substituenterne R , R , R og R er ethyl, og de øvrige er methyl, og et vundet produkt, om ønsket, omdannes til et farmaceutisk tolerabelt salt deraf.Wherein one of the substituents R, R, R and R is ethyl and the others are methyl and a product obtained, if desired, is converted into a pharmaceutically tolerable salt thereof.
Det har vist sig, at antibiotika med formlen I og de farmaceutisk tolerable salte deraf har coccidiostatisk og antibakteriel virkning.It has been found that antibiotics of formula I and their pharmaceutically tolerable salts have coccidiostatic and antibacterial effects.
De kan således anvendes som coccidiostatiske og antibakterielle midler.Thus, they can be used as coccidiostatic and antibacterial agents.
Den antibiotikumdannende mikroorganisme hører til slægten Streptomyces og er isoleret fra en i Hyde Park, Massachusetts, fundet jordprøve. Frysetørrede prøver af den med laboratoriebetegnelsen X-537 mærkede kultur er deponeret i mikroorganismesamlingen i United States Department for Agriculture, Northern Utilization Research and Development Division, Peoria, Illinois, USA under nr. NRRL 3382. Denne kultur er almindelig tilgængelig gennem NRRL.The antibiotic-forming microorganism belongs to the genus Streptomyces and is isolated from a soil sample found in Hyde Park, Massachusetts. Freeze-dried specimens of laboratory labeled X-537 culture are deposited in the Microorganism Collection of the United States Department of Agriculture, Northern Utilization Research and Development Division, Peoria, Illinois, USA under No. NRRL 3382. This culture is commonly available through NRRL.
Nedenfor er anført en almen beskrivelse af en typisk stamme af Streptomyces X-537.Below is a general description of a typical strain of Streptomyces X-537.
Når kulturen afprøves efter de i Shirling, E.B. og D. Gottlieb, "Methods for Characterization of Streptomyces Species", Intern. J. Systematic Bacteriol. 16, 313 - 340, 1966" (herefter betegnet som "Shirling & Gottlieb, 1966") givne forskrifter, viser den et godt udviklet og forgrenet mycelium. Sporekæderne opviser fra hinanden trukne vindinger (retinaculum-apertum ifølge den af Ralf Hutter: Systematic der Streptomyceten, side 10, Publ. S. Karger, 1967 givne terminologi). Hver sporekæde bærer i gennemsnit ca. 25 sporer; sporeoverfladen er ru.When culture is tested after those in Shirling, E.B. and D. Gottlieb, "Methods for Characterization of Streptomyces Species", Intern. J. Systematic Bacteriol. 16, 313 - 340, 1966 "(hereinafter referred to as" Shirling & Gottlieb, 1966 "), it shows a well-developed and branched mycelium. The spore chains exhibit pulled twists (retinaculum apertum according to that of Ralf Hutter: Systematic der Streptomycetes, page 10, Publ. S. Karger, 1967 given terminology.) Each trace chain carries an average of about 25 spores; the spore surface is rough.
Koloniernes morphologi på forskellige agarmedier er som følger:The morphology of the colonies on different agar media is as follows:
Agarmedium 1) Kolonioverfladens Koloniens bagsides Opløseligt farve 2) farve 3) pigment 4) Gær-malt 2dc (lys brun- 0c5r (gul- Gul-brunt (ISP nr. 2) lig-grå) -brun) 3 141582Agar Medium 1) Colony Surface Back of Colony Soluble Color 2) Color 3) Pigment 4) Yeast-Painted 2dc (Light Brown-0c5r (Yellow-Yellow-Brown (ISP No. 2) Light-Gray)-Brown) 3 141582
Havremel e (lys metal- Co5a (hvidlig Svagt gul-brunt (ISP nr. 3) lisk grå) gul)Oatmeal e (light metal Co5a (whitish Light yellow-brown (ISP # 3) lily gray) yellow)
Uorganiske e Coo4s (rød- Gullig-brunt salte og stivel- lig gul-brun) se (ISP nr. 4)Inorganic e Coo4s (red-yellow-brown salty and starchy yellow-brown) see (ISP # 4)
Glucose-aspara- 2dc Coo2m (gylden Lyst gulliggin (ISP nr. 5) gul-brun) -brunt 1) Medier ifølge Shirling & Gottlieb, 1966 2) Tresner-Backus-farveskala 3) Prauser's (1964) farveskala 4) Ingen forandring i 0,05N HC1 eller NaOH.Glucose-asparagus- 2dc Coo2m (golden Light yellow liggin (ISP # 5) yellow-brown)-brown 1) Media according to Shirling & Gottlieb, 1966 2) Tresner-Backus color scale 3) Prauser's (1964) color scale 4) No change in 0.05N HCl or NaOH.
Når kulturen afprøves ifølge Shirling & Gottlieb, 1966, udnytter den carbonhydrater på følgende måde:When tested according to Shirling & Gottlieb, 1966, the culture utilizes carbohydrates as follows:
Arabinose 3+, cellulose +, fructose 3+, glucose 3+, inositol 4+, mannitol 4+, raffinose +, rhamnose 2+, saccharose + og xylose 3+.Arabinose 3+, cellulose +, fructose 3+, glucose 3+, inositol 4+, mannitol 4+, raffinose +, rhamnose 2+, sucrose + and xylose 3+.
