NO152134B - ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTICALLY EFFECTIVE DERIVATIVES - Google Patents

ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTICALLY EFFECTIVE DERIVATIVES Download PDF

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NO152134B
NO152134B NO793876A NO793876A NO152134B NO 152134 B NO152134 B NO 152134B NO 793876 A NO793876 A NO 793876A NO 793876 A NO793876 A NO 793876A NO 152134 B NO152134 B NO 152134B
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formula
preparation
compounds
ethyl
phenyl
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NO152134C (en
NO793876L (en
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Chao-Min Liu
John Westley
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Hoffmann La Roche
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Priority claimed from US06/077,415 external-priority patent/US4263427A/en
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Publication of NO793876L publication Critical patent/NO793876L/en
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Publication of NO152134C publication Critical patent/NO152134C/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/01—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing oxygen
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K20/00—Accessory food factors for animal feeding-stuffs
    • A23K20/10—Organic substances
    • A23K20/195—Antibiotics
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • 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
    • C12N1/20—Bacteria; Culture media therefor
    • C12N1/205—Bacterial isolates
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
    • C12P17/18—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms containing at least two hetero rings condensed among themselves or condensed with a common carbocyclic ring system, e.g. rifamycin
    • C12P17/181—Heterocyclic compounds containing oxygen atoms as the only ring heteroatoms in the condensed system, e.g. Salinomycin, Septamycin
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P19/00—Preparation of compounds containing saccharide radicals
    • C12P19/44—Preparation of O-glycosides, e.g. glucosides
    • C12P19/445—The saccharide radical is condensed with a heterocyclic radical, e.g. everninomycin, papulacandin
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12R—INDEXING SCHEME ASSOCIATED WITH SUBCLASSES C12C - C12Q, RELATING TO MICROORGANISMS
    • C12R2001/00—Microorganisms ; Processes using microorganisms
    • C12R2001/01—Bacteria or Actinomycetales ; using bacteria or Actinomycetales
    • C12R2001/465—Streptomyces

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Zoology (AREA)
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  • Wood Science & Technology (AREA)
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  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
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  • General Engineering & Computer Science (AREA)
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  • General Chemical & Material Sciences (AREA)
  • Biomedical Technology (AREA)
  • Animal Husbandry (AREA)
  • Molecular Biology (AREA)
  • Medicinal Chemistry (AREA)
  • Tropical Medicine & Parasitology (AREA)
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  • Food Science & Technology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Saccharide Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Micro-Organisms Or Cultivation Processes Thereof (AREA)
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  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

Urethane derivatives of the formula <IMAGE> wherein R<1> is aryl, alkylaryl, haloaryl, nitroaryl, alkoxyaryl, aryloxyaryl acylaryl, alkyl, cycloalkyl, arylalkyl, haloarylalkyl or arylcycloalkyl and R<2> is methyl or ethyl, and their pharmaceutically acceptable salts. Moreover, the manufacture of the above urethane derivatives as well as compositions containing same. Also the use of these derivatives for the treatment or prophylaxis of diseases and to promote animal growth.

Description

Foreliggende oppfinnelse vedrører en analogifremgangsmåte ved f remsti-lling av terapeutisk virksomme uretanderivater med den generelle formel The present invention relates to an analogous method for the production of therapeutically active urethane derivatives with the general formula

hvori R er fenyl, 4-halogenfenyl, p-tolyl, 4-nitrofenyl, 4-fenoksyfenyl, n-butyl, cykloheksyl, fenetyl, 4-brom-fenetyl eller 2-fenylcyklopropyl og R <2>er metyl eller etyl, wherein R is phenyl, 4-halophenyl, p-tolyl, 4-nitrophenyl, 4-phenoxyphenyl, n-butyl, cyclohexyl, phenethyl, 4-bromo-phenethyl or 2-phenylcyclopropyl and R <2> is methyl or ethyl,

og deres farmasøytisk fordragelige salter. and their pharmaceutically acceptable salts.

Det i formel I anvendte symbol Me betyr metylgruppen. The symbol Me used in formula I means the methyl group.

Forbindelsene som fremstilles ifølge foreliggende oppfinnelse og deres salter er virksomme som antibakterielle midler og som midler mot for høyt blodtrykk, malaria og svinedysen+ teri. The compounds produced according to the present invention and their salts are effective as antibacterial agents and as agents against high blood pressure, malaria and swine dysentery.

Uretanderivatene som fremstilles ifølge foreliggende oppfinnelse er polyeterantibiotika og danner flere farmasøytisk fordragelige salter. Disse salter fremstilles ifølge i og for seg kjente metoder fra den frie syreform av antibiotika-ene, f.eks. ved vasking av den frie syre i løsning med en egnet base hhv. et egnet salt. Eksempler på slike farmasøy-tisk fordragelige basiske saltdannende stoffer er alkalime-tallbaser så som natriumhydroksyd, kaliumhydroksyd, litium-hydroksyd o.l., jordalkalimetallbaser så som f.eks. kalsium-hydroksyd, bariumhydroksyd o.l., og ammoniumhydroksyd. Alka-li- eller jordalkalimetallsalter som kan anvendes for fremstilling av farmasøytisk fordragelige salter av uretanderivatene med formel I er f.eks. karbonater, bikarbonater og sulfater. The urethane derivatives produced according to the present invention are polyether antibiotics and form several pharmaceutically acceptable salts. These salts are prepared according to known methods from the free acid form of the antibiotics, e.g. by washing the free acid in solution with a suitable base or a suitable salt. Examples of such pharmaceutically acceptable basic salt-forming substances are alkali metal bases such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like, alkaline earth metal bases such as e.g. calcium hydroxide, barium hydroxide, etc., and ammonium hydroxide. Alkali or alkaline earth metal salts which can be used for the production of pharmaceutically acceptable salts of the urethane derivatives of formula I are, for example, carbonates, bicarbonates and sulfates.

Eksempler på organiske baser som med uretanderivatene ifølge oppfinnelsen kan danne farmasøytisk fordragelige salter er lavere alkylaminer eller primære, sekundære eller tertiære hydroksy-lavere alkylaminer så som f.eks. etylamin, isopro-pylamin, dietylamin, metyl-n-butylamin, etanolamin og di-etanolamin. Examples of organic bases which with the urethane derivatives according to the invention can form pharmaceutically acceptable salts are lower alkylamines or primary, secondary or tertiary hydroxy-lower alkylamines such as e.g. ethylamine, isopropylamine, diethylamine, methyl-n-butylamine, ethanolamine and diethanolamine.

Et særlig foretrukket amin er N-metylglukamin. Salter av N-metylglukamin er av særlig verdi på grunn av sin vannlø-selighet hvorigjennom forbindelsene kan anvendes for paren-teralt bruk. A particularly preferred amine is N-methylglucamine. Salts of N-methylglucamine are of particular value due to their water solubility, through which the compounds can be used for parenteral use.

Den antibiotiske virkning av uretanderivatene ifølge oppfinnelsen anskueliggjøres gjennom den følgende tabell 1.Uretanderivatene ifølge oppfinnelsen er likeledes virksomme mot Treponema hyodysenteriae. De tilsvarende minste hemmende konsentrasjoner av uretanderivater er som følger: The antibiotic effect of the urethane derivatives according to the invention is illustrated in the following table 1. The urethane derivatives according to the invention are likewise effective against Treponema hyodysenteriae. The corresponding minimum inhibitory concentrations of urethane derivatives are as follows:

Forsøksmetodikken for måling av virksomheten mot Treponema hyodysenteriae, en kilde til svinedysenteri, består i å in-okulere blodagarskåler med en serie av 2- eller 4 gangers fortynning av uretanderivater med 10 gangers fortynning av T. hyodysenteriae-stammen. Etter 48 timers dyrking ved 42°C i en anaerob atmosfære måles den minste hemmekonsentrasjon som den laveste konsentrasjon av en forbindelse hvilken fullstendig hemmer det sterkest fortynnede inokulum av hver enkelt T. hyodysenteriae-stamme. The test methodology for measuring the activity against Treponema hyodysenteriae, a source of swine dysentery, consists in inoculating blood agar plates with a series of 2- or 4-fold dilutions of urethane derivatives with 10-fold dilutions of the T. hyodysenteriae strain. After 48 hours of cultivation at 42°C in an anaerobic atmosphere, the minimum inhibitory concentration is measured as the lowest concentration of a compound which completely inhibits the most highly diluted inoculum of each individual T. hyodysenteriae strain.