Når kulturen afprøves ifølge R.E. Gordon "The Taxonomy of Soil Bacteria" i Ecology of Soil Bacteria, forlægger T.R.G. Gray £ D. Parkinson, Liverpool University Press, Liverpool, 1967, iagttages nedenstående fysiologiske reaktioner:When the culture is tested according to R.E. Gordon "The Taxonomy of Soil Bacteria" in Ecology of Soil Bacteria, publisher T.R.G. Gray £ D. Parkinson, Liverpool University Press, Liverpool, 1967, observed the following physiological reactions:
Hydrolyse af: adenin +, casein + , hypoxanthin +, tyrosin +, kartoffelstivelse + .Hydrolysis of: adenine +, casein +, hypoxanthine +, tyrosine +, potato starch +.
Dannelse af: urease -, nitratreduktase -.Formation of: urease, nitrate reductase -.
Udnyttelse af: citrat +, lactat -, malat +, mucat -, oxalat -, suc-cinat +.Utilization of: citrate +, lactate -, malate +, mucate -, oxalate -, succinate +.
Syre af: adonitol -, arabinose -, dulcitol -, erythritol -, galactose + glucose +, inositol +, lactose +, maltose +, mannitol +, mannose +, melibiose +, α-methyl-D-glucosid +, raffinose -, rhamnose +, sorbitol -, trehalose +, xylose +.Acid of: adonitol -, arabinose -, dulcitol -, erythritol -, galactose + glucose +, inositol +, lactose +, maltose +, mannitol +, mannose +, melibiosis +, α-methyl-D-glucoside +, raffinose -, rhamnose +, sorbitol -, trehalose +, xylose +.
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Vækst ved: 10°C +, 42°C + , 53°CGrowth at: 10 ° C +, 42 ° C +, 53 ° C
Vækst i:'lysozymdyrkningsvæske -, salicylatdyrkningsvæske -, glyceroldyrkning s væske + .Growth in: lysozyme culture liquid, salicylate culture liquid, glycerol culture liquid +.
Ved anvendelse af de ifølge International Streptomyces Project (ISP) (Shirling & Gottlieb, 1966) anførte metoder og den af Nonomura (J. Nonomura: Key for Classification and Identification of 458 Species of Streptomycetes Included in ISP; J. Ferment. Technol. 52: 78-92, 1974) angivne nøgle fremgår det, at kulturen ikke svarer til nogle af de i disse studier undersøgte streptomyceter. Kulturen indeholder L-isomeren af diaminopimelinsyre.Using the International Streptomyces Project (ISP) (Shirling & Gottlieb, 1966) methods and Nonomura (J. Nonomura: Key for Classification and Identification of 458 Species of Streptomycetes Included in ISP; J. Ferment. Technol. 52 : 78-92, 1974), it appears that the culture does not match some of the streptomycetes examined in these studies. The culture contains the L-isomer of diaminopimelic acid.
Det tidligere som antibiotikum X-537A (lasalocid A) betegnede, kendte antibiotikum er 6-[7(R)-[5(S)-ethyl-5-(5(R)-ethyltetrahydro--5-hydroxy-6(S)-methyl-2H-pyran-2(R)-yl)-tetrahydro-3(S)-methyl--2(S)-furyl]-4(S)-hydroxy-3(R) ,5(S)-dimethyl-6-oxononyl]-2,3-kre-sotinsyre, dvs. en forbindelse med formlen COOH CH3 Cp3 C2H5 PH3 h°Jxy* I I I h/\o/ A A oh J OH 0 %The formerly known antibiotic X-537A (lasalocid A) is known as 6- [7 (R) - [5 (S) -ethyl-5- (5 (R) -ethyltetrahydro-5-hydroxy-6 (S) ) -methyl-2H-pyran-2 (R) -yl) -tetrahydro-3 (S) -methyl-2 (S) -furyl] -4 (S) -hydroxy-3 (R), 5 (S) -Dimethyl-6-oxononyl] -2,3-creatinic acid, ie a compound of the formula COOH CH3 Cp3 C2H5 PH3 h ° Jxy * I I I h / \ o / A A oh J OH 0%
Up/ ^ “3^ CH3Up / ^ “3 ^ CH3
Antibiotiket X-537A (lasalocid A) er beskrevet i J. Am. Chem. Soc. bind 73, 1951, side 5295 - 98, og denne forbindelse kan ifølge den kendte teknik fremstilles ad fermentativ vej ved dyrkning af Streptomyces X-537. Den fermentative fremstilling af de omhandlede homologe af antibiotiket lasalocid A adskiller sig ikke væsentligt fra de kendte fremgangsmåder. Ifølge opfindelsen er der dog ved anvendelse af andre isoleringsmetoder fundet, at dyrkningsvæsken indeholder hidtil ukendte homologe med formlen I, der udmærker sig i forhold til lasalocid A ved at have overraskende fordele såsom lavere toxicitet eller mere intensiv antibiotisk virkning.The antibiotic X-537A (lasalocid A) is described in J. Am. Chem. Soc. Vol. 73, 1951, pages 5295-98, and this compound can be prepared by fermentative route by cultivation of Streptomyces X-537. The fermentative preparation of the subject homologue of the antibiotic lasalocid A does not differ significantly from the known methods. However, according to the invention, using other isolation methods, it has been found that the culture fluid contains novel homologues of Formula I which are distinguished from lasalocid A by having surprising advantages such as lower toxicity or more intense antibiotic action.