Forbindelsene med formel I hvor R er fenyl, halogenfenyl eller nitrofenyl og deres farmasøytisk fordragelige salter er oralt virksomme som antimalariamidler, Denne virkning anskue-liggjøres gjennom de følgende aktiviteter mot malariafremkal-leren Plasmodium berghei hos mus: The compounds of formula I where R is phenyl, halophenyl or nitrophenyl and their pharmaceutically tolerable salts are orally active as antimalarials. This effect can be seen through the following activities against the malaria agent Plasmodium berghei in mice:

Forbindelsene med formel I og deres farmasøytisk fordragelige salter er oralt virksomme som blodtrykksenkende midler. Virk-ningen anskueliggjøres gjennom den følgende tabell 2. The compounds of formula I and their pharmaceutically acceptable salts are orally active as blood pressure lowering agents. The effect is visualized through the following table 2.

Forbindelsene kan ifølge oppfinnelsen fremstilles ved omset-ning av monensin A eller B, dvs. en forbindelse med den generelle formel hvor R 2 er metyl, (monensin B) eller etyl (monensin A), eller et salt derav med et isocyanat med formelen According to the invention, the compounds can be produced by reacting monensin A or B, i.e. a compound with the general formula where R 2 is methyl, (monensin B) or ethyl (monensin A), or a salt thereof with an isocyanate of the formula

hvor R^ har ovenfor angitte betydning. where R^ has the meaning given above.

Fortrinnsvis anvendes et salt av utgangsforbindelsene med formel II, spesielt natriumsaltet. Isocyanatet med formel III tilsettes fortrinnsvis i svakt, f.eks. ca. 10% overskudd, for å optimalisere dannelsen av monoderivatet. Om-setningen utføres fortrinnsvis i et inert løsningsmiddel som f.eks. et klorert hydrokarbon, f.eks. karbontetraklorid, metylenklorid eller kloroform; dietyleter, etylacetat eller i et aromatisk hydrokarbonløsningsmiddel som benzen eller toluen. Reaksjonstemperaturen er ikke kritisk, men den ligger likevel mellom ca. 0°C og reaksjonsblandingens koke-punkt, fortrinnsvis rundt romtemperatur. Preferably, a salt of the starting compounds of formula II is used, especially the sodium salt. The isocyanate of formula III is preferably added weakly, e.g. about. 10% excess, to optimize the formation of the monoderivative. The reaction is preferably carried out in an inert solvent such as e.g. a chlorinated hydrocarbon, e.g. carbon tetrachloride, methylene chloride or chloroform; diethyl ether, ethyl acetate or in an aromatic hydrocarbon solvent such as benzene or toluene. The reaction temperature is not critical, but it still lies between approx. 0°C and the boiling point of the reaction mixture, preferably around room temperature.

EKSEMPEL 1 EXAMPLE 1

Fremstilling av 4- bromfenyluretaner av monensin A ut fra monensin A ( fri syre) 10 mmol (6,89 g) monensin A-hydrat oppløses i 100 ml benzen. Denne løsningen blandes med et overskudd (11 mmol) 4-brom-fenylisocyanat i samme volum benzen og reaksjonsblandingen røres ved romtemperatur. Reaksjonen følges ved tynnskikt-kromatografi på kiselgel med etylacetat-n-heksan-etanol (80:20:2) som løsningsmiddel og vanillin-fosforsyre som fremkaller. Preparation of 4-bromophenylurethanes of monensin A from monensin A (free acid) 10 mmol (6.89 g) of monensin A hydrate is dissolved in 100 ml of benzene. This solution is mixed with an excess (11 mmol) of 4-bromo-phenyl isocyanate in the same volume of benzene and the reaction mixture is stirred at room temperature. The reaction is followed by thin-layer chromatography on silica gel with ethyl acetate-n-hexane-ethanol (80:20:2) as solvent and vanillin-phosphoric acid as developer.

Etter en uke vaskes reaksjonsblandingen med 0,5N vandig salt-syre, vann, mettet vandig natriumkarbonatløsning og vann etter hverandre. Benzenløsningen tørkes over natriumsul-fat og inndampes under redusert trykk til et amorft fast stoff. Etter krystallisering fra acetonitril får man natriumsaltet av 4-bromfenyluretanet av monensin A, smp. 201° til 203°C [a]D + 65,3° (CHC13, C=l%). After one week, the reaction mixture is washed successively with 0.5N aqueous hydrochloric acid, water, saturated aqueous sodium carbonate solution and water. The benzene solution is dried over sodium sulphate and evaporated under reduced pressure to an amorphous solid. After crystallization from acetonitrile, the sodium salt of the 4-bromophenylurethane of monensin A is obtained, m.p. 201° to 203°C [α]D + 65.3° (CHCl 3 , C=1%).