5 1A15825 1A1582
De omhandlede lasalocldhomologe er forbindelser med nedenstående formler og nomenklatur:The lasalocld homologs in question are compounds of the following formulas and nomenclature:
Lasalocid BLasalocid B
CO OH CHo §R3 pH3 I I f X /2Hr-A *C2H5 \# / V 2 5 T i I ηΛ/α-Λοη η c OH 0 H5C2 CH3 6- [7 (R) - [5 (S) -ethyl-5- (5 (R) -ethyltetrahydro-5-hydroxy-6 (S)-methyl-2H--pyran-2(R)-yl)-tetrahydro-3(S)-methyl-2(S)-furyl]-4(S)-hydroxy-3(R),5-(S)-dimethyl-6-oxononyl]-2-hydroxy-3-ethylbenzoesyre.CO OH CHo §R3 pH3 II f X / 2Hr-A * C2H5 \ # / V 2 5 T i I ηΛ / α-Λοη η c OH 0 H5C2 CH3 6- [7 (R) - [5 (S) -ethyl -5- (5 (R) -ethyltetrahydro-5-hydroxy-6 (S) -methyl-2H-pyran-2 (R) -yl) -tetrahydro-3 (S) -methyl-2 (S) -furyl ] -4 (S) -hydroxy-3 (R), 5 (S) -dimethyl-6-oxononyl] -2-hydroxy-3-ethylbenzoic acid.
Lasalocid C: COOH C2H5 CH, *2H5 _ H0Lasalocid C: COOH C2H5 CH, * 2H5 _ H0
II T T Λ0/Λ /oHII T T Λ0 / Λ / oH
ix J OH 0 \ H3c ch3 6—[7(R)—[5(S)-ethyl-5-(5(R)-ethyltetrahydro-5-hydroxy-6(S)-methyl-2H--pyran-2(R)-yl)-tetrahydro-3(S)-methyl-2(S)-furyl]-3(R)-ethyl-4(S)--hydroxy-5(S)-methyl-6-oxononyl]-2,3-kresotinsyre.6x [7 (R) - [5 (S) -ethyl-5- (5 (R) -ethyltetrahydro-5-hydroxy-6 (S) -methyl-2H-pyran-2) (R) -yl) tetrahydro-3 (S) -methyl-2 (S) furyl] -3 (R) -ethyl-4 (S) - hydroxy-5 (S) -methyl-6-oxononyl] 2,3-cresotic.
Lasalocid D: COOH CH, C_H5 C2H fH3 F ^ I Ϊ i /—\^2H5 /-WC2H5 /Vy oh o % H3C ch3 6- [7(R) — [5(S)-ethyl-5-(5(R)-ethyltetrahydro-5-hydroxy-6(S)-methyl--2H-pyran- 2(R)-yl)-tetrahydro-3(S)-methyl-2(S)-furyl]-5(S)-ethyl--4(S)-hydroxy-3(R)-methyl-6-oxononyl]-2,3-kresotinsyre.Lasalocid D: COOH CH, C_H5 C2H fH3 F ^ I Ϊ i / - \ ^ 2H5 / -WC2H5 / Vy oh o% H3C ch3 6- [7 (R) - [5 (S) -ethyl-5- (5 ( R) -ethyltetrahydro-5-hydroxy-6 (S) -methyl-2H-pyran-2 (R) -yl) -tetrahydro-3 (S) -methyl-2 (S) -furyl] -5 (S) ethyl - 4 (S) -hydroxy-3 (R) -methyl-6-oxononyl] -2,3-cresotic.
141582 6141582 6
Lasalocid E:Lasalocid E:
COOH CH3 5H3 S2H5f* CHCOOH CH3 5H3 S2H5f * CH
H0 \ JvV2 VVCAH0 \ JvV2 VVCA
TT 1 ' AMTTT 1 'AMT
J OH O “ % H-.C ^ ^ 3 CH3 6- [7 (R) - [5 (S) -ethy 1-5-(5 (R) -ethyltetrahydro-5-hydroxy-6 (S)-methyl--2H-pyran-2(R)-yl)-tetrahydro-3(S)-ethy1-2(S)-furylj“4(S)-hydroxy--3 (R) , 5 (S)-dimethyl-6-oxononylJ-2,3-kresotinsyre.6 OH [% H-C3 CH3 6- [7 (R) - [5 (S) -ethyl 1-5- (5 (R) -ethyltetrahydro-5-hydroxy-6 (S) -methyl) - 2H-Pyran-2 (R) -yl) -tetrahydro-3 (S) -ethyl-2 (S) -furyl] -4 (S) -hydroxy-3 (R), 5 (S) -dimethyl 6-oxononylJ-2,3-cresotic.
De omhandlede lasalocidhomologe fremstilles som nævnt ved fermentation af Streptomyces X-537 under aerobe submerse betingelser, idet pH-vær-dien i gæringsopløsningen indstilles på omtrentlig neutral værdi, dvs. ca. 6,5 - 7,5. Den anvendte næringsvæske indeholder en nitrogenkilde, f.eks. gær, et gærprodukt, majsmel eller bønnemel, hvorhos sojabønnemel foretrækkes; salte såsom kaliumphosphat og calciumcarbonat og sporgrundstoffer; en carbonhydratkilde såsom sukker eller melasse, fortrinsvis brunt sukker; og vegetabilsk eller animalsk fedt eller olie, f.eks. sojabønneolie eller lardolie, som carbonkilde og agens til skumbekæmpelse samt til forbedring af udbyttet af det ønskede slutprodukt. Fermentationen udføres ved let forhøjet temperatur, dvs. mellem ca. 25 og 35°C, især ved ca. 28°C. Efter en inkubationstid på ca. 4 - 6 dage filtreres gæringsopløsningen, og råproduktet indeholdende lasalociderne isoleres ved ekstraktion.The aforementioned lasalocide homologues are prepared as mentioned by fermentation of Streptomyces X-537 under aerobic sub-ambient conditions, setting the pH of the fermentation solution to approximately neutral value, i.e. ca. 6.5 - 7.5. The nutrient liquid used contains a nitrogen source, e.g. yeast, a yeast product, cornmeal or bean flour, which soybean meal is preferred; salts such as potassium phosphate and calcium carbonate and trace elements; a source of carbohydrate such as sugar or molasses, preferably brown sugar; and vegetable or animal fat or oil, e.g. soybean oil or lard oil, as a carbon source and anti-foaming agent and to improve the yield of the desired final product. The fermentation is carried out at slightly elevated temperature, ie. between approx. 25 and 35 ° C, especially at approx. 28 ° C. After an incubation time of approx. For 4 to 6 days, the fermentation solution is filtered and the crude product containing the lasalocides is isolated by extraction.
Efter isolering af råproduktet kan der anvendes adskillige metoder til isolering og rensning af de omhandlede lasalocidhomologe. Eksempler herpå er opløsningsmiddel-ekstraktionsfremgangsmåder, f.eks. intermitterende ekstraktion eller væske-væske-ekstraktion i modstrømsfordelingsfremgangsmåder eller gelpermeationschromatografi i et ikke-vandigt system.After isolation of the crude product, several methods can be used to isolate and purify the lasalocide homologs. Examples thereof are solvent extraction methods, e.g. intermittent extraction or liquid-liquid extraction in countercurrent distribution methods or gel permeation chromatography in a non-aqueous system.
På grund af de særlige fordele med hensyn til isoleringen af lasa-locidhomologene foretrækkes det, at råproduktet isoleres ved filtrering af den vandige næringsopløsning, ekstraktion af filtratet med et vanduopløseligt opløsningsmiddel og fraskillelse af slutprodukter 141582 7 ne fra opløsningsmiddelekstrakten, især at filtratet ekstraheres med n-butylacetat, og ekstrakten behandles med petroleumsether til opnåelse af en med de ønskede slutprodukter beriget moderlud.Due to the particular advantages of the isolation of the lasa-locid homologs, it is preferred that the crude product be isolated by filtration of the aqueous nutrient solution, extraction of the filtrate with a water-insoluble solvent and separation of final products from the solvent extract, especially the filtrate extracted with n. -butyl acetate and the extract is treated with petroleum ether to obtain a mother liquor enriched with the desired end products.
En særlig foretrukken metode til isolering af lasalociderne fra råproduktet, som foretrækkes ifølge opfindelsen, går ud på, at råproduktet underkastes modstrømsfordeling, og at denne modstrømsfordeling udføres på den måde, at der først anvendes et opløsningsmiddelsystem bestående af heptan-ethylacetat-methanol-vand, hvorefter den fraktion, som indeholder de ønskede produkter, underkastes en yderligere modstrømsfordeling med heptan-ethylacetat-ethanol-vand--iseddike som opløsningsmiddelsystem. På grund af de særlig gode udbytter, der fås derved, går en ifølge opfindelsen foretrukken variant ud på, at opløsningsmiddelsystemet til den første modstrømsfordeling består af heptan-ethylacetat-methanol-vand i et volumenforhold på ca. 27:18:18:2, og at opløsningsmidlet til den anden modstrømsfordeling består af heptan-ethylacetat-ethanol-vand--iseddike i et volumenforhold på ca. 10:5:9:3:1.A particularly preferred method of isolating the lasalocides from the crude product preferred by the invention is that the crude product is subjected to countercurrent distribution and that countercurrent distribution is carried out by first using a solvent system consisting of heptane-ethyl acetate-methanol water. whereupon the fraction containing the desired products is subjected to a further countercurrent distribution with heptane-ethyl acetate-ethanol-water-glacial acetic acid as a solvent system. Due to the particularly good yields thereby obtained, a preferred variant according to the invention assumes that the solvent system for the first countercurrent distribution consists of heptane-ethyl acetate-methanol-water in a volume ratio of approx. 27: 18: 18: 2 and that the solvent for the second countercurrent distribution consists of heptane-ethyl acetate-ethanol-water-glacial acetic acid in a volume ratio of approx. 10: 5: 9: 3: 1.