Elementæranalyse: Ber. for C43 HggO^NBrNa (891,87) % C, 57,90; H, 7,46; N, 1,57; Br, 8,96. fun. %C, 58,57; H, 7,36; N, 1,23; Br, 8,90. Elementary analysis: Ber. for C43 HggO^NBrNa (891.87) % C, 57.90; H, 7.46; N, 1.57; Br, 8.96. fun. %C, 58.57; H, 7.36; N, 1.23; Bro, 8.90.

EKSEMPEL 2 EXAMPLE 2

Fremstilling av 4- bromfenyluretaner av monensin A utfra natriumsaltet av monensin Production of 4-bromophenylurethanes of monensin A from the sodium salt of monensin

Ut fra 5 g natriumsalt av monensin A (7 mmol) og 2 g 4-brom-fenylisocyanat lar man reaksjonen gå som ifølge eksempel 1, men natriumsaltet synes å reagere hurtigere. Ifølge tynn-sjiktkromatografi synes reaksjonen å være. fullstendig etter 2 dager. Starting from 5 g of the sodium salt of monensin A (7 mmol) and 2 g of 4-bromo-phenyl isocyanate, the reaction is allowed to proceed as in example 1, but the sodium salt seems to react faster. According to thin-layer chromatography, the reaction appears to be completely after 2 days.

Etter opparbeiding på den ovenfor angitte måte får man 4-bromfenyluretanet av monensin A. After working up in the manner indicated above, the 4-bromophenylurethane of monensin A is obtained.

EKSEMPEL 3 EXAMPLE 3

På samme måte som i eksemplene 1 og 2 får man ved å anvende det tilsvarende isocyanat følgende forbindelser: In the same way as in examples 1 and 2, the following compounds are obtained by using the corresponding isocyanate:

Claims (5)

1. Analogifremgangsmåte ved fremstilling av terapeutisk virksomme uretanderivater med den generelle formel hvori R"*" er f enyl, 4-halogenf enyl, p-tolyl, 4-nitrof enyl, 4-fenoksyfenyl, n-butyl, cykloheksyl, fenetyl, 4-brom-fenetyl eller 2-fenylcyklopropyl og R 2er metyl eller etyl, og deres farmasøytisk fordragelige salter, karakterisert ved at man omsetter en forbindelse, med formel hvori R<2> er metyl eller etyl; med et isocyanat med formelen hvori R<1> har den ovenfor angitte betydning. og, om ønsket,overfører de erholdte forbindelser med formel (I) i farmasøytisk fordragelige salter derav.;1. Analogy method for the production of therapeutically active urethane derivatives with the general formula wherein R"*" is phenyl, 4-halophenyl, p-tolyl, 4-nitrophenyl, 4-phenoxyphenyl, n-butyl, cyclohexyl, phenethyl, 4-bromophenethyl or 2-phenylcyclopropyl and R 2 is methyl or ethyl , and their pharmaceutically acceptable salts, characterized in that one reacts a compound, with formula wherein R<2> is methyl or ethyl; with an isocyanate of the formula wherein R<1> has the meaning given above. and, if desired, convert the obtained compounds of formula (I) into pharmaceutically acceptable salts thereof.; 2. Fremgangsmåte ifølge krav 1, ved fremstilling av forbindelser hvori R<1> er fenyl, p-tolyl, 4-halogenfenyl, 4-nitrofenyl, 4-fenoksyfenyl eller 2-fenyl-cyklopropyl, karakterisert ved at man anvender et tilsvarende substituert isocyanat med formel III.;2. Method according to claim 1, in the preparation of compounds in which R<1> is phenyl, p-tolyl, 4-halophenyl, 4-nitrophenyl, 4-phenoxyphenyl or 2-phenyl-cyclopropyl, characterized in that a correspondingly substituted isocyanate is used with formula III.; 3. Fremgangsmåte ifølge krav 1 ved fremstilling av forbindelser hvori R"*" er f enyl, p-tolyl eller 4-halogenf enyl, karakterisert ved at man anvender et tilsvarende substituert isocyanat med formel III.3. Process according to claim 1 for the preparation of compounds in which R"*" is phenyl, p-tolyl or 4-halophenyl, characterized in that a correspondingly substituted isocyanate with formula III is used. 4. Fremgangsmåte ifølge et av kravene 1-3 ved fremstilling av en forbindelse hvori R 2 er etyl, karakterisert ved at man anvender en tilsvarende substituert utgangs-forbindelse med formel II, hvori R har den i krav 1 angitte betydning.4. Method according to one of claims 1-3 for the preparation of a compound in which R 2 is ethyl, characterized in that a correspondingly substituted starting compound of formula II is used, in which R has the meaning stated in claim 1. 5. Fremgangsmåte ifølge krav 3 og 4 ved fremstilling av forbindelser hvori R 1 er 4-bromfenyl og R 2 etyl, karakterisert ved at man anvender tilsvarende substi-tuerte utgangsforbindelser med formler II og III.5. Process according to claims 3 and 4 for the preparation of compounds in which R 1 is 4-bromophenyl and R 2 ethyl, characterized in that correspondingly substituted starting compounds with formulas II and III are used.
NO793876A 1978-11-29 1979-11-28 ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTICALLY EFFECTIVE DERIVATIVES NO152134C (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US96456478A 1978-11-29 1978-11-29
US7281879A 1979-09-05 1979-09-05
US06/077,415 US4263427A (en) 1978-11-29 1979-09-20 Monensin urethane derivatives