De farmaceutisk tolerable salte af de omhandlede lasalocidhomologe kan fremstilles på sædvanlig måde. Disse salte fremstilles ud fra den frie syreform af antibiotiket eller et derivat deraf efter i og for sig kendte metoder, f.eks. ved vask af den frie syre i opløsning med en egnet base eller et egnet salt. Eksempler på sådanne farmaceutisk tolerable basiske, til saltdannelse egnede stoffer er alkalimetalbaser, f.eks. natriumhydroxid, kaliumhydroxid eller lithiumhydroxid; jordalkalimetalbaser såsom calciumhydroxid og kaliumhydroxid; og ammoniak. Alkalimetal- eller jordalkaliraetal-salte, som kan anvendes til fremstilling af de omhandlede farmaceutisk tolerable salte, er f.eks. carbonater, hydrogencarbonater og sulfater.The pharmaceutically tolerable salts of the present lasalocid homologs may be prepared in the usual manner. These salts are prepared from the free acid form of the antibiotic or a derivative thereof by methods known per se, e.g. by washing the free acid in solution with a suitable base or salt. Examples of such pharmaceutically tolerable basic salts are alkali metal bases, e.g. sodium hydroxide, potassium hydroxide or lithium hydroxide; alkaline earth metal bases such as calcium hydroxide and potassium hydroxide; and ammonia. Alkali metal or alkaline earth metal salts which can be used to prepare the pharmaceutically tolerable salts of this invention are e.g. carbonates, hydrogen carbonates and sulfates.
Den relative antibiotiske virkning af de lasalocidhomologe B, C, D og E i forsøg in vitro mod mikroorganismen Bacillus TA konstateres ved sammenligning af et rent natriumsalt af lasalocid A med de fire homologe under anvendelse af agardiffusionsmetoden på hulplader. De beregnede talværdier for de fem komponenter er baseret på en vilkårligt sat aktivitet på 100 for lasalocid A-basen og fremgår af nedenstående tabel: 1 Al 582The relative antibiotic effect of the lasalocid homologs B, C, D and E in in vitro experiments against the microorganism Bacillus TA is found by comparing a pure sodium salt of lasalocid A with the four homologs using the agar diffusion method on hollow plates. The calculated numerical values for the five components are based on any set activity of 100 for the lasalocid A base and are shown in the table below: 1 Al 582
Forbindelse Beregnet aktivitet in vitro mod ______ Bacillus TA_Compound In vitro activity against ______ Bacillus TA_
Lasalocid A 100Lasalocid A 100
Lasaloeid B 90Lasaloeid B 90
Lasalocid C 180Lasalocid C 180
Lasalocid D 160Lasalocid D 160
Lasalocid E 170Lasalocid E 170
Med hensyn til toxicitet er de ved fremgangsmåden ifølge opfindelsen fremstillede lasalocider B, C, D og E lasalocid A overlegne, hvilket fremgår af de nedenfor anførte data for den akutte toxicitet (forsøg udført på mus, værdier efter 24 timers forløb):In terms of toxicity, the lasalocides A, C, D and E lasalocid A produced by the method according to the invention are superior, as can be seen from the acute toxicity data (experiments performed on mice, values after 24 hours):
Produkt LD50 mg/kg peroralt til musProduct LD50 mg / kg orally for mice
Lasalocid B + CLasalocid B + C
(i forholdet 1:1) 210 - 30(in a 1: 1 ratio) 210 - 30
Lasalocid D + ELasalocid D + E
(i forholdet 1:1) 195 - 32(in a 1: 1 ratio) 195 - 32
Lasalocid A 146Lasalocid A 146
Det fremgår af de i tabellerne anførte værdier, at de hidtil ukendte stoffer har overraskende fordele fremfor lasalocid A.It is apparent from the values given in the tables that the novel substances have surprising advantages over lasalocid A.
Der kan fremstilles coccidiostatiske præparater, der som virksom bestanddel indeholder homologe af antibiotiket Lasalocid A eller et farmaceutisk tolerabelt salt deraf, ved blanding af den aktive bestanddel med et inert bærestof. Det inerte bærestof kan være et foderstof eller erstatningsmateriale. Med udtrykket "inert bærestof" forstås et materiale, der ikke virker som antiparasitært middel, f.eks. som coccidiostatikum, og som er uskadeligt for de dyr, som skal behandles.Coccidiostatic compositions containing as an active ingredient homologous to the antibiotic Lasalocid A or a pharmaceutically tolerable salt thereof can be prepared by mixing the active ingredient with an inert carrier. The inert carrier may be a feed or substitute material. By the term "inert carrier" is meant a material which does not act as an antiparasitic agent, e.g. as coccidiostats and which are harmless to the animals to be treated.
Den aktive bestanddel undertrykker coccidiose hos nyttefjerkræ, især kalkuner og kyllinger, enten ved profylakse eller, ved allerede tilstedeværende sygdom, helbredelse deraf efter oral administration som en bestanddel af foderstoffet. Endvidere beholder de behandlede dyr deres vægt, eller de forøger endog deres vægt i sammenligning med kontroldyr. De omhandlede midler bekæmper således ikke kun coccidiose, men virker desuden som vækstfremmende middel.The active ingredient suppresses coccidiosis in utility poultry, especially turkeys and chickens, either by prophylaxis or, in the presence of disease, its healing after oral administration as a constituent of the feed. Furthermore, the treated animals retain their weight, or even increase their weight compared to control animals. Thus, the agents in question not only combat coccidiosis but also act as growth promoters.
141582 9141582 9
Koncentrationen af det aktive stof i foderstoffer kan varieres alt efter det individuelle behov. F.eks. kan en foderforblanding eller et fuldstændigt foderstof beriges med en tilstrækkelig mængde aktivstof, således at det udgør ca. 0,006 - ca. 0,03 vægtprocent af den daglige foderstofmængde. Der anvendes fortrinsvis ca. 0,015 -0,03 vægtprocent. I almindelighed er det tilstrækkeligt med ca. 0,015 vægtprocent af det aktive stof til effektivt at undertrykke eller bekæmpe coccidiose. Større mængder end 0,015% er ganske vist virksomme, men viser dog i almindelighed ingen fordele i forhold til 0,015% og kan i nogle tilfælde øve negativ indflydelse på væksten, foderomdannelsen og mortaliteten.The concentration of the active substance in feed can be varied according to individual needs. Eg. For example, a feed premix or a complete feed may be enriched with a sufficient amount of active ingredient such that it constitutes approx. 0.006 - approx. 0.03% by weight of daily feed quantity. Preferably, approx. 0.015 -0.03% by weight. In general, approx. 0.015% by weight of the active substance to effectively suppress or combat coccidiosis. Larger amounts than 0.015% are effective, but generally show no benefits over 0.015% and in some cases can adversely affect growth, feed conversion and mortality.
Selv om mængder på over 0,03 vægtprocent er virksomme til bekæmpelse af coccidiose, er disse mængder af økonomiske grunde den foretrukne overgrænse, dvs. omkostningerne pr. virkningsenhed er lavest inden for dette område. Under 0,006 vægtprocent er aktivstofferne ikke virksomme til bekæmpelse af coccidiose. Der foretrækkes en nedre grænse på 0,015%, da denne koncentration sikrer optimal virkning.Although amounts greater than 0.03 wt.% Are effective in controlling coccidiosis, these amounts for economic reasons are the preferred upper limit, ie. the cost per unit of action is lowest in this area. Below 0.006% by weight, the active substances are not effective in the control of coccidiosis. A lower limit of 0.015% is preferred as this concentration ensures optimum effect.
Den særligt foretrukne koncentration, dvs. 0,015 vægtprocent af den daglige foderstofindtagelse, er derfor særlig foretrukken, da den fremkalder maksimal virkning ved minimal dosering.The particularly preferred concentration, i.e. Therefore, 0.015% by weight of daily feed intake is particularly preferred as it produces maximum effect at minimal dosage.
Til behandling eller profylakse af coccidiose kan aktivstofferne først bringes i form af et koncentrat, en fodertilsætningsstoffor-blanding eller et fodertilsætningsmiddel. Ud fra disse kan helfoder eller fodertilsætningsstof fremstilles ved fortynding. Eksempler på bærestoffer er: kommercielt fjerkræfoder, formalede cerealier, biprodukter fra mølleriindustrien, planteproteinkoncentrater (f.eks. soja og jordnødder), biprodukter fra fermentationer, salt, kalksten og uorganiske forbindelser eller blandinger heraf. Flydende dispersioner kan fremstilles under anvendelse af vand eller vegetabilske olier, fortrinsvis under inkorporering af et overfladeaktivt middel eller en emulgator, f.eks. ethylendiamintetraeddikesyre, og opløsningsformidler. Som inerte bærestoffer kan der også anvendes andre bærestoffer eller erstatningsmaterialer, såfremt de forholder sig inerte i forhold til aktivstoffet og ikke er toxiske for de dyr, til hvilke de skal administreres.For the treatment or prophylaxis of coccidiosis, the active substances can first be brought in the form of a concentrate, a feed additive mixture or a feed additive. From these, whole feed or feed additive can be prepared by dilution. Examples of carriers are: commercial poultry feed, milled cereals, by-products of the milling industry, plant protein concentrates (eg soy and peanuts), by-products of fermentations, salt, limestone and inorganic compounds or mixtures thereof. Liquid dispersions can be prepared using water or vegetable oils, preferably with the incorporation of a surfactant or emulsifier, e.g. ethylene diamine tetraacetic acid, and solvent. As inert carriers, other carriers or substitutes may also be used if they are inert to the active substance and are non-toxic to the animals to which they are to be administered.