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NO793876L NO793876L (en) 1980-05-30
NO152134B true NO152134B (en) 1985-04-29
NO152134C NO152134C (en) 1985-08-07

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EP (1) EP0011859B1 (en)
AT (1) ATE2081T1 (en)
AU (1) AU531276B2 (en)
CA (1) CA1128505A (en)
DE (1) DE2964383D1 (en)
ES (1) ES8100255A1 (en)
FI (1) FI66386C (en)
GB (1) GB2036741B (en)
HK (1) HK70283A (en)
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IL (1) IL58785A (en)
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Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4542027A (en) * 1984-02-23 1985-09-17 Syntex (U.S.A.) Inc. Laidlomycin phenylcarbamate
FR2570378B1 (en) * 1984-09-19 1987-05-22 Sanofi Sa NOVEL POLYETHER IONOPHORE, PROCESS FOR OBTAINING SAME, AND VETERINARY FOOD OR THERAPEUTIC COMPOSITIONS CONTAINING THE SAME
US5217993A (en) * 1992-07-20 1993-06-08 Eli Lilly And Company Monensin derivatives
DE60136067D1 (en) * 2000-04-26 2008-11-20 Meiji Seika Kaisha MIXTURES FOR THE TREATMENT OR PREVENTION OF MALARIA AND METHOD FOR THE TREATMENT OF MALARIA

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3501568A (en) * 1964-09-28 1970-03-17 Lilly Co Eli Novel antibiotic a3823 complex and process for production thereof
US3839557A (en) * 1972-01-24 1974-10-01 Lilly Co Eli Antibiotics monensin and a204 for improving ruminant feed efficiency
BE794487A (en) * 1972-01-24 1973-05-16 Lilly Co Eli IMPROVING THE USE OF FOOD IN RUMINANTS
US4027034A (en) * 1974-05-20 1977-05-31 Hoffmann-La Roche Inc. Method of combatting swine dysentery
US4058620A (en) * 1974-07-19 1977-11-15 Hoffmann-La Roche Inc. Therapeutic agents for improving cardiovascular function
US3995027A (en) * 1975-06-04 1976-11-30 Eli Lilly And Company Anti-viral method in animals
US4061755A (en) * 1976-03-25 1977-12-06 Eli Lilly And Company Coccidiocidal combination of monensin and metichlorpindol
US4075323A (en) * 1976-03-25 1978-02-21 Eli Lilly And Company Coccidiocidal combinations

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ATE2081T1 (en) 1983-01-15
KE3322A (en) 1983-09-16
EP0011859B1 (en) 1982-12-22
GB2036741B (en) 1983-04-13
GB2036741A (en) 1980-07-02
PH16764A (en) 1984-02-15
IE792287L (en) 1980-05-29
MY8400342A (en) 1984-12-31
ES486399A0 (en) 1980-11-01
NZ192228A (en) 1985-02-28
ES8100255A1 (en) 1980-11-01
HK70283A (en) 1983-12-30
NO152134C (en) 1985-08-07
CA1128505A (en) 1982-07-27
AU531276B2 (en) 1983-08-18
AU5272879A (en) 1980-06-19
FI66386B (en) 1984-06-29
DE2964383D1 (en) 1983-01-27
IE48999B1 (en) 1985-07-10
FI793705A (en) 1980-05-30
EP0011859A1 (en) 1980-06-11
IL58785A (en) 1983-05-15
NO793876L (en) 1980-05-30
FI66386C (en) 1984-10-10
IL58785A0 (en) 1980-02-29

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