Typiske fjerkræfoderstoffer, som kan blandes med aktivstoffet, indeholder f.eks. kornprodukter såsom majs, hvede, havre, byg, milokorn, 10 141582 havremel og eftermel (f.eks. hvedeeftermel); stabiliserede fedtstoffer; planteproteiner såsom sojamel, majsglutenmel og jordnødderne1; vegetabilske proteiner såsom fiskemel, vandopløselige dele af fisk ("fish solubles") og kødaffald; kilder til UGF ("unidentified growth factor") og andre B-vitaminbærestoffer såsom tørmælkprodukter, tørret bryggerigær, tørrede opløslige remanenser fra destillationsindustrien, tørrede remanenser fra fermentationer og lucernegrønmel; samt forskellige specialtilsætningsstoffer såsom riboflavin, vitamin B^/ calciumpantothenat, niacin, cholin, vitamin K, vitamin E, stabiliseret vitamin A, vitamin (aktiverede animalske steroler), calcium-og phosphorsupplementstoffer såsom dicalciumphosphat, dampbehandlet benmel, defluoriseret phosphat og kalksten, ioderet salt, mangansulfat, zinkcarbonat, methionin eller hydroxyanaloge deraf, antioxidan-ter samt andre antibiotisk aktive foderstoftilsætningsstoffer.Typical poultry feed materials which can be mixed with the active ingredient contain e.g. cereal products such as maize, wheat, oats, barley, milk cereals, oatmeal and after-meal (eg wheat aftermeal); stabilized fats; plant proteins such as soybean meal, corn gluten meal and peanuts1; vegetable proteins such as fish meal, water-soluble parts of fish (fish solubles) and meat waste; sources of UGF ("unidentified growth factor") and other vitamin B carriers such as dry milk products, dried brewer's yeast, dried soluble residues from the distillation industry, dried residues from fermentations and lucerne green flour; and various special additives such as riboflavin, vitamin B 2 / calcium pantothenate, niacin, choline, vitamin K, vitamin E, stabilized vitamin A, vitamin (activated animal sterols), calcium and phosphorus supplements such as dicalcium phosphate, steam-treated bone meal, defluorinated phosphate and limestone, iodized salt , manganese sulphate, zinc carbonate, methionine or hydroxy analogs thereof, antioxidants and other antibiotically active feed additives.
Fremgangsmåden ifølge opfindelsen belyses nærmere ved nedenstående eksempel:The process according to the invention is further illustrated by the following example:
Eksempel.Example.
Fremstilling af de lasalocidhomologe B , C , D og E.Preparation of the lasalocid homologs B, C, D and E.
Streptomyces x-537 dyrkes i beluftet submers næringsopløsning i rysteflasker. pH-værdien i gasringsopløsningen indstilles på 6,5 - 7,5 ved tilsætning af vandig kaliumhydroxidopløsning; derefter steriliseres næringsopløsningen. Der udføres en tankgæring, idet der anvendes et S - 10%'s inokulum bestående af en 3 dage gammel submers kultur fra de beluftede kolber. Næringsmediet indeholder 2% søjabønnemel, 2% brunt sukker, 0,1% dikaliumphosphat og 0,5% majsstøbevand. Fermentationen udføres ved 28°C under positivt lufttryk, idet der indblæses luftmængder på 150 - 300 liter/minut pr. 150 -300 liter opløsning. Gæringen afbrydes efter 4-6 dages forløb, gæringsopløsningen filtreres, og antibiotiket isoleres ved ekstraktion. Ekstraktionen udføres på følgende måde: 204 liter gæringsopløsning filtreres. Den våde filterkage opslaanmes i 100 liter n-butylacetat, og blandingen omrøres natten over ved stuetemperatur. Derefter filtreres blandingen, og vandfasen fraskil- ' : ’ : ·*·’ 141582 11 les og kasseres, n-Butylacetatopløsningen, som indeholder en anti-biotikumkoncentration svarende til 30 millioner Bacillus E-enheder, inddampes til 3 liter under reduceret tryk, vaskes med 10%'s vandig natriumcarbonatopløsning og tørres over vandfrit natriumsulfat.Streptomyces x-537 is grown in the aerated submersible nutrient solution in shake bottles. The pH of the gas ring solution is adjusted to 6.5 - 7.5 by the addition of aqueous potassium hydroxide solution; then the nutrient solution is sterilized. A tank fermentation is performed using an S - 10% inoculum consisting of a 3 day old submers culture from the aerated flasks. The nutrient medium contains 2% bean flour, 2% brown sugar, 0.1% dipotassium phosphate and 0.5% corn cast water. The fermentation is carried out at 28 ° C under positive air pressure, with air volumes of 150 - 300 liters / minute per day being injected. 150-300 liters of solution. The fermentation is stopped after 4-6 days, the fermentation solution is filtered and the antibiotic is isolated by extraction. The extraction is carried out as follows: Filter 204 liters of fermentation solution. The wet filter cake is poured into 100 liters of n-butyl acetate and the mixture is stirred overnight at room temperature. The mixture is then filtered and the aqueous phase is separated and discarded, the n-butyl acetate solution containing an anti-biotic concentration corresponding to 30 million Bacillus E units, evaporated to 3 liters under reduced pressure, washed with 10% aqueous sodium carbonate solution and dried over anhydrous sodium sulfate.
Efter yderligere inddampning til 300 ml og fortynding med 350 ral petroleumsether (kogeinterval 50 - 60°C) fraskilles 41 g faststof, som svarer til 25 millioner Bacillus E-enheder. Dette faststof ekstraheres derefter i Soxhlet^apparatur med 4 liter petroleumsether (kogeinterval 50 - 60°C) i 40 timer. Ekstrakten inddampes til tørhed under reduceret tryk, og den krystallinske remanens dis-pergeres i petroleumsether og filtrenes. Efter gentagne krystallisationer fås en med de lasalocidhomologe B, C, D og E beriget moderlud. -After further evaporation to 300 ml and dilution with 350 ral petroleum ether (boiling range 50 - 60 ° C), 41 g of solid, corresponding to 25 million Bacillus E units, is separated. This solid is then extracted in Soxhlet® apparatus with 4 liters of petroleum ether (boiling range 50 - 60 ° C) for 40 hours. The extract is evaporated to dryness under reduced pressure and the crystalline residue is dispersed in petroleum ether and the filters. After repeated crystallisations, one enriched mother liquor with the lasalocide homologues B, C, D and E. -
Isolering af de lasalocidhomologe B, C, D pg E.Isolation of the lasalocid homologs B, C, D and E.
En portion (svarende til 22 g faststof) af den vundne moderlud chromatograferes i et med 200 små rør (hver med et rumfang på 80 ml) udstyret modstrømsfordelingsapparatur. Prøven opløses i 160 ml af de blandede faser (heptan-ethylacetat-methanol--vand i forholdet 27:18:18:2), og opløsningen hældes på de to første små rør. Efter 380 fordelinger fås følgende fraktioner, idet de vundne faste stoffer efter inddampning identificeres på følgende måde: A. Blanding af de lasalocidhomologe B, C, D og E, B. Lasalocid A, C. Isolasalocid A. Dette produkt er en isomer af Lasalocid A med en fra lasalociderne A - E afvigende struktur.A portion (corresponding to 22 g of solid) of the obtained mother liquor is chromatographed in a counterflow distribution apparatus equipped with 200 small tubes (each with a volume of 80 ml). The sample is dissolved in 160 ml of the mixed phases (heptane-ethyl acetate-methanol - 27: 18: 18: 2 water) and the solution is poured onto the first two small tubes. After 380 distributions, the following fractions are obtained, the solids obtained after evaporation being identified as follows: A. Mixture of the lasalocid homologs B, C, D and E, B. Lasalocid A, C. Isolasalocide A. This product is an isomer of Lasalocid A with a structure different from the lasalocides A - E.
Fraktion A opløses i 20 ml af de blandede faser af opløsningsmiddelsystemet heptan-ethylacetat-ethanol-vand-iseddike (10:5:9:3;!) og chromatograferes i et med 500 små rør forsynet modstrømsfordelingsapparatur. Efter 2800 fordelinger separeres ca. 200 mg af hver af Lasalocid B, C, D og E med nedenstående smeltepunkter:Fraction A is dissolved in 20 ml of the mixed phases of the solvent system heptane-ethyl acetate-ethanol-water glacial acetic acid (10: 5: 9: 3;) and chromatographed in a counterflow distribution apparatus equipped with 500 small tubes. After 2800 distributions, approx. 200 mg of each of Lasalocid B, C, D and E with the following melting points:
Claims (2)
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US45729674 | 1974-04-02 |
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DD (1) | DD117474A5 (en) |
DK (1) | DK141582B (en) |
ES (1) | ES436177A1 (en) |
FI (1) | FI56979C (en) |
IE (1) | IE40896B1 (en) |
IL (1) | IL46971A (en) |
NO (1) | NO143669C (en) |
NZ (1) | NZ177066A (en) |
PH (1) | PH12815A (en) |
SE (1) | SE7503716L (en) |
ZA (1) | ZA751801B (en) |
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1975
- 1975-03-21 ZA ZA00751801A patent/ZA751801B/en unknown
- 1975-03-27 NZ NZ177066A patent/NZ177066A/en unknown
- 1975-03-31 IL IL46971A patent/IL46971A/en unknown
- 1975-04-01 SE SE7503716A patent/SE7503716L/xx unknown
- 1975-04-01 DK DK137675AA patent/DK141582B/en unknown
- 1975-04-01 PH PH16999A patent/PH12815A/en unknown
- 1975-04-01 DD DD185141A patent/DD117474A5/xx unknown
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IL46971A0 (en) | 1975-05-22 |
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NO143669B (en) | 1980-12-15 |
NO751097L (en) | 1975-10-03 |
AR213070A1 (en) | 1978-12-15 |
ES436177A1 (en) | 1977-04-01 |
DK141582C (en) | 1980-10-06 |
FI56979C (en) | 1980-05-12 |
SE7503716L (en) | 1975-10-03 |
IE40896B1 (en) | 1979-09-12 |
NO143669C (en) | 1981-03-25 |
PH12815A (en) | 1979-08-28 |
FI56979B (en) | 1980-01-31 |
NZ177066A (en) | 1978-09-20 |
ZA751801B (en) | 1976-02-25 |
DD117474A5 (en) | 1976-01-12 |
IE40896L (en) | 1975-10-02 |
